CA2030178C

CA2030178C - Transdermal therapeutic system comprising as active component buprenorphine

Info

Publication number: CA2030178C
Application number: CA002030178A
Authority: CA
Inventors: Thomas Hille; Lothar Deurer; Hans-Rainer Hoffmann
Original assignee: LTS Lohmann Therapie Systeme AG
Current assignee: LTS Lohmann Therapie Systeme AG
Priority date: 1989-11-29
Filing date: 1990-11-16
Publication date: 1995-08-15
Anticipated expiration: 2010-11-16
Also published as: CZ282557B6; PL287989A1; KR950015061B1; DE59010192D1; HUT55643A; JPH03193732A; SI9012260B; ZA909544B; NO905103L; NO905103D0; YU226090A; DK0430019T3; HRP930675A2; GR3020177T3; KR910009249A; HU206266B; IE904290A1; IE73247B1; MY105347A; SI9012260A

Abstract

The controlled release of buprenorphine or the pharma-ceutically acceptable salts thereof to the skin over a period of time of at least 24 hours is ensured by a transdermal therapeutic system consisting of a backing layer which is impermeable to the active substance, a pressure-sensitive adhesive reservoir layer, and op-tionally a removable protective layer. Said reservoir layer of said system comprises 20 to 90%-wt polymeric material, 0.1 to 30%-wt softener, 0.1 to 20%-wt bupre-norphine base or one of the pharmaceutically accepta-ble salts thereof, and 0.1 to 30%-wt solvent for the active substance base.

Description

DESCRIPTION

The present invention relates to a transdermal thera-peutic system (TTS) which contains as active component buprenorphine (17-(cyclopropylmethyl)-a-(1,1-dimethyl-ethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-a-methyl-6,14-ethenomorphinane-7-methanol).

Buprenorphine is a partially synthetic opiate. Com-pared to other compounds of this class of substances, the advantage of buprenorphine is higher effective-ness. 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 bioavaila-bility of these substances in case of oral administra-tion. For example, the bioavailability from the gas-trointestinal 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, bupre-norphine is subject to the German narcotics act, afterit 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 ad-diction. This can easily be understood in case of high-potency analgesics in the therapy of extreme paln.

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 pa-tient starts to long for the next dosage - an iatro-genic addiction is created.

In case of buprenorphine 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 domi-3 2~3~17~

ciliary care; inflammations frequently result at theplace where the cannula is inserted.

Even an oral depot preparation cannot be the suitable form to administer buprenorphine, since the low bio-availability in case of oral application requires ap-proximately ten times the amount of active substance compared to the required intravenous dosage. In this connection, buprenorphine, as partial opiate antago-nist, involves great problems, since a respiratory depression caused by an overdosage of the active sub-stance cannot be treated by the administration of an antagonist, such as nalorphine which is the suitable antidote in case of poisonings caused by opiates. Al-though the oral bioavailability for buprenorphine is stated to be 10%, overdosages may nevertheless occur, since buprenorphine shall also be administered to pa-tients with the probability of liver function disturb-ances 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 medici-nal 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 effective-ness as those original preparations. This means that overdosages and underdosages may arise due to uncon-trolled release in vivo. Both cases are disastrous in case of buprenorphine. In case of underdosage, the patient suffers from intense pain. In case of over-dosage, fatal respiratory depressions which cannot be treated with nalorphine could be the most severe con-sequence.
In addition, it has been left out of consideration until now, that an oral depot preparation which became damaged and thus does not retard buprenorphine, but releases it at one blow (called "dosedumping" among experts) cannot immediately be removed from the human body.

The reservations with respect to forms of administra-tion which release buprenorphine in a retarded manner are avoided by the merits of the transdermal thera-peutic 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 O.order is safeguarded; the supply may be interrupted at any time by tearing the system off. Thus, transdermal therapeu-tic systems seem to be the most suitable form to ad-minister buprenorphine.

However, one has to consider the objection that bupre-norphine 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 sub-stances.
On the other hand, the solubility must not be increas-ed by salt formation, since bases in ionized form are not absorbed.
Until today, all attempts failed to bring buprenor-phine 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 administra-tion for this active substance.

