US20050214353A1 - Transdermal therapeutic system - Google Patents
Transdermal therapeutic system Download PDFInfo
- Publication number
- US20050214353A1 US20050214353A1 US11/116,278 US11627805A US2005214353A1 US 20050214353 A1 US20050214353 A1 US 20050214353A1 US 11627805 A US11627805 A US 11627805A US 2005214353 A1 US2005214353 A1 US 2005214353A1
- Authority
- US
- United States
- Prior art keywords
- active ingredient
- tts
- matrix
- use according
- diffusion barrier
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 0 [1*]/C1=C2\CC3c(cC(NC(=O)N(CC)CC)CN3[2*])C3=CC=CC(=C32)N1 Chemical compound [1*]/C1=C2\CC3c(cC(NC(=O)N(CC)CC)CN3[2*])C3=CC=CC(=C32)N1 0.000 description 13
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
- A61K9/7061—Polyacrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
Definitions
- This invention relates to a transdermal therapeutic system (TTS) comprising a pharmaceutical layer containing at least one matrix having an active ingredient and/or an active ingredient reservoir; a diffusion barrier that is permeable to said active ingredient and arranged on the skin side of the active ingredient reservoir; and an ergoline derivative or salt thereof as an active ingredient for producing an agent for obtaining and maintaining the circadian rhythm under dopamine therapy.
- TTS transdermal therapeutic system
- TTS percutaneously acting but also transmucosal systems.
- a TTS typically has a sheet-like structure and is attached to an area of the skin.
- the system can optionally be attached to the skin by an additional skin-side adhesive that is permeable to the active ingredient.
- the matrix and/or diffusion barrier can itself have adhesive properties.
- a non-adhesive TTS can be attached to the skin using other auxiliary means such as adhesive tapes or bandages.
- the matrix is a material in which the active ingredient is immobilized. An active agent in an active ingredient reservoir however is not necessarily immobilized, which is why the active ingredient reservoir must be enclosed.
- the diffusion barrier forms the skin-side portion of this shell.
- a TTS of the design mentioned above is known in principle from publication WO 92/20339. It specifically describes the effect of propylene glycol lauric acid on the flux, i.e. a considerable increase in flux.
- the values specified therein relate to solutions applied to skin samples and not to the actual TTS. No specification is given regarding flux from a TTS.
- a TTS containing lisuride is further known from publication WO 91/00746.
- the flux values for human skin samples specified therein cannot be directly transferred to any achievable in-vivo values.
- TTSs of the design described above are used for various indications including Parkinson's disease.
- Parkinson's disease When treating Parkinson's disease, the highest possible doses are desirable.
- a transdermal therapeutic system also improves compliance, which is of critical importance for any combinatory treatment of this disease as patients tend to be older and have multiple diseases. Improved control and the chance to reach circadian profiles (e.g. by low stimulation as constantly as possible at night or during a break) are particularly important and have not yet been achieved (e.g. to prevent psychoses and improve the quality of sleep).
- the ergoline derivatives of the Formula I have a partially dopamine-agonistic or partially antagonistic effect that contributes to preventing the development of psychoses and can improve existing psychoses and similar problems.
- transdermal therapeutic system can ensure individually dosable, adjustable, and controlled action time (if required, by removing the patch) without influencing the circadian rhythm that is often disturbed as a result of treating Parkinson's disease and other dopaminergic diseases.
- the ⁇ -adrenolytic effect of lisuride and the ergoline derivatives of the Formula I has another benefit for this application in that it also noticeably diminishes urinary urgency at nighttime and other bladder dysfunctions that are rather common in Parkinson patients (such as prostatic hyperplasia), which adds to the success of the therapy.
- a transdermal therapeutic system comprising a pharmaceutical layer containing at least one matrix having an active ingredient, and/or an active ingredient reservoir; a diffusion barrier which is permeable to active ingredients and which is arranged on the skin side of the active ingredient reservoir; and an ergoline derivative according to Formula I or physiologically compatible salt thereof with an acid, wherein is a single or double bond wherein R1 is a H atom or a halogen atom, particularly a bromine atom, and wherein R2 is a C1-C4 alkyl, particularly methyl, as means of obtaining and maintaining the circadian rhythm under continuous dopamine therapy.
- Suitable salts of the active ingredients include sulfates, phosphates, maleates, citrates and succinates, especially hydrogen maleate.
- the invention is based on the surprising finding that circadian disturbances under dopamine therapies can be prevented using an ergoline derivative of the Formula I or a salt thereof that is highly effective and has a short half-life (0.5 to 4 hours, particularly 1 to 2 hours).
- a special benefit this invention offers is the establishment of a continuous active ingredient flux so that plasma concentrations can be set as defined and variations can be controlled. This mainly prevents the dopaminergic side effects such as fatigue, dizziness, etc. that are observed with single oral administrations or using a TTS containing an active ingredient with a long half-life. It was found that these side effects can be prevented when the level of active ingredient in the plasma is not subject to any major and rapid variation, an automatic occurrence with oral administration, but is set slowly and continuously.
- the flux F and the active surface area for reaching an effective dose in the range from 10 ⁇ g to 2 mg of active ingredient (such as lisuride), preferably 50 ⁇ g to 1 mg, throughout the day or over 24 hours in the patient's system on the second day of application.
- active ingredient such as lisuride
- the matrix and/or diffusion barrier so that the transdermal flux F through human skin measured as described in Example A1 is in the range from 0.1 to 5.0 ⁇ g/cm 2 /h, preferably 0.5 to 2.5 ⁇ g/cm 2 /h.
- a patch with these specifications is particularly suited for obtaining continuous lisuride concentrations in the plasma in the range from 0.05 to 5.0 ng/ml, preferably 0.1 to 0.5 ng/ml.
- the list of ergoline derivatives that can be used includes the following: Bromolisuride (3-(2-bromo-9,10-didehydro-6-methyl-8 ⁇ -erg-olinyl)-1,1-diethyl urea), terguride (3-(6-methyl-8 ⁇ -ergolinyl)-1,1-diethyl urea) and proterguride (3-(6-propyl-8 ⁇ -ergolinyl)-1,1-diethyl urea).
- the ergoline derivative is lisuride (3-(9,10-didehydro-6-methyl-8 ⁇ -ergolinyl)-1,1-diethyl urea) or a physiologically compatible salt thereof with an acid.
- Suitable salts of the ergoline derivative include sulfates, phosphates, maleates, citrates and succinates, especially hydrogen maleate.
- the TTS can be designed as follows.
- a covering layer can be arranged on the side of the matrix and/or active ingredient reservoir facing away from the skin. It may be formed by films of polyethylene or polyester. It is typically 10 to 100 microns in thickness.
- the covering layer may be pigmented and/or metal plated to ensure sufficient protection from light. Metal plating involves applying a very thin layer (typically less than 1 micron, mostly in the 10-100 nm range) of a metal such as aluminum to the covering layer. Pigments can be all pigments commonly used for coating including effect pigments as long as these are physiologically harmless.
- a detachable liner such as a siliconized or fluoropolymer-coated protective film can be provided on the application side.
- the matrix and/or diffusion barrier may comprise as their main matrix component a substance selected from the group consisting of polyacrylate, polyurethane, cellulose ether, silicone, polyvinyl compounds, silicate and mixtures of these substances as well as copolymers of these polymeric compounds, preferably hydrophilic polyacrylate with basic substituents.
- a main matrix component makes up at least 50 percent by weight, e.g. at least 80-90 percent by weight of the matrix (matrix to be understood as the finished layer, i.e. main matrix component(s) with adjuvant(s) and active ingredient(s)).
- the desired flux is set by selecting the substance depending on the diffusion coefficient of the active ingredient and, if required, by selecting the layer thickness of the matrix in orthogonal direction to the skin surface. Matrix thickness is typically in the range from 10 to 500 microns.
- a preferred polyacrylate adhesive as main matrix component is commercially available under the brand name GELVA® multipolymer solution 7881, provided by Monsanto Kunststoff GmbH, Dusseldorf. We expressly refer to the product sold under this name and its datasheet in the version of Apr. 23, 1996.
- Eudragit® E100 provided by Rohm, Germany, is a copolymerisate from dimethyl aminomethyl methacrylate with neutral methacrylate esters and particularly well suited for use.
- polyacrylate adhesives listed above provide an advantageous non-trivial combination of properties, namely optimum flux, good adhesive power, good skin compatibility, and durability.
- the diffusion barrier can alternatively comprise as its main barrier component a polymer selected from the group consisting of cellulose ester, cellulose ether, silicone, polyolefin and mixtures as well as copolymers of these substances. What has been said about the term of the main matrix component above analogously applies to the term of the main barrier component.
- the diffusion barrier can be a film with a thickness from 10 to 300 microns; the actual film thickness is selected (in conjunction with the diffusion coefficient of the active ingredient in the polymer) according to the desired flux.
- the matrix and/or active ingredient reservoir and/or diffusion barrier may contain the common adjuvants used in TTSs. It is preferred to use a penetration-enhancing agent that is preferably selected from the group consisting of C1-C8 aliphatic, cycloaliphatic and aromatic alcohols, saturated and unsaturated C8-18 fatty alcohols, saturated and unsaturated C8-18 fatty acids, hydrocarbons and hydrocarbon mixtures, fatty acid esters from C3-19 fatty acids and C1-6 alkyl monools, dicarboxylic acid dieesters from C4-8 dicarboxylic acids and C1-6 alkyl monools, and mixtures of these substances.
- Penetration-enhancing agents improve the flux of the active ingredient through the skin to which the TTS is attached.
- Examples of the substances listed above are: 1,2-propane diol, menthol, dexpanthenol, benzyl alcohol, lauryl alcohol, isocetyl alcohol, cetyl alcohol, mineral oil, lauric acid, isopalmitic acid, isostearic acid, oleic acid; methyl ester, ethyl ester, 2-hydroxyethyl ester, glycerol ester, propyl ester, isopropyl ester, butyl ester, sec. butyl ester or isobutyl ester of lauric acid, myristic acid, stearic acid, or palmitic acid.
- Suitable crystallization inhibitors are highly dispersed silicon dioxide or macromolecular substances such as polyvinyl pyrrolidone, polyvinyl alcohols, dextrines, dextranes, sterines, bile acids and, in particular, vinyl pyrrolidone vinylacetate copolymers such as Kollidon® VA 64. It goes without saying that the penetration-enhancing agent has to be able to diffuse to a sufficient extent through the matrix or diffusion barrier. If a matrix and lauryl alcohol as an adjuvant are used, it is preferred that the lauryl alcohol makes up 10 to 30 percent by weight, most preferred 15 to 20 percent by weight, of the matrix.
- antioxidants such as glutathione or sodium hydrogensulfite are added to the matrix as antioxidants because studies have surprisingly shown that this can prevent or dramatically reduce the formation of toxic oxidation products of lisuride such as lisuride-N-oxide.
- Antioxidants like glutathione can also have a synergistic effect on Parkinson's disease as oxidative stress plays an important part her; it has been known that even from early stages on there is a glutathione shortage in the dopaminergic substantia nigra.
- Methionine again is particularly desirable as a methyl donor because levodopa is mainly decomposed through oxygen methylation (COMT); homoserine levels increase due to the required levodopa quantities (daily dose up to the gram range), which is suspected to be a risk factor for cardial and cerebral events.
- COT oxygen methylation
- the adjuvants can basically make up from 0 to 50 percent by weight of the matrix.
- the active ingredient can make up 0.2 to 20 percent by weight, preferably 1 to 10 percent by weight, of the matrix.
- the sum total of main matrix component, adjuvants and active ingredients is always 100 percent by weight.
- the active ingredient dose in a human body carrying a TTS is dependent on the diffusion-related properties of the TTS mentioned above and also on its active surface area on the skin.
- Active surface area means the area over which the matrix or diffusion barrier comes to rest on the skin. Variation in accordance with the desired dosage will preferably be in a range from 1 to 100 cm 2 .
- a physician can easily set up personalized dose variations for a flux adjusted to the given indication by selecting a suitable patch size.
- the treatment can easily be adjusted to different body weights, age groups, etc.
- the respective subsections can easily be printed on the covering layer.
- B—A phase with enhanced stimulation e.g. when adjusting the therapy or for bridging a patient's “off” phase
- by applying the second patch while the first is still attached to the skin or by using patches with a high initial flux rate (tmax ⁇ t/2) or very low initial elimination rate e.g. when the application area is small and the diffusion of the active ingredient increases with the decrease of the concentration gradient
- the invention also includes a TTS set for obtaining and maintaining a continuous receptor stimulation with circadian rhythm, particularly for Parkinson's disease, said set containing multiple TTS elements that are set up for releasing different doses.
- the TTS elements can be separated for this purpose, each TTS element being configured for a continuously ascending sequence of F ranging from 0.1 to 5 ⁇ g/cm 2 /h.
- TTS elements can be equipped with a continuous sequence of differing active areas. In the latter case it is possible to use uniform F values.
- the TTS elements can be arranged on a big TTS design showing markings that indicate the areas to be used. An embodiment in which these elements are separated is conceivable as well, of course.
- the invention can also be used for other indications.
- One application is the use of a TTS according to the invention to produce an agent for the treatment or prevention of the premenstrual syndrome or its symptoms, wherein F preferably is in the range from 0.1 to 0.5 ⁇ g/cm 2 /h, another one to produce an agent that inhibits lactation, wherein F preferably is in the range from 0.1 to 0.5 ⁇ g/cm 2 /h.
- a FRANZ flow-through diffusion ceil is used for flux measurement.
- the measuring area is 2 cm 2 . 4 cm 2 of ventral and dorsal skin of a male hairless mouse (MF1 hr/hr Ola/Hsd, provided by Harlan Olac, UK) are used as our skin sample after carefully removing any subcutaneous fatty tissue.
- a 2 cm 2 TTS is applied to the skin sample.
- the acceptor medium is placed on the opposite side. It is diluted HHBSS (Hepes Hanks Balanced Salt Solution) containing 5.96 g/l of Hepes, 0.35 g/l of NaHCO 3 and 0.1 ml/l 10 ⁇ of HBSS (provided by Gibco, Eggenstein, Del.).
- 1000 I.U./ml of penicillin (benzylpenicillin potassium salt, provided by Fluka, Neu-Ulm, Del.) are used.
- the flux is measured as described below.
- the TTS to be measured is applied to the skin.
- the skin is mounted in the diffusion cell immediately thereafter.
- 1 ml of acceptor medium per hour is pumped through the diffusion cell using a peristaltic pump.
- the temperature of the acceptor medium is controlled using a circulating water bath which keeps the skin at a temperature of 31° C. with an accuracy of 1° C.
- the active ingredient concentration in the acceptor medium is determined in accordance with the following specifications using a radioimmunoassay.
- Calibration Curves These are constructed using two different methanol solutions of non-radioactive lisuride hydrogen maleate salt, each containing 1 mg/ml. These solutions are individually diluted with BSA buffer (0.041 M of Na 2 HPO 2 *2H 2 O, 0.026 M of KH 2 PO 4 , 0.154 M of NaCl, 0.015 M of NaN 3 , 0.1% (w/v) of BSA, pH 7, supplemented with 0.05% (w/v) of ascorbic acid) to obtain lisuride-free base concentrations in the range from 1000-3.9 pg/0.1 ml. In addition, a sample without active ingredient (0 pg) is used. The calibration samples are analyzed three times. The lisuride concentrations are calculated using the pharmacokinetic PC program RIO 2.5 (other common software may also be used).
- Sample Preparation The acceptor medium is diluted with BSA buffer prior to the analysis to set the concentrations to an analyzable range of the calibration curve. 100 ⁇ l of diluted sample are directly subjected to radioimmunological analysis.
- the antiserum (rabbit) is obtained by immunizing with lisuride-1-succinyl-BSA, an immunogen.
- the antiserum in the assay is diluted 1:12500.
- antibody-bound lisuride is separated from free lisuride by adding 0.2 ml of charcoal suspension (1.25% (w/v) and 0.125% (w/v) of dextrane in BSA buffer) and incubation for 30 minutes at 0° C.
- the charcoal is sedimented by centrifuging for 15 minutes at 3000 g.
- the supernatant liquid (containing antibody-bound active ingredient) is decanted and subjected to radiometric analysis.
- Radiometric Analysis 4 ml of Atomlight (NEN) scintillation cocktail are added to the supernatant. The count is carried out using a WALLAC 1409 or 1410 ⁇ -scintillation counter without quench control.
- the maximum transdermal active ingredient flux is obtained directly from the data.
- Flux measurements as described in Example A1 showed an F value of 0.43 on day 1, 0.44 on day 2, and a maximum F value of 0.85 (each in ⁇ g/cm 2 /h).
- dimethyl isosorbide 12.5 mg are suspended with 2 mg of lisuride in 15 mg of isopropanol.
- 80 mg of polyacrylate adhesive (Gelva 7881) are placed in a beaker, and the above suspension is added while rerinsing with 30 mg of isopropanol.
- the crystal-free wet mix obtained is thoroughly intermixed and spread on a siliconized liner using a 500 micron blade.
- the product is dried at 60° C. for 20 minutes, and finally a covering layer is laminated onto it.
- Flux measurements as described in Example A1 showed an F value of 0.23 on day 1, 0.28 on day 2, and a maximum F value of 0.50 (each in ⁇ g/cm 2 /h).
- Flux measurements as described in Example A1 showed an F value of 0.90 on day 1, 1.6 on day 2, and a maximum F value of 2.4 (each in ⁇ g/cm 2 /h).
- This invention relates to a transdermal therapeutic system (TTS) comprising a pharmaceutical layer containing at least one matrix having an active ingredient and/or an active ingredient reservoir; a diffusion barrier that is permeable to said active ingredient and arranged on the skin side of the active ingredient reservoir; and an ergoline derivative or salt thereof as an active ingredient to produce an agent for treating restless legs syndrome.
- TTS transdermal therapeutic system
- Restless legs syndrome is a neurological disease that can occur at all ages but is more frequent in older people; its main symptoms are cramps and pain in the legs due to dysesthesias and paresthesias that trigger an urge to move. As these symptoms mostly occur in periods of reduced activity such as when sitting or resting, the urge to move results in restlessness during the day and sleep disturbances at night. This considerably impairs the quality of life of those affected.
- agent concentration in the plasma is not constant but subject to great variation, not only for kinetic reasons but also depending on the conditions of drug intake (type and time of food intake, etc.). This is why there is a risk of temporary overdosing, which may result in REM suppression and the resulting problems and sleep disturbances.
- peroral dopaminergic therapies often lead to rebound problems on the following day and to so-called augmentations, i.e. hypertonus, restlessness and an urge to move.
- a transdermal therapeutic system according to the invention described below can ensure an individually desired and controlled effective time (if required, by removing the patch). Bioavailability is increased by the TTS as compared to peroral administration, which typically reduces the overall dose required to achieve the therapeutically desirable effect.
- the ⁇ -adrenolytic effect of lisuride and its derivatives has another benefit with this form of application in that it also noticeably diminishes urinary urgency at nighttime and other bladder dysfunctions that are rather common in Parkinson patients (such as prostatic hyperplasia), which adds to the success of the therapy.
- the invention relates to the use of a transdermal therapeutic system (TTS) comprising a pharmaceutical layer containing at least one matrix having an active ingredient, and/or an active ingredient reservoir; a diffusion barrier which is permeable to active ingredients and which is arranged on the skin side of the active ingredient reservoir; and an ergoline derivative according to Formula I or physiologically compatible salt thereof with an acid, wherein is a single or double bond wherein R1 is an H atom or a halogen atom, particularly a bromine atom, and wherein R2 is C1-C4 alkyl, particularly methyl, as an agent for treating restless leg syndrome.
- TTS transdermal therapeutic system
- a special benefit this invention offers is that—other than with the common one-time oral intake per day—a continuous active ingredient flux is established so that plasma concentrations can be set as defined and variations can be controlled. This mainly prevents the side effects typically observed with one-time oral administration such as fatigue, dizziness, vomiting, constipation, etc. It was found that these side effects can be prevented when the level of active ingredient in the plasma is not subject to any major and rapid variation, an automatic occurrence with oral administration, but is set slowly and continuously. In addition, the problems encountered with oral administration such as greatly varying absorption rates and a not too well-defined time of maximum concentration in the plasma depending on the type and time of food intake are virtually eliminated by this invention.
- the matrix and/or diffusion barrier are selected so that the transdermal flux F through human skin measured as described in Example B1 is in the range from 0.1 to 2.0 ⁇ g/cm 2 /h.
- the list of ergoline derivatives that can be used includes the following: Bromolisuride (3-(2-bromo-9, 10-didehydro-6-methyl8 ⁇ -ergo-linyl)-1,1-diethyl urea), terguride (3-(6-methyl-8 ⁇ -ergolinyl)-1,1-d-iethyl urea) and proterguride (3-(6-propyl-8 ⁇ -ergolinyl)-1,1-diethyl urea).
- the ergoline derivative is lisuride (3-(9,10-didehydro-6-methyl-8 ⁇ -ergolinyl)-1,1-diethyl urea) or its physiologically compatible salt with an acid.
- Suitable salts of the ergoline derivative include sulfates, phosphates, maleates, citrates and succinates, especially hydrogen maleate.
