RU2829135C1 - Percutaneous absorption preparation with improved stability, including donepezil - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: group of inventions can be used to treat dementia. Proposed is a donepezil preparation for percutaneous absorption for the treatment of dementia, comprising a support layer, a drug-containing layer and a release substrate, wherein the drug-containing layer includes donepezil or a pharmaceutically acceptable salt thereof as an active ingredient; pressure sensitive adhesive and a combination of stabilizers. Combination of stabilizers is either (i) a mixture of potassium thiocyanate and a stabilizer, selected from the group comprising tea catechin, (+)-catechin, epigallocatechin gallate, ascorbic acid and isoascorbic acid, or (ii) a mixture of monothioglycerol and a stabilizer, selected from a group comprising tea catechin, (+)-catechin and epigallocatechin gallate. Also disclosed is a method of producing said preparation of donepezil. In the disclosed percutaneous absorption preparation containing donepezil, the formation of impurities is reduced by inhibiting the decomposition of donepezil, which provides improved stability of donepezil during long-term storage.

EFFECT: obtained preparation meets the criteria for acceptability of the content of decomposition products of donepezil presented in the US Pharmacopoeia, under conditions of short-term stress and long-term accelerated test.

10 cl, 13 tbl, 4 ex

Description

Field of technology

The present invention relates to a transdermal absorption preparation comprising donepezil, with improved stability due to inhibition of impurity formation under long-term storage conditions as well as short-term storage.

State of the art

The acetylcholinesterase inhibitor donepezil was developed for the treatment of Alzheimer's disease. It is commercially available as oral tablets Aricept®. The recommended starting dose is 5 mg for the first 4-6 weeks due to potential side effects. During this period, the dose may be increased to 10 mg based on the clinical response. For patients who have been taking 10 mg for at least 3 months, the dose may be increased to 23 mg. However, oral tablets containing donepezil are known to cause side effects such as nausea, vomiting, and diarrhea due to the rapid increase in blood concentration. They are also difficult to take for elderly patients with impaired swallowing ability. In addition, patients with dementia have difficulty taking them regularly on their own. These factors contribute to low patient compliance.

In order to overcome these shortcomings, various efforts have been made in Korea and around the world to research and develop transdermal absorption preparations containing donepezil or its salt. Transdermal absorption preparations are usually formulated with high concentrations of donepezil in order to ensure systemic action. However, various environmental factors such as heat, light, and moisture cause impurities in donepezil, making it difficult to ensure storage stability. Therefore, the need for a stabilizer to solve the above-mentioned problem has been a subject of interest for a long time. Consistent research efforts have also been made to solve the said problem.

The Guideline on the quality of transdermal patches published by the European Medicines Agency recommends that impurity limits for transdermal absorbents should be in accordance with ICH Q3B, a guideline published by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. ICH Q3B provides a limit for total impurities according to the daily dose and for impurities resulting from degradation of the drug substance, which limit may be increased or decreased depending on the toxicity of the impurity.

The United States Pharmacopoeia has a specific standard for impurities that may form during degradation of donepezil in tablets containing donepezil and prohibits the use of donepezil tablets that exceed the maximum limit for impurities due to the potential for toxicity of the impurities.

Impurities resulting from degradation of the parent compound are typically assessed using liquid chromatography. The analytical conditions (e.g., column, mobile phase conditions, absorption wavelength) determine the types of impurities that can be analyzed. The USP provides two methods for analyzing donepezil for impurities.

The first method (hereinafter referred to as "Procedure 1") can be used to detect debenzyldonepezil, donepezil ring-opened impurities, and donepezil N-oxide. USP recommends that each of these impurities be less than 0.5% and other unknown impurities less than 0.2%. The second method ("Procedure 2") can be used to detect debenzyldonepezil, donepezil pyridine analog, donepezil quaternary salt, donepezil indene analog, or deoxidonepezil. USP recommends that each of these impurities be less than 0.15%, other unknown impurities be less than 0.1%, and total impurities be less than 1.0%. Procedure 2 is recommended instead of Procedure 1 if there is a potential for the formation of the above 5 impurities in a donepezil-containing product.

Research efforts to improve the stability of donepezil are disclosed in U.S. Patent No. 6,372,760, Korean Patent Application No. 10-2009-0086565, Korean Patent Registration No. 10-0866720, Korean Patent Registration No. 10-1408500, Korean Patent Registration No. 10-1408454 and Korean Patent Application No. 2018-0167289.

U.S. Patent No. 6,372,760 attempts to improve the stability of donepezil by adding an organic acid. Korean Patent No. 10-0866720 relates to a method for improving the stability of donepezil by adding a high-molecular acidic substance and a high-molecular basic substance for oral preparations and syrups. However, the above prior art does not disclose the use of a stabilizer for a transdermal preparation.

Korean Patent Application No. 10-2009-0086565 discloses the use of one or more stabilizers selected from the group consisting of ascorbic acid or a metal salt or ester thereof, iso(isomer) ascorbic acid or a metal salt thereof, ethylenediaminetetraacetic acid or a metal salt thereof, cysteine, acetylcysteine, 2-mercaptobenzimidazole, 3(2)-tert-butyl-4-hydroxyanisole, 2,6-di-tert-butyl-4-methylphenol, tetrakis[3-(3',5'-di-tert-butyl-4'-hydroxyphenyl)propionate]pentaerythritol, 3-mercapto-1,2-propanediol, tocopherol acetate, rutin, quercetin, hydroquinone, a metal salt of hydroxymethanesulfinic acid, a metabisulfite salt metal, metal sulfite salt and metal thiosulfate salt, for inhibiting the formation of donepezil impurities in transdermal absorption preparations. The above-mentioned prior art literature reports that one or more stabilizers can inhibit the formation of donepezil N-oxide, desbenzyldonepezil and common impurities. However, the evaluation was made using only procedure 1 of the methods proposed by the USP under short-term stress conditions (70°C, 48 hours). Therefore, it is difficult to say that they effectively inhibit various impurities that may be formed from donepezil over a long period.

Also, in Korean Patent Registration No. 10-1408500 and 10-1408454, methods for inhibiting the formation of impurities from donepezil in transdermal absorption preparations are disclosed using a combination of two stabilizers selected from the group consisting of isoascorbic acid, 2-mercaptobenzimidazole, a metal salt of hydroxymethanesulfonic acid, rutin, 2,6-di-tert-butyl-4-methylphenol, ascorbic acid and its metal salt metabisulfite. The above-mentioned prior art shows that one stabilizer cannot effectively inhibit two types of impurities (N-oxide of donepezil and debenzyldonepezil) or common impurities. It also shows that a combination of two stabilizers can inhibit N-oxide of donepezil and debenzyldonepezil, and also common impurities. However, the evaluation was performed using only USP Procedure 1 under short-term stress conditions. Therefore, it is difficult to say whether various impurities that may form from donepezil are effectively inhibited over a long period.

Korean Patent Application No. 2018-0167289 discloses that the use of a thiocyanate salt (preferably a potassium salt), monothioglycerol or dimethyl urea as the only stabilizer inhibits the formation of impurities of donepezil in transdermal absorption preparations. Unlike other known technologies, the inhibition of impurities under short-term stress conditions was confirmed by both Procedure 1 and Procedure 2 of the USP. This also shows that the transdermal absorption preparations of donepezil described in other prior art documents (Korean Patent Registration Nos. 10-1408500 and 10-1408454) do not meet the requirements of Procedure 1 and/or Procedure 2 of the USP.

In their research and development for commercialization of the transdermal absorption preparation containing donepezil in Korean Patent Application No. 2018-0167289, the inventors of the present invention found that the preparations did not meet the impurity acceptance criteria of Procedure 1 and Procedure 2 provided in the United States Pharmacopoeia upon long-term storage, indicating very poor long-term stability. (Dimethylthiourea, one of the stabilizers disclosed in Korean Patent Application No. 2018-0167289, is excluded from the candidates for the present invention because it is not approved for pharmaceutical use.)

Therefore, the present inventors studied transdermal absorption preparations containing donepezil that can maintain stability under both short-term and long-term storage conditions using thiocyanate salt and monothioglycerol, which are stabilizers disclosed in Korean Patent Application No. 2018-0167289. As a result, they found corresponding stabilizers that meet the criteria of Procedure 1 and Procedure 2 provided by the United States Pharmacopoeia by effectively inhibiting various impurities generated by the decomposition of donepezil under both short-term and long-term storage conditions, and arrived at the present invention.

Disclosure

Technical problem

An object of the present invention is to provide a transdermal absorption preparation comprising donepezil, which can maintain stability under short-term and long-term storage, with a thiocyanate salt and monothioglycerol, which are stabilizers disclosed in Korean Patent Application No. 2018-0167289.

Another object of the present invention is to provide a transdermal absorption preparation comprising donepezil which meets the criteria of Procedure 1 and Procedure 2 of the United States Pharmacopoeia under short-term stress and long-term stress conditions in accelerated tests.

