WO2000002537A1 - Composition containing glycerol trinitrate, method for producing said composition and use of the same - Google Patents

Composition containing glycerol trinitrate, method for producing said composition and use of the same Download PDF

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Publication number
WO2000002537A1
WO2000002537A1 PCT/EP1999/004610 EP9904610W WO0002537A1 WO 2000002537 A1 WO2000002537 A1 WO 2000002537A1 EP 9904610 W EP9904610 W EP 9904610W WO 0002537 A1 WO0002537 A1 WO 0002537A1
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WO
WIPO (PCT)
Prior art keywords
active ingredient
self
glycerol trinitrate
preparation
vinyl acetate
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PCT/EP1999/004610
Other languages
German (de)
French (fr)
Inventor
Achim Berthold
Original Assignee
Lts Lohmann Therapie-Systeme Ag
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Publication date
Application filed by Lts Lohmann Therapie-Systeme Ag filed Critical Lts Lohmann Therapie-Systeme Ag
Priority to PL99345545A priority Critical patent/PL345545A1/en
Priority to IL14073999A priority patent/IL140739A0/en
Priority to KR1020017000346A priority patent/KR20010074687A/en
Priority to EP99931244A priority patent/EP1094793A1/en
Priority to CA002336704A priority patent/CA2336704A1/en
Priority to BR9911984-6A priority patent/BR9911984A/en
Priority to JP2000558797A priority patent/JP2002520268A/en
Priority to AU47814/99A priority patent/AU4781499A/en
Priority to MXPA01000127A priority patent/MXPA01000127A/en
Publication of WO2000002537A1 publication Critical patent/WO2000002537A1/en

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • composition containing glycerol trinitrate process for its preparation and its use
  • the invention relates to a preparation for the transdermal therapeutic application of glycerol trinitrate through human skin into an organism, containing a therapeutically effective portion of the active ingredient in a polyacrylate-based self-adhesive layer with an active ingredient-impermeable backing layer, furthermore a process for the preparation of the preparation and its use.
  • the preparation is aimed at a continuous and constantly meterable delivery of glycerol trinitrate to or through the skin, whereby it serves as an active substance reservoir.
  • Patches for the transdermal delivery of medicinally active substances have been known for many years and are used successfully in medicine. With the known preparations, a slow and metered release of the substances is generally to be achieved, the preparation serving as an active ingredient depot. It is desirable that the active ingredient is released slowly and over a longer period of time.
  • the transdermal application has the great advantage that the intestinal and the hematological first pass effect is avoided. As a result, the bioavailability of substances that are subject to strong metabolism during the absorption process from the intestine and the first passage through the liver is increased. Furthermore, the repeated daily application of substances with a short elimination half-life can be avoided since the plasma curves obtained with a transdermal system are similar to those of a continuous infusion.
  • Active agents that are customary in therapy and are used for prophylaxis or for the treatment of coranary heart disease are organic esters of nitric acid. Glycerol trinitrate is preferably used. This active ingredient relaxes the smooth vascular muscles, leads to peripheral vasodilation and reduces the cardiac preload and afterload.
  • Glycerol trinitrate also reduces the extravascular component of the conor resistance and thereby improves the oxygen supply.
  • Acute attacks of angina pectoris can be treated quickly and effectively by sublingual glycerol trinitrate.
  • This type of application quickly leads to a high concentration of active substances in the plasma.
  • the plasma half-life of glycerol trinitrate is only 1-3 minutes, the plasma concentration flattens very quickly and does not maintain the plasma concentration in the therapeutic range over a longer period of time. Sublingual administration is therefore not suitable for seizure prophylaxis.
  • Transdermal administration is more suitable for preventing angina pectoris attacks.
  • the systemic uptake of glycerol trinitrate through the skin is about 20 ⁇ g / cm 2 / h, depending on the application site. It is advantageous here that the biological availability is not seriously reduced as a result of circumventing the extensive intestinal or hepatic first-pass effect.
  • a bioavailability of approximately 70% results when glycerol trinitrate is administered transdermally.
  • the stratum corneum of the skin and the size of the application area are decisive factors for the amount of active ingredient circulating in the blood.
  • a relatively constant steady state plasma concentration is achieved over a longer period of time.
  • the steady-state plasma concentration depends on the dose of the patch and the corresponding absorption rate. With an absorption tion rate of 0.4 mg / h, for example, the plasma concentration averages 0.2 ⁇ l / 1.
  • transdermal administration of glycerol trinitrate is the method of choice for effective angina pectoris prophylaxis.
  • glycerol trinitrate Numerous preparations for the transdermal application of glycerol trinitrate are state of the art. Patch-like systems are predominant. Glycerol trinitrate is either dissolved or adsorbed on an auxiliary. Simple matrix systems, for example in accordance with US Pat. No. 4,751,087, are also known as complex reservoir systems, for example in accordance with US Pat. No. 4,725,272, and systems which contain the active ingredient in microcapsules, for example in accordance with US Pat. No. 3,742,951 and US Pat. No. 4,336,243.
  • the active ingredient is released from the preparation to a therapeutically effective extent and then the skin is permeated. While the release properties of the preparation are determined by active substances and auxiliary substances, the transdermal absorption of the active substance is decisively determined by the stratum corneum of the skin. The absorption can be increased by using additives which improve performance.
  • the use of N-methyl-2-pyrrolidone and oleic acid to increase the glycerol trinitrate absorption is described in US Pat. No. 5,262,165.
  • Synthetic acrylate polymers are often used as a preparation base due to their non-allergenic character, for example according to US 4,505,891.
  • the disadvantage is that most acrylate polymers dissolve glycerol trinitrate very well.
  • the good solubility is synonymous with low thermodynamic activity.
  • glycerol trinitrate must therefore be used in a high concentration. be worked to achieve a therapeutically satisfactory release of active ingredients.
  • EP 0 622 075 A1 describes a preparation which contains glycerol trinitrate in a concentration of 50-65% by weight.
