IL96243A - Transdermal therapeutic system comprising buprenorphine comprising buprenorphine as active component - Google Patents

Abstract

The controlled delivery of buprenorphine or its pharmaceutically compatible salts over at least 24 hours onto the skin is ensured by a transdermal therapeutic system composed of a backing layer which is impermeable to active substance, of an adhesive reservoir layer and, where appropriate, of a protective layer which can be detached again, which system is characterised in that the reservoir layer contains 20-90% by weight of polymeric material, 0.1-30% by weight of plasticiser, 0.1-20% of buprenorphine base or of one of its pharmaceutically acceptable salts and 0.1-30% by weight of solvent for the active substance base.

Description

Transdermal therapeutic system comprising as active component buprenorphine LTS Lohmann Therapie-Systeme GmbH & Co. KG.

C: 82012 DESCRIPTION The present invention relates to a transdermal therapeutic system (TTS) which contains as active component buprenorphi ne ( 17- ( eyelopropy 1 meth l )-a-( 1 , 1 -dimethyl -eth l )-4 , 5-epoxy- 18,19-d i hydro-3-hydroxy-6-methoxy-a-methyl -6 , 14-ethenomorphi nane-7-methanol ) .

Buprenorphine is a partially synthetic opiate. Compared to other compounds of this class of substances, the advantage of buprenorphine is higher effectiveness. This means that patients suffering from cancer or a tumor with unfavorable diagnosis in final stage can be relieved from pain with daily doses of about 1 mg. However, buprenorphine does not solve two major problems occuring in connection with opiates, i.e., the danger of habit formation and the low bioavailabil ty of these substances in case of oral administration. For example, the bioavailability from the gastrointestinal tract amounts to only about 10%, and in case of sublingual application only about 50%.

When buprenorphine was introduced as analgesic, it was regarded as non-habit-forming. However, this initial assumption has been corrected. In the meantime, buprenorphine is subject to the German narcotics act, after it had been increasingly abused by addicts.

However, since quite recently, experts are of the opinion that it is the form of administration of a medicinal drug which contributes to the risk of addiction. This can easily be understood in case of high-potency analgesics in the therapy of extreme pai n .

Immediately after application the blood level of the analgesic is higher than therapeutically required and causes euphoria, however, then drastically decreases and rapidly effects blood levels which do no longer treat the pain successfully. Due to his pain, the patient starts to long for the next dosage - an iatrogenic addiction is created.

In case of buprenorphi ne and other highly effective opiates continuous infusion would therefore be the most suitable kind of administration to avoid said iatrogenic habit formation by means of constant blood levels.

However, continuous infusion cannot be applied and controlled without any aid of a physician during domiciliary care; inflammations frequently result at the place where the cannula is inserted.

Even an oral depot preparation cannot be the suitable form to administer buprenorphi ne , since the low bioavailability in case of oral application requires approximately ten times the amount of active substance compared to the required intravenous dosage. In this connection, buprenorphine, as partial opiate antagonist, involves great problems, since a respiratory depression caused by an overdosage of the active substance cannot be treated by the administration of an antagonist, such as nalorphine which is the suitable antidote in case of poisonings caused by opiates. Although the oral bioavailability for buprenorphine is stated to be 10%, overdosages may nevertheless occur, since buprenorphine shall also be administered to patients with the probability of liver function disturbances so that quite more than 10% of buprenorphine may survive the first liver passage without having been subjected to metabolism.

In addition, the development on the market for medicinal agents during the last years has shown that oral depot preparations are not always suitable. Generics having the same in-vitro-release as preparations of the original suppliers do not have the same effectiveness as those original preparations. This means that overdosages and underdosages may arise due to uncontrolled release in vivo. Both cases are disastrous in case of buprenorphi ne . In case of underdosage, the patient suffers from intense pain. In case of overdosage, fatal respiratory depressions which cannot be treated with nalorphine could be the most severe consequence .