It is accordingly the object of the present invention to provide buprenorphine or one of the pharmaceutical-ly compatible salts thereof in the form of a transder-mal therapeutic system which releases buprenorphine or the pharmaceutically acceptable salt thereof over a period of at least 24 hours in a controlled manner and 20~0178 ensures that the buprenorphine does not notably decom-pose when the prefabricated transdermal therapeutic system is stored, and which further ensures that bu-prenorphine, 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 ther-apeutic system for the administration of buprenorphine to the skin. The system comprises a backing layer which is impermeable to the active substance, a pres-sure-sensitive adhesive reservoir layer, and, option-ally, a removable protective layer, and is character-ized in that 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 pharmaceu-tically 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 admin-istered sublingually. Since the first liver passage is evaded by this mode of application, the low bioavaila-bility can only be due to insufficient absorbability of the substance by the oral mucosa. However, a sub-7 203~1 7~

stance which only hardly passes the mucosa of themouth, 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 mate-rial. 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 foil.

The reservoir layer consists of a polymeric matrix and the active substance, whereby the polymeric matrix en-sures the coherence of the system. The polymeric mat-rix consists of a basic polymer and, optionally, con-ventional additives. The selection of the basic poly-mer depends on the chemical and physical properties of the buprenorphine. Examples of polymers are rubber, rubber-like synthetic homo-, co- or blockpolymers, polyacrylic esters and the copolymers thereof, poly-urethanes and silicones. In principle all polymers are suitable which can be used in the production of pres-8 203~I78 sure-sensitive adhesives and which are physiologically acceptable. Particularly preferred are those consist-ing of block copolymers based on styrene and 1,3-dienes, polyisobutylenes, polymers based on acrylate and/or methacrylate.

Amongst the blockcopolymers based on styrene and 1,3-dienes, linear styrene-isoprene-blockcopolymers or styrene-butadiene-blockcopolymers 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-linking ac-rylate copolymers without titanium chelate ester are preferred for the use as acrylate-based polymers.

Suitable polymers which are added to the basic polymer are polymethacrylates, esters of hydrogenated colopho-ny, and polyvinyls.

Copolymers based on dimethylaminoethyl methacrylates and on neutral methacrylic 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. Poly-203~78 vinylpyrrolidones and polyvinyl alcohols are prefer-ably used as polyvinyls.

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

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 buprenorphine.

The choice of softener depends on the polymer. Higher alcohols, such as dodecanol, undecanol, octanol, the esters of carboxylic acids whereby the alcohol compo-nent may also be a polyethoxylated alcohol, diesters of dicarboxylic acids, such as di-n-butyladipate and triglycerides, particularly medium-chain triglycerides of the caprylic/capric 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.

203~78 - -The significance of the buprenorphine solvent is proved by the examples. The examples show that the solvent is an indispensable component of the formula-tion. The combination softener/solvent according to the teaching of the present invention builds the pre-condition for the penetration of the buprenorphine base through the skin.

Suitable solvents for buprenorphine 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, penetra-tion through the skin can no longer be expected.

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

The removable protective layer which is in contact with the reservoir layer and removed prior to appli-cation, 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 11 ~o~al7s silicone treatment. Other removable protective layers, for example, are polytetrafluoroethylene, treated pa-per, 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 dimen-sions 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 easily.

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, op-tionally 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.
Subsequently, 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 exam-ples:

ExamPle I:

10.0 9 each of glutaric acid monomethyl ester, methan-ol, and butanone, and 15.0 9 1-dodecanol are mixed under stirring. Subsequently, 10.0 9 buprenorphine base are added; it is stirred until the solid sub-stance is completely dissolved (approximately 30 min., visual control). Then 133.0 9 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 stir-ring; homogenization follows. Subsequently, 1.3 9 alu-minum acetylacetonate are additionally added, and it is stirred at room temperature for 3 hours. The evapo-ration loss is compensated.
189.3 9 52.8%-wt of active substance-containing adhe-sive solution are obt~ined which is spread on an alu-minzed and siliconized polyethylene foil by means of a 350 ~m coating bar. After the solvents have been re-moved by drying to 60C for 30 min., the adhesive film is covered with a polyester foil of 15 ~m thickness.
An area of 16 cm2 is punched by means of suitable cut-_ 13 203a~7~

ting tools, the edges are separated off. The releaseof 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 compo-nents are mixed, then the buprenorphine base is added.
After dissolution of the buprenorphine base, optional-ly a methacrylate copolymer based on dimethylamino-ethyl methacrylate and neutral methacrylic esters is added, and, after dissolution thereof, the adhesive solution is added. The following table shows the com-ponents of the formulation after drying. Their mean-ings are as follows:

