PERCUTANEOUS ABSORPTION PREPARATION COMPRISING DONEPEZIL WITH IMPROVED STABILITY

Abstract

A percutaneous absorption preparation for the treatment of dementia wherein the drug-containing layer contains donepezil or a pharmaceutically acceptable salt thereof as an active ingredient and a stabilizer that is either (i) a mixture of a thiocyanate salt and a compound selected from the group consisting of tea catechin, (+)-catechin, epigallocatechin gallate, ascorbic acid, and isoascorbic acid, or (ii) a mixture of monothioglycerol and a compound selected from the group consisting of tea catechin, (+)-catechin, epigallocatechin gallate, and ascorbic acid is disclosed. The percutaneous absorption preparation meets the criteria of Procedure 1 and Procedure 2 of the U.S. Pharmacopoeia in short-term stress test (70° C. 48 hours storage), long-term accelerated test 1 (40° C. relative humidity 75% 1 month storage), and long-term accelerated test 2 (40° C. relative humidity 75% 3 months storage), and exhibits improved stability for long-term preservation.

Claims

1: A donepezil percutaneous absorption preparation for the treatment of dementia comprising a support layer, a drug-containing layer, and a release layer, 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 which is either (i) a mixture of 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.

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 combination is a mixture of thiocyanate salt and a stabilizer selected from the group consisting of tea catechin, (+)-catechin, epigallocatechin gallate, ascorbic acid and isoascorbic acid.

4: The preparation of claim 1, wherein the thiocyanate salt is potassium thiocyanate.

5: The preparation of claim 3, wherein the stabilizer combination also comprises monothioglycerol.

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

7: A method of preparing donepezil percutaneous absorption preparation comprising a support layer, a drug-containing layer, and a release layer, wherein the method comprises comprising the following steps: i) dissolving various ingredients including donepezil or a pharmaceutically acceptable salt thereof, an adhesive, and a stabilizer combination which is either a mixture of and a thiocyanate salt 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 in an organic solvent; ii) applying the solution prepared in the above step to the release layer and drying it to form a drug-containing layer; and iii) laminating the drug-containing layer with the support layer.

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

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

10: The method of claim 7, wherein the stabilizer combination is 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.

11: The method of claim 7, wherein the thiocyanate salt is potassium thiocyanate.

12: The method of claim 10, wherein the stabilizer combination further comprises monothioglycerol.

13: The method of claim 7, wherein the stabilizer combination is a mixture of monothioglycerol and a stabilizer selected from the group consisting of tea catechin, (+)-catechin and epigallocatechin gallate.

14: The preparation of claim 3, wherein the thiocyanate salt is potassium thiocyanate.

15: The method of claim 10, wherein the thiocyanate salt is potassium thiocyanate.

Description

BEST MODE FOR CARRYING OUT THE INVENTION

[0040] The present invention is further described below with examples and experimental examples. The examples and experimental examples provided below are provided to further describe the present invention in detail to a skilled person and shall not be construed as limiting the scope of the present invention.

<Examples 1 Through 13> Percutaneous Absorption Preparation According to the Present Invention

[0041] Dissolve 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 in 27 g of ethyl acetate to obtain an ethyl acetate solution comprising donepezil. Then, dissolve 0.13 g total (1/n each) of the stabilizers specified in Table 1 in 1 g of methanol and mix it with the ethyl acetate solution from the previous step.

[0042] Apply this mixture onto a silicone-coated PET film and dry it in an oven at 80° C. for 30 minutes. Afterwards, laminate it with a backing film. The obtained percutaneous absorption preparation are Examples 1 through 13 of the present invention.

TABLE-US-00001 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 —

<Comparative Example 1> Percutaneous Absorption Preparation without Stabilizer

[0043] Comparative example 1 is a percutaneous absorption preparation that is identical to Example 1 in composition and method of preparation except that it does not contain a stabilizer.

<Comparative Examples 2 Through 4> Percutaneous Absorption Preparation with Potassium Thiocyanate and/or Monothioglycerol Described in Korean Patent Application No. 2018-0167289 Added as Stabilizer

[0044] Percutaneous absorption preparations were prepared according to the same composition and preparation method as Example 1, with the addition of potassium thiocyanate and/or monothioglycerol, which are stabilizers described in Korean Patent Application No. 2018-0167289. The resulting preparation was labeled as comparative Examples 2 through 4.