  • the disadvantage of such high amounts of glycerol trinitrate is due to its properties. Glycerol trinitrate reacts adversely to thermal and mechanical loads with explosions or leads to undesirable changes in the adhesive properties e.g. to reduce stickiness, adhesion and cohesion.
  • US Pat. No. 5,474,783 describes the possibility of modifying the thermodynamic activity of acrylate polymers by adding a polysiloxane.
  • Polysiloxanes have a low solubility for glycerol trinitrate, which reduces the overall solubility in the preparation. The reduced saturation solubility is reflected in an increased release rate. The release kinetics can be controlled by varying the amount of polysiloxane added. Since the system described is a multi-phase system, segregation and thus inhomogeneities can occur during production.
  • the present invention is based on the object of specifying a preparation for the transdermal therapeutic application of glycerol trinitrate by human skin of the type mentioned in the preamble of claim 1 and a process for its preparation which develops a high thermodynamic activity while overcoming the aforementioned difficulties and technical limits, in order to avoid the problems caused by avoiding comparatively high proportions of the active ingredient glycerol trinitrate and, with significantly increased bioavailability, to enable effective drug therapy with long-lasting and constantly controllable active ingredient release, which it is also inexpensive to manufacture and user-friendly to use.
  • a self-adhesive composition based on polyacrylate is used for the active substance-containing layer
  • the concentration of active substance in the mass is at most 25% by weight.
  • the preparation has a high thermodynamic activity, which ensures a high release rate when using small amounts of active ingredient.
  • This high thermodynamic activity is achieved by reducing the saturation solubility of the corresponding active ingredient.
  • This can be achieved by using a base material for the preparation, which as such has a low solubility in the active ingredient, and avoiding additives which lead to an increase in the solubility of the active ingredient.
  • a self-adhesive composition based on polyacrylate is used for the composition according to the invention.
  • the mass is characterized according to the invention in that the vinyl acetate content is at most 6% by weight.
  • This reduction in the vinyl acetate content is due to the fact that, as will be demonstrated in the following, vinyl acetate leads to a decrease in the release rate of glycerol trinitrate with increasing concentration.
  • vinyl acetate is used both as a copolymer of the acrylate polymer and as a set homopolymer reduces the release rate.
  • the glycerol trinitrate content is generally in a range from 10-30% by weight, preferably below 25% by weight.
  • FIG. 1 shows the rate of peracetate of glycerol trinitrate through an artificial membrane as a function of the vinyl acetate concentration of a polyacrylate composition.
  • vinyl acetate in the form of a homopoly er polyvinyl acetate
  • the figure shows that the permeation rate or release rate is increasingly increased as the vinyl acetate content decreases.
  • FIG. 2 describes the permeation of glycerol trinitrate through whole human skin.
  • a vinyl acetate-free polyacrylate composition shown as filled squares, or a polyacrylate-vinyl acetate copolymer, shown as empty circles, were used to produce the compositions. It can be seen that the use of vinyl acetate-free polyacrylate increases the degree of permeation through the full human skin.
  • the decrease in permeation caused by vinyl acetate can be explained by an increased solubility of glycerol trinitrate in the self-adhesive polyacrylate composition.
  • Vinyl acetate acts as a solubilizer. Due to the increased solubility, the migration of the active substance from the mass into a membrane is reduced, since a substance is distributed between two phases in accordance with the saturation solubility. As a result, permeation is also reduced because the flow of active substance through a membrane is in a proportional relationship to the distribution coefficient.
  • the self-adhesive composition based on polyacrylate used to produce a composition according to the invention is characterized in that acrylic acid and / or alkyl acrylic acid, in particular methacrylic acid or their derivatives, in particular the alkyl esters, are used for their preparation.
  • alkyl esters those with 1 to 18 carbon atoms in the alkyl radical are preferred, in particular methyl, ethyl, n-butyl, isobutyl, pentyl, 2-ethylbutyl, n-hexyl, heptyl, n-octyl, Isooctyl, 2-ethylhexyl, n-decyl, isodecyl, n-dodecyl and stearyl acrylate or methacrylate.
  • other comonomers can be involved in the construction of the polymer / copolymer.
  • Examples are acrylic and / or methacrylamide, hydroxyalkyl esters and polyalkylene glycol esters of acrylic and / or methacrylic acid, nitrogen-containing monomers of acrylic and / or methacrylic acid or their salts, ethylene, vinyl acetate, vinyl propionate, vinyl butyrate,. Vinyl pyrrolidone, vinyl chloride, vinyl toluene, acrylonitrile, styrene and the like.
  • a backing layer connected to the self-adhesive composition. This is impermeable to the active ingredient and has an occlusive character.
  • Any materials that are used in conventional preparations can be used. Examples of such materials are cellulose acetate, ethyl cellulose, polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymers, nylon, ethylene-vinyl acetate copolymers, plasticized polyvinyl chloride, polyurethane, polyvinylidene chloride, polypropylene, polyethylene, polyamide or aluminum.
  • the composition may further contain: tackifiers, penetration enhancers or agents for relieving skin irritation and metal ions, for example aluminum or titanium.
  • Plasticizers, paraffins, cyclic hydrocarbons or vegetable oils can be added to increase cohesion. Rosin, polyterpene resin, petroleum resin, coumarone-indene resin, terpene-phenol resin, hydrocarbon resin or liquid polybutene resin can be used as an agent for increasing the stickiness.
  • agents which improve the penetration of the active ingredient are: pyrrolidone derivatives, fatty acids, fatty alcohols, fatty acid esters, fatty ethers, paraffin derivatives, terpenes, ethylene glycol monoalkyl ethers, polyoxyethylene alkyl ethers, polyoxyethylene aryl ethers, polyoxyethylene alkyl esters, polyoxypropylene alkyl ethers, propylene glycol ester polyglyceramate fatty acid derivatives, glycerol fatty acid derivatives, Dialkyl sulfoxides, urea and derivatives, glycerol, native oils, laurocaprame, phospholipids, ide, amino acids, N, N-dimethylformamide, N-methylformamide, acetonides, calcium thio-glycolate, propylene glycol, polyethylene glycol, alkyl sulfate ⁇ , sodium lauryl sulfate, tetrahydrofuran ,
  • composition according to the invention can also contain to relieve skin irritation.