- TTS percutaneously acting but also transmucosal systems.
- a TTS typically has a sheet-like structure and is attached to an area of the skin.
- the system can optionally be attached to the skin by an additional skin-side adhesive that is permeable to the active ingredient.
- the matrix and/or diffusion barrier can itself have adhesive properties.
- a non-adhesive TTS can be attached to the skin using other auxiliary means such as adhesive tapes or bandages.
- the matrix is a material in which the active ingredient is immobilized. An active agent in an active ingredient reservoir however is not necessarily immobilized, which is why the active ingredient reservoir must be enclosed.
- the diffusion barrier forms the skin-side portion of this shell.
- a TTS of the design mentioned above is known in principle from publication WO 92/20339. It specifically describes the effect of propylene glycol lauric acid on the flux, i.e. a considerable increase in flux.
- the values specified therein relate to solutions applied to skin samples and not to the actual TTS. No specification is given regarding flux from a TTS. The flux values reached with a TTS are considerably lower than the values from applying a solution.
- a TTS containing lisuride is further known from publication WO 91/00746.
- the flux values for human skin samples specified therein cannot be directly transferred to any achievable in-vivo values.
- TTSs of the design described above are used for various indications including Parkinson's disease.
- Parkinson's disease When treating Parkinson's disease, the highest possible doses are desirable.
- a transdermal therapeutic system also improves compliance, which is of critical importance for any combinatory treatment of this disease as patients tend to be older and have multiple diseases. Improved control and the chance to reach circadian profiles (e.g. by low stimulation as constantly as possible at night or during a break) are particularly important and have not yet been achieved (e.g. to prevent psychoses and improve sleep quality).
- the ergoline derivatives lisuride, terguride, and bromerguride have a partially dopamine-agonistic or partially antagonistic effect that contributes to preventing the development of psychoses and can improve existing psychoses and similar problems.
- the TTS can be designed as follows.
- a covering layer can be arranged on the side of the matrix and/or active ingredient reservoir facing away from the skin. It may be formed by films of polyethylene or polyester. It is typically 10 to 100 microns in thickness.
- the covering layer may be pigmented and/or metal plated to ensure sufficient protection from light. Metal plating involves applying a very thin layer (typically less than 1 micron, mostly in the 10-100 nm range) of a metal such as aluminum to the covering layer. Pigments can be all pigments commonly used for coating including effect pigments as long as these are physiologically harmless.
- a detachable liner such as a siliconized or fluoropolymer-coated protective film can be provided on the application side.
- the matrix and/or diffusion barrier may comprise as their main matrix component a substance selected from the group consisting of polyacrylate, polyurethane, cellulose ether, silicone, polyvinyl compounds, silicate and mixtures of these substances as well as copolymers of these polymeric compounds, preferably polyacrylate.
- a main matrix component makes up at least 50 percent by weight, e.g. at least 80-90 percent by weight of the matrix (matrix to be understood as the finished layer, i.e. main matrix component(s) with adjuvant(s) and active ingredient(s)).
- the desired flux is set by selecting the substance depending on the diffusion coefficient of the active ingredient and, if required, by selecting the layer thickness of the matrix in orthogonal direction to the skin surface. Matrix thickness is typically in the range from 10 to 500 microns.
- a preferred polyacrylate adhesive as main matrix component is commercially available under the brand name GELVA® multipolymer solution 7881, provided by Monsanto Kunststoff GmbH, Dusseldorf. We expressly refer to the product sold under this name and its datasheet in the version of Apr. 23, 1996. Another suitable product is Eudragit® E100 provided by Rohm, Germany.
- polyacrylate adhesives listed above provide an advantageous non-trivial combination of properties, namely optimum flux, good adhesive power, good skin compatibility, and durability.
- the diffusion barrier can alternatively comprise as its main barrier component a polymer selected from the group consisting of cellulose ester, cellulose ether, silicone, polyolefin and mixtures as well as copolymers of these substances. What has been said about the term of the main matrix component above analogously applies to the term of the main barrier component.
- the diffusion barrier can be a film with a thickness from 10 to 300 microns; the actual film thickness is selected (in conjunction with the diffusion coefficient of the active ingredient in the polymer) according to the desired flux.
- the matrix and/or active ingredient reservoir and/or diffusion barrier may contain the common adjuvants used in TTSs. It is preferred to use a penetration-enhancing agent that is preferably selected from the group consisting of C1-C8 aliphatic, cycloaliphatic and aromatic alcohols, saturated and unsaturated C8-18 fatty alcohols, saturated and unsaturated C8-18 fatty acids, hydrocarbons and hydrocarbon mixtures, fatty acid esters from C3-19 fatty acids and C1-6 alkyl monools, dicarboxylic acid dieesters from C4-8 dicarboxylic acids and C1-6 alkyl monools, and mixtures of these substances.
- Penetration-enhancing agents improve the flux of the active ingredient through the skin to which the TTS is attached.
- Examples of the substances listed above are: 1,2-propane diol, menthol, dexpanthenol, benzyl alcohol, lauryl alcohol, isocetyl alcohol, cetyl alcohol, mineral oil, lauric acid, isopalmitic acid, isostearic acid, oleic acid; methyl ester, ethyl ester, 2-hydroxyethyl ester, glycerol ester, propyl ester, isopropyl ester, butyl ester, sec. butyl ester or isobutyl ester of lauric acid, myristic acid, stearic acid, or palmitic acid.
- crystallization inhibitors are highly dispersed silicon dioxide or macromolecular substances such as polyvinyl pyrrolidone, polyvinyl alcohols, dextrines, dextranes, sterines, bile acids and, in particular, vinyl pyrrolidone vinylacetate copolymers such as Kollidon® VA 64.
- the penetration-enhancing agent has to be able to diffuse to a sufficient extent through the matrix or diffusion barrier. If a matrix and lauryl alcohol as an adjuvant are used, it is preferred that the lauryl alcohol makes up 10 to 30 percent by weight, most preferred 15 to 20 percent by weight, of the matrix.
- the adjuvants can basically make up from 0 to 50 percent by weight of the matrix.
- the active ingredient can make up 0.2 to 20 percent by weight, preferably 1 to 10 percent by weight, of the matrix.
- the sum total of main matrix component, adjuvants and active ingredients is always 100 percent by weight.
- the active ingredient dose in a human body carrying a TTS is dependent on the diffusion-related properties of the TTS mentioned above and also on its active surface area on the skin.
- Active surface area means the area over which the matrix or diffusion barrier comes to rest on the skin. Variation in accordance with the desired dosage will preferably be in a range from 1 to 100 cm 2 .
- a physician can easily set up personalized dose variations for a flux adjusted to the given indication by selecting a suitable patch size.
- the treatment can easily be adjusted to different body weights, age groups, etc.
- the respective subsections can easily be printed on the covering layer.
- TTS a TTS according to the invention to produce an agent for the treatment or prevention of the premenstrual syndrome or its symptoms, wherein F preferably is in the range from 0.1 to 0.5 ⁇ g/cm 2 /h, another one to produce an agent that inhibits lactation, wherein F preferably is in the range from 0.1 to 0.5 ⁇ g/cm 2 /h.
- the flux is measured as described below.
- the TTS to be measured is applied to the skin.
- the skin is mounted in the diffusion cell immediately thereafter.
- 1 ml of acceptor medium per hour is pumped through the diffusion cell-using a peristaltic pump.
- the temperature of the acceptor medium is controlled using a circulating water bath which keeps the skin at a temperature of 31° C. with an accuracy of 1° C.
- the active ingredient concentration in the acceptor medium is determined in accordance with the following specifications using a radioimmunoassay.
- Calibration curves are constructed using two different methanol solutions of non-radioactive lisuride hydrogen maleate salt, each containing 1 mg/ml. These solutions are individually diluted with BSA buffer (0.041 M of Na 2 HPO 2 .2H 2 O, 0.026 M of KH 2 PO 4 , 0.154 M of NaCl, 0.015 M of NaN 3 , 0.1% (w/v) of BSA, pH 7, supplemented with 0.05% (w/v) of ascorbic acid) to obtain lisuride-free base concentrations in the range from 1000-3.9 pg/0.1 ml. In addition, a sample without active ingredient (0 pg) is used. The calibration samples are analyzed three times. The lisuride concentrations are calculated using the pharmacokinetic PC program RIO 2.5 (other common software may also be used).
- Sample preparation The acceptor medium is diluted with BSA buffer prior to the analysis to set the concentrations to an analyzable range of the calibration curve. 100 ⁇ l of diluted sample are directly subjected to radioimmunological analysis.
- the antiserum (rabbit) is obtained by immunizing with lisuride-1-succinyl-BSA, an immunogen.
- the antiserum in the assay is diluted 1:12500.
- antibody-bound lisuride is separated, from free lisuride by adding 0.2 ml of charcoal suspension (1.25% (w/v) and 0.125% (w/v) of dextrane in BSA buffer) and incubation for 30 minutes at 0° C.
- the charcoal is sedimented by centrifuging for 15 minutes at 3000 g.
- the supernatant liquid (containing antibody-bound active ingredient) is decanted and subjected to radiometric analysis.
- Radiometric analysis 4 ml of Atomlight (NEN) scintillation cocktail are added to the supernatant. The count is carried out using a WALLAC 1409 or 1410 ⁇ -scintillation counter without quench control.
- NNN Atomlight
- the maximum transdermal active ingredient flux is obtained directly from the data.
- Flux measurements as described in Example B1 showed an F value of 0.43 on day 1, 0.44 on day 2, and a maximum F value of 0.85 (each in ⁇ g/cm 2 /h).
- dimethyl isosorbide 12.5 mg are suspended with 2 mg of lisuride in 15 mg of isopropanol.
- 80 mg of polyacrylate adhesive (Gelva 7881) are placed in a beaker, and the above suspension is added while rerinsing with 30 mg of isopropanol.
- the crystal-free wet mix obtained is thoroughly intermixed and spread on a siliconized liner using a 500 micron blade.
- the product is dried at 60° C. for 20 minutes, and finally a covering layer is laminated onto it.
- Flux measurements as described in Example B1 showed an F value of 0.23 on day 1, 0.28 on day 2, and a maximum F value of 0.50 (each in ⁇ g/cm 2 /h).
- Flux measurements as described in Example B1 showed an F value of 0.90 on day 1, 1.76 on day 2, and a maximum F value of 2.53 (each in ⁇ g/cm 2 /h).
- the invention relates to the use of a means including a transdermal therapeutic system (TTS) containing a dopamine agonist for treating dopaminergic disease states under a special treatment plan.
- TTS transdermal therapeutic system
- a TTS containing lisuride is known from publication WO 91/00746.
- Diseases for which a dopamine therapy is indicated such as Parkinson's disease are severe chronic and disabling diseases from which older and polymorbid patients suffer frequently.
- the state-of-the-art practice is oral administration of a combination of dopaminergic substances.
- levodopa high initial flux rate, normal or slow release
- levodopa boosters such as decarboxylase inhibitors as the base and optionally COMT inhibitors or MAO-B inhibitors
- dopamine agonists such as bromocriptine, lisuride, cabergoline, pergolide, ropinirole, pramipexole as well as amantadines and, occasionally, anticholinergic agents.
- the pharmacokinetics of fast-acting levodopa is hard to control for various reasons, and dopamine agonists frequently do not allow safe bioavailability and thus efficacy predictions. All these active agents also can interact for pharmacological and pharmacokinetic reasons, in addition to their interaction with other active agents or pharmaceuticals that older patients with multiple diseases frequently need.
- Either a continuous or a discontinuous stimulation may be required depending on the stage of the disease and the actual status of the patient.
- a good foundation is laid when the level of dopaminergic agents is kept stable across the entire day.
- kick acute motoric disturbances, severe and painful dystonia, etc.
- injectable active agents such as apomorphine.
- strong and fast efficacy hikes can cause disturbing side effects (e.g.
- a typical patient would for example start with fast-acting levodopa in the morning, followed by a dose of MAO-B inhibitor and, throughout the day, four or five doses of normally acting levodopa in combination with a dopamine agonist and, eventually, a slow-acting preparation containing levodopa (or a low dose of a long-term acting dopamine agonist) at bedtime ensuring sufficient mobility in the sleep and consequently a high relaxation value.
- the invention solves this technological problem by using a dopamine agonist in the form of an agent, comprising at least two discrete compositions, of which one is a transdermal therapeutic system (TTS) containing the dopaminergic agent and another one containing the same dopaminergic agent and suitable for oral and/or parenteral administration, both suitable for the treatment of dopaminergically treatable diseases with the following elements: a) the TTS is continuously applied, b) within the duration of application in a) the composition for oral or parenteral dosage is administered. Phase b) preferably begins 7 days, more preferably 14 days, most preferably 28 days after phase a) was started.
- TTS transdermal therapeutic system
- the invention involves in this context the use of a dopamine agonist in the form of an agent consisting of at least one spatially discrete composition, of which one is a transdermal therapeutic system (TTS) containing the dopaminergic agent for the treatment of dopaminergically treatable diseases with the following elements: a) the TTS is continuously applied, b) within the duration of application in a), no dopaminergic agent is applied that differs from the dopamine agonistic agent of the TTS.
- TTS transdermal therapeutic system
- Continuous application means that a new TTS is applied before the agent level in the plasma drops disturbingly due to the consumption of the previous TTS, such as below the 0.25-fold of the maximum plasma concentration.
- the invention is based on the surprising finding that dopaminergically treatable diseases, particularly Parkinson's disease, can be treated better using a single dopaminergic agent that is highly effective and has a short half-life in the plasma, if the combination of the invention is optionally carried out using one of the treatment plans according to the invention.
- Lasting or continuous dopaminergic stimulation is achieved using the TTS. It provides agent concentrations in the plasma that can be well controlled or adjusted. The concentration in the plasma can easily be dosed by varying, for example, the effective surface area of the TTS or its size.
- a slow increase of the concentration of the active agent in the plasma can be achieved by applying the TTS; the benefit is that initial side effects are prevented.
- daily application at relatively early times e.g. between 6:00 a.m. and 3:00 p.m., for example, can reliably prevent undesirable overstimulation at night and the risk of psychotic states.
- the treatment is supplemented as may be required in advanced stages of a disease by administering oral or parenteral preparations with the same dopaminergic agent.
- the tablets comprise a preferred tmax of 15 to 120 minutes, particularly preferred of 30 to 60 minutes, and a preferred half-life of 0.5 to 4 hours, particularly preferred 1 to 2 hours.
- tmax indicates the period of time between oral administration and the buildup of the concentration of the tablet's active agent in the plasma.
- Half-life is the period of time during which the concentration in the plasma drops by half in the descending portion of the time function. Motoric blockages and akinesia are removed whenever required by such oral administration and the fast extra action as needed.
- the same active agent may be administered parenterally (i.m., i.v., subcutaneously, as contained in the TTS).
- parenterally i.m., i.v., subcutaneously, as contained in the TTS.
- tmax is typically less than 15 minutes, mostly less than 5 minutes.
- Lasting side effects if unexpected side effects occur, can reliably be prevented due to the short half-life of the active agent.
- a short-term drop of the agent concentration in the plasma is achieved by just removing the TTS. This is a particular advantage over orally administered, long-term acting agents such as pergolide or cabergoline the side effects of which after an administration or overdosage may last several days.
- the invention facilitates relatively high total absorption quantities of the active agent as compared to combinatory therapy where it is highly underdosed to prevent side effects resulting from the complex kinetics and interaction of combining different substances.
- the invention considerably increases clinical efficacy.
- This fact combined with better tolerability also allows considerably longer treatment with the respective active agent and avoids the use of levodopa formulations. This is particularly important for younger patients with a high remaining life expectancy as levodopa, the gold standard of dopamine therapy) is known to cause long-term effects resulting in severe and unpredictable dyskinesia and hyperkinesia, which makes the patients eventually dependable on outside help and confines them to bed.
- the actual dosage load can be kept low ( ⁇ 10 mg per day, particularly preferred ⁇ 5 mg per day) so that the treatment is relatively independent of any liver or kidney dysfunctions. Potential interaction with other drugs is rather low and predictable as only one active agent is involved in the treatment according to the invention; interaction with the common other Parkinson agents is completely eliminated.
- the dopaminergically treatable disease may be a disease from the group consisting of Parkinson's disease, parkinsonism, restless legs syndrome, and disturbances of the dopaminergic system.
- the dopamine agonist with a short half-life is an ergoline derivative of the Formula I or a physiologically tolerable salt thereof with an acid, where is a single or doublebond wherein R1 is an H atom or a halogen atom, particularly a bromine atom, and wherein R2 is C1-4 alkyl, particularly methyl.
- the list of ergoline derivatives that can be used particularly includes the following: Lisuride, bromolisuride (3-(2-bromo-9,10-didehydr-o-6-methyl-8 ⁇ -ergolinyl)-1,1-diethyl urea), terguride (3-(6-methyl-8 ⁇ -ergolinyl)-1,1-diethyl urea) and proterguride (3-(6-propyl-8 ⁇ -ergolinyl)-1,1-diethyl urea).
- the ergoline derivative is lisuride (3-(9,10-didehydro-6-methyl-8 ⁇ -ergolinyl)-1,1-diethyl urea) or a physiologically compatible salt thereof with an acid.
- Suitable salts of the active ingredients include sulfates, phosphates, maleates, citrates and succinates, especially hydrogen maleate.
- the TTS can be applied at various intervals depending on the kinetics of active agent release. It is important that the active agent concentration in the plasma does not show any disturbing variation when the TTS is used continuously. It is preferred that the TTS is applied daily.
- the preparation prepared for oral or parenteral administration is preferably administered directly in the event of a dopamine-related malfunction. It may be administered preventively if malfunctions are predictable.
- TTS percutaneously acting but also transmucosal systems.
- a TTS typically has a sheet-like structure and is attached to an area of the skin.
- a TTS mostly includes a matrix containing an active ingredient (e.g. in the form of a salt) and/or an active ingredient reservoir, and a diffusion barrier that is permeable to the active ingredient on the skin side of the active ingredient reservoir.
- the system can optionally be attached to the skin by an additional skin-side adhesive that is permeable to the active ingredient.
- the matrix and/or diffusion barrier can itself have adhesive properties.
- a non-adhesive TTS can be attached to the skin using other auxiliary means such as adhesive tapes or bandages.
- the matrix is a material in which the active ingredient is immobilized.
- An active agent in an active ingredient reservoir however is not necessarily immobilized, which is why the active ingredient reservoir must be enclosed.
- the diffusion barrier forms the skin-side portion of this shell. It goes without saying that all other parts of the shell should be as impermeable as possible, including diffusion paths, to the active ingredient. Immobilized means in this context that any uncontrolled active ingredient flow is prevented. However diffusion of an active agent in a matrix and/or through a diffusion barrier is not only possible but intended.
- the diffusion coefficients eventually determine the active ingredient flux from the TTS into a patient's skin.
- the dose released into a patient's skin is in first approximation a linear function of the active area of the TTS.
- the active area is the contact area of those TTS portions that allow active ingredient diffusion.
- a TTS designed as described above with lisuride as the active ingredient and its use for treating Parkinson's disease are known in principle from publication WO 92/20339. It specifically describes the effect of propylene glycol lauric acid on the flux, i.e. a considerable increase in flux.
- a TTS containing lisuride is further known from publication WO 91/00746.
- the active ingredient in a transdermal patch can of course be formulated in accordance with the pharmaceutical methods known as the state of the art.
- the TTS comprises a pharmaceutical layer containing at least one matrix containing the active ingredient and/or an active ingredient reservoir, and a diffusion barrier that is permeable to the active ingredient on the skin side of the active ingredient reservoir; and an ergoline derivative of the Formula I or a salt thereof as an active ingredient.
- the matrix and/or diffusion barrier may be selected so that the transdermal flux F through human skin measured as described in Example C1 is in the range from 0.1 to 5.0 ⁇ g/cm 2 /h, preferably 0.1 to 4.0 ⁇ g/cm 2 /h.
- TTS set as part of a means wherein the set contains a multitude of TTS elements and wherein said elements are configured for releasing different doses.
- the TTS elements can be separated, each TTS element being configured for a continuously ascending sequence of F ranging from 0.1 to 5 ⁇ g/cm 2 /h. It is also conceivable to arrange several TTSs with the same F value in a subgroup wherein the F values of the various subgroups form a continuously ascending sequence and other subgroups comprise constant F values, their value being the maximum of the sequence mentioned above.
- TTS elements can also have a continuous sequence of different active areas. These may also be divided into subgroups as described above. Suitable according to the invention are also other transdermal forms of application known from the state of the art.
- the preparation for oral administration can either be in the form of a tablet, a powder, a capsule or a solution, is formulated using the known state-of-the-art methods as required for the respective form of application, and as a tablet preferably contains 25 to 1000 ⁇ g of the dopaminergic agent (per tablet), resulting in a dose of 0.075 mg to 5.0 mg per day for lisuride, for example.
- the preparation for parenteral administration in the form of an injection or infusion solution is formulated in accordance with known methods and preferably contains 25 to 2000 ⁇ g of the dopaminergic agent (per ml of solution).
