Transdermal therapeutic systems with improved stability and a method for the production thereof

Description

Transdermal therapeutic systems (TTR), if we disregard the special forms that are rarely used, can be classified into two basic types, the so-called matrix systems and the so-called reservoir systems. In the simplest case of the so-called matrix systems, the active ingredient is dissolved in a self-adhesive layer, Hl. partly in the form of crystals, only suspended or dispersed. Reservoir systems form a kind of bag with an inert back layer and a membrane permeable to the active ingredient; the active ingredient is in the bag in the form of a liquid preparation. The membrane is usually provided with an adhesive layer, with which the system is fixed on the skin. Regardless of the different embodiments of transdermal systems, during use the active ingredient is delivered to the skin by diffusion and must therefore be at least partially dissolved. In the dissolved state, the active substance is particularly prone to react with the ingredients of the formulation, which can lead to a decrease in stability. Such reactions include the following: a) the active ingredient is attached via an amide or ester bond to the carboxyl or ester groups of the polymers or permeation enhancers used; b) the carboxyl or ester group of the active ingredient may react with the alcohol groups of the adhesion promoter resins or permeation agents; e) ester groups can undergo hydrolysis or alcoholysis in the presence of water or alcohol. Such reactions arise directly from the reactive groups of the active ingredients and excipients and are not surprising to the skilled person. The stability risk is usually quickly eliminated by compatibility tests at elevated temperatures and the unfavorable combination of active ingredient and excipient is eliminated. The stability of the active ingredient and excipients is also compromised by reaction with active oxygen. Of course, oxygen in the air is also active oxygen. The active ingredient in a transdermal therapeutic system is effectively protected from oxygen by packaging the transdermal system under a nitrogen atmosphere and / or by additionally placing an antioxidant in the package. Despite the above precautions, when transdermal systems containing active ingredients sensitive to oxidation are stored for a longer period of time, a greater or lesser decrease in the active ingredient content has often been observed. The reason for this has not been known. Surprisingly, we have found that the raw materials used to produce TTR systems can contain a significant amount of active oxygen in another form, namely in the form of hydroperoxide. These hydroperoxides can be formed according to the following mechanism according to the autoxidation reactions described in the literature: Equation (la): in the first step, the so-called induction phase, a free radical is formed by the loss of a hydrogen atom under the influence of heat and light, aided by traces of heavy metals. Equation (lb): in the second step, these radicals react with oxygen, forming peroxide radicals. Equation (lc): these peroxide radicals attack further molecules, forming hydroperoxide and another free radical. This starts a chain reaction that continues until this chain is broken by the reaction of two radicals with each other, as shown, for example, in equation (Id). Due to its relatively low reactivity, the peroxide radical acting as a chain transfer agent is particularly susceptible to attack at sites where the energy on the substrate is X * φ X* is formed. Such exceptional sites are the C-H bonds, tertiary C-H bonds and CR bonds in the vicinity of ether oxygen in the benzyl or allyl group. According to E, especially raw materials that have such groups are prone to the formation of hydroperoxide. Antioxidants, or stabilizers, used to protect active ingredients sensitive to oxidation can interfere with the above reaction. Antioxidants can be divided into radical scavengers and oxygen scavengers. Radical scavengers, such as tocopherol and its derivatives, remove or inactivate radicals and thus interrupt the chain mechanism of autoxidation. Oxygen scavengers, such as ascorbyl palmitate, react directly with the oxidizing agent, thus preventing the initiation of the chain reaction. However, the addition of antioxidants / sialibilizers is only effective if the starting materials do not contain oxidizing hydroperoxides and the pharmaceutical product is protected from the effects of oxygen by suitable packaging. Surprisingly, we found that in all raw material groups used for the production of transdermal therapeutic systems - with the exception of film-shaped materials - there are materials that are already loaded with a considerable amount of hydroperoxide during transport or after a short storage. This means in