CA2017442A1 - Transdermal therapeutic composition - Google Patents
Transdermal therapeutic compositionInfo
- Publication number
- CA2017442A1 CA2017442A1 CA002017442A CA2017442A CA2017442A1 CA 2017442 A1 CA2017442 A1 CA 2017442A1 CA 002017442 A CA002017442 A CA 002017442A CA 2017442 A CA2017442 A CA 2017442A CA 2017442 A1 CA2017442 A1 CA 2017442A1
- Authority
- CA
- Canada
- Prior art keywords
- water
- therapeutic composition
- transdermal therapeutic
- composition according
- transdermal
- 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
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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT
When a transdermal therapeutic composition which contains a pharmaceutically effective ingredient, a water-soluble absorption enhancer, a fat-soluble absorption enhancer and a super water-absorbent resin is applied to the skin of mammals, release of the pharmaceutically effective ingredient and the absorption enhancers is controlled and the pharmacological action lasts for a long period of time.
When a transdermal therapeutic composition which contains a pharmaceutically effective ingredient, a water-soluble absorption enhancer, a fat-soluble absorption enhancer and a super water-absorbent resin is applied to the skin of mammals, release of the pharmaceutically effective ingredient and the absorption enhancers is controlled and the pharmacological action lasts for a long period of time.
Description
2~7~2 TRANSDERMAL THERAPEUTIC CQMPOSITION
Industrial Field of Utilization This invention relates to a transdermal therapeutic composition which contains (i) a pharmaceutically effectivë ingredient, (ii) a water-soluble substance enhancing transdermal absorption of the pharmaceutically effective ingredient, (iii) a fat-soluble substance enhancing transdermal absorption of the pharmaceutically effective ingredient, and (iv) a super water-absorbent resin.
Prior Art Recently, there has been a great interest in a transdermal therapeutic system (TTS) which is a system designed to deliver a drug through the skin to implement the intended systemic effect, and several preparations have already been developed. Thus, nitroglycerol and isosorbide dinitrate, which are antianginal drugs, and clonid~ne which is a hypotensive agent have been available in TTS
preparations. 5ince drugs such as nitroglycerol msntioned above are per se readily absorbed through tne skin and exhibi~ pharmaceutical effects at a relatively low concentration in ~lood, ~hey can be formulated without great di~ficulties. On the other hand, since most of the drugs are poorly absorbed transdermally, it is necessary to enhance their transdermal absorption.
As the method of enhancing the absorption, mention is made of a method comprising incorporation of an absorption enhancer or a method resor~ing to iontophorasis or supersonic waves. While intensive studies on the promotion of transdermal absorption with the aid of an absorption enhancer have been made, no satisfactory result has been obtained yet. Several research efforts have been reported so far, and, among them, the present ~ 2 - 24205-~PJ~ 7 inventor~ reported that multl-lngredient absorption snhancor~ contalnin~ one or more specle3 of fat-~oluble ~ubskance~ promotiny ~,ran~dermal ab~orption o a pharmaceutically effective ingred.Lent, such as an S allphatlc carboxylic acid, it~ lower alcohol ester and an nliph~tic alcohol (hereinafteL sometimes abbreviated a~ ~at ~oluble absorption enhancer~) and one or more ~pecl~ o~ water-~oluble ~ub~tance~ promoting txan~dermal pbaorption oE a pharmaceutically e~fective in~rodi0n~, guch a~ an alkane polyol (hereina~ter ~omet1me~ ~bbrevl~ted as water-soluble ab~orption enhancers) are excellent ln the ab~orption-enhanclng effect and produce le~ lrrltatlon of the skin. These are ingredients that hav~ been u~ed prevlou~ly and been consldered preferable (a.e. the ~eclXlcat:lon o~ Japanese Patent ~ppllc~tion No. 63-222081).
~he amount~ o~ the~ multi~ingrediont absorption-; ~nhancor~ ~re experlmon~ally determ~ned in accordance with tho propertle~ o~ drugs or their concentration~ in blood. However, in the de~ign ~nd productlon of tr~n~dermal therapeutic compo~itionq, ~hexe are enaount~xed various problom~ cau~d by incorporation of ~ th~e multl-lngxedle~ ab~oxptiQn-enhancers. For : ex~m~le, problem~ with compatibillty between the above-men~ion~d ~t~soluble ~b~orp~.ton-enhancers an~ water-~olubl~ on~ ~r~ men~loned. Tho~e are ~ubstan~ially in~mpatibl~, ~nd, o~peciall~ in the c~e o~ tape8, po~ ~omp~bllity betwe~n ~he adh~siv~ and ~he ~b~orption~onh~nce~ ~hu~ smplo~ed o~en make~ it imposslble ~o pr~p~re intended ~apes or, e~en if intended ~pO8 could be prepared, ~para~lon oten ~ occur~ wl~h th~ lap~o o~ t iMe . Further, in ~ha casa o~
: prop~rin~ pla~er~, water-~oluble ingredion~ includlng wAtex ~nd ~t~olubl~ ingr~di0nt~ are, in most case~, incorpor~ted. Even ln thQse cases ~ compatibility i~ a problem. For 901~ing such problems as 2 ~ 4 ~
mentioned above, there has been known a method comprising incorporation of a surfactant or a polymer, such as polyvinyl pyrrolidone, having a surface-active property. However, depending on the properties or amounts of absorption-enhancers, o~ten these surfactants or polymers do not work effectively.
Therefore, transdermal absorption of a pharmaceutically effective ingredient is not performed as designed, so as to : display only insufficient pharmacological actions, which is a problem to be solved.
Problems that the Invention is to solve The present inventors unexpectedly found that, in the design and preparation of a transdermal therapeutic : 15 composition such as a plaster (tape) containing a pharmaceutically effective ingredient and a multi-ingredient absorption-enhancer compri ing a water-soluble one and fat-soluble one, separation of the fat-soluble ingredient from ~he water-soluble ingredient and separation of these ingredients from an adhesive are suppressed by incorporating a super water-absorbent resin into the composition. The present inventors also determined that a homogeneous transdenmal therapeutic composition of which the ~tability with the lapse of time is improved can be obtained, and they conducted ~` further research work and completed the present invention.
: ' Means of Solvina the Problems : 30 The present invention provides, as mentioned hereinbefore, a transdermal therapeutic composition .~ which co~tains (i) a pharmaceutically effective ingredient;
(ii) a water-soluble substance enhancing transdermal : 35 absorption of the pharmaceutically effective ingredient;
, ~ :
, (iii) a fat-soluble substance enhancing transdermal absorption of the pharmaceutically effective inyredient; and (iv) a super water-absorbent resin.
The "ingredient (i)", which is the pharmaceutically active ingredient to be used for the transdermal therapeutic composition of this invention, is preferably, taking the design of the composition into consideration, a drug having such a property as poor transdermal absorbability, but any one can be use~ so long as it is expected to exhibit systemic action through transdermal absorption. Practical examples of such drugs as above include cardiovascular drugs (e.g.
angiotensin I converting enzyme inhibitors such as (R)-3-[(S)-l-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2,-3,4,5-tetrahydro-1,5-henzothiazepin-5-acetic acid (hereinafter sometimes re~erred to as Compound (I)) [cf: JP-A-60-231668], Delapril and Captopril;
adrenaline ~-receptor blockers such as pindolol and propranolol; adrenaline a2-receptor agonists such as clonidine; Ca antagonists such as nifedipine; and other hypotensive agents; coronary vasodilators such as nitroglycerol, isosorbide dinitrate and molsidomine;
cardiotonic glycosides such as digoxin; peripheral vasodilators such as cyclandelate; and cerebral vasoactive agent such as vinpocetine, drugs for cerebral nerves system (e~g. neurotropic drugs such as diazepam and imipyramine, drugs for autonomic nerve system such as dl-methylephsdrine hydrochloride; drugs for anti-vertigo such as diphenhydramine; antipyretics and analgesics such as salicylic acid), drugs for respiratory diseases (e.g. bronchodilators such as epinephrine), drugs for digestive diseases (e.g.
dige~tive canal antispasmodics such as scoporamine), drugs for endocrinic metabolism ~e.g. antarthritics such as indomethacin; vitamins such as ~itamin D and 5 24205-~7~ ~
vi~amin E; polypeptide hormones such as LH-RH and TRH;
androgens such as testosterone; estrogens such as estradiol; adrenal cortical steroids such as corticosteroid), and anti-tumor drugs (e.g. 5-fluorouracil). These drugs can be incorporated in an optional amount, and the amount varies with the kind of drug and the purpose of use, etc., but an amount of 0.1 to 20~W/~) is usually preferable. And, the drugs may be either water-soluble ones or fat-soluble ones, and two or more of such drugs can be incorporated into a transdermal therapeutic composition so long as they do not cause undesirable effects by interaction among them.
As the super water-absorbent resin "ingredient (iv)", mention is made of such resins which are capable of absorbing water of several tens to more than one thousand times as much as its own weight, forming a hydrogel by swelling with water and not releasing water even under elevated pressure. Practical examples include saponified vinyl acetate-~; acrylic acid ester copolymers, polyacrylates, cross-linked polyvinyl alcohol-maleic anhydride copolymers, cross-linked isobutylene-maleic acid copolymexs, saponified polyacrylonitrile graft polymers, starch-acrylic acid graft polymers. Among them, polymers which are capable of absorbing water of about 50 to ~- 2000 times as much as ~heir own weight are preferable.
The amount of a supex water-absor~ent resin to be incorporated into a transdermal therapeutic composition ` 30 i5 optional, but, preferably, about 0.1 to 10%(W/W), `~- more preferably, about 0.5 to 5~(W/W).
The fat-soluble substance enhancing the transdermal ~-`; absorption of the pharmaceutically effective ingredient (fat-soluble absorption enhancer), which is used as "ingredient (iii)", includes, for example, aliphatic carboxylic acid containing 6 to 2a carbon atoms, lower ,~ .
- 6 ~ 2 alcohol esters thereof and aliphatic alcohol containing 6 to 20 carbon atoms.
The aliphatic carboxylic acid containing 6 to 20 carbon atoms includes, among others, saturated or unsaturated aliphatic monocarboxylic acids and dicarboxylic acids, such as caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachic acid, decenoic acid, linderic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, and sebacic acid. The lower : alcohol ester of aliphatic carboxylic acid containing 6 to 20 carbon atoms includes esters of the above-mentioned aliphatic carboxylic acids with lower alcohols containing 1 to about S carbon atoms (for example, methanol, ethanol, propanol, 2-propanol, butanol, pentanol). The lower alcohol ester of aliphatic dicarboxylic acid includes the mono- or diesters formPd as one or both of the available carboxyl groups are esterified. As examples a~ the lower alcohol ester of an aliphatic carboxylic acid containing 6 to 20 carbon atoms, there may be mentioned diethyl sebacate, isopropyl myristate and so on.
The aliphatic alcohol containing 6 to 20 carbon atoms includes saturated and unsaturated aliphatic alcohols such as caproyl alcohol, caprylyl alcohol, capryl alcohol, lauryl alcohol r myristyl alcohol, cetyl alcohol, ~tearyl alcohol, oleyl alcoholl linoleyl alcohol, and linolenyl alcohol.
Preferred, among the aliphatic carboxylic acids, lower alcohol esters thereof and aliphatic alcohols, is . an ester of an aliphatic monocarboxylic acid with a lower (C1g) alcohol. The most desirable is isopropyl myristate.
As the water-soluble substance enhancing transdermal absorption of the pharmaceutically effectiva ingredient (water-soluble absorption enhancer) [ingredient (ii)], mentio~ is made of, for example, an alkanepolyol, etc.
The alkanepolyol includes, among others, lower alkanediols containing about 2 to 5 carbon atoms, such as ethylene glycol (1,2-ethane~iol), propylene glycol (1,2-propanediol3, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 2,3-butanediol and 1,5-pentanediol, and low~r alkanetriols containing about 2 to 5 carbon atoms, such as glycProl. Particularly preferred 2re propylene glycol and 1,3-butanediol.