In addition, it has been left out of consideration until now, that an oral depot preparation which became damaged and thus does not retard buprenorphi ne , but releases it at one blow (called "dosedumpi ng" among experts) cannot immediately be removed from the human body.

The reservations with respect to forms of administration which release buprenorphi ne in a retarded manner are avoided by the merits of the transdermal therapeutic systems, since the medicinal agent need not be administered to the human body via cannulae so that it can be applied even by nonprofessionals. At the same time, active substance supply according to 0. order is safeguarded; the supply may be interrupted at any time by tearing the system off. Thus, transdermal therapeutic systems seem to be the most suitable form to administer buprenorphi ne .

However, one has to consider the objection that buprenorphine only badly penetrates through the human skin. This is due to its high molecular weight (m.w. 468) and - above all - its high melting point and very slight solubility in conventional organic solvents and water, and diffusion which is the precondition for penetration through human skin requires dissolved substances .

On the other hand, the solubility must not be increased by salt formation, since bases in^ onized form are not absorbed.

Until today, all attempts failed to bring buprenorphine on a transdermal basis to a resorption in the required amount, although - for the reasons described above - a TTS is the most suitable form of administration for this active substance.

It is accordingly the object of the present invention to provide buprenorphine or one of the pharmaceutically compatible salts thereof in the form of a transdermal therapeutic system which releases buprenorphine or the pharmaceuticall acceptable salt thereof over a period of at least 24 hours in a controlled manner and ensures that the buprenorphine does not notably decompose when the prefabricated transdermal therapeutic system is stored, and which further ensures that buprenorphine, which insufficiently passes through skin, in vivo penetrates through the skin at the required amount.

According to the present invention this object is achieved in a surprising manner by a transdermal therapeutic system for the administration of buprenorph ne to the skin. The system comprises a backing layer which is impermeable to the active substance, a pres- sure-sensitive adhesive reservoir layer, and, optionally, a removable protective layer, and is characterized in that the reservoir layer comprises 20 to 90%-wt polymeric material, 0.1 to 30%-wt softener, 0.1 to 20%-wt buprenorphi ne base or one of the pharmaceutically acceptable salts thereof, and 0.1 to 30%-wt solvent for the active substance base.

This solution is surprising all the more since bupre-norphine has a bioavailability of only 50% when administered subl i ngual 1 y . Since the first liver passage is evaded by this mode of application, the low bioavailability can only be due to insufficient absorbab lity of the substance by the oral mucosa. However, a substance which only hardly passes the mucosa of the mouth, will be absorbed by the human skin even harder.

The backing layer which is impermeable to the active substance may consist of flexible or inflexible material. Substances suitable for the production of the backing layer are polymeric foils and metal foils, such as aluminum foil which may be used alone or coated with a polymeric substrate. Textile fabrics may be used too, if the components of the reservoir cannot penetrate the fabric due to their physical properties. In a preferred embodiment of the present invention the backing layer is a composite material of an aluminized foi 1.

The reservoir layer consists of a polymeric matrix and the active substance, whereby the polymeric matrix ensures the coherence of the system. The polymeric matrix consists of a basic polymer and, optionally, conventional additives. The selection of the basic polymer depends on the chemical and physical properties of the buprenorph ne . Examples of polymers are rubber, rubber-like synthetic homo-, co- or blockpol mers , polyacrylic esters and the copolymers thereof, poly-urethanes and silicones. In principle all polymers are suitable which can be used in the production of pressure-sensitive adhesives and which are physiologically acceptable. Particularly preferred are those consisting of block copolymers based on styrene and 1,3-dienes, pol y i sobutyl enes , polymers based on acrylate and/or methacr 1 ate .

Amongst the bl ockcopol ymers based on styrene and 1,3-dienes, linear styrene-isoprene-blockcopolymers or styrene-butadiene-blockcopol mers are particularly used .

Self cross-linking acrylate copolymers of 2-ethyl hexyl acrylate, vinyl acetate, and acrylic acid with titanium chelate ester, or non-self-cross-link ng acrylate copolymers without titanium chelate ester are preferred for the use as acr l ate-based polymers.