Solution to the problem

In order to achieve the above object, the present invention provides a donepezil-containing preparation for transdermal absorption for treating dementia, comprising a supporting layer, a drug-containing layer and a release substrate, wherein the drug-containing layer comprises donepezil or a pharmaceutically acceptable salt thereof as an active ingredient; a pressure-sensitive adhesive and a combination of stabilizers, which is either (i) a mixture of a thiocyanate salt and a stabilizer selected from the group consisting of tea catechin, (+)-catechin, epigallocatechin gallate, ascorbic acid and isoascorbic acid, or (ii) a mixture of monothioglycerol and a stabilizer selected from the group consisting of tea catechin, (+)-catechin and epigallocatechin gallate.

The present invention is further described below.

Donepezil is an acetylcholinesterase inhibitor and can be used in the form of a free base or as a pharmaceutically acceptable salt thereof. Among the pharmaceutically acceptable salts of donepezil, acid addition salts formed with pharmaceutically acceptable free acids are useful. Preferred acid addition salts are obtained with inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, nitrous acid and phosphoric acid, or with non-toxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoates, hydroxyalkanoates, hydroxyalkandioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butene-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate and mandelate, but are not limited to.

From the viewpoint of dispersibility and percutaneous absorbability, donepezil free base may be preferable in the drug-containing layer. Although no particular limitation is suggested on the concentration of donepezil in the preparation for transdermal absorption of the present invention, in order to better disperse donepezil in the drug-containing layer and to better percutaneously absorb donepezil from the drug-containing layer, the preferred range of the content of donepezil is 1-20% by weight (based on the weight of the drug-containing layer), preferably 1.5-15% by weight, and more preferably 2-10% by weight.

In the present invention, the combination of stabilizers is (i) a mixture of a thiocyanate salt and a stabilizer selected from the group consisting of tea catechin and (+)-catechin, epigallocatechin gallate, ascorbic acid and isoascorbic acid; or (ii) a mixture of monothioglycerol and a stabilizer selected from the group consisting of tea catechin, (+)-catechin and epigallocatechin gallate. In addition, the mixture of a thiocyanate salt and a stabilizer selected from the group consisting of tea catechin and (+)-catechin, epigallocatechin gallate, ascorbic acid and isoascorbic acid may also further comprise monothioglycerol as a stabilizer.

The thiocyanate salt used in the present invention is an antioxidant and a pharmaceutically acceptable salt, including but not limited to inorganic salts such as potassium, sodium, ammonium, calcium, magnesium, mercury, cobalt, lead, copper, silver, lithium, iron, nickel, cadmium, zinc, cesium, thallium and barium, and organic salts such as ethyl-containing, methyl-containing, guanidine, benzyl-containing, 1-ethyl-3-methylimidazolium, 1-butyl-3-methylimidazolium, tetramethylammonium. Potassium thiocyanate can be preferably used.

In the present invention, a stabilizer is contained in the drug-containing layer, and the mass ratio of the stabilizer is not particularly limited as long as it does not adversely affect the physical properties of the drug-containing layer. When determining a preferable example of the upper limit of the proportion of the stabilizer relative to the mass of the drug-containing layer (i.e., the total mass of the solid content of the combination used in forming the drug-containing layer), several factors are taken into account. When the content is over 5 mass%, the physical properties of the drug-containing layer such as adhesion may be impaired. When the content is below 0.0005 mass%, a sufficient stabilizing effect may not be achieved. Therefore, a preferable range of the mass ratio of the stabilizer is from 0.0005 mass% to 5 mass%, more preferably from 0.005 mass% to 3 mass%, and still more preferably from 0.05 mass% to 2 mass%. For example, when three stabilizers are mixed, the amount of thiocyanate salt is 0.001-50% by weight of the total weight of donepezil, and the amount of a mixture of two or three stabilizers may be 1-500% by weight of the total weight of thiocyanate salt.

The pressure-sensitive adhesive in the present invention is not particularly limited. Examples include an acrylic pressure-sensitive adhesive; rubber-based pressure-sensitive adhesives such as those using polyisoprene, styrene-butadiene, styrene-isoprene-styrene block copolymer or styrene-butadiene-styrene block copolymer as a base polymer; silicone adhesive; and vinyl-based polymer adhesives such as those using polyvinyl alcohol, polyvinyl alkyl ether and polyvinyl acetate as a base polymer.

A more preferable example of the pressure-sensitive adhesives in the present invention is a rubber-based pressure-sensitive adhesive using a styrene-isoprene-styrene block copolymer as a base polymer. The styrene-isoprene-styrene block copolymer is a thermoplastic elastomer comprising styrene and isoprene. Its properties, such as melting point and solution viscosity, vary greatly depending on factors such as the content of styrene and the diblock copolymer.

The styrene-isoprene-styrene block copolymer used in the present invention is not particularly limited. Preferably, the viscosity of the solution thereof is more than 0.5 Pa*s, preferably 0.7 Pa*s, and more preferably 0.9 Pa*s, when measured according to the “Method of measuring viscosity of styrene-isoprene-styrene block copolymer” described in the 2013 edition of Japanese Pharmaceutical Excipients. The upper limit of the viscosity of the solution is not particularly limited, but it is preferably less than 2.0 Pa*s, and more preferably 1.8 Pa*s.

If the drug-containing layer does not contain a sufficient amount of the base polymer of the pressure-sensitive adhesive, the drug-containing layer may become unable to maintain its shape. If too much of the base polymer is used, the permeability of the preparation into the skin decreases. Therefore, the content of the base polymer in the drug-containing layer of the present invention is preferably 10% by mass to 70% by mass, more preferably 15% by mass to 65% by mass, still more preferably 20% by mass to 60% by mass, and still more preferably 25% by mass to 55% by mass.

The pressure-sensitive adhesive composition in the transdermal absorption preparation may contain a plasticizer. Examples of plasticizers that can be used in the present invention include, but are not limited to, paraffinic processing oils, naphthenic processing oils, aromatic processing oils, olive oil, camellia oil, tall oil, castor oil, isopropyl myristate, hexyl laurate, mineral oil, octyldodecyl myristate, propylene glycol and propylene glycol monocaprylate. A combination of two or more of the above plasticizers can be used. The amount of plasticizers added for maintaining sufficient cohesive strength of the pressure-sensitive adhesive composition is preferably 10% by weight to 80% by weight. More preferably, it is 20% by weight to 75% by weight, more preferably 25% by weight to 70% by weight, and still more preferably 35% by weight to 65% by weight.

A tackifying resin may be added to the drug-containing layer of the present invention in order to adjust the tackiness of the transdermal absorption preparation. Tackifying resins that can be used in the present invention include, but are not limited to, rosin derivatives, alicyclic saturated hydrocarbon resin, and aliphatic hydrocarbon resin. Although a terpene resin is used in the examples of the present invention, this should not be construed as limiting the scope of the present invention.

If a tackifier is included in the drug-containing layer, the content of the tackifier is preferably 20% by mass or lower in order to reduce skin irritation. More preferably, it is less than 15% by mass, more preferably 10% by mass, and even more preferably 8% by mass. It is most preferable that there is no tackifier at all. That is, from the viewpoint of the adhesion of the patch to the skin, the content of the tackifier can be adjusted depending on the mixing ratio of donepezil, the styrene-isoprene-styrene block copolymer, the solubilizer, and the plasticizer in the drug-containing layer. The tackifier may not be needed at all if sufficient adhesion to the skin is achieved without the tackifier.

In the present invention, the "carrier" in the "carrier layer" is not particularly limited, and one which is widely used for producing a drug for transdermal absorption and the like can be used. For example, an elastic or non-elastic woven fabric or a non-woven fabric made of polyethylene, polypropylene, polyethylene terephthalate and the like, polyester films such as polyethylene terephthalate and the like, polyolefins such as polyethylene, polypropylene and the like, films such as polyurethane, ethylene-vinyl copolymer, polyvinyl chloride and the like, or a foamed carrier made of polyolefin, polyurethane and the like can be used. These can be used singly, or a laminate of several kinds thereof can be used.

In addition, in order to prevent the accumulation of static electricity on the carrier layer, the above-mentioned woven fabric, non-woven fabric, film, etc. constituting the carrier layer may contain an antistatic agent. In addition, in order to achieve good adhesion to the adhesive layer, a woven fabric or a non-woven fabric or a laminate thereof with a film may be used as the carrier layer. The thickness of the film as the carrier layer is generally 10-100 μm, preferably 15-50 μm, and the thickness of the woven fabric, non-woven fabric, and porous sheets such as a foamed carrier layer, etc. is generally 50-2000 μm, preferably 100-1000 μm.

The transdermal absorption preparation of the present invention can also be provided with a release support commonly used in the art. As the release support, glassine, polymer films of polyolefin such as polyethylene, polypropylene, etc., polyesters such as polyethylene terephthalate, etc., polystyrene, etc., aluminum film, foamed polyethylene film, or foamed polypropylene film, etc., or a laminate of two or more kinds of materials mentioned above, which can be subjected to silicone treatment or fluorinated polymer treatment, profiling, hydrophilic treatment, hydrophobic treatment, etc., etc. can be used. The thickness of the release support is usually 10 µm - 200 µm, preferably 15 µm - 150 µm.

In addition, the preparation for transdermal absorption of the present invention may contain an excipient, a solubilizer, a permeation enhancer, a flavoring agent, a coloring agent, etc. as optional components.

There is no particular limitation on the method for producing the preparation for transdermal absorption. Conventional methods for producing the preparation for transdermal absorption, such as those described in the Korean Pharmacopoeia, i.e., dissolving or dispersing a pressure sensitive adhesive agent, donepezil, a stabilizer and a plasticizer in a solvent; applying the solution or dispersion to the surface of a release substrate; drying; and layering a carrier thereon. One embodiment of the present invention is a method for producing a preparation for transdermal absorption with donepezil, comprising the following steps: (1) dissolving a mixture of donepezil and a combination of stabilizers according to the present invention in an organic solvent; (2) applying the solution obtained in (1) to a release substrate and drying it to form a drug-containing layer; and (3) layering a carrier layer on the drug-containing layer obtained in (ii).

Examples of possible solvents that can be used in the above-mentioned method according to the present invention include ethyl acetate, toluene, hexane, 2-propanol, methanol, ethanol, methylene chloride and tetrahydrofuran. The temperature at which the adhesive is dissolved or dispersed in the solvent is not particularly limited. However, higher temperatures may increase the likelihood of evaporation of the solvent and may increase the decomposition of donepezil, causing the formation of more impurities. Therefore, a preferable temperature range is 80°C or lower, and more preferably 60°C or lower.

In addition, the above-described method of applying the solution or dispersion to the release substrate, drying it, and laminating the carrier of the present invention can be carried out by conventional methods for producing a preparation for transdermal absorption.

Beneficial effects of the invention

The present invention provides a transdermal absorption preparation comprising donepezil that meets the criteria of procedure 1 and procedure 2 of the United States Pharmacopeia with impurity change over time as demonstrated by the short-term stress test (storage at 70°C for 48 hours), long-term accelerated test 1 (storage at 40°C, 75% relative humidity for 1 month) and long-term accelerated test 2 (storage at 40°C, 75% relative humidity for 3 months).

In the transdermal absorption preparation comprising donepezil according to the present invention, the formation of impurities is reduced by inhibiting the degradation of donepezil under short-term stress conditions as well as under acceleration conditions of a long-term accelerated test, satisfying the impurity criteria of Procedure 1 and Procedure 2 of the United States Pharmacopoeia. Therefore, according to the present invention, a transdermal absorption preparation comprising donepezil with improved stability under long-term storage can be obtained.

The best embodiment of the invention

The present invention is further described below with examples and experimental examples. The following examples and experimental examples are provided to further describe the present invention in detail for those skilled in the art and should not be construed as limiting the scope of the present invention.

Examples 1 - 13. Preparation for transdermal absorption according to the present invention

16 g of styrene-isoprene-styrene block copolymer, 4.7 g of octyldodecyl myristate, 2 g of terpene resin, 6.5 g of propylene glycol monocaprylate and 1.3 g of donepezil are dissolved in 27 g of ethyl acetate to obtain a solution in ethyl acetate containing donepezil. Then a total of 0.13 g (1/n each) of the stabilizers listed in Table 1 are dissolved in 1 g of methanol and mixed with the ethyl acetate solution from the previous step.

The resulting mixture is applied to a silicone-coated PET film and dried in a drying cabinet at 80°C for 30 minutes. After that, a layer of protective film is layered. The resulting transdermal absorption preparation is Examples 1-13 of the present invention.

Table 1

Stabilizer 2 Stabilizer 1 Stabilizer 3 Example 1 Potassium thiocyanate Tea catechin - Example 2 Potassium thiocyanate (+)-Catechin - Example 3 Potassium thiocyanate Epigallocatechin gallate - Example 4 Potassium thiocyanate Ascorbic acid - Example 5 Potassium thiocyanate Isoascorbic acid - Example 6 Potassium thiocyanate Tea catechin Monothioglycerol Example 7 Potassium thiocyanate (+)-Catechin Monothioglycerol Example 8 Potassium thiocyanate Epigallocatechin gallate Monothioglycerol Example 9 Potassium thiocyanate Ascorbic acid Monothioglycerol Example 10 Potassium thiocyanate Isoascorbic acid Monothioglycerol Example 11 Monothioglycerol Tea catechin - Example 12 Monothioglycerol (+)-Catechin - Example 13 Monothioglycerol Epigallocatechin gallate -

Comparison example 1. Drug for transdermal absorption without stabilizer

Comparative Example 1 is a transdermal absorption preparation identical to the preparation of Example 1 in composition and method of preparation, except that it does not contain a stabilizer.

Comparative Examples 2-4: Percutaneous Absorption Preparation Adding Potassium Thiocyanate and/or Monothioglycerol as a Stabilizer Described in Korean Patent Application No. 2018-0167289

Preparations for transdermal absorption were obtained according to the composition and preparation method described in Example 1, with the addition of potassium thiocyanate and/or monothioglycerol, which are stabilizers described in Korean Patent Application No. 2018-0167289. The obtained preparation was labeled as Comparative Examples 2 to 4.

Comparative Examples 5-16. A preparation for transdermal absorption by adding citric acid, tartaric acid, or benzoic acid described in Korean Patent Application No. 2018-0167289 as a stabilizer to the preparation of Comparative Examples 2-4

Comparative Examples 5-7 are transdermal absorption preparations comprising citric acid, tartaric acid or benzoic acid, respectively, from the stabilizers described in U.S. Patent Publication No. 6,372,760. Comparative Examples 8-16 are transdermal absorption preparations prepared by adding citric acid, tartaric acid or benzoic acid (described in U.S. Patent Publication No. 6,372,760) to Comparative Examples 2-4 prepared by the same method as in Example 1.

Table 2

Stabilizer 2 Stabilizer 1 Stabilizer 3 Example for comparison 5 - Citric acid - Example for comparison 6 - Tartaric acid - Example for comparison 7 - Benzoic acid - Example for comparison 8 Potassium thiocyanate Citric acid - Example for comparison 9 Potassium thiocyanate Tartaric acid - Example for comparison 10 Potassium thiocyanate Benzoic acid - Example for comparison 11 Monothioglycerol Citric acid - Example for comparison 12 Monothioglycerol Tartaric acid - Example for comparison 13 Monothioglycerol Benzoic acid - Example for comparison 14 Potassium thiocyanate Monothioglycerol Citric acid Example for comparison 15 Potassium thiocyanate Monothioglycerol Tartaric acid Example for comparison 16 Potassium thiocyanate Monothioglycerol Benzoic acid

Comparative Examples 17-20. Transdermal Absorption Preparation with Two Stabilizers Described in Korean Patent Publication, Registration No. 10-1408500

Percutaneous absorption preparations of the same composition and method as in Example 1 were prepared by adding one of the four pairs of stabilizers in Table 3, which are most effective in inhibiting donepezil N-oxide, debenzyldonepezil and all impurities, from the pairs of stabilizers described in Korean Patent Publication Registration No. 10-1408500. They were labeled as Comparative Examples 17 to 20.

Table 3

Stabilizer 1 Stabilizer 2 Example for comparison 17 Isoascorbic acid 2-Mercaptobenzimidazole Example for comparison 2-Mercaptobenzimidazole 2,6-Di-tert-butyl-4-methylphenol Example for comparison 2-Mercaptobenzimidazole Routine Example for comparison 2,6-Di-tert-butyl-4-methylphenol Sodium hydroxymethanesulfonate

Comparative example 21. A transdermal absorption preparation with two added stabilizers

A preparation for transdermal absorption was prepared according to the composition and preparation method described in Example 1, with the addition of ascorbic acid and sodium metabisulfite (0.13 g each), which are stabilizers disclosed in Korean Patent Registration No. 10-1408454. The resulting preparation was labeled as Comparative Example 21.

Comparative Examples 22-49. Preparation for transdermal absorption with various stabilizers described in Korean Patent Application No. 10-2009-0086565

Preparations for transdermal absorption were prepared according to the composition and production method described in Example 1 by adding stabilizers described in Korean Patent Application No. 10-2009-0086565 and various known stabilizers shown in Table 4 below. They were labeled as Comparative Examples 22 to 49.

Table 4

Stabilizer 1 Stabilizer 2 Example for comparison 22 Ethylenediaminetetraacetic acid
(EDTA) Example for comparison 23 Cysteine Example for comparison 24 2-Mercaptobenzimidazole Example for comparison 25 Butylated hydroxyanisole Example for comparison 26 2,6-Di-tert-butyl-4-methylphenol Example for comparison 27 Pentaerythrityl tetra-di-tert-butylhydroxyhydrocinnamate Example for comparison 28 Quercetin dihydrate Example for comparison 29 Hydroquinone Example for comparison 30 Sodium hydroxymethanesulfonate Example for comparison 31 Sodium metabisulfite Example for comparison 32 Sodium sulfite Example for comparison 33 Sodium thiosulfate Example for comparison 34 Propyl gallate Example for comparison 35 1,3-Butanediol Example for comparison 36 (+)-Alpha-tocopherol Example for comparison 37 Alpha-tocopherol acetate Example for comparison 38 Benzotriazole Example for comparison 39 Routine Example for comparison 40 Ascorbic acid Example for comparison 41 Isoascorbic acid Example for comparison 42 Tea catechin Example for comparison 43 (+)-Catechin Example for comparison 44 Epigallocatechin gallate Example for comparison 45 2,6-Di-tert-butyl-4-methylphenol Tea catechin Example for comparison 46 Butylated hydroxyanisole Tea catechin Example for comparison 47 Sodium thiosulfate Tea catechin Example for comparison 48 2,6-Di-tert-butyl-4-methylphenol Isoascorbic acid Example for comparison 49 Butylated hydroxyanisole Isoascorbic acid

Comparative Examples 50-67. Preparations for transdermal absorption with potassium thiocyanate and various stabilizers described in Korean Patent Application No. 10-2009-0086565

Preparations for transdermal absorption were prepared according to the composition and production method described in Example 1, with the addition of potassium thiocyanate and one of the stabilizers described in Korean Patent Application No. 10-2009-0086565 indicated in Table 5 below. They were labeled as Comparative Examples 50 to 67.