- the parenteral dose needed to achieve a fast additional effect for lisuride is up to 5.0 mg with a continuous infusion over 24 or 16 hours and from 25 up to 200 ⁇ g in a bolus injection for a single application.
- the TTS can be designed as follows.
- a covering layer can be arranged on the side of the matrix and/or active ingredient reservoir facing away from the skin. It may be formed by films of polyethylene or polyester. It is typically 10 to 100 microns in thickness.
- the covering layer may be pigmented, varnished, and/or metal plated to ensure sufficient protection from light. Metal plating involves applying a very thin layer (typically less than 1 micron, mostly in the 10-100 nm range) of a metal such as aluminum to the covering layer. Pigments can be all pigments commonly used for coating including effect pigments as long as these are physiologically harmless.
- a detachable liner such as a siliconized or fluoropolymer-coated protective film can be provided on the application side.
- the matrix and/or diffusion barrier may comprise as their main matrix component a substance selected from the group consisting of polyacrylate, polyurethane, cellulose ether, silicone, polyvinyl compounds, polyisobutylene compounds, silicate and mixtures of these substances as well as copolymers of these polymeric compounds, preferably polyacrylate.
- a main matrix component makes up at least 50 percent by weight, e.g. at least 80-90 percent by weight of the matrix (matrix to be understood as the finished layer, i.e. main matrix component(s) with adjuvant(s) and active ingredient(s)).
- the desired flux is set by selecting the substance depending on the diffusion coefficient of the active ingredient and, if required, by selecting the layer thickness of the matrix in orthogonal direction to the skin surface. Matrix thickness is typically in the range from 10 to 500 microns.
- a preferred polyacrylate adhesive as main matrix component is commercially available under the brand name GELVA® multipolymer solution 7881, provided by Monsanto Kunststoff GmbH, Dusseldorf. We expressly refer to the product sold under this name and its datasheet in the version of Apr. 23, 1996. Another suitable product is Eudragit® E100 provided by Rohm, Germany.
- polyacrylate adhesives listed above provide an advantageous non-trivial combination of properties, namely optimum flux, good adhesive power, good skin compatibility, and durability.
- the diffusion barrier can alternatively comprise as its main barrier component a polymer selected from the group consisting of cellulose ester, cellulose ether, silicone, polyolefin and mixtures as well as copolymers of these substances.
- a polymer selected from the group consisting of cellulose ester, cellulose ether, silicone, polyolefin and mixtures as well as copolymers of these substances.
- the diffusion barrier can be a film with a thickness from 10 to 300 microns; the actual film thickness is selected (in conjunction with the diffusion coefficient of the active ingredient in the polymer) according to the desired flux.
- the matrix and/or active ingredient reservoir and/or diffusion barrier may contain the common adjuvants used in TTSs. It is preferred to use a penetration-enhancing agent that is preferably selected from the group consisting of C1-C8 aliphatic, cycloaliphatic and aromatic alcohols, saturated and unsaturated C8-18 fatty alcohols, saturated and unsaturated C8-18 fatty acids, hydrocarbons and hydrocarbon mixtures, fatty acid esters from C3-19 fatty acids and C1-6 alkyl monools, dicarboxylic acid dieesters from C4-8 dicarboxylic acids and C1-6 alkyl monools, and mixtures of these substances.
- Penetration-enhancing agents improve the flux of the active ingredient through the skin to which the TTS is attached.
- Examples of the substances listed above are: 1,2-propane diol, menthol, dexpanthenol, benzyl alcohol, lauryl alcohol, isocetyl alcohol, cetyl alcohol, mineral oil, lauric acid, isopalmitic acid, isostearic acid, oleic acid; methyl ester, ethyl ester, 2-hydroxyethyl ester, glycerol ester, propyl ester, isopropyl ester, butyl ester, sec. butyl ester or isobutyl ester of lauric acid, myristic acid, stearic acid, or palmitic acid.
- crystallization inhibitors are highly dispersed silicon dioxide or macromolecular substances such as polyvinyl pyrrolidone, polyvinyl alcohols, dextrines, dextranes, sterines, bile acids and, in particular, polyvinyl pyrrolidone vinylacetate copolymers such as Kollidon® VA 64.
- the penetration-enhancing agent has to be able to diffuse to a sufficient extent through the matrix or diffusion barrier. If a matrix and lauryl alcohol as an adjuvant are used, it is preferred that the lauryl alcohol makes up 10 to 30 percent by weight, most preferred 15 to 20 percent by weight, of the matrix.
- the adjuvants can basically make up from 0 to 50 percent by weight of the matrix.
- the active ingredient can make up 0.5 to 20 percent by weight, preferably 1 to 10 percent by weight, of the matrix.
- the sum total of main matrix component, adjuvants and active ingredients is always 100 percent by weight.
- the active ingredient dose in a human body carrying a TTS is dependent on the diffusion-related properties of the TTS mentioned above and also on its active surface area on the skin.
- Active surface area means the area over which the matrix or diffusion barrier comes to rest on the skin.
- Variation in accordance with the desired dosage will preferably be in a range from 1 to 100 cm 2 .
- a physician can easily set up personalized dose variations for a flux adjusted to the given indication by selecting a suitable patch size.
- the treatment can easily be adjusted to different body weights, age groups, etc.
- the respective subsections can easily be printed on the covering layer.
- a transdermal and an oral or parenteral form of application of an active ingredient can easily be offered as one kit for a monotherapy of dopaminergic diseases.
- the invention also relates to a combination of a transdermal therapeutic system and an oral and/or parenteral preparation containing one and the same dopamine agonist with a short half-life to produce a pharmaceutical for the treatment of dopaminergic diseases.
- a FRANZ flow-through diffusion cell is used for flux measurement.
- the measuring area is 2 cm 2 . 4 cm 2 of ventral and dorsal skin of a male hairless mouse (MF1 hr/hr Ola/Hsd, provided by Harlan Olac, UK) are used as our skin sample after carefully removing any subcutaneous fatty tissue.
- a 2 cm 2 TTS is applied to the skin sample.
- the acceptor medium is placed on the opposite side. It is diluted HHBSS (Hepes Hanks Balanced Salt Solution) containing 5.96 g/l of Hepes, 0.35 g/l of NaHCO 3 and 0.1 ml/10 ⁇ of HBSS (provided by Gibco, Eggenstein, Del.).
- 1000 I.U./ml of penicillin (benzylpenicillin potassium salt, provided by Fluka, Neu-Ulm, Del.) are used.
- the flux is measured as described below.
- the TTS to be measured is applied to the skin.
- the skin is mounted in the diffusion cell immediately thereafter.
- 1 ml of acceptor medium per hour is pumped through the diffusion cell using a peristaltic pump.
- the temperature of the acceptor medium is controlled using a circulating water bath which keeps the skin at a temperature of 31° C. with an accuracy of 1° C.
- the active ingredient concentration in the acceptor medium is determined in accordance with the following specifications using a radioimmunoassay.
- Calibration curves are constructed using two different methanol solutions of non-radioactive lisuride hydrogen maleate salt, each containing 1 mg/ml. These solutions are individually diluted with BSA buffer (0.041 M of Na 2 HPO 2 .2H 2 O, 0.026 M of KH 2 PO 4 , 0.154 M of NaCl, 0.015 M of NaN 3 , 0.1% (w/v) of BSA, pH 7, supplemented with 0.05% (w/v) of ascorbic acid) to obtain lisuride-free base concentrations in the range from 1000-3.9 pg/0.1 ml. In addition, a sample without active ingredient (0 pg) is used. The calibration samples are analyzed three times. The lisuride concentrations are calculated using the pharmacokinetic PC program RIO 2.5 (other common software may also be used).
- Sample preparation The acceptor medium is diluted with BSA buffer prior to the analysis to set the concentrations to an analyzable range of the calibration curve. 100 ⁇ l of diluted sample are directly subjected to radioimmunological analysis.
- the antiserum (rabbit) is obtained by immunizing with lisuride-1-succinyl-BSA, an immunogen.
- the antiserum in the assay is diluted 1:12500.
- antibody-bound lisuride is separated from free lisuride by adding 0.2 ml of charcoal suspension (1.25% (w/v) and 0.125% (w/v) of dextrane in BSA buffer) and incubation for 30 minutes at 0° C.
- the charcoal is sedimented by centrifuging for 15 minutes at 3000 g.
- the supernatant liquid (containing antibody-bound active ingredient) is decanted and subjected to radiometric analysis.
- Radiometric analysis 4 ml of Atomlight (NEN) scintillation cocktail are added to the supernatant. The count is carried out using a WALLAC 1409 or 1410 ⁇ -scintillation counter without quench control.
- NNN Atomlight
- the maximum transdermal active ingredient flux is obtained directly from the data.
- Flux measurements as described in Example C1 showed an F value of 0.43 on day 1, 0.44 on day 2, and a maximum F value of 0.85 (each in ⁇ g/cm 2 /h).
- dimethyl isosorbide 12.5 mg are suspended with 2 mg of lisuride in 15 mg of isopropanol.
- 80 mg of polyacrylate adhesive (Gelva 7881) are placed in a beaker, and the above suspension is added while rerinsing with 30 mg of isopropanol.
- the crystal-free wet mix obtained is thoroughly intermixed and spread on a siliconized liner using a 500 micron blade.
- the product is dried at 60° C. for 20 minutes, and finally a covering layer is laminated onto it.
- Flux measurements as described in Example C1 showed an F value of 0.23 on day 1, 0.28 on day 2, and a maximum F value of 0.50 (each in ⁇ g/cm 2 /h).
- Flux measurements as described in Example C1 showed an F value of 0.90 on day 1, 1.76 on day 2, and a maximum F value of 2.53 (each in ⁇ g/cm 2 /h).
- a tablet base composition containing lactose, microcrystalline cellulose, corn starch, crosscarmellose and magnesium stearate in the usual quantitative composition is intermixed with 2000 ⁇ g of lisuride per each gram of tablet basis composition and pressed into tablets, each of which containing 200 ⁇ g of lisuride.
- An injection base solution containing lactose, NaCl and aqua p.i. in the usual quantitative composition is intermixed with 50 ⁇ g of lisuride per gram of injection base solution and filled into amber glass ampoules containing 50 ⁇ g of lisuride per ml of solution and preferably lyophilized.
- TTSs divided into the four groups as described in Example C2 are put together.
- the fluxes F of lisuride through human skin of the TTSs of each group comprise are 0.25 ⁇ g/cm 2 /h, 0.5 ⁇ g/cm 2 /h, 0.75 ⁇ g/cm 2 /h and 1.0 ⁇ g/cm 2 /h.
- At least 7 TTSs are to be in the three groups where F is low.
- 28 or more TTSs are to be in the group with the highest F.
- a multitude of tablets from Example C5 and/or a multitude of ampoules from Example C6 is packed with the TTSs compiled in this way.
- the compilation is accompanied by an instruction sheet that refers to the treatment plan according to the invention.
- TTS from Example C7 per day is applied to a Parkinson's disease patient over a period of 28 days.
- the area of the TTS remains unchanged for seven consecutive days.
- the TTSs applied in series of 7 consecutive days increase in area so that there will be a four-step increase in lisuride concentration in the plasma (averaged over a day).
- the lisuride flux F of the TTSs applied in four steps is 0.25 ⁇ g/cm 2 /h, 0.5 ⁇ g/cm 2 /h, 0.75 ⁇ g/cm 2 /h, and 1.0 ⁇ g/cm 2 /h.
- a tablet from Example C7 is administered, or the content of an ampoule from Example C7 is injected i.m.
- a tablet from Example C7 or the content of an ampoule from Example C7 may be administered in the morning for preventive reasons.
Abstract
Description
- This application claims priority under 35 U.S.C. § 120 to U.S. Ser. No. 10/362,248 filed Jul. 7, 2003; PCT/EP01/09824 filed Aug. 24, 2001; Ser. No. 10/362,183 filed Jul. 21, 2003; PCT/EP01/09823 filed Aug. 24, 2001; and U.S. Ser. No. 10/362,182 filed Jul. 3, 2003, PCT/EP01/09826 filed Aug. 24, 2001, each of which is incorporated herein by reference in its entirety.
- I. Description A—Transdermal Therapeutic System
- This invention relates to a transdermal therapeutic system (TTS) comprising a pharmaceutical layer containing at least one matrix having an active ingredient and/or an active ingredient reservoir; a diffusion barrier that is permeable to said active ingredient and arranged on the skin side of the active ingredient reservoir; and an ergoline derivative or salt thereof as an active ingredient for producing an agent for obtaining and maintaining the circadian rhythm under dopamine therapy.
- The term “TTS” mostly denotes percutaneously acting but also transmucosal systems. A TTS typically has a sheet-like structure and is attached to an area of the skin. The system can optionally be attached to the skin by an additional skin-side adhesive that is permeable to the active ingredient. Alternatively, the matrix and/or diffusion barrier can itself have adhesive properties. And finally a non-adhesive TTS can be attached to the skin using other auxiliary means such as adhesive tapes or bandages. The matrix is a material in which the active ingredient is immobilized. An active agent in an active ingredient reservoir however is not necessarily immobilized, which is why the active ingredient reservoir must be enclosed. The diffusion barrier forms the skin-side portion of this shell. It goes without saying that all other parts of the shell should be as impermeable as possible, including diffusion paths, to the active ingredient. Immobilized means in this context that any uncontrolled active ingredient flow is prevented. However diffusion of an active agent in a matrix and/or through a diffusion barrier is not only possible but intended. The diffusion coefficients eventually determine the active ingredient flux from the TTS into a patient's skin. The dose released into a patient's skin is in first approximation a linear function of the active area of the TTS. The active area is the contact area of those TTS portions that allow active ingredient diffusion. TTSs can be used in human and veterinary medicine.
- A TTS of the design mentioned above is known in principle from publication WO 92/20339. It specifically describes the effect of propylene glycol lauric acid on the flux, i.e. a considerable increase in flux. However the values specified therein relate to solutions applied to skin samples and not to the actual TTS. No specification is given regarding flux from a TTS.
- A TTS containing lisuride is further known from publication WO 91/00746. The flux values for human skin samples specified therein cannot be directly transferred to any achievable in-vivo values.
- TTSs of the design described above are used for various indications including Parkinson's disease. When treating Parkinson's disease, the highest possible doses are desirable. A transdermal therapeutic system also improves compliance, which is of critical importance for any combinatory treatment of this disease as patients tend to be older and have multiple diseases. Improved control and the chance to reach circadian profiles (e.g. by low stimulation as constantly as possible at night or during a break) are particularly important and have not yet been achieved (e.g. to prevent psychoses and improve the quality of sleep). The ergoline derivatives of the Formula I have a partially dopamine-agonistic or partially antagonistic effect that contributes to preventing the development of psychoses and can improve existing psychoses and similar problems.
- In the treatment of Parkinson's disease in which dopamine drugs and combinations thereof are taken throughout the day, concentrations in the plasma are not constant but subject to great variation, and this not only for kinetic reasons (highly variable first pass effect depending on the metabolization type) but also depending on individual administration conditions (type and times of food intake, effect of other drugs on resorption and metabolism, etc.). This is why there is a risk of temporary overdosing, which may result in REM suppression and the resulting sleep disturbances or psychoses.
- In addition, currently used dopamine therapies frequently have lasting and severe side effects. This is where a transdermal therapeutic system according to the invention described below can ensure individually dosable, adjustable, and controlled action time (if required, by removing the patch) without influencing the circadian rhythm that is often disturbed as a result of treating Parkinson's disease and other dopaminergic diseases.
- It is the technological problem of the invention to provide an agent for obtaining and maintaining the circadian rhythm that can be individually dosed and adjusted and whose efficacy period can be controlled so that circadian disturbances that occur under dopamine therapy when treating dopaminergic diseases, in particular, when treating patients with Parkinson's disease, are prevented. The α-adrenolytic effect of lisuride and the ergoline derivatives of the Formula I has another benefit for this application in that it also noticeably diminishes urinary urgency at nighttime and other bladder dysfunctions that are rather common in Parkinson patients (such as prostatic hyperplasia), which adds to the success of the therapy.
- The technological problem is solved according to the invention in that a transdermal therapeutic system (TTS) is used comprising a pharmaceutical layer containing at least one matrix having an active ingredient, and/or an active ingredient reservoir; a diffusion barrier which is permeable to active ingredients and which is arranged on the skin side of the active ingredient reservoir; and an ergoline derivative according to Formula I or physiologically compatible salt thereof with an acid,
wherein
is a single or double bond wherein R1 is a H atom or a halogen atom, particularly a bromine atom, and wherein R2 is a C1-C4 alkyl, particularly methyl, as means of obtaining and maintaining the circadian rhythm under continuous dopamine therapy. Suitable salts of the active ingredients include sulfates, phosphates, maleates, citrates and succinates, especially hydrogen maleate. - The invention is based on the surprising finding that circadian disturbances under dopamine therapies can be prevented using an ergoline derivative of the Formula I or a salt thereof that is highly effective and has a short half-life (0.5 to 4 hours, particularly 1 to 2 hours). A special benefit this invention offers is the establishment of a continuous active ingredient flux so that plasma concentrations can be set as defined and variations can be controlled. This mainly prevents the dopaminergic side effects such as fatigue, dizziness, etc. that are observed with single oral administrations or using a TTS containing an active ingredient with a long half-life. It was found that these side effects can be prevented when the level of active ingredient in the plasma is not subject to any major and rapid variation, an automatic occurrence with oral administration, but is set slowly and continuously. In addition, the problems encountered with oral administration such as greatly varying absorption rates and a not too well-defined time of maximum concentration in the plasma depending on the type and time of food intake are virtually eliminated by this invention. Most of all, it prevents overdosing (and thus REM suppression and other disruptions of the sleep pattern). Furthermore, administration can easily be canceled by just removing the TTS. The drop in agent concentration in the plasma when removing the TTS is further accelerated because of the short half-life of the suitable agents according to the invention. Unlike discontinuing an orally administered active agent or an active agent with a long half-life, decomposition in the plasma is fast and controlled, which also prevents a hangover. Finally it is easy to administer exact individual doses by selecting the flux F and/or the active surface area. It is preferred to select the flux F and the active surface area for reaching an effective dose in the range from 10 μg to 2 mg of active ingredient (such as lisuride), preferably 50 μg to 1 mg, throughout the day or over 24 hours in the patient's system on the second day of application.
- It is further preferred to select the matrix and/or diffusion barrier so that the transdermal flux F through human skin measured as described in Example A1 is in the range from 0.1 to 5.0 μg/cm2/h, preferably 0.5 to 2.5 μg/cm2/h. A patch with these specifications is particularly suited for obtaining continuous lisuride concentrations in the plasma in the range from 0.05 to 5.0 ng/ml, preferably 0.1 to 0.5 ng/ml. The use of a TTS comprising a matrix and an ergoline derivative of the Formula I or salt thereof as the active ingredient.
- The list of ergoline derivatives that can be used includes the following: Bromolisuride (3-(2-bromo-9,10-didehydro-6-methyl-8α-erg-olinyl)-1,1-diethyl urea), terguride (3-(6-methyl-8α-ergolinyl)-1,1-diethyl urea) and proterguride (3-(6-propyl-8α-ergolinyl)-1,1-diethyl urea). However it is preferred when the ergoline derivative is lisuride (3-(9,10-didehydro-6-methyl-8α-ergolinyl)-1,1-diethyl urea) or a physiologically compatible salt thereof with an acid. The production of lisuride and other suitable ergolines according to the invention is described, inter alia, in U.S. Pat. No. 3,953,454, EP 056 358 and U.S. Pat. No. 4,379,790. Suitable salts of the ergoline derivative include sulfates, phosphates, maleates, citrates and succinates, especially hydrogen maleate.
- The TTS can be designed as follows. A covering layer can be arranged on the side of the matrix and/or active ingredient reservoir facing away from the skin. It may be formed by films of polyethylene or polyester. It is typically 10 to 100 microns in thickness. The covering layer may be pigmented and/or metal plated to ensure sufficient protection from light. Metal plating involves applying a very thin layer (typically less than 1 micron, mostly in the 10-100 nm range) of a metal such as aluminum to the covering layer. Pigments can be all pigments commonly used for coating including effect pigments as long as these are physiologically harmless. A detachable liner such as a siliconized or fluoropolymer-coated protective film can be provided on the application side.
- The matrix and/or diffusion barrier may comprise as their main matrix component a substance selected from the group consisting of polyacrylate, polyurethane, cellulose ether, silicone, polyvinyl compounds, silicate and mixtures of these substances as well as copolymers of these polymeric compounds, preferably hydrophilic polyacrylate with basic substituents. A main matrix component makes up at least 50 percent by weight, e.g. at least 80-90 percent by weight of the matrix (matrix to be understood as the finished layer, i.e. main matrix component(s) with adjuvant(s) and active ingredient(s)). The desired flux is set by selecting the substance depending on the diffusion coefficient of the active ingredient and, if required, by selecting the layer thickness of the matrix in orthogonal direction to the skin surface. Matrix thickness is typically in the range from 10 to 500 microns.