Acrylate: Acrylate copolymer of 2-ethyl hexyl acrylate, vinyl acetate and acrylic acid Semi-ester: Monomethylester of glutaric acid (in-dicated by G) or adipic acid (indicated by A) G.L.: Polyethoxylated glycerol with C8 /Ct O -ethoxy groups polymeric b: copolymer with basic character based _ 14 2~30~7Y

additives: on dimethylaminoethyl methacrylate and neutral methacrylic esters;
n: copolymer with neutral character based on methacrylic methylester and methacrylic butyl ester;
PVP: polyvinylpyrrolidone The in-vitro-release was determined in a shaking-wa-ter-bath at 37C. The acceptor medium was 100 ml phys-iological 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 illus-trated in Figure 1 and 2.

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~ 16 2 030~ 7 INTERPRETATION OF THE IN-VITRO-RESULTS

Examples VII, XIV, and XVII prove the necessity of in-corporating 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 in-vitro-penetration amounts to 0.l 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 monomethylester is used. Example XII
proves that a softener has to be added to the solubil-izer, 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-ubilizer.

Examples XIV, XIII, XX, and XVIII serve to examine the influence of the quantity of the semi-esters on the in-vitro-penetration; the semi-ester portion was in-creased (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 in-vitro-pen-203~8 _ 17 etration 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 Exam-ples show the influence of the polymeric additives on the in-vitro-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 in-vention and that other embodiments within the spirit and scope of the invention will suggest themselves to those skilled in the art.

Claims

1. A transdermal therapeutic system for the administration of buprenorphine, as active substance to the skin via a backing layer which is impermeable to the active substance and a pressure-sensitive adhesive reservoir layer, in which transdermal thera-peutic 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. A transdermal therapeutic system according to claim 1 further comprising a removable protective layer.

3. A transdermal therepeutic system according to claim 1 wherein the backing layer is composed of flexible or inflexible material.

4. A transdermal therapeutic system according to claim 1 wherein the backing layer is composed of a composite of an alumin-ized foil.

5. A transdermal therapeutic system according to claim 1 wherein the polymeric material comprises linear styrene-butadiene-styrene- or styrene-isoprene-styrene blockcopolymer.

6. A 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.

7. A transdermal therapeutic system according to claim 1 wherein the polymeric material comprises polymers based on methacrylates.

8. A transdermal therapeutic system according to claim 1 wherein the polymeric material comprises a copolymer based on dimethylaminoethyl methacrylate and neutral methacrylic esters based on methacrylic methylesters and methacrylic butyl esters.

9. A transdermal therapeutic system according to claim 1 wherein the polymeric material comprises polymers based on hydrogenated colophony.

10. A transdermal therapeutic system according to claim 1 wherein the polymeric material comprises polymers based on the methylesters or glycerol esters of hydrogenated colophony.

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

12. A transdermal therapeutic system according to claim 1 wherein the reservoir layer comprises dodecanol as softening agent.

13. A transdermal therapeutic system according to claim 1 wherein the reservoir layer comprises as softener polyethoxylated glycerol with C8/C10-ethoxy groups, part of the free hydroxyl groups of which are esterified with caprylic/capric acids.

14. A transdermal therapeutic system according to claim 1 wherein the buprenorphine solvent within the reservoir layer is a compound with at least on acidic group.

15. A transdermal therapeutic system according to claim 14 wherein the compound with at least one acidic group is a monoester of a dicarboxylic acid.

16. A transdermal therapeutic system according to claim 15 wherein the monoester of a dicarboxylic acid is glutaric acid- or adipic acid-monomethylester.

17. A transdermal therapeutic system according to any one of claims 3 to 16 further comprising a removable protective layer.

18. The use of a transdermal therapeutic system according to any one of claims 1 to 16 as an analgesic.

19. The use of a transdermal therapeutic system according to claim 17 as an analgesic.