particular that polymers, adhesion-enhancing resins, permeation promoters, solvents and solubilizers can contain so much hydroperoxide that the stability of the oxidation-sensitive active ingredient can be greatly impaired. The peroxide content is usually expressed as POZ, the so-called peroxide value, which gives how many milliequivalents of active oxygen are present in one kg of a substance. There are various methods for determining the peroxide value, the most commonly used being the reaction of a defined amount of a substance in a chloroform-acetic acid solution with an excess of iodine ions, followed by the precipitation of the resulting iodine with sodium hydroxide. * ♦ * Less commonly used and only applicable in aqueous solutions is the reaction of the substance with titanium(IV) ions, followed by photometric determination of the formed peroxo-complex. A semi-quantitative peroxide test with commercially available test strips is particularly simple in execution. The table below shows the measured peroxide values ​​of some selected materials suitable for the production of reservoir and matrix systems after approximately 6 months of storage at room temperature. The peroxide values ​​were measured using the two methods mentioned above. Raw Material Function COOKING Hydrocarbon resin Matrix part 180 Kolbdon Matrix part 110 Partially hydrogenated glycerin ester of pine rosin adhesion promoter 190 Pine rosin, hydrogenated glycerin ester adhesion promoter 80 Poly-β-pyrene adhesion promoter 1.50 Diethyl glycol-mottoethyl ether solvent / permeation promoter 120 Oleyl alcohol solvent / permeation promoter 50 Lintonene permeation promoter 15 The peroxide value of the finished plasters can be determined by the same method, although there is some difficulty in dissolving enough plasters in a not too large amount of chloroform. It is simpler to measure the peroxide value of each substance and calculate the peroxide value of the active ingredient part of the plaster using the following equation: n Σ (N; POZ / lOO) i-í n: the number of components of the active ingredient part of the system N: percentage of the components of the active ingredient-containing part of the system (numerical value) ΡΟΖ: peroxide number of each component. Experimentally, we have found that peroxides in raw materials can react very differently with the active ingredient in contact with them. Active ingredients that have one of the following structural parts have proven to be particularly sensitive: » secondary or tertiary anion groups * CC-double bonds * CH-groups in the alkyl position * benzylic CH-groups « tertiary CH-groups » parent or sulfoxide groups. The corresponding reaction products are shown by reaction equations (2a), (2b), (2c), (2d), (2e), (2f), and (2g), in which R is an organic group. In many cases, these reactions trigger further reactions on the reactive groups of the active ingredients. For example, we found that in the case of 1?$-estradiol, hydroxylation first occurs at the benzyl position (C 9), and then the hydroxyl group is removed as water during the formation of A9(l 1)--I7p-estradiol {Scheme (3)]. This reaction is preferred because it involves the formation of a conjugated double bond, In the case of an active ingredient containing an anion-substituted tetrahydronaphthol fragment (N-0923), we found that an N-oxide is first formed, which reacts further during an elimination reaction (Cope elimination) to form dihydronaphthol and hydroxyanion ((Scheme 4))]. In the case of dihydropyridine-type calcium antagonists, the decomposition mechanism shown in Schemes (5a) and (5b) was found. It is not clear whether the first attack occurs on the nitrogen atom or the tertiary CH bond of the dihydropyridine ring, but water cleavage occurs here as well, which is energetically preferred due to the formation of an aromatic state. The further reaction to the N-oxide following the oxidation of the dihydropyridine ring was observed only in the reaction with t-butyl hydroperoxide [Scheme 5b). In patch systems, the amount formed is too small to be observed in the case of low conversion. The above examples show that the reaction products do not always show that hydroperoxides are directly involved in the decomposition reaction. In order to determine how sensitive an active ingredient is to hydroperoxide oxidation processes, a simple test has been developed. In this process, the active ingredient is reacted with tert-butyl hydroperoxide in chloroform or another suitable solvent under reflux. If oxidized decomposition products of the active ingredient are found in the reaction mixture, these can only be traced back to the hydroperoxide reaction. Often, the decomposition of the active ingredient can be determined very simply from the discoloration of the test solution. If the test results in a positive result, it can be concluded