SI9012260A - Process for preparation of transdermal therapeutic systems containing buprenorphine as the 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

Buprenorphine is a partially synthetic opiate whose advantage over other compounds of this class of compounds lies in its higher activity. Navoy knows that pain relief for patients with cancer or a tumor with an unfavorable end-stage diagnosis can be achieved with a daily dose of about 1 mg.

But two significant problems - opiates - do not solve Buprenorphine, namely the subtle habit. and low bioavailability of the ovine-coated substance. Thus, from the gastrointestinal tract, bioavailability is approximately only IC.j and in sublingual administration also only about 5CM ·

Technical problem

In the recent past, she has certainly been represented

The original assumption of low potential,. Habits of 3uprenorphine after its introduction as a pain reliever

Subsequently, the increase in abuse by drug addicts is subject to the Buprenorphin Federal German Drug Law.

-2 tense that the form of the drug contributes to the potential of the drug habit. This can easily be confirmed for very active analgesics in the therapy of extremely high pain.

Immediately after administration, the blood levels of the painkiller are higher than necessary and cause euphoria, but then decrease exponentially and quickly reach a level in the blood that can no longer be successfully treated. Based on his pain, the patient begins to crave the next dose, thus creating a habit iatrogenically. A continuous infusion would therefore be a choice of form of medicine for Buprenorphine and other highly active opiates to avoid this iatrogenic habit formation at a constant blood level.

Permanent infusion, however, cannot be performed and controlled in the braking connection without medical attention and often leads to inflammation at the cannula's inlet.

Neither can the oral depot formulation be suitable for the Buprenorphine drug system, since, due to the low bioavailability of oral administration, approximately 10 times the amount of active substance should be given in comparison to the required intravenous dosage. But here Buprenorphine, as a partial opiate antagonist, causes so many problems, since the respiratory depression caused by an overdose of the active substance cannot be treated by administering an antagonist, something Nalorphin, the antidote of choice for opiate poisoning. An overdose can be given since oral bioavailability is admittedly 10%, but this can be absolutely higher since Buprenorphine should be given to patients who have to deal with liver disorders so that more than 10% can the first passage of the liver to come out not metabolized.

In addition, oral depot forms are not optimal in every respect, as developments in the drug market in recent years clearly show. Generics with the same in vitro release as origi5 primers do not have the same escape activity as. c you obviously have blue preparations, which means that uncontrolled release in vivo can lead to overdose or underdose. Both are particularly fatal with Buprenorphin. If the patient does not dose enough, the patient suffers severe pain. If overdosed, fatal respiratory depression, which cannot be treated with Nalorphin, can occur in the worst case.

Until now, it has not been taken into account that the oral depot form, which is damaged and therefore does not retard Buprenorphine, but releases it at once (known in English as dOSedumping) cannot immediately; sc is removed from the human body.

All restrictions described so far. Against the form of a slow-release drug Beprenorphin avoids the benefits of transdermal therapy systems, since medication does not have to be injected into the human body through cannulas. At the same time, the drug is supplied to O.red, who can be interrupted at any time. The transdermal therapy system seems to be the girl for Bupranorphin as a form of drug of choice.

But torn states that because of its high molecular mass (mm 465) and above all because of its high point melting and its probable poor solubility in organic solvents in use and water, Buprenorphine penetrates the scheme extremely poorly through human skin, since diffusion, the assumption is for penetration through human skin, it requires soluble substances. But solubility should not be increased by salt formation, since the bases are not absorbed in ionized form.

Until the day _with s, Buprenorphine failed to transdermally transduce the required amount transdermally, although for the reasons described above, TTS for this active substance represents the best possible form of the drug.

The object of the present invention is to provide a process for the manufacture of a transdermal therapeutic system, which Burprenor or one of its pharmaceutically tolerable salts gives a controlled control over a 24-hour interval and guarantees that Burprenorphin does not decompose significantly during storage of the pre-fabricated transdermal system and ensures that insufficiently permeable to the skin Buprenorphine penetrates to the extent required in vivo through human skin.