The above-mentioned absorption enhancer consists of one or more species of fat-soluble absorption enhancers and one or more species of water-soluble absorption enhancers. The proportion of fat-soluble absorption enhancers and water-soluble enhancer~ in the : 15 transdermal therapeutic composition is virtually optional, but preferably in the range of about 0.1 to ~ 80%(W/W), more preferably about 1 to 50%(W/W)-:~:
The aliphatic carboxylic acid or the aliphatic alcohol, which is used as ingredient (iii), is used in :/ a proportion of, prefera~ly, about 0.5 to 10% (W/W) - and, for still better results, about 0.5 to 5% (W~W) based on the total weight of the composition. The lower alcohol ester of an aliphatic carboxylic acid, ii which may also be u~ed as ingredient ~iii), is used in a proportion of, preferably, about 1 to 50% (W/W) and, for still better results, about 5 to 30% (W/W) on the same.hasis. When two or more kinds of aliphatic : carboxylic acids, lower alcohol esters of aliphatic carboxylic acids or aliphatic alcohols are used, the total amount o~ the aliphatic carbo~ylic acids is - preferably about 0.5 to 20~ (W/W) andl for still better results, about 0.5 to 10% (W/W), the total amount of the lower alcohol estexs of aliphatic carboxylic acids is preferably about 1 to 50% (W/W) and, for still `~ better results, about 5 to 30~ (W~W), and the total ~ ~ _L ~
amount of the aliphatic alcohols is preferably about 0.5 to 20% (W/W) and, for still better results, about 0.5 to 10% (W/W).
The proportion of the alkanepolyol in this 5 transdermal therapeutic composition, which is used as ingredient (ii), is preferably about 1 to 50% (W/W), for still better results, about 1 to 30% (W/W).
For insuring more uniform blending of the ingredients of this transdermal therapeutic 10 compo~ition, a nonionic suxfactant is preferably incorporated.
The nonionic surfactant includes, among others, polyoxyethylene sorbitan fatty acid esters (for example, polyoxyethylene sorbitan monooleate, ~5 polyoxyethylene sorbitan monosteara~e, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monolaurate, etc.), polyoxyethylene sorbitol fatty acid esters (for example, poIyoxyethylene sorbitol monolaurate etc.), polyoxyethylene fatty acid esters 20 (for example, polyoxyethylene stearate etc.), polyoxyethyl~ne higher alcohol ethers (for example, polyoxyethylene lauryl alcohol, polyoxyethylene oleyl alcohol, etc.), polyoxyethylene alkylaryl ethers (for example, polyoxyethylene nonylphenol etc.), 25 polyoxyethylene castor oil derivatives (~or example, polyoxyethylene hydrogenated castor oil derivatives such as HC0-50, and HCO 60, etc.), polyoxyethylene lanolin derivative~, polyoxyethylene lanolin alcohol deriv~tives, and block polymer nonionic surfactants 30 (for example, Pluronic L-62, L-64, F-68, etc.). The proportion of the nonionic surfactant(s) of which the HLB value ranges from 5 to 20 is optional based on the total compo~ition~ but preferably about 0.5 to 20~ and, for better re~ults, about 0.5 to 10~, and for still ; 35 better results, about 1 to 5%(W~W).
The transdermal therapeuti~ composition of this *Trade-mark /L ~
~ 9 --invention may further contain an inorganic base.
Examples of ~he inorganic base include alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkali metal hydrogencarbonate (e.g. sodium hydrogencarbonate, potassium hydrogencarbonate), etc.
The amount of the inorganic base to be added varies with the kinds of inorganic bases to be employed, but it ranges generally from 0.02 to 5%(W/W) so that the pH
of the resulting composition may be in the range of from 6 to 9. In the case that an alkali metal hydroxide or an alkali metal hydrogencarbonate is used as the inorganic base, the amount usually ranges from about 0.8 to about 1.2 mole relati~e to 1 mole of ~he pharmaceutically effective ingredient, and, in the case that an alkali metal carbonatQ is used as the inorganic base, the amount usually ranges from about 0.4 to about 0.6 mole relative to 1 mole of the pharmaceutically effective ingredient. Besides the above-mentioned inorganic bases, an acid such as hydrochloric acid, citric acid or the like may be further added. These ~; are added for dissolving the pharmaceutically effective ingredient, and, therefore, the amount to be added is optional.
- ~ The tran~dermal therapeutic composition of this invention is provided in such dosage forms as patch, cataplasma, ointment (inclusi~e of cream), hard ointment, tape, suppository, lotion, solution, suspension, emulsion and aerosol mist. ~mong them, -~ transdermal therapeutic plasters (e.g. patch, cataplasma, hard ointment, tape, etc.) are preferable.
The ointment (inclusive of cream), suppository, lo~ion, solution, suspension, emulsion and aerosol can be manufactured b~ formulating the above-mentioned ingredients (i), (ii), (iii) and (iv), and, if necessary, the nonionic surfactant, inorganic base and acid, with a solvent, suspending agent, emulsifi~r, 2420~-878 propellant, ointment base, suppository base, or the like, which are well known in pharmaceutical industry.
If necessary, a preservative (for example, ethyl p-hydroxybenzoate, benzalkonium chloride), antiphlogistic agent (for example, glycyrrhizinoic acid), etc. can be : further incorporatQd. The plasters such as patch, cataplasma, hard ointment and tape can be manufactured by mixing the above-mentioned ingredients (i~, (ii), (iii) and (iv), and, when necessary, the nonionic surfactant, inorganic base or acid, with a base which is well known in pharmaceutical industry and, if necessary, after addition of a preservative, an antiphlogistic agent, etc., subjecting the mixture to - absorption into, or adhesive to~ an appropriate support material. The support material may be a high polymer film, a web of woven or nonwoven fabric, a sheet of paper or the like. The adhesive agent to be used in ~ the manufacture of the patch, cataplasma or tape :: includes, among others, polyalXyl vinyl ether, ~: 20 polyalXyl ac~ylate (JP-B-58-23846~, polyisobutylene, natural rubber and synthetic ru~ber adhesives. For assuring suitabl plasticity and tackin~ss, animal oil for example, squalene~ squalane. etc.) or vegetable : oil (for exampl~, oliYe oil, ~ojoba oil, etc.), petrolatum, lanolin, etc. may be added.
In the manufacture of the ointment, hard ointment, supposito~y, tape, patch and cataplasma, there may ~e incorporated ingredients for modulating the transdermal absorption, such as lecithin and other phospholipids~
solid paraffin, bee~-wax, carnauba waxl hydrogenated castor oil, lanolin, petrolatum, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, glycerol fatty acid e~ter, cholesterol, Carbopol, carboxymethylcellulose, carboxyethylcellulose, silicone resin and a lower alcohol (for example, ethanol, i~opropyl alcohol, etc.).
*Trade-mark ~7~2 242~5-878 -- 11 ~
The solvent includes, among others, water, e~hanol and glycerol. The suspending agent and emulsifying agent include, among others, gum arabic, carboxymethylcellulose, methylcellulose ænd sodium S a~ginate. The aerosol propellant ln~ludes, among others, non-combustible liquefied gases (for example, freon 11, freon 12, freon 113, etc.). The ointment base includes, among others, petrolatum, solid paraffin, vegetable oil, animal oil, mineral oil, lanolin, waxes, and macrogols. The hard ointment includes, among others, bees-wax, paraffin, macrogols and glycerol fatty acid esters. The suppository base includes, among others, cacao butter, lanolin fat, macrogols, Witepsol and glycerogelatin.
The application of the transdermal therapeutic composition of this invention depends on symptoms of the subject. When compound (I) is applied to an adult human for the treatment of hypertension, about 1 to 200 mg, preferably about 10 to 150 mg, of compound (I) which is used as the pharmaceutically e~fective ingredient i5 used in a single dos~ge form and applied once in 1 to 7 days, preferably once a day (by sticking, coating, spraying or insertion into the rectum). And, when plasters are used, they may be applied to any part ~f the body.
The mixing of the respective ingredients and the manufacture of a transdermal therapeutic composition can be performed by the per se Xnown procedures such as those described in the~Japanese Pharmacopeia.
In case that ingredient (i) is a substance which can be dissolved in water in the presence or absence of an inorganic base or an acid or a substance which ca~ be dissolved in ingredient (ii3, i~ is pre~erable that ingredients ~i), (ii) and (iv) are first mixed in the presence of water ~o that ingredients (i~ and (ii3 with water can be absorbed int~ ingredient ~iv~ and that *Trade-mark ~7~
24205-~7 thP obtained mixture is then dispersed in ingredient ~iii) or a mixture of ingredient (iii) and a nonionic surfactant. Ingredient (iii) or a mixture of ingredient (iii) and a nonionic surfactant can be dissolved in a suitable organic solvent (e.g. ethyl acetate) before use. After dispersion, the obtained mixture is subjected to drying, if necessary.
When ingredient ~i) is a fat-soluble substance, it is preferable that ingredient (ii) and water are first absorbed into ingredient (iv) and that the obtained mixture is then dispersed in a mixture of ingredients (i) and (iii) or a mixture of ingredients (i) and (iii) and a nonionic surfactant. A mixture of ingredients li) and (iii) or a mixture of ingredients ti~ and (iii) with a nonionic surfactant can be dissolved in a suitable organic solvent (e.g. ethyl acetate) before use. After dispersion, the obtained mixture is subjected to drying, if necessary.
Actions and Effects In the transdermal therapeutic composition of this invention, due to in~orporation of a super water-absorbent resin, no separation of the ingredients from one another occurs. Therefore, release of ~he pharmaceutically effecti~e ingredient and ~he absorption enhancers is controlled, and transdermal absorption of the pharmaceutically effe~tive ingredient as designed is observed and the pharmacological action lasts for a sufficiently long period of time.
Therefore, the transdermal therapeutic composition of this in~ention can be applied ~o the skin of mammals (for example, human, monkey, dog, catl etc.) as a prophylactic and therapeutic agent for various diseases.
Examples The following examples are intended to illustrate the present invention in further detail and should not be construed as limiting the scope of the invention.
Example 1 [Preparation of a transdermal therapeutic plaster]
First, an aqueous phase was prepared by mixing and dissolving 10 g of Compound ~I), i.e. (R)-3-~S)-1-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid, an angiotensin con~erting enæyme inhibitor, 50 ml of w~ter, 20 g of propylene glycol, 1.15 g of NaOH and 1 g of a super water-absorbent resin [a vinyl ~cetate-acrylic acid ester copolymer hydrolyzate (Sumikagel SP-510, manufactured by Sumitomo Chemical Co., ~td.)]. On the other hand, an oily phase was prepared by mixing and dissolving, in ethyl acet~te, 43 g of a purified polymer fraction of polyalkyl acrylate adhesive [methyl acrylate-~-ethylhexyl acrylate copolymer emulsion, Nikasol TS-620, manufactured by Nippon Carbide Industries, Co., ~,td.], 5 g of Tween 80 and 20 g of isopropyl myristate. The above aqueous and oily pha~es were combined and mixed well, and a polyethylene sheet was coated with the mixture in a coverage corre~ponding to a dry thickness of about 100 ~m and dried at 80C
for 5 minutes. After drying, the coated sheet was covered with a separator (a release sheet) to provide a transdermal therapeutic plaster (tape).
[Transder%lal absorp~ion test~
; Using g-week-old male SD rats, the transdermal therapeutic tape (6 mg as compound (I)/rat) was applied to a clipped area (6 cm2) of the abdominal skin and the area of exposure was covered by the occluded dressing method. The transdermal absorption effect was evaluated daily by monitor.ing the inhibition rate [~) against hypertensive reaction by induced angiotensin I.