that a transdermal system with the given active ingredient can only be prepared if excipients that are practically free of hydroperoxides are used. The object of the present invention is to develop a transdermal therapeutic system (TTR) in which the formation of oxidation degradation products of the oxidation-sensitive active ingredient contained therein during storage is reduced. As already explained, the solution to the problem is that during the production of TTR containing one or more oxidation-sensitive active ingredients, only such excipients are used which are almost completely free of hydroperoxide. According to the invention, these are excipients which have a peroxide number (P0Z) in the proportion given in the TTR formulation of up to 20, preferably up to 10, particularly preferably up to 5, tr « «« » X ♦ ♦ * X β ♦ ♦ * ♦ 0 » 0 Μ * 9 4 » > * «0 0 XX 0 0« The term excipients here means all substances of the TTR containing the active ingredient, with the exception of the active ingredient(s). These include: hydrocarbon polymers as materials for the single- or multi-layer matrix or reservoir system, such as polyethylene, polypropylene, polyacrylate, polymethacrylate, polyurethane, polyisobutylene, polyvinyl pyrrolidone; hydrocarbon resins, such as silicones, rubber; copolymers of vinyl pyrrolidone with acrylic acid, acrylic acid derivatives, ethylene and / or vinyl acetate; resins based on pine resin derivatives and / or polyterpenes; functional auxiliaries and additives: plasticizers, adhesion promoters, such as rosin esters, for example hydrogenated or partially hydrogenated glycerol esters of rosin, polyterpenes, permeation enhancers, for example terpenes or terpene derivatives, derivatives of unsaturated fatty acids or acetyls, esters of long-chain fatty acids, diethylene glycol and its derivatives; alkyl methyl sulfoxides, azoles.and limonenes; crystallization inhibitors, such as polyvinylpyrrolidone; polyacrylic acid or cellulose derivatives; solvents, such as polyethylene glycol, diethylene glycol and / or its derivatives, propanediol or oleyl alcohol. If the excipients and additives intended for the production of transdermal therapeutic systems containing oxidation-sensitive active ingredients already contain a significant amount of hydroperoxides upon delivery, these materials must be hydroperoxide-free before use. This can be done by breaking down the hydroperoxides with a strongly reducing agent. A very suitable reducing agent and also a pharmaceutically acceptable excipient is, for example, sodium hydrogen sulfite. An aqueous or predominantly aqueous solution of the compound quickly breaks down the peroxides. However, most of the polymers and excipients used in transdermal systems are either insoluble in water or incompatible with water. Surprisingly, however, we have found that the decomposition of the hydroperoxides is also possible by dissolving the solid in a water-miscible solvent, preferably ethanol or methanol, and the * « 4« * X **« * » * x « ♦ An aqueous solution of an inorganic sulfide, such as sodium hydrogen sulfide, is added slowly and with stirring to the solution. Although precipitation occurs quite quickly from the solution of the auxiliary, the sulfite has enough time to reduce the hydroperoxide. If the hydrogen sulphite solution is sufficiently concentrated, the introduction of small amounts of water will cause more problems. This is especially true if the water is removed together with the other solvents during coating and drying. Liquid excipients can be reacted with an aqueous solution of sodium hydrogen sulphite without additional solvent. After the above treatment, the patches are practically peroxide-free and can be used without concern, even if their previous peroxide content was high. Additional improvement of stability can be achieved by adding antioxidants that suppress or slow down the formation of new peroxides during storage of the patches. Regarding the tolerable upper limit of the peroxide content of excipients in contact with the active substance, the peroxide number should not be greater than 20, better than 10, preferably not greater than 5. The upper limit of .10 is derived from the following exemplary calculation. The surface area of ​​the assumed transdermal therapeutic matrix system is 20 cm, the surface area of ​​the coating is 100 g / m", and the active ingredient concentration is 10% g / g. If the molecular weight of the active ingredient is 200, the system therefore contains 20 mg or 0.1 mmol of active ingredient and at a peroxide value of 10, 0.2 ♦ KP mmol of active oxygen, which means that at most 2% of the active ingredient in the system can be oxidized. Considering that the reaction takes time and the reaction slows down due to the depletion of oxygen, at a peroxide value of 10 to 20, the chances are good that the system