Description of a solution to a technical problem with examples of execution

This task is surprisingly solved by the invention according to the invention for the manufacture of a transdermal therapeutic system for the administration of Buprenorphin on the skin, consisting of a back layer impermeable to the active substance, a layer of a reservoir that adheres to the skin and, in this case, a removable protective layer, and is by homogenizing a mixture of 20 to 90% by weight of polymeric material, 0.1 to 30% by weight of softener, 0.1 to 20% by weight to produce a reservoir layer. buprenorphine base or one of its pharmaceutically acceptable salts and 0.1 to 30 wt-% solvents for the active substance base with the possible addition of easily volatile solvents and applied to the backing or protective layer, after which the easily volatile solvents are removed.

When referring to burprenorphine, its chemical composition is (17-cyclopropylmethyl) α- (1,1-dimethylethyl) -4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-α-methyl-6. 14etenomorphinan-7-methanol.

-4aThis is even more strange since Buprenorphine, as mentioned, has only 50% bioavailability sublingually. Since the first passage of the liver is bypassed in this type of administration, the low bioavailability may be reduced to insufficient ability to absorb the substance by oral mucosa. But matter, which passes through the mucous membrane of the mouth only hard, is just difficult to receive by human skin. The active substance impermeable back layer may consist of flexible or inflexible material. The substances that can be used to make it are polymer films or metal films, such as aluminum foils, which are still applied alone or coated with a polymer substrate. Textile flat products may also be applied if tank constituents cannot, through their physical properties, pass through them.

In the embodiment, the backing layer is assumed to be a bonding material, for example, of a foil not deposited in a steam wick.

The reservoir layer consists of a polymeric matrix and an active matrix, with the polymeric matrix guaranteeing the connection of the system. It consists of a basic polymer and, in the case in question, conventional additives. ^ The assembly of the basic polymer is zealous for the chemical and physical properties of Buprenorphin. Examples of polymers are rubber, rubber-like, synthetic mono-, co- or block-polymers, polyacrylic acid esters and its copolymers, polyurethanes and silicones. All polymers, which can be used for making adhesive adhesives and are not physiologically suspicious, are generally considered. In particular, matches are made consisting of block polymer n? styrene and 1,3-diene, polyisobutylene, acrylate-based polymers and / or methacrylate8.

Cd block copolymers based on styrene and 1.5 “dienes are particularly suitable for linear styrene-isoprene or styrene-butadiene block polymers.

Acrylate-based polymers include self-crosslinking acrylate copolymers of 2-ethylhexyl acrylate, vinyl ecetate-1-acrylic acid, or acrylate copolymers without titanium ------- chelate ester, which do not crosslink themselves.

^K ao polymers koji were added to osnovnom polymer they come in consideration polimetekrilsti, esters hidrirenog kolofonijurns and polyvinyl !.

Methacrylates are assumed to be copolymers based on dimethylaminoethyl methyl methacrylate and neutral methacrylic acid esters. ^{xi and} the esters of hydrated rosin are used primarily with methyl and glycerine esters, Keo-polyvinyls with 'st' v 'are primarily polyvinyl pyrrolidones and polyvinyl alcohols.

The type of common additives depends on the polymer formed: according to their function, they can be divided, for example, into adhesives, stabilizers, carriers and fillers. The expert is aware of the physiologically unsubstantiated substances that come to mind.

According to the invention, it has been shown that the required softener in connection with ^ uprenorphine is for transdermal administration of Buprenorphine.

The choice of softener is controlled by polymer, preferably higher alcohols such as dedecanol, undecanol, octanol and carboxylic esters are suitable wherein the alcohol component may also be polyethoxylated alcohol, dicarboxylic acid diesters lin8, not ^ example di * »n-butyl oedipate as and triglycerides, in particular the mid-chain triglycerides of capri1 / capric acids of & c axis. Further examples of suitable softeners are multivalent alcohols, e.g., glycerin and propanediol * (1,2), which may also be etherified by polyethylene glycols.

The role of the solvent for the Buprenorphine base is confirmed by examples. They show that the solvent is an ingredient that cannot be dispensed with in the recipe, the softener / solvent combinations according to the teachings of the invention create an assumption for the penetration of Buprenorphine birch through the skin.