<Comparative Examples 5 Through 16> Percutaneous Absorption Preparation with Citric Acid, Tartaric Acid, or Benzoic Acid Described in Korean Patent Application No. 2018-0167289 Added as Stabilizer to Comparative Examples 2 Through 4

[0045] Comparative Examples 5 through 7 are percutaneous absorption preparations comprising citric acid, tartaric acid, or benzoic acid, respectively, among the stabilizers described in U.S. Pat. No. 6,372,760. Comparative Examples 8 through 16 are percutaneous absorption preparations prepared by adding citric acid, tartaric acid, or benzoic acid (described in U.S. Pat. No. 6,372,760) to Comparative Examples 2 through 4, prepared according to the same method as Example 1.

TABLE-US-00002 TABLE 2 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 Monothioglycerol Citric acid — Comparative Example 12 Monothioglycerol Tartaric acid — Comparative Example 13 Monothioglycerol Benzoic acid — Comparative Example 14 Potassium thiocyanate Monothioglycerol Citric acid Comparative Example 15 Potassium thiocyanate Monothioglycerol Tartaric acid Comparative Example 16 Potassium thiocyanate Monothioglycerol Benzoic acid

<Comparative Examples 17 Through 20> Percutaneous Absorption Preparation with Two Stabilizers Described in Korean Patent Registration Publication No. 10-1408500

[0046] Percutaneous absorption preparations were prepared in the same composition and method as in Example 1, with the addition of one of the four pairs of stabilizers in Table 3 which were the most effectively at inhibiting donepezil N-oxide, desbenzyl donepezil, and total impurities out of the ones described in Korean Patent Registration Publication No. 10-1408500. They are labeled Comparative Examples 17 to 20.

TABLE-US-00003 TABLE 3 Stabilizer 1 Stabilizer 2 Comparative Example 17 Isoascorbic acid 2-mercaptobenzimidazole Comparative Example 18 2-mercaptobenzimidazole 2,6-di-t-butyl-4-methylphenol Comparative Example 19 2-mercaptobenzimidazole Rutin Comparative Example 20 2,6-di-t-butyl-4-methylphenol Sodium hydroxymethane sulfonate

<Comparative Example 21> Percutaneous Absorption Preparation with Two Stabilizers Added

[0047] A percutaneous absorption preparation was prepared according to the same composition and preparation method as example 1, with the addition of ascorbic acid and sodium metabisulfite (0.13 g of each), which are stabilizers disclosed in Korea Patent Registration No. 10-1408454. The resulting preparation was labeled as comparative example 21.

<Comparative Examples 22 Through 49> Percutaneous Absorption Preparation with Various Stabilizers Described in Korean Patent Application No. 10-2009-0086565

[0048] Percutaneous absorption preparations were prepared according to the same composition and preparation method as example 1, with the addition of stabilizers described in Korean Patent Application No. 10-2009-0086565 and various known stabilizers as specified in Table 4 below. They are labeled Comparative Examples 22 through 49.

TABLE-US-00004 TABLE 4 Stabilizer 1 Stabilizer 2 Comparative Example 22 Ethylenediaminetetraacetic acid (EDTA) — Comparative Example 23 Cysteine — Comparative Example 24 2-mercaptobenzimidazole — Comparative Example 25 Butylhydroxyanisole — Comparative Example 26 2,6-di-t-butyl-4-methylphenol — Comparative Example 27 Pentaerythrityl tetra-di-t-butyl — hydroxyhydrocinnamate Comparative Example 28 Quercetin dihydrate — Comparative Example 29 Hydroquinone — Comparative Example 30 Sodium hydroxymethane sulfonate — Comparative Example 31 Sodium metabisulfite — Comparative Example 32 Sodium sulfite — Comparative Example 33 Sodium thiosulfate — Comparative Example 34 Propyl gallate — Comparative Example 35 1,3-butanediol — Comparative Example 36 (+)-Alpha-tocopherol — Comparative Example 37 Alpha-tocopherol acetate Comparative Example 38 Benzotriazole — Comparative Example 39 Rutin — Comparative Example 40 ascorbic acid — Comparative Example 41 isoascorbic acid — Comparative Example 42 tea catechin — Comparative Example 43 (+)-catechin — Comparative Example 44 Epigallocatechin gallate — Comparative Example 45 2,6-di-t-butyl-4-methylphenol tea catechin Comparative Example 46 butylated hydroxyanisole tea catechin Comparative Example 47 sodium thiosulfate tea catechin Comparative Example 48 2,6-di-t-butyl-4-methylphenol isoascorbic acid Comparative Example 49 butylated hydroxyanisole isoascorbic acid

<Comparative Examples 50 Through 67> Percutaneous Absorption Preparations with Potassium Thiocyanate and Various Stabilizers Described in Korean Patent Application No. 10-2009-0086565

[0049] Percutaneous absorption preparations were prepared according to the same composition and preparation method as example 1, with the addition of potassium thiocyanate and one of the stabilizers described in Korean Patent Application No. 10-2009-0086565 as specified in Table 5 below. They are labeled Comparative Examples 50 through 67.

TABLE-US-00005 TABLE 5 Stabilizer 2 Stabilizer 1 Comparative Example 50 Potassium thiocyanate Ethylenediaminetetraacetic acid (EDTA) Comparative Example 51 Cysteine Comparative Example 52 2-mercaptobenzimidazole Comparative Example 53 butylated hydroxyanisole Comparative Example 54 dibutyl hydroxy toluene Comparative Example 55 Pentaerythryltetra-di-t-butyl hydroxyhydrocinnamate Comparative Example 56 Quercetin dihydrate Comparative Example 57 Hydroquinone Comparative Example 58 Sodium hydroxymethane sulfonate Comparative Example 59 Sodium bisulfite Comparative Example 60 Sodium sulfite Comparative Example 61 sodium thiosulfate Comparative Example 62 Propyl gallate Comparative Example 63 1,3-butanediol Comparative Example 64 (+)-Alpha-tocopherol Comparative Example 65 Alpha-tocopherol acetate Comparative Example 66 Benzotriazole Comparative Example 67 Rutin

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

[0050] Percutaneous absorption preparations were prepared according to the same composition and preparation method as example 1, with the addition of 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 Publication No. 10-2009-0086565 as specified in Table 6 below. The resulting preparations are labeled Comparative Examples 68 to 86.

TABLE-US-00006 TABLE 6 Stabilizer 2 Stabilizer 1 Comparative Example 68 Monothioglycerol Ethylenediaminetetraacetic acid (EDTA) Comparative Example 69 Cysteine Comparative Example 70 2-mercaptobenzimidazole Comparative Example 71 butylated hydroxyanisole Comparative Example 72 dibutyl hydroxy toluene Comparative Example 73 Pentaerythryltetra-di-t-butyl hydroxyhydrocinnamate Comparative Example 74 Quercetin dihydrate Comparative Example 75 Hydroquinone Comparative Example 76 Sodium hydroxymethane sulfonate Comparative Example 77 Sodium bisulfite Comparative Example 78 Sodium sulfite Comparative Example 79 Sodium thiosulfate Comparative Example 80 Propyl gallate Comparative Example 81 1,3-Butanediol Comparative Example 82 (+)-alpha-tocopherol Comparative Example 83 alpha-tocopherol acetate Comparative Example 84 Benzotriazole Comparative Example 85 Rutin Comparative Example 86 isoascorbic acid

<Comparative Examples 87 Through 104> Percutaneous Absorption Preparation with Potassium Thiocyanate and Monothioglycerol and Various Stabilizers Described in Korean Patent Application No. 10-2009-0086565

[0051] Percutaneous absorption preparations were prepared according to the same composition and preparation method as example 1, with the addition of potassium thiocyanate and monothioglycerol and one of the stabilizers described in Korean Patent Application No. 10-2009-0086565 as specified in Table 7 below. They are labeled Comparative Examples 87 through 104.

TABLE-US-00007 TABLE 7 Example No. Stabilizer 2 Stabilizer 3 Stabilizer 1 Comparative Example 87 Potassium Monothioglycerol Ethylenediaminetetraacetic acid thiocyanate (EDTA) Comparative Example 88 Cysteine Comparative Example 89 2-mercaptobenzimidazole Comparative Example 90 Butylhydroxyanisole Comparative Example 91 Dibutylhydroxytoluene Comparative Example 92 Pentaerythrityl tetra-di-t-butyl hydroxyhydrocinnamate Comparative Example 93 Quercetin dihydrate Comparative Example 94 Hydroquinone Comparative Example 95 Sodium hydroxymethane sulfonate Comparative Example 96 Sodium metabisulfite Comparative Example 97 Sodium sulfite Comparative Example 98 Sodium thiosulfate Comparative Example 99 Propyl gallate Comparative Example 100 1,3-butanediol Comparative Example 101 (+)-Alpha-tocopherol Comparative Example 102 Alpha-tocopherol acetate Comparative Example 103 Benzotriazole Comparative Example 104 Rutin

<Experimental Example 1> Impurities Evaluation by Procedure 1 after Short-Term Stress Conditions 70° c. for 48 Hours

[0052] To test for donepezil impurities under short-term storage, percutaneous absorption preparations of examples and comparative examples were tested for donepezil impurities according to Procedure 1 as below, after short-term stress condition of 48 hours of storage at 70° C.