- A preferred polyacrylate adhesive as main matrix component is commercially available under the brand name GELVA® multipolymer solution 7881, provided by Monsanto Deutschland GmbH, Dusseldorf. We expressly refer to the product sold under this name and its datasheet in the version of Apr. 23, 1996. Eudragit® E100, provided by Rohm, Germany, is a copolymerisate from dimethyl aminomethyl methacrylate with neutral methacrylate esters and particularly well suited for use.
- The polyacrylate adhesives listed above provide an advantageous non-trivial combination of properties, namely optimum flux, good adhesive power, good skin compatibility, and durability.
- The diffusion barrier can alternatively comprise as its main barrier component a polymer selected from the group consisting of cellulose ester, cellulose ether, silicone, polyolefin and mixtures as well as copolymers of these substances. What has been said about the term of the main matrix component above analogously applies to the term of the main barrier component. The diffusion barrier can be a film with a thickness from 10 to 300 microns; the actual film thickness is selected (in conjunction with the diffusion coefficient of the active ingredient in the polymer) according to the desired flux.
- The matrix and/or active ingredient reservoir and/or diffusion barrier may contain the common adjuvants used in TTSs. It is preferred to use a penetration-enhancing agent that is preferably selected from the group consisting of C1-C8 aliphatic, cycloaliphatic and aromatic alcohols, saturated and unsaturated C8-18 fatty alcohols, saturated and unsaturated C8-18 fatty acids, hydrocarbons and hydrocarbon mixtures, fatty acid esters from C3-19 fatty acids and C1-6 alkyl monools, dicarboxylic acid dieesters from C4-8 dicarboxylic acids and C1-6 alkyl monools, and mixtures of these substances. Penetration-enhancing agents improve the flux of the active ingredient through the skin to which the TTS is attached. Examples of the substances listed above are: 1,2-propane diol, menthol, dexpanthenol, benzyl alcohol, lauryl alcohol, isocetyl alcohol, cetyl alcohol, mineral oil, lauric acid, isopalmitic acid, isostearic acid, oleic acid; methyl ester, ethyl ester, 2-hydroxyethyl ester, glycerol ester, propyl ester, isopropyl ester, butyl ester, sec. butyl ester or isobutyl ester of lauric acid, myristic acid, stearic acid, or palmitic acid. Use of dimethyl isosorbide, isopropyl myristate and lauryl alcohol is preferred, use of lauryl alcohol is most preferred. Other adjuvants are, for example, crystallization inhibitors. Suitable crystallization inhibitors are highly dispersed silicon dioxide or macromolecular substances such as polyvinyl pyrrolidone, polyvinyl alcohols, dextrines, dextranes, sterines, bile acids and, in particular, vinyl pyrrolidone vinylacetate copolymers such as Kollidon® VA 64. It goes without saying that the penetration-enhancing agent has to be able to diffuse to a sufficient extent through the matrix or diffusion barrier. If a matrix and lauryl alcohol as an adjuvant are used, it is preferred that the lauryl alcohol makes up 10 to 30 percent by weight, most preferred 15 to 20 percent by weight, of the matrix.
- In addition to the ingredients listed above, sufficient quantities of sulfur-containing amino acids such as cysteine, methyl donors such as methionine, or antioxidants such as glutathione or sodium hydrogensulfite are added to the matrix as antioxidants because studies have surprisingly shown that this can prevent or dramatically reduce the formation of toxic oxidation products of lisuride such as lisuride-N-oxide. Antioxidants like glutathione can also have a synergistic effect on Parkinson's disease as oxidative stress plays an important part her; it has been known that even from early stages on there is a glutathione shortage in the dopaminergic substantia nigra. Methionine again is particularly desirable as a methyl donor because levodopa is mainly decomposed through oxygen methylation (COMT); homoserine levels increase due to the required levodopa quantities (daily dose up to the gram range), which is suspected to be a risk factor for cardial and cerebral events.
- The adjuvants can basically make up from 0 to 50 percent by weight of the matrix. The active ingredient can make up 0.2 to 20 percent by weight, preferably 1 to 10 percent by weight, of the matrix. The sum total of main matrix component, adjuvants and active ingredients is always 100 percent by weight.
- The active ingredient dose in a human body carrying a TTS is dependent on the diffusion-related properties of the TTS mentioned above and also on its active surface area on the skin. Active surface area means the area over which the matrix or diffusion barrier comes to rest on the skin. Variation in accordance with the desired dosage will preferably be in a range from 1 to 100 cm2.
- Within the scope of this invention, a physician can easily set up personalized dose variations for a flux adjusted to the given indication by selecting a suitable patch size. Thus the treatment can easily be adjusted to different body weights, age groups, etc. It is particularly feasible to equip a TTS comprising a (rather large) standard area with subdivision markers for partial doses so that a user can just remove the protective film from a partial are a corresponding to the specified dose. The respective subsections can easily be printed on the covering layer.
- The use of lisuride, its salts or derivatives with comparably favorable properties as active ingredients offers the following therapeutic benefits:
-
- These substances can be applied at extremely low doses (for lisuride: from 0.075 mg orally at a high first pass effect) due to their extraordinarily strong affinity for dopamine and other monoamine receptors; thus a TTS with a relatively small application area can easily build an effective and well adjustable active ingredient level across the area over 24 hours or longer;
- Unlike long-acting oral active ingredients such as cabergoline, transdermal dosing of lisuride not only is much improved (elimination of the considerable and highly variable first pass effect after oral administration of cabergoline or the like), the effects can also easily be discontinued whenever required (e.g. when side effects occur) by removing the patch. Then the short half-life of lisuride in the blood (ca. 2 hrs) comes in useful—a great contrast to oral dopamine agonists where side effects last for days once they are administered.
- The combination of these effects has surprisingly resulted in combining the benefits of continuous and long-lasting dopaminergic stimulation with the other benefits of short-term acting dopaminergic pharmaceuticals in one application.
- Combining these properties enables physicians to tailor the application to a patient's individual situation and needs as they can select the application scheme of two patches (simultaneous removal and reattachment, overlapping replacement or replacement at an interval) or, even better, to obtain almost any circadian rhythm of dopaminergic therapy by modifying the initial flux rate of the ITS formulation:
- A—Continuous stimulation when the initial flux rate of the patch matches the terminal half-life after patch removal (tmax˜t/2 optionally a short interval, or when simultaneously applying a new ITS with a relatively high initial flux rate);
- B—A phase with enhanced stimulation (e.g. when adjusting the therapy or for bridging a patient's “off” phase) by applying the second patch while the first is still attached to the skin or by using patches with a high initial flux rate (tmax<<t/2) or very low initial elimination rate (e.g. when the application area is small and the diffusion of the active ingredient increases with the decrease of the concentration gradient), and;
- C—A phase of reduced dopaminergic stimulation such as reducing time-of-day-specific side effects by either complying with an interval between patch removal and attachment of the new patch, or, even simpler, by simultaneously using the new patch with a very low initial flux rate (tmax>>t/2) at the time of removal.
- In all, we are surprisingly facing the chance of using just one active ingredient with suitable receptor affinity, efficacy and kinetics and opening all options of an easily applicable and well adjustable dopamine treatment for the patient. As the side effects that are almost inevitable when using state-of-the-art oral and transdermal therapies are prevented, stronger efficacy and a clearly improved therapeutic effect are obtained with simple means.
- This means that levodopa therapy and its long-term complications can be prevented or delayed or that this or any other oral dopamine therapy has to be applied at low doses only and is thus more compatible.
- In this context, the invention also includes a TTS set for obtaining and maintaining a continuous receptor stimulation with circadian rhythm, particularly for Parkinson's disease, said set containing multiple TTS elements that are set up for releasing different doses. The TTS elements can be separated for this purpose, each TTS element being configured for a continuously ascending sequence of F ranging from 0.1 to 5 μg/cm2/h. In addition, or separately, TTS elements can be equipped with a continuous sequence of differing active areas. In the latter case it is possible to use uniform F values. The TTS elements can be arranged on a big TTS design showing markings that indicate the areas to be used. An embodiment in which these elements are separated is conceivable as well, of course.
- The invention can also be used for other indications. One application is the use of a TTS according to the invention to produce an agent for the treatment or prevention of the premenstrual syndrome or its symptoms, wherein F preferably is in the range from 0.1 to 0.5 μg/cm2/h, another one to produce an agent that inhibits lactation, wherein F preferably is in the range from 0.1 to 0.5 μg/cm2/h.
- The invention will be explained in more detail below based on various examples (Examples A1-A4).
- A FRANZ flow-through diffusion ceil is used for flux measurement. The measuring area is 2 cm2. 4 cm2 of ventral and dorsal skin of a male hairless mouse (MF1 hr/hr Ola/Hsd, provided by Harlan Olac, UK) are used as our skin sample after carefully removing any subcutaneous fatty tissue. A 2 cm2 TTS is applied to the skin sample. The acceptor medium is placed on the opposite side. It is diluted HHBSS (Hepes Hanks Balanced Salt Solution) containing 5.96 g/l of Hepes, 0.35 g/l of NaHCO3 and 0.1 ml/l 10× of HBSS (provided by Gibco, Eggenstein, Del.). Furthermore, 1000 I.U./ml of penicillin (benzylpenicillin potassium salt, provided by Fluka, Neu-Ulm, Del.) are used.
- The flux is measured as described below. First, the TTS to be measured is applied to the skin. The skin is mounted in the diffusion cell immediately thereafter. Samples of the acceptor medium are taken at 2-hour intervals between t=0 hrs and t=6 hrs and at 8-hour intervals between t=6 hrs and t=54 hrs. 1 ml of acceptor medium per hour is pumped through the diffusion cell using a peristaltic pump. The temperature of the acceptor medium is controlled using a circulating water bath which keeps the skin at a temperature of 31° C. with an accuracy of 1° C.
- The active ingredient concentration in the acceptor medium is determined in accordance with the following specifications using a radioimmunoassay.
- Calibration Curves: These are constructed using two different methanol solutions of non-radioactive lisuride hydrogen maleate salt, each containing 1 mg/ml. These solutions are individually diluted with BSA buffer (0.041 M of Na2HPO2*2H2O, 0.026 M of KH2PO4, 0.154 M of NaCl, 0.015 M of NaN3, 0.1% (w/v) of BSA, pH 7, supplemented with 0.05% (w/v) of ascorbic acid) to obtain lisuride-free base concentrations in the range from 1000-3.9 pg/0.1 ml. In addition, a sample without active ingredient (0 pg) is used. The calibration samples are analyzed three times. The lisuride concentrations are calculated using the pharmacokinetic PC program RIO 2.5 (other common software may also be used).
- Sample Preparation: The acceptor medium is diluted with BSA buffer prior to the analysis to set the concentrations to an analyzable range of the calibration curve. 100 μl of diluted sample are directly subjected to radioimmunological analysis.
- Antiserum: The antiserum (rabbit) is obtained by immunizing with lisuride-1-succinyl-BSA, an immunogen. The antiserum in the assay is diluted 1:12500.
- Tracer: 3H-lisuride hydrogen maleate with a specific activity of 4.3 GBq/mg is used.
- Incubation: 0.1 ml of BSA buffer with active ingredient, 0.1 ml of tracer solution (ca. 5000 cpm/0.1 ml of BSA buffer) and 0.1 ml of diluted antiserum (1:12500) are added to 0.7 ml of BSA buffer and incubated for 18 hours at 4° C.
- Separation: antibody-bound lisuride is separated from free lisuride by adding 0.2 ml of charcoal suspension (1.25% (w/v) and 0.125% (w/v) of dextrane in BSA buffer) and incubation for 30 minutes at 0° C. The charcoal is sedimented by centrifuging for 15 minutes at 3000 g. The supernatant liquid (containing antibody-bound active ingredient) is decanted and subjected to radiometric analysis.
- Radiometric Analysis: 4 ml of Atomlight (NEN) scintillation cocktail are added to the supernatant. The count is carried out using a WALLAC 1409 or 1410 β-scintillation counter without quench control.
- Analysis: The percutaneous skin flux is calculated as follows:
F=(C*R)/(A*T),
where F is the percutaneous flux [ng/cm2/h], C the active ingredient concentration in the acceptor medium [ng/ml], R the acceptor medium flow [1 ml/h], A the measured area [2 cm2] and T the sample-taking interval [h]. - The maximum transdermal active ingredient flux is obtained directly from the data. Mean percutaneous flux values are determined during days 1 and 2 of the experiment based on the cumulative absorbed dose in time intervals t=0-22 and t=22-54.
- Specifications for the Production of TTS
- 15 mg of Kollidon VA 64 (crystallization inhibitor) are dissolved in 15 mg of isopropanol. Then 5 mg of lisuride are sprinkled in. 80 mg of polyacrylate adhesive (Gelva 7881) are placed in a beaker, and the above suspension is added while rerinsing with 30 mg of isopropanol. The crystal-free wet mix obtained is thoroughly intermixed and spread on a siliconized liner using a 500 micron blade. The product is dried at 60° C. for 20 minutes, and finally a covering layer is laminated onto it.
- Flux measurements as described in Example A1 showed an F value of 0.43 on day 1, 0.44 on day 2, and a maximum F value of 0.85 (each in μg/cm2/h).
- 12.5 mg of dimethyl isosorbide are suspended with 2 mg of lisuride in 15 mg of isopropanol. 80 mg of polyacrylate adhesive (Gelva 7881) are placed in a beaker, and the above suspension is added while rerinsing with 30 mg of isopropanol. The crystal-free wet mix obtained is thoroughly intermixed and spread on a siliconized liner using a 500 micron blade. The product is dried at 60° C. for 20 minutes, and finally a covering layer is laminated onto it.
- Flux measurements as described in Example A1 showed an F value of 0.23 on day 1, 0.28 on day 2, and a maximum F value of 0.50 (each in μg/cm2/h).
- 27.2 mg of polyvinyl pyrrolidone (crystallization inhibitor) and 16.3 mg of lauryl alcohol are dissolved at 60° C. Then 2 mg of lisuride and 0.5 mg of glutathione are dissolved in this solution at 60° C. 39.38 mg of Eudragit E100, 13.41 mg of Citroflex 4A and 1.71 mg of succinic acid are molten at 150-200° C. The lisuride solution is added after the batch has cooled down to 80° C. The product is spread at 80° C. on a siliconized liner using a 500 micron blade. Then the product is cooled down to 20° C.; optionally, a covering layer may be laminated onto it.
- Flux measurements as described in Example A1 showed an F value of 0.90 on day 1, 1.6 on day 2, and a maximum F value of 2.4 (each in μg/cm2/h).
- II. Description B—Transdermal Therapeutic System for Treating Restless Leg Syndrome
- This invention relates to a transdermal therapeutic system (TTS) comprising a pharmaceutical layer containing at least one matrix having an active ingredient and/or an active ingredient reservoir; a diffusion barrier that is permeable to said active ingredient and arranged on the skin side of the active ingredient reservoir; and an ergoline derivative or salt thereof as an active ingredient to produce an agent for treating restless legs syndrome.
- Restless legs syndrome (RLS) is a neurological disease that can occur at all ages but is more frequent in older people; its main symptoms are cramps and pain in the legs due to dysesthesias and paresthesias that trigger an urge to move. As these symptoms mostly occur in periods of reduced activity such as when sitting or resting, the urge to move results in restlessness during the day and sleep disturbances at night. This considerably impairs the quality of life of those affected.
- It is known that treating restless legs syndrome with single oral administrations of dopaminergic drugs such as lisuride in the evening reduces the symptoms and has a positive influence on the patients quality of life. Unlike the treatment of Parkinson's disease where dopaminergic pharmaceuticals and combinations thereof are administered throughout the day, one-time peroral intake of these drugs for the treatment of restless legs syndrome impairs the building of a tolerance against acute dopaminergic side effects (due to the initial flux rate); this means that the known side effects such as orthostasis, hypotonia, dizziness, nausea, and vomiting may occur with each effective dose. Unpredictable and uncontrollable sleep attacks that have recently been reported more frequently may also occur. Furthermore, agent concentration in the plasma is not constant but subject to great variation, not only for kinetic reasons but also depending on the conditions of drug intake (type and time of food intake, etc.). This is why there is a risk of temporary overdosing, which may result in REM suppression and the resulting problems and sleep disturbances.
- In addition, peroral dopaminergic therapies often lead to rebound problems on the following day and to so-called augmentations, i.e. hypertonus, restlessness and an urge to move.
- It is the technological problem of this invention to provide an agent for the treatment of restless legs syndrome that is free of side effects or at least shows considerably reduced side effects as compared to oral administrations, that has a slow initial flux rate and can be controlled well in terms of quantity administered and effective time.
- A transdermal therapeutic system according to the invention described below can ensure an individually desired and controlled effective time (if required, by removing the patch). Bioavailability is increased by the TTS as compared to peroral administration, which typically reduces the overall dose required to achieve the therapeutically desirable effect. The α-adrenolytic effect of lisuride and its derivatives has another benefit with this form of application in that it also noticeably diminishes urinary urgency at nighttime and other bladder dysfunctions that are rather common in Parkinson patients (such as prostatic hyperplasia), which adds to the success of the therapy.
- The invention relates to the use of a transdermal therapeutic system (TTS) comprising a pharmaceutical layer containing at least one matrix having an active ingredient, and/or an active ingredient reservoir; a diffusion barrier which is permeable to active ingredients and which is arranged on the skin side of the active ingredient reservoir; and an ergoline derivative according to Formula I or physiologically compatible salt thereof with an acid,
wherein
is a single or double bond wherein R1 is an H atom or a halogen atom, particularly a bromine atom, and wherein R2 is C1-C4 alkyl, particularly methyl, as an agent for treating restless leg syndrome. - A special benefit this invention offers is that—other than with the common one-time oral intake per day—a continuous active ingredient flux is established so that plasma concentrations can be set as defined and variations can be controlled. This mainly prevents the side effects typically observed with one-time oral administration such as fatigue, dizziness, vomiting, constipation, etc. It was found that these side effects can be prevented when the level of active ingredient in the plasma is not subject to any major and rapid variation, an automatic occurrence with oral administration, but is set slowly and continuously. In addition, the problems encountered with oral administration such as greatly varying absorption rates and a not too well-defined time of maximum concentration in the plasma depending on the type and time of food intake are virtually eliminated by this invention. Most of all, it prevents overdosing (and thus REM suppression and other disruptions of the sleep pattern). Furthermore, administration can easily be canceled by just removing the TTS. Unlike discontinuing an orally administered active agent, decomposition in the plasma is fast and controlled, which also prevents a hangover, rebound, or augmentation effect. Finally it is easy to administer exact individual doses by selecting the flux F and/or the active surface area. It is preferred to select F and active area so that a dose in the range from 10 μg to 2 mg of active ingredient (for example, lisuride), most preferred 50 to 200 μg, is built up per day.
- It is preferred that the matrix and/or diffusion barrier are selected so that the transdermal flux F through human skin measured as described in Example B1 is in the range from 0.1 to 2.0 μg/cm2/h.
- The list of ergoline derivatives that can be used includes the following: Bromolisuride (3-(2-bromo-9, 10-didehydro-6-methyl8α-ergo-linyl)-1,1-diethyl urea), terguride (3-(6-methyl-8α-ergolinyl)-1,1-d-iethyl urea) and proterguride (3-(6-propyl-8α-ergolinyl)-1,1-diethyl urea). However it is preferred when the ergoline derivative is lisuride (3-(9,10-didehydro-6-methyl-8α-ergolinyl)-1,1-diethyl urea) or its physiologically compatible salt with an acid. The production of lisuride and other suitable ergolines according to the invention is described, inter alia, in U.S. Pat. No. 3,953,454, EP 056 358 and U.S. Pat. No. 4,379,790. Suitable salts of the ergoline derivative include sulfates, phosphates, maleates, citrates and succinates, especially hydrogen maleate.
- The term “TTS” mostly denotes percutaneously acting but also transmucosal systems. A TTS typically has a sheet-like structure and is attached to an area of the skin. The system can optionally be attached to the skin by an additional skin-side adhesive that is permeable to the active ingredient. Alternatively, the matrix and/or diffusion barrier can itself have adhesive properties. And finally a non-adhesive TTS can be attached to the skin using other auxiliary means such as adhesive tapes or bandages. The matrix is a material in which the active ingredient is immobilized. An active agent in an active ingredient reservoir however is not necessarily immobilized, which is why the active ingredient reservoir must be enclosed. The diffusion barrier forms the skin-side portion of this shell. It goes without saying that all other parts of the shell should be as impermeable as possible, including diffusion paths, to the active ingredient. Immobilized means in this context that any uncontrolled active ingredient flow is prevented. However diffusion of an active agent in a matrix and/or through a diffusion barrier is not only possible but intended. The diffusion coefficients eventually determine the active ingredient flux from the TTS into a patient's skin. The dose released into a patient's skin is in first approximation a linear function of the active area of the TTS. The active area is the contact area of those TTS portions that allow active ingredient diffusion. TTSs can be used in human and veterinary medicine.
- A TTS of the design mentioned above is known in principle from publication WO 92/20339. It specifically describes the effect of propylene glycol lauric acid on the flux, i.e. a considerable increase in flux. However the values specified therein relate to solutions applied to skin samples and not to the actual TTS. No specification is given regarding flux from a TTS. The flux values reached with a TTS are considerably lower than the values from applying a solution.