Angiotensin I was administered in an intravenous dose ~ rl~4~
24Z05-g78 of 300 ng/kg (rats). The degree and duration of absorption were evaluated using, as indexes, initiation and duration time of an inhibition of not less than 80% against hype~-tensive reaction induced by angiotensin I after the tape was administered.
~Results]
The transdermal therapeutic tape thus prepared had smooth surface and uniform thickness, without causing separation of the absorption enhancers and the adhesive even after storage at 40C for three months or at room temperature for six months. The compound (I) was sufficiently absorbed transdermally, and 80% inhibition against hypertensive reactivity induced by angiotensin I was observed fi~e hours after the administration and this ~- 15 effect lasted for longer ~han 24 hours.
Example 2 [Preparation of a transdermal therapeutic plaster]
First~ an aqueous phase was prepared by mixing and dissolving 15 g of Compound (I), 70 ml of water, 15 g of propylene glycol, 10 g of 1,3-butylenP glycol, 1.15 g of NaOH and 2 g of a super water-absorbent resin ~a vinyl acetate-acrylic acid ester copolymer hydrolyzate, Sumikagel SP-510, Sumitomo Chemical Co., Ltd.]. On the other hand, an oily phase was prepared by dissolving, in ethy} acetate, 38 g o~ polyalkyl vinyl ether adhesive [polyvinyl ethyl ether (Tg:-30C~/polyvinyl ethyl ether (Tg:-60C) = 60 parts/40 parts], 5 g of ~ween 80 and 15 g of isopropyl myristate. ~he above aqueous and oily phases were combined and mixed well, and a polyethylene sheet was coated with the mixture in the coverage corresponding to a dry thickness of about 100 ~m and dried at 100C for 3 minutes. After drying, the coated heet was covered with a separator to provide a transdermal therapeutic plaster (tape).
~Transdermal absorption test]
24~05-878 - 15 ~
The test procedure described in Example 1 was followed.
r ResultS ]
The transdermal th~rapeutic tape thus prepared had a smooth surface and uniform thickness, without causing separation of the absorption enhancers and the adhesive even after storage at 40C for three months or at room temperature for six months. The compound (I) was sufficiently absorbed transdermally, and 80% inhibition against hypertensive reaction by angiotensin I was observed three hours after the administration and this effect lasted for longer than 24 hours.
~xample 3 - 15 [Preparation of a transdermal therapeutic plaster]
First, an aqueous phase was pre~ared by mixing and ; dissolving 10 g of Compound (I), 50 ml of water, 20 g of propylene glycol, 1.15 g of NaOH and 1 g of a super :~ water-absorbent resin [polyacrylate, Sumikagel NP-1010 Sumitomo Chemical Co., Ltd.]. On the other hand, an oily phase was prepared by mixing and dissolving, in ethyl acetate, 50 g of a purified polymer fraction of a polyalkyl acrylate adhesive [methyl acrylate-2-ethylhexyl acxylate copolymer emulsion, Nikasol* TS-620, :~ 25 Nippon Carbide Industries, Co., Ltd.], 8 g of Tween* 20 and 10 g of oIeyl alcohol. ~he above a~ueous and oily phases were combined and mixed well, and a polyethylene sheet was coated with the mixture in a coverage corresponding to a dr~ thickness of about 100 ~m and dried at 80C for 5 minutes. After drying, the coated sheet was covered with a separator to provide a transdermal therapeutic plaster (tape).
tTransdermal absorption test]
The test procedure described in Example 1 was followed.
~Results ]
f~ ~ ~
The transdermal therapeutic tape thus prepared had smooth surface and uniform thic~ness, without causing separation of the absorption enhancers and the adhesive even after storage at 40C for three months or at room temperature for six months. The compound (I) was sufficiently absorbed transdermally, and 80% inhibition against hypertensive reaction by angiotensin I was observed five hours after the administration and this effect lasted for longer than 24 hours.
Example 4 [Preparation of a transdermal therapeutic plaster]
An aqueous phase was prepared by mixing and dissolving 15 g of Compound (I)l 30 ml of water, 20 g of propylene glycol, 1.3 g of NaOH and 1 g of a super water-absorbent resin [a vinyl acetate-acrylic arid ester copolymer hydrolyzate (Sumikagel SP-510, manufactured by Sumitomo Chemical Co., ~td.)]. On the other hand, an oily phase was prepared by mixing and dissolving, in ethyl acetate, 37.7 ~ of a polyalkyl acrylate adhesive ~a copol~mer prepared by polymerization of S5 weight parts of 2-ethylhexyl acrylate, 30 weight parts of methoxyethyl acrylate and 15 weight parts of vinyl a tate ~sing ethyl acetate as a Solvent], S g of Tween 80 and 20 g of isopropyl myristate. The above aqueous and oily phases were combined and mixed well, and a polyethylene sheet was coated with the mixture in a coverage corresponding to a dry thickne~s of about 100 ~m and dried at 70C for 5 minutes. After drying, the coated sheet was covered with a separator (a release sheet) to provide a transdermal therapeutic plaster (tape).
[Transdermal absorpkion test]
Using 9-week old male SD rats, the transdermal therapeutic tape ~9 mg as compound (I)/rat) was applied to a clipped area (6 cm2) of the abdominal skin and r~
24 ~05-87g the area of exposure was covered by the occluded dressing method. The test procedure described in Example l was followed.
LResults ]
S The transdermal therapeutic tape thus prepared had a smooth surface and uniform thickness, without causing separation of the absorption enhancers and the adhesive even after storage at 40C for three months or at room temperature for six months. The compound (I) was sufficiently absorbed transdermally, and 80% inhibition agains~ hypertensive reactivity by angiotensin I was observed five hours after the administration and this effect lasted for longer than 24 hours.
Example 5 [Preparation of transdermal therapeutic composition]
In a mixture of 16 g of propylene glycol and 5 g of water was dissolved 5 g of molsidomine (N-ethoxycarbonyl-3-morpholinosydnonimine~, and 1 g of Sumikagel SP-510 was further added. The mixture was homogeneously mixed with a homogenizer, and then 3 g of polysorbate 80 and 5 g of oleic acid were added. The resulting mixture was emulsified with a homogenizer, and 0.35 g of the emulsion was absorbed into a rayon web of nonwoven fabric and put into a silicone chamber having an area of 3 cm2 and a depth of 1 mm, to provi~e a transdermal tharapeutic composition.
[~herapeutic absorption test]
The above transd~rmal therapeutic composition was put on a clipped abdomen of male SD rats ~7-week-old, 240 to 270 g, 5 heads~ and fixed with a surgical tape.
After 1, 2, 4, 6 and 24 hours, the blood was collected from the tail vein, and the concentration of molsidomine in the plasma was determined by HPLC.
[Results]
As shown in Table 1, mol idomine was sufficiently , - 18 - 2420~-~78 absorbed so that a high concentration of molsidomine in the blood was observed.
Table 1 5Elapsed time after Average concentration a~ministration (h) in plasma (ng/ml) 1 123.0 2 234.9 4 451.4 6 321.6 24 169.2 On the other hand, 0.5 g of molsidomine was di~solved in 3 g of propyléne glycol, and 0.35 g of the solution was absorbed into a rayon web of nonwoven fabric and applied to SD rats in the same manner as mentioned abo~e. The concentration of molsidomine in the plasma was below the detection limit.
Example 6 [Preparation of transdermal therapeutic composition]
In a mixture of 20 g of propylene glycol and 5 g of water was dissolved 9 g of TRH ~-pyroglutamyl L-histidyl-L~prolinamide), and 1 g of Sumikagel SP-510 was further added. T~e mixture was homogeneously mixed with a homogenizer, and then 5 g of polysorbate 80 was added. The mixture was homogeneously mixed with a : homogenizer, and 20 g o~ isopropyl myristate were added. The re~ulting mixture was emulsified with a homogenizer, and 0..35 g of the emulsion was absorbed into a rayon web of nonwo~en fabric and put into a silicone chamber having an area of 3 cm2 and a depth of 1 mm, to provide a ~ransdermal therapeu~ic composition.
[Therapeutic absorption test3 The above transdermal ~herap~utic composition was put on a clipped abdomen of male SD rats (7-week-old, 240 to 270 g, 4 heads) and fixed with a surgical tape.
After 0.5, l, 2, 4, 6 and 24 hours, the blood was collected from the tail vein. After the blood was treated with heparin, 50 ~1 of a reagent (aqueous solution containing 0.01 g/l of 8-hydroxyquinoline sulfate, 0.15 g/l of EDTA-2Na and 0.05 g/l of Tween 20) was added to 0.5 ml of the blood to separate the plasma. The TRH concentration in the plasma was determined by the below-mentioned radioimmunoassay.
To 100 ~l of the separated plasma were added 100 ~1 of 0.7% bovine serum albumin, 100 ~l of anti-TRH
antibody (500-fold dilution) and 100 ~1 of 125I-labeled TRH (about 10000 dpm), and the resulting mixture was incubated at 4C for 3 days. The secondary antibody (100 ~1 of anti-7-globulin serum and 100 ~l of normal rabbit serum) was then added, and the mixture was incubated at 4C for 1 day. The supernatant was removed by centrifu~ation at 3000 rpm, and the radioactivity of the precipitate was determined by a 7 counterO
~Results3 As shown in ~able 2, th TRH concentration in the plasma rapidly increased, and the maximum concentration (about 400 ng/ml~ was observed 4 hours after the administration. Even after 24 hours, a high concentration of TRH was main~ained (82.4 ng/ml~.
~, .
" , , - 2~ -Table 2 Elapsed time afterAverage concentration administration (h)in plasma (ngtml) 0.5 59.0 1 88.9 2 110.0 4 3gl.3 Ç 325.7 24 82.4 On the other hand, 10% polyvinyl alcohol gel (pH 4, : ~ 15 buffered with 0.01M citric acid-0.01M disodium phosphate) containing 2% TRH was formulated to make the : diameter and thickness 3.2 cm and 0.1 cm respectively (sticking area: 8 cm2 ; TRH content: 16 mg), and applied to SD rats (4 heads) in the same manner as mentioned a~ove. The TRH concentration in the plasma was determined by the radioimmunoassay in the same manner as mentioned above. As shown in Table 3, the TRH concentration was very low.
Table 3 Elapsed time afterA~erage concentration administration (h)in plasma ~ng/ml) :
0.5 8.3 l 8.0 2 ~.5 6 1.8 Example 7 tPreparation of transdermal therapeutic composition]
In 5 g of lN hydrochloric acid was dissolved 2.15 g of vinpocetine (apovincamic acid ethyl ester), and 1 g of Sumikagel SP-510 was added. The mixture was homogeneously mixed with a homogenizer, and then 20 g of propylene glycol and 5 g of polysorbate 80 were added. The resulting mixture was homogeneously mixed, and then 20 g of isopropyl myristate was added. The resulting mixture was emulsified with a homogenizer, and 0.35 g of the emulsion was a~sorbed into a rayon web of nonwo~en fabric and put into a silicone chamber having an area of 3 cm2 and a depth of 1 mm to prepare a transdermal therapeutic composition.
t~ransdermal absorption test]
The above transdermal therapeutic composition was pu~ on a clipped abdomen of male SD rats (7-week-old, 240 to 270 g, 4 heads) and fixed with a surgical tape.
Just before the administration and after 0.5, 1, 2, 4, 6 and 24 hours, the blood was collected from ~he tail veinO After the blood was treated with heparin, the plasma was separated. The concentration of vinpocetine in the plasma was detexmined by HPLC after the plasma was cleaned up by Sep-Pak C18 (Waters).
tReSults ]
: 25 A8 shown in Table 4, the concentration of vinpocetine in the plasma rapidly increased, and the required concentration was maintained during ~ period of 24 hours.
*Trade-mark ;
~ ~ 7L~J,~
Table 4 .