  • relief agents are: bisabolol, chamomile oil, allantin, glycerin or dipanthenol.
  • 163 g of acrylic adhesive e.g. Durotak® 387-2353
  • 19 g of dioctylcyclohexane (Cetiol S)
  • 19 g of hydrogenated rosin e.g. Staybelite Ester 3E
  • 50 g of glycerol trinitrate 22.1% by weight in ethyl acetate
  • 50 g of ethyl acetate 15 g of acetyl acetone
  • 0.1 g of aluminum acetylacetonate 4% by weight in ethyl acetate
  • the moist film was dried at 40 ° C. for 30 minutes and then laminated with a polyester film (eg Hostaphan®).
  • the weight per unit area of an adhesive film produced in this way was approximately 67 g / m 2 .
  • the desired size of plaster was punched out of the laminate by means of a punch and the in vitro permeation through isolated human skin was measured. The results of skin permeation are shown in FIG. 2 (filled squares). By using the vinyl acetate-free composition, the permeation was increased by about 65 s.

Abstract

The invention relates to a preparation for the transdermal, therapeutic introduction of glycerol trinitrate into an organism, through human skin. A therapeutically effective proportion of the active agent is contained in a polyacrylate-based self-adhesive layer and a rear layer which is impermeable to the active agent is provided. The invention is characterised in that a polyacrylate-based self-adhesive substance is used for the layer containing the active agent, in that the concentration of vinyl acetate in this substance is 6 wt.% maximum, and in that the concentration of the active agent in the substance is 25 wt.% maximum.

Description

Glyceroltrinitrathaltige Zusammensetzung, Verfahren zu ihrer Herstellung und ihre VerwendungComposition containing glycerol trinitrate, process for its preparation and its use
Die Erfindung betrifft eine Zubereitung zur transdermalen therapeutischen Applikation von Glyceroltrinitrat durch menschliche Haut in einen Organismus, enthaltend in einer selbstklebenden Schicht auf Polyacrylatbasis mit einer wirkstoffundurchlässigen Rüσkschicht einen therapeutisch wirksamen Anteil des Wirkstoffs, weiterhin ein Verfahren zur Herstellung der Zubereitung sowie deren Verwendung. Mit der Zubereitung wird eine kontinuierliche und konstant dosierbare Abgabe von Glyceroltrinitrat an bzw. durch die Haut angestrebt, wobei sie als Wirkstoffreservoir dient.The invention relates to a preparation for the transdermal therapeutic application of glycerol trinitrate through human skin into an organism, containing a therapeutically effective portion of the active ingredient in a polyacrylate-based self-adhesive layer with an active ingredient-impermeable backing layer, furthermore a process for the preparation of the preparation and its use. The preparation is aimed at a continuous and constantly meterable delivery of glycerol trinitrate to or through the skin, whereby it serves as an active substance reservoir.
Pflaster zur transdermalen Abgabe von arzneilich wirkenden Substanzen sind bereits seit vielen Jahren bekannt und werden erfolgreich in der Medizin eingesetzt. Mit den bekannten Zubereitungen soll in der Regel eine langsame und dosierte Abgabe der Substanzen erzielt werden, wobei die Zubereitung als Wirkstoffdepot dient. Hierbei ist es wünschenswert, daß der Wirkstoff langsam und über einen längeren Zeitraum abgegeben wird. Die transdermale Applikation bietet den großen Vorteil, daß der intestinale und der he- patische First-Pass-Effekt umgangen wird. Demzufolge ist die Bioverfügbarkeit von Substanzen, die einer starken Me- tabolisierung während des Absorptionsvorganges aus dem Darm und der ersten Leberpassage unterworfen sind, gesteigert. Ferner läßt sich die mehrmalige tägliche Applikation von Substanzen mit kurzer Eliminationshalbwertzeit vermeiden, da die mit einem transdermalen System erzielten Plasmakurven denen einer Dauerinfusion gleichen.Patches for the transdermal delivery of medicinally active substances have been known for many years and are used successfully in medicine. With the known preparations, a slow and metered release of the substances is generally to be achieved, the preparation serving as an active ingredient depot. It is desirable that the active ingredient is released slowly and over a longer period of time. The transdermal application has the great advantage that the intestinal and the hematological first pass effect is avoided. As a result, the bioavailability of substances that are subject to strong metabolism during the absorption process from the intestine and the first passage through the liver is increased. Furthermore, the repeated daily application of substances with a short elimination half-life can be avoided since the plasma curves obtained with a transdermal system are similar to those of a continuous infusion.
Bei therapieüblichen Wirkstoffen, die zur Prophylaxe oder zur Behandlung der koranaren Herzkrankheit eingesetzt werden, handelt es sich um organische Ester der Salpetersäure. Vorzugsweise wird Glyceroltrinitrat eingesetzt. Dieser Wirkstoff relaxiert die gl tte Gefäßmuskulatur, führt zu einer peripheren Vasodilatation und bewirkt eine Reduktion der kardialen Vor- und Nachlast.Active agents that are customary in therapy and are used for prophylaxis or for the treatment of coranary heart disease are organic esters of nitric acid. Glycerol trinitrate is preferably used. This active ingredient relaxes the smooth vascular muscles, leads to peripheral vasodilation and reduces the cardiac preload and afterload.
Durch diese Reduktion und die dadurch bedingte Verringerung der Herzarbeit sinkt der Sauerstoffbedarf des Herzens. Ferner bewirkt Glyceroltrinitrat eine Reduktion der extravasa- len Komponente des Konorarwiderstandes und dadurch eine Verbesserung des Sauerstoffangebotes .As a result of this reduction and the consequent reduction in cardiac work, the oxygen requirement of the heart drops. Glycerol trinitrate also reduces the extravascular component of the conor resistance and thereby improves the oxygen supply.