- A TTS containing lisuride is further known from publication WO 91/00746. The flux values for human skin samples specified therein cannot be directly transferred to any achievable in-vivo values.
- TTSs of the design described above are used for various indications including Parkinson's disease. When treating Parkinson's disease, the highest possible doses are desirable. A transdermal therapeutic system also improves compliance, which is of critical importance for any combinatory treatment of this disease as patients tend to be older and have multiple diseases. Improved control and the chance to reach circadian profiles (e.g. by low stimulation as constantly as possible at night or during a break) are particularly important and have not yet been achieved (e.g. to prevent psychoses and improve sleep quality). The ergoline derivatives lisuride, terguride, and bromerguride have a partially dopamine-agonistic or partially antagonistic effect that contributes to preventing the development of psychoses and can improve existing psychoses and similar problems.
- The TTS can be designed as follows. A covering layer can be arranged on the side of the matrix and/or active ingredient reservoir facing away from the skin. It may be formed by films of polyethylene or polyester. It is typically 10 to 100 microns in thickness. The covering layer may be pigmented and/or metal plated to ensure sufficient protection from light. Metal plating involves applying a very thin layer (typically less than 1 micron, mostly in the 10-100 nm range) of a metal such as aluminum to the covering layer. Pigments can be all pigments commonly used for coating including effect pigments as long as these are physiologically harmless. A detachable liner such as a siliconized or fluoropolymer-coated protective film can be provided on the application side.
- The matrix and/or diffusion barrier may comprise as their main matrix component a substance selected from the group consisting of polyacrylate, polyurethane, cellulose ether, silicone, polyvinyl compounds, silicate and mixtures of these substances as well as copolymers of these polymeric compounds, preferably polyacrylate. A main matrix component makes up at least 50 percent by weight, e.g. at least 80-90 percent by weight of the matrix (matrix to be understood as the finished layer, i.e. main matrix component(s) with adjuvant(s) and active ingredient(s)). The desired flux is set by selecting the substance depending on the diffusion coefficient of the active ingredient and, if required, by selecting the layer thickness of the matrix in orthogonal direction to the skin surface. Matrix thickness is typically in the range from 10 to 500 microns.
- A preferred polyacrylate adhesive as main matrix component is commercially available under the brand name GELVA® multipolymer solution 7881, provided by Monsanto Deutschland GmbH, Dusseldorf. We expressly refer to the product sold under this name and its datasheet in the version of Apr. 23, 1996. Another suitable product is Eudragit® E100 provided by Rohm, Germany.
- The polyacrylate adhesives listed above provide an advantageous non-trivial combination of properties, namely optimum flux, good adhesive power, good skin compatibility, and durability.
- The diffusion barrier can alternatively comprise as its main barrier component a polymer selected from the group consisting of cellulose ester, cellulose ether, silicone, polyolefin and mixtures as well as copolymers of these substances. What has been said about the term of the main matrix component above analogously applies to the term of the main barrier component.
- The diffusion barrier can be a film with a thickness from 10 to 300 microns; the actual film thickness is selected (in conjunction with the diffusion coefficient of the active ingredient in the polymer) according to the desired flux.
- The matrix and/or active ingredient reservoir and/or diffusion barrier may contain the common adjuvants used in TTSs. It is preferred to use a penetration-enhancing agent that is preferably selected from the group consisting of C1-C8 aliphatic, cycloaliphatic and aromatic alcohols, saturated and unsaturated C8-18 fatty alcohols, saturated and unsaturated C8-18 fatty acids, hydrocarbons and hydrocarbon mixtures, fatty acid esters from C3-19 fatty acids and C1-6 alkyl monools, dicarboxylic acid dieesters from C4-8 dicarboxylic acids and C1-6 alkyl monools, and mixtures of these substances. Penetration-enhancing agents improve the flux of the active ingredient through the skin to which the TTS is attached. Examples of the substances listed above are: 1,2-propane diol, menthol, dexpanthenol, benzyl alcohol, lauryl alcohol, isocetyl alcohol, cetyl alcohol, mineral oil, lauric acid, isopalmitic acid, isostearic acid, oleic acid; methyl ester, ethyl ester, 2-hydroxyethyl ester, glycerol ester, propyl ester, isopropyl ester, butyl ester, sec. butyl ester or isobutyl ester of lauric acid, myristic acid, stearic acid, or palmitic acid. Use of dimethyl isosorbide, isopropyl myristate and lauryl alcohol is preferred, use of lauryl alcohol is most preferred. Other adjuvants are, for example, crystallization inhibitors. Suitable crystallization inhibitors are highly dispersed silicon dioxide or macromolecular substances such as polyvinyl pyrrolidone, polyvinyl alcohols, dextrines, dextranes, sterines, bile acids and, in particular, vinyl pyrrolidone vinylacetate copolymers such as Kollidon® VA 64.
- It goes without saying that the penetration-enhancing agent has to be able to diffuse to a sufficient extent through the matrix or diffusion barrier. If a matrix and lauryl alcohol as an adjuvant are used, it is preferred that the lauryl alcohol makes up 10 to 30 percent by weight, most preferred 15 to 20 percent by weight, of the matrix.
- The adjuvants can basically make up from 0 to 50 percent by weight of the matrix. The active ingredient can make up 0.2 to 20 percent by weight, preferably 1 to 10 percent by weight, of the matrix. The sum total of main matrix component, adjuvants and active ingredients is always 100 percent by weight.
- The active ingredient dose in a human body carrying a TTS is dependent on the diffusion-related properties of the TTS mentioned above and also on its active surface area on the skin. Active surface area means the area over which the matrix or diffusion barrier comes to rest on the skin. Variation in accordance with the desired dosage will preferably be in a range from 1 to 100 cm2.
- Within the scope of this invention, a physician can easily set up personalized dose variations for a flux adjusted to the given indication by selecting a suitable patch size. Thus the treatment can easily be adjusted to different body weights, age groups, etc. It is particularly feasible to equip a TTS comprising a (rather large) standard area with subdivision markers for partial doses so that a user can just remove the protective film from a partial area corresponding to the specified dose. The respective subsections can easily be printed on the covering layer.
- Another application is the use of a TTS according to the invention to produce an agent for the treatment or prevention of the premenstrual syndrome or its symptoms, wherein F preferably is in the range from 0.1 to 0.5 μg/cm2/h, another one to produce an agent that inhibits lactation, wherein F preferably is in the range from 0.1 to 0.5 μg/cm2/h.
- The invention will be explained in more detail below based on various examples (Examples B1-B4).
- A FRANZ flow-through diffusion cell is used for flux measurement. The measured area is 2 cm2. 4 cm2 of ventral and dorsal skin of a male hairless mouse (MF1 hr/hr Ola/Hsd, provided by Harlan Olac, UK) are used as our skin sample after carefully removing any subcutaneous fatty tissue. A 2 cm2 TTS is applied to the skin sample. The acceptor medium is placed on the opposite side. It is diluted HHBSS (Hepes Hanks Balanced Salt Solution) containing 5.96 μl of Hepes, 0.35 g/l of NaHCO3 and 0.1 ml/110× of HBSS (provided by Gibco, Eggenstein, Del.). Furthermore, 1000 I.U./ml of penicillin (benzylpenicillin potassium salt, provided by Fluka, Neu-Ulm, Del.) are used.
- The flux is measured as described below. First, the TTS to be measured is applied to the skin. The skin is mounted in the diffusion cell immediately thereafter. Samples of the acceptor medium are taken at 2-hour intervals between t=0 hrs and t=6 hrs and at 8-hour intervals between t=6 hrs and t=54 hrs. 1 ml of acceptor medium per hour is pumped through the diffusion cell-using a peristaltic pump. The temperature of the acceptor medium is controlled using a circulating water bath which keeps the skin at a temperature of 31° C. with an accuracy of 1° C.
- The active ingredient concentration in the acceptor medium is determined in accordance with the following specifications using a radioimmunoassay.
- Calibration curves: These are constructed using two different methanol solutions of non-radioactive lisuride hydrogen maleate salt, each containing 1 mg/ml. These solutions are individually diluted with BSA buffer (0.041 M of Na2HPO2.2H2O, 0.026 M of KH2PO4, 0.154 M of NaCl, 0.015 M of NaN3, 0.1% (w/v) of BSA, pH 7, supplemented with 0.05% (w/v) of ascorbic acid) to obtain lisuride-free base concentrations in the range from 1000-3.9 pg/0.1 ml. In addition, a sample without active ingredient (0 pg) is used. The calibration samples are analyzed three times. The lisuride concentrations are calculated using the pharmacokinetic PC program RIO 2.5 (other common software may also be used).
- Sample preparation: The acceptor medium is diluted with BSA buffer prior to the analysis to set the concentrations to an analyzable range of the calibration curve. 100 μl of diluted sample are directly subjected to radioimmunological analysis.
- Antiserum: The antiserum (rabbit) is obtained by immunizing with lisuride-1-succinyl-BSA, an immunogen. The antiserum in the assay is diluted 1:12500.
- Tracer: 3H-lisuride hydrogen maleate with a specific activity of 4.3 GBq/mg is used.
- Incubation: 0.1 ml of BSA buffer with active ingredient, 0.1 ml of tracer solution (ca. 5000 cpm/0.1 ml of BSA buffer) and 0.1 ml of diluted antiserum (1:12500) are added to 0.7 ml of BSA buffer and incubated for 18 hours at 4° C.
- Separation: antibody-bound lisuride is separated, from free lisuride by adding 0.2 ml of charcoal suspension (1.25% (w/v) and 0.125% (w/v) of dextrane in BSA buffer) and incubation for 30 minutes at 0° C. The charcoal is sedimented by centrifuging for 15 minutes at 3000 g. The supernatant liquid (containing antibody-bound active ingredient) is decanted and subjected to radiometric analysis.
- Radiometric analysis: 4 ml of Atomlight (NEN) scintillation cocktail are added to the supernatant. The count is carried out using a WALLAC 1409 or 1410 β-scintillation counter without quench control.
- Analysis: The percutaneous skin flux is calculated as follows:
F=(C*R)/(A*T),
where F is the percutaneous flux [ng/cm2/h], C the active ingredient concentration in the acceptor medium [ng/ml], R the acceptor medium flow [1 ml/h], A the measured area [2 cm2] and T the sample-taking interval [h]. - The maximum transdermal active ingredient flux is obtained directly from the data. Mean percutaneous flux values are determined during days 1 and 2 of the experiment based on the cumulative absorbed dose in time intervals t=0-22 and t=22-54.
- Specifications for the Production of TTS
- 15 mg of Kollidon VA 64 (crystallization inhibitor) are dissolved in 15 mg of isopropanol. Then 5 mg of lisuride are sprinkled in. 80 mg of polyacrylate adhesive (Gelva 7881) are placed in a beaker, and the above suspension is added while rerinsing with 30 mg of isopropanol. The crystal-free wet mix obtained is thoroughly intermixed and spread on a siliconized liner using a 500 micron blade. The product is dried at 60° C. for 20 minutes, and finally a covering layer is laminated onto it.
- Flux measurements as described in Example B1 showed an F value of 0.43 on day 1, 0.44 on day 2, and a maximum F value of 0.85 (each in μg/cm2/h).
- 12.5 mg of dimethyl isosorbide are suspended with 2 mg of lisuride in 15 mg of isopropanol. 80 mg of polyacrylate adhesive (Gelva 7881) are placed in a beaker, and the above suspension is added while rerinsing with 30 mg of isopropanol. The crystal-free wet mix obtained is thoroughly intermixed and spread on a siliconized liner using a 500 micron blade. The product is dried at 60° C. for 20 minutes, and finally a covering layer is laminated onto it.
- Flux measurements as described in Example B1 showed an F value of 0.23 on day 1, 0.28 on day 2, and a maximum F value of 0.50 (each in μg/cm2/h).
- 27.2 mg of Kollidon VA 64 (crystallization inhibitor) and 16.3 mg of lauryl alcohol are dissolved at 60° C. Then 2 mg of lisuride are dissolved in this solution at 60° C. 39.38 mg of Eudragit E100, 13.41 mg of Citroflex 4A and 1.71 mg of succinic acid are molten at 150-200° C. The lisuride solution is added after the batch has cooled down to 80° C. The product is spread at 80° C. on a siliconized liner using a 500 micron blade. Then the product is cooled down to 20° C.; optionally, a covering layer may be laminated onto it.
- Flux measurements as described in Example B1 showed an F value of 0.90 on day 1, 1.76 on day 2, and a maximum F value of 2.53 (each in μg/cm2/h).
- III. Description C—Combination of a Transdermal Therapeutic System and an Oral and/or Parenteral Preparation Containing Dopamine Agonists for the Treatment Dopaminergic Disease State
- The invention relates to the use of a means including a transdermal therapeutic system (TTS) containing a dopamine agonist for treating dopaminergic disease states under a special treatment plan.
- A TTS containing lisuride is known from publication WO 91/00746. Diseases for which a dopamine therapy is indicated such as Parkinson's disease are severe chronic and disabling diseases from which older and polymorbid patients suffer frequently. The state-of-the-art practice is oral administration of a combination of dopaminergic substances. These generally include various formulations of levodopa (high initial flux rate, normal or slow release), levodopa boosters such as decarboxylase inhibitors as the base and optionally COMT inhibitors or MAO-B inhibitors, and various dopamine agonists such as bromocriptine, lisuride, cabergoline, pergolide, ropinirole, pramipexole as well as amantadines and, occasionally, anticholinergic agents. The pharmacokinetics of fast-acting levodopa is hard to control for various reasons, and dopamine agonists frequently do not allow safe bioavailability and thus efficacy predictions. All these active agents also can interact for pharmacological and pharmacokinetic reasons, in addition to their interaction with other active agents or pharmaceuticals that older patients with multiple diseases frequently need.
- Either a continuous or a discontinuous stimulation may be required depending on the stage of the disease and the actual status of the patient. A good foundation is laid when the level of dopaminergic agents is kept stable across the entire day. However patients frequently report that they often need to take a fast-acting dopaminergic agent at certain times of the day to overcome acute motoric disturbances, severe and painful dystonia, etc. (“kick”). In extreme cases, such sudden “off” states of motoric performance and akinesia (sometimes predictable early in the morning or afternoon, but frequently all of the sudden and unexpectedly) can only be controlled with injectable active agents such as apomorphine. On the other hand, strong and fast efficacy hikes can cause disturbing side effects (e.g. nausea, emesis, orthostatic hypotension, narcoleptic attacks). Overdoses due to the narrow therapeutic time window of all these dopaminergic agents can result in severe dyskinesia, dystonia or, especially in older patients, psychoses. The latter severe problem is mainly connected with high active agent concentrations in the plasma over night that are known to destroy regular sleeping patterns and to prevent the REM sleep phase (with REM rebound during daytime as indication of a psychosis).
- Because of the interrelations described, a practical dopamine treatment is started at very low doses of one or several active agents with subsequent, for example, weekly, dose increases until side effects indicate bioavailability. After a subsequent and rather arbitrary reduction of the dose or dose stabilization, the next active agent is administered and set or dosed (“titrated”) accordingly. As a result, treatment plans and most of all dosages vary considerably depending on the severity of the disease, the patient's individual body constitution and metabolization type. Mostly 3 or more different active agents are administered orally. A typical patient would for example start with fast-acting levodopa in the morning, followed by a dose of MAO-B inhibitor and, throughout the day, four or five doses of normally acting levodopa in combination with a dopamine agonist and, eventually, a slow-acting preparation containing levodopa (or a low dose of a long-term acting dopamine agonist) at bedtime ensuring sufficient mobility in the sleep and consequently a high relaxation value.
- Such a complicated treatment plan is more often the rule than an exception and is not very well compatible, especially not with older patients, is unstable and sensitive to interaction with other factors such as other agents administered or infection-related diseases as well as dehydration by inadequate fluid intake or excessive fluid loss or liver or kidney dysfunctions. This is unsatisfactory for obvious reasons for both the physicians and the patients. Patients must therefore often be adapted to side effects over several weeks as indoor patients in more or less specialized hospitals.
- It is the technological problem of the invention to provide an agent and a treatment plan for treating dopaminergic disease states while preventing or at least reducing disturbing side effects, controlling the initial flux rate of the active agent and keeping good control of agent levels in the plasma and effective time.
- The invention solves this technological problem by using a dopamine agonist in the form of an agent, comprising at least two discrete compositions, of which one is a transdermal therapeutic system (TTS) containing the dopaminergic agent and another one containing the same dopaminergic agent and suitable for oral and/or parenteral administration, both suitable for the treatment of dopaminergically treatable diseases with the following elements: a) the TTS is continuously applied, b) within the duration of application in a) the composition for oral or parenteral dosage is administered. Phase b) preferably begins 7 days, more preferably 14 days, most preferably 28 days after phase a) was started. The invention involves in this context the use of a dopamine agonist in the form of an agent consisting of at least one spatially discrete composition, of which one is a transdermal therapeutic system (TTS) containing the dopaminergic agent for the treatment of dopaminergically treatable diseases with the following elements: a) the TTS is continuously applied, b) within the duration of application in a), no dopaminergic agent is applied that differs from the dopamine agonistic agent of the TTS.
- Continuous application means that a new TTS is applied before the agent level in the plasma drops disturbingly due to the consumption of the previous TTS, such as below the 0.25-fold of the maximum plasma concentration.
- The invention is based on the surprising finding that dopaminergically treatable diseases, particularly Parkinson's disease, can be treated better using a single dopaminergic agent that is highly effective and has a short half-life in the plasma, if the combination of the invention is optionally carried out using one of the treatment plans according to the invention. This means it is important that no other agent than the active ingredient of the TTS is used for treating dopaminergic dysfunctions during the treatment period. Lasting or continuous dopaminergic stimulation is achieved using the TTS. It provides agent concentrations in the plasma that can be well controlled or adjusted. The concentration in the plasma can easily be dosed by varying, for example, the effective surface area of the TTS or its size.
- Furthermore, a slow increase of the concentration of the active agent in the plasma (over days and weeks) can be achieved by applying the TTS; the benefit is that initial side effects are prevented. Moreover, daily application at relatively early times (e.g. between 6:00 a.m. and 3:00 p.m.), for example, can reliably prevent undesirable overstimulation at night and the risk of psychotic states.
- The treatment is supplemented as may be required in advanced stages of a disease by administering oral or parenteral preparations with the same dopaminergic agent. The tablets comprise a preferred tmax of 15 to 120 minutes, particularly preferred of 30 to 60 minutes, and a preferred half-life of 0.5 to 4 hours, particularly preferred 1 to 2 hours. tmax indicates the period of time between oral administration and the buildup of the concentration of the tablet's active agent in the plasma. Half-life is the period of time during which the concentration in the plasma drops by half in the descending portion of the time function. Motoric blockages and akinesia are removed whenever required by such oral administration and the fast extra action as needed.
- If oral administrations is started only after starting the continuous application of the TTS, considerable tolerance against dopaminergic side effects has built up and it is no longer required to carry out tedious titrations (sometimes over several months) as would be required for setting up different dopaminergic agents under a combinatory therapy. This makes the treatment particularly well tolerable.
- Where indicated—for example, because of the severity of an acute condition (e.g. akinesia or dystonia in the morning or during off periods at other times), the same active agent may be administered parenterally (i.m., i.v., subcutaneously, as contained in the TTS). The same benefits apply in principle as described for oral administration. tmax is typically less than 15 minutes, mostly less than 5 minutes.
- Lasting side effects, if unexpected side effects occur, can reliably be prevented due to the short half-life of the active agent. A short-term drop of the agent concentration in the plasma is achieved by just removing the TTS. This is a particular advantage over orally administered, long-term acting agents such as pergolide or cabergoline the side effects of which after an administration or overdosage may last several days.
- The invention facilitates relatively high total absorption quantities of the active agent as compared to combinatory therapy where it is highly underdosed to prevent side effects resulting from the complex kinetics and interaction of combining different substances. Thus the invention considerably increases clinical efficacy. This fact combined with better tolerability also allows considerably longer treatment with the respective active agent and avoids the use of levodopa formulations. This is particularly important for younger patients with a high remaining life expectancy as levodopa, the gold standard of dopamine therapy) is known to cause long-term effects resulting in severe and unpredictable dyskinesia and hyperkinesia, which makes the patients eventually dependable on outside help and confines them to bed. Animal experiments have also shown that even short-term levodopa treatment, even at low doses as are common in combinatory therapies, causes lasting priming or sensitization by some kind of inciting mechanism resulting in long-term complications in the motoric and mental dopamine systems. Things being what they are, most patients have to rely on levodopa administrations within the first years of the disease and are exposed to the detrimental long-term disadvantages of levodopa due to the underdosage of active agents administered to avoid side effects.
- Despite the relatively high total absorption quantities compared to the underdosage practice that is the state of the art, the actual dosage load can be kept low (≦10 mg per day, particularly preferred≦5 mg per day) so that the treatment is relatively independent of any liver or kidney dysfunctions. Potential interaction with other drugs is rather low and predictable as only one active agent is involved in the treatment according to the invention; interaction with the common other Parkinson agents is completely eliminated.