Suitable polymers which are added to the basic polymer are pol methacryl ates , esters of hydrogenated colophony, and polyvinyls.

Copolymers based on di methyl ami noethyl methacryl ates and on neutral methacryl ic esters are preferably used as methacrylates. The methylesters and glycerol esters of hydrogenated colophony are particularly preferred for the use as esters of hydrogenated colophony. Polyvinylpyrrol dones and polyvinyl alcohols are preferably used as polyvinyls.

The kind of common additives depends on the polymer used: According to their function they can be divided, e.g., in tackifiers, stabilizers, carrier substances, and fillers. The physiologically acceptable substances suitable for this purpose are known to the skilled artisan .

According to the present invention it turned out that a softening agent combined with a solvent for bupre-norphine is required to permit transdermal application of buprenorphi ne .

The choice of softener depends on the polymer. Higher alcohols, such as dodecanol , undecanol , octanol , the esters of carboxylic acids whereby the alcohol component may also be a pol yethoxy 1 ated alcohol, diesters of dicarboxylic acids, such as di-n-butyladipate and triglycerides, particularly medium-chain triglycerides of the capryl i c/capr i c acids of coconut oil, have proved to be particularly suitable. Further examples of suitable softeners are multivalent alcohols, for example, glycerol and 1 , 2-propanediol , which can also be etherified by polyethylene glycols.

The significance of the buprenorph ne solvent is proved by the examples. The examples show that the solvent is an indispensable component of the formulation. The combination softener/solvent according to the teaching of the present invention builds the precondition for the penetration of the buprenorphi ne base through the skin.

Suitable solvents for buprenorphi ne within the matrix are those with at least one acidic group. Particularly suitable are the monoesters of dicarboxylic acids, such as monomethyl glutarate and monomethyl adipate. In principle all acids are suitable which dissolve bu-prenorphine to a sufficient extent thereby avoiding complete salt formation. In the latter case, penetration through the skin can no longer be expected.

Permanent contact to the skin is ensured by a sufficient self-adhesiveness of the reservoir layer.

The removable protective layer which is in contact with the reservoir layer and removed prior to application, for example, consists of the same materials as used for the production of the backing layer provided that they are rendered removable, for example, by a silicone treatment. Other removable protective layers, for example, are polytetraf luoroethylene, treated paper, cellophane, polyvinyl chloride, and the like. If the laminate according to the present invention is divided into formats suitable for the therapeutical purpose (plasters) prior to application, the dimensions of the protective layers to be applied thereto may have a projecting end with the help of which the protective layer can be removed from the plaster more eas ly.

The transdermal therapeutic system according to the present invention is produced by mixing homogeneously the active substance together with the components of the pressure-sensitive adhesive reservoir layer, optionally in solution, and spreading it on the backing layer, which is impermeable to the active substance, whereupon the solvent/s is/are removed, if necessary. Subsequentl , the adhesive layer is provided with an adequate protective layer.

In principle, the reverse way is possible too, i.e., that the adhesive solution is spread on the protective layer. The solvents are removed too, and it is covered with the backing layer.

The invention is illustrated by the following examples: Example I: 10.0 g each of glutaric acid monomethyl ester, methanol, and butanone, and 15.0 g 1-dodecanol are mixed under stirring. Subsequently, 10.0 g buprenorphi ne base are added; it is stirred until the solid substance is completely dissolved (approximately 30 min., visual control). Then 133.0 g of a self cross-linking acrylate copolymer of 2-ethyl hexyl acrylate, vinyl acetate, and acrylic acid 46% in a solvent mixture (ethyl acetate : heptane : isopropanol : toluene: ace-tylacetone 37 : 26 : 26 : 4 : 1 ) are added under stirring; homogeni zation follows. Subsequently, 1.3 g aluminum acetyl acetonate are additionally added, and it is stirred at room temperature for 3 hours. The evaporation loss is compensated. 189.3 g 52.8%-wt of active substance-containing adhesive solution are obtained which is spread on an alu-minzed and siliconized polyethylene foil by means of a 350 Mm coating bar. After the solvents have been removed by drying to 60°C for 30 min., the adhesive film is covered with a polyester foil of 15 pm thickness. An area of 16 cm2 is punched by means of suitable cutting tools, the edges are separated off. The release of this example and that of the other examples are shown in the table. The table shows both the control- led release into physiological saline and through excised rodent skin.