Elapsed time afterAverage concentration administration (h)in plasma (ng/ml) Just before adminstration 0 0.5 149.3 1 155.4 2 80.1 4 60.7 : 6 74.1 24 64.3 _ ~: On the other hand, 0.35 g of 4% aqueous suspension :~ 15 of vinpocetine was absorbed into a web of nonwoven fabric and applied to SD rats in the same manner as mentioned above. The concentration of vinpocetine in the plasma was below the detection limit.
2~
~;:
~ . .
,
Industrial Field of Utilization This invention relates to a transdermal therapeutic composition which contains (i) a pharmaceutically effectivë ingredient, (ii) a water-soluble substance enhancing transdermal absorption of the pharmaceutically effective ingredient, (iii) a fat-soluble substance enhancing transdermal absorption of the pharmaceutically effective ingredient, and (iv) a super water-absorbent resin.
Prior Art Recently, there has been a great interest in a transdermal therapeutic system (TTS) which is a system designed to deliver a drug through the skin to implement the intended systemic effect, and several preparations have already been developed. Thus, nitroglycerol and isosorbide dinitrate, which are antianginal drugs, and clonid~ne which is a hypotensive agent have been available in TTS
preparations. 5ince drugs such as nitroglycerol msntioned above are per se readily absorbed through tne skin and exhibi~ pharmaceutical effects at a relatively low concentration in ~lood, ~hey can be formulated without great di~ficulties. On the other hand, since most of the drugs are poorly absorbed transdermally, it is necessary to enhance their transdermal absorption.
As the method of enhancing the absorption, mention is made of a method comprising incorporation of an absorption enhancer or a method resor~ing to iontophorasis or supersonic waves. While intensive studies on the promotion of transdermal absorption with the aid of an absorption enhancer have been made, no satisfactory result has been obtained yet. Several research efforts have been reported so far, and, among them, the present ~ 2 - 24205-~PJ~ 7 inventor~ reported that multl-lngredient absorption snhancor~ contalnin~ one or more specle3 of fat-~oluble ~ubskance~ promotiny ~,ran~dermal ab~orption o a pharmaceutically effective ingred.Lent, such as an S allphatlc carboxylic acid, it~ lower alcohol ester and an nliph~tic alcohol (hereinafteL sometimes abbreviated a~ ~at ~oluble absorption enhancer~) and one or more ~pecl~ o~ water-~oluble ~ub~tance~ promoting txan~dermal pbaorption oE a pharmaceutically e~fective in~rodi0n~, guch a~ an alkane polyol (hereina~ter ~omet1me~ ~bbrevl~ted as water-soluble ab~orption enhancers) are excellent ln the ab~orption-enhanclng effect and produce le~ lrrltatlon of the skin. These are ingredients that hav~ been u~ed prevlou~ly and been consldered preferable (a.e. the ~eclXlcat:lon o~ Japanese Patent ~ppllc~tion No. 63-222081).
~he amount~ o~ the~ multi~ingrediont absorption-; ~nhancor~ ~re experlmon~ally determ~ned in accordance with tho propertle~ o~ drugs or their concentration~ in blood. However, in the de~ign ~nd productlon of tr~n~dermal therapeutic compo~itionq, ~hexe are enaount~xed various problom~ cau~d by incorporation of ~ th~e multl-lngxedle~ ab~oxptiQn-enhancers. For : ex~m~le, problem~ with compatibillty between the above-men~ion~d ~t~soluble ~b~orp~.ton-enhancers an~ water-~olubl~ on~ ~r~ men~loned. Tho~e are ~ubstan~ially in~mpatibl~, ~nd, o~peciall~ in the c~e o~ tape8, po~ ~omp~bllity betwe~n ~he adh~siv~ and ~he ~b~orption~onh~nce~ ~hu~ smplo~ed o~en make~ it imposslble ~o pr~p~re intended ~apes or, e~en if intended ~pO8 could be prepared, ~para~lon oten ~ occur~ wl~h th~ lap~o o~ t iMe . Further, in ~ha casa o~
: prop~rin~ pla~er~, water-~oluble ingredion~ includlng wAtex ~nd ~t~olubl~ ingr~di0nt~ are, in most case~, incorpor~ted. Even ln thQse cases ~ compatibility i~ a problem. For 901~ing such problems as 2 ~ 4 ~
mentioned above, there has been known a method comprising incorporation of a surfactant or a polymer, such as polyvinyl pyrrolidone, having a surface-active property. However, depending on the properties or amounts of absorption-enhancers, o~ten these surfactants or polymers do not work effectively.
Therefore, transdermal absorption of a pharmaceutically effective ingredient is not performed as designed, so as to : display only insufficient pharmacological actions, which is a problem to be solved.
Problems that the Invention is to solve The present inventors unexpectedly found that, in the design and preparation of a transdermal therapeutic : 15 composition such as a plaster (tape) containing a pharmaceutically effective ingredient and a multi-ingredient absorption-enhancer compri ing a water-soluble one and fat-soluble one, separation of the fat-soluble ingredient from ~he water-soluble ingredient and separation of these ingredients from an adhesive are suppressed by incorporating a super water-absorbent resin into the composition. The present inventors also determined that a homogeneous transdenmal therapeutic composition of which the ~tability with the lapse of time is improved can be obtained, and they conducted ~` further research work and completed the present invention.
: ' Means of Solvina the Problems : 30 The present invention provides, as mentioned hereinbefore, a transdermal therapeutic composition .~ which co~tains (i) a pharmaceutically effective ingredient;
(ii) a water-soluble substance enhancing transdermal : 35 absorption of the pharmaceutically effective ingredient;
, ~ :
, (iii) a fat-soluble substance enhancing transdermal absorption of the pharmaceutically effective inyredient; and (iv) a super water-absorbent resin.
The "ingredient (i)", which is the pharmaceutically active ingredient to be used for the transdermal therapeutic composition of this invention, is preferably, taking the design of the composition into consideration, a drug having such a property as poor transdermal absorbability, but any one can be use~ so long as it is expected to exhibit systemic action through transdermal absorption. Practical examples of such drugs as above include cardiovascular drugs (e.g.
angiotensin I converting enzyme inhibitors such as (R)-3-[(S)-l-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2,-3,4,5-tetrahydro-1,5-henzothiazepin-5-acetic acid (hereinafter sometimes re~erred to as Compound (I)) [cf: JP-A-60-231668], Delapril and Captopril;
adrenaline ~-receptor blockers such as pindolol and propranolol; adrenaline a2-receptor agonists such as clonidine; Ca antagonists such as nifedipine; and other hypotensive agents; coronary vasodilators such as nitroglycerol, isosorbide dinitrate and molsidomine;
cardiotonic glycosides such as digoxin; peripheral vasodilators such as cyclandelate; and cerebral vasoactive agent such as vinpocetine, drugs for cerebral nerves system (e~g. neurotropic drugs such as diazepam and imipyramine, drugs for autonomic nerve system such as dl-methylephsdrine hydrochloride; drugs for anti-vertigo such as diphenhydramine; antipyretics and analgesics such as salicylic acid), drugs for respiratory diseases (e.g. bronchodilators such as epinephrine), drugs for digestive diseases (e.g.
dige~tive canal antispasmodics such as scoporamine), drugs for endocrinic metabolism ~e.g. antarthritics such as indomethacin; vitamins such as ~itamin D and 5 24205-~7~ ~
vi~amin E; polypeptide hormones such as LH-RH and TRH;
androgens such as testosterone; estrogens such as estradiol; adrenal cortical steroids such as corticosteroid), and anti-tumor drugs (e.g. 5-fluorouracil). These drugs can be incorporated in an optional amount, and the amount varies with the kind of drug and the purpose of use, etc., but an amount of 0.1 to 20~W/~) is usually preferable. And, the drugs may be either water-soluble ones or fat-soluble ones, and two or more of such drugs can be incorporated into a transdermal therapeutic composition so long as they do not cause undesirable effects by interaction among them.
As the super water-absorbent resin "ingredient (iv)", mention is made of such resins which are capable of absorbing water of several tens to more than one thousand times as much as its own weight, forming a hydrogel by swelling with water and not releasing water even under elevated pressure. Practical examples include saponified vinyl acetate-~; acrylic acid ester copolymers, polyacrylates, cross-linked polyvinyl alcohol-maleic anhydride copolymers, cross-linked isobutylene-maleic acid copolymexs, saponified polyacrylonitrile graft polymers, starch-acrylic acid graft polymers. Among them, polymers which are capable of absorbing water of about 50 to ~- 2000 times as much as ~heir own weight are preferable.
The amount of a supex water-absor~ent resin to be incorporated into a transdermal therapeutic composition ` 30 i5 optional, but, preferably, about 0.1 to 10%(W/W), `~- more preferably, about 0.5 to 5~(W/W).
The fat-soluble substance enhancing the transdermal ~-`; absorption of the pharmaceutically effective ingredient (fat-soluble absorption enhancer), which is used as "ingredient (iii)", includes, for example, aliphatic carboxylic acid containing 6 to 2a carbon atoms, lower ,~ .
- 6 ~ 2 alcohol esters thereof and aliphatic alcohol containing 6 to 20 carbon atoms.
The aliphatic carboxylic acid containing 6 to 20 carbon atoms includes, among others, saturated or unsaturated aliphatic monocarboxylic acids and dicarboxylic acids, such as caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachic acid, decenoic acid, linderic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, and sebacic acid. The lower : alcohol ester of aliphatic carboxylic acid containing 6 to 20 carbon atoms includes esters of the above-mentioned aliphatic carboxylic acids with lower alcohols containing 1 to about S carbon atoms (for example, methanol, ethanol, propanol, 2-propanol, butanol, pentanol). The lower alcohol ester of aliphatic dicarboxylic acid includes the mono- or diesters formPd as one or both of the available carboxyl groups are esterified. As examples a~ the lower alcohol ester of an aliphatic carboxylic acid containing 6 to 20 carbon atoms, there may be mentioned diethyl sebacate, isopropyl myristate and so on.
The aliphatic alcohol containing 6 to 20 carbon atoms includes saturated and unsaturated aliphatic alcohols such as caproyl alcohol, caprylyl alcohol, capryl alcohol, lauryl alcohol r myristyl alcohol, cetyl alcohol, ~tearyl alcohol, oleyl alcoholl linoleyl alcohol, and linolenyl alcohol.
Preferred, among the aliphatic carboxylic acids, lower alcohol esters thereof and aliphatic alcohols, is . an ester of an aliphatic monocarboxylic acid with a lower (C1g) alcohol. The most desirable is isopropyl myristate.
As the water-soluble substance enhancing transdermal absorption of the pharmaceutically effectiva ingredient (water-soluble absorption enhancer) [ingredient (ii)], mentio~ is made of, for example, an alkanepolyol, etc.
The alkanepolyol includes, among others, lower alkanediols containing about 2 to 5 carbon atoms, such as ethylene glycol (1,2-ethane~iol), propylene glycol (1,2-propanediol3, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 2,3-butanediol and 1,5-pentanediol, and low~r alkanetriols containing about 2 to 5 carbon atoms, such as glycProl. Particularly preferred 2re propylene glycol and 1,3-butanediol.
The above-mentioned absorption enhancer consists of one or more species of fat-soluble absorption enhancers and one or more species of water-soluble absorption enhancers. The proportion of fat-soluble absorption enhancers and water-soluble enhancer~ in the : 15 transdermal therapeutic composition is virtually optional, but preferably in the range of about 0.1 to ~ 80%(W/W), more preferably about 1 to 50%(W/W)-:~:
The aliphatic carboxylic acid or the aliphatic alcohol, which is used as ingredient (iii), is used in :/ a proportion of, prefera~ly, about 0.5 to 10% (W/W) - and, for still better results, about 0.5 to 5% (W~W) based on the total weight of the composition. The lower alcohol ester of an aliphatic carboxylic acid, ii which may also be u~ed as ingredient ~iii), is used in a proportion of, preferably, about 1 to 50% (W/W) and, for still better results, about 5 to 30% (W/W) on the same.hasis. When two or more kinds of aliphatic : carboxylic acids, lower alcohol esters of aliphatic carboxylic acids or aliphatic alcohols are used, the total amount o~ the aliphatic carbo~ylic acids is - preferably about 0.5 to 20~ (W/W) andl for still better results, about 0.5 to 10% (W/W), the total amount of the lower alcohol estexs of aliphatic carboxylic acids is preferably about 1 to 50% (W/W) and, for still `~ better results, about 5 to 30~ (W~W), and the total ~ ~ _L ~
amount of the aliphatic alcohols is preferably about 0.5 to 20% (W/W) and, for still better results, about 0.5 to 10% (W/W).