- The dopaminergically treatable disease may be a disease from the group consisting of Parkinson's disease, parkinsonism, restless legs syndrome, and disturbances of the dopaminergic system.
- It is preferred when the dopamine agonist with a short half-life is an ergoline derivative of the Formula I or a physiologically tolerable salt thereof with an acid,
where
is a single or doublebond wherein R1 is an H atom or a halogen atom, particularly a bromine atom, and wherein R2 is C1-4 alkyl, particularly methyl. - The list of ergoline derivatives that can be used particularly includes the following: Lisuride, bromolisuride (3-(2-bromo-9,10-didehydr-o-6-methyl-8α-ergolinyl)-1,1-diethyl urea), terguride (3-(6-methyl-8α-ergolinyl)-1,1-diethyl urea) and proterguride (3-(6-propyl-8α-ergolinyl)-1,1-diethyl urea). However it is preferred when the ergoline derivative is lisuride (3-(9,10-didehydro-6-methyl-8 α-ergolinyl)-1,1-diethyl urea) or a physiologically compatible salt thereof with an acid.
- Suitable salts of the active ingredients include sulfates, phosphates, maleates, citrates and succinates, especially hydrogen maleate.
- The TTS can be applied at various intervals depending on the kinetics of active agent release. It is important that the active agent concentration in the plasma does not show any disturbing variation when the TTS is used continuously. It is preferred that the TTS is applied daily.
- The preparation prepared for oral or parenteral administration is preferably administered directly in the event of a dopamine-related malfunction. It may be administered preventively if malfunctions are predictable.
- The term “TTS” mostly denotes percutaneously acting but also transmucosal systems. A TTS typically has a sheet-like structure and is attached to an area of the skin. A TTS mostly includes a matrix containing an active ingredient (e.g. in the form of a salt) and/or an active ingredient reservoir, and a diffusion barrier that is permeable to the active ingredient on the skin side of the active ingredient reservoir. The system can optionally be attached to the skin by an additional skin-side adhesive that is permeable to the active ingredient. Alternatively, the matrix and/or diffusion barrier can itself have adhesive properties. And finally a non-adhesive TTS can be attached to the skin using other auxiliary means such as adhesive tapes or bandages. The matrix is a material in which the active ingredient is immobilized. An active agent in an active ingredient reservoir however is not necessarily immobilized, which is why the active ingredient reservoir must be enclosed. The diffusion barrier forms the skin-side portion of this shell. It goes without saying that all other parts of the shell should be as impermeable as possible, including diffusion paths, to the active ingredient. Immobilized means in this context that any uncontrolled active ingredient flow is prevented. However diffusion of an active agent in a matrix and/or through a diffusion barrier is not only possible but intended. The diffusion coefficients eventually determine the active ingredient flux from the TTS into a patient's skin. The dose released into a patient's skin is in first approximation a linear function of the active area of the TTS. The active area is the contact area of those TTS portions that allow active ingredient diffusion.
- A TTS designed as described above with lisuride as the active ingredient and its use for treating Parkinson's disease are known in principle from publication WO 92/20339. It specifically describes the effect of propylene glycol lauric acid on the flux, i.e. a considerable increase in flux. A TTS containing lisuride is further known from publication WO 91/00746. The active ingredient in a transdermal patch can of course be formulated in accordance with the pharmaceutical methods known as the state of the art.
- It is preferred for the TTS to comprise a pharmaceutical layer containing at least one matrix containing the active ingredient and/or an active ingredient reservoir, and a diffusion barrier that is permeable to the active ingredient on the skin side of the active ingredient reservoir; and an ergoline derivative of the Formula I or a salt thereof as an active ingredient.
- The matrix and/or diffusion barrier may be selected so that the transdermal flux F through human skin measured as described in Example C1 is in the range from 0.1 to 5.0 μg/cm2/h, preferably 0.1 to 4.0 μg/cm2/h.
- It is preferred to arrange a TTS set as part of a means wherein the set contains a multitude of TTS elements and wherein said elements are configured for releasing different doses. The TTS elements can be separated, each TTS element being configured for a continuously ascending sequence of F ranging from 0.1 to 5 μg/cm2/h. It is also conceivable to arrange several TTSs with the same F value in a subgroup wherein the F values of the various subgroups form a continuously ascending sequence and other subgroups comprise constant F values, their value being the maximum of the sequence mentioned above. It is preferred to select F and the active area of the TTS so that a dose in the range from 10 μg to 2 mg of active ingredient (such as lisuride) builds up during the day or within 24 hours as from the second day of application, and that this dose subsequently rises in steps. The TTS elements can also have a continuous sequence of different active areas. These may also be divided into subgroups as described above. Suitable according to the invention are also other transdermal forms of application known from the state of the art.
- The preparation for oral administration can either be in the form of a tablet, a powder, a capsule or a solution, is formulated using the known state-of-the-art methods as required for the respective form of application, and as a tablet preferably contains 25 to 1000 μg of the dopaminergic agent (per tablet), resulting in a dose of 0.075 mg to 5.0 mg per day for lisuride, for example.
- The preparation for parenteral administration in the form of an injection or infusion solution is formulated in accordance with known methods and preferably contains 25 to 2000 μg of the dopaminergic agent (per ml of solution). For example, the parenteral dose needed to achieve a fast additional effect for lisuride is up to 5.0 mg with a continuous infusion over 24 or 16 hours and from 25 up to 200 μg in a bolus injection for a single application.
- The TTS can be designed as follows. A covering layer can be arranged on the side of the matrix and/or active ingredient reservoir facing away from the skin. It may be formed by films of polyethylene or polyester. It is typically 10 to 100 microns in thickness. The covering layer may be pigmented, varnished, and/or metal plated to ensure sufficient protection from light. Metal plating involves applying a very thin layer (typically less than 1 micron, mostly in the 10-100 nm range) of a metal such as aluminum to the covering layer. Pigments can be all pigments commonly used for coating including effect pigments as long as these are physiologically harmless. A detachable liner such as a siliconized or fluoropolymer-coated protective film can be provided on the application side.
- The matrix and/or diffusion barrier may comprise as their main matrix component a substance selected from the group consisting of polyacrylate, polyurethane, cellulose ether, silicone, polyvinyl compounds, polyisobutylene compounds, silicate and mixtures of these substances as well as copolymers of these polymeric compounds, preferably polyacrylate. A main matrix component makes up at least 50 percent by weight, e.g. at least 80-90 percent by weight of the matrix (matrix to be understood as the finished layer, i.e. main matrix component(s) with adjuvant(s) and active ingredient(s)). The desired flux is set by selecting the substance depending on the diffusion coefficient of the active ingredient and, if required, by selecting the layer thickness of the matrix in orthogonal direction to the skin surface. Matrix thickness is typically in the range from 10 to 500 microns.
- A preferred polyacrylate adhesive as main matrix component is commercially available under the brand name GELVA® multipolymer solution 7881, provided by Monsanto Deutschland GmbH, Dusseldorf. We expressly refer to the product sold under this name and its datasheet in the version of Apr. 23, 1996. Another suitable product is Eudragit® E100 provided by Rohm, Germany.
- The polyacrylate adhesives listed above provide an advantageous non-trivial combination of properties, namely optimum flux, good adhesive power, good skin compatibility, and durability.
- The diffusion barrier can alternatively comprise as its main barrier component a polymer selected from the group consisting of cellulose ester, cellulose ether, silicone, polyolefin and mixtures as well as copolymers of these substances. what has been said about the term of the main matrix component above analogously applies to the term of the main barrier component. The diffusion barrier can be a film with a thickness from 10 to 300 microns; the actual film thickness is selected (in conjunction with the diffusion coefficient of the active ingredient in the polymer) according to the desired flux.
- The matrix and/or active ingredient reservoir and/or diffusion barrier may contain the common adjuvants used in TTSs. It is preferred to use a penetration-enhancing agent that is preferably selected from the group consisting of C1-C8 aliphatic, cycloaliphatic and aromatic alcohols, saturated and unsaturated C8-18 fatty alcohols, saturated and unsaturated C8-18 fatty acids, hydrocarbons and hydrocarbon mixtures, fatty acid esters from C3-19 fatty acids and C1-6 alkyl monools, dicarboxylic acid dieesters from C4-8 dicarboxylic acids and C1-6 alkyl monools, and mixtures of these substances. Penetration-enhancing agents improve the flux of the active ingredient through the skin to which the TTS is attached. Examples of the substances listed above are: 1,2-propane diol, menthol, dexpanthenol, benzyl alcohol, lauryl alcohol, isocetyl alcohol, cetyl alcohol, mineral oil, lauric acid, isopalmitic acid, isostearic acid, oleic acid; methyl ester, ethyl ester, 2-hydroxyethyl ester, glycerol ester, propyl ester, isopropyl ester, butyl ester, sec. butyl ester or isobutyl ester of lauric acid, myristic acid, stearic acid, or palmitic acid. Use of dimethyl isosorbide, isopropyl myristate and lauryl alcohol is preferred, use of lauryl alcohol is most preferred. Other adjuvants are, for example, crystallization inhibitors. Suitable crystallization inhibitors are highly dispersed silicon dioxide or macromolecular substances such as polyvinyl pyrrolidone, polyvinyl alcohols, dextrines, dextranes, sterines, bile acids and, in particular, polyvinyl pyrrolidone vinylacetate copolymers such as Kollidon® VA 64.
- It goes without saying that the penetration-enhancing agent has to be able to diffuse to a sufficient extent through the matrix or diffusion barrier. If a matrix and lauryl alcohol as an adjuvant are used, it is preferred that the lauryl alcohol makes up 10 to 30 percent by weight, most preferred 15 to 20 percent by weight, of the matrix.
- The adjuvants can basically make up from 0 to 50 percent by weight of the matrix. The active ingredient can make up 0.5 to 20 percent by weight, preferably 1 to 10 percent by weight, of the matrix. The sum total of main matrix component, adjuvants and active ingredients is always 100 percent by weight.
- The active ingredient dose in a human body carrying a TTS is dependent on the diffusion-related properties of the TTS mentioned above and also on its active surface area on the skin. Active surface area means the area over which the matrix or diffusion barrier comes to rest on the skin. Variation in accordance with the desired dosage will preferably be in a range from 1 to 100 cm2. Within the scope of this invention, a physician can easily set up personalized dose variations for a flux adjusted to the given indication by selecting a suitable patch size. Thus the treatment can easily be adjusted to different body weights, age groups, etc. It is particularly feasible to equip a TTS comprising a (rather large) standard area with subdivision markers for partial doses so that a user can just remove the protective film from a partial area corresponding to the specified dose. The respective subsections can easily be printed on the covering layer.
- A transdermal and an oral or parenteral form of application of an active ingredient can easily be offered as one kit for a monotherapy of dopaminergic diseases.
- The invention also relates to a combination of a transdermal therapeutic system and an oral and/or parenteral preparation containing one and the same dopamine agonist with a short half-life to produce a pharmaceutical for the treatment of dopaminergic diseases.
- The invention will be explained in more detail below based on various non-limiting examples (Examples C1-C8).
- A FRANZ flow-through diffusion cell is used for flux measurement. The measuring area is 2 cm2. 4 cm2 of ventral and dorsal skin of a male hairless mouse (MF1 hr/hr Ola/Hsd, provided by Harlan Olac, UK) are used as our skin sample after carefully removing any subcutaneous fatty tissue. A 2 cm2 TTS is applied to the skin sample. The acceptor medium is placed on the opposite side. It is diluted HHBSS (Hepes Hanks Balanced Salt Solution) containing 5.96 g/l of Hepes, 0.35 g/l of NaHCO3 and 0.1 ml/10× of HBSS (provided by Gibco, Eggenstein, Del.). Furthermore, 1000 I.U./ml of penicillin (benzylpenicillin potassium salt, provided by Fluka, Neu-Ulm, Del.) are used.
- The flux is measured as described below. First, the TTS to be measured is applied to the skin. The skin is mounted in the diffusion cell immediately thereafter. Samples of the acceptor medium are taken at 2-hour intervals between t=0 hrs and t=6 hrs and at 8-hour intervals between t=6 hrs and t=54 hrs. 1 ml of acceptor medium per hour is pumped through the diffusion cell using a peristaltic pump. The temperature of the acceptor medium is controlled using a circulating water bath which keeps the skin at a temperature of 31° C. with an accuracy of 1° C.
- The active ingredient concentration in the acceptor medium is determined in accordance with the following specifications using a radioimmunoassay.
- Calibration curves: These are constructed using two different methanol solutions of non-radioactive lisuride hydrogen maleate salt, each containing 1 mg/ml. These solutions are individually diluted with BSA buffer (0.041 M of Na2HPO2.2H2O, 0.026 M of KH2PO4, 0.154 M of NaCl, 0.015 M of NaN3, 0.1% (w/v) of BSA, pH 7, supplemented with 0.05% (w/v) of ascorbic acid) to obtain lisuride-free base concentrations in the range from 1000-3.9 pg/0.1 ml. In addition, a sample without active ingredient (0 pg) is used. The calibration samples are analyzed three times. The lisuride concentrations are calculated using the pharmacokinetic PC program RIO 2.5 (other common software may also be used).
- Sample preparation: The acceptor medium is diluted with BSA buffer prior to the analysis to set the concentrations to an analyzable range of the calibration curve. 100 μl of diluted sample are directly subjected to radioimmunological analysis.
- Antiserum: The antiserum (rabbit) is obtained by immunizing with lisuride-1-succinyl-BSA, an immunogen. The antiserum in the assay is diluted 1:12500.
- Tracer: 3H-lisuride hydrogen maleate with a specific activity of 4.3 GBq/mg is used.
- Incubation: 0.1 ml of BSA buffer with active ingredient, 0.1 ml of tracer solution (ca. 5000 cpm/0.1 ml of BSA buffer) and 0.1 ml of diluted antiserum (1:12500) are added to 0.7 ml of BSA buffer and incubated for 18 hours at 4° C.
- Separation: antibody-bound lisuride is separated from free lisuride by adding 0.2 ml of charcoal suspension (1.25% (w/v) and 0.125% (w/v) of dextrane in BSA buffer) and incubation for 30 minutes at 0° C. The charcoal is sedimented by centrifuging for 15 minutes at 3000 g. The supernatant liquid (containing antibody-bound active ingredient) is decanted and subjected to radiometric analysis.
- Radiometric analysis: 4 ml of Atomlight (NEN) scintillation cocktail are added to the supernatant. The count is carried out using a WALLAC 1409 or 1410 β-scintillation counter without quench control.
- Analysis: The percutaneous skin flux is calculated as follows:
F=(C*R)/(A*T),
where F is the percutaneous flux [ng/cm2/h], C the active ingredient concentration in the acceptor medium [ng/ml], R the acceptor medium flow [1 ml/h], A the measured area [2 cm2] and T the sample-taking interval [h]. - The maximum transdermal active ingredient flux is obtained directly from the data. Mean percutaneous flux values are determined during days 1 and 2 of the experiment based on the cumulative absorbed dose in time intervals t=0-22 and t=22-54.
- 15 mg of Kollidon VA 64 (crystallization inhibitor) are dissolved in 15 mg of isopropanol. Then 5 mg of lisuride are sprinkled in. 80 mg of polyacrylate adhesive (Gelva 7881) are placed in a beaker, and the above suspension is added while rerinsing with 30 mg of isopropanol. The crystal-free wet mix obtained is thoroughly intermixed and spread on a siliconized liner using a 500 micron blade. The product is dried at 60° C. for 20 minutes, and finally a covering layer is laminated onto it.
- Flux measurements as described in Example C1 showed an F value of 0.43 on day 1, 0.44 on day 2, and a maximum F value of 0.85 (each in μg/cm2/h).
- 12.5 mg of dimethyl isosorbide are suspended with 2 mg of lisuride in 15 mg of isopropanol. 80 mg of polyacrylate adhesive (Gelva 7881) are placed in a beaker, and the above suspension is added while rerinsing with 30 mg of isopropanol. The crystal-free wet mix obtained is thoroughly intermixed and spread on a siliconized liner using a 500 micron blade. The product is dried at 60° C. for 20 minutes, and finally a covering layer is laminated onto it.
- Flux measurements as described in Example C1 showed an F value of 0.23 on day 1, 0.28 on day 2, and a maximum F value of 0.50 (each in μg/cm2/h).
- 27.2 mg of Kollidon VA 64 (crystallization inhibitor) and 16.3 mg of lauryl alcohol are dissolved at 60° C. Then 2 mg of lisuride are dissolved in this solution at 60° C. 39.38 mg of Eudragit E100, 13.41 mg of Citroflex 4A and 1.71 mg of succinic acid are molten at 150-200° C. The lisuride solution is added after the batch has cooled down to 80° C. The product is spread at 80° C. on a siliconized liner using a 500 micron blade. Then the product is cooled down to 20° C.; optionally, a covering layer may be laminated onto it.
- Flux measurements as described in Example C1 showed an F value of 0.90 on day 1, 1.76 on day 2, and a maximum F value of 2.53 (each in μg/cm2/h).
- A tablet base composition containing lactose, microcrystalline cellulose, corn starch, crosscarmellose and magnesium stearate in the usual quantitative composition is intermixed with 2000 μg of lisuride per each gram of tablet basis composition and pressed into tablets, each of which containing 200 μg of lisuride.
- An injection base solution containing lactose, NaCl and aqua p.i. in the usual quantitative composition is intermixed with 50 μg of lisuride per gram of injection base solution and filled into amber glass ampoules containing 50 μg of lisuride per ml of solution and preferably lyophilized.
- A number of TTSs divided into the four groups as described in Example C2 is put together. The fluxes F of lisuride through human skin of the TTSs of each group comprise are 0.25 μg/cm2/h, 0.5 μg/cm2/h, 0.75 μg/cm2/h and 1.0 μg/cm2/h. At least 7 TTSs are to be in the three groups where F is low. 28 or more TTSs are to be in the group with the highest F. A multitude of tablets from Example C5 and/or a multitude of ampoules from Example C6 is packed with the TTSs compiled in this way. The compilation is accompanied by an instruction sheet that refers to the treatment plan according to the invention.
- One TTS from Example C7 per day is applied to a Parkinson's disease patient over a period of 28 days. The area of the TTS remains unchanged for seven consecutive days. The TTSs applied in series of 7 consecutive days increase in area so that there will be a four-step increase in lisuride concentration in the plasma (averaged over a day). The lisuride flux F of the TTSs applied in four steps is 0.25 μg/cm2/h, 0.5 μg/cm2/h, 0.75 μg/cm2/h, and 1.0 μg/cm2/h. The daily application of a TTS with an F of 1.0 μg/cm2/h after day 28, i.e. there is no further increase of the dose. Whenever a new TTS is applied, the old one is removed, of course.
- After day 28, whenever acute conditions such as severe dystonias occur, a tablet from Example C7 is administered, or the content of an ampoule from Example C7 is injected i.m. Instead, or in addition, a tablet from Example C7 or the content of an ampoule from Example C7 may be administered in the morning for preventive reasons.
- The patient will at no time during the treatment show any considerable side effects. The oral or parenteral administrations because of acute conditions are particularly well tolerated, and even after these we did not observe any noticeable disruption of the regular REM sleep.
- If against all expectations any disturbing side affects do occur, they can be effectively attenuated by removing the TTS without a replacement, which will soon result in a reduction of agent concentration in the plasma.