All further examples are carried out according to the pattern given in Example I. At first the liquid components are mixed, then the buprenorphi ne base is added. After dissolution of the buprenorphi ne base, optionally a methacrylate copolymer based on dimethyl ami no-ethyl methacrylate and neutral methacrylic esters is added, and, after dissolution thereof, the adhesive solution is added. The following table shows the components of the formulation after drying. Their meanings are as follows: Acryl ate : Acrylate copolymer of 2-ethyl hexyl acrylate, vinyl acetate and acrylic aci d Semi-ester : onomethyl ester of glutaric acid (indicated by G) or adipic acid (indicated by A) G. L. : Pol yethoxylated glycerol with Ce/Cio- ethoxy groups pol ymeri c b: copolymer with basic character based addi ti ves : on dimethylaminoethyl methacrylate and neutral methacrylic esters; n: copolymer with neutral character based on methacrylic methylester and methacrylic butyl ester; PVP: pol vinylpyrrolidone The in-vi tro-release was determined in a shaking-water-bath at 37° C. The acceptor medium was 100 ml physiological saline which was completely renewed after 2, 4, and 8 hours. The concentration was determined by HPLC after 2, 4, and 8, and 24 hours. The penetration through the mice skin was measured on the basis of Franz' diffusion cells.

The release curves according to Example 1 are illustrated in Figure 1 and 2.

Example Acrylate Bupre- Semi- Softener Polymeric Release Penetration norphine ester additive [mg/16cmix24h] of mice skin [mg/2.54cm¾4h] I 65* 10* 10* G 1-dodecanol 15* - 16.0 : 746* 0.95 II 65* 10* 10* G G.L. 10* 5* b 116 ^ 63 * 0.57 I!I 60* 10* 10* G 1-dodecanol 10* 10* b 17.0 = 85 X 0.47 IV 60* 10* 10* G G.L. 10* 10* n - 0.92 V 50* 10* 10* G G.L. 10* 20* n - 0.71 V! 40* 10* 10* G G.L. 20* 20* n - 0.56 VII 50* 10* - G.L. 20* 20* n - 0.09 VIII 80* 10* 5* G G.L, 5* - - 0.28 IX 67.5* 10* 10* G G.L. 10* PVP 2.5* - 0.78 X 65* 10* 10* G G.L. 10* 5* b - 0.44 XI 65* 10* 10* G 1-dodecanol 10* 5* b 14,6 : 77.1* 0.81 XII 75* 10* 10* G - 5* b - 0.22 XIII 70* 10* 2.5* G 1-dodecanol 17.5* - - 0.43 XIV 80* 10* - 1-dodecanol 10* - - 0.11 XV 72.5* 10* 2.5* G 1-dodecanol 10* 5* b - 0.51 XVI 65* 10* 5* G 1-dodecanol 15* 5* b - 0,4 XVII 65* 10* - 1-dodecanol 20* 5* b - 0.1 XVIII 70* 10* 10* G 1-dodecanol 10* - 116 : 65* 0.84 XIX 60* 10* 10* G 1-dodecanol 10* 10* n 15.3 : 68* 0.94 XX 70* 10* 5* G 1-dodecanol 15* - 14.6 - 63.6X 0.64 XXI 65* 10* 10* A 1-dodecanol 15* - 16.5 : 73.1X 0.85 INTERPRETATION OF THE IN-VITRO-RESULTS Examples VII, XIV, and XVII prove the necessity of incorporating into the transdermal systems a solubilizer with at least one acidic group, since the in-vitro-penetration apparently decreases drastically, if such a solubilizer is not present. In these examples the i n-vi tro-penetrati on amounts to 0.1 mg/2.54 cm2 x h. At the same time, Examples I and XXI demonstrate that it is nearly of no importance whether glutaric acid-or adipic acid monomethyl ester is used. Example XII proves that a softener has to be added to the solubilizer, since in the absence of a softener the in-vitro-penetration amounts to 0.22 mg/2.54 cm2 x 24 h, and thus is only slightly above the systems without sol-ubi 1 i zer .