will be sufficiently stable for two years. Better stability can of course be achieved by further reducing the peroxide number (the peroxide number PÓZ is preferably below 5), by treating peroxide-laden excipients with sulfite, or by choosing excipients that are not prone to peroxide formation. Examples To 0.5 h of the active ingredient, 80 ml of chloroform and 1 g of tert-butyl hydroperoxide are added and the mixture is refluxed for 6 hours while stirring. The color of the reaction mixture is then evaluated and whether it contains decomposition products is examined using a suitable chromatographic method. Example 2 Stability of Ν-0923-base in a matrix with peroxide number 38 and 2.6, respectively The decomposition occurs according to reaction scheme (4), the identified oxidative decomposition reactions are: 1,2-dihydro-«att-8-ol Matrix 2a (peroxide number: 38) Polyisobutylene / styrene block polymer, partially hydrogenated rosin glycerol ester of hydrocarbon resin, polyisobutylene liquid paraffin Ν-0923-base 2b. matrix (peroxide number 2.6) polyacrylate adhesive oleyl alcohol N-0923-base 16% 10% or % 22% 7% % 20% % 10% 30% After three months The active ingredient content, based on a starting active ingredient content of 100%, was as follows: 10 **· ** * ** *♦ > « Φ ** « * « » ♦ *** ·> ♦ * * * * 94 ** *·*♦.* *** * * Temperature (°C| | 2a, matrix 2b. matrix 25 1 85 % 99.5 % 40 | 44 % 89.9% Oxidative decomposition reactions of 1,2-dihydro-nayl-8-ol in the area percentage of the HPLC chromatogram: Temperature (pC) Matrix 2a Matrix 2b | 1 25 8.1 % not measurable J 40 34.1 % 0.5 % The decomposition product found and identified in the tert-butylhydropeoxy reaction of Example 1 is 1,2-dihydronaphth-8-ol. Example 3 Stability of Bstradlol in a matrix with a peroxide number of 35, Ul. 2 Matrix 3a (peroxide number: 35) Polyacrylate adhesive 16% glycerol 10% partially hydrogenated rosin glycerol ester 22% estradiol 20% Matrix 3b (peroxide number: 2-3) Its composition corresponds to that of matrix 3a, but the glycerol ester of partially hydrogenated rosin was treated with Na-hydrogen sulfide solution. Content of A9(II)-estradiol after 6 months of storage, as surface area percentage of the HPLC chromatogram Temperature pC| 3a, matrix 3b. matrix 25 0.43% not detectable 40 0.75% not detectable Example 4 Stability of bopindolol in peroxide-rich and peroxide-poor matrices Matrix composition Bopjndobl 15 % polyacrylate adhesive 65 % partially hydrogenated rosin glycerol ester 20 % Matrix 4a was prepared by using the glycerol ester of partially hydrogenated rosin with a peroxide number of 160. Matrix 4b: for its preparation, the glycerol ester of partially hydrogenated rosin treated with sodium hydrogen sulfite was used. After thirty days of storage at 40 °C, matrix 4a turned brown, while matrix 4b remained brown. matrix is ​​not colored. Stability of nifedipine in peroxide-rich and peroxide-poor matrices After the tert-butylhydroperoxide test, the following degradation signs were found; I) The dihydropyridine ring becomes aromatic according to equation (5a), II) N-oxide formation according to equation (5b). Nifedipine 10% diethylene glycol monoethyl ether 90% Reservoir 5a was prepared with diethylene glycol monoethyl ether with a peroxide number of 150, and reservoir 5b was prepared with diethylene glycol monoethyl ether treated with sodium hydrogen sulfite solutions. The concentration of degradation product 1 after 30 days of storage is shown in the table below: Temperature í°Cj 5a. Reservoir [ 5b, Reservoir 25 1.6% ! not detectable 40 4.5% 1 0.3% Λ........................................................- « * AX ♦ * * ψ ♦ ♦ A ♦ « X * ♦ *x* * * ««« »x The decomposition products of 11.. ((5b.) ], due to their low concentration, were not found in the systems. Example 6. Stability of pergolide in peroxide-rich and peroxide-poor matrices After oxidation with tert-butyl hydroperoxide, we found that the sulfide sulfur was oxidized to sulfoxide 6a. matrix, peroxide value approx. 32 Pergolide 10% polyacrylate adhesive 70% partially hydrogenated rosin 20% 6b. matrix, peroxide value approx. 2-3 Pergolide 10% polyacrylate adhesive 90% The sulfoxide concentration after 30 days of storage is shown in the table below: Temperature (°Cj í 6a. Matrix i 6b. Matrix 25 4— í iv..... . ------ ....... not detectable 40 „J.......... 4.2% i 0 3 % Example 7 Decomposition of peroxide with sodium hydrogen sulfite The raw material to be treated is dissolved in a water-miscible solvent, preferably methanol or ethanol, and about 10-30% sodium hydrogen sulfite is added, chosen so that the stoichiome is: decomposes. The amount of sodium hydrogen sulfite solution should be adjusted to all or at least sufficient peroxide φφ The precipitated sodium hydrogen carbonate can be separated by centrifugation or filtration if desired or necessary.

Claims

Patent h 1.. Transdermal therapeutic system <TTR), amelyben a benne léve, hidroperoxldos oxidációra érzékeny hatóanyag oxidációs bomlási termékeinek tárolás közbeni képződése csökkent, és amelyben a hatóanyaggal érintkező segédanyagok a TTR receptúrája adta részarányukkal súlyozott peroxídszámának összege legfeljebb 20 2. The transdermal therapeutic system according to claim 1, wherein the sum of the peroxide numbers is at most 10, preferably at most 5.

3. Transdermal therapeutic system according to claim 1 or 2, the active ingredient(s) of which contain(s) at least one secondary or tertiary amino group, double bond, allyl-type CH bond, benzylic C-bond, tertiary CH group or sulfide group.

4. A transdermal therapeutic system according to any one of claims 1-2, comprising a single- or multi-layer matrix system and the active ingredient-containing matrix comprising a hydrocarbon, polyvinylpyrrolidone or a copolymer of vinylpyrrolidone with acrylic acid, acrylic acid derivatives, ethylene and / or vinyl acetate.

5. Transdermal therapeutic system according to any one of claims 1-4, which consists of one or more self-adhesive active ingredient-containing layers comprising colophony derivatives and / or a polyterpene-based adhesion-enhancing resin.

6. A transdermal therapeutic system according to any one of claims 1-5, comprising a permeation enhancer and / or a crystallization inhibitor as an excipient.

7. A transdermal therapeutic system according to any one of claims 1-4, which is a reservoir system containing the active ingredient in a solvent or solvent mixture having at least one ether oxygen, one tertiary carbon atom and / or one allylic C-H bond.

8. A transdermal therapeutic system according to any one of claims 1-7, which comprises terpenes or terpene derivatives, an unsaturated fatty acid or derivative thereof, a fatty alcohol or derivative thereof, or diethylene glycol or derivative thereof as a permeation enhancer.

9. Method for producing a transdermal therapeutic system according to claim 1, characterized in that a) the excipients are selected such that the sum of the peroxide number weighted by their proportion given by the TTR formulation is at most 20, or b) hydroperoxide-containing excipients are dissolved in a short-chain alcohol and an aqueous solution of inorganic mild or hydrogen sulfite is added to the solution, optionally the precipitated products are separated. Then a transdermal therapeutic system is produced in a known manner from the excipients selected according to a) or treated according to ah) and at least one active ingredient 10. The process according to claim 9, characterized in that the solid or liquid excipients are treated with an aqueous solution of sodium hydrogen sulfite in a solution of lower carbon alkanols.

11. The method according to claim 9 or 10, wherein the excipients are treated in a methanolic or ethanolic solution.