The proportion of the alkanepolyol in this 5 transdermal therapeutic composition, which is used as ingredient (ii), is preferably about 1 to 50% (W/W), for still better results, about 1 to 30% (W/W).
For insuring more uniform blending of the ingredients of this transdermal therapeutic 10 compo~ition, a nonionic suxfactant is preferably incorporated.
The nonionic surfactant includes, among others, polyoxyethylene sorbitan fatty acid esters (for example, polyoxyethylene sorbitan monooleate, ~5 polyoxyethylene sorbitan monosteara~e, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monolaurate, etc.), polyoxyethylene sorbitol fatty acid esters (for example, poIyoxyethylene sorbitol monolaurate etc.), polyoxyethylene fatty acid esters 20 (for example, polyoxyethylene stearate etc.), polyoxyethyl~ne higher alcohol ethers (for example, polyoxyethylene lauryl alcohol, polyoxyethylene oleyl alcohol, etc.), polyoxyethylene alkylaryl ethers (for example, polyoxyethylene nonylphenol etc.), 25 polyoxyethylene castor oil derivatives (~or example, polyoxyethylene hydrogenated castor oil derivatives such as HC0-50, and HCO 60, etc.), polyoxyethylene lanolin derivative~, polyoxyethylene lanolin alcohol deriv~tives, and block polymer nonionic surfactants 30 (for example, Pluronic L-62, L-64, F-68, etc.). The proportion of the nonionic surfactant(s) of which the HLB value ranges from 5 to 20 is optional based on the total compo~ition~ but preferably about 0.5 to 20~ and, for better re~ults, about 0.5 to 10~, and for still ; 35 better results, about 1 to 5%(W~W).
The transdermal therapeuti~ composition of this *Trade-mark /L ~
~ 9 --invention may further contain an inorganic base.
Examples of ~he inorganic base include alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkali metal hydrogencarbonate (e.g. sodium hydrogencarbonate, potassium hydrogencarbonate), etc.
The amount of the inorganic base to be added varies with the kinds of inorganic bases to be employed, but it ranges generally from 0.02 to 5%(W/W) so that the pH
of the resulting composition may be in the range of from 6 to 9. In the case that an alkali metal hydroxide or an alkali metal hydrogencarbonate is used as the inorganic base, the amount usually ranges from about 0.8 to about 1.2 mole relati~e to 1 mole of ~he pharmaceutically effective ingredient, and, in the case that an alkali metal carbonatQ is used as the inorganic base, the amount usually ranges from about 0.4 to about 0.6 mole relative to 1 mole of the pharmaceutically effective ingredient. Besides the above-mentioned inorganic bases, an acid such as hydrochloric acid, citric acid or the like may be further added. These ~; are added for dissolving the pharmaceutically effective ingredient, and, therefore, the amount to be added is optional.
- ~ The tran~dermal therapeutic composition of this invention is provided in such dosage forms as patch, cataplasma, ointment (inclusi~e of cream), hard ointment, tape, suppository, lotion, solution, suspension, emulsion and aerosol mist. ~mong them, -~ transdermal therapeutic plasters (e.g. patch, cataplasma, hard ointment, tape, etc.) are preferable.
The ointment (inclusive of cream), suppository, lo~ion, solution, suspension, emulsion and aerosol can be manufactured b~ formulating the above-mentioned ingredients (i), (ii), (iii) and (iv), and, if necessary, the nonionic surfactant, inorganic base and acid, with a solvent, suspending agent, emulsifi~r, 2420~-878 propellant, ointment base, suppository base, or the like, which are well known in pharmaceutical industry.
If necessary, a preservative (for example, ethyl p-hydroxybenzoate, benzalkonium chloride), antiphlogistic agent (for example, glycyrrhizinoic acid), etc. can be : further incorporatQd. The plasters such as patch, cataplasma, hard ointment and tape can be manufactured by mixing the above-mentioned ingredients (i~, (ii), (iii) and (iv), and, when necessary, the nonionic surfactant, inorganic base or acid, with a base which is well known in pharmaceutical industry and, if necessary, after addition of a preservative, an antiphlogistic agent, etc., subjecting the mixture to - absorption into, or adhesive to~ an appropriate support material. The support material may be a high polymer film, a web of woven or nonwoven fabric, a sheet of paper or the like. The adhesive agent to be used in ~ the manufacture of the patch, cataplasma or tape :: includes, among others, polyalXyl vinyl ether, ~: 20 polyalXyl ac~ylate (JP-B-58-23846~, polyisobutylene, natural rubber and synthetic ru~ber adhesives. For assuring suitabl plasticity and tackin~ss, animal oil for example, squalene~ squalane. etc.) or vegetable : oil (for exampl~, oliYe oil, ~ojoba oil, etc.), petrolatum, lanolin, etc. may be added.
In the manufacture of the ointment, hard ointment, supposito~y, tape, patch and cataplasma, there may ~e incorporated ingredients for modulating the transdermal absorption, such as lecithin and other phospholipids~
solid paraffin, bee~-wax, carnauba waxl hydrogenated castor oil, lanolin, petrolatum, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, glycerol fatty acid e~ter, cholesterol, Carbopol, carboxymethylcellulose, carboxyethylcellulose, silicone resin and a lower alcohol (for example, ethanol, i~opropyl alcohol, etc.).
*Trade-mark ~7~2 242~5-878 -- 11 ~
The solvent includes, among others, water, e~hanol and glycerol. The suspending agent and emulsifying agent include, among others, gum arabic, carboxymethylcellulose, methylcellulose ænd sodium S a~ginate. The aerosol propellant ln~ludes, among others, non-combustible liquefied gases (for example, freon 11, freon 12, freon 113, etc.). The ointment base includes, among others, petrolatum, solid paraffin, vegetable oil, animal oil, mineral oil, lanolin, waxes, and macrogols. The hard ointment includes, among others, bees-wax, paraffin, macrogols and glycerol fatty acid esters. The suppository base includes, among others, cacao butter, lanolin fat, macrogols, Witepsol and glycerogelatin.
The application of the transdermal therapeutic composition of this invention depends on symptoms of the subject. When compound (I) is applied to an adult human for the treatment of hypertension, about 1 to 200 mg, preferably about 10 to 150 mg, of compound (I) which is used as the pharmaceutically e~fective ingredient i5 used in a single dos~ge form and applied once in 1 to 7 days, preferably once a day (by sticking, coating, spraying or insertion into the rectum). And, when plasters are used, they may be applied to any part ~f the body.
The mixing of the respective ingredients and the manufacture of a transdermal therapeutic composition can be performed by the per se Xnown procedures such as those described in the~Japanese Pharmacopeia.
In case that ingredient (i) is a substance which can be dissolved in water in the presence or absence of an inorganic base or an acid or a substance which ca~ be dissolved in ingredient (ii3, i~ is pre~erable that ingredients ~i), (ii) and (iv) are first mixed in the presence of water ~o that ingredients (i~ and (ii3 with water can be absorbed int~ ingredient ~iv~ and that *Trade-mark ~7~
24205-~7 thP obtained mixture is then dispersed in ingredient ~iii) or a mixture of ingredient (iii) and a nonionic surfactant. Ingredient (iii) or a mixture of ingredient (iii) and a nonionic surfactant can be dissolved in a suitable organic solvent (e.g. ethyl acetate) before use. After dispersion, the obtained mixture is subjected to drying, if necessary.
When ingredient ~i) is a fat-soluble substance, it is preferable that ingredient (ii) and water are first absorbed into ingredient (iv) and that the obtained mixture is then dispersed in a mixture of ingredients (i) and (iii) or a mixture of ingredients (i) and (iii) and a nonionic surfactant. A mixture of ingredients li) and (iii) or a mixture of ingredients ti~ and (iii) with a nonionic surfactant can be dissolved in a suitable organic solvent (e.g. ethyl acetate) before use. After dispersion, the obtained mixture is subjected to drying, if necessary.
Actions and Effects In the transdermal therapeutic composition of this invention, due to in~orporation of a super water-absorbent resin, no separation of the ingredients from one another occurs. Therefore, release of ~he pharmaceutically effecti~e ingredient and ~he absorption enhancers is controlled, and transdermal absorption of the pharmaceutically effe~tive ingredient as designed is observed and the pharmacological action lasts for a sufficiently long period of time.
Therefore, the transdermal therapeutic composition of this in~ention can be applied ~o the skin of mammals (for example, human, monkey, dog, catl etc.) as a prophylactic and therapeutic agent for various diseases.
Examples The following examples are intended to illustrate the present invention in further detail and should not be construed as limiting the scope of the invention.
Example 1 [Preparation of a transdermal therapeutic plaster]
First, an aqueous phase was prepared by mixing and dissolving 10 g of Compound ~I), i.e. (R)-3-~S)-1-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid, an angiotensin con~erting enæyme inhibitor, 50 ml of w~ter, 20 g of propylene glycol, 1.15 g of NaOH and 1 g of a super water-absorbent resin [a vinyl ~cetate-acrylic acid ester copolymer hydrolyzate (Sumikagel SP-510, manufactured by Sumitomo Chemical Co., ~td.)]. On the other hand, an oily phase was prepared by mixing and dissolving, in ethyl acet~te, 43 g of a purified polymer fraction of polyalkyl acrylate adhesive [methyl acrylate-~-ethylhexyl acrylate copolymer emulsion, Nikasol TS-620, manufactured by Nippon Carbide Industries, Co., ~,td.], 5 g of Tween 80 and 20 g of isopropyl myristate. The above aqueous and oily pha~es were combined and mixed well, and a polyethylene sheet was coated with the mixture in a coverage corre~ponding to a dry thickness of about 100 ~m and dried at 80C
for 5 minutes. After drying, the coated sheet was covered with a separator (a release sheet) to provide a transdermal therapeutic plaster (tape).
[Transder%lal absorp~ion test~
; Using g-week-old male SD rats, the transdermal therapeutic tape (6 mg as compound (I)/rat) was applied to a clipped area (6 cm2) of the abdominal skin and the area of exposure was covered by the occluded dressing method. The transdermal absorption effect was evaluated daily by monitor.ing the inhibition rate [~) against hypertensive reaction by induced angiotensin I.
Angiotensin I was administered in an intravenous dose ~ rl~4~
24Z05-g78 of 300 ng/kg (rats). The degree and duration of absorption were evaluated using, as indexes, initiation and duration time of an inhibition of not less than 80% against hype~-tensive reaction induced by angiotensin I after the tape was administered.
~Results]
The transdermal therapeutic tape thus prepared had smooth surface and uniform thickness, without causing separation of the absorption enhancers and the adhesive even after storage at 40C for three months or at room temperature for six months. The compound (I) was sufficiently absorbed transdermally, and 80% inhibition against hypertensive reactivity induced by angiotensin I was observed fi~e hours after the administration and this ~- 15 effect lasted for longer ~han 24 hours.
