Transdermal absorption preparation containing donepezil with improved stability

Abstract

The present invention relates to a transdermal absorption preparation for treating dementia, wherein the drug-containing layer contains donepezil or a pharmaceutically acceptable salt thereof as an active ingredient and a stabilizer, wherein the stabilizer is (i) a mixture of thiocyanate and a compound selected from the group consisting of tea catechins, (+)-catechins, epigallocatechin gallate, ascorbic acid and isoascorbic acid, or (ii) a mixture of thioglycerol and a compound selected from the group consisting of tea catechins, (+)-catechins, epigallocatechin gallate and ascorbic acid. The present invention provides a transdermal absorption preparation containing donepezil that meets the standards of the first method and the second method set forth in the United States Pharmacopoeia. The transdermal absorption preparation containing donepezil can reduce the generation of impurities by inhibiting the degradation of donepezil, thereby producing a transdermal absorption preparation containing donepezil with improved long-term storage stability.

Description

Technical Field

[0001] The present invention relates to a donepezil-containing percutaneous absorption preparation having improved stability and capable of suppressing the generation of donepezil impurities under short-term or long-term storage conditions. Background Art

[0002] Donepezil, an acetylcholine degrading enzyme inhibitor, is a drug developed for the treatment of Alzheimer's dementia. Take oral tablets as an example. Initial users take 5 mg for the first 4-6 weeks due to side effects, and the dosage can be increased to 10 mg after evaluating the clinical response during the period. In addition, for patients who have taken 10 mg for at least three months, the dosage can be increased to 23 mg. However, when taking oral tablets containing donepezil, serious side effects such as nausea, vomiting, and diarrhea may occur due to a sharp increase in blood concentrations. For elderly patients with reduced swallowing ability, there is also the problem of poor medication convenience. Moreover, it is difficult for dementia patients to consciously and regularly take the therapeutic agent, which will lead to a significant decrease in patient compliance.

[0003] Due to the above-mentioned problems, many countries around the world are actively conducting a large number of research activities related to the development of transdermal absorption preparations for the treatment of dementia containing donepezil or its salt. However, in general, transdermal absorption preparations need to be mixed with donepezil at a high concentration in the preparation in order to obtain systemic effects, but donepezil has the problem of generating various impurities due to environmental factors such as heat / light / moisture, making it difficult to ensure stability during storage. Therefore, it is urgent to develop a stabilizer that can solve the above problems, and people are also actively conducting research activities related to it.

[0004] In addition, according to the "Guideline on quality of transdermal patches" issued by the European Medicines Agency, impurities in transdermal absorbable products are managed in accordance with the guidelines and ICHQ3B issued by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). For impurities in ICH Q3B, general impurity setting standards are proposed based on the daily dosage, and the standards of the impurities can be raised or lowered according to the toxicity of specific impurities among the impurities generated by the degradation of the main components.

[0005] The United States Pharmacopoeia sets a standard for the impurities allowed to be generated due to the degradation of donepezil and uses it to regulate tablets containing donepezil. When the impurities generated exceed the standard, the tablets are prohibited from use in consideration of the toxicity of the impurities.

[0006] As a method for evaluating impurities generated by degradation of the main component, evaluation is generally performed by liquid chromatography, and the types of impurities that can be analyzed will also change depending on the analysis conditions used in the liquid chromatography (such as chromatographic column conditions, mobile phase conditions, and absorption wavelength, etc.). The United States Pharmacopoeia provides two methods for analyzing donepezil impurities as described below.

[0007] As a first method (hereinafter referred to as "first method"), desbenzyl donepezil, donepezil open ring and donepezil N-oxide in donepezil impurities can be analyzed, and it is recommended to manage the three impurities below 0.5% respectively, and it is recommended to manage other unknown impurities below 0.2%. As a second method (hereinafter referred to as the "second method"), desbenzyl donepezil, donepezil pyridine analog, donepezil quaternary salt, donepezil indene analog and deoxydonepezil can be analyzed among the donepezil impurities. It is recommended that the above five impurities be managed within 0.15% respectively, other unknown impurities be managed below 0.1%, and total impurities be managed within 1.0%. Moreover, when there is a potential possibility of generating the above five impurities in the donepezil preparation, it is recommended to use the second method rather than the first method to manage the impurities.

[0008] Studies for improving the impurity stability of donepezil include U.S. Patent No. 6,372,760, Korean Patent Publication No. 10-2009-0086565, Korean Registered Patent No. 10-0866720, No. 10-1408500, No. 10-1408454, and Korean Patent Application No. 2018-0167289.

[0009] In U.S. Patent Publication No. 6,372,760, an attempt was made to improve the stability of donepezil by adding an organic acid, and in Korean Registered Patent Publication No. 10-0866720, an attempt was made to improve the stability of donepezil by adding a high molecular weight acidic substance and a high molecular weight alkaline substance. However, the prior art only proposes oral preparations such as oral agents and syrups, and does not teach how to use a stabilizer in a transdermal absorbent.

[0010] Korean Patent Publication No. 10-2009-0086565 discloses a method for suppressing the generation of donepezil impurities in a transdermal absorption preparation by using one or more stabilizers selected from the group consisting of ascorbic acid or a metal salt or ester thereof, isoascorbic acid or a metal salt thereof, ethylenediaminetetraacetic acid or a metal salt thereof, cysteine, acetylcysteine, 2-mercaptobenzimidazole, 3(2)-tert-butyl-4-hydroxybenzoic acid sol, 2,6-di-tert-butyl-4-methylphenol, pentaerythritol tetrakis[3-(3',5'-di-tert-butyl-4'-hydroxyphenyl)propanoate], 3-mercapto-1,2-propanediol, tocopherol acetate, rutin, quercetin, hydroquinone, hydroxymethanesulfinic acid metal salt, pyrosulfite metal salt, sulfite metal salt and metal thiosulfate. According to the records in the prior art, one or more stabilizers can inhibit the generation of impurities (donepezil N-oxide and desbenzyl donepezil) and total impurities. However, since the impurities are only evaluated under short-term harsh conditions (70° C., 48 hours) by the first method of the analytical method proposed in the United States Pharmacopoeia, it is difficult to believe that it can effectively inhibit various impurities that may be generated by donepezil for a long time.

[0011] Korean Patent Registration Nos. 10-1408500 and 10-1408454 disclose a method for suppressing the generation of donepezil impurities in a transdermal absorption preparation by using two stabilizers such as isoascorbic acid, 2-mercaptobenzimidazole, a metal salt of hydroxymethanesulfonate, rutin, 2,6-di-tert-butyl-4-methylphenol, ascorbic acid, and a metal pyrosulfite in combination. According to the records in the prior art, when a single stabilizer is used, two impurities (donepezil N-oxide and desbenzyl donepezil) and total impurities cannot be effectively suppressed, while when two stabilizers are used in combination, two impurities (donepezil N-oxide and desbenzyl donepezil) and total impurities generated by donepezil degradation can be suppressed. However, because the impurities are only evaluated under short-term harsh conditions by the first method of the analytical methods proposed in the United States Pharmacopoeia, it is difficult to believe that it can effectively suppress various impurities that may be generated by donepezil over a long period of time.

[0012] In Korean Patent Application No. 2018-0167289, a method for inhibiting the generation of donepezil impurities in a transdermal absorbable preparation using only a single stabilizer when using thiocyanate (preferably potassium salt), thioglycerol or dimethylthiourea is disclosed. The prior art is different from other prior arts in that the first method and the second method of the analytical method proposed in the United States Pharmacopoeia are simultaneously evaluated and confirmed to be able to appropriately inhibit the generation of impurities under short-term harsh conditions, and in particular, it is pointed out that the donepezil transdermal absorbable preparation disclosed in other prior arts (Korean Registered Patent Gazette Nos. 10-1408500 and 10-1408454) does not meet the standards of the analytical method proposed in the United States Pharmacopoeia, i.e., the first method and / or the second method.

[0013] During the development activities for commercialization of the transdermal absorption preparation containing donepezil disclosed in Korean Patent Application No. 2018-0167289, the inventors confirmed that the impurity compliance standards of the first and second analysis methods proposed in the United States Pharmacopoeia were exceeded in the stability evaluation during long-term storage, resulting in a significant decrease in stability (because the stabilizer dimethylthiourea disclosed in Korean Patent Application No. 2018-0167289 is a substance not approved in the field of pharmaceuticals, it is excluded from the development candidate group of the present invention).

[0014] Therefore, the present inventors have studied the results of using the stabilizers disclosed in Korean Patent Application No. 2018-0167289, namely thiocyanate and thioglycerol, to study a transdermal absorption preparation containing donepezil that can maintain stability even during short-term or long-term storage. As a result, the present inventors have discovered a stabilizer that can effectively inhibit various impurities generated due to the degradation of donepezil even under short-term or long-term storage conditions and that meets the first method and second method standards set forth in the United States Pharmacopoeia, thereby completing the present invention. Summary of the invention

[0015] Technical issues

[0016] The object of the present invention is to provide a transdermal absorption preparation containing donepezil which can maintain stability even during short-term or long-term storage by using thiocyanate and thioglycerol, which are stabilizers disclosed in Korean Patent Application No. 2018-0167289.

[0017] Furthermore, an object of the present invention is to provide a donepezil-containing percutaneous absorption preparation that meets the standards of the first method and the second method set forth in the United States Pharmacopoeia in short-term severe conditions and long-term accelerated conditions tests.

[0018] Technical Solution

[0019] In order to achieve the above object, the present invention provides a transdermal absorption preparation containing donepezil for treating dementia, which comprises a support layer, a drug-containing layer and a release liner, wherein the drug-containing layer comprises donepezil or a pharmaceutically acceptable salt thereof as an active ingredient; a pressure-sensitive adhesive; and a stabilizer combination, wherein the stabilizer combination is (i) a mixture of thiocyanate and a stabilizer selected from the group consisting of tea catechins, (+)-catechins, epigallocatechin gallate, ascorbic acid and erythorbic acid, or (ii) a mixture of thioglycerol and a stabilizer selected from the group consisting of tea catechins, (+)-catechins and epigallocatechin gallate.

[0020] The present invention is further described below.

[0021] The donepezil used in the drug-containing layer of the present invention is an acetylcholinesterase inhibitor and can be used in the form of a free base or a pharmaceutically acceptable salt thereof. As the pharmaceutically acceptable donepezil salt, it is preferable to use an acid addition salt formed by a pharmaceutically acceptable free acid. Preferably, the acid addition salt is obtained using inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic monomers and carboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, hydroxyalkandioates, aromatic acids, aliphatic and aromatic sulfonic acids and other non-toxic organic acids. As the pharmaceutically nontoxic salts, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, decanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexane The present invention may include, but is not limited to, alkane-1,6-dioic acid salts, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, benzenesulfonates, toluenesulfonates, chlorobenzenesulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrate, citrates, lactates, β-hydroxybutyrates, glycolates, malates, tartrates, methanesulfonates, propylsulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates or mandelate salts.

[0022] From the viewpoint of dispersibility and transdermal absorbability, it is preferable to use donepezil in the form of a free base in the drug-containing layer of the present invention. The content of donepezil contained in the percutaneous absorbable preparation of the present invention is not particularly limited, but considering the dispersibility and transdermal absorbability of donepezil in the drug-containing layer, the content of donepezil compared to the drug-containing layer may preferably be 1-20% by weight, more preferably 1.5-15% by weight, and most preferably 2-10% by weight.

[0023] In the present invention, the stabilizer composition is (i) a mixture of thiocyanate and a stabilizer selected from the group consisting of tea catechins, (+)-catechins, epigallocatechin gallate, ascorbic acid and isoascorbic acid, or (ii) a mixture of thioglycerol and a stabilizer selected from the group consisting of tea catechins, (+)-catechins, and epigallocatechin gallate. In addition, the mixture of thiocyanate and a stabilizer selected from the group consisting of tea catechins, (+)-catechins, epigallocatechin gallate, ascorbic acid and isoascorbic acid may further contain thioglycerol as a stabilizer.

[0024] The stabilizer used in the present invention, i.e., thiocyanate, is an antioxidant component. As the thiocyanate, pharmaceutically acceptable salts can be used. Pharmaceutically acceptable inorganic salts include potassium, sodium, ammonium, calcium, magnesium, mercury, cobalt, lead, copper, silver, lithium, iron, nickel, barium, cadmium, zinc, cesium and thallium, etc., and organic salts include ethyl, methyl, guanidine, benzyl, 1-ethyl-3-methylimidazole, 1-butyl-3-methylimidazole and tetramethylammonium, etc. Preferably, potassium thiocyanate can be used.

[0025] In the present invention, the stabilizer composition is included in the drug-containing layer, and as long as the physical properties of the drug-containing layer are not adversely affected, the weight ratio of the stabilizer composition is not particularly limited. As a preferred example of the upper limit value of the stabilizer ratio, when the weight based on the drug-containing layer (i.e., the total weight of the solid components of the composition used when forming the drug-containing layer) exceeds 5% by weight, it may cause the problem of decreased physical properties such as the adhesion of the drug-containing layer, and when it is less than 0.0005% by weight, it may cause the problem of not being able to achieve a sufficient stabilizing effect. Therefore, the weight ratio of the stabilizer composition relative to the drug-containing layer can preferably be 0.0005% by weight to 5% by weight, more preferably 0.005% by weight to 3% by weight, and particularly preferably 0.05% by weight to 2% by weight. For example, when three stabilizers are mixed, the content of thiocyanate relative to the total weight of donepezil can be 0.01-50% by weight, and the content of the mixture of two or three stabilizers relative to the total weight of thiocyanate can be 1-500% by weight.

[0026] Regarding the pressure-sensitive adhesive of the present invention, the pressure-sensitive adhesive is not particularly limited, and examples thereof include acrylic adhesives; rubber adhesives such as polyisoprene, polyisobutylene, styrene-butadiene, styrene-isoprene-styrene block copolymers and styrene-butadiene-styrene block copolymers; silicone adhesives; and vinyl polymer adhesives such as polyvinyl alcohol, polyvinyl alkyl ether and polyvinyl acetate.

[0027] In the present invention, as a preferred pressure-sensitive adhesive, a rubber adhesive, namely styrene-isoprene-styrene block copolymer, can be used. Styrene-isoprene-styrene block copolymer is a thermoplastic elastomer composed of styrene and isoprene, and its melting point, solution viscosity and other properties will change according to the styrene content and diblock content in the styrene-isoprene-styrene block copolymer rubber.

[0028] The styrene-isoprene-styrene block copolymer used in the present invention is not subject to any particular limitation, but when the viscosity of the styrene-isoprene-styrene block copolymer solution is measured according to the "Method for Determining the Viscosity of Styrene-Isoprene-Styrene Block Copolymer" described in the Japanese Pharmaceutical Additive Standards 2013 Edition, the lower limit of the solution viscosity is 0.5 Pa*s or more, preferably 0.7 Pa*s or more, and more preferably 0.9 Pa*s or more, and the upper limit of the solution viscosity is not subject to any particular limitation, but is 2.0 Pa*s or less, and preferably 1.8 Pa*s or less.

[0029] When the content of the pressure-sensitive adhesive in the drug-containing layer is too low, the shape of the drug-containing layer may not be maintained, while when the content is too high, the skin permeability of the drug may decrease. Therefore, the content of the pressure-sensitive adhesive in the drug-containing layer of the present invention is 10% by weight or more and 70% by weight or less, preferably 15% by weight or more and 65% by weight or less, more preferably 20% by weight or more and 60% by weight or less, and particularly preferably 25% by weight or more and 55% by weight or less.

[0030] In the transdermal absorption type dosage form provided by the present invention, the adhesive composition may also include a plasticizer. Plasticizers that can be used in the present invention include paraffin processing oil, cycloparaffin processing oil, aromatic processing oil, olive oil, camellia oil, tall oil, castor oil, isopropyl myristate, hexyl laurate, mineral oil, octyl dodecanol myristate, propylene glycol, propylene glycol monooctyl ester, etc., but are not limited to this. The above components can also be mixed with two or more for use, and the mixing amount of the plasticizer as described above is based on the premise of maintaining sufficient cohesive force of the transdermal absorbent. The content of the plasticizer in the drug-containing layer is 10% by weight or more and 80% by weight or less, preferably 20% by weight or more and 75% by weight or less, more preferably 25% by weight or more and 70% by weight or less, and more preferably 35% by weight or more and 65% by weight or less.

[0031] In the drug-containing layer of the present invention, a tackifying resin for adjusting the adhesive force of the percutaneous absorbent may be added. The tackifying resin that can be used includes rosin derivatives, alicyclic saturated hydrocarbon resins, aliphatic hydrocarbon resins, etc. In the present invention, terpene resins are representatively used, but are not limited thereto.

[0032] However, when a tackifier is included in the drug-containing layer, in order to reduce skin irritation, etc., the content of the tackifier in the drug-containing layer is preferably less than 20 weight %. The content is preferably less than 15 weight %, more preferably less than 10 weight %, more preferably less than 8 weight %, and most preferably does not include a tackifier. That is, regarding the skin adhesion of the patch, the content of the tackifier can be adjusted according to the type and mixing ratio of donepezil, styrene-isoprene-styrene block copolymer, solubilizer and plasticizer in the drug-containing layer. In addition, when sufficient skin adhesion can be achieved without adding a tackifier, it is not necessary to add a tackifier.

[0033] In the present invention, the "support" of the "support layer" is not particularly identified, and supports widely used in percutaneous absorbents and the like can be used. For example, stretchable or non-stretchable woven or non-woven fabrics such as polyethylene, polypropylene, and polyethylene terephthalate, polyester films such as polyethylene terephthalate, polyolefins such as polyethylene and polypropylene, films such as polyurethane, ethylene-vinyl acetate copolymers, and polyvinyl chloride, or foamable supports such as polyolefins and polyethylene can be used. These materials can be used alone, or multiple types can be stacked and used.

[0034] In addition, in order to prevent static electricity from accumulating in the support, an antistatic agent may be contained in the electrospun fabric, nonwoven fabric, and film constituting the support. In addition, in order to obtain good anchoring properties with the adhesive layer, a nonwoven fabric or a woven fabric, or a laminate of a film may be used as the support. Regarding the thickness of the support, for a film, it is generally 10 μm-100 μm, preferably 15 μm-50 μm, and for a woven fabric, a nonwoven fabric, and a foaming support, it is generally 50-2,000 μm, preferably 100 μm-1,000 μm.

[0035] In addition, the release layer of the present invention can use a general release liner commonly used in percutaneous absorbents, etc. As the release liner, polyolefins such as cellophane and polyethylene and polypropylene, polyesters such as polyethylene terephthalate, resin films such as polystyrene, aluminum films, foamed polyethylene films or foamed polypropylene films, or laminates of two or more of the above materials can be used, and in particular, silicone resin processed products, fluororesin processed products, relief processed products, hydrophilic processed products, and hydrophobic processed products can be used. The thickness of the release liner is generally 10μm-200μm, preferably 15μm-150μm.

[0036] At the same time, the percutaneous absorption preparation of the present invention may further contain additives, solubilizers, percutaneous absorption accelerators, flavoring agents, coloring agents, and the like.

[0037] In the present invention, the method for producing a transdermal absorbable agent is not particularly limited, and a general method for producing a transdermal absorbable agent may be used, for example, the method for producing a transdermal absorbable agent described in the Korean Pharmacopoeia General Rules for Preparations is described as follows: first, a pressure-sensitive adhesive, donepezil, a stabilizer, and a plasticizer are dissolved or dispersed in a solvent and mixed, and then the obtained solution or dispersion is applied to the surface of a release layer and then dried, and then laminated with a support. As one embodiment of the present invention, the method for producing a transdermal absorbable agent of donepezil may include: (1) dissolving donepezil and a stabilizer composition applicable to the present invention in an organic solvent; (2) forming a drug-containing layer by applying the solution produced in the step to a release layer and drying it; and (3) laminating the drug-containing layer and a support layer.

[0038] As the solvent used in the production method of the present invention, for example, ethyl acetate, toluene, hexane, 2-propanol, methanol, ethanol, dichloromethane and tetrahydrofuran can be used as examples. The temperature when the pressure-sensitive adhesive is dissolved or dispersed in the solvent is not particularly limited. However, since the solvent is more likely to evaporate when the temperature rises and high temperature may also cause donepezil to dissolve and thus generate a large amount of impurities, it is preferably 80° C. or less, and more preferably 60° C. or less.

[0039] In the present invention, the method of coating the solution or dispersion obtained in the above-described embodiment on the surface of the release layer, the drying method, and the lamination method on the support can be carried out according to a common method for producing a percutaneous absorption agent.

[0040] Beneficial effects of the present invention

[0041] The present invention provides a transdermal absorption preparation containing donepezil that complies with the first method and the second method proposed in the United States Pharmacopoeia by confirming the change of impurities over time through a short-term severe test (storage at 70°C for 48 hours), a long-term accelerated test 1 (storage at 40°C and 75% relative humidity for one month) and a long-term accelerated test 2 (storage at 40°C and 75% relative humidity for three months).

[0042] The transdermal absorption preparation containing donepezil applicable to the present invention can reduce the generation of impurities by inhibiting the degradation of donepezil under short-term harsh conditions or even long-term accelerated conditions, and meets the impurity management standards of the first method and the second method of the United States Pharmacopoeia, thereby producing a transdermal absorption preparation containing donepezil with improved long-term storage stability. DETAILED DESCRIPTION

[0043] Next, the present invention will be described in more detail with reference to the embodiments and test examples. The following embodiments and test examples are only used to describe the present invention in detail, and the scope of the present invention is not limited by the following embodiments and test examples.

[0044] <Examples 1 to 13> Transdermal Absorbable Agents Applicable to the Present Invention

[0045] An ethyl acetate solution containing donepezil was obtained by dissolving 16 g of styrene-isoprene-styrene block copolymer, 4.7 g of octyl dodecanol myristate, 6.5 g of propylene glycol monooctyl ester, 2 g of terpene resin and 1.3 g of donepezil in 27 g of ethyl acetate. Next, a total amount of 0.13 g (including 1 / n) of the stabilizers listed in Table 1 below was dissolved in 1 g of methanol and then mixed with the ethyl acetate solution.

[0046] The obtained solution was applied to a silicon-coated polyethylene terephthalate (PET) film and dried in an oven at 80° C. for 30 minutes, followed by lamination with a backing film to produce transdermal absorbents, which were respectively named Examples 1 to 13.

[0047] [Table 1]

[0048]

[0049]

[0050] <Comparative Example 1> Transdermal Absorption Preparation without Addition of Stabilizer

[0051] A percutaneous absorption preparation was produced according to the same composition and method as in Example 1 without adding a stabilizer, and used as Comparative Example 1.

[0052] <Comparative Examples 2 to 4> Transdermal Absorbable Agents Adding Potassium Thiocyanate and / or Thioglycerol, Stabilizers Described in Korean Patent Application No. 2018-0167289

[0053] After adding potassium thiocyanate or thioglycerol from the stabilizers described in Korean Patent Application No. 2018-0167289 independently or in combination, a transdermal absorption preparation was also prepared according to the same composition and method as Example 1, and they were respectively used as Comparative Examples 2 to 4.

[0054] <Comparative Examples 5 to 16> In Comparative Examples 2 to 4, a percutaneous absorbent of citric acid, tartaric acid or benzoic acid described in Korean Patent Application No. 2018-0167289 was added as a stabilizer.

[0055] The transdermal absorbable preparations containing citric acid, tartaric acid or benzoic acid among the stabilizers described in U.S. Patent No. 6,372,760 were respectively designated as Comparative Examples 5 to 7. Subsequently, one of the stabilizers among citric acid, tartaric acid and benzoic acid among the stabilizers described in U.S. Patent No. 6,372,760 was added to Comparative Examples 2 to 4, respectively, and then the transdermal absorbable preparations were manufactured according to the same composition and method as Example 1, and were respectively designated as Comparative Examples 8 to 16.

[0056] [Table 2]

[0057] Stabilizer 2 Stabilizer 1 Stabilizer 3 Comparative Example 5 -Citric acid - Comparative Example 6 -tartaric acid - Comparative Example 7 -benzoic acid - Comparative Example 8 Potassium Thiocyanate Citric Acid - Comparative Example 9 Potassium Thiocyanate Tartaric Acid - Comparative Example 10 Potassium Thiocyanate Benzoic Acid - Comparative Example 11 Thiothioglycerol citrate - Comparative Example 12 Thioglycerol tartaric acid - Comparative Example 13 Thioglycerol Benzoate - Comparative Example 14 Potassium Thiocyanate Monothioglycerol Citric acid Comparative Example 15 Potassium Thiocyanate Monothioglycerol tartaric acid Comparative Example 16 Potassium Thiocyanate Monothioglycerol benzoic acid

[0058] <Comparative Examples 17 to 20> Transdermal Absorption Preparations Adding Two Stabilizers Described in Korean Patent Registration No. 10-1408500

[0059] Among the stabilizers described in Korean Patent Registration No. 10-1408500, two stabilizers described in Table 3 below that have the best inhibitory effect on impurities, namely donepezil N-oxide, desbenzyl donepezil, and total impurities were selected and added to form four groups, and transdermal absorption preparations were prepared according to the same composition and method as in Example 1, and these were used as Comparative Examples 17 to 20.

[0060] [Table 3]

[0061] Stabilizer 1 Stabilizer 2 Comparative Example 17 Erythorbic Acid 2-Mercaptobenzimidazole Comparative Example 18 2-Mercaptobenzimidazole 2,6-Di-tert-butyl-4-methylphenol Comparative Example 19 2-Mercaptobenzimidazole Rutin Comparative Example 20 2,6-Di-tert-butyl-4-methylphenol Sodium Hydroxymethanesulfonate

[0062] <Comparative Example 21> Transdermal Absorption Preparation with Two Stabilizers

[0063] A percutaneous absorption preparation was prepared as Comparative Example 21 by the same composition and method as in Example 1 except that ascorbic acid and sodium pyrosulfite, which are stabilizers described in Korean Patent Registration No. 10-1408454, were added.

[0064] <Comparative Examples 22 to 49> Transdermal Absorption Preparations Adding Various Stabilizers Described in Korean Patent Publication No. 10-2009-0086565

[0065] Transdermal absorption preparations were prepared in the same composition and method as in Example 1 except that the stabilizer described in Korean Patent Publication No. 10-2009-0086565 and various stabilizers described in Table 4 were added. These preparations are referred to as Comparative Examples 22 to 49.

[0066] [Table 4]

[0067]

[0068]

[0069] <Comparative Examples 50 to 67> Transdermal Absorption Preparations Adding Potassium Thiocyanate and Various Stabilizers Described in Korean Patent Publication No. 10-2009-0086565

[0070] Percutaneous absorption preparations were prepared in the same composition and method as in Example 1, except that potassium thiocyanate and the stabilizers listed in Table 5 of the stabilizers described in Korean Patent Publication No. 10-2009-0086565 were mixed and added as stabilizers. These preparations were named Comparative Examples 50 to 67.

[0071] [Table 5]

[0072]

[0073] <Comparative Examples 68 to 86> Transdermal Absorption Preparations Adding Thioglycerol and Various Stabilizers Described in Korean Patent Publication No. 10-2009-0086565

[0074] After adding thioglycerol (the same compound as 3-mercapto-1,2-propanediol described in Korean Patent Publication No. 10-2009-0086565) and the stabilizers listed in Table 6 among the stabilizers described in Korean Patent Publication No. 10-2009-0086565 as stabilizers, percutaneous absorption preparations were prepared according to the same composition and method as in Example 1, and they were respectively named Comparative Examples 68 to 86.

[0075] [Table 6]

[0076]

[0077] <Comparative Examples 87 to 104> Transdermal Absorption Preparations Adding Potassium Thiocyanate and Thioglycerol and Various Stabilizers Described in Korean Patent Publication No. 10-2009-0086565

[0078] Percutaneous absorption preparations were prepared in the same composition and method as in Example 1, except that potassium thiocyanate and thioglycerol were mixed as stabilizers, and stabilizers listed in Table 7 among the stabilizers listed in Korean Patent Publication No. 10-2009-0086565 were added as stabilizers. These preparations were named Comparative Examples 87 to 104.

[0079] [Table 7]

[0080]

[0081] <Test Example 1> Evaluation of impurities by the first method after short-term harsh conditions, i.e. storage at 70°C for 48 hours

[0082] In order to evaluate the impurities of donepezil during short-term storage, the percutaneous absorption preparations prepared in Examples and Comparative Examples were stored at 70° C. for 48 hours under short-term severe conditions, and then the impurities were evaluated by the first method as described below.

[0083] 1. Impurity Analysis Method First Method

[0084] In the first method of the impurity analysis method, each percutaneous absorption preparation was dissolved in ethyl acetate by stirring for 60 minutes, methanol was added and stirred for 60 minutes, and then the supernatant was centrifuged for 5 minutes as a test solution, and the impurity analysis method of the item "Donepezil Tablets" of the United States Pharmacopoeia was evaluated according to the first method of the impurity analysis method. The donepezil hydrochloride standard was dissolved to 0.8 μg / mL in a mixed solvent of ethyl acetate:methanol = 15:85 (volume ratio) and used as a standard solution.

[0085] <First Method Liquid Chromatography Conditions>

[0086] Column: Inertsil ODS-2 (4.6X 150mm, C 18, 5μm)

[0087] Mobile phase: As the mobile phase, a solution prepared by dissolving 2.5 g of sodium 1-decanesulfonate in 650 mL of purified water and then adding 1 mL of a perchloric acid solution and 350 mL of acetonitrile was used.

[0088] Column temperature: 35°C

[0089] Flow rate: 1.4 mL / min

[0090] Sample injection volume: 20uL

[0091] UV absorbance spectrophotometer: 271nm

[0092] Impurity calculation formula

[0093] Impurity % = (Ru / Rs) X (Cs / Cu) X (1 / F) X 100

[0094] Ru: Peak area of ​​impurities in the test solution

[0095] Rs: donepezil peak area in standard solution

[0096] Cs: Standard solution concentration (mg / mL)

[0097] Cu: Test solution concentration (mg / mL)

[0098] F: Relative correction coefficient of each impurity

[0099]

[0100] 2. Impurity Assessment

[0101] Table 8 shows the amounts of donepezil impurities generated after the percutaneous absorption preparations produced by the examples and comparative examples of the present invention were stored at 70° C. for 48 hours under short-term severe conditions.

[0102] As shown in the following Table 8, in Comparative Example 1 not containing a stabilizer, analysis by the first method revealed that due to the degradation of donepezil, a large amount of impurities were generated at relative retention times 0.53 (unknown impurities), 1.2 (donepezil N-oxide) and total impurities, indicating that the donepezil percutaneous absorption preparation is a preparation that requires the addition of a stabilizer to suppress the generation of impurities.

[0103] In the percutaneous absorption preparation containing the stabilizers described in Korean Patent Application No. 2018-0167289, namely potassium thiocyanate (Comparative Example 2) and thioglycerol (Comparative Example 3) and a mixture of the two stabilizers (potassium thiocyanate / thioglycerol), the amount of impurities generated under short-term harsh conditions met the first method standard proposed in the United States Pharmacopoeia, confirming that it has excellent stability.

[0104] In Comparative Examples 5 to 7 using the organic acids described in U.S. Patent No. 6,372,760, namely citric acid, tartaric acid and benzoic acid, the relative retention time 1.2 (Donepezil N-oxide) does not meet the standard set forth in the United States Pharmacopoeia, but in Comparative Examples 8 to 16 which mix them into Comparative Examples 2 to 4, respectively, the relative retention time 1.2 (Donepezil N-oxide) can be significantly reduced, thereby meeting the first method standard set forth in the United States Pharmacopoeia under short-term harsh conditions.

[0105] In Comparative Examples 17 to 21 in which two stabilizers described in Korean Registered Patent Publication No. 10-1408500 or Korean Registered Patent Gazette No. 10-1408454 were mixed, impurities under short-term severe conditions all met the first method standard proposed in the United States Pharmacopoeia.

[0106] In the percutaneous absorbents to which the stabilizers described in Korean Patent Publication No. 10-2009-0086565 were added, namely Comparative Examples 22 to 44, the impurities of Comparative Example 23 (cysteine), Comparative Example 24 (2-mercaptobenzimidazole), Comparative Example 30 (sodium hydroxymethanesulfonate), and Comparative Example 33 (sodium thiosulfate) met the first method standard proposed in the United States Pharmacopoeia under short-term severe conditions, but most of the stabilizers did not meet the standard when added alone.

[0107] In addition, in Comparative Examples 45 to 49 in which the stabilizer described in Korean Patent Publication No. 10-2009-0086565 is mixed with a currently known stabilizer, Comparative Example 45 (2,6-di-tert-butyl-4-methylphenol / tea catechins), Comparative Example 48 (2,6-di-tert-butyl-4-methylphenol / isoascorbic acid) and Comparative Example 49 (butylated hydroxyanisole / isoascorbic acid) meet the first method standard of the United States Pharmacopoeia, while Comparative Example 46 (butylated hydroxyanisole / tea catechins) and Comparative Example 47 (sodium thiosulfate / tea catechins) do not meet the first method standard proposed in the United States Pharmacopoeia.

[0108] In the percutaneous absorption preparations, i.e., Comparative Examples 50 to 67, which were added after mixing potassium thiocyanate, a stabilizer described in Korean Patent Application No. 2018-0167289, with a stabilizer described in Korean Patent Publication No. 10-2009-0086565, most of the stabilizers met the first method standard proposed in the United States Pharmacopoeia, but the impurities of Comparative Example 54 (potassium thiocyanate / butylated hydroxyanisole), Comparative Example 57 (potassium thiocyanate / hydroquinone), Comparative Example 62 (potassium thiocyanate / propyl gallate), and Comparative Example 64 (potassium thiocyanate / (+)-α-tocopherol) did not meet the first method standard proposed in the United States Pharmacopoeia under short-term severe conditions.

[0109] In the percutaneous absorption preparations, i.e., Comparative Examples 68 to 86, which were added after mixing the stabilizer described in Korean Patent Application No. 2018-0167289, i.e., thioglycerol, with a stabilizer described in Korean Patent Publication No. 10-2009-0086565, most of the stabilizers met the first method standard proposed in the United States Pharmacopoeia, but the impurities in Comparative Example 71 (thioglycerol / butylated hydroxyanisole) and Comparative Example 82 (thioglycerol / (+)-α-tocopherol) did not meet the first method standard proposed in the United States Pharmacopoeia under short-term severe conditions.

[0110] In addition, in the percutaneous absorption preparations, namely, Comparative Examples 87 to 104, which were added after mixing the stabilizers described in Korean Patent Application No. 2018-0167289, namely potassium thiocyanate and thioglycerol, with a stabilizer described in Korean Patent Publication No. 10-2009-0086565, most of the stabilizers met the first method standard proposed in the United States Pharmacopoeia, but the impurities of Comparative Example 90 (potassium thiocyanate / thioglycerol / butylated hydroxyanisole), Comparative Example 94 (potassium thiocyanate / thioglycerol / hydroquinone), Comparative Example 99 (potassium thiocyanate / thioglycerol / propyl gallate) and Comparative Example 101 (potassium thiocyanate / thioglycerol / (+)-α-tocopherol) did not meet the first method standard proposed in the United States Pharmacopoeia under short-term severe conditions.

[0111] In this regard, in Examples 1 to 13 to which the present invention is applied, each impurity meets the first method standard set forth in the United States Pharmacopoeia under short-term severe conditions, thereby confirming that it has an excellent stabilization effect.

[0112] [Table 8]

[0113] Short-term harsh conditions, i.e. 70°C, 48 hours, impurity analysis method No. 1

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121] 1) RRT 0.33: Desbenzyl donepezil, within 0.5%

[0122] 2) RRT 0.48: unknown impurities, within 0.2%

[0123] 3) RRT 0.53: unknown impurities, within 0.2%

[0124] 4) RRT 0.7: Donepezil open ring, within 0.5%

[0125] 5) RRT 1.2: Donepezil N-oxide, within 0.5%

[0126] <Test Example 2> Evaluation of impurities by the second method after short-term harsh conditions, i.e. storage at 70°C for 48 hours

[0127] In order to evaluate the impurities of donepezil, the percutaneous absorption preparations prepared in Examples and Comparative Examples were stored at 70° C. for 48 hours under short-term severe conditions, and then the impurities were evaluated by the second method as described below.

[0128] 1. Impurity analysis method Second method

[0129] As the second impurity analysis method, each percutaneous absorption preparation was dissolved in ethyl acetate by stirring for 60 minutes, and then a solution of 0.1N hydrochloric acid:methanol in a ratio of 25:75 was added and stirred for 60 minutes, and then the supernatant was centrifuged for 5 minutes as a test solution, and evaluation was performed according to the second impurity analysis method of the item "Donepezil Tablets" of the United States Pharmacopoeia based on the criteria of the following Table 10. The donepezil hydrochloride standard was dissolved to 10 μg / mL in a solvent mixed with ethyl acetate:methanol:0.1N hydrochloric acid=100:675:225 (volume ratio) and used as a standard solution.

[0130] <Second Method Liquid Chromatography Conditions>

[0131] Column: Capcellpak (4.6×250mm, C18, 5μm)

[0132] Mobile phase A: 1 mL of phosphoric acid was added to 1 L of purified water, and then the pH was adjusted to 6.5 with triethylamine. The obtained solution was filtered, and then air bubbles were removed with an ultrasonic cleaner, and then used as a mobile phase.

[0133] Mobile phase B: acetonitrile

[0134] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 75 25 10 40 60 40 40 60 41 75 25 50 75 25

[0135] Column temperature: 50°C

[0136] Flow rate: 1.5mL / min

[0137] Sample injection volume: 20uL

[0138] UV absorbance spectrophotometer: 286nm

[0139] Impurity calculation formula

[0140] Impurity % = (Ru / Rs) X (Cs / Cu) X (1 / F) X 100

[0141] Ru: Peak area of ​​impurities in the test solution

[0142] Rs: donepezil peak area in standard solution

[0143] Cs: Standard solution concentration (mg / mL)

[0144] Cu: Test solution concentration (mg / mL)

[0145] F: Relative correction coefficient of each impurity

[0146]

[0147] 2. Impurity Assessment

[0148] Table 9 shows the amounts of donepezil impurities generated after the percutaneous absorption preparations produced by the examples and comparative examples of the present invention were stored at 70° C. for 48 hours under short-term severe conditions and analyzed by the second method.

[0149] As can be confirmed from the following Table 9, the percutaneous absorption preparation not containing a stabilizer (Comparative Example 1) generates impurities exceeding the standard at relative retention times of 0.49 (Donepezilpyridine analog), 0.57 (unknown impurities), 1.08 (unknown impurities) and total impurities due to degradation of donepezil in the test results of the second method, indicating that it is a preparation requiring a stabilizer.

[0150] In the percutaneous absorption preparation containing the stabilizers described in Korean Patent Application No. 2018-0167289, namely potassium thiocyanate (Comparative Example 2) and thioglycerol (Comparative Example 3) and a mixture of the two stabilizers (Comparative Example 4), the amount of impurities generated under short-term harsh conditions (storage at 70°C for 48 hours) meets the second method standard proposed in the United States Pharmacopoeia, confirming that it has excellent stability.

[0151] In Comparative Examples 5 to 7 using organic acids described in U.S. Patent No. 6,372,760, namely citric acid, tartaric acid and benzoic acid, the second method standard proposed in the United States Pharmacopoeia was not met, and in Comparative Examples 8 to 16 in which the stabilizers were mixed with the stabilizers of Comparative Examples 2 to 4, the impurities under short-term harsh conditions were different from the test results that met the first method standard proposed in the United States Pharmacopoeia, and all did not meet the second method standard.

[0152] In Comparative Examples 17 to 21 in which two stabilizers described in Korean Registered Patent Publication No. 10-1408500 or Korean Registered Patent Gazette No. 10-1408454 were mixed, the impurities under short-term severe conditions were different from the test results that met the first method standard proposed in the United States Pharmacopoeia, and all did not meet the second method standard.

[0153] In the percutaneous absorbents to which the stabilizer described in Korean Patent Publication No. 10-2009-0086565 and the currently known stabilizer were added, namely, Comparative Examples 22 to 44, the impurities of the percutaneous absorbents containing a part of the stabilizer under short-term harsh conditions were different from the test results that met the first method standard proposed in the United States Pharmacopoeia, and all did not meet the second method standard.

[0154] In addition, Comparative Examples 45 to 49 in which the stabilizer described in Korean Patent Publication No. 10-2009-0086565 and a conventionally known stabilizer were mixed also failed to meet the second method standard.

[0155] In the percutaneous absorbents, i.e., Comparative Examples 50 to 67, which were added after mixing the stabilizer described in Korean Patent Application No. 2018-0167289, i.e., potassium thiocyanate, with a stabilizer described in Korean Patent Publication No. 10-2009-0086565, the impurities under short-term harsh conditions were different from the test results that most of them met the first method standards proposed in the United States Pharmacopoeia. Only Comparative Example 67 (potassium thiocyanate / rutin) met the second method standards proposed in the United States Pharmacopoeia, and the others did not meet the second method standards proposed in the United States Pharmacopoeia.

[0156] In the percutaneous absorbable preparations, i.e., Comparative Examples 68 to 86, which were added after mixing thioglycerol, a stabilizer described in Korean Patent Application No. 2018-0167289, with a stabilizer described in Korean Patent Publication No. 10-2009-0086565, the impurities under short-term harsh conditions were different from most of the test results that met the first method standard proposed in the United States Pharmacopoeia, except for Comparative Example 68 (thioglycerol / ethylenediaminetetraacetic acid), Comparative Example 70 (thioglycerol / 2-mercaptobenzimidazole), Comparative Example 72 (thioglycerol / butylhydroxytoluene), Comparative Example 74 (thioglycerol / quercetin dihydrate), Comparative Example 75 (thioglycerol / hydroquinone), Comparative Example 78 (thioglycerol / sodium sulfite), Comparative Example 79 (thioglycerol / sodium thiosulfate), and Comparative Example 80 (thioglycerol / 2-mercaptobenzimidazole). Example 80 (thioglycerol / propyl gallate), Comparative Example 81 (thioglycerol / 1,3-butylene glycol), Comparative Example 83 (thioglycerol / α-tocopheryl acetate), Comparative Example 85 (thioglycerol / rutin) and Comparative Example 86 (thioglycerol / isoascorbic acid) mostly meet the second method standard set forth in the United States Pharmacopoeia, while Comparative Example 69 (thioglycerol / cysteine), Comparative Example 71 (thioglycerol / butylhydroxyanisole), Comparative Example 73 (thioglycerol / pentaerythritol tetra-di-tert-butylhydroxyhydrocinnamate), Comparative Example 76 (thioglycerol / sodium hydroxymethanesulfonate), Comparative Example 77 (thioglycerol / sodium metabisulfite), Comparative Example 82 (thioglycerol / (+)-α-tocopherol) and Comparative Example 84 (thioglycerol / benzotriazole) do not meet the second method standard set forth in the United States Pharmacopoeia.

[0157] In addition, in the percutaneous absorption agents, namely Comparative Examples 87 to 104, which were added after mixing the stabilizers described in Korean Patent Application No. 2018-0167289, namely thioglycerol and potassium thiocyanate, with a stabilizer described in Korean Patent Publication No. 10-2009-0086565, the impurities under short-term harsh conditions were different from the test results that most of them met the first method standards proposed in the United States Pharmacopoeia. Only Comparative Example 104 (thioglycerol / potassium thiocyanate / rutin) met the second method standards proposed in the United States Pharmacopoeia, and the others did not meet the second method standards.

[0158] In this regard, in Examples 1 to 13 to which the present invention is applied, each impurity meets the second method standard proposed in the United States Pharmacopoeia under short-term severe conditions, thereby confirming that it has an excellent stabilization effect.

[0159] [Table 9]

[0160] Short-term harsh conditions, i.e. 70°C, 48 hours, impurity analysis method 2

[0161]

[0162]

[0163]

[0164]

[0165]

[0166] 1) RRT 0.23: Desbenzyl donepezil, within 0.15%

[0167] 2) RRT 0.49: Donepezil pyridine analog, within 0.15%

[0168] 3) RRT 0.57: unknown impurities, within 0.1%

[0169] 4) RRT 0.68: Donepezil quaternary salt, within 0.15%

[0170] 5) RRT 1.03: unknown impurities, within 0.1%

[0171] 6) RRT 1.08: unknown impurities, within 0.1%

[0172] 7) RRT 1.7: Donepezil indene analog, within 0.15%

[0173] 8) RRT 2.1: Deoxydonepezil, within 0.15%

[0174] Among the embodiments and comparative examples of the present invention, the first and second methods of the impurity analysis methods proposed in the United States Pharmacopoeia are met under the short-term harsh conditions of 70°C for 48 hours. The examples of the present invention and comparative examples 2 to 4 (percutaneous absorbents containing potassium thiocyanate and / or thioglycerol as stabilizers described in Korean Patent Application No. 2018-0167289), comparative example 67 (potassium thiocyanate / rutin), comparative example 68 (thioglycerol / ethylenediaminetetraacetic acid), comparative example 70 (thioglycerol / 2-mercaptobenzimidazole), comparative example 72 (thioglycerol / dibutylhydroxybenzoate) are met. The percutaneous absorption preparations prepared in Comparative Example 74 (thioglycerol / quercetin dihydrate), Comparative Example 75 (thioglycerol / hydroquinone), Comparative Example 78 (thioglycerol / sodium sulfite), Comparative Example 79 (thioglycerol / sodium thiosulfate), Comparative Example 80 (thioglycerol / propyl gallate), Comparative Example 81 (thioglycerol / 1,3-butylene glycol), Comparative Example 83 (thioglycerol / α-tocopheryl acetate), Comparative Example 85 (thioglycerol / rutin), Comparative Example 86 (thioglycerol / isoascorbic acid) and Comparative Example 104 (thioglycerol / potassium thiocyanate / rutin) are described herein.

[0175] <Test Example 3> Evaluation of impurities under long-term accelerated conditions (storage for one month at 40°C and 75% relative humidity)

[0176] In order to confirm the stability of the percutaneous absorption preparation of donepezil during long-term storage, Examples 1 to 13 and Comparative Examples 2, 3, 4, 67, 68, 70, 72, 74, 75, 78, 79, 80, 81, 83, 85, 86 and 104, whose impurity generation evaluation results under the short-term severe conditions of Test Examples 1 and 2 met the standards of the first method and the second method set forth in the United States Pharmacopoeia, were stored for one month under the long-term accelerated test conditions of 40° C. and 75% relative humidity, and then the impurities were evaluated in the same manner as the first method and the second method of Test Example 1. The results are shown in Tables 10 and 11.

[0177] 1. Impurity assessment using the first method

[0178] As can be confirmed from the following Table 10, the percutaneous absorption preparation (Comparative Example 1) containing no stabilizer in the test results of the first method under the long-term accelerated test conditions (stored at 40°C and 75% relative humidity for one month) produced impurities exceeding the standard at relative retention times 0.53 (unknown impurities), 1.2 (donepezil N-oxide) and total impurities due to degradation of donepezil, indicating that it is a preparation requiring a stabilizer.

[0179] The stabilizer described in Korean Patent Application No. 2018-0167289, namely potassium thiocyanate (Comparison Example 2), does not meet the first method standard under the long-term accelerated test conditions (stored at 40°C and 75% relative humidity for one month), but the percutaneous absorption agent (Comparison Example 4) containing thioglycerol (Comparison 3) and a mixture of the two stabilizers (potassium thiocyanate / thioglycerol) meets the first method standard under the long-term accelerated test conditions (stored at 40°C and 75% relative humidity for one month).

[0180] In Comparison Example 67, a percutaneous absorbent added after mixing potassium thiocyanate, a stabilizer described in Korean Patent Application No. 2018-0167289, and rutin, a stabilizer described in Korean Patent Publication No. 10-2009-0086565, it meets the first method standard under long-term accelerated test conditions (stored at 40°C and 75% relative humidity for one month).

[0181] In the percutaneous absorption preparations, namely, Comparative Example 75 (thioglycerol / hydroquinone) and Comparative Example 80 (thioglycerol / propyl gallate), which were added after mixing the stabilizer described in Korean Patent Application No. 2018-0167289 with a stabilizer described in Korean Patent Publication No. 10-2009-0086565, unlike meeting the first method standard proposed in the United States Pharmacopoeia under short-term harsh conditions, they did not meet the first method standard under long-term accelerated test conditions (storage at 40°C and 75% relative humidity for one month), but Comparative Example 68 (thioglycerol / ethylenediaminetetraacetic acid) and Comparative Example 70 (thioglycerol / Comparative Example 72 (thioglycerol / butylated hydroxytoluene), Comparative Example 74 (thioglycerol / quercetin dihydrate), Comparative Example 78 (thioglycerol / sodium sulfite), Comparative Example 79 (thioglycerol / sodium thiosulfate), Comparative Example 80 (thioglycerol / propyl gallate), Comparative Example 81 (thioglycerol / 1,3-butylene glycol), Comparative Example 83 (thioglycerol / α-tocopheryl acetate), Comparative Example 85 (thioglycerol / rutin) and Comparative Example 86 (thioglycerol / isoascorbic acid) meet the first method standard proposed in the United States Pharmacopoeia under the long-term accelerated test conditions (stored at 40°C and 75% relative humidity for one month).

[0182] In addition, in the percutaneous absorption agent, Comparative Example 104, which is added after mixing the stabilizers described in Korean Patent Application No. 2018-0167289, namely thioglycerol and potassium thiocyanate, and the stabilizer described in Korean Patent Publication No. 10-2009-0086565, namely rutin, the long-term accelerated test conditions (stored for one month at 40°C and 75% relative humidity) meet the first method standard proposed in the United States Pharmacopoeia.

[0183] In this regard, in Examples 1 to 13 to which the present invention is applied, all meet the first method standard proposed in the United States Pharmacopoeia under long-term accelerated test conditions (storage for one month at 40°C and 75% relative humidity), thereby confirming that they have an excellent stabilization effect.

[0184] [Table 10]

[0185] Method 1 under long-term accelerated test conditions (storage at 40°C and 75% relative humidity for one month)

[0186]

[0187]

[0188] 1) RRT 0.33: Desbenzyl donepezil, within 0.5%

[0189] 2) RRT 0.48: unknown impurities, within 0.2%

[0190] 3) RRT 0.53: unknown impurities, within 0.2%

[0191] 4) RRT 0.7: Donepezil open ring, within 0.5%

[0192] 5) RRT 1.2: Donepezil N-oxide, within 0.5%

[0193] 2. Impurity Assessment Using the Second Method

[0194] As can be seen from the following Table 11, the percutaneous absorption preparation (Comparative Example 1) containing no stabilizer, in the test results of the second method under the long-term accelerated test conditions (stored at 40°C and 75% relative humidity for one month), produced impurities exceeding the standard at relative retention times of 0.49 (Donepezil pyridine analog), 0.57 (unknown impurities) and total impurities due to degradation of donepezil, indicating that it is a preparation requiring a stabilizer.

[0195] Among the stabilizers described in Korean Patent Application No. 2018-0167289, namely potassium thiocyanate (Comparative Example 2) and thioglycerol (Comparative Example 3), they do not meet the second method standard under the long-term accelerated test conditions (stored at 40°C and 75% relative humidity for one month), but the percutaneous absorption agent (Comparative Example 4) containing a mixture of the two stabilizers (potassium thiocyanate / thioglycerol) meets the second method standard under the long-term accelerated test conditions (stored at 40°C and 75% relative humidity for one month).

[0196] In the percutaneous absorption agent, Comparison Example 67, which is added after mixing the stabilizer described in Korean Patent Application No. 2018-0167289, namely potassium thiocyanate, and the stabilizer described in Korean Patent Publication No. 10-2009-0086565, namely rutin, it is different from the second method standard proposed in the United States Pharmacopoeia under short-term harsh conditions, and does not meet the second method standard under long-term accelerated test conditions (stored at 40°C and 75% relative humidity for one month).

[0197] The percutaneous absorption agents, namely, Comparative Example 68 (thioglycerol / ethylenediaminetetraacetic acid), Comparative Example 70 (thioglycerol / 2-mercaptobenzimidazole), Comparative Example 72 (thioglycerol / butylhydroxytoluene), Comparative Example 74 (thioglycerol / quercetin dihydrate), Comparative Example 75 (thioglycerol / hydroquinone), Comparative Example 78 (thioglycerol / sodium sulfite), Comparative Example 79 (thioglycerol / sulfuric acid), which were added after mixing the stabilizer described in Korean Patent Application No. 2018-0167289 with a stabilizer described in Korean Patent Publication No. 10-2009-0086565, were added. Comparative Example 80 (thioglycerol / propyl gallate), Comparative Example 81 (thioglycerol / 1,3-butylene glycol) and Comparative Example 83 (thioglycerol / α-tocopherol acetate) do not meet the second method standard under the long-term accelerated test conditions (stored at 40°C and 75% relative humidity for one month), which is different from the second method standard proposed in the United States Pharmacopoeia under short-term severe conditions. However, Comparative Example 85 (thioglycerol / rutin) and Comparative Example 86 (thioglycerol / isoascorbic acid) meet the second method standard under the long-term accelerated test conditions (stored at 40°C and 75% relative humidity for one month).

[0198] In addition, in the percutaneous absorption agent, Comparison Example 104, which is added after mixing the stabilizers described in Korean Patent Application No. 2018-0167289, namely thioglycerol and potassium thiocyanate, and the stabilizer described in Korean Patent Publication No. 10-2009-0086565, namely rutin, it meets the second method standard of the long-term accelerated test conditions (stored for one month at 40°C and 75% relative humidity).

[0199] In this regard, in Examples 1 to 13 to which the present invention is applied, all meet the second method standard proposed in the United States Pharmacopoeia under long-term accelerated test conditions (storage for one month at 40°C and 75% relative humidity), thereby confirming that they have an excellent stabilization effect.

[0200] [Table 11]

[0201] Method 1 under long-term accelerated test conditions (storage at 40°C and 75% relative humidity for one month)

[0202]

[0203]

[0204] 1) RRT 0.23: Desbenzyl donepezil, within 0.15%

[0205] 2) RRT 0.49: Donepezil pyridine analog, within 0.15%

[0206] 3) RRT 0.57: unknown impurities, within 0.1%

[0207] 4) RRT 0.68: Donepezil quaternary salt, within 0.15%

[0208] 5) RRT 1.03: unknown impurities, within 0.1%

[0209] 6) RRT 1.08: unknown impurities, within 0.1%

[0210] 7) RRT 1.7: Donepezil indene analog, within 0.15%

[0211] 8) RRT 2.1: Deoxydonepezil, within 0.15%

[0212] <Test Example 4> Evaluation of impurities under long-term accelerated conditions (stored at 40°C and 75% relative humidity for three months)

[0213] In order to confirm the stability of the donepezil percutaneous absorption preparation during long-term storage, Examples 1 to 13 and Comparative Examples 4, 85, 86 and 104, whose impurity generation evaluation results under the long-term accelerated test conditions of Test Example 3 (storage for one month at 40° C. and 75% relative humidity) met the first method and second method standards set forth in the United States Pharmacopoeia, were used as the subjects. After storage for three months under the long-term accelerated test conditions of 40° C. and 75% relative humidity, impurities were evaluated in the same manner as the first method and the second method of Test Example 1. The results are shown in Tables 12 and 13.

[0214] 1. Impurity assessment using the first method

[0215] It can be confirmed from the following Table 12 that the percutaneous absorption preparation (Comparative Example 1) containing no stabilizer in the test results of the first method under the long-term accelerated test conditions (stored at 40°C and 75% relative humidity for three months) produced impurities exceeding the standard at relative retention times 0.53 (unknown impurities), 1.2 (donepezil N-oxide) and total impurities due to degradation of donepezil, indicating that it is a preparation requiring a stabilizer.

[0216] In the transdermal absorption preparation (Comparative Example 4) containing both potassium thiocyanate and thioglycerol, the stabilizers described in Korean Patent Application No. 2018-0167289, it does not meet the first method standard proposed in the United States Pharmacopoeia under the long-term accelerated test conditions (stored at 40°C and 75% relative humidity for three months).

[0217] In the percutaneous absorption preparation in which thioglycerol, a stabilizer described in Korean Patent Application No. 2018-0167289, is mixed with a stabilizer described in Korean Patent Publication No. 10-2009-0086565 and then added, Comparative Example 86 (thioglycerol / isoascorbic acid) meets the first method standard proposed in the United States Pharmacopoeia under the long-term accelerated test conditions (stored at 40°C and 75% relative humidity for three months), but Comparative Example 85 (thioglycerol / rutin) does not meet the requirements.

[0218] In addition, in the percutaneous absorption agent, Comparative Example 104, which is added after mixing the stabilizers described in Korean Patent Application No. 2018-0167289, namely thioglycerol and potassium thiocyanate, with the stabilizer described in Korean Patent Publication No. 10-2009-0086565, namely rutin, it also does not meet the first method standard proposed in the United States Pharmacopoeia under the long-term accelerated test conditions (stored for three months at 40°C and 75% relative humidity).

[0219] In this regard, in Examples 1 to 13 to which the present invention is applied, all meet the first method standard proposed in the United States Pharmacopoeia under long-term accelerated test conditions (storage for three months at 40°C and 75% relative humidity), thereby confirming that they have an excellent stabilization effect.

[0220] [Table 12]

[0221] Method 1 under long-term accelerated test conditions (storage at 40°C and 75% relative humidity for three months)

[0222]

[0223]

[0224] 1) RRT 0.33: Desbenzyl donepezil, within 0.5%

[0225] 2) RRT 0.48: unknown impurities, within 0.2%

[0226] 3) RRT 0.53: unknown impurities, within 0.2%

[0227] 4) RRT 0.7: Donepezil open ring, within 0.5%

[0228] 5) RRT 1.2: Donepezil N-oxide, within 0.5%

[0229] 2. Impurity Assessment Using the Second Method

[0230] As can be seen from the following Table 13, the percutaneous absorption preparation (Comparative Example 1) containing no stabilizer, in the test results of the second method proposed in the United States Pharmacopoeia under the long-term accelerated test conditions (stored at 40°C and 75% relative humidity for three months), produced impurities exceeding the standard at relative retention times of 0.49 (Donepezilpyridine analog), 0.57 (unknown impurities) and total impurities due to degradation of donepezil, indicating that it is a preparation requiring a stabilizer.

[0231] In the transdermal absorption preparation (Comparative Example 4) containing both potassium thiocyanate and thioglycerol, two stabilizers described in Korean Patent Application No. 2018-0167289, impurities exceeding the standard were generated under the conditions of storage for three months at 40°C and 75% relative humidity, and therefore did not meet the second method standard proposed in the United States Pharmacopoeia.

[0232] In addition, in the percutaneous absorption agent, Comparative Example 104, which is added after mixing the stabilizers described in Korean Patent Application No. 2018-0167289, namely thioglycerol and potassium thiocyanate, and the stabilizer described in Korean Patent Publication No. 10-2009-0086565, namely rutin, it does not meet the second method standard proposed in the United States Pharmacopoeia under the long-term accelerated test conditions (stored for three months at 40°C and 75% relative humidity).

[0233] In this regard, in Examples 1 to 13 to which the present invention is applied, all meet the second method standard proposed in the United States Pharmacopoeia under long-term accelerated test conditions (storage for three months at 40°C and 75% relative humidity), thereby confirming that they have an excellent stabilization effect.

[0234] [Table 13]

[0235] Method 2 under long-term accelerated test conditions (storage at 40°C and 75% relative humidity for three months)

[0236]

[0237]

[0238] 1) RRT 0.23: Desbenzyl donepezil, within 0.15%

[0239] 2) RRT 0.49: Donepezil pyridine analog, within 0.15%

[0240] 3) RRT 0.57: unknown impurities, within 0.1%

[0241] 4) RRT 0.68: Donepezil quaternary salt, within 0.15%

[0242] 5) RRT 1.03: unknown impurities, within 0.1%

[0243] 6) RRT 1.08: unknown impurities, within 0.1%

[0244] 7) RRT 1.7: Donepezil indene analog, within 0.15%

[0245] 8) RRT 2.1: Deoxydonepezil, within 0.15%

[0246] The test results show that the storage stability of donepezil cannot be confirmed by only one of the first method and the second method among the methods for analyzing the impurities of donepezil.

[0247] Donepezil is a dementia treatment drug that is taken for a long time with gradually increasing dosage. When a preparation containing impurities is continuously administered, potential dangers may occur due to the toxicity of unknown impurities. Therefore, for the long-term storage stability of the drug, the percutaneous absorption preparation of donepezil needs to set and manage the permissible standard value of impurities in the preparation.

[0248] The impurities of donepezil recorded in the United States Pharmacopoeia can be confirmed by the first method for a total of three impurities, and by the second method for a total of species of impurities, and the impurities confirmed by the first method and the second method are all different types of impurities except for Desbenzyl donepezil. Considering the toxicity of the impurities as described above, the standard values ​​allowed in the preparation are set and managed.

[0249] The present invention uses a stabilizer including potassium thiocyanate and thioglycerol disclosed in Korean Patent Application No. 2018-0167289, and confirms the time-dependent changes of impurities through a short-term harsh test (storage at 70°C for 48 hours), a long-term accelerated test 1 (storage at 40°C and 75% relative humidity for one month) and a long-term accelerated test 2 (storage at 40°C and 75% relative humidity for three months), thereby providing a transdermal absorption preparation containing donepezil that complies with the first method and the second method proposed in the United States Pharmacopoeia.

[0250] The examples of the present invention, Comparative Examples 2 to 4 (potassium thiocyanate and / or thioglycerol), Comparative Example 67 (potassium thiocyanate / rutin) and Comparative Example 104 (thioglycerol / potassium thiocyanate / rutin) meet the standards of both the first and second methods of impurity analysis methods proposed in the United States Pharmacopoeia under short-term harsh conditions of 70°C for 48 hours.

[0251] However, although one or two stabilizers disclosed in the examples of Korean Patent Publication No. 10-2009-0086565 do not meet the first method and / or second method standards of the impurity analysis method proposed in the United States Pharmacopoeia under short-term severe conditions, i.e., 70°C for 48 hours, in the transdermal absorption preparation containing two stabilizers in any combination with a compound similar to thioglycerol, i.e., 3-mercapto-1,2-propanediol, in Comparative Example 68 (thioglycerol / ethylenediaminetetraacetic acid), Comparative Example 70 (thioglycerol / 2-mercaptobenzimidazole), Comparative Example 72 (thioglycerol / butylhydroxytoluene), Comparative Example 74 (thioglycerol / butylhydroxytoluene), The percutaneous absorption preparations prepared in Comparative Example 70 (thioglycerol / quercetin dihydrate), Comparative Example 75 (thioglycerol / hydroquinone), Comparative Example 78 (thioglycerol / sodium sulfite), Comparative Example 79 (thioglycerol / sodium thiosulfate), Comparative Example 80 (thioglycerol / propyl gallate), Comparative Example 81 (thioglycerol / 1,3-butylene glycol), Comparative Example 83 (thioglycerol / α-tocopheryl acetate), Comparative Example 85 (thioglycerol / rutin), and Comparative Example 86 (thioglycerol / isoascorbic acid) all meet the standards of the first method and the second method of impurity analysis methods proposed in the United States Pharmacopoeia under short-term harsh conditions, i.e., 70°C for 48 hours.

[0252] In Test Example 3 described in the present invention, in order to confirm the stability of the donepezil percutaneous absorption preparation during long-term storage, the Examples and Comparative Examples 2, 3, 4, 67, 68, 70, 72, 74, 75, 78, 79, 80, 81, 83, 85, 86 and 104 of the present invention, whose impurity generation evaluation results under the short-term severe conditions of Test Examples 1 and 2 conformed to the first method and second method standards proposed in the United States Pharmacopoeia, were evaluated for impurities after being stored for one month under long-term accelerated test conditions of 40° C. and 75% relative humidity.

[0253] In Test Example 3 of the present invention, only the percutaneous absorbent containing both potassium thiocyanate and thioglycerol, the stabilizers described in Korean Patent Application No. 2018-0167289, met the standards set forth in the United States Pharmacopoeia (Comparative Example 4), while Comparative Example 2 (potassium thiocyanate) and Comparative Example 3 (thioglycerol) did not meet the long-term accelerated test under the accelerated test conditions of storage at 40°C and 75% relative humidity for one month. In addition, in Comparative Example 104, the percutaneous absorbent containing thioglycerol and potassium thiocyanate, the stabilizers described in Korean Patent Application No. 2018-0167289, and rutin, the stabilizer described in Korean Patent Publication No. 10-2009-0086565, after being mixed and added, also met the first method and second method standards of impurities set forth in the United States Pharmacopoeia under the long-term accelerated test conditions (storage at 40°C and 75% relative humidity for one month).

[0254] However, among the percutaneous absorption preparations in which thioglycerol (3-mercapto-1,2-propanediol described in Korean Patent Application No. 2018-0167289) and a stabilizer described in Korean Patent Publication No. 10-2009-0086565) were mixed arbitrarily and then added, only Comparative Example 85 (thioglycerol / rutin) and Comparative Example 86 (thioglycerol / isoascorbic acid) met the first method and second method standards for impurities set forth in the United States Pharmacopoeia, while Comparative Examples 68, 70, 72, 74, 75, 78, 79, 80, 81, and 83 did not meet the first method and second method standards for impurities set forth in the United States Pharmacopoeia under the long-term accelerated test conditions (storage at 40°C and 75% relative humidity for one month).

[0255] In Test Example 4 described in the present invention, the evaluation results of impurity generation under long-term accelerated conditions of storage at 40°C and 75% relative humidity for one month meet the standards set forth in the United States Pharmacopoeia. For the embodiments of the present invention and Comparative Examples 4, 85, 86 and 104, the impurities set forth in the United States Pharmacopoeia were evaluated after storage at 40°C and 75% relative humidity for three months, and the changes in the impurities over time were confirmed.

[0256] In Test Example 4 of the present invention, the percutaneous absorption agent containing potassium thiocyanate and thioglycerol, which are stabilizers described in Korean Patent Application No. 2018-0167289, namely Comparative Example 4 (potassium thiocyanate / thioglycerol), and the percutaneous absorption agent added after mixing the stabilizers, namely thioglycerol and potassium thiocyanate described in Korean Patent Application No. 2018-0167289 and the stabilizer, namely rutin described in Korean Patent Publication No. 10-2009-0086565, namely Comparative Example 104 (potassium thiocyanate / thioglycerol / rutin) were stored at 40° C. and 75% relative humidity for one month, and thus did not meet the first method and second method standards proposed in the United States Pharmacopoeia after three months of storage.

[0257] However, in the percutaneous absorption preparation in which the stabilizer described in Korean Patent Application No. 2018-0167289, namely thioglycerol (3-mercapto-1,2-propanediol described in Korean Patent Publication No. 10-2009-0086565) and a stabilizer described in Korean Patent Publication No. 10-2009-0086565 are randomly mixed and then added, Comparative Example 85 (thioglycerol / rutin) does not meet the first method and second method standards of impurities proposed in the United States Pharmacopoeia, and Comparative Example 86 (thioglycerol / isoascorbic acid) meets the first method standard of impurities proposed in the United States Pharmacopoeia, but does not meet the second method standard proposed in the United States Pharmacopoeia.

[0258] Therefore, the present invention provides a donepezil-containing transdermal absorption preparation that meets the standards of the first method and the second method set forth in the United States Pharmacopoeia in a short-term severe test (storage at 70° C. for 48 hours), a long-term accelerated test 1 (storage at 40° C. and 75% relative humidity for one month), and a long-term accelerated test 2 (storage at 40° C. and 75% relative humidity for three months). The donepezil-containing transdermal absorption preparation can produce a donepezil-containing transdermal absorption preparation having improved long-term storage stability by suppressing the degradation of donepezil and reducing the generation of impurities.

Claims

1. A transdermal absorption preparation of donepezil for treating dementia, comprising a support layer, a drug-containing layer and a peeling layer, in, The drug-containing layer contains donepezil or a pharmaceutically acceptable salt thereof as an active ingredient, a pressure-sensitive adhesive, and a stabilizer composition, wherein the stabilizer composition is (i) a mixture of thiocyanate and a stabilizer selected from the group consisting of tea catechins, (+)-catechins, epigallocatechin gallate, ascorbic acid, and isoascorbic acid, or (ii) a mixture of thioglycerol and a stabilizer selected from the group consisting of tea catechins, (+)-catechins, and epigallocatechin gallate.

2. The percutaneous absorption preparation according to claim 1, wherein The donepezil is in the form of a free base.

3. The percutaneous absorption preparation according to claim 1, wherein The stabilizer composition is a mixture of thiocyanate and a stabilizer selected from the group consisting of tea catechins, (+)-catechins, epigallocatechin gallate, ascorbic acid and isoascorbic acid.

4. The percutaneous absorption preparation according to claim 1 or claim 3, wherein The thiocyanate is potassium thiocyanate.

5. The percutaneous absorption preparation according to claim 3, wherein The stabilizer composition further comprises thioglycerol.

6. The percutaneous absorption preparation according to claim 1, wherein The stabilizer composition is a mixture of thioglycerol and a stabilizer selected from the group consisting of tea catechins, (+)-catechins and epigallocatechin gallate.

7. A method for producing a transdermal absorption preparation of donepezil, the transdermal absorption preparation of donepezil comprising a support layer, a drug-containing layer and a peeling layer, wherein: The method comprises the following steps: i) dissolving various components including donepezil or a pharmaceutically acceptable salt thereof, a binder, and a stabilizer composition in an organic solvent, wherein the stabilizer composition is a mixture of thiocyanate and a stabilizer selected from the group consisting of tea catechins, (+)-catechins, epigallocatechin gallate, ascorbic acid, and erythorbic acid, or a mixture of thioglycerol and a stabilizer selected from the group consisting of tea catechins, (+)-catechins, and epigallocatechin gallate; ii) applying the solution produced in the above step to the release layer and drying it to form a drug-containing layer; and iii) laminating the drug-containing layer and the support layer.

8. The method according to claim 7, wherein: The organic solvent is selected from the group consisting of ethyl acetate, toluene, hexane, 2-propanol, methanol, ethanol, dichloromethane and tetrahydrofuran.

9. The method according to claim 7, wherein: The donepezil is in the form of a free base.

10. The method according to claim 7, wherein: The stabilizer composition is a mixture of thiocyanate and a stabilizer selected from the group consisting of tea catechins, (+)-catechins, epigallocatechin gallate, ascorbic acid and isoascorbic acid.

11. The method according to claim 7 or claim 10, wherein: The thiocyanate is potassium thiocyanate.

12. The method according to claim 10, wherein: The stabilizer composition further comprises thioglycerol.

13. The method according to claim 7, wherein: The stabilizer composition is a mixture of thioglycerol and a stabilizer selected from the group consisting of tea catechins, (+)-catechins and epigallocatechin gallate.

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