Claims (38)
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10053397A DE10053397A1 (en) | 2000-10-20 | 2000-10-20 | Use of a dopaminergic active ingredient for the treatment of dopaminerg treatable diseases |
PCT/EP2001/009824 WO2002015890A1 (en) | 2000-08-24 | 2001-08-24 | Transdermal therapeutic system |
PCT/EP2001/009826 WO2002034267A1 (en) | 2000-10-20 | 2001-08-24 | Combination of a transdermal therapeutic system and an oral and/or parenteral preparation containing dopamine agonists for the treatment of dopaminergic disease states |
WOPCT/EP01/09826 | 2001-08-24 | ||
WOPCT/EP01/09824 | 2001-08-24 | ||
WOPCT/EP01/09823 | 2001-08-24 | ||
PCT/EP2001/009823 WO2002015889A1 (en) | 2000-08-24 | 2001-08-24 | Transdermal therapeutic system for treating restless-legs-syndrome |
Publications (1)
Publication Number | Publication Date |
---|---|
US20050214353A1 true US20050214353A1 (en) | 2005-09-29 |
Family
ID=7661331
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/362,182 Expired - Fee Related US7258871B2 (en) | 2000-08-24 | 2001-08-24 | Combination of a transdermal therapeutic system and an oral and/or parenteral preparation containing dopamine agonists for the treatment of dopaminergic disease states |
US11/116,278 Abandoned US20050214353A1 (en) | 2000-10-20 | 2005-04-28 | Transdermal therapeutic system |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/362,182 Expired - Fee Related US7258871B2 (en) | 2000-08-24 | 2001-08-24 | Combination of a transdermal therapeutic system and an oral and/or parenteral preparation containing dopamine agonists for the treatment of dopaminergic disease states |
Country Status (9)
Country | Link |
---|---|
US (2) | US7258871B2 (en) |
EP (1) | EP1303278B1 (en) |
JP (1) | JP2004512305A (en) |
AT (1) | ATE413177T1 (en) |
AU (2) | AU9551201A (en) |
DE (2) | DE10053397A1 (en) |
DK (1) | DK1303278T3 (en) |
ES (1) | ES2315309T3 (en) |
WO (1) | WO2002034267A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040048779A1 (en) * | 2002-05-06 | 2004-03-11 | Erwin Schollmayer | Use of rotigotine for treating the restless leg syndrome |
WO2008001200A2 (en) * | 2006-06-29 | 2008-01-03 | Antares Pharma Ipl Ag | Transdermal composition having enhanced color stability |
EP1987815A1 (en) * | 2007-05-04 | 2008-11-05 | Schwarz Pharma Ag | Oronasopharyngeally deliverable pharmaceutical compositions of dopamine agonists for the prevention and/or treatment of restless limb disorders |
US11179469B2 (en) | 2017-04-28 | 2021-11-23 | Nitto Denko Corporation | Transdermal absorption preparation |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070243240A9 (en) * | 2000-08-24 | 2007-10-18 | Fred Windt-Hanke | Transdermal therapeutic system |
DE10053397A1 (en) * | 2000-10-20 | 2002-05-02 | Schering Ag | Use of a dopaminergic active ingredient for the treatment of dopaminerg treatable diseases |
DE10043321B4 (en) * | 2000-08-24 | 2005-07-28 | Neurobiotec Gmbh | Use of a transdermal therapeutic system for the treatment of Parkinson's disease, for the treatment and prevention of premenstrual syndrome and for lactation inhibition |
DE10064453A1 (en) * | 2000-12-16 | 2002-07-04 | Schering Ag | Use of a dopaminergic active ingredient for the treatment of dopaminerg treatable diseases |
DE10226459A1 (en) * | 2002-06-13 | 2004-01-08 | Neurobiotec Gmbh | Use of dopamine partial agonists to treat restless legs syndrome |
US8821915B2 (en) | 2002-08-09 | 2014-09-02 | Veroscience, Llc | Therapeutic process for the treatment of the metabolic syndrome and associated metabolic disorders |
US20100035886A1 (en) | 2007-06-21 | 2010-02-11 | Veroscience, Llc | Parenteral formulations of dopamine agonists |
US8741918B2 (en) * | 2007-06-21 | 2014-06-03 | Veroscience Llc | Parenteral formulations of dopamine agonists |
AU2015201255B2 (en) * | 2008-01-14 | 2016-05-19 | Veroscience, Llc | Parenteral formulations of dopamine agonists |
US9352025B2 (en) | 2009-06-05 | 2016-05-31 | Veroscience Llc | Combination of dopamine agonists plus first phase insulin secretagogues for the treatment of metabolic disorders |
AU2011227202A1 (en) * | 2010-03-17 | 2012-10-04 | Arbonne International Llc | Oral supplement |
EP2635272A1 (en) * | 2010-11-01 | 2013-09-11 | Intec Pharma Ltd. | Accordion pill comprising levodopa for an improved treatment of parkinson's disease symptoms |
US9657020B2 (en) | 2015-01-20 | 2017-05-23 | Xoc Pharmaceuticals, Inc. | Ergoline compounds and uses thereof |
WO2018223065A1 (en) | 2017-06-01 | 2018-12-06 | Xoc Pharmaceuticals, Inc. | Ergoline derivatives for use in medicine |
Citations (91)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US559782A (en) * | 1896-05-05 | Aaron mosley | ||
US3953454A (en) * | 1971-08-05 | 1976-04-27 | Spofa, United Pharmeceutical Works | N-(D-6-methyl-8-isoergoline-I-yl)-N',N'-diethylurea |
US3954988A (en) * | 1973-11-24 | 1976-05-04 | Schering Aktiengesellschaft | Use of lisuride and physiologically acceptable salts thereof to achieve psychic energizer effects |
US4166182A (en) * | 1978-02-08 | 1979-08-28 | Eli Lilly And Company | 6-n-propyl-8-methoxymethyl or methylmercaptomethylergolines and related compounds |
US4202979A (en) * | 1979-01-11 | 1980-05-13 | Eli Lilly And Company | 6-Ethyl(or allyl)-8-methoxymethyl or methylmercaptomethylergolines and related compounds |
US4379790A (en) * | 1979-06-13 | 1983-04-12 | Schering Aktiengesellschaft | (Erolinyl)-N,N-diethylurea derivatives, and their preparation and use |
US4673681A (en) * | 1985-04-04 | 1987-06-16 | Poli Industria Chimica S.P.A. | Pharmaceutical methods having dopaminergic activity |
US4742054A (en) * | 1982-11-23 | 1988-05-03 | Naftchi Nosrat E | Treatment of mammals suffering from damage to the central nervous system |
US4797405A (en) * | 1987-10-26 | 1989-01-10 | Eli Lilly And Company | Stabilized pergolide compositions |
US4798834A (en) * | 1987-08-31 | 1989-01-17 | Eli Lilly And Company | Optionally substituted (3β-9,10-didehydro-2,3-dihydro ergoline as serotonergic function enhancement |
US4800204A (en) * | 1987-05-07 | 1989-01-24 | Mueller Peter S | Method of controlling tobacco use |
US4935429A (en) * | 1985-10-25 | 1990-06-19 | Dackis Charles A | Method of treating psychostimulant addiction |
US5057321A (en) * | 1990-06-13 | 1991-10-15 | Alza Corporation | Dosage form comprising drug and maltodextrin |
US5114948A (en) * | 1989-10-19 | 1992-05-19 | Eli Lilly And Company | Stabilized pergolide compositions |
US5190763A (en) * | 1990-05-07 | 1993-03-02 | Alza Corporation | Dosage form indicated for the management of abnormal posture, tremor and involuntary movement |
US5192550A (en) * | 1990-05-07 | 1993-03-09 | Alza Corporation | Dosage form for treating central nervous system disorders |
US5221536A (en) * | 1990-05-07 | 1993-06-22 | Alza Corporation | Dosage form indicated for the management of abnormal posture, tremor and involuntary movement |
US5229129A (en) * | 1989-07-12 | 1993-07-20 | Cygnus Therapeutic Systems | Transdermal administration of lisuride |
US5252335A (en) * | 1989-07-12 | 1993-10-12 | Cygnus Therapeutic Systems | Transdermal administration of lisuride |
US5378730A (en) * | 1988-06-09 | 1995-01-03 | Alza Corporation | Permeation enhancer comprising ethanol and monoglycerides |
US5399355A (en) * | 1991-05-18 | 1995-03-21 | Schering Aktiengesellschaft | Agent for transdermal administration containing ergoline derivatives |
US5462744A (en) * | 1989-12-01 | 1995-10-31 | Boehringer Ingelheim Kg | Transdermal system for the administration of pharmacological compounds under pH-controlled conditions |
US5593686A (en) * | 1984-03-01 | 1997-01-14 | Sandoz Ltd. | Pharmaceutical compositions |
US5607691A (en) * | 1992-06-12 | 1997-03-04 | Affymax Technologies N.V. | Compositions and methods for enhanced drug delivery |
US5643586A (en) * | 1995-04-27 | 1997-07-01 | Perricone; Nicholas V. | Topical compositions and methods for treatment of skin damage and aging using catecholamines and related compounds |
US5650420A (en) * | 1994-12-15 | 1997-07-22 | Pharmacia & Upjohn Company | Pramipexole as a neuroprotective agent |
US5656286A (en) * | 1988-03-04 | 1997-08-12 | Noven Pharmaceuticals, Inc. | Solubility parameter based drug delivery system and method for altering drug saturation concentration |
US5674875A (en) * | 1993-05-04 | 1997-10-07 | Eli Lilly And Company | Method of blocking human 5-hydroxytryptamine-2 receptors |
US5679685A (en) * | 1993-12-22 | 1997-10-21 | Ergo Science, Incorporated | Accelerated release composition containing bromocriptine |
US5728378A (en) * | 1992-06-03 | 1998-03-17 | Maxim Pharmaceuticals, Inc. | Preparation for activation of natural killer cells (NK-cells), said preparation containing interferon-alpha and histamine, serotonin, amines or substances with corresponding receptor activity |
US5738869A (en) * | 1993-04-23 | 1998-04-14 | Haxal Ag | Transdermal drug preparation |
US5858410A (en) * | 1994-11-11 | 1999-01-12 | Medac Gesellschaft Fur Klinische Spezialpraparate | Pharmaceutical nanosuspensions for medicament administration as systems with increased saturation solubility and rate of solution |
US5872145A (en) * | 1996-08-16 | 1999-02-16 | Pozen, Inc. | Formulation of 5-HT agonist and NSAID for treatment of migraine |
US5877183A (en) * | 1996-06-06 | 1999-03-02 | Ergo Research Corporation | Treatment of lipid and glucose metabolism disorders with dopamine and serotonin agonists |
US5902815A (en) * | 1996-09-03 | 1999-05-11 | Washington University | Use of 5HT-2A serotonin agonists to prevent adverse effects of NMDA receptor hypofunction |
US6114326A (en) * | 1998-03-27 | 2000-09-05 | Pharmacia & Upjohn Company | Use of cabergoline in the treatment of restless legs syndrome |
US6187756B1 (en) * | 1996-09-05 | 2001-02-13 | The Massachusetts Institute Of Technology | Composition and methods for treatment of neurological disorders and neurodegenerative diseases |
US6191132B1 (en) * | 1990-12-21 | 2001-02-20 | Schering Aktiengesellschaft | Use of quisqualate receptor antagonists |
US6221870B1 (en) * | 1997-05-29 | 2001-04-24 | Novartis Ag | Ergoline derivatives and their use as somatostatin receptor antagonists |
US6299900B1 (en) * | 1996-02-19 | 2001-10-09 | Monash University | Dermal penetration enhancers and drug delivery systems involving same |
US20020009486A1 (en) * | 1999-11-30 | 2002-01-24 | 3M Innovative Properties Company | Therapeutic agent delivery incorporating reflective optical film |
US20020013332A1 (en) * | 1998-11-24 | 2002-01-31 | Michel Dib | Use of nicergoline for treating spasticity |
US20020019421A1 (en) * | 2000-07-05 | 2002-02-14 | Roni Biberman | Compositions and therapy for substance addiction |
US6348208B1 (en) * | 1995-01-13 | 2002-02-19 | Somerset Pharmaceuticals, Inc. | Methods and pharmaceutical compositions employing desmethylselegiline |
US6380267B1 (en) * | 1999-09-13 | 2002-04-30 | David M. Swope | Composition and method for decreasing neurologic symptomatology |
US6384083B1 (en) * | 1996-10-30 | 2002-05-07 | Hanns Ludwig | Use of adamantane amines or structurally similar compounds for combating borna disease virus and for the prevention and treatment of affective diseases and other disorders associated with bdv infections in humans and animals |
US6388079B1 (en) * | 2000-08-29 | 2002-05-14 | Scinopharm Singapore Pte Ltd. | Process for preparing pergolide |
US6391871B1 (en) * | 1996-09-20 | 2002-05-21 | John W. Olney | Preventing neuronal degeneration in Alzheimer's disease |
US6395901B1 (en) * | 1999-01-27 | 2002-05-28 | Poli Industria Chimica S.P A. | Process for the preparation of alkyl mercapto methyl ergoline derivatives |
US20020068092A1 (en) * | 1999-10-08 | 2002-06-06 | H. William Bosch | Bioadhesive nanoparticulate compositions having cationic surface stabilizers |
US20020110585A1 (en) * | 1999-11-30 | 2002-08-15 | Godbey Kristin J. | Patch therapeutic agent delivery device having texturized backing |
US20020123503A1 (en) * | 2000-12-21 | 2002-09-05 | Malcolm Ross | Cabergoline pharmaceutical compositions and methods of use thereof |
US20020132827A1 (en) * | 2001-01-16 | 2002-09-19 | NICHOLS David E. | Method of treatment of dopamine-related dysfunction |
US6461636B1 (en) * | 1998-05-15 | 2002-10-08 | Schwarz Pharma Ag | Transdermal therapeutic system containing pergolide |
US6503920B1 (en) * | 1998-05-15 | 2003-01-07 | Pharmacia & Upjohn Company | Cabergoline and pramipexole: new uses and combinations |
US6514482B1 (en) * | 2000-09-19 | 2003-02-04 | Advanced Inhalation Research, Inc. | Pulmonary delivery in treating disorders of the central nervous system |
US20030026830A1 (en) * | 2001-05-08 | 2003-02-06 | Thomas Lauterback | Transdermal therapeutic system for parkinson's disease inducing high plasma levels of rotigotine |
US6572879B1 (en) * | 1995-06-07 | 2003-06-03 | Alza Corporation | Formulations for transdermal delivery of pergolide |
US6576671B1 (en) * | 1999-06-09 | 2003-06-10 | Chiese Farmaceutici S.P.A. | Aminotetralin derivatives for the therapy of cardiovascular diseases |
US20030114476A1 (en) * | 1999-03-26 | 2003-06-19 | Pozen Inc. | High potency dihydroergotamine compositions |
US6602868B2 (en) * | 2000-10-31 | 2003-08-05 | Pharmacia & Upjohn Company | Treatments for restless legs syndrome |
US6613507B1 (en) * | 2000-03-21 | 2003-09-02 | Yu-an Chang | Boraadamantane compounds for the treatment of pathogenic viruses and other medical applications |
US20030166709A1 (en) * | 2000-08-24 | 2003-09-04 | Stephan Rimpler | Novel pharmaceutical compositions administering n-0923 |
US6620429B1 (en) * | 1998-03-30 | 2003-09-16 | Lts Lohmann Therapie-Systeme Ag | Use of basic alkali metal salts for manufacturing transdermal therapeutic system |
US6623752B1 (en) * | 1996-07-02 | 2003-09-23 | Hexal Ag | Patch for transdermal application for pergolid |
US20030181462A1 (en) * | 2001-08-17 | 2003-09-25 | Boehringer Ingelheim Pharma Kg | Use of BIBN4096 in combination with other antimigraine drugs for the treatment of migraine |
US6632217B2 (en) * | 2001-04-19 | 2003-10-14 | Microsolutions, Inc. | Implantable osmotic pump |
US6673806B2 (en) * | 2000-03-24 | 2004-01-06 | Pharmacia Italia S.P.A. | Crystalline form II cabergoline |
US6680327B2 (en) * | 2000-03-24 | 2004-01-20 | Pharmacia Italia Spa | Crystalline form VII of cabergoline |
US20040013620A1 (en) * | 1996-02-19 | 2004-01-22 | Monash University | Transdermal delivery of antiparkinson agents |
US6685959B1 (en) * | 1999-04-26 | 2004-02-03 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Pharmaceutical compositions comprising 2-isoxazoles-8-aminotetralin derivatives |
US6689118B2 (en) * | 1999-10-14 | 2004-02-10 | Becton Dickinson And Company | Method of intradermally injecting substances |
US20040028723A1 (en) * | 2000-08-24 | 2004-02-12 | Reinhard Horowski | Transdermal therapeutic system for treating restless-legs-syndrome |
US6699498B1 (en) * | 1999-11-29 | 2004-03-02 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic systems having improved stability and their production |
US20040048779A1 (en) * | 2002-05-06 | 2004-03-11 | Erwin Schollmayer | Use of rotigotine for treating the restless leg syndrome |
US6727363B2 (en) * | 2000-03-24 | 2004-04-27 | Pharmacia Italia Spa | Process for preparing crystalline form I of cabergoline |
US20040081683A1 (en) * | 2002-07-30 | 2004-04-29 | Schacht Dietrich Wilhelm | Transdermal delivery system |
US20040087596A1 (en) * | 2002-09-13 | 2004-05-06 | Schneider Jay S. | Methods and kit for treating Parkinson's disease |
US20040092544A1 (en) * | 2000-10-20 | 2004-05-13 | Reinhard Horowski | Combination of a transdermal therapeutic system and an oral and/or parenteral preparation containing dopamine agonists for the treatment of dopaminergic disease states |
US20040096491A1 (en) * | 2001-03-07 | 2004-05-20 | Tetsuro Tateishi | Adhesive patch |
US20040102652A1 (en) * | 2000-05-12 | 2004-05-27 | Gabriele Amari | Optically active2-aminotetralin derivatives, the processes for the preparation thereof and the therapeutical use of pharmaceutical compositions containing them |
US20040105889A1 (en) * | 2002-12-03 | 2004-06-03 | Elan Pharma International Limited | Low viscosity liquid dosage forms |
US20040120995A1 (en) * | 2002-04-01 | 2004-06-24 | Martin Debra A | Transdermal delivery of pergolide |
US20040137045A1 (en) * | 2002-07-30 | 2004-07-15 | Armin Breitenbach | Hot-melt TTS for administering Rotigotine |
US20040138235A1 (en) * | 2002-12-19 | 2004-07-15 | Schering Corporation | Adenosine A2a receptor antagonists for the treatment of extra-pyramidal syndrome and other movement disorders |
US20040147581A1 (en) * | 2002-11-18 | 2004-07-29 | Pharmacia Corporation | Method of using a Cox-2 inhibitor and a 5-HT1A receptor modulator as a combination therapy |
US6770638B2 (en) * | 2001-04-20 | 2004-08-03 | Spectrum Pharmaceuticals, Inc. | Tetrahydroindolone and purine derivatives linked to arylpiperazines |
US20040166159A1 (en) * | 2002-05-29 | 2004-08-26 | Chien-Hsuan Han | Pharmaceutical dosage forms having immediate and controlled release properties that contain an aromatic amino acid decarboxylase inhibitor and levodopa |
US20040170672A1 (en) * | 2001-03-07 | 2004-09-02 | Thorsten Selzer | Transdermal therapeutic system for administration of partial dopamine-d2 agonists |
US20040180904A1 (en) * | 2001-05-11 | 2004-09-16 | Beck Jurgen K. | Novel use of 2h-benzimidazol-2-one, 1,3-Dihydro-1-(2{4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}ethyl)-and its physiologically acceptable addition salts |
US20050031667A1 (en) * | 2003-03-31 | 2005-02-10 | Patel Rajesh A. | Implantable polymeric device for sustained release of dopamine agonist |
Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HU180467B (en) * | 1979-07-12 | 1983-03-28 | Gyogyszerkutato Intezet | Process for producing new ergol-8-ene- and ergoline-sceleted compounds |
DE3333240A1 (en) * | 1983-09-12 | 1985-03-28 | Schering AG, 1000 Berlin und 4709 Bergkamen | MEDIUM FOR TRANSDERMAL APPLICATION OF MEDICINAL PRODUCTS |
DE3445784A1 (en) * | 1984-12-13 | 1986-06-26 | Schering AG, Berlin und Bergkamen, 1000 Berlin | METHOD FOR PRODUCING ERGOLIN DERIVATIVES |
US4970200A (en) * | 1988-03-01 | 1990-11-13 | Schering Aktiengesellschaft | Agent for treatment of Parkinson's disease |
US5063234A (en) * | 1990-05-25 | 1991-11-05 | Eli Lilly And Company | Method of inhibiting demineralization of bone |
CA2080119A1 (en) * | 1991-02-08 | 1992-08-09 | Heidi Hummel-Maquardt | Process for the production of ergoline derivatives |
IT1252163B (en) * | 1991-12-03 | 1995-06-05 | Poli Ind Chimica Spa | PHARMACEUTICAL COMPOSITIONS FOR NEUROPROTECTION IN DEGENERATIVE OR ISCHEMIC-BASED NEUROLOGICAL DISEASES |
US5696128A (en) * | 1994-07-07 | 1997-12-09 | The Board Of Supervisors Of Louisiana University And Agricultural And Mechanical College | Method of regulating immune function |
PT690863E (en) * | 1993-04-06 | 2003-07-31 | Abbott Lab | TETRACICLIC COMPOUNDS AS DOPAMINE AGONISTS |
JP3489831B2 (en) * | 1993-04-20 | 2004-01-26 | ヘクサル・アクチエンゲゼルシャフト | Active ingredient patch |
US5696125A (en) | 1995-02-24 | 1997-12-09 | Research Foundation Of The State University Of New York | Substance abuse-induced hemorrhagic stoke in an animal model |
US6001861A (en) | 1998-01-16 | 1999-12-14 | Pharmacia & Upjohn Company | Use of pramipexole in the treatment of restless legs syndrome |
US5849800A (en) * | 1997-03-28 | 1998-12-15 | The Penn State Research Foundation | Use of amantadine for treatment of Hepatitis C |
US5994363A (en) | 1998-08-24 | 1999-11-30 | Pentech Pharmaceuticals, Inc. | Amelioration of apomorphine adverse effects |
DE19938823A1 (en) * | 1999-08-19 | 2001-02-22 | Boehringer Ingelheim Pharma | Treatment of restless leg syndrome symptoms, using synergistic combination of alpha-2 agonist, preferably clonidine, and another neuro-psychic drug, e.g. pramipexol |
US6720001B2 (en) * | 1999-10-18 | 2004-04-13 | Lipocine, Inc. | Emulsion compositions for polyfunctional active ingredients |
US6500857B1 (en) | 2001-08-16 | 2002-12-31 | Nicholas V. Perricone | Subcutaneous muscle treatment using electronic stimulation and topical compositions |
US20020193758A1 (en) | 2001-06-18 | 2002-12-19 | Sca Hygiene Products Ab | Product |
-
2000
- 2000-10-20 DE DE10053397A patent/DE10053397A1/en not_active Withdrawn
-
2001
- 2001-08-24 JP JP2002537318A patent/JP2004512305A/en active Pending
- 2001-08-24 AT AT01976150T patent/ATE413177T1/en not_active IP Right Cessation
- 2001-08-24 US US10/362,182 patent/US7258871B2/en not_active Expired - Fee Related
- 2001-08-24 EP EP01976150A patent/EP1303278B1/en not_active Expired - Lifetime
- 2001-08-24 DK DK01976150T patent/DK1303278T3/en active
- 2001-08-24 AU AU9551201A patent/AU9551201A/en active Pending
- 2001-08-24 DE DE50114474T patent/DE50114474D1/en not_active Expired - Lifetime
- 2001-08-24 AU AU2001295512A patent/AU2001295512B2/en not_active Ceased
- 2001-08-24 WO PCT/EP2001/009826 patent/WO2002034267A1/en active Application Filing
- 2001-08-24 ES ES01976150T patent/ES2315309T3/en not_active Expired - Lifetime
-
2005
- 2005-04-28 US US11/116,278 patent/US20050214353A1/en not_active Abandoned
Patent Citations (99)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US559782A (en) * | 1896-05-05 | Aaron mosley | ||
US3953454A (en) * | 1971-08-05 | 1976-04-27 | Spofa, United Pharmeceutical Works | N-(D-6-methyl-8-isoergoline-I-yl)-N',N'-diethylurea |
US3954988A (en) * | 1973-11-24 | 1976-05-04 | Schering Aktiengesellschaft | Use of lisuride and physiologically acceptable salts thereof to achieve psychic energizer effects |
US4166182A (en) * | 1978-02-08 | 1979-08-28 | Eli Lilly And Company | 6-n-propyl-8-methoxymethyl or methylmercaptomethylergolines and related compounds |
US4202979A (en) * | 1979-01-11 | 1980-05-13 | Eli Lilly And Company | 6-Ethyl(or allyl)-8-methoxymethyl or methylmercaptomethylergolines and related compounds |
US4379790A (en) * | 1979-06-13 | 1983-04-12 | Schering Aktiengesellschaft | (Erolinyl)-N,N-diethylurea derivatives, and their preparation and use |
US4742054A (en) * | 1982-11-23 | 1988-05-03 | Naftchi Nosrat E | Treatment of mammals suffering from damage to the central nervous system |
US5593686A (en) * | 1984-03-01 | 1997-01-14 | Sandoz Ltd. | Pharmaceutical compositions |
US4673681A (en) * | 1985-04-04 | 1987-06-16 | Poli Industria Chimica S.P.A. | Pharmaceutical methods having dopaminergic activity |
US4935429A (en) * | 1985-10-25 | 1990-06-19 | Dackis Charles A | Method of treating psychostimulant addiction |
US4800204A (en) * | 1987-05-07 | 1989-01-24 | Mueller Peter S | Method of controlling tobacco use |
US4798834A (en) * | 1987-08-31 | 1989-01-17 | Eli Lilly And Company | Optionally substituted (3β-9,10-didehydro-2,3-dihydro ergoline as serotonergic function enhancement |
US4797405A (en) * | 1987-10-26 | 1989-01-10 | Eli Lilly And Company | Stabilized pergolide compositions |
US5656286A (en) * | 1988-03-04 | 1997-08-12 | Noven Pharmaceuticals, Inc. | Solubility parameter based drug delivery system and method for altering drug saturation concentration |
US5378730A (en) * | 1988-06-09 | 1995-01-03 | Alza Corporation | Permeation enhancer comprising ethanol and monoglycerides |
US5229129A (en) * | 1989-07-12 | 1993-07-20 | Cygnus Therapeutic Systems | Transdermal administration of lisuride |
US5252335A (en) * | 1989-07-12 | 1993-10-12 | Cygnus Therapeutic Systems | Transdermal administration of lisuride |
US5114948A (en) * | 1989-10-19 | 1992-05-19 | Eli Lilly And Company | Stabilized pergolide compositions |
US5462744A (en) * | 1989-12-01 | 1995-10-31 | Boehringer Ingelheim Kg | Transdermal system for the administration of pharmacological compounds under pH-controlled conditions |
US5221536A (en) * | 1990-05-07 | 1993-06-22 | Alza Corporation | Dosage form indicated for the management of abnormal posture, tremor and involuntary movement |
US5192550A (en) * | 1990-05-07 | 1993-03-09 | Alza Corporation | Dosage form for treating central nervous system disorders |
US6217905B1 (en) * | 1990-05-07 | 2001-04-17 | Alza Corporation | Antiparkinson dosage form |
US5190763A (en) * | 1990-05-07 | 1993-03-02 | Alza Corporation | Dosage form indicated for the management of abnormal posture, tremor and involuntary movement |
US5057321A (en) * | 1990-06-13 | 1991-10-15 | Alza Corporation | Dosage form comprising drug and maltodextrin |
US6191132B1 (en) * | 1990-12-21 | 2001-02-20 | Schering Aktiengesellschaft | Use of quisqualate receptor antagonists |
US5399355A (en) * | 1991-05-18 | 1995-03-21 | Schering Aktiengesellschaft | Agent for transdermal administration containing ergoline derivatives |
US5728378A (en) * | 1992-06-03 | 1998-03-17 | Maxim Pharmaceuticals, Inc. | Preparation for activation of natural killer cells (NK-cells), said preparation containing interferon-alpha and histamine, serotonin, amines or substances with corresponding receptor activity |
US5607691A (en) * | 1992-06-12 | 1997-03-04 | Affymax Technologies N.V. | Compositions and methods for enhanced drug delivery |
US5738869A (en) * | 1993-04-23 | 1998-04-14 | Haxal Ag | Transdermal drug preparation |
US5674875A (en) * | 1993-05-04 | 1997-10-07 | Eli Lilly And Company | Method of blocking human 5-hydroxytryptamine-2 receptors |
US5679685A (en) * | 1993-12-22 | 1997-10-21 | Ergo Science, Incorporated | Accelerated release composition containing bromocriptine |
US5858410A (en) * | 1994-11-11 | 1999-01-12 | Medac Gesellschaft Fur Klinische Spezialpraparate | Pharmaceutical nanosuspensions for medicament administration as systems with increased saturation solubility and rate of solution |
US5650420A (en) * | 1994-12-15 | 1997-07-22 | Pharmacia & Upjohn Company | Pramipexole as a neuroprotective agent |
US6699495B2 (en) * | 1995-01-13 | 2004-03-02 | Somerset Pharmaceuticals, Inc. | Methods for treating multiple sclerosis employing desmethylselegiline |
US6562365B2 (en) * | 1995-01-13 | 2003-05-13 | Somerset Pharmaceuticals, Inc. | Methods employing R(−)-desmethylselegiline |
US6348208B1 (en) * | 1995-01-13 | 2002-02-19 | Somerset Pharmaceuticals, Inc. | Methods and pharmaceutical compositions employing desmethylselegiline |
US5643586A (en) * | 1995-04-27 | 1997-07-01 | Perricone; Nicholas V. | Topical compositions and methods for treatment of skin damage and aging using catecholamines and related compounds |
US6572879B1 (en) * | 1995-06-07 | 2003-06-03 | Alza Corporation | Formulations for transdermal delivery of pergolide |
US20040013620A1 (en) * | 1996-02-19 | 2004-01-22 | Monash University | Transdermal delivery of antiparkinson agents |
US6299900B1 (en) * | 1996-02-19 | 2001-10-09 | Monash University | Dermal penetration enhancers and drug delivery systems involving same |
US5877183A (en) * | 1996-06-06 | 1999-03-02 | Ergo Research Corporation | Treatment of lipid and glucose metabolism disorders with dopamine and serotonin agonists |
US6623752B1 (en) * | 1996-07-02 | 2003-09-23 | Hexal Ag | Patch for transdermal application for pergolid |
US5872145A (en) * | 1996-08-16 | 1999-02-16 | Pozen, Inc. | Formulation of 5-HT agonist and NSAID for treatment of migraine |
US5902815A (en) * | 1996-09-03 | 1999-05-11 | Washington University | Use of 5HT-2A serotonin agonists to prevent adverse effects of NMDA receptor hypofunction |
US6187756B1 (en) * | 1996-09-05 | 2001-02-13 | The Massachusetts Institute Of Technology | Composition and methods for treatment of neurological disorders and neurodegenerative diseases |
US6391871B1 (en) * | 1996-09-20 | 2002-05-21 | John W. Olney | Preventing neuronal degeneration in Alzheimer's disease |
US6384083B1 (en) * | 1996-10-30 | 2002-05-07 | Hanns Ludwig | Use of adamantane amines or structurally similar compounds for combating borna disease virus and for the prevention and treatment of affective diseases and other disorders associated with bdv infections in humans and animals |
US6221870B1 (en) * | 1997-05-29 | 2001-04-24 | Novartis Ag | Ergoline derivatives and their use as somatostatin receptor antagonists |
US6114326A (en) * | 1998-03-27 | 2000-09-05 | Pharmacia & Upjohn Company | Use of cabergoline in the treatment of restless legs syndrome |
US6620429B1 (en) * | 1998-03-30 | 2003-09-16 | Lts Lohmann Therapie-Systeme Ag | Use of basic alkali metal salts for manufacturing transdermal therapeutic system |
US6461636B1 (en) * | 1998-05-15 | 2002-10-08 | Schwarz Pharma Ag | Transdermal therapeutic system containing pergolide |
US6503920B1 (en) * | 1998-05-15 | 2003-01-07 | Pharmacia & Upjohn Company | Cabergoline and pramipexole: new uses and combinations |
US20020013332A1 (en) * | 1998-11-24 | 2002-01-31 | Michel Dib | Use of nicergoline for treating spasticity |
US6713493B2 (en) * | 1998-11-24 | 2004-03-30 | Aventis Pharma S.A. | Use of nicergoline in the treatment of spasticity |
US6380208B2 (en) * | 1998-11-24 | 2002-04-30 | Aventis Pharma S.A. | Use of nicergoline for treating spasticity |
US6395901B1 (en) * | 1999-01-27 | 2002-05-28 | Poli Industria Chimica S.P A. | Process for the preparation of alkyl mercapto methyl ergoline derivatives |
US20030114476A1 (en) * | 1999-03-26 | 2003-06-19 | Pozen Inc. | High potency dihydroergotamine compositions |
US6685959B1 (en) * | 1999-04-26 | 2004-02-03 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Pharmaceutical compositions comprising 2-isoxazoles-8-aminotetralin derivatives |
US6576671B1 (en) * | 1999-06-09 | 2003-06-10 | Chiese Farmaceutici S.P.A. | Aminotetralin derivatives for the therapy of cardiovascular diseases |
US6380267B1 (en) * | 1999-09-13 | 2002-04-30 | David M. Swope | Composition and method for decreasing neurologic symptomatology |
US20030108611A1 (en) * | 1999-10-08 | 2003-06-12 | Elan Pharma International Ltd. | Bioadhesive nanoparticulate compositions having cationic surface stabilizers |
US20020068092A1 (en) * | 1999-10-08 | 2002-06-06 | H. William Bosch | Bioadhesive nanoparticulate compositions having cationic surface stabilizers |
US6689118B2 (en) * | 1999-10-14 | 2004-02-10 | Becton Dickinson And Company | Method of intradermally injecting substances |
US6699498B1 (en) * | 1999-11-29 | 2004-03-02 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic systems having improved stability and their production |
US20020110585A1 (en) * | 1999-11-30 | 2002-08-15 | Godbey Kristin J. | Patch therapeutic agent delivery device having texturized backing |
US20020009486A1 (en) * | 1999-11-30 | 2002-01-24 | 3M Innovative Properties Company | Therapeutic agent delivery incorporating reflective optical film |
US6613507B1 (en) * | 2000-03-21 | 2003-09-02 | Yu-an Chang | Boraadamantane compounds for the treatment of pathogenic viruses and other medical applications |
US6727363B2 (en) * | 2000-03-24 | 2004-04-27 | Pharmacia Italia Spa | Process for preparing crystalline form I of cabergoline |
US6680327B2 (en) * | 2000-03-24 | 2004-01-20 | Pharmacia Italia Spa | Crystalline form VII of cabergoline |
US6673806B2 (en) * | 2000-03-24 | 2004-01-06 | Pharmacia Italia S.P.A. | Crystalline form II cabergoline |
US20040102652A1 (en) * | 2000-05-12 | 2004-05-27 | Gabriele Amari | Optically active2-aminotetralin derivatives, the processes for the preparation thereof and the therapeutical use of pharmaceutical compositions containing them |
US20020019421A1 (en) * | 2000-07-05 | 2002-02-14 | Roni Biberman | Compositions and therapy for substance addiction |
US20030166709A1 (en) * | 2000-08-24 | 2003-09-04 | Stephan Rimpler | Novel pharmaceutical compositions administering n-0923 |
US20040028723A1 (en) * | 2000-08-24 | 2004-02-12 | Reinhard Horowski | Transdermal therapeutic system for treating restless-legs-syndrome |
US20040101550A1 (en) * | 2000-08-24 | 2004-05-27 | Fred Windt-Hanke | Transdermal therapeutic system |
US6388079B1 (en) * | 2000-08-29 | 2002-05-14 | Scinopharm Singapore Pte Ltd. | Process for preparing pergolide |
US6514482B1 (en) * | 2000-09-19 | 2003-02-04 | Advanced Inhalation Research, Inc. | Pulmonary delivery in treating disorders of the central nervous system |
US20040092544A1 (en) * | 2000-10-20 | 2004-05-13 | Reinhard Horowski | Combination of a transdermal therapeutic system and an oral and/or parenteral preparation containing dopamine agonists for the treatment of dopaminergic disease states |
US6602868B2 (en) * | 2000-10-31 | 2003-08-05 | Pharmacia & Upjohn Company | Treatments for restless legs syndrome |
US6716854B2 (en) * | 2000-10-31 | 2004-04-06 | Pfizer, Inc. | Treatments for restless legs syndrome |
US20020123503A1 (en) * | 2000-12-21 | 2002-09-05 | Malcolm Ross | Cabergoline pharmaceutical compositions and methods of use thereof |
US20020132827A1 (en) * | 2001-01-16 | 2002-09-19 | NICHOLS David E. | Method of treatment of dopamine-related dysfunction |
US20040170672A1 (en) * | 2001-03-07 | 2004-09-02 | Thorsten Selzer | Transdermal therapeutic system for administration of partial dopamine-d2 agonists |
US20040096491A1 (en) * | 2001-03-07 | 2004-05-20 | Tetsuro Tateishi | Adhesive patch |
US6632217B2 (en) * | 2001-04-19 | 2003-10-14 | Microsolutions, Inc. | Implantable osmotic pump |
US6770638B2 (en) * | 2001-04-20 | 2004-08-03 | Spectrum Pharmaceuticals, Inc. | Tetrahydroindolone and purine derivatives linked to arylpiperazines |
US20030026830A1 (en) * | 2001-05-08 | 2003-02-06 | Thomas Lauterback | Transdermal therapeutic system for parkinson's disease inducing high plasma levels of rotigotine |
US20040180904A1 (en) * | 2001-05-11 | 2004-09-16 | Beck Jurgen K. | Novel use of 2h-benzimidazol-2-one, 1,3-Dihydro-1-(2{4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}ethyl)-and its physiologically acceptable addition salts |
US20030181462A1 (en) * | 2001-08-17 | 2003-09-25 | Boehringer Ingelheim Pharma Kg | Use of BIBN4096 in combination with other antimigraine drugs for the treatment of migraine |
US20040120995A1 (en) * | 2002-04-01 | 2004-06-24 | Martin Debra A | Transdermal delivery of pergolide |
US20040048779A1 (en) * | 2002-05-06 | 2004-03-11 | Erwin Schollmayer | Use of rotigotine for treating the restless leg syndrome |
US20040166159A1 (en) * | 2002-05-29 | 2004-08-26 | Chien-Hsuan Han | Pharmaceutical dosage forms having immediate and controlled release properties that contain an aromatic amino acid decarboxylase inhibitor and levodopa |
US20040137045A1 (en) * | 2002-07-30 | 2004-07-15 | Armin Breitenbach | Hot-melt TTS for administering Rotigotine |
US20040081683A1 (en) * | 2002-07-30 | 2004-04-29 | Schacht Dietrich Wilhelm | Transdermal delivery system |
US20040087596A1 (en) * | 2002-09-13 | 2004-05-06 | Schneider Jay S. | Methods and kit for treating Parkinson's disease |
US20040147581A1 (en) * | 2002-11-18 | 2004-07-29 | Pharmacia Corporation | Method of using a Cox-2 inhibitor and a 5-HT1A receptor modulator as a combination therapy |
US20040105889A1 (en) * | 2002-12-03 | 2004-06-03 | Elan Pharma International Limited | Low viscosity liquid dosage forms |
US20040138235A1 (en) * | 2002-12-19 | 2004-07-15 | Schering Corporation | Adenosine A2a receptor antagonists for the treatment of extra-pyramidal syndrome and other movement disorders |
US20050031667A1 (en) * | 2003-03-31 | 2005-02-10 | Patel Rajesh A. | Implantable polymeric device for sustained release of dopamine agonist |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040048779A1 (en) * | 2002-05-06 | 2004-03-11 | Erwin Schollmayer | Use of rotigotine for treating the restless leg syndrome |
WO2008001200A2 (en) * | 2006-06-29 | 2008-01-03 | Antares Pharma Ipl Ag | Transdermal composition having enhanced color stability |
WO2008001200A3 (en) * | 2006-06-29 | 2008-06-05 | Antares Pharma Ipl Ag | Transdermal composition having enhanced color stability |
US20080233179A1 (en) * | 2006-06-29 | 2008-09-25 | Arnaud Grenier | Transdermal composition having enhanced color stability |
EP1987815A1 (en) * | 2007-05-04 | 2008-11-05 | Schwarz Pharma Ag | Oronasopharyngeally deliverable pharmaceutical compositions of dopamine agonists for the prevention and/or treatment of restless limb disorders |
US20080274061A1 (en) * | 2007-05-04 | 2008-11-06 | Erwin Schollmayer | Method for Treating a Restless Limb Disorder |
US11179469B2 (en) | 2017-04-28 | 2021-11-23 | Nitto Denko Corporation | Transdermal absorption preparation |
Also Published As
Publication number | Publication date |
---|---|
EP1303278A1 (en) | 2003-04-23 |
DE10053397A1 (en) | 2002-05-02 |
ATE413177T1 (en) | 2008-11-15 |
JP2004512305A (en) | 2004-04-22 |
AU2001295512B2 (en) | 2006-09-21 |
DE50114474D1 (en) | 2008-12-18 |
AU9551201A (en) | 2002-05-06 |
ES2315309T3 (en) | 2009-04-01 |
WO2002034267A8 (en) | 2002-05-23 |
EP1303278B1 (en) | 2008-11-05 |
WO2002034267A1 (en) | 2002-05-02 |
US20040092544A1 (en) | 2004-05-13 |
US7258871B2 (en) | 2007-08-21 |
DK1303278T3 (en) | 2009-02-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20050214353A1 (en) | Transdermal therapeutic system | |
US20050220855A1 (en) | Transdermal therapeutic system | |
US20060105030A1 (en) | Transdermal therapeutic system | |
CA2029524C (en) | Transdermal administration of 2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole | |
EP0404807B1 (en) | Deprenyl for systemic transdermal administration | |
CA2535063C (en) | Medicament preparations for transdermal application containing active ingredient combinations for treating parkinson's disease | |
JP4925823B2 (en) | Transdermal therapeutic system containing pramipexole active agent | |
EP0708627A1 (en) | Method and device for providing nicotine replacement therapy transdermally/transbuccally | |
CZ289395A3 (en) | Transdermic therapeutic system for administration of serotonin agonists | |
CA2502142A1 (en) | Transdermal therapeutic systems | |
US20040219191A1 (en) | Use of a dopamine agonist with a short half-life for treating illnesses which can be treated by dopaminergic means | |
JP6978417B2 (en) | Pramipexole transdermal delivery system and its use | |
TW201813634A (en) | Pramipexole transdermal delivery system and uses thereof | |
TW200820996A (en) | Transdermal method and patch for emesis |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: NEUROBIOTEC GMBH, GERMANY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HOROWSKI, REINHARD;TACK, JOHANNES;WINDT-HANKE, FRED;AND OTHERS;REEL/FRAME:016696/0515;SIGNING DATES FROM 20050524 TO 20050530 |
|
AS | Assignment |
Owner name: NEUROBIOTEC PHARMA AG, GERMANY Free format text: MERGER;ASSIGNOR:NEUROBIOTEC GMBH;REEL/FRAME:019246/0212 Effective date: 20060830 |
|
AS | Assignment |
Owner name: AXXONIS PHARMA AG, GERMANY Free format text: CHANGE OF NAME;ASSIGNOR:NEUROBIOTEC PHARMA AG;REEL/FRAME:019246/0457 Effective date: 20070122 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |