KR20020058045A - Transdermal therapeutic systems with improved stability and a method for the production thereof - Google Patents

Abstract

The present invention relates to a transthermal therapeutic system (TTS). In such systems, the production of oxidative degradation products is reduced by one or more active ingredients contained in the system and can be oxidized by hydroperoxide during storage of TTS. The system is characterized in that the maximum sum of the peroxide values (POZ) represented by the component parts of the formulation containing the active ingredient (s) defined by the preparation of TTS is 20. The present invention also relates to a method of manufacturing a transdermal treatment system of this type.

Description

TRANSDERMAL THERAPEUTIC SYSTEMS WITH IMPROVED STABILITY AND A METHOD FOR THE PRODUCTION THEREOF

With the exception of some very rare forms, transdermal therapeutic systems (TTS) can be divided into two basic groups: the group known as the matrix system and the group known as the reservoir system. In the case of therapeutic systems known as matrix systems, in the simplest case the active substance is dissolved in the self-adhesive layer or in some cases only suspended in the form of crystals. The reservoir system exhibits a type of pouch comprising an inert backing layer and an active material permeable membrane, wherein the active material is present in the liquid formulation within the pouch. Typically, the membrane is provided with a layer of adhesive that serves to secure the system to the skin.

Regardless of the particular aspect of the transdermal system, the active substance is delivered to the skin by diffusion during use and, therefore, needs to be present at least partially in dissolved form.

In this form, the active substance is particularly sensitive to reactions with formulation components which can lead to a decrease in stability.

Examples of the reaction include (a) binding of the active substance via amide or ester linkage to the carboxyl or ester group of the polymer or permeation enhancer employed; (b) the reaction of the alcoholic groups of the tacky resin or permeation enhancer with the carboxyl or ester groups of the active substance; (c) hydrolyzing or alcoholic decomposition of ester groups with water or alcohol, respectively.

The reactions, which can be estimated directly from the functional groups of the active substances and auxiliaries, are not surprising to those skilled in the art. Therefore, the risk corresponding to stability can generally be found very quickly by appropriate compatibility studies at elevated temperatures and then ruled out by proper rearrangement of the reverse active substance / adjuvant mixture.

In addition, the stability of the active substances and auxiliaries may be lowered by reaction with active oxygen.

The active oxygen is naturally oxygen in the air. An effective way to protect the active materials present in TTS against oxygen is to package the TTS under a nitrogen atmosphere and / or incorporate an antioxidant into the packaging.

However, in spite of these precautions, to date, it is essential to tolerate a somewhat reduced amount of active substance very often when stored for a long period of time TTS containing oxidatively sensitive active substance. The cause of this phenomenon has not been known before.

It has now been surprisingly found that the raw materials used to prepare the TTS can contain up to a considerable extent active oxygen in other forms, ie in the form of hydroperoxides.

The hydroperoxides can be produced by the mechanism shown in Schemes 1a-1c according to the antioxidant reactions described in the literature:

In the first stage, known as the induction stage, free radicals are produced by exposure to heat and / or light, which are promoted by trace amounts of heavy metals and the hydrogen atoms are lost.

In the second stage, known as the development stage, the radicals react with oxygen to produce peroxy radicals.

The peroxy radicals then further attack the molecule to produce hydroperoxides and new free radicals. This initiated a chain reaction, for example, which continued until two radicals reacted with each other and the chain was terminated, as shown in Scheme 1d:

Peroxide radicals that act as chain transfer agents, because of their relatively low reactivity, particularly attack sites that induce low-energy radicals on the substrate. Preferred these types of sites are C-H bonds, tertiary C-H bonds at the benzyl or allyl position and C-H bonds adjacent to ether oxygen. As a result, raw materials having such groups are particularly likely to produce hydroperoxides.

Antioxidants or stabilizers used to protect oxidation sensitive active materials may intervene in the reaction chain. Antioxidants can be divided into free-radical scavengers and oxygen scavengers. Free-radical scavengers, such as tocopherols and derivatives thereof, interfere with the chain mechanism of the autooxidation reaction, for example by removing or inactivating free radicals. Oxygen scavengers, such as ascorbyl palmitate, for example, react directly with oxidants to prevent initiation of chain reactions.

However, the addition of antioxidants / stabilizers only makes sense if the starting material itself does not contain hydroperoxides having an oxidative action or if the drug form is protected against oxygen ingress by packaging.

Surprisingly, all classes of raw materials used to make transdermal treatment systems, with the exception of films in the form of films, have been found to have instances in which significant amounts of hydroperoxide are already loaded upon supply or after storage for a while. lost. Specifically, this means that polymers, adhesive resins, permeation enhancers and solvents or solubilizers may have a hydroperoxide content that can degrade the stability of oxidation sensitive active materials to a significant extent.

The peroxide content is usually expressed as the so-called peroxide number (PON), which represents the amount of milligrams of active oxygen per kilogram of material. There are various methods of measuring the peroxide number. It is most common to react a limited amount of material with excess iodide ions in a chloroform / glacial acetic acid solution and then back-titrate the resulting iodine with sodium thiosulfate. A less common method, limited to aqueous solutions, is to react the material with titanium (IV) ions and determine the resulting peroxo complex photometrically. Semiquantitative tests for peroxides that are particularly easy to implement are performed using commercially available test electrodes.

The table below shows the peroxide values of several representative materials used to make reservoirs and matrix systems after storage at room temperature for about six months. Peroxide value was measured by the first two methods mentioned.

Raw material function PON Hydrocarbon resin Matrix component 180 Collidone Matrix component 110 Partially Hydrogenated Glycerol Esters of Rosin adhesive 190 Hydrogenated Glycerol Esters of Rosin adhesive 80 Poly-β-pinene adhesive 150 Diethylene glycol monoethyl ether Solvent / Permeation Enhancer 120 Oleyl alcohol Solvent / Permeation Enhancer 50 Limonene Penetration enhancer 15

The peroxide value of the finished patch can be measured by the same method as above. However, it is rather difficult to dissolve a sufficient amount of patches in a reasonable amount of chloroform.

An easier method is to measure the peroxide loading of each material and calculate the peroxide value of the active material component of the patch according to the following equation:

Where

n is the number of formulation components of the active substance component of the system;

N is the percent content (value) of the formulation component of the active substance components of the system;

PON is the peroxide value of the individual components of the active substance component of the system.

It has been found experimentally that hydroperoxides present in the raw materials can react with the active materials in contact in various ways. Active substances found to be particularly sensitive include secondary or tertiary amino groups; C-C double bonds; C-H groups at the allyl position; Benzyl C-H groups; Tertiary C-H groups; And structures of sulfide or sulfoxide groups.

Corresponding reaction products are shown in Schemes 2a-2g:

In the above formulas,

R is an organic radical.

In many cases, the reactions in the corresponding functional groups of the active substances involve subsequent reactions.

For example, in the case of 17-β-estradiol, the hydroxyl group in water form is removed after initial hydroxylation at the benzyl position (C9), followed by the production of Δ9 (11) 17-β-estradiol. (See Scheme 3 below). The reaction is advantageous because as a result conjugated double bonds are formed.

In the case of the active material (N-0923) having an amine-substituted tetrahydronaphthol fragment, first N-oxide is produced, and then the oxide is further reacted in a removal reaction (Cope removal) according to Scheme 4 below. It was found to produce dihydronaphthol and hydroxylamine:

In the case of dihydropyridine type calcium antagonists, the degradation mechanisms of Schemes 5a and 5b have been found:

It is not clear whether the initial attack takes place on the nitrogen of the dihydropyridine ring or on the tertiary C-H bond. In either case, the reaction that follows again is the removal of water, which is energy-efficient because it forms an aromatic state. Subsequent reaction to the N-oxide after oxidation of the dihydropyridine ring is only observed during the reaction with t-butyl hydroperoxide according to Scheme 5b. In patch systems, the amount produced is too small to be observed at low conversions.

The examples mentioned above often show that hydroperoxides from the reaction product cannot be perceived as directly involved in the decomposition reaction. In order to measure the sensitivity of the active substance to the oxidation reaction by hydroperoxide, a test reaction which has been carried out easily has been developed. For this purpose, the active substance in chloroform or other suitable solvent is reacted with t-butyl hydroperoxide under reflux. If oxidative degradation products of the active substances are found in the reaction mixture, they may be due to the reaction with hydroperoxides. Often, degradation of the active substance is also demonstrated very simply from discoloration of the test solution. A substantial conclusion inferred from the positive results of the test response is that the adjuvant used when formulating transdermal systems using the active substance should include only adjuvant substantially free of hydroperoxide.

It is an object of the present invention to provide a transdermal therapeutic system (TTS) in which the production of oxidative degradation products of the oxidatively sensitive active substances contained in the transdermal therapeutic system (TTS) is reduced during storage of TTS. As already mentioned above, the achievement of this object depends on the preparation of a TTS comprising one or more oxidation sensitive active substances, consisting solely of formulation components substantially free of hydroperoxide. According to the invention, the formulation components together have a peroxide number (PON) of 20 or less, preferably 10 or less, particularly preferably 5 or less, together in the portions defined by the formula for TTS.

The term formulation component includes all substances (except active pharmaceutical substances or substances) of TTS in which the active substance (s) are present.

The material may be a structural unit of a single layer or multilayer matrix and / or reservoir system, for example polyethylene, polypropylene, polyacrylate, polymethacrylate, polyurethane, polyisobutylene or polyvinylpyrrolidone Polymers of hydrocarbons such as; Hydrocarbon resins; silicon; Rubber; Copolymers of vinylpyrrolidone with acrylic acid, acrylic acid derivatives, ethylene and / or vinyl acetate; Resins based on rosin derivatives and / or polyterpenes. Functional additives or auxiliaries include, for example, plasticizers or pressure sensitive adhesives such as rosin esters, for example hydrogenated or partially hydrogenated glycerol esters of rosin or polyterpenes; Permeation enhancers such as, for example, terpenes or terpene derivatives, unsaturated fatty acids or derivatives thereof, esters of long chain fatty acids, or diethylene glycol or derivatives thereof; Alkyl methyl sulfoxides, azones and limonenes; Crystallization inhibitors such as, for example, polyvinylpyrrolidone, polyacrylic acid or cellulose derivatives; For example, solvents such as polyethylene glycol, diethylene glycol and / or derivatives thereof, propanediol or oleyl alcohol are included.

If a substantial amount of hydroperoxide is loaded at the time of delivery to a formulation component for preparing a transdermal therapeutic system comprising an oxidation sensitive active substance, it is necessary to remove most of the substance from the hydroperoxide before use. This process can be carried out by destroying the hydroperoxide using a strong reducing material. One highly suitable reducing agent and pharmaceutically acceptable adjuvant is, for example, sodium bisulfate or sodium hydrogen sulfite. In aqueous or predominantly aqueous solutions, the peroxide can break down without problems in the rapid reaction with the material. Unfortunately, most of the auxiliaries and polymers used in transdermal systems are insoluble in water or incompatible with other adjuvants in which water is used.

Surprisingly, when the solid material is dissolved in a water-miscible solvent, preferably ethanol or methanol and the aqueous solution of inorganic sulfite, for example sodium hydrogen sulfite is slowly added to the first solution while stirring, the destruction of the hydroperoxide also results in It turns out that it is possible. Precipitation occurs very quickly when the sulfite solution is added to the auxiliary solution, but the sulfite still has enough time to destroy the hydroperoxide by reduction.

If the hydrogen sulfite solution has a sufficient concentration, a small amount of water introduced can usually be tolerated without causing problems. This situation is especially true when water is removed with other solvents during coating and drying.

Liquid aids can be reacted with an aqueous solution of sodium hydrogen sulfite without additional solvent.

After the treatment, the materials are substantially free of peroxides and can be used regardless of their preload. Further improvement in stability can be achieved by the addition of antioxidants, which delays or inhibits the production of new peroxides during storage of the system.

With regard to the permissible upper limit of the peroxide content of the components in contact with the active substance, the upper limit of peroxide should not exceed 20, preferably 10, more preferably 5.

The limit of 10 is an exemplary calculation as follows for a typical transdermal therapeutic matrix system having a size of 20 cm ² and a coating weight of 100 g / m ² and an active substance concentration of 10% g / g.

Thus, for an estimated molecular weight of 200 Daltons of active substance, the system contains 20 mg or 0.1 mmol of active substance and 10 and a total of 0.2 × 10 ⁻² mmol of active oxygen peroxide. This means that up to 2% of the active substances present in the system can be oxidized. In view of the fact that the reaction takes time and is delayed by the consumption of active oxygen, there is a good possibility that the system will be sufficiently stable for two years (10 peroxide, in certain circumstances with an upper limit of 20 peroxide). exist.

Improved stability is achieved by further reducing the peroxide loading (preferably 5 or less PONs) and treating the peroxide-loaded adjuvant with sulfite and / or selecting an adjuvant that does not produce peroxides according to the described method. Of course.

Example 1

80 ml of chloroform and 1 g of t-butyl hydroperoxide were added to 0.5 g of active material and the system was heated under reflux with stirring for 6 hours. The reaction mixture was then evaluated for color and analyzed using the appropriate chromatography method on the resulting degradation product.

Example 2

Stability of N-0923 Base in Matrix with Peroxide 38 and Peroxide 2.6

The oxidative degradation product by decomposition according to Scheme 4 was found to be 1,2-dihydronaphth-8ol.

Matrix 2a: Peroxide 38 Styrene / Polyisobutylene / Styrene Block Polymer 16% Oleyl alcohol 10% Hydrocarbon resin 22% Glycerol Esters of Partially Hydrogenated Rosin 22% Polyisobutylene 7% Liquid paraffin 3% N-0923 base 20% Matrix 2b: Peroxide 2.6 Polyacrylate adhesive 60% Oleyl alcohol 10% N-0923 base 30%

Based on the initial content of 100%, the active substance content after 3 months is as follows:

Matrix 2a Matrix 2b 25 ℃ 85% 99.5% 40 ℃ 44% 89.9%

The oxidative degradation product 1,2-dihydronaphth-8-ol content as area% in the HPLC chromatogram is as follows:

Matrix 2a Matrix 2b 25 ℃ 8.1% Not quantifiable 40 ℃ 34.1% 0.4%

The degradation product exhibited in the reaction with t-butyl hydroperoxide according to Example 1 was identified as 1,2-dihydronaphth-8-ol.

Example 3

Stability of Estradiol in Matrix with Peroxide 35 and Peroxide 2

Matrix 3a: 35 peroxide Polyacrylate adhesive 16% Glycerol 10% Glycerol Esters of Partially Hydrogenated Rosin 22% Estradiol 20% Matrix 3b: 2 to 3 peroxide Corresponds to matrix 3a, except using the glycerol ester of partially hydrogenated rosin treated with sodium bisulfate solution.

The Δ9 (11) 17-β-estradiol content in the matrix after 6 months, expressed as area% in the HPLC chromatogram, is as follows:

Matrix 3a Matrix 3b 25 ℃ 0.43% Not detectable 40 ℃ 0.75% Not detectable

Example 4

Stability of bopindolol in peroxide-high and peroxide-low matrices

The matrix composition is as follows:

Boffindolol 15% Polyacrylate adhesive 65% Glycerol Esters of Partially Hydrogenated Rosin 20%

Matrix 4a was made from the glycerol esters of partially hydrogenated rosin with PON 160.

Matrix 4b was prepared from glycerol esters of partially hydrogenated rosin treated with sodium bisulfate solution.

After 30 days at 40 ° C., the matrix 4a turned brown and the matrix 4b did not discolor. When reacted with t-butyl hydroperoxide according to Example 1, it quickly turned yellow and became dark brown.

It was not possible to elucidate the structure of the decomposition product.

Example 5

Stability of nifedipine in peroxide-rich and peroxide-low reservoirs

The degradation product after oxidation with t-butyl hydroperoxide was (A) the dihydropyridine ring was aromaticized according to Scheme 5a, and (II) the N-oxide was produced according to Scheme 5b.

The reservoir consisted of 10% nifedipine and 90% diethylene glycol monoethyl ether.

Reservoir 5a was made from diethylene glycol monoethyl ether with a PON of 150 and the PON of the reservoir was 90.

Reservoir 5b was prepared from diethylene glycol monoethyl ether treated with sodium bisulfate solution.