Table 5

Stabilizer 2 Stabilizer 1 Example for comparison 50 Potassium thiocyanate Ethylenediaminetetraacetic acid Example for comparison 51 Cysteine Example for comparison 52 2-Mercaptobenzimidazole Example for comparison 53 Butylated hydroxyantisole Example for comparison 54 Dibutylated hydroxytoluene Example for comparison 55 Pentaerythryl tetra-di-tert-butylhydroxyhydrocinnamate Example for comparison 56 Quercetin dihydrate Example for comparison 57 Hydroquinone Example for comparison 58 Sodium hydroxymethanesulfonate Example for comparison 59 Sodium bisulfite Example for comparison 60 Sodium sulfite Example for comparison 61 Sodium thiosulfate Example for comparison 62 Propyl gallate Example for comparison 63 1,3-Butanediol Example for comparison 64 (+)-Alpha-tocopherol Example for comparison 65 Alpha-tocopherol acetate Example for comparison 66 Benzotriazole Example for comparison 67 Routine

Comparative Examples 68-86. Percutaneous Absorption Preparation with Monothioglycerol and Various Stabilizers Described in Korean Patent Application No. 10-2009-0086565

Preparations for transdermal absorption were obtained according to the composition and production method described in Example 1 by adding monothioglycerol (the same compound as 3-mercapto-1,2-propanediol described in Korean Patent Application No. 10-2009-0086565) and one of the stabilizers described in Korean Patent Application No. 10-2009-0086565 shown in Table 6 below. The obtained preparations were labeled as Comparative Examples 68 to 86.

Table 6

Stabilizer 2 Stabilizer 1 Example for comparison 68 Monothioglycerol Ethylenediaminetetraacetic acid (EDTA) Example for comparison 69 Cysteine Example for comparison 70 2-Mercaptobenzimidazole Example for comparison 71 Butylated hydroxyanisole Example for comparison 72 Dibutylated hydroxytoluene Example for comparison 73 Pentaerythryl tetra-di-tert-butylhydroxyhydrocinnamate Example for comparison 74 Quercetin dihydrate Example for comparison 75 Hydroquinone Example for comparison 76 Sodium hydroxymethanesulfonate Example for comparison 77 Sodium bisulfite Example for comparison 78 Sodium sulfite Example for comparison 79 Sodium thiosulfate Example for comparison 80 Propyl gallate Example for comparison 81 1,3-Butanediol Example for comparison 82 (+)-Alpha-tocopherol Example for comparison 83 Alpha-tocopherol acetate Example for comparison 84 Benzotriazole Example for comparison 85 Routine Example for comparison 86 Isoascorbic acid

Comparative Examples 87-104. Preparation for transdermal absorption with potassium thiocyanate and monothioglycerol and various stabilizers described in Korean Patent Application No. 10-2009-0086565

Preparations for transdermal absorption were prepared according to the composition and production method described in Example 1 by adding potassium thiocyanate and monothioglycerol and one of the stabilizers described in Korean Patent Application No. 10-2009-0086565 indicated in Table 7 below. They were labeled as Comparative Examples 87 to 104.

Table 7

Example No. Stabilizer 2 Stabilizer 3 Stabilizer 1 Example for comparison 87 Potassium thiocyanate Monothioglycerine Ethylenediaminetetraacetic acid (EDTA) Example for comparison 88 Cysteine Example for comparison 89 2-Mercaptobenzimidazole Example for comparison 90 Butylated hydroxyanisole Example for comparison 91 Dibutylated hydroxytoluene Example for comparison 92 Pentaerythryl tetra-di-tert-butylhydroxyhydrocinnamate Example for comparison 93 Quercetin dihydrate Example for comparison 94 Hydroquinone Example for comparison 95 Sodium hydroxymethanesulfonate Example for comparison 96 Sodium metabisulfite Example for comparison 97 Sodium sulfite Example for comparison 98 Sodium thiosulfate Example for comparison 99 Propyl gallate Example for comparison 100 1,3-Butanediol Example for comparison 101 (+)-Alpha-tocopherol Example for comparison 102 Alpha-tocopherol acetate Example for comparison 103 Benzotriazole Example for comparison 104 Routine

Experimental example 1. Evaluation of impurities according to procedure 1 after a short-term stress condition at 70° for 48 hours

In order to test the presence of donepezil impurity during short-term storage, the transdermal absorption preparations of Examples and Comparative Examples were tested for donepezil impurity according to Procedure 1 as described below after a short-term stress condition of 48 hours storage at 70°C.

1. Analysis of impurities according to procedure 1

Each transdermal absorption preparation was dissolved in ethyl acetate for 60 minutes with stirring. Methanol was added, and the resulting solution was stirred for 60 minutes and centrifuged for 5 minutes. The resulting supernatant was used as the sample solution for USP procedure 1. A standard solution was prepared using a solvent mixture of ethyl acetate:methanol = 15:85 (volume ratio) so that the concentration of donepezil hydrochloride standard was 0.8 μg/mL.

Procedure 1. Liquid chromatographic conditions

Column Inertsil ODS-2 (4.6 × 150 mm, C18.5 µm)

Mobile phase. Dissolve 2.5 g of sodium 1-decanesulfonate in 650 ml of distilled water. Then add 1 ml of 70% perchloric acid solution and 350 ml of acetonitrile.

Column temperature - 35°C

Flow rate - 1.4 ml/min

Injection size - 20 µl

The wavelength of UV radiation is 271 nm

Calculations

Impurity percentage = (Ru/Rs) × (Cs/Cu) × (1/F) × 100

Ru: the maximum response of any single impurity from the sample solution

Rs: maximal response of donepezil compared to standard solution

Cs: concentration in standard solution (mg/ml)

Cu: concentration in sample solution (mg/ml)

F: relative correction factor for each impurity

Admixture Relative retention time (RRT) Relative correction factor (F) Acceptance Criteria (%) Debenzyldonepezil 0.33 1 0.5 Donepezil open loop 0.7 0.6 0.5 Donepezil N-Oxide 1,2 1 0.5 Any single unspecified decomposition product - - 0.2

2. Evaluation of impurities

The transdermal absorption preparations of the Examples of the present invention and the Comparative Examples were subjected to a short-term stress condition for 48 hours at 70°C and then tested for donepezil impurity according to Procedure 1. The results are shown in Table 8.

As shown in Table 8 below, in Comparative Example 1 without stabilizer, the degradation of donepezil produces a large amount of impurities by Procedure 1 with relative retention times (RRT) of 0.53 (unidentified impurity), 1.2 (donepezil N-oxide), and all impurities, demonstrating the need for stabilizers in transdermal absorption preparations of donepezil.

Regarding the transdermal absorption preparations including the stabilizers potassium thiocyanate (Comparative Example 2) or monothioglycerol (Comparative Example 3) described in Korean Patent Application No. 2018-0167289, or a mixture thereof (potassium thiocyanate and monothioglycerol), the amount of impurities generated under short-term stress meets the criteria of Procedure 1 proposed by the United States Pharmacopoeia, confirming outstanding stability.

As for Comparative Examples 5-7 using citric acid, tartaric acid and benzoic acid, which are organic acids described in U.S. Patent No. 6,372,760, the relative retention time of 1,2 (N-oxide of donepezil) does not meet the standards set in the United States Pharmacopoeia. As for Comparative Examples 8-16, which are Comparative Examples 2-4 with the addition of the above stabilizers, the relative retention time of 1,2 (N-oxide of donepezil) is significantly reduced, which meets the criteria of Procedure 1 provided in the United States Pharmacopoeia for the short-term stress condition.

In the case of Comparative Examples 17-21 using a combination of two stabilizers described in Korean Patent Publication Registration No. 10-1408500 or Korean Patent Publication Registration No. 10-1408454, the impurities meet the criteria of Procedure 1 for the short-term stress condition provided in the United States Pharmacopoeia.

As for Comparative Examples 22 to 44, which are transdermal absorption preparations added with stabilizers described in Korean Patent Publication No. 10-2009-0086565, Comparative Example 23 (cysteine), Comparative Example 24 (2-mercaptobenzimidazole), Comparative Example 30 (sodium hydroxymethanesulfonate), and Comparative Example 33 (sodium thiosulfate) meet the criteria of Procedure 1 for the acute stress condition specified in the United States Pharmacopoeia in terms of an individual impurity, but most of the stabilizers do not give the corresponding result when added alone.