As a matter of fact, 8-chi-buprenorphine in the matrix is found to be a single acidic group. Particularly suitable are dicarboxylic acid monoesters, e.g., monomeryl glutarate and monomethyl adipet. All acids, which are sufficiently dissolved by Buprenorphine without reaching complete salt formation, are taken into consideration, since in the latter case no more ds can be counted on penetrating the skin.

The reservoir layer has such a general adhesiveness that it provides a lasting touch for the skin. The detachable protective layer, which is in contact with the reservoir layer and is removed prior to application, consists, for example, of the same materials as they are used to make the back layer, assuming ds are rendered detachable, such as silicon rite. Other detachable protective layers are e.g. polytetrafluoroethylene, treated paper, cellophane, polyvinyl chloride, etc. If the laminate according to the invention is applied prior to application of a protective layer. divide into therapeutic. suitable formats (fl8sters), then the formats of the coating to be applied have leakage discharges, which can be easily removed from the patch.

The transdermal therapeutic system of the invention is fabricated, which, together with the components of the adhesive reservoir layer, is homogeneously mixed in the solution in this case and coated on the last layer impermeable to the active substance, after which the solvent or solvents are removed / removed. . The adhesive layer is then supplied with a protective layer.

It is also possible in principle to reverse the way the adhesive solution is coated with the protective layer. The ' ^A ' nodes are removed in this case as well, and then covered with the backing. The invention is explained by the following Examples:

Example__X:

10.0 g of glutaric acid monomethyl ester, methanol and butanones and> 15 »0 g of 1-dodecanol are mixed with stirring. Then 10.0 Buprenorphine bases are introduced; until complete solids are recovered (approx. $ 0 oin, visual inspection). With ₈ , 133 »θ g of a self-cross-linked acrylate copolymer of 2-ethylhexyl 8-acrylate, vinyl acetate and 46% acrylic acid were added in a solvent mixture (ethyl acetate: heptane: from opio ^ anol: -tol-ol: acetylacetone 37: 26) : 26: 4: 1); it is homogenized. Subsequently, 1.3 g of aluminum acetylacetonate are further stirred with stirring and stirred for 3 hours at ambient temperature. Evaporation loss is compensated.

189.3 6 52.8 wt-% solution of adhesive containing the active substance is formed, which is mixed with the help of 350 pm gap for application to aluminized or siliconized polyethylene! foil. Subsequently, the salt was removed by solvent for 3 minutes by drying to 60 ° C, covering the adhesive layer with polyester film for 15 hours. With a suitable cutting tool, they cut 16 cm and cut; loosen edges · The release of this and other recipe examples are listed in the Table; topics are listed as controlled release in saline and through cut rodent skin.

All of the examples are prepared according to the scheme of Example I. The liquid constituents are always mixed, followed by Buprenorphine. After its dissolution, a matacrylate copolymer based on dimethylaminoethyl methacrylate and neutral methacrylic acid esters is added in this case and after their dissolution a glue solution is added. The following Table lists the ingredients of the recipe after drying. In doing so, they mean:

Acrylic: An acrylic copolymer of 2-ethylhexylacrylate, vinyl acetate and acrylic acid. _________ Glutaric monomethyl ester (designated aid

G) or. adipic acids (indicated by A)

G.L .: Polyethoxylated glycerin with Cg / C ^ g-ethoxy groups

Polymeric additives: b: copolymer having a base character based on di methylgminoethyl methacrylate and neutral / methacrylic acid esters n: The copolymer does not escape the methacrylic acid esters and butyl methacrylic acid esters

PVP: polyvinyl pyrrolidone in vitro release is determined in a bath shaker at 37 ° C · Acceptor media were 100 ml of saline, completely altered after 2} 4 and 8 sets Concentration was determined after 2, 4 and 8 and 24 Set help with HPLC. The penetration of non-mouse skin was measured not by Frenz diffusion cells.