Akute Angina-Pectoris-Anfälle lassen sich schnell und effektiv durch sublinguale Glyceroltrinitratgabe therapieren. Diese Art der Applikation führt schnell zu einer hohen Wirkstoffkonzentration im Plasma. Da die Plasmahalbwerts- zeit von Glyceroltrinitrat jedoch nur 1-3 Minuten beträgt, flacht die Plasmakonzentration sehr schnell ab und hält die Plasmakonzentration nicht über einen längeren Zeitraum im therapeutischen Bereich aufrecht. Die sublinguale Gabe ist demzufolge nicht zur Anfallsprophylaxe geeignet.Acute attacks of angina pectoris can be treated quickly and effectively by sublingual glycerol trinitrate. This type of application quickly leads to a high concentration of active substances in the plasma. However, since the plasma half-life of glycerol trinitrate is only 1-3 minutes, the plasma concentration flattens very quickly and does not maintain the plasma concentration in the therapeutic range over a longer period of time. Sublingual administration is therefore not suitable for seizure prophylaxis.
Zur Vorbeugung von Angina-Pectoris-Anfällen besser geeignet ist die transdermale Gabe. Die systemische Glyceroltrini- trat-Aufnahme durch die Haut beträgt in Abhängigkeit vom Applikationsort etwa 20 μg/cm2/h. Vorteilhaft hierbei ist, daß die biologische Verfügbarkeit infolge Umgehung des extensiven intestinalen bzw. hepatischen First-Pass-Effektes nicht ernsthaft verringert wird. Verglichen mit intravenöser Applikation resultiert eine Bioverfügbarkeit von etwa 70 %, wenn Glyceroltrinitrat transdermal verabreicht wird.Transdermal administration is more suitable for preventing angina pectoris attacks. The systemic uptake of glycerol trinitrate through the skin is about 20 μg / cm 2 / h, depending on the application site. It is advantageous here that the biological availability is not seriously reduced as a result of circumventing the extensive intestinal or hepatic first-pass effect. Compared to intravenous administration, a bioavailability of approximately 70% results when glycerol trinitrate is administered transdermally.
Zunächst sind nur das Stratum Corneum der Haut und die Größe der Applikationsfläche bestimmende Faktoren für die im Blut zirkulierende Wirkstoffmenge. Dabei wird eine relativ konstante Steady-State-Plasmakonzentration über eine längere Zeit erzielt. Die Steady-State-Plasmakonzentration richtet sich nach der jeweiligen Dosierung des Pflasters und der entsprechenden Absorptionsrate. Bei einer Absorp- tionsrate von 0,4 mg/h liegt beispielsweise die Plasmakonzentration durchschnittlich bei 0,2 μl/1.First of all, only the stratum corneum of the skin and the size of the application area are decisive factors for the amount of active ingredient circulating in the blood. A relatively constant steady state plasma concentration is achieved over a longer period of time. The steady-state plasma concentration depends on the dose of the patch and the corresponding absorption rate. With an absorption tion rate of 0.4 mg / h, for example, the plasma concentration averages 0.2 μl / 1.
Aus genannten Gründen wird klar, daß die transdermale Gabe von Glyceroltrinitrat Mittel der Wahl zur effektiven Angi- na-Pectoris-Prophylaxe ist.For the reasons mentioned, it is clear that transdermal administration of glycerol trinitrate is the method of choice for effective angina pectoris prophylaxis.
Zahlreiche Zubereitungen zur transdermalen Applikation von Glyceroltrinitrat sind Stand der Technik. Vorherrschend sind pflasterartige System. Glyceroltrinitrat liegt dabei entweder gelöst oder an einem Hilfsstoff adsorbiert vor. Bekannt sind einfache Matrixsysteme, beispielsweise gemäß US 4,751,087, weiterhin komplex aufgebaute Reservoirsysteme, beispielsweise gemäß US 4,725,272, sowie Systeme, die den Wirkstoff in Mikrokapseln enthalten, beispielsweise gemäß US 3,742,951 und US 4,336,243.Numerous preparations for the transdermal application of glycerol trinitrate are state of the art. Patch-like systems are predominant. Glycerol trinitrate is either dissolved or adsorbed on an auxiliary. Simple matrix systems, for example in accordance with US Pat. No. 4,751,087, are also known as complex reservoir systems, for example in accordance with US Pat. No. 4,725,272, and systems which contain the active ingredient in microcapsules, for example in accordance with US Pat. No. 3,742,951 and US Pat. No. 4,336,243.
Für eine erfolgreiche Therapie ist es wichtig, daß der Wirkstoff in einem therapeutisch wirksamen Ausmaß aus der Zubereitung freigegeben wird und anschließend die Haut permeiert. Während die Freisetzungseigenschaft der Zubereitung durch Wirk- und Hilfsstoffe festgelegt ist, wird die trans- dermale Wirkstoffabsorption entscheidend durch das Stratum Corneum der Haut bestimmt. Die Absorption kann durch den Einsatz von die Per eation verbessernden Zusätzen gesteigert werden. So ist im US-Patent 5,262,165 der Einsatz von N-Methyl-2-Pyrrolidon und Ölsäure zur Steigerung der Gly- ceroltrinitratabsorption beschrieben.For successful therapy, it is important that the active ingredient is released from the preparation to a therapeutically effective extent and then the skin is permeated. While the release properties of the preparation are determined by active substances and auxiliary substances, the transdermal absorption of the active substance is decisively determined by the stratum corneum of the skin. The absorption can be increased by using additives which improve performance. The use of N-methyl-2-pyrrolidone and oleic acid to increase the glycerol trinitrate absorption is described in US Pat. No. 5,262,165.
Synthetische Acrylatpolymere werden oftmals aufgrund ihres nichtallergenen Charakters als Zubereitungsgrundlage verwendet, beispielsweise gemäß US 4,505,891. Von Nachteil ist, daß die meisten Acrylatpolymere Glyceroltrinitrat sehr gut lösen. Die gute Löslichkeit ist gleichbedeutend mit niedriger thermodynamischer Aktivität. Zum Ausgleich muß deshalb Glyceroltrinitrat in einer hohen Konzentration ein- gearbeitet werden, um eine therapeutisch zufriedenstellende Wirkstofffreigäbe zu erzielen.Synthetic acrylate polymers are often used as a preparation base due to their non-allergenic character, for example according to US 4,505,891. The disadvantage is that most acrylate polymers dissolve glycerol trinitrate very well. The good solubility is synonymous with low thermodynamic activity. To compensate, glycerol trinitrate must therefore be used in a high concentration. be worked to achieve a therapeutically satisfactory release of active ingredients.