Also, regarding Comparative Examples 45 to 49 which have a combination of the stabilizers described in Korean Patent Application Publication No. 10-2009-0086565 and a conventionally known stabilizer, Comparative Example 45 (2,6-di-tert-butyl-4-methylphenol/tea catechin), Comparative Example 48 (2,6-di-tert-butyl-4-methylphenol/isoascorbic acid) and Comparative Example 49 (butylhydroxyanisole/isoascorbic acid) meet the criteria of Procedure 1 described in the United States Pharmacopoeia. On the other hand, Comparative Example 46 (butylhydroxyanisole/tea catechin) and Comparative Example 47 (sodium thiosulfate/tea catechin) do not meet the criteria of Procedure 1 provided in the United States Pharmacopoeia.

As for Comparative Examples 50 to 67, which are transdermal absorption preparations that have a combination of potassium thiocyanate, a stabilizer described in Korean Patent Application No. 2018-0167289, and one stabilizer described in Korean Patent Application Publication No. 10-2009-0086565, most of the stabilizers meet the criteria of Procedure 1 proposed by the United States Pharmacopoeia, but Comparative Example 53 (potassium thiocyanate/butylhydroxyanisole), Comparative Example 57 (potassium thiocyanate/hydroquinone), Comparative Example 62 (potassium thiocyanate/propyl gallate), and Comparative Example 64 (potassium thiocyanate/(+)-alpha-tocopherol) are not compliant in terms of individual impurities with Procedure 1 proposed by the United States Pharmacopoeia for acute stress conditions.

As for Comparative Examples 68 to 86, which are transdermal absorption preparations containing monothioglycerol, which is a stabilizer described in Korean Patent Application Publication No. 2018-0167289 and one of the stabilizers described in Korean Patent Application Publication No. 10-2009-0086565, most of the stabilizers comply with the criteria of Procedure 1 provided in the United States Pharmacopoeia, but Comparative Example 71 (monothioglycerol/butylhydroxyanisole) and Comparative Example 82 (monothioglycerol/(+)-alpha-tocopherol/) do not comply with Procedure 1 for individual impurities proposed by the United States Pharmacopoeia for acute stress conditions.

Also, with regard to Comparative Examples 87 to 104, which are transdermal absorption preparations containing monothioglycerol and potassium thiocyanate described in Korean Patent Application Publication No. 2018-0167289 and one stabilizer described in Korean Patent Application Publication No. 10-2009-0086565, most of the stabilizers meet the criteria of Procedure 1 proposed by the United States Pharmacopoeia, but Comparative Example 90 (potassium thiocyanate/monothioglycerol/butylhydroxyanisole), Comparative Example 94 (potassium thiocyanate/monothioglycerol/hydroquinone), Comparative Example 99 (potassium thiocyanate/monothioglycerol/propyl gallate) and Comparative Example 101 (potassium thiocyanate/monothioglycerol/(+)-alpha-tocopherol) do not meet the criteria from the point of view of individual impurities, procedure 1 proposed by the United States Pharmacopoeia for the short-term stress condition.

On the other hand, Examples 1 to 13 according to the present invention meet the criteria of Procedure 1 proposed by the United States Pharmacopoeia for the short-term stress condition in terms of individual impurities, showing an outstanding stabilizing effect.

1) RRT 0.33: debenzyldonepezil, within 0.5%

2) RRT 0.48: unidentified impurities, within 0.2%

2) RRT 0.53: unidentified impurities, within 0.2%

2) RRT 0.7: donepezil with open cycle, within 0.5%

2) RRT 1,2: Donepezil N-oxide, within 0.5%

Experimental example 2. Evaluation of impurities using method 2 after short-term stress at 70°C for 48 hours

The transdermal absorption preparations of the Examples and Comparative Examples are tested for the presence of donepezil impurities according to Procedure 2 as described below after a short-term stress condition for 48 hours of storage at 70°C.

1. Analysis of impurities according to procedure 2

Regarding the procedure 2 for impurity analysis, each percutaneous absorption preparation is dissolved in ethyl acetate for 60 minutes with stirring, and then a mixture of 0.1 N hydrochloric acid and methanol at an appropriate ratio of 25:75 is added to the solution, stirred for 60 minutes, and centrifuged for 5 minutes. The supernatant is used as a sample solution and evaluated according to the criteria of Table 10 below in accordance with the procedure 2 of the United States Pharmacopoeia. A standard solution is prepared using a solvent mixture of ethyl acetate:methanol:0.1 N hydrochloric acid = 100:675:225 (volume ratio) so that the standard concentration of donepezil hydrochloride is 10 μg/mL.

Procedure 2. Liquid chromatography conditions

Capcellpak Column (4.6 x 250 mm, C18.5 µm)

Mobile phase A: Add 1 ml phosphoric acid to 1 liter of distilled water. Adjust the mixture to pH 6.5 with triethylamine. Pass through a filter, remove bubbles, and use as the mobile phase.

Mobile phase B: acetonitrile

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

Column temperature - 50°C

Flow rate - 1.5 ml/min

Injection volume - 20 µl

UV wavelength - 286 nm

Calculations

Impurity percentage = (Ru/Rs) × (Cs/Cu) × (1/F) × 100

Ru: the maximum response of any single impurity from the sample solution

Rs: maximal response of donepezil from standard solution

Cs: concentration in standard solution (mg/ml)

Cu: concentration in sample solution (mg/ml)

F: relative correction factor for each impurity

Admixture Relative retention time (RRT) Relative correction factor (F) Acceptance Criteria
(%) Debenzyldonepezil 0.23 1.5 0.15 Pyridine analogue of donepezil 0.49 1.9 0.15 Quaternary salt of donepezil 0.68 0.74 0.15 Indene analogue of donepezil 1.7 2,2 0.15 Deoxydonepezil 2.1 1.3 0.15 Any single decomposition product - 1.0 0,1 All impurities - - 1.0

2. Evaluation of impurities

The transdermal absorption preparations of the examples according to the present invention and the comparative examples were stored under short-term stress conditions for 48 hours at 70°C, and then tested for the presence of donepezil impurities according to Procedure 2. The results are shown in Table 9.

As shown in Table 9 below, when analyzed using Procedure 2, the transdermal absorption product without stabilizer (Comparison Example 1) produces impurities that exceed the criteria for donepezil degradation at relative retention times of 0.49 (pyridine analogue of donepezil), 0.57 (unknown related substances), 1.08 (unknown related substances) and all impurities, indicating that stabilizers are required for the product.

Regarding the transdermal absorption preparations including the stabilizers potassium thiocyanate (Comparative Example 2) or monothioglycerol (Comparative Example 3) described in Korean Patent Application No. 2018-0167289, or a mixture thereof (Comparative Example 4), the amount of impurities generated under short-term stress (storage at 70°C for 48 hours) met the criteria of Procedure 2 proposed by the United States Pharmacopoeia, confirming outstanding stability.

Comparative Examples 5-7 using citric acid, tartaric acid, and benzoic acid, which are organic acids described in U.S. Patent Publication No. 6,372,760, do not meet the requirements of Procedure 2 of the United States Pharmacopeia. Comparative Examples 8-16, which are Comparative Examples 2-4 with the addition of the above stabilizers, do not meet the requirements of Procedure 2 of the United States Pharmacopeia, even though they meet the criteria of Procedure 1.

In the case of Comparative Examples 17 to 21 using a combination of two stabilizers described in Korean Patent Publication Registration No. 10-1408500 or Korean Patent Publication Registration No. 10-1408454, the impurities do not meet the criteria of Procedure 2 of the USP under short-term stress conditions even though they meet the criteria of Procedure 1.

Comparative Examples 22 to 44, which are transdermal absorption preparations with stabilizers described in Korean Patent Application Publication No. 10-2009-0086565 and conventionally known stabilizers added, all do not satisfy the criteria of Procedure 2 even though some satisfy the criteria of Procedure 1 under short-term stress conditions.

Also, Comparative Examples 45 to 49, which contain a mixture of the stabilizers described in Korean Patent Publication No. 10-2009-0086565 and a conventionally known stabilizer, also do not meet the criteria of Procedure 2.

With respect to Comparative Examples 50-67, which are transdermal absorption preparations containing potassium thiocyanate, a stabilizer described in Corny Patent Application Publication No. 2018-0167289, and one of the stabilizers described in Corny Patent Application Publication No. 10-2009-0086565, all except Comparative Example 67 (potassium thiocyanate/rutin) do not meet the criteria of USP Procedure 2, although most of them meet the criteria of Procedure 1 for short-term stress conditions.

As for Comparative Examples 68 to 86, which are transdermal absorption preparations with the stabilizer described in Korean Patent Application Publication No. 2018-0167289 mixed with one of the stabilizers described in Korean Patent Application Publication No. 10-2009-0086565, although most of them meet the criteria of Procedure 1 for impurities under short-term stress, only Comparative Example 68 (monothioglycerol/ethylenediaminetetraacetic acid), Comparative Example 70 (monothioglycerol/2-mercaptobenzimidazole), Comparative Example 72 (monothioglycerol/dibutylhydroxytoluene), Comparative Example 74 (monothioglycerol/quercetin dihydrate), Comparative Example 75 (monothioglycerol/hydroquinone), Comparative Example 78 (monothioglycerol/sodium sulfite), Comparative Example 79 (monothioglycerol/sodium thiosulfate), Comparative Example 80 (monothioglycerol/propyl gallate), Comparative Example 81 (monothioglycerol/1,3-butanediol), Comparative Example 82 (monothioglycerol/alpha-tocopherol acetate), Comparative Example 85 (monothioglycerol/rutin), and Comparative Example 86 (monothioglycerol/isoascorbic acid) comply with the criteria of United States Pharmacopoeia Procedure 2. Comparative Example 69 (monothioglycerol/cysteine), Comparative Example 71 (monothioglycerol/butylhydroxyanisole), Comparative Example 73 (monothioglycerol/pentaerythrityl tetra-di-tert-butylhydroxyhydrocinnamate), Comparative Example 76 (monothioglycerol/sodium hydroxymethanesulfonate), Comparative Example 77 (monothioglycerol/sodium metabisulfite), Comparative Example 82 (monothioglycerol/(+)-alpha-tocopherol), and Comparative Example 84 (monothioglycerol/benzotriazole) do not meet the criteria of Procedure 2 as provided in the United States Pharmacopoeia.

Also, regarding Comparative Examples 87 to 104, transdermal absorption preparations containing monothioglycerol and potassium thiocyanate (the stabilizers described in Korean Patent Application Publication No. 2018-0167289) and one of the stabilizers described in Korean Patent Application Publication No. 10-2009-0086565, all except Comparative Example 104 (monothioglycerol/potassium thiocyanate/rutin), do not meet the criteria of USP Procedure 2, although most of them meet the criteria of Procedure 1 for short-term stress conditions.

On the other hand, Examples 1-13 according to the present invention meet the criteria of Procedure 2 proposed by the United States Pharmacopoeia for short-term stress conditions for individual impurities, showing an outstanding stabilizing effect.

1) RRT 0.23: debenzyldonepezil, within 0.15%

2) RRT 0.49: pyridine analogue of donepezil, within 0.15%

3) RRT 0.49: unknown impurities, within 0.1%

4) RRT 0.08: donepezil quaternary salt, within 0.15%

5) RRT 1.03: unknown impurities, within 0.1%

6) RRT 1.03: unknown impurities, within 0.1%

7) RRT 1.7: indene analogue of donepezil, within 0.15%

8) RRT 2.1: deoxidonepezil, within 0.15%

Of the Comparative Examples and the Examples of the present invention, only the Examples of the present invention and Comparative Examples 4 (a preparation for transdermal absorption with a stabilizer of potassium thiocyanate and/or monothioglycerol added, described in Korean Patent Application No. 2018-0167289), Comparative Example 67 (potassium thiocyanate/rutin), Comparative Example 68 (monothioglycerol/ethylenediaminetetraacetic acid), Comparative Example 70 (monothioglycerol/2-mercaptobenzimidazole), Comparative Example 72 (monothioglycerol/dibutylhydroxytoluene), Comparative Example 74 (monothioglycerol/quercetin dihydrate), Comparative Example 75 (monothioglycerol/hydroquinone), Comparative Example 78 (monothioglycerol/sodium sulfite), Comparative Example 79 (monothioglycerol/sodium thiosulfate), Comparative Example 80 (monothioglycerol/propyl gallate), Comparative Example 81 (monothioglycerol/1,3-butanediol), Comparative Example 83 (monothioglycerol/alpha-tocopherol acetate), Comparative Example 85 (monothioglycerol/rutin), Comparative Example 86 (monothioglycerol/isoascorbic acid), and Comparative Example 104 (monothioglycerol/potassium thiocyanate/rutin) meet the criteria of both Procedure 1 and Procedure 2 of the United States Pharmacopoeia impurity test method for short-term stress conditions at 70°C for 48 hours.

Experimental example 3. Analysis of impurities under conditions of accelerated long-term storage (storage for 1 month at a temperature of 40°C, relative humidity 75%)

In order to test the stability of the transdermal absorption preparations of donepezil during long-term storage, Examples 1 through 13 and Comparative Examples 2, 3, 4, 67, 68, 70, 72, 74, 75, 78, 79, 80, 81, 83, 85, 86 and 104 (which meet the criteria of USP Procedure 1 and Procedure 2) were stored for 1 month under accelerated conditions at 40°C and 75% relative humidity. After 1 month of storage, the preparations were tested in Procedures 1 and 2 as before. The results are shown in Tables 10 and 11.

1. Analysis of impurities according to procedure 1

As shown in Table 10 below, in the transdermal absorption preparation without stabilizer (Comparative Example 1), according to the analysis according to Procedure 1 under the condition of accelerated long-term storage (1 month storage at 40°C and 75% relative humidity), impurities exceeding the criteria are formed as a result of the degradation of donepezil at a relative retention time of 0.53 (unknown impurity), 1.2 (N-oxide of donepezil) and all impurities, which indicates that the preparation requires stabilizers.

Potassium thiocyanate (Comparative Example 2), a stabilizer described in Korean Patent Application No. 2018-0167289, does not meet the criteria of Procedure 1 under accelerated test conditions (75% relative humidity at 40°C, stored for 1 month). On the other hand, Comparative Example 4, which includes a combination of monothioglycerol (Comparative Example 3) and the above two stabilizers (potassium thiocyanate/monothioglycerol), meets the criteria of Procedure 1 under accelerated test conditions (75% relative humidity at 40°C, stored for 1 month).

Comparative Example 67, which is a transdermal absorption preparation with a combination of potassium thiocyanate, a stabilizer described in Korean Patent Application Publication No. 2018-0167289, and rutin, a stabilizer described in Korean Patent Application Publication No. 10-2009-0086565, meets the criteria of Procedure 1 under accelerated test conditions (relative humidity of 75% at 40°C, storage for 1 month).

Comparative Example 75 (monothioglycerol/hydroquinone) and Comparative Example 80 (monothioglycerol/propyl gallate), which are transdermal absorption preparations with the stabilizer described in Korean Patent Application Publication No. 2018-0167289 and one of the stabilizers described in Korean Patent Application Publication No. 10-2009-0086565, meet the criteria of Procedure 1 provided in the United States Pharmacopoeia under short-term stress conditions, but do not meet the criteria of Procedure 1 under accelerated test conditions (40°C, 75% relative humidity). On the other hand, Comparative Example 68 (monothioglycerol/ethylenediaminetetraacetic acid), Comparative Example 70 (monothioglycerol/2-mercaptobenzimidazole), Comparative Example 72 (monothioglycerol/dibutylhydroxytoluene), Comparative Example 74 (monothioglycerol/quercetin dihydrate), Comparative Example 78 (monothioglycerol/sodium sulfite), Comparative Example 79 (monothioglycerol/sodium thiosulfate), Comparative Example 80 (monothioglycerol/propyl gallate), Comparative Example 81 (monothioglycerol/1,3-butanediol), Comparative Example 83 (monothioglycerol/alpha-tocopherol acetate), Comparative Example 85 (monothioglycerol/rutin) and Comparative Example 86 (monothioglycerol/isoascorbic acid) meet the criteria procedure 1 of the United States Pharmacopoeia, under accelerated testing conditions (40°C, 75% relative humidity, 1 month storage),

Also, Comparative Example 104, which is a transdermal absorption preparation with a combination of monothioglycerol, a stabilizer described in Korean Patent Application Publication No. 2018-0167289, and potassium thiocyanate, a stabilizer described in Korean Patent Application Publication No. 10-2009-0086565, satisfies the criteria of Procedure 1 under accelerated test conditions (40°C, 75% relative humidity, stored for 1 month).

On the other hand, Examples 1 to 13 according to the present invention meet the criteria of Procedure 1 provided in the United States Pharmacopoeia under accelerated test conditions (40°C, 75% relative humidity, storage for 1 month), confirming the outstanding stabilizing effect.

1) RRT 0.33: debenzyldonepezil, within 0.5%

2) RRT 0.48: unknown impurities, within 0.2%

3) RRT 0.53: unknown impurities, within 0.2%

4) RRT 0.7: donepezil open loop, within 0.5%

5) RRT 1,2: Donepezil N-oxide, within 0.5%

2. Analysis of impurities according to procedure 2

As shown in Table 11 below, in the transdermal absorption preparation without stabilizer (Comparative Example 1), when analyzed according to Procedure 2 under accelerated test conditions (40°C, 75% relative humidity, stored for 1 month), impurities are formed by degradation of donepezil with a relative retention time of 0.49 (pyridine analogue of donepezil), 0.57 (unknown related substance), 1.08 (unknown related substance), and all impurities, which indicates that the preparation requires stabilizers.

Potassium thiocyanate (Comparative Example 2) and monothioglycerol (Comparative Example 3), the stabilizers described in Korean Patent Application No. 2018-0167289, did not satisfy the criteria of Procedure 2 under the accelerated test conditions (40°C, 75% relative humidity, stored for 1 month). On the other hand, Comparative Example 4, which contained a combination of monothioglycerol (Comparative Example 3) and the above two stabilizers (potassium thiocyanate/monothioglycerol), satisfied the criteria of Procedure 2 under the accelerated test conditions (40°C, 75% relative humidity, stored for 1 month).

Comparative Example 67, which is a transdermal absorption preparation with a combination of potassium thiocyanate, a stabilizer described in Korean Patent Application Publication No. 2018-0167289, and rutin, a stabilizer described in Korean Patent Application Publication No. 10-2009-0086565, meets the criteria of Procedure 2 under accelerated test conditions, but does not meet the criteria of Procedure 2 under accelerated test conditions (40°C, 75% relative humidity, stored for 1 month).

Comparative Example 68 (monothioglycerin/ethylenediaminetetraacetic acid), Comparative Example 70 (monothioglycerin/2-mercaptobenzimidazole), Comparative Example 72 (monothioglycerin/dibutylhydroxytoluene), Comparative Example 74 (monothioglycerin/quercetin dihydrate), Comparative Example 75 (monothioglycerin/hydroquinone), Comparative Example 78 (monothioglycerin/sodium sulfite), Comparative Example 79 (monothioglycerin/sodium thiosulfite), Comparative Example 80 (monothioglycerin/propyl gallate), Comparative Example 81 (monothioglycerin/1,3-butanediol) and Comparative Examples 83 (monothioglycerin/alpha-tocopherol acetate), which include the monothioglycerin described in Korean Patent Application No. 2018-0167289 and one of the stabilizers described in Korean Patent Application Publication No. 10-2009-0086565 meet the criteria of Procedure 2 provided in the United States Pharmacopoeia for short-term stress conditions, but do not meet the criteria of Procedure 2 under accelerated test conditions (40°C, 75% relative humidity, stored for 1 month). On the other hand, Comparative Example 85 (monothioglycerol/rutin) and Comparative Example 86 (monothioglycerol/isoascorbic acid) meet the criteria of Procedure 2 under accelerated test conditions (40°C, 75% relative humidity, stored for 1 month).

Also, Comparative Example 104, which is a transdermal absorption preparation with a combination of monothioglycerol, a stabilizer described in Korean Patent Application Publication No. 2018-0167289, and potassium thiocyanate, a stabilizer described in Korean Patent Application Publication No. 10-2009-0086565, meets the criteria of Procedure 2 under accelerated test conditions (40°C, 75% relative humidity, stored for 1 month).

On the other hand, Examples 1 to 13 according to the present invention meet the criteria of Procedure 2 of the United States Pharmacopoeia under accelerated test conditions (40°C, 75% relative humidity, storage for 1 month), confirming the outstanding stabilizing effect.

1) RRT 0.23: debenzyldonepezil, within 0.15%

2) RRT 0.49: pyridine analogue of donepezil, within 0.15%

3) RRT 0.57: unknown impurities, within 0.1%

4) RRT 0.68: quaternary salt of donepezil, within 0.15%

5) RRT 1.03: unknown impurities, within 0.1%

6) RRT 1.08: unknown impurities, within 0.1%

7) RRT 1.7: indene analogue of donepezil, within 0.15%

8) RRT 2.1: deoxidonepezil, within 0.15%

Experimental example 4. Analysis of impurities under long-term accelerated testing conditions (storage for 3 months at 40°C, relative humidity 75%)

In order to test the transdermal absorption preparations of donepezil for long-term storage stability, Examples 1 to 13 and Comparative Examples 4, 85, 86 and 104, which meet the criteria of Procedure 1 and Procedure 2 of the USP under the long-term accelerated test condition (40°C, 75% relative humidity, stored for 1 month) in Experimental Example 3, were stored for 3 months under the accelerated test condition of 40°C and 75% relative humidity. Then, the preparations were tested by Procedure 1 and Procedure 2 in the same manner as in the above Experimental Experiment 1. The results are shown in Tables 12 and 13.

1. Analysis of impurities according to procedure 1

As shown in Table 12 below, the transdermal absorption product without stabilizer (Comparative Example 1) by the analysis according to Procedure 1 under long-term accelerated storage conditions (3 months storage at 40°C and 75% relative humidity) contains impurities due to the degradation of donepezil with a relative retention time of 0.53 (unknown impurity), 1.2 (N-oxide of donepezil) and all impurities exceeding the criteria, which indicates that the product requires stabilizers.

The transdermal absorption preparation (Comparative Example 4) including both potassium thiocyanate and monothioglycerol, which are stabilizers described in Korean Patent Application No. 2018-0167289, did not meet the criteria of USP Procedure 1 under the conditions of long-term accelerated testing (40°C, 75% relative humidity, stored for 3 months).

Among the transdermal absorption preparations comprising monothioglycerol, the stabilizer described in Korean Patent Application Publication No. 2018-0167289, and one of the stabilizers described in Korean Patent Application Publication No. 10-2009-0086565, Comparative Example 86 (monothioglycerol/isoascorbic acid) meets the criteria of USP Procedure 1 under the conditions of long-term accelerated test (40°C, 75% relative humidity, stored for 3 months), while Comparative Example 85 (monothioglycerol/rutin) does not meet the criteria.

Also, Comparative Example 104, which is a transdermal absorption preparation with a combination of monothioglycerol and potassium thiocyanate, which are described in Korean Patent Application No. 2018-0167289, and rutin, which is described in Korean Patent Application Publication No. 10-2009-0086565, also does not meet the criteria of Procedure 1 provided in the United States Pharmacopoeia.

On the other hand, Examples 1 to 13 according to the present invention meet the criteria of Procedure 1 provided in the United States Pharmacopoeia under the conditions of a long-term accelerated test (40°C, 75% relative humidity, storage for 3 months), confirming the outstanding stabilizing effect.

1) RRT 0.33: debenzyldonepezil, within 0.5%

2) RRT 0.48: unknown impurities, within 0.2%

3) RRT 0.53: unknown impurities, within 0.2%

4) RRT 0.7: donepezil with open cycle, within 0.5%

5) RRT 1,2: Donepezil N-oxides, within 0.5%

2, Analysis of impurities according to procedure 2

As shown in Table 13 below, in the transdermal absorption preparation without stabilizer (Comparative Example 1), when analyzed according to Procedure 2 under the conditions of the long-term accelerated test (40°C, relative humidity 75%, storage for 3 months), the impurities formed as a result of the degradation of donepezil at a relative retention time of 0.49 (pyridine analogue of donepezil), 0.57 (unknown related substance), 1.08 (unknown related substance) and all impurities exceed the criteria, which indicates that the preparation requires stabilizers.

A transdermal absorption preparation (Comparative Example 4) including both potassium thiocyanate and monothioglycerol, which are stabilizers described in Korean Patent Application No. 2018-0167289, did not meet the criteria of Procedure 2 of the United States Pharmacopoeia under the storage conditions of 40°C, 75% relative humidity, and storage for 3 months, due to the formation of impurities exceeding the criteria.

In addition, Comparative Example 104, which is a transdermal absorption preparation with a combination of monothioglycerol and potassium thiocyanate, which are described in Korean Patent Application No. 2018-0167289, and rutin, which is described in Korean Patent Application Publication No. 10-2009-0086565, also did not meet the criteria of Procedure 2 provided in the United States Pharmacopoeia under the conditions of a long-term accelerated test (40°C, 75% relative humidity, stored for 3 months).

On the other hand, Examples 1 to 13 according to the present invention meet the criteria of Procedure 2 provided in the United States Pharmacopoeia under the conditions of a long-term accelerated test (40°C, 75% relative humidity, storage for 3 months), confirming the outstanding stabilizing effect.

1) RRT 0.23: debenzyldonepezil, within 0.15%

2) RRT 0.49: pyridine analogue of donepezil, within 0.15%

3) RRT 0.57: unknown impurities, within 0.1%

4) RRT 0.68: quaternary salt of donepezil, within 0.15%

5) RRT 1.03: unknown impurities, within 0.1%

6) RRT 1.08: unknown impurities, within 0.1%

7) RRT 1.7: indene analogue of donepezil, within 0.15%

8) RRT 2.1: deoxidonepezil, within 0.15%

The above experimental results show that the storage stability of donepezil cannot be confirmed using only Procedure 1 or only Procedure 2 of donepezil impurity analysis.

Donepezil is a dementia treatment that is administered over a long period of time by gradually increasing the dose. If the drug containing impurities is administered continuously, there is a possibility of potential risk due to toxicity of unknown impurities. For the stability of donepezil percutaneous absorption during long-term storage, impurity tolerance criteria should be established and managed.

Regarding the impurities associated with donepezil that are described in the United States Pharmacopoeia, 3 types of impurities can be identified by procedure 1, and 5 types of impurities can be identified by procedure 2. Except for debenzyldonepezil, which can be identified by either procedure, no other impurities are overlapped by the two procedures. There are criteria for acceptable limits for these impurities in the drug, taking into account toxicity.

The present invention provides a transdermal absorption preparation comprising donepezil, which satisfies the criteria of procedure 1 and procedure 2 by incorporating potassium thiocyanate or monothioglycerol, the stabilizers disclosed in Korean Patent Application No. 2018-0167289. The change in impurity content over time was confirmed by a short-term stress test (storage at 70°C for 48 hours), a long-term accelerated test 1 (storage at 40°C, 75% relative humidity for 1 month), and a long-term accelerated test 2 (storage at 40°C, 75% relative humidity for 3 months).