[0053] 1. Impurities Analysis by Procedure 1

[0054] Each percutaneous absorption preparation was dissolved in ethyl acetate for 60 minutes by 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 Procedure 1 of the U.S. Pharmacopoeia. The standard solution was prepared so that the concentration of donepezil hydrochloride standard was 0.8 ug/mL using a solvent mixture of ethyl acetate:methanol=15:85 (volume ratio).

[0055] <Procedure 1: Liquid Chromatography Conditions>

[0056] Column: Inertsil ODS-2 (4.6×150 mm, C18, 5 um)

[0057] Mobile phase: Dissolve 2.5 g of Sodium 1-decanesulfonate 2.5 g in 650 mL of purified water. Then, add 1 mL of 70% perchloric acid solution and 350 mL of acetonitrile.

[0058] Column temperature:35° C.

[0059] Flow rate:1.4 mL/min

[0060] Injection size:20 uL

[0061] UV wavelength:271 nm

[0062] Calculation:

[0063] Impurity %=(Ru/Rs)×(Cs/Cu)×(1/F)×100

[0064] Ru: peak response of any individual impurity from the sample solution

[0065] Rs: peak response of donepezil from the standard solution

[0066] Cs: concentration in the standard solution (mg/mL)

[0067] Cu: concentration in the sample solution (mg/mL)

[0068] F: relative correction factor for each impurity

TABLE-US-00008 Relative Relative retention correction Acceptance Impurity time (RRT) factor (F) criteria (%) Desbenzyl donepezil 0.33 1 0.5 Donepezil open ring 0.7 0.6 0.5 Donepezil N-oxide 1.2 1 0.5 Any individual unspecified — — 0.2 degradation product

[0069] 2. Impurities Evaluation

[0070] The percutaneous absorption preparations of the examples according to the present invention and comparative examples were subject to short-term stress condition of storage for 48 hours at 70° C. and then tested for donepezil impurities according to Procedure 1. The results are shown in Table 8.

[0071] As seen in Table 8 below, in Comparative Example 1 without stabilizer, a large amount of impurities were produced from decomposition of donepezil by Procedure 1 at the relative retention times (RRT) 0.53 (unidentified impurity), 1.2 (donepezil N-oxide), as well as for total impurities, demonstrating the need for stabilizers in percutaneous absorption preparations of donepezil.

[0072] As for the percutaneous absorption preparations comprising the stabilizers potassium thiocyanate (Comparative Example 2) or monothioglycerol (Comparative Example 3) described in Korean Patent Application No. 2018-0167289 or a mixture of the two (potassium thiocyanate and monothioglycerol), the amount of impurities produced under short-term stress condition met the criteria of Procedure 1 proposed by the U.S. Pharmacopeia, confirming outstanding stability.

[0073] As for Comparative Examples 5 through 7 using citric acid, tartaric acid, and benzoic acid, which are the organic acids described in U.S. Pat. No. 6,372,760, the relative retention time of 1.2 (Donepezil N-oxide) was inadequate to the standards set forth in the United States Pharmacopeia. As for Comparative Examples 8 through 16 which are Comparative Examples 2 through 4 with the above stabilizers added, the relative retention time of 1.2 (Donepezil N-oxide) was significantly reduced, meeting the criteria of Procedure 1 presented in the U.S. Pharmacopeia under short-term stress condition.

[0074] In the case of Comparative Examples 17 through 21 using a combination of two stabilizers described in Korean Registered Patent Publication No. 10-1408500 or Korean Registered Patent Publication No. 10-1408454, the impurities met the criteria of Procedure 1 presented in the U.S. Pharmacopeia under short-term stress conditions.

[0075] As for Comparative Examples 22 through 44, which are percutaneous absorption preparations with stabilizers described in Korean Patent Publication No. 10-2009-0086565 added, Comparative Example 23 (cysteine), Comparative Example 24 (2-mercaptobenzimidazole), Comparative Example 30 (sodium hydroxymethanesulfonate) and Comparative Example 33 (sodium thiosulfate) met the criteria of Procedure 1 set forth in the U.S. Pharmacopeia under short-term stress conditions in terms of individual impurity, but most of the stabilizers were did not produce adequate result when added alone.

[0076] Also, as for Comparative Examples 45 through 49 which have a combination of a stabilizer described in Korean Patent Application Publication No. 10-2009-0086565 and a conventionally known stabilizer, Comparative Example 45 (2,6-di-t-butyl-4-methylphenol/chacatechin), Comparative Example 48 (2,6-di-t-butyl-4-methylphenol/isoascorbic acid) and Comparative Example 49 (butylhydroxyanisole/isoascorbic acid) met the criteria of Procedure 1 described in the United States Pharmacopoeia. On the other hand, Comparative Example 46 (butyl hydroxyanisole/chacatechin) and Comparative Example 47 (sodium thiosulfate/chacatechin) did not meet the criteria of Procedure 1 presented in the United States Pharmacopeia.

[0077] As for Comparative Examples 50 through 67, which are percutaneous absorption preparations which 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 met the criteria of Procedure 1 suggested by the United States Pharmacopeia, 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) were not adequate in terms of individual impurities by Procedure 1 suggested by the United States Pharmacopeia under of short-term stress condition.

[0078] As for Comparative Examples 68 through 86, which are percutaneous absorption preparations with monothioglycerol which is stabilizer described in Korean Patent Application No. 2018-0167289 and one of the stabilizers described in Korean Patent Application Publication No. 10-2009-0086565, most of the stabilizers met the criteria of Procedure 1 presented in U.S. Pharmacopoeia, but Comparative Example 71 (monothioglycerol/butylhydroxyanisole) and Comparative Example 82 (monothioglycerol/(+)-alpha-tocopherol/) were not adequate interns of individual impurities by Procedure 1 proposed by the United States Pharmacopeia under short-term stress conditions.

[0079] Also, as for Comparative Examples 87 through 104, which are percutaneous absorption preparations which have monothioglycerol and potassium thiocyanate 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 met the criteria of Procedure 1 suggested by the United States Pharmacopeia, 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) were not adequate in terms of individual impurities by Procedure 1 suggested by the United States Pharmacopeia under of short-term stress condition.

[0080] On the other hand, Examples 1 through 13 according to the present invention met the criteria of Procedure 1 suggested by the United States Pharmacopeia under short-term stress conditions in terms of individual impurities, demonstrating outstanding stabilizing effect.

TABLE-US-00009 TABLE 8 Short-term stress condition of 70° C., 48 hr, Procedure 1 of impurities analysis Content (%) of each impurity according to RRT RRT RRT RRT RRT RRT Stabilizer 1 Stabilizer 2 Stabilizer 3 0.33.sup.1) 0.48.sup.2) 0.53.sup.3) 0.7.sup.4) 1.2.sup.5) Total Example 1 Potassium Tea catechin — 0.01 0.00 0.04 0.00 0.05 0.17 Example 2 thiocyanate (+)-catechin — 0.00 0.00 0.04 0.00 0.06 0.15 Example 3 Epigallocatechin — 0.03 0.00 0.04 0.00 0.09 0.26 gallate Example 4 Ascorbic acid — 0.00 0.00 0.00 0.00 0.08 0.14 Example 5 Isoascorbic acid — 0.00 0.00 0.00 0.00 0.09 0.15 Example 6 Potassium Tea catechin Monothioglycerol 0.00 0.00 0.00 0.00 0.08 0.10 Example 7 thiocyanate (+)-catechin 0.00 0.00 0.04 0.00 0.06 0.11 Example 8 Epigallocatechin 0.02 0.00 0.00 0.00 0.07 0.15 gallate Example 9 Ascorbic acid 0.00 0.00 0.00 0.00 0.06 0.09 Example 10 Isoascorbic acid 0.00 0.00 0.00 0.00 0.08 0.13 Example 11 Monothioglycerol tea catechin — 0.00 0.00 0.00 0.00 0.12 0.20 Example 12 (+)-catechin — 0.00 0.00 0.04 0.00 0.14 0.19 Example 13 Epigallocatechin — 0.00 0.00 0.03 0.00 0.14 0.21 gallate Comparative — — — 0.02 0.00 0.23 0.31 1.00 1.76 Example 1 Comparative Potassium — — 0.00 0.00 0.13 0.00 0.00 0.20 Example 2 thiocyanate Comparative — Monothioglycerol — 0.13 0.00 0.05 0.00 0.09 0.34 Example 3 Comparative Potassium Monothioglycerol — 0.00 0.00 0.07 0.00 0.07 0.20 Example 4 thiocyanate Comparative — Citric acid — 0.00 0.09 0.09 0.00 0.73 0.91 Example 5 Comparative — Tartaric acid — 0.00 0.00 0.09 0.00 0.80 0.91 Example 6 Comparative — Benzoic acid — 0.00 0.00 0.09 0.39 1.33 2.06 Example 7 Comparative Potassium Citric acid — 0.00 0.04 0.09 0.00 0.07 0.22 Example 8 thiocyanate Comparative Monothioglycerol Tartaric acid — 0.00 0.05 0.10 0.05 0.06 0.29 Example 9 Comparative Benzoic acid — 0.00 0.11 0.10 0.00 0.05 0.33 Example 10 Comparative Citric acid — 0.05 0.00 0.06 0.00 0.39 0.55 Example 11 Comparative Tartaric acid — 0.03 0.03 0.06 0.08 0.46 0.68 Example 12 Comparative Benzoic acid — 0.04 0.03 0.10 0.05 0.42 0.67 Example 13 Comparative Potassium Monothioglycerol Citric acid 0.03 0.00 0.06 0.00 0.12 0.23 Example 14 thiocyanate Comparative Tartaric acid 0.00 0.04 0.05 0.00 0.09 0.40 Example 15 Comparative Benzoic acid 0.03 0.04 0.07 0.00 0.07 0.23 Example 16 Comparative — 2- Isoascorbic 0.02 0.00 0.01 0.04 0.04 0.14 Example 17 mercaptobenzimidazole acid Comparative — 2,6-di-t-butyl-4- 2- 0.00 0.00 0.10 0.00 0.00 0.13 Example 18 methylphenol mercaptobenzimidazole Comparative — 2- Rutin 0.02 0.12 0.11 0.00 0.00 0.28 Example 19 mercaptobenzimidazole Comparative — Sodium 2,6-di-t- 0.14 0.00 0.06 0.16 0.13 0.72 Example 20 hydroxymethane butyl-4- sulfonate methylphenol Comparative — Sodium Ascorbic 0.03 0.00 0.00 0.02 0.44 0.57 Example 21 metabisulfite acid Comparative — Ethylenediaminetetraacetic — 0.00 0.00 0.16 0.15 0.79 1.17 Example 22 acid (EDTA) Comparative — Cysteine — 0.00 0.00 0.07 0.00 0.26 0.36 Example 23 Comparative — 2- — 0.00 0.00 0.07 0.00 0.02 0.08 Example 24 mercaptobenzimidazole Comparative — Butylhydroxyanisole — 0.00 0.00 0.49 2.23 2.76 5.85 Example 25 Comparative — 2,6-di-t-butyl-4- — 0.00 0.00 0.14 0.42 0.78 1.47 Example 26 methylphenol Comparative — Pentaerythrityl — 0.00 0.00 0.28 0.59 1.21 2.18 Example 27 tetra-di-t-butyl hydroxyhydrocinnamate Comparative — Quercetin — 0.00 0.00 0.08 0.00 0.75 0.86 Example 28 dihydrate Comparative — Hydroquinone — 0.00 0.00 0.44 0.00 1.92 4.13 Example 29 Comparative — Sodium — 0.00 0.00 0.00 0.15 0.23 0.53 Example 30 hydroxymethane sulfonate Comparative — Sodium — 0.00 0.00 0.00 0.12 0.22 0.43 Example 31 metabisulfite Comparative — Sodium sulfite — 0.00 0.00 0.18 0.25 0.98 1.48 Example 32 Comparative — Sodium — 0.00 0.00 0.10 0.06 0.09 0.28 Example 33 thiosulfate Comparative — Propyl gallate — 0.00 0.00 1.12 0.08 1.69 3.05 Example 34 Comparative — 1,3-butanediol — 0.00 0.00 0.21 0.34 0.92 1.56 Example 35 Comparative — (+)-alpha- — 0.00 0.00 4.65 6.12 11.01 24.07 Example 36 tocopherol Comparative — Alpha- — 0.00 0.00 0.14 0.34 0.77 1.40 Example 37 tocopherol acetate Comparative — Benzotriazole — 0.06 0.13 0.28 0.40 1.33 2.40 Example 38 Comparative — Rutin — 0.00 0.00 0.33 0.11 0.83 1.37 Example 39 Comparative — Ascorbic acid — 0.03 0.00 0.12 0.04 0.54 0.77 Example 40 Comparative — Isoascorbic acid — 0.02 0.00 0.04 0.06 0.56 0.74 Example 41 Comparative — Tea catechin — 0.00 0.00 0.08 0.03 0.68 0.82 Example 42 Comparative — (+)-catechin — 0.00 0.00 0.07 0.01 0.81 0.92 Example 43 Comparative — Epigallocatechin — 0.00 0.00 0.16 0.03 0.60 0.91 Example 44 gallate Comparative — 2,6-di-t-butyl-4- Tea catechin 0.00 0.00 0.05 0.00 0.34 0.42 Example 45 methylphenol Comparative — Butylhydroxyanisole Tea catechin 0.00 0.07 0.21 0.00 0.53 0.97 Example 46 Comparative — Sodium Tea catechin 0.03 0.00 0.14 0.20 0.56 1.09 Example 47 thiosulfate Comparative — 2,6-di-t-butyl-4- Isoascorbic 0.00 0.00 0.00 0.05 0.33 0.52 Example 48 methylphenol acid Comparative — Butylhydroxyanisole Isoascorbic 0.00 0.00 0.00 0.00 0.35 0.57 Example 49 acid Comparative Potassium Ethylenediaminetetraacetic 0.00 0.05 0.12 0.00 0.06 0.25 Example 50 thiocyanate acid (EDTA) Comparative Cysteine 0.00 0.00 0.08 0.00 0.04 0.15 Example 51 Comparative 2- 0.00 0.07 0.10 0.00 0.02 0.19 Example 52 mercaptobenzimidazole Comparative Butylhydroxyanisole 0.00 0.97 0.97 0.16 0.05 1.29 Example 53 Comparative Dibutylhydroxytoluene 0.00 0.06 0.16 0.00 0.04 0.28 Example 54 Comparative Pentaerythrityl 0.00 0.05 0.05 0.00 0.02 0.18 Example 55 tetra-di-t-butyl hydroxyhydrocinnamate Comparative Quercetin 0.00 0.05 0.17 0.00 0.05 0.36 Example 56 dihydrate Comparative Hydroquinone 0.00 0.06 1.11 0.00 0.90 4.24 Example 57 Comparative Sodium 0.00 0.09 0.11 0.00 0.05 0.29 Example 58 hydroxymethane sulfonate Comparative Sodium 0.00 0.03 0.17 0.00 0.03 0.31 Example 59 metabisulfite Comparative Sodium sulfite 0.00 0.06 0.00 0.00 0.03 0.23 Example 60 Comparative Sodium 0.00 0.03 0.09 0.00 0.03 0.15 Example 61 thiosulfate Comparative Propyl gallate 0.00 0.13 0.79 0.09 0.05 1.67 Example 62 Comparative 1,3-butanediol 0.00 0.06 0.11 0.00 0.05 0.25 Example 63 Comparative (+)-alpha- 0.00 0.16 8.26 0.85 0.44 9.80 Example 64 tocopherol Comparative Alpha- 0.00 0.06 0.12 0.00 0.03 0.24 Example 65 tocopherol acetate Comparative Benzotriazole 0.00 0.12 0.13 0.00 0.03 0.38 Example 66 Comparative Rutin 0.00 0.00 0.11 0.00 0.08 0.24 Example 67 Comparative Monothioglycerol Ethylenediaminetetraacetic 0.02 0.02 0.07 0.00 0.23 0.32 Example 68 acid (EDTA) Comparative Cysteine 0.00 0.00 0.12 0.00 0.25 0.41 Example 69 Comparative 2- 0.00 0.00 0.06 0.00 0.05 0.11 Example 70 mercaptobenzimidazole Comparative Butylhydroxyanisole 0.00 0.00 0.33 0.00 0.27 0.75 Example 71 Comparative Dibutylhydroxytoluene 0.02 