After 30 days, the content of decomposition products (I) of reservoirs 5a and 5b, respectively, is as follows:

30 days Reservoir 5a Decomposition Product (I) Reservoir 5b Decomposition Product (I) 25 ℃ 1.6% Not quantifiable 40 ℃ 4.5% 0.3%

Decomposition product (II) according to Scheme 5b was not found because of its low concentration in the system.

Example 6

Stability of Pergolide in Peroxide-High and Peroxide-Low Matrix

After oxidation with t-butyl hydroperoxide it was found that sulfide sulfur was oxidized to sulfoxide as decomposition product.

Matrix 6a: PON approximately 32 Pergolide 10% Polyacrylate adhesive 70% Glycerol Esters of Partially Hydrogenated Rosin 20% Matrix 6b: PON about 2-3 Pergolide 10% Polyacrylate adhesive 90%

30 days Matrix 6a sulfoxide Matrix 6b sulfoxide 25 ℃ 0.8% Not quantifiable 40 ℃ 4.2% Impossible to quantify

Example 7

Destruction of Peroxides with Sodium Bisulfate Solution

The raw material to be treated was dissolved in a water-miscible solvent, preferably methanol or ethanol, and the solution was mixed with stirring with a solution of sodium bisulfite (sodium hydrogen sulfite) at a concentration of about 10-30%. The amount of sodium bisulfate solution is such that stoichiometrically all peroxides are destroyed or all peroxides are destroyed to a sufficient degree.

Sodium hydrogen sulfate, which is a precipitation reaction product of sodium hydrogen sulfite, may be separated by centrifugation, sedimentation, or filtration if desired.

Claims (11)

The production of oxidative degradation products of one or more active substances present in the transdermal therapeutic system (TTS) and capable of being oxidized by hydroperoxides is reduced during storage of the TTS and is proportional to the weight defined by the formula for the TTS. And wherein the sum of peroxide values of the formulation components in contact with the active substance or substances is 20 or less. The method of claim 1, A transdermal therapeutic system wherein the sum of peroxide values is 10 or less, preferably 5 or less. The method according to claim 1 or 2, A transdermal therapeutic system in which the active substance or substances each have at least one secondary or tertiary amino group, a double bond, a CH bond at the allyl position, a C-H bond at the benzyl position, a tertiary CH and / or sulfide group. The method according to any one of claims 1 to 3, A single layer or multilayer matrix system wherein the matrix comprising the active material (s) comprises a hydrocarbon resin, polyvinylpyrrolidone, or a copolymer of vinylpyrrolidone with acrylic acid, acrylic acid derivatives, ethylene and / or vinyl acetate Transdermal treatment system. The method according to any one of claims 1 to 4, A transdermal therapeutic system comprising one or more self-adhesive active material layers having a tacky resin based on rosin derivatives and / or polyterpenes. The method according to any one of claims 1 to 5, A transdermal therapeutic system in which penetration enhancers and / or crystallization inhibitors are included in the formulation components. The method according to any one of claims 1 to 4, A reservoir system, wherein the transdermal therapeutic system is an oxidizable active substance dissolved in a solvent or mixture of solvents having one or more ether oxygens, tertiary carbon atoms and / or CH groups at allyl positions. The method according to any one of claims 1 to 7, A percutaneous therapeutic system wherein the permeation enhancer used comprises terpenes or terpene derivatives, unsaturated fatty acids or derivatives thereof, fatty alcohols or derivatives thereof, or diethylene glycol or derivatives thereof. (a) selecting formulation components whose total peroxide value of the moieties specified by the formula for TTS is 20 or less, or (b) reacting the hydroperoxide-containing formulation components with an aqueous solution of inorganic sulfite or hydrogen sulfite in a lower-alkanol solution, optionally separating the precipitated reaction product, The method according to claim 1 comprising preparing a transdermal therapeutic system by a conventional method from a formulation component treated according to (a) or formulation component treated according to (b) using at least one active substance. Method of making a transdermal treatment system. The method of claim 9, A method of reacting a solid or liquid formulation component with sodium sulfite or sodium hydrogen sulfite in an aqueous solution in a lower alkanol solution. The method according to claim 9 or 10, A method of reacting a formulation component with methanol or ethanol solution.