Examples XIV, XIII, XX, and XVIII serve to examine the influence of the quantity of the semi-esters on the in-vi tro-penetration; the semi-ester portion was increased (succession of Examples as stated above) from 0% over 2.5% and 5% to 10%. Due to this, the in-vitro-penetration at the mice skin increased from 0.1 over 0.48 and 0.64 to 0.84 mg/2.54 cm2 x 24 h. When semi-esters are added, the increase of the i n-vi tro-penetration is nearly linear. This is illustrated by the following Figure 3.

The comparison of Examples X and XI shows that 1-dode-canol is preferably used as softener. The other Examples show the influence of the polymeric additives on the i n-vi tro-penetration - the use of these substances is necessary to ensure film formation, adhesiveness, adherence, and coherence.

It is understood that the specification and examples are illustrative but not limitative of the present invention and that other embodiments within the spirit and scope of the invention will suggest themselves to those skilled in the art.

Claims (12)

C L A I M S

1. Transdermal therapeutic system for the administration of buprenorphine to the skin via a backing layer which is impermeable to the active substance, a pressure-sensitive adhesive reservoir layer, and optionally a removable protective layer, in which transdermal therapeutic system the reservoir layer comprises 20 to 90%-wt polymeric material, 0.1 to 30%-wt softener, 0.1 to 20%-wt buprenorphine base or one of the pharmaceutically acceptable salts thereof, and 0.1 to 30%-wt solvent for the active substance base.

2. The transdermal therapeutic system according to claim 1 wherein the backing layer is composed of flexible or inflexible material, perferably of a composite of an aluminized foil.

3. The transdermal therapeutic system according to claim 1 wherein the polymeric material comprises linear styrene-butadi ene-styrene- or styrene- i soprene-styrene blockcopolymer .

4. The transdermal therapeutic system according to claim 1 wherein the polymeric material comprises a self-cross-linking acrylate copolymer of 2-ethyl hexyl acrylate, vinyl acetate, acrylic acid, and titanium chelate ester, or a non-self-cross-linking acrylate copolymer of 2-ethyl hexyl acrylate, vinyl acetate, and acrylic acid.

5. The transdermal therapeutic system according to claim 1 wherein the polymeric material comprises polymers based on methacryl ates , preferably a copolymer based on d meth l ami noethyl methacrylate and neutral methacrylic esters or based on methacrylic methyl-esters and methacrylic butyl esters.

6. The transdermal therapeutic system according to claim 1 wherein the polymeric material comprises polymers based on hydrogenated colophony, preferably on the methylesters or glycerol esters of hydrogenated col ophon .

7. The transdermal therapeutic system according to claim 1 wherein the polymeric material comprises polyvinylpyrrolidone or polyvinyl alcohol.

8. The transdermal therapeutic system according to claim 1 wherein the reservoir layer comprises dode-canol as softening agent.

9. The transdermal therapeutic system according to claim 1 wherein the reservoir layer comprises as softener pol ethoxyl ated glycerol with Ce /Ci o -ethoxy groups, part of the free hydroxyl groups of which are esterified with capryl ic/capric acids.

10. The transdermal therapeutic system according to claim 1 wherein the buprenorphi ne solvent within the reservoir layer is a compound with at least one acidic group .

11. The transdermal therapeutic system according to claim 10 wherein the compound with at least one acidic group is a monoester of a dicarboxylic acid.

12. The transdermal therapeutic system according to claim 11 wherein the monoester of a dicarboxylic acid is glutaric acid- or adipic acid-monomethylester . For the Applicants""" — OR REiNHOmOMN AND PARTNERS