Example 2 [Preparation of a transdermal therapeutic plaster]
First~ an aqueous phase was prepared by mixing and dissolving 15 g of Compound (I), 70 ml of water, 15 g of propylene glycol, 10 g of 1,3-butylenP glycol, 1.15 g of NaOH and 2 g of a super water-absorbent resin ~a vinyl acetate-acrylic acid ester copolymer hydrolyzate, Sumikagel SP-510, Sumitomo Chemical Co., Ltd.]. On the other hand, an oily phase was prepared by dissolving, in ethy} acetate, 38 g o~ polyalkyl vinyl ether adhesive [polyvinyl ethyl ether (Tg:-30C~/polyvinyl ethyl ether (Tg:-60C) = 60 parts/40 parts], 5 g of ~ween 80 and 15 g of isopropyl myristate. ~he above aqueous and oily phases were combined and mixed well, and a polyethylene sheet was coated with the mixture in the coverage corresponding to a dry thickness of about 100 ~m and dried at 100C for 3 minutes. After drying, the coated heet was covered with a separator to provide a transdermal therapeutic plaster (tape).
~Transdermal absorption test]
24~05-878 - 15 ~
The test procedure described in Example 1 was followed.
r ResultS ]
The transdermal th~rapeutic tape thus prepared had a smooth surface and uniform thickness, without causing separation of the absorption enhancers and the adhesive even after storage at 40C for three months or at room temperature for six months. The compound (I) was sufficiently absorbed transdermally, and 80% inhibition against hypertensive reaction by angiotensin I was observed three hours after the administration and this effect lasted for longer than 24 hours.
~xample 3 - 15 [Preparation of a transdermal therapeutic plaster]
First, an aqueous phase was pre~ared by mixing and ; dissolving 10 g of Compound (I), 50 ml of water, 20 g of propylene glycol, 1.15 g of NaOH and 1 g of a super :~ water-absorbent resin [polyacrylate, Sumikagel NP-1010 Sumitomo Chemical Co., Ltd.]. On the other hand, an oily phase was prepared by mixing and dissolving, in ethyl acetate, 50 g of a purified polymer fraction of a polyalkyl acrylate adhesive [methyl acrylate-2-ethylhexyl acxylate copolymer emulsion, Nikasol* TS-620, :~ 25 Nippon Carbide Industries, Co., Ltd.], 8 g of Tween* 20 and 10 g of oIeyl alcohol. ~he above a~ueous and oily phases were combined and mixed well, and a polyethylene sheet was coated with the mixture in a coverage corresponding to a dr~ thickness of about 100 ~m and dried at 80C for 5 minutes. After drying, the coated sheet was covered with a separator to provide a transdermal therapeutic plaster (tape).
tTransdermal absorption test]
The test procedure described in Example 1 was followed.
~Results ]
f~ ~ ~
The transdermal therapeutic tape thus prepared had smooth surface and uniform thic~ness, without causing separation of the absorption enhancers and the adhesive even after storage at 40C for three months or at room temperature for six months. The compound (I) was sufficiently absorbed transdermally, and 80% inhibition against hypertensive reaction by angiotensin I was observed five hours after the administration and this effect lasted for longer than 24 hours.
Example 4 [Preparation of a transdermal therapeutic plaster]
An aqueous phase was prepared by mixing and dissolving 15 g of Compound (I)l 30 ml of water, 20 g of propylene glycol, 1.3 g of NaOH and 1 g of a super water-absorbent resin [a vinyl acetate-acrylic arid ester copolymer hydrolyzate (Sumikagel SP-510, manufactured by Sumitomo Chemical Co., ~td.)]. On the other hand, an oily phase was prepared by mixing and dissolving, in ethyl acetate, 37.7 ~ of a polyalkyl acrylate adhesive ~a copol~mer prepared by polymerization of S5 weight parts of 2-ethylhexyl acrylate, 30 weight parts of methoxyethyl acrylate and 15 weight parts of vinyl a tate ~sing ethyl acetate as a Solvent], S g of Tween 80 and 20 g of isopropyl myristate. The above aqueous and oily phases were combined and mixed well, and a polyethylene sheet was coated with the mixture in a coverage corresponding to a dry thickne~s of about 100 ~m and dried at 70C for 5 minutes. After drying, the coated sheet was covered with a separator (a release sheet) to provide a transdermal therapeutic plaster (tape).
[Transdermal absorpkion test]
Using 9-week old male SD rats, the transdermal therapeutic tape ~9 mg as compound (I)/rat) was applied to a clipped area (6 cm2) of the abdominal skin and r~
24 ~05-87g the area of exposure was covered by the occluded dressing method. The test procedure described in Example l was followed.
LResults ]
S The transdermal therapeutic tape thus prepared had a smooth surface and uniform thickness, without causing separation of the absorption enhancers and the adhesive even after storage at 40C for three months or at room temperature for six months. The compound (I) was sufficiently absorbed transdermally, and 80% inhibition agains~ hypertensive reactivity by angiotensin I was observed five hours after the administration and this effect lasted for longer than 24 hours.
Example 5 [Preparation of transdermal therapeutic composition]
In a mixture of 16 g of propylene glycol and 5 g of water was dissolved 5 g of molsidomine (N-ethoxycarbonyl-3-morpholinosydnonimine~, and 1 g of Sumikagel SP-510 was further added. The mixture was homogeneously mixed with a homogenizer, and then 3 g of polysorbate 80 and 5 g of oleic acid were added. The resulting mixture was emulsified with a homogenizer, and 0.35 g of the emulsion was absorbed into a rayon web of nonwoven fabric and put into a silicone chamber having an area of 3 cm2 and a depth of 1 mm, to provi~e a transdermal tharapeutic composition.
[~herapeutic absorption test]
The above transd~rmal therapeutic composition was put on a clipped abdomen of male SD rats ~7-week-old, 240 to 270 g, 5 heads~ and fixed with a surgical tape.
After 1, 2, 4, 6 and 24 hours, the blood was collected from the tail vein, and the concentration of molsidomine in the plasma was determined by HPLC.
[Results]
As shown in Table 1, mol idomine was sufficiently , - 18 - 2420~-~78 absorbed so that a high concentration of molsidomine in the blood was observed.
Table 1 5Elapsed time after Average concentration a~ministration (h) in plasma (ng/ml) 1 123.0 2 234.9 4 451.4 6 321.6 24 169.2 On the other hand, 0.5 g of molsidomine was di~solved in 3 g of propyléne glycol, and 0.35 g of the solution was absorbed into a rayon web of nonwoven fabric and applied to SD rats in the same manner as mentioned abo~e. The concentration of molsidomine in the plasma was below the detection limit.
Example 6 [Preparation of transdermal therapeutic composition]
In a mixture of 20 g of propylene glycol and 5 g of water was dissolved 9 g of TRH ~-pyroglutamyl L-histidyl-L~prolinamide), and 1 g of Sumikagel SP-510 was further added. T~e mixture was homogeneously mixed with a homogenizer, and then 5 g of polysorbate 80 was added. The mixture was homogeneously mixed with a : homogenizer, and 20 g o~ isopropyl myristate were added. The re~ulting mixture was emulsified with a homogenizer, and 0..35 g of the emulsion was absorbed into a rayon web of nonwo~en fabric and put into a silicone chamber having an area of 3 cm2 and a depth of 1 mm, to provide a ~ransdermal therapeu~ic composition.
[Therapeutic absorption test3 The above transdermal ~herap~utic composition was put on a clipped abdomen of male SD rats (7-week-old, 240 to 270 g, 4 heads) and fixed with a surgical tape.
After 0.5, l, 2, 4, 6 and 24 hours, the blood was collected from the tail vein. After the blood was treated with heparin, 50 ~1 of a reagent (aqueous solution containing 0.01 g/l of 8-hydroxyquinoline sulfate, 0.15 g/l of EDTA-2Na and 0.05 g/l of Tween 20) was added to 0.5 ml of the blood to separate the plasma. The TRH concentration in the plasma was determined by the below-mentioned radioimmunoassay.
To 100 ~l of the separated plasma were added 100 ~1 of 0.7% bovine serum albumin, 100 ~l of anti-TRH
antibody (500-fold dilution) and 100 ~1 of 125I-labeled TRH (about 10000 dpm), and the resulting mixture was incubated at 4C for 3 days. The secondary antibody (100 ~1 of anti-7-globulin serum and 100 ~l of normal rabbit serum) was then added, and the mixture was incubated at 4C for 1 day. The supernatant was removed by centrifu~ation at 3000 rpm, and the radioactivity of the precipitate was determined by a 7 counterO
~Results3 As shown in ~able 2, th TRH concentration in the plasma rapidly increased, and the maximum concentration (about 400 ng/ml~ was observed 4 hours after the administration. Even after 24 hours, a high concentration of TRH was main~ained (82.4 ng/ml~.
~, .
" , , - 2~ -Table 2 Elapsed time afterAverage concentration administration (h)in plasma (ngtml) 0.5 59.0 1 88.9 2 110.0 4 3gl.3 Ç 325.7 24 82.4 On the other hand, 10% polyvinyl alcohol gel (pH 4, : ~ 15 buffered with 0.01M citric acid-0.01M disodium phosphate) containing 2% TRH was formulated to make the : diameter and thickness 3.2 cm and 0.1 cm respectively (sticking area: 8 cm2 ; TRH content: 16 mg), and applied to SD rats (4 heads) in the same manner as mentioned a~ove. The TRH concentration in the plasma was determined by the radioimmunoassay in the same manner as mentioned above. As shown in Table 3, the TRH concentration was very low.
Table 3 Elapsed time afterA~erage concentration administration (h)in plasma ~ng/ml) :
0.5 8.3 l 8.0 2 ~.5 6 1.8 Example 7 tPreparation of transdermal therapeutic composition]
In 5 g of lN hydrochloric acid was dissolved 2.15 g of vinpocetine (apovincamic acid ethyl ester), and 1 g of Sumikagel SP-510 was added. The mixture was homogeneously mixed with a homogenizer, and then 20 g of propylene glycol and 5 g of polysorbate 80 were added. The resulting mixture was homogeneously mixed, and then 20 g of isopropyl myristate was added. The resulting mixture was emulsified with a homogenizer, and 0.35 g of the emulsion was a~sorbed into a rayon web of nonwo~en fabric and put into a silicone chamber having an area of 3 cm2 and a depth of 1 mm to prepare a transdermal therapeutic composition.
t~ransdermal absorption test]
The above transdermal therapeutic composition was pu~ on a clipped abdomen of male SD rats (7-week-old, 240 to 270 g, 4 heads) and fixed with a surgical tape.
Just before the administration and after 0.5, 1, 2, 4, 6 and 24 hours, the blood was collected from ~he tail veinO After the blood was treated with heparin, the plasma was separated. The concentration of vinpocetine in the plasma was detexmined by HPLC after the plasma was cleaned up by Sep-Pak C18 (Waters).
tReSults ]
: 25 A8 shown in Table 4, the concentration of vinpocetine in the plasma rapidly increased, and the required concentration was maintained during ~ period of 24 hours.
*Trade-mark ;
~ ~ 7L~J,~
Table 4 .
Elapsed time afterAverage concentration administration (h)in plasma (ng/ml) Just before adminstration 0 0.5 149.3 1 155.4 2 80.1 4 60.7 : 6 74.1 24 64.3 _ ~: On the other hand, 0.35 g of 4% aqueous suspension :~ 15 of vinpocetine was absorbed into a web of nonwoven fabric and applied to SD rats in the same manner as mentioned above. The concentration of vinpocetine in the plasma was below the detection limit.
2~
~;:
~ . .
,
Claims (15)
1. A transdermal therapeutic composition which contains:
(i) a pharmaceutically effective ingredient;
(ii) a water-soluble substance which enhances transdermal absorption of the pharmaceutically effective ingredient;
(iii) a fat-soluble substance which enhances transdermal absorption of the pharmaceutically effective ingredient; and (iv) a super water-absorbent resin.
(i) a pharmaceutically effective ingredient;
(ii) a water-soluble substance which enhances transdermal absorption of the pharmaceutically effective ingredient;
(iii) a fat-soluble substance which enhances transdermal absorption of the pharmaceutically effective ingredient; and (iv) a super water-absorbent resin.