Under short-term stress conditions at 70° for 48 hours, all of the present Examples, Comparative Examples 2-4 (potassium thiocyanate and/or monothioglycerol), Comparative Example 67 (potassium thiocyanate/rutin), and Comparative Example 104 (monothioglycerol/potassium thiocyanate/rutin) meet the criteria of both Procedure 1 and Procedure 2 of the United States Pharmacopoeia Impurity Assay Methods.

The stabilizers of the first and second types disclosed in the examples in Korean Patent Application Publication No. 10-2009-0086565 do not meet the criteria of Procedure 1 and/or Procedure 2 of the United States Pharmacopoeia under short-term stress conditions at 70°C for 48 hours. But among the transdermal preparations including 3-mercapto-1,2-propanediol (also known as monothioglycerol) and other stabilizers, which are included in Comparative Examples 68 (monothioglycerol/ethylenediaminetetraacetic acid), Comparative Example 70 (monothioglycerol/2-mercaptobenzimidazole), Comparative Example 72 (monothioglycerol/dibutyl hydride), Comparative Example 74 (monothioglycerol/quercetin dihydrate), Comparative Example 75 (monothioglycerol/hydroquinone), Comparative Example 78 (monothioglycerol/sodium sulfite), Comparative Example 79 (monothioglycerol/sodium thiosulfate), Comparative Example 80 (monothioglycerol/propyl gallate), Comparative Example 81 (monothioglycerol/1,3-butanediol), Comparative Example Comparative Example 83 (monothioglycerol/alpha-tocopherol acetate), Comparative Example 85 (monothioglycerol/rutin), and the transdermal absorption product obtained in Comparative Example 86 (monothioglycerol/isoascorbic acid) all meet the criteria of both Procedure 1 and Procedure 2 of the United States Pharmacopoeia under short-term stress conditions at 70°C for 48 hours.

In Experimental Example 3 described in the present invention, the stability of the transdermal absorption preparations of donepezil under long-term storage of the examples of the present invention and comparative examples 2, 3, 4, 67, 68, 70, 72, 74, 75, 78, 79, 80, 81, 83, 85, 86 and 104 (which meet the criteria of Procedure 1 and Procedure 2 of the USP under short-term stress conditions in the test in Experimental Examples 1 and 2) was tested under long-term accelerated storage conditions during 1 month at 40°C and a relative humidity of 75%. Then, the preparations were tested for impurities.

In Experimental Example 3 described in the present invention, only Comparative Example 4, a transdermal absorption preparation comprising both potassium thiocyanate and monothioglycerol (described in Korean Patent Application No. 2018-0167289), met the criteria set forth in the United States Pharmacopoeia. Comparative Example 2 (potassium thiocyanate) and Comparative Example 3 (monothioglycerol) did not meet the criteria in the long-term accelerated storage test under the storage condition of 1 month at a relative humidity of 75%. Also, Comparative Example 104, which is a transdermal absorption preparation with a combination of monothioglycerol and potassium thiocyanate, which are described in Korean Patent Application No. 2018-0167289, and rutin, which is described in Korean Patent Application Publication No. 10-2009-0086565, meets the criteria of Procedure 1 and Procedure 2 of the United States Pharmacopeia under long-term accelerated testing conditions (40°C, 75% relative humidity, 1 month storage).

However, among the transdermal absorption preparations comprising a combination of monothioglycerol described in Korean Patent Application Publication No. 2018-0167289 (which is the same as 3-mercapto-1,2-propanediol described in Korean Patent Application Publication No. 10-2009-0086565) and the stabilizer described in Korean Patent Application Publication No. 10-2009-0086565, Comparative Example 85 (monothioglycerol/rutin) and Comparative Example 86 (monothioglycerol/isoascorbic acid) met the criteria of Procedure 1 and Procedure 2 under the long-term accelerated test condition (40°C, 75% relative humidity, stored for 1 month), while Comparative Examples 68, 70, 72, 74, 75, 78, 79, 80, 81 and 83 do not meet the criteria of Procedure 1 and Procedure 2 under long-term accelerated test conditions (40°C, 75% relative humidity, 1 month storage).

In Experimental Example 4, Examples of the present invention and Comparative Examples 4, 85, 86 and 104, which meet the criteria for impurities provided in the United States Pharmacopoeia under long-term accelerated testing at 40°C and 75% relative humidity for 1 month, were subjected to accelerated storage testing for 3 months at 40°C and 75% relative humidity and analyzed for impurities by the methods provided in the United States Pharmacopoeia in order to observe the change in impurities over time.

In Experimental Example 4, Comparative Example 4 (potassium thiocyanate/monothioglycerol), which is a transdermal absorption preparation including both potassium thiocyanate and monothioglycerol described in Korean Patent Application No. 2018-0167289, and Comparative Example 104 (potassium thiocyanate/monothioglycerol/rutin), which is a transdermal absorption preparation including monoglycerol and potassium thiocyanate described in Korean Patent Application No. 2018-0167289 and rutin described in Korean Patent Application Publication No. 10-2009-0086565, increased impurity formation after 1 month of storage at 40°C and 75% relative humidity, did not meet the criteria of Procedure 1 and Procedure 2 provided in the United States Pharmacopoeia for 3 months storage.

However, among the transdermal absorption preparations obtained by using a combination of monothioglycerol, the stabilizer described in Korean Patent Application Publication No. 2018-0167289 (which is the same as 3-mercapto-1,2-propanediol described in Korean Patent Application Publication No. 10-2009-0086565), and the stabilizer described in Korean Patent Application Publication No. 10-2009-0086565, Comparative Example 85 (monothioglycerol/rutin) does not meet the criteria for impurities of Procedure 1 and Procedure 2 provided in the United States Pharmacopoeia. Comparative Example 86 (monothioglycerol/isoascorbic acid) meets the criteria of Procedure 1 but does not meet the criteria of Procedure 2.

Therefore, the present invention provides a transdermal absorption preparation comprising donepezil, which meets the criteria of procedure 1 and procedure 2 provided in the US Pharmacopoeia under short-term stress (storage at 70°C for 48 hours), long-term accelerated test 1 (40°C, relative humidity 75%, 1 month of storage) and long-term accelerated test 2 (40°C, relative humidity 75%, 3 months of storage). In the transdermal absorption preparation comprising donepezil, the formation of impurities is reduced by inhibiting the degradation of donepezil, thereby making it possible to provide a transdermal absorption preparation comprising donepezil with improved stability during long-term storage.

Claims (16)

1. A transdermal absorption preparation of donepezil for the treatment of dementia, comprising a supporting layer, a drug-containing layer and a releasing substrate, wherein the drug-containing layer comprises donepezil or a pharmaceutically acceptable salt thereof as an active ingredient; a pressure-sensitive adhesive and a combination of stabilizers, wherein the combination of stabilizers is either (i) a mixture of potassium thiocyanate and a stabilizer selected from the group consisting of tea catechin, (+)-catechin, epigallocatechin gallate, ascorbic acid and isoascorbic acid, or (ii) a mixture of monothioglycerol and a stabilizer selected from the group consisting of tea catechin, (+)-catechin and epigallocatechin gallate. 2. A preparation for transdermal absorption according to claim 1, wherein donepezil is in the form of a free base. 3. A preparation for transdermal absorption according to claim 1, wherein the combination of stabilizers is a mixture of potassium thiocyanate and a stabilizer selected from the group consisting of tea catechin, (+)-catechin, epigallocatechin gallate, ascorbic acid and isoascorbic acid. 4. The preparation according to item 3, wherein the combination of stabilizers additionally includes monothioglycerol. 5. A preparation for transdermal absorption according to claim 1, wherein the combination of stabilizers is a mixture of monothioglycerol and a stabilizer selected from the group consisting of tea catechin, (+)-catechin and epigallocatechin gallate. 6. A method for producing a donepezil preparation for transdermal absorption, comprising a supporting layer, a drug-containing layer and a releasing substrate, comprising the following steps: i) preparing a solution of ingredients for forming a layer containing a drug, including donepezil or its pharmaceutically acceptable salt, glue and a combination of stabilizers, in organic solvents; ii) applying the solution obtained in the above step to a release substrate and drying it to form a layer containing the drug; and iii) layering a supporting layer on the drug-containing layer, characterized in that the combination of stabilizers is either a mixture of potassium thiocyanate and a stabilizer selected from the group consisting of tea catechin, (+)-catechin, epigallocatechin gallate, ascorbic acid and isoascorbic acid, or a mixture of monothioglycerol and a stabilizer selected from the group consisting of tea catechin, (+)-catechin and epigallocatechin gallate. 7. The method according to claim 6, wherein donepezil is in the form of a free base. 8. The method of claim 6, wherein the combination of stabilizers is a mixture of potassium thiocyanate and a stabilizer selected from the group consisting of tea catechin, (+)-catechin, epigallocatechin gallate, ascorbic acid and isoascorbic acid. 9. The method according to claim 8, wherein the combination of stabilizers additionally includes monothioglycerol. 10. The method of claim 6, wherein the combination of stabilizers is a mixture of monothioglycerol and a stabilizer selected from the group consisting of tea catechin, (+)-catechin, and epigallocatechin gallate.