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Interpretation of in vitro results

Examples VII, XIV, and XVII confirm the need for dermal systems to interfere with at least one acidic group in instantaneous dermal systems, since without such a solvent, in vitro penetration is clearly drastically reduced. in vitro penetration in all three primers lies at 0.1 mg / 2.54 cm x h. At the same time, Examples I and XXI show that virtually no in vitro penetration plays a role, whether monomethyl ester of glutaric acid or oedipic acid. Example XII serves as proof that in addition to the solvent mediator, a softener must be placed, since without fcce lies in vitro propagation of 0.22 mg / 2.54 2 cm x 24 just slightly below the penetration of the solvent-free system by the "mean" 8.

Examples XIV, XIII, XX and XVIII serve to investigate the effect of the amount of polyester on in vitro penetration; u ovom radosledu is povišavan udao poluastra from 0% over 2.5% and 5% not 10 ¢, ^h e Report of NaCl is increased, and the in vitro penetration of the skin of a mouse of 0.1 over 0.48 and 0.64 to * S, 84 mg / 2.54 cm ^ χ 24 h. The business of adding a peninsula increases the in vitro penetration approximately linearly. This \ is shown in the next Section 5 ·

A comparison of Example ^ X and XI shows that "l-dodecanol is assumed to be a softener. Other Examples show how polymer additives are exerted on the in vitro penetration, since the application of these materials is necessary to guarantee the formation of a film of adhesive, adhesion and cohesion forces.

Claims (11)

PATENT APPLICATIONS 1. A process for the manufacture of a transdermal therapeutic system for administering buprenorphine to the skin, consisting of an active substance of an impermeable back layer, a adhesive adhesive layer, and possibly a removable buffer layer, characterized in that, for the manufacture of a reservoir layer of homogeneous% by weight, polymeric material, 0.1 to 30% by weight of plasticizer, 0.1 to 20% by weight of buprenorphine base or one of its pharmaceutically acceptable salts, and 0.1 to 30% by weight of solvents for the active substance with the possible addition of volatile solvents and applied on the back layer or on the protective layer, after which the volatile solvents can be removed. Method according to claim 1, characterized in that for the manufacture of a reservoir containing 20 to 90% by weight of polymeric material, 0.1 to 30% by weight of plasticizer, 0.1 to 20% by weight of buprenorphine base or its pharmaceutically acceptable salts and 0.1 to 30% by weight of solvents for the active substance base, first mix the liquid component of the solvent and the plasticizer, then introduce the buprenorphine active substance and after dissolving it add the polymeric material containing adhesive solution and apply the adhesive-containing solvent after homogenizing dorsal or. protective layer and removes volatile solvent. Method according to claim 1, characterized in that the active substance-containing adhesive solution is applied to the backing layer of flexible / 3 or inflexible material, preferably, of a bonded aluminum foil material. Process according to claim 1, characterized in that a reservoir layer is formed using polymeric material made of linear styrene · butadiene styrene or styrene isoprene styrene block polymers. Method according to claim 1, characterized in that a reservoir layer is formed using a polymeric material from a self-cross-linked acrylic copolymer of 2-ethylhexyl acrylate, vinyl acetate, acrylic acid or titanacetate, or a non-cross-linked acrylate-copolymer of 2-ethylhexyl acrylate acrylate. A process according to claim 1, characterized in that a reservoir is formed using a polymeric material to which methacrylate-based polymers, preferably copolymers based on dimethylaminoethylmethacrylate and neutral methacrylic acid esters or methacrylic acid methyl ester, are added. A process according to claim 1, characterized in that a reservoir is formed using a polymeric material to which polymers based on hydrated rosin, preferably its methyl or glycerine ester, are added. Process according to claim 1, characterized in that a reservoir layer is formed using a polymeric material to which polyvinylpyrrolidone or polyvinyl alcohol is added. 9. A process according to claim 1, characterized in that the layer is formed using a dodecanol as a plasticizer. A process according to claim 1, characterized in that a reservoir is formed using polyethoxylated glycerin with ethoxy groups Cg / Cj ^, whose free hydroxyl groups are partially obscured by caprylic / capric acid, as a plasticizer. A process according to claim 1, characterized in that as a solvent for buprenorphine in the reservoir layer a compound with at least one acidic group, preferably a dicarboxylic acid monoester, in particular preferably a glutaric acid ester or adipic acid monomethyl ester.