2. A transdermal therapeutic composition according to claim 1, wherein the transdermal absorption-enhancing water-soluble substance is an alkanediol containing 2 to 5 carbon atoms or an alkanetriol containing 2 to 5 carbon atoms.
3. A transdermal therapeutic composition according to claim 1, wherein the transdermal absorption-enhancing water-soluble substance is propylene glycol or 1,3-butanediol.
4. A transdermal therapeutic composition according to claim 1, wherein the transdermal absorption-enhancing fat-soluble substance is an aliphatic carboxylic acid containing 6 to 20 carbon atoms t an ester of an aliphatic carboxylic acid containing 6 to 20 carbon atoms with an alcohol containing 1 to 5 carbon atoms, or an aliphatic alcohol containing 6 to 20 carbon atoms.
5. A transdermal therapeutic composition according to claim 1, wherein the transdermal absorption-enhancing fat-soluble substance is an ester of an aliphatic monocarboxylic acid with an alcohol containing 1 to 5 carbon atoms.
6. A transdermal therapeutic composition according to claim 1, wherein the super water-absorbent resin is a polymer which is capable of absorbing water of about 50 to 2000 times as much as its own weight, and forming hydrogel by swelling with water.
7. A transdermal therapeutic composition according to claim 1, wherein the super water-absorbent resin is a vinyl acetate-acrylic acid ester copolymer hydrolyzate.
8. A transdermal therapeutic composition according to claim 1, wherein the pharmaceutically effective ingredient is an angiotensin converting enzyme inhibitor, an adrenaline .beta.-receptor blocker, an adrenaline .alpha.2-receptor agonist, a calcium antagonist, a coronary vasodilator, a cardiotonic glycoside, a peripheral vasodilator, a cerebral vasoactive agent, a neurotropic drug, a drug for autonomic nerve system, a drug for anti-vertigo, an antipyretic, an analgesic, a bronchodilator, a digestive canal antispasmodic, an antarthritic, a vitamin, a polypeptide hormone, an androgen, an estrogen, an adrenal cortical steroid, or an anti-tumor drug.
9. A transdermal therapeutic composition according to claim 1, wherein the pharmaceutically effective ingredient is an angiotensin converting enzyme inhibitor.
10. A transdermal therapeutic composition according to claim 1, wherein the pharmaceutically effective ingredient is (R)-3-[(S)-1-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5 acetic acid.
11. A transdermal therapeutic composition according to claim 1, which is in the form of patch, cataplasma, hard ointment or tape.
12. A transdermal therapeutic composition according to claim l, which contains (i) (R)-3-[(S)-1-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid, (ii) propylene glycol, (iii) isopropyl myristate, (iv) a vinyl acetate-acrylic acid ester copolymer hydrolyzate, (v) an inorganic base and water.
13. A transdermal therapeutic composition according to claim 12, wherein the inorganic base is sodium hydroxide.
14. A uniform transdermal therapeutic composition which comprises:
(i) 0.1 to 20 W/W % of a pharmaceutically effective ingredient;
(ii) 1 to 50 W/W % of a water-soluble substance which enhances transdermal absorption of the pharmaceutically effective ingredient and is selected from the group consisting of alkane-polyols having up to 5 carbon atoms;
(iii) 0.5 to 50 W/W % of a fat-soluble substance which enhances transdermal absorption of the pharmaceutically effective ingredient and is selected from the group consisting of aliphatic carboxylic acids having 6 to 20 carbon atoms, lower alcohol esters thereof and aliphatic alcohol having 6 to 20 carbon atoms; and (iv) a super water-absorbent resin which is capable of absorbing water of about 50 to 2,000 times as much as its own weight and of forming hydrogel by swelling with water, wherein:
(a) the total amount of the water-soluble substance (ii) and the fat-soluble substance (iii) is not more than 80 W/W %, and (b) the water-soluble substance (ii) and the fat-soluble substance (iii) are incompatible by themselves but are made compatible by the super water-absorbent resin (iv).
(i) 0.1 to 20 W/W % of a pharmaceutically effective ingredient;
(ii) 1 to 50 W/W % of a water-soluble substance which enhances transdermal absorption of the pharmaceutically effective ingredient and is selected from the group consisting of alkane-polyols having up to 5 carbon atoms;
(iii) 0.5 to 50 W/W % of a fat-soluble substance which enhances transdermal absorption of the pharmaceutically effective ingredient and is selected from the group consisting of aliphatic carboxylic acids having 6 to 20 carbon atoms, lower alcohol esters thereof and aliphatic alcohol having 6 to 20 carbon atoms; and (iv) a super water-absorbent resin which is capable of absorbing water of about 50 to 2,000 times as much as its own weight and of forming hydrogel by swelling with water, wherein:
(a) the total amount of the water-soluble substance (ii) and the fat-soluble substance (iii) is not more than 80 W/W %, and (b) the water-soluble substance (ii) and the fat-soluble substance (iii) are incompatible by themselves but are made compatible by the super water-absorbent resin (iv).
15. The transdermal therapeutic composition according to claim 14, wherein the super water-absorbent resin is selected from the group consisting of saponified vinyl acetate-acrylic acid ester copolymers, polyacrylates, cross-linked polyvinyl alcohol-maleic anhydride copolymers, cross-linked isobutylene-maleic anhydride copolymers, saponified polyacrylonitrile graft polymers, and starch-acrylic acid graft polymers and is employed in an amount of 0.1 to 10 W/W %.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13336489 | 1989-05-25 | ||
| JP133364-1989 | 1989-05-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2017442A1 true CA2017442A1 (en) | 1990-11-25 |
Family
ID=15102997
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002017442A Abandoned CA2017442A1 (en) | 1989-05-25 | 1990-05-24 | Transdermal therapeutic composition |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US5362497A (en) |
| EP (1) | EP0399432B1 (en) |
| JP (1) | JPH0372416A (en) |
| AT (1) | ATE107517T1 (en) |
| CA (1) | CA2017442A1 (en) |
| DE (1) | DE69010076T2 (en) |
Families Citing this family (82)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5252334A (en) * | 1989-09-08 | 1993-10-12 | Cygnus Therapeutic Systems | Solid matrix system for transdermal drug delivery |
| DE4210165A1 (en) * | 1991-07-30 | 1993-02-04 | Schering Ag | TRANSDERMAL THERAPEUTIC SYSTEMS |
| WO1993023019A1 (en) * | 1992-05-11 | 1993-11-25 | Sri International | Transdermal drug delivery systems and related compositions and methods of use |
| DE4305881C1 (en) * | 1993-02-26 | 1994-03-03 | Lohmann Therapie Syst Lts | Transdermal therapeutic system for topical and systemic application of active agents - includes cpd(s) from which nitrogen oxide is released by human or animal metabolism or cpds which release nitrogen oxide in organism |
| JPH0776527A (en) * | 1993-06-28 | 1995-03-20 | Hayashibara Biochem Lab Inc | Semi-solid preparation and production thereof |
| JPH09503997A (en) * | 1993-07-08 | 1997-04-22 | シグナス，インコーポレイテッド | Monolithic matrix transdermal delivery system |
| US5552153A (en) * | 1994-04-28 | 1996-09-03 | Hoffman-La Roche Inc. | Pharmaceutical composition for transdermal delivery |
| US5580574A (en) * | 1994-04-28 | 1996-12-03 | Hoffmann-La Roche Inc. | Pharmaceutical composition for transdermal delivery |
| US5888984A (en) | 1994-05-12 | 1999-03-30 | Dermal Research Laboratories, Inc. | Pharmaceutical composition of complex carbohydrates and essential oils and methods of using the same |
| GR1002079B (en) * | 1994-07-26 | 1995-12-05 | Lavipharm A E | System of a special structure and composition for the rapid transdermal administration of oestrogens. |
| DE4429663C2 (en) * | 1994-08-20 | 1997-09-11 | Lohmann Therapie Syst Lts | Transdermal therapeutic system with hydrolysis protection |
| EP0781122B1 (en) | 1994-09-14 | 2000-07-05 | Minnesota Mining And Manufacturing Company | Matrix for transdermal drug delivery |
| JP3908795B2 (en) * | 1994-11-29 | 2007-04-25 | 久光製薬株式会社 | Ketotifen-containing transdermal preparation |
| US5573778A (en) * | 1995-03-17 | 1996-11-12 | Adhesives Research, Inc. | Drug flux enhancer-tolerant pressure sensitive adhesive composition |
| JPH0912448A (en) * | 1995-04-28 | 1997-01-14 | Read Chem Kk | Medicine release-control type percutaneous absorptive formulation |
| US5861431A (en) * | 1995-06-07 | 1999-01-19 | Iotek, Inc. | Incontinence treatment |
| DE19526864A1 (en) * | 1995-07-22 | 1997-01-23 | Labtec Gmbh | Hormone patches |
| WO1997009971A2 (en) * | 1995-09-14 | 1997-03-20 | Cygnus, Inc. | High capacity, superabsorbent drug reservoirs for use in transdermal drug delivery systems |
| US6121508A (en) * | 1995-12-29 | 2000-09-19 | 3M Innovative Properties Company | Polar, lipophilic pressure-sensitive adhesive compositions and medical devices using same |
| AU1429697A (en) * | 1995-12-29 | 1997-07-28 | Cygnus, Inc. | Systems and methods for the transdermal administration of androgenic agents |
| SE9601665D0 (en) * | 1996-04-30 | 1996-04-30 | Bioglan Ab | Biologically active composition |
| AU2746397A (en) * | 1996-04-30 | 1997-11-19 | Theratech, Inc. | Transdermal administration of steroid hormones using diethanolamides of c12-c18 fatty acids as permeation enhancers |
| IT1283102B1 (en) * | 1996-06-06 | 1998-04-07 | Permatec Nv | THERAPEUTIC COMPOSITION FOR THE TRANSDERMAL ADMINISTRATION OF AN ESTROGENIC OR PROGESTINIC ACTIVE SUBSTANCE OR OF THEIR MIXTURES |
| US6060636A (en) * | 1996-09-04 | 2000-05-09 | Kimberly-Clark Worldwide, Inc. | Treatment of materials to improve handling of viscoelastic fluids |
| US6028016A (en) * | 1996-09-04 | 2000-02-22 | Kimberly-Clark Worldwide, Inc. | Nonwoven Fabric Substrates Having a Durable Treatment |
| US6296936B1 (en) | 1996-09-04 | 2001-10-02 | Kimberly-Clark Worldwide, Inc. | Coform material having improved fluid handling and method for producing |
| US6204208B1 (en) | 1996-09-04 | 2001-03-20 | Kimberly-Clark Worldwide, Inc. | Method and composition for treating substrates for wettability and skin wellness |
| US6017832A (en) * | 1996-09-04 | 2000-01-25 | Kimberly-Clark Worldwide, Inc. | Method and composition for treating substrates for wettability |
| KR100215027B1 (en) * | 1997-01-27 | 1999-08-16 | 성재갑 | Composition for transdermal administration of steroid drugs and formulation containing same |
| DE19728516C2 (en) * | 1997-07-04 | 1999-11-11 | Sanol Arznei Schwarz Gmbh | TTS for administration of levonorgestrel and possibly estradiol |
| CN1278737A (en) * | 1997-11-12 | 2001-01-03 | 阿尔萨公司 | Method for decreasing self-association of polypeptides |
| HUP0101439A3 (en) | 1998-03-04 | 2002-09-30 | Takeda Chemical Industries Ltd | Sustained-release preparation for a ii antagonist, production and use thereof |