0.02 0.08 0.00 0.19 0.29 Example 72 Comparative Pentaerythrityl 0.00 0.00 0.09 0.00 0.18 0.29 Example 73 tetra-di-t-butyl hydroxyhydrocinnamate Comparative Quercetin 0.00 0.00 0.05 0.00 0.28 0.35 Example 74 dihydrate Comparative Hydroquinone 0.00 0.00 0.08 0.00 0.19 0.28 Example 75 Comparative Sodium 0.15 0.15 0.06 0.09 0.19 0.55 Example 76 hydroxymethane sulfonate Comparative Sodium 0.06 0.06 0.09 0.00 0.27 0.42 Example 77 metabisulfite Comparative Sodium sulfite 0.04 0.00 0.07 0.00 0.21 0.34 Example 78 Comparative Sodium 0.03 0.00 0.08 0.00 0.17 0.27 Example 79 thiosulfate Comparative Propyl gallate 0.00 0.00 0.07 0.00 0.34 0.44 Example 80 Comparative 1,3-butanediol 0.03 0.00 0.05 0.00 0.23 0.32 Example 81 Comparative (+)-alpha- 0.05 0.00 1.31 0.07 0.37 1.80 Example 82 tocopherol Comparative Alpha- 0.00 0.00 0.06 0.00 0.17 0.25 Example 83 tocopherol acetate Comparative Benzotriazole 0.04 0.06 0.11 0.00 0.21 0.48 Example 84 Comparative Rutin 0.00 0.00 0.06 0.00 0.22 0.38 Example 85 Comparative Isoascorbic acid 0.00 0.00 0.00 0.03 0.12 0.16 Example 86 Comparative Potassium Ethylenediaminetetraacetic Monothioglycerol 0.00 0.06 0.09 0.00 0.03 0.22 Example 87 thiocyanate acid (EDTA) Comparative Cysteine 0.00 0.05 0.07 0.00 0.04 0.18 Example 88 Comparative 2- 0.04 0.00 0.07 0.00 0.03 0.17 Example 89 mercaptobenzimidazole Comparative Butylhydroxyanisole 0.00 0.03 0.50 0.00 0.05 0.71 Example 90 Comparative Dibutylhydroxytoluene 0.00 0.06 0.12 0.00 0.03 0.25 Example 91 Comparative Pentaerythrityl 0.00 0.10 0.12 0.00 0.04 0.32 Example 92 tetra-di-t-butyl hydroxyhydrocinnamate Comparative Quercetin 0.00 0.03 0.03 0.00 0.04 0.11 Example 93 dihydrate Comparative Hydroquinone 0.00 0.05 0.61 0.00 0.32 2.24 Example 94 Comparative Sodium 0.06 0.08 0.09 0.00 0.09 0.44 Example 95 hydroxymethane sulfonate Comparative Sodium 0.00 0.03 0.08 0.00 0.03 0.19 Example 96 metabisulfite Comparative Sodium sulfite 0.00 0.12 0.09 0.00 0.05 0.31 Example 97 Comparative Sodium 0.00 0.03 0.11 0.00 0.03 0.19 Example 98 thiosulfate Comparative Propyl gallate 0.00 0.07 0.23 0.00 0.05 0.58 Example 99 Comparative 1,3-butanediol 0.00 0.04 0.08 0.00 0.03 0.20 Example 100 Comparative (+)-alpha- 0.00 0.07 3.95 0.27 0.19 4.54 Example 101 tocopherol Comparative Alpha- 0.00 0.05 0.08 0.00 0.05 0.21 Example 102 tocopherol acetate Comparative Benzotriazole 0.04 0.14 0.10 0.00 0.03 0.35 Example 103 Comparative Rutin 0.00 0.00 0.05 0.00 0.09 0.19 Example 104 .sup.1)RRT 0.33: Desbenzyldonepezil, within 0.5% .sup.2)RRT 0.48: Unknown impurities, within 0.2% .sup.3)RRT 0.53: Unknown impurities, within 0.2% .sup.4)RRT 0.7: Donepezil open ring, within 0.5% .sup.5)RRT 1.2: Donepezil N-oxide, within 0.5%

<Experimental Example 2> Impurities Evaluation by Procedure 2 after Short-Term Stress Conditions 70° c. for 48 Hours

[0081] Percutaneous absorption preparations of examples and comparative examples were tested for donepezil impurities according to Procedure 2 as below, after short-term stress condition of 48 hours of storage at 70° C.

[0082] 1. Impurities Analysis by Procedure 2

[0083] As for Procedure 2 for impurities analysis, each percutaneous absorption preparation was dissolved in ethyl acetate for 60 minutes by stirring, and then added to a mixture solution of 0.1N hydrochloric acid and methanol of respective ratio 25:75, stirred for 60 minutes, and centrifuged for 5 minutes