In EP 0 622 075 AI ist eine Zubereitung beschrieben, die Glyceroltrinitrat in einer Konzentration von 50-65 Gew.% enthält. Der Nachteil von derart hohen Glyceroltrinitrat- mengen ist in dessen Eigenschaften begründet. Glyceroltrinitrat reagiert nachteilig auf thermische und mechanische Belastungen mit Explosionen oder es führt zu unerwünschten Veränderungen der Klebereigenschaften z.B. zur Reduktion der Klebrigkeit, Adhäsion und Kohäsion.EP 0 622 075 A1 describes a preparation which contains glycerol trinitrate in a concentration of 50-65% by weight. The disadvantage of such high amounts of glycerol trinitrate is due to its properties. Glycerol trinitrate reacts adversely to thermal and mechanical loads with explosions or leads to undesirable changes in the adhesive properties e.g. to reduce stickiness, adhesion and cohesion.
Um Zubereitungen mit akzeptablen Klebereigenschaften zu erhalten, beschreibt US 5,474,783 die Möglichkeit, die thβr- modynamische Aktivität von Acrylatpolymeren durch Beimengung eines Polysiloxans zu modifizieren. Polysiloxane haben eine geringe Löslichkeit für Glyceroltrinitrat, wodurch die Gesamtlöslichkeit in der Zubereitung verringert wird. Die reduzierte Sättigungslöslichkeit schlägt sich in einer erhöhten Freisetzungsrate nieder. Durch Variation der beigemengten Polysiloxanmenge läßt sich die Freisetzungskinetik steuern. Da es sich bei dem beschriebenen System um ein mehrphasiges System handelt, kann es bei der Herstellung zu Entmischungen und damit zu Inhomogenitäten kommen.In order to obtain preparations with acceptable adhesive properties, US Pat. No. 5,474,783 describes the possibility of modifying the thermodynamic activity of acrylate polymers by adding a polysiloxane. Polysiloxanes have a low solubility for glycerol trinitrate, which reduces the overall solubility in the preparation. The reduced saturation solubility is reflected in an increased release rate. The release kinetics can be controlled by varying the amount of polysiloxane added. Since the system described is a multi-phase system, segregation and thus inhomogeneities can occur during production.
Der vorliegenden Erfindung liegt die Aufgabe zugrunde, eine Zubereitung zur transdermalen therapeutischen Applikation von Glyceroltrinitrat durch menschliche Haut der im Oberbegriff von Anspruch 1 genannten Art und ein Verfahren zu deren Herstellung anzugeben, die unter Überwindung der vorgenannten Schwierigkeiten und technischen Grenzen eine hohe thermodynamische Aktivität entfaltet, um unter Vermeidung vergleichsweise hoher Anteile des Wirkstoffs Glyceroltrinitrat die dadurch verursachten Probleme zu umgehen und bei signifikant gesteigerter Bioverfügbarkeit eine effektive Arzneimitteltherapie mit langandauernder und konstant kontrollierbarer Wirkstofffreisetzung zu ermöglichen, welche darüber hinaus kostengünstig herstellbar sowie anwender- freundlich bei der Applikation ist.The present invention is based on the object of specifying a preparation for the transdermal therapeutic application of glycerol trinitrate by human skin of the type mentioned in the preamble of claim 1 and a process for its preparation which develops a high thermodynamic activity while overcoming the aforementioned difficulties and technical limits, in order to avoid the problems caused by avoiding comparatively high proportions of the active ingredient glycerol trinitrate and, with significantly increased bioavailability, to enable effective drug therapy with long-lasting and constantly controllable active ingredient release, which it is also inexpensive to manufacture and user-friendly to use.
Zur Lösung der Aufgabe wird eine Zubereitung der eingangs genannten Art vorgeschlagen, die dadurch gekennzeichnet ist, daßTo solve the problem, a preparation of the type mentioned is proposed, which is characterized in that
- für die wirkstoffhaltige Schicht eine selbstklebende Masse auf Polyacrylatbasis eingesetzt wird,a self-adhesive composition based on polyacrylate is used for the active substance-containing layer,
- die Konzentration von Vinylacetat in der Masse höchstens 6 Gew.5s, und- the concentration of vinyl acetate in the mass not more than 6 wt.5s, and
- die Konzentration von Wirkstoff in der Masse höchstens 25 Gew.?s beträgt.- The concentration of active substance in the mass is at most 25% by weight.
Weitere vorteilhafte Ausgestaltungen der Erfindung sind entsprechend den Unteransprüchen vorgesehen.Further advantageous embodiments of the invention are provided in accordance with the subclaims.
Die Zubereitung weist eine hohe thermodynamische Aktivität auf, wodurch eine hohe Freisetzungsrate bei Einsatz niedriger Wirkstoffmengen gesichert ist. Diese hohe thermodynamische Aktivität wird durch Reduktion der Sättigungslöslich- keit des entsprechenden Wirkstoffs erzielt. Dies kann dadurch verwirklicht werden, daß für die Zubereitung ein Grundmaterial verwendet wird, welches als solches eine niedrige Wirkstofflöslichkeit aufweist, und daß Zusätze vermieden werden, die zu einer Steigerung der Wirkstofflös- liσhkeit führen.The preparation has a high thermodynamic activity, which ensures a high release rate when using small amounts of active ingredient. This high thermodynamic activity is achieved by reducing the saturation solubility of the corresponding active ingredient. This can be achieved by using a base material for the preparation, which as such has a low solubility in the active ingredient, and avoiding additives which lead to an increase in the solubility of the active ingredient.
Für die erfindungsgemäße Zusammensetzung wird eine selbstklebende Masse auf Polyacrylatbasis eingesetzt. Die Masse ist erfindungsgemäß dadurch gekennzeichnet, daß der Vinyl- acetatanteil höchstens 6 Gew.?s beträgt. Diese Reduktion des Vinylacetatanteils begründet sich darin, daß - wie im folgenden belegt wird - Vinylacetat bei zunehmender Konzentration zur Abnahme der Freisetzungsrate von Glyceroltrinitrat führt. Es ist zu berücksichtigen, daß Vinylacetat sowohl als Copolymer des Acrylatpolymerisats als auch als zuge- setztes Homopolymer die Freisetzungsrate reduziert. Durch die beschriebene Maßnahme nach der Erfindung liegt der Gly- ceroltrinitratgehalt in der Regel in einem Bereich von 10- 30 Gew.s, vorzugsweise unterhalb von 25 Gew.s.A self-adhesive composition based on polyacrylate is used for the composition according to the invention. The mass is characterized according to the invention in that the vinyl acetate content is at most 6% by weight. This reduction in the vinyl acetate content is due to the fact that, as will be demonstrated in the following, vinyl acetate leads to a decrease in the release rate of glycerol trinitrate with increasing concentration. It should be noted that vinyl acetate is used both as a copolymer of the acrylate polymer and as a set homopolymer reduces the release rate. As a result of the measure according to the invention described, the glycerol trinitrate content is generally in a range from 10-30% by weight, preferably below 25% by weight.
In FIG.l ist die Per eationsrate von Glyceroltrinitrat durch eine artifizielle Membran als Funktion der Vinylace- tatkonzentration einer Polyacrylatmasse dargestellt. Dabei wurde Vinylacetat in Form eines Homopoly ers (Polyvinylace- tat) einer selbstklebenden Masse auf Polyacrylatbasis zugegeben. In der Figur ist gezeigt, daß mit sinkendem Vinyla- ceatanteil die Permeationsrate bzw. Freisetzungsrate zunehmend gesteigert wird.FIG. 1 shows the rate of peracetate of glycerol trinitrate through an artificial membrane as a function of the vinyl acetate concentration of a polyacrylate composition. In this case, vinyl acetate in the form of a homopoly er (polyvinyl acetate) was added to a self-adhesive composition based on polyacrylate. The figure shows that the permeation rate or release rate is increasingly increased as the vinyl acetate content decreases.
FIG.2 beschreibt die Permeation von Glyceroltrinitrat durch humane Vollhaut. Zur Herstellung der Zusammensetzungen wurde eine Vinylacetat-freie Polyacrylatmasse, als gefüllte Quadrate dargestellt, bzw. ein Polyacrylat-Vinylacetat- Copolymer, als leere Kreise dargestellt, eingesetzt. Es zeigt sich, daß durch den Einsatz von Vinylacetat-freiem Polyacrylat das Ausmaß der Permeation durch die humane Vollhaut gesteigert wird.FIG. 2 describes the permeation of glycerol trinitrate through whole human skin. A vinyl acetate-free polyacrylate composition, shown as filled squares, or a polyacrylate-vinyl acetate copolymer, shown as empty circles, were used to produce the compositions. It can be seen that the use of vinyl acetate-free polyacrylate increases the degree of permeation through the full human skin.
Die durch Vinylacetat bedingte Senkung der Permeation läßt sich durch eine gesteigerte Löslichkeit von Glyceroltrinitrat in der selbstklebenden Polyacrylatmasse erklären. Dabei wirkt Vinylacetat als Löslichkeitsvermittler. Bedingt durch die erhöhte Lδslichkeit, ist die Wanderung des Wirkstoffs aus der Masse in eine Membran herabgesetzt, da sich eine Substanz entsprechend der Sättigungslöslichkeit zwischen zwei Phasen verteilt. Demzufolge ist auch die Permeation verringert, weil der Wirkstofffluß durch eine Membran in einem proportionalen Verhältnis zum Verteilungskoeffizienten steht.The decrease in permeation caused by vinyl acetate can be explained by an increased solubility of glycerol trinitrate in the self-adhesive polyacrylate composition. Vinyl acetate acts as a solubilizer. Due to the increased solubility, the migration of the active substance from the mass into a membrane is reduced, since a substance is distributed between two phases in accordance with the saturation solubility. As a result, permeation is also reduced because the flow of active substance through a membrane is in a proportional relationship to the distribution coefficient.
Die zur Herstellung einer erfindungsgemäßen Zusammensetzung verwendete selbstklebende Masse auf Polyacrylatbasis ist dadurch gekennzeichnet, daß zu ihrer Herstellung Acrylsäure und/oder Alkylacrylsäure, insbesondere Methacrylsäure oder deren Derivate, insbesondere die Alkylester, eingesetzt werden. Unter den Alkylestern sind diejenigen mit 1 bis 18 Kohlenstoffatomen im Alkylrest bevorzugt, insbesondere Methyl-, Ethyl-, n-Butyl-, Isobutyl-, Pentyl-, 2-Ethylbutyl-, n-Hexyl-, Heptyl-, n-Octyl-, Isooctyl-, 2-Ethylhexyl-, n- Decyl-, Isodecyl-, n-Dodecyl- und Stearylacrylat bzw. -methacrylat. Daneben können weitere Comonomere am Aufbau des Polymers/Copolymers beteiligt sein. Beispiele sind Acryl- und/oder Methacrylamid, Hydroxyalkylester und Po- lyalkylenglykolester der Acryl- und/oder Methacrylsäure, stickstoffhaltige Monomere der Acryl- und/oder Methacrylsäure oder deren Salze, Ethylen, Vinylacetat, Vinylpropio- nat, Vinylbutyrat, . Vinylpyrrolidon, Vinylchlorid, Vinylto- luol, Acrylnitril, Styrol und dergleichen.The self-adhesive composition based on polyacrylate used to produce a composition according to the invention is characterized in that acrylic acid and / or alkyl acrylic acid, in particular methacrylic acid or their derivatives, in particular the alkyl esters, are used for their preparation. Among the alkyl esters, those with 1 to 18 carbon atoms in the alkyl radical are preferred, in particular methyl, ethyl, n-butyl, isobutyl, pentyl, 2-ethylbutyl, n-hexyl, heptyl, n-octyl, Isooctyl, 2-ethylhexyl, n-decyl, isodecyl, n-dodecyl and stearyl acrylate or methacrylate. In addition, other comonomers can be involved in the construction of the polymer / copolymer. Examples are acrylic and / or methacrylamide, hydroxyalkyl esters and polyalkylene glycol esters of acrylic and / or methacrylic acid, nitrogen-containing monomers of acrylic and / or methacrylic acid or their salts, ethylene, vinyl acetate, vinyl propionate, vinyl butyrate,. Vinyl pyrrolidone, vinyl chloride, vinyl toluene, acrylonitrile, styrene and the like.
Ferner enthalten ist eine mit der selbstklebenden Masse verbundene Rückschicht. Diese ist undurchlässig für den Wirkstoff und besitzt okklusiven Charakter. Es können beliebige Materialien eingesetzt werden, die in herkömmlichen Präparaten Verwendung finden. Beispiele für derartige Materialien sind Celluloseacetat, Ethylcellulose, Polyethylen- terephthalat, weichgemachte Vinylacetat-Vinylchlorid- Copolymerisate, Nylon, Ethylen-Vinylacetat-Copolymerisate, weichgemachtes Polyvinylchlorid, Polyurethan, Polyvinyli- denchlorid, Polypropylen, Polyethylen, Polyamid oder Aluminium.Also included is a backing layer connected to the self-adhesive composition. This is impermeable to the active ingredient and has an occlusive character. Any materials that are used in conventional preparations can be used. Examples of such materials are cellulose acetate, ethyl cellulose, polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymers, nylon, ethylene-vinyl acetate copolymers, plasticized polyvinyl chloride, polyurethane, polyvinylidene chloride, polypropylene, polyethylene, polyamide or aluminum.
Die Zusammensetzung kann ferner enthalten: Klebrigmacher, Penetationsverbesserer oder Mittel zur Linderung von Hautreizungen sowie Metallionen, z.B. Aluminium oder Titan. Zur Erhöhung der Kohäsion können Weichmacher, Paraffine, zyklische Kohlenwasserstoffe oder pflanzliche Öle zugesetzt werden. Als Mittel zur Erhöhung der Klebrigkeit können Kolophoniumharze, Polyterpenharzθ, Petroleumharze, Cumaron-Inden- Harze, Terpenphenolharze, Kohlenwasserstoffharze oder flüssige Polybutenharze verwendet werden.The composition may further contain: tackifiers, penetration enhancers or agents for relieving skin irritation and metal ions, for example aluminum or titanium. Plasticizers, paraffins, cyclic hydrocarbons or vegetable oils can be added to increase cohesion. Rosin, polyterpene resin, petroleum resin, coumarone-indene resin, terpene-phenol resin, hydrocarbon resin or liquid polybutene resin can be used as an agent for increasing the stickiness.
Beispiele für die Penetration des Wirkstoffes verbessernde Mittel sind: Pyrrolidonderivate, Fettsäuren, Fettalkohole, Fettsaureester, Fettether, Paraffinderivate, Terpene, Ethy- lenglykolmonoalkylether, Polyoxyethylenalkylether, Po- lyoxyethylenarylether, Polyoxyethylenalkylester, Polyoxy- propylenalkylether, Propylenglykolfettsäurederivate, Glyce- rinfettsäureester, Polysorbate, Poloxamere, Dialkylsulfoxi- de, Harnstoff und -derivate, Glycerin, native Öle, Lauroca- prame, Phospholipide, A ide, Aminosäuren, N,N- Dimethylformamid, N-Methylformamid, Acetonide, Calciumthio- glycolat, Propylenglycol, Polyethylenglycol, Alkylsulfatθ, Natriumlaurylsulfat, Tetrahydrofurfurylalkohol, N,N- Diethyl-m-toluamide, Anticholinergika, makrocyclische Verbindungen, polare Lösungsmittel wie Isosorbitol oder Pan- thenol .Examples of agents which improve the penetration of the active ingredient are: pyrrolidone derivatives, fatty acids, fatty alcohols, fatty acid esters, fatty ethers, paraffin derivatives, terpenes, ethylene glycol monoalkyl ethers, polyoxyethylene alkyl ethers, polyoxyethylene aryl ethers, polyoxyethylene alkyl esters, polyoxypropylene alkyl ethers, propylene glycol ester polyglyceramate fatty acid derivatives, glycerol fatty acid derivatives, Dialkyl sulfoxides, urea and derivatives, glycerol, native oils, laurocaprame, phospholipids, ide, amino acids, N, N-dimethylformamide, N-methylformamide, acetonides, calcium thio-glycolate, propylene glycol, polyethylene glycol, alkyl sulfate θ, sodium lauryl sulfate, tetrahydrofuran , N, N-diethyl-m-toluamide, anticholinergics, macrocyclic compounds, polar solvents such as isosorbitol or panthenol.
Die erfindungsgemäße Zusammensetzung kann darüber hinaus zur Linderung von Hautreizungen enthalten. Beispiele für solche Linderungmittel sind: Bisabolol, Kamillenöl, Allan- toin, Glycerin oder Dipanthenol.The composition according to the invention can also contain to relieve skin irritation. Examples of such relief agents are: bisabolol, chamomile oil, allantin, glycerin or dipanthenol.
Im folgenden wird die Erfindung anhand eines Beispiels näher erläutert:The invention is explained in more detail below using an example:
163 g Acrylatklebstoff (z.B. Durotak® 387-2353), 19 g Dioctylcyclohexan (Cetiol S), 19 g hydriertes Kolophoniumharz (z.B. Staybelite Ester 3E) , 50 g Glyceroltrinitrat (22,1 Gew.s in Ethylacetat) , 50 g Ethylacetat, 15 g Acetyl- aceton und 0,1 g Aluminiumacetylacetonat (4 Gew. -s in Ethylacetat) wurden gemischt. Die Lösung wurde mit einer Naß- schichtdicke von 350 um mit Hilfe einer Rakel auf eine si- likonisierte Polyesterfolie (z.B. Hostaphan®) aufgetragen. Der feuchte Film wurde für 30 Minuten bei 40 °C getrocknet und anschließend mit einer Polyesterfolie (z.B. Hostaphan®) laminiert. Das Flächengewicht eines derartig hergestellten Klebefilms betrug ca. 67 g/m2. Aus dem Laminat wurden mittels Stanze Pflaster der gewünschten Größe ausgestanzt und die in-vitro-Permeation durch isolierte humane Haut gemessen. Die Ergebnisse der Hautpermeation sind in FIG.2 dargestellt (gefüllte Quadrate). Durch Einsatz der vinylacetatfreien Zusammensetzung wurde die Permeation um ca. 65 s gesteigert. 163 g of acrylic adhesive (e.g. Durotak® 387-2353), 19 g of dioctylcyclohexane (Cetiol S), 19 g of hydrogenated rosin (e.g. Staybelite Ester 3E), 50 g of glycerol trinitrate (22.1% by weight in ethyl acetate), 50 g of ethyl acetate, 15 g of acetyl acetone and 0.1 g of aluminum acetylacetonate (4% by weight in ethyl acetate) were mixed. The solution was applied with a wet film thickness of 350 μm to a Siliconized polyester film (e.g. Hostaphan®) applied. The moist film was dried at 40 ° C. for 30 minutes and then laminated with a polyester film (eg Hostaphan®). The weight per unit area of an adhesive film produced in this way was approximately 67 g / m 2 . The desired size of plaster was punched out of the laminate by means of a punch and the in vitro permeation through isolated human skin was measured. The results of skin permeation are shown in FIG. 2 (filled squares). By using the vinyl acetate-free composition, the permeation was increased by about 65 s.

Claims

AN S P R Ü C H E EXPECTATIONS
1. Zubereitung zur transdermalen therapeutischen Applikation von Glyceroltrinitrat durch menschliche Haut in einem Organismus, enthaltend in einer selbstklebenden Schicht auf Polyacrylatbasis mit einer wirkstoffundurchlässigen Rückschicht einen therapeutisch wirksamen Anteil des Wirkstoffs, dadurch gekennzeichnet, daß1. Preparation for transdermal therapeutic application of glycerol trinitrate through human skin in an organism, containing a therapeutically effective portion of the active ingredient in a self-adhesive layer based on polyacrylate with an active ingredient-impermeable backing layer, characterized in that
- für die wirkstoffhaltige Schicht eine selbstklebende Masse auf Polyacrylatbasis eingesetzt wird,a self-adhesive composition based on polyacrylate is used for the active ingredient-containing layer,
- die Konzentration von Vinylacetat in der Masse höchstens
Figure imgf000012_0001
- The maximum concentration of vinyl acetate in the mass
Figure imgf000012_0001
- die Konzentration von Wirkstoff in der Masse höchstens 25 Gew.5s beträgt.- The concentration of active ingredient in the mass is a maximum of 25 wt.5s.
2. Zubereitung nach Anspruch 1, dadurch gekennzeichnet, daß die in der Masse der selbstklebenden Schicht eingesetzten Monomere Acrylsäure und/oder Methacrylsäure oder deren Derivate, insbesondere die Alkylester, enthalten.2. Preparation according to claim 1, characterized in that the monomers used in the mass of the self-adhesive layer contain acrylic acid and / or methacrylic acid or their derivatives, in particular the alkyl esters.
3. Zubereitung nach Anspruch 1, dadurch gekennzeichnet, daß in der selbstklebenden Masse Vinylacetat als Homopoly- mer vorliegt.3. Preparation according to claim 1, characterized in that vinyl acetate is present as a homopolymer in the self-adhesive composition.
4. Zubereitung nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß in der selbstklebenden Masse Vinylacetat als Copolymer vorliegt.4. Preparation according to claim 1 or 2, characterized in that vinyl acetate is present as a copolymer in the self-adhesive composition.
5. Verfahren zur Herstellung der Zubereitung nach einem oder mehreren der Ansprüche 1 bis 4, dadurch gekennzeichnet, daß einer Acylatklebstoff enthaltende Lösung Glyceroltrinitrat zugegeben, das Gemisch homogenisiert und in Form eines feuchten Films auf einer Unterlage aufgestrichen und anschließend der Film getrocknet wird. 5. A process for the preparation of the preparation according to one or more of claims 1 to 4, characterized in that glycerol trinitrate is added to a solution containing acylate adhesive, the mixture is homogenized and spread in the form of a moist film on a base, and the film is then dried.
6. Verwendung der Zubereitung nach einem oder mehreren der Ansprüche 1 bis 4 zur Vorbeugung von Angina-Pectoris- Anfällen sowie zur Dauerbehandlung von koronaren Herzkrankheiten. 6. Use of the preparation according to one or more of claims 1 to 4 for the prevention of angina pectoris attacks and for the long-term treatment of coronary heart diseases.
PCT/EP1999/004610 1998-07-09 1999-07-02 Composition containing glycerol trinitrate, method for producing said composition and use of the same WO2000002537A1 (en)

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IL14073999A IL140739A0 (en) 1998-07-09 1999-07-02 Glyceryl trinitrate-containing preparation, method for its production, and its use
KR1020017000346A KR20010074687A (en) 1998-07-09 1999-07-02 Composition containing glycerol trinitrate, method for producing said composition and use of the same
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CA002336704A CA2336704A1 (en) 1998-07-09 1999-07-02 Composition containing glycerol trinitrate, method for producing said composition and use of the same
BR9911984-6A BR9911984A (en) 1998-07-09 1999-07-02 Composition containing gricerol trinitrate, processes for its preparation and application
JP2000558797A JP2002520268A (en) 1998-07-09 1999-07-02 Compositions comprising glycerol trinitrate, methods of making the compositions, and uses thereof
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US4751087A (en) * 1985-04-19 1988-06-14 Riker Laboratories, Inc. Transdermal nitroglycerin delivery system
US4751087B1 (en) * 1985-04-19 1993-03-02 Riker Laboratories Inc
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