| US6103771A (en) * | 1998-03-20 | 2000-08-15 | Caldwell Galer Incorporated | Method of treating neuroma pain |
| DE19820151A1 (en) * | 1998-05-06 | 1999-11-11 | Hexal Ag | Transdermal therapeutic system for the application of candesartan |
| US20020182260A1 (en) * | 1998-05-29 | 2002-12-05 | Cellegy Pharmaceuticals, Inc. | Anti-inflammatory agents and methods for their preparation and use |
| WO2000044367A2 (en) | 1999-02-01 | 2000-08-03 | Dermal Research Laboratories, Inc. | A pharmaceutical composition of complex carbohydrates and essential oils and methods of using the same |
| US6313370B1 (en) * | 1999-04-29 | 2001-11-06 | Morton Hyson | Medicated wrap |
| US20030104041A1 (en) * | 1999-12-16 | 2003-06-05 | Tsung-Min Hsu | Transdermal and topical administration of drugs using basic permeation enhancers |
| US6562370B2 (en) * | 1999-12-16 | 2003-05-13 | Dermatrends, Inc. | Transdermal administration of steroid drugs using hydroxide-releasing agents as permeation enhancers |
| US6562369B2 (en) * | 1999-12-16 | 2003-05-13 | Dermatrends, Inc. | Transdermal administration of androgenic drugs hydroxide-releasing agents as permeation enhancers |
| US6673363B2 (en) | 1999-12-16 | 2004-01-06 | Dermatrends, Inc. | Transdermal and topical administration of local anesthetic agents using basic enhancers |
| KR100452972B1 (en) * | 2000-05-16 | 2004-10-14 | 주식회사 삼양사 | Hydrogel composition for transdermal drug |
| DE10033855A1 (en) * | 2000-07-12 | 2002-01-31 | Hexal Ag | Transdermal therapeutic system for long-term treatment of hypertension, containing dicarboxylic acid angiotensin converting enzyme inhibitor converted into salt or ester derivative to improve stability |
| US7879824B2 (en) * | 2001-07-31 | 2011-02-01 | Dermal Research Laboratories, Inc. | Methods of preventing or treating diseases and conditions using complex carbohydrates |
| US6503894B1 (en) | 2000-08-30 | 2003-01-07 | Unimed Pharmaceuticals, Inc. | Pharmaceutical composition and method for treating hypogonadism |
| US20040092494A9 (en) * | 2000-08-30 | 2004-05-13 | Dudley Robert E. | Method of increasing testosterone and related steroid concentrations in women |
| US6479060B1 (en) | 2001-09-04 | 2002-11-12 | Healthpoint, Ltd. | Elegant hydrogenated castor oil ointments |
| US8323693B2 (en) * | 2002-03-14 | 2012-12-04 | Medrx Co., Ltd. | External preparation for wounds |
| US7572780B2 (en) | 2003-01-21 | 2009-08-11 | Dimera, Incorporated | Method and kit for reducing the symptoms of peripheral vascular disease |
| DE10304988A1 (en) * | 2003-02-07 | 2004-09-09 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system with improved skin adhesion |
| US9278155B2 (en) * | 2003-06-05 | 2016-03-08 | 3M Innovative Properties Company | Adhesive compositions, articles incorporating same and methods of manufacture |
| US20040247654A1 (en) * | 2003-06-05 | 2004-12-09 | 3M Innovative Properties Company | Hydrophilic adhesives for delivery of herbal medicines |
| NZ550963A (en) * | 2004-04-29 | 2008-11-28 | Caldwell Galer Inc | Topical methadone compositions and methods for using the same |
| JP2008512425A (en) * | 2004-09-09 | 2008-04-24 | ラボラトワール ブザン アンテルナスィヨナル | Testosterone gel with propylene glycol as a penetration enhancer |
| US8252319B2 (en) | 2004-10-21 | 2012-08-28 | Durect Corporation | Transdermal delivery system for sufentanil |
| SI1814531T1 (en) | 2004-10-21 | 2010-10-29 | Durect Corp | Transdermal delivery systems |
| TR201815853T4 (en) | 2005-10-12 | 2018-11-21 | Besins Healthcare Sarl | Testosterone gel for use in the treatment of hypogonadism. |
| EP2124907B1 (en) * | 2007-03-19 | 2018-05-30 | Vita Sciences, Llc | Transdermal patch and method for delivery of vitamin b12 |
| EP2339413B1 (en) * | 2009-12-22 | 2012-09-12 | The Swatch Group Research and Development Ltd. | Timepiece movement equipped with a vibrating alarm |
| US20120213717A1 (en) * | 2011-02-18 | 2012-08-23 | Mcneil-Ppc, Inc. | Soothing Agents |
| HUE055562T2 (en) | 2011-11-23 | 2021-11-29 | Therapeuticsmd Inc | Natural combination hormone replacement formulations and therapies |
| US9301920B2 (en) | 2012-06-18 | 2016-04-05 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
| US10806740B2 (en) | 2012-06-18 | 2020-10-20 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
| US10806697B2 (en) | 2012-12-21 | 2020-10-20 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| US20130338122A1 (en) | 2012-06-18 | 2013-12-19 | Therapeuticsmd, Inc. | Transdermal hormone replacement therapies |
| US20150196640A1 (en) | 2012-06-18 | 2015-07-16 | Therapeuticsmd, Inc. | Progesterone formulations having a desirable pk profile |
| US9180091B2 (en) | 2012-12-21 | 2015-11-10 | Therapeuticsmd, Inc. | Soluble estradiol capsule for vaginal insertion |
| US11246875B2 (en) | 2012-12-21 | 2022-02-15 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| US11266661B2 (en) | 2012-12-21 | 2022-03-08 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| US10471072B2 (en) | 2012-12-21 | 2019-11-12 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| US10568891B2 (en) | 2012-12-21 | 2020-02-25 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| US10537581B2 (en) | 2012-12-21 | 2020-01-21 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| WO2015025935A1 (en) * | 2013-08-23 | 2015-02-26 | 久光製薬株式会社 | Cataplasm and method for producing same |
| EP3145489A1 (en) | 2014-05-22 | 2017-03-29 | TherapeuticsMD, Inc. | Natural combination hormone replacement formulations and therapies |
| US20170348248A1 (en) * | 2014-12-22 | 2017-12-07 | Hisamitsu Pharmaceutical Co., Inc. | Gel Patch |
| US10328087B2 (en) | 2015-07-23 | 2019-06-25 | Therapeuticsmd, Inc. | Formulations for solubilizing hormones |
| US10286077B2 (en) | 2016-04-01 | 2019-05-14 | Therapeuticsmd, Inc. | Steroid hormone compositions in medium chain oils |
| BR112018070199A2 (en) | 2016-04-01 | 2019-01-29 | Therapeuticsmd Inc | pharmaceutical composition of steroid hormone |
| CN109922796B (en) | 2016-06-23 | 2023-04-07 | 考里安有限责任公司 | Adhesive matrix with hydrophilic and hydrophobic domains and therapeutic agents |
| KR102508993B1 (en) * | 2016-07-27 | 2023-03-10 | 코리움, 인크. | Memantine Transdermal Delivery System |
| ES2878331T3 (en) | 2018-10-15 | 2021-11-18 | Technocrats Corp | Clamping unit and mold extrusion mechanism with clamping unit |
| US11633405B2 (en) | 2020-02-07 | 2023-04-25 | Therapeuticsmd, Inc. | Steroid hormone pharmaceutical formulations |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1165240A (en) * | 1980-07-09 | 1984-04-10 | The Procter & Gamble Company | Penetrating topical pharmaceutical compositions |
| JPS5948413A (en) * | 1982-09-14 | 1984-03-19 | Grelan Pharmaceut Co Ltd | Anti-inflammatory and analgesic agent for external use containing clidanac |
| DE3305689A1 (en) * | 1983-02-18 | 1984-08-23 | Mack Chem Pharm | PHARMACEUTICAL PREPARATION WITH RETARDIVE EFFECT |
| EP0127426A1 (en) * | 1983-05-23 | 1984-12-05 | Takeda Chemical Industries, Ltd. | Percutaneous pharmaceutical compositions for external use |
| DK243084A (en) * | 1983-05-26 | 1984-11-27 | Takeda Chemical Industries Ltd | PERCUTANEOUS PHARMACEUTICAL PREPARATIONS FOR EXTERNAL USE |
| US4879119A (en) * | 1984-02-21 | 1989-11-07 | Yamanouchi Pharmaceutical Co., Ltd. | Patch |
| IL74004A (en) * | 1984-03-24 | 1991-12-15 | Takeda Chemical Industries Ltd | 3-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine derivatives,their production and pharmaceutical compositions containing them |
| US4626539A (en) * | 1984-08-10 | 1986-12-02 | E. I. Dupont De Nemours And Company | Trandermal delivery of opioids |
| DE3569368D1 (en) * | 1984-11-30 | 1989-05-18 | Fisons Plc | Angiotensin converting enzyme inhibitors and their production and use as pharmaceuticals |
| US4656188A (en) * | 1985-10-09 | 1987-04-07 | Merck & Co., Inc. | Ace inhibitors in macular degeneration |
| US4789547A (en) * | 1987-06-17 | 1988-12-06 | Warner-Lambert Company | Transdermal matrix system |
-
1990
- 1990-05-21 AT AT90109593T patent/ATE107517T1/en not_active IP Right Cessation
- 1990-05-21 DE DE69010076T patent/DE69010076T2/en not_active Expired - Fee Related
- 1990-05-21 EP EP90109593A patent/EP0399432B1/en not_active Expired - Lifetime
- 1990-05-24 JP JP2136332A patent/JPH0372416A/en active Pending
- 1990-05-24 CA CA002017442A patent/CA2017442A1/en not_active Abandoned
-
1992
- 1992-01-13 US US07/820,020 patent/US5362497A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| ATE107517T1 (en) | 1994-07-15 |
| DE69010076D1 (en) | 1994-07-28 |
| EP0399432A3 (en) | 1991-05-22 |
| EP0399432B1 (en) | 1994-06-22 |
| DE69010076T2 (en) | 1994-12-08 |
| EP0399432A2 (en) | 1990-11-28 |
| US5362497A (en) | 1994-11-08 |
| JPH0372416A (en) | 1991-03-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0399432B1 (en) | Transdermal therapeutic composition | |
| EP0698393B1 (en) | 3-l-MENTHOXY-PROPANE-1, 2-DIOL AS SOLUBILIZING AGENT AND EXTERNAL PREPARATION CONTAINING THE SAME | |
| JP3778937B2 (en) | Pharmaceutical composition for transdermal delivery | |
| CA2222133C (en) | Transdermal patch and method for administering 17-deacetyl norgestimate alone or in combination with an estrogen | |
| US4933184A (en) | Menthol enhancement of transdermal drug delivery | |
| US5654337A (en) | Topical formulation for local delivery of a pharmaceutically active agent | |
| KR100452972B1 (en) | Hydrogel composition for transdermal drug | |
| US4906475A (en) | Estradiol transdermal delivery system | |
| US5026556A (en) | Compositions for the transdermal delivery of pharmaceutical actives | |
| US9364487B2 (en) | Dermal delivery compositions and methods | |
| US4789547A (en) | Transdermal matrix system | |
| JPH041127A (en) | Plaster for medical treatment | |
| CA2101496A1 (en) | Base for transdermal administration | |
| JP2007007189A (en) | External treatment composition, plaster, and percutaneous absorption medicine | |
| US5811117A (en) | Percutaneously absorbable preparation containing cohesive strength improving agent | |
| JP2003313122A (en) | Bisoprolol-containing plaster | |
| JP2003530354A (en) | Compositions for use as permeation enhancers for highly lipophilic active ingredients in transdermal formulations | |
| US4837025A (en) | Self-adhesive device for the percutaneous administration of an active ingredient | |
| JPH02115119A (en) | Automatic adhesive apparatus for percutaneous administration of effective component | |
| US20130211352A1 (en) | Percutaneously absorbed preparation | |
| JPH0753671B2 (en) | Transdermal / transmucosal preparation | |
| JPH09208469A (en) | Percutaneous absorption pasting agent | |
| JPH062666B2 (en) | Patch | |
| KR19980053291A (en) | Percutaneous Absorption of Diclofenac Sodium | |
| JPH09169636A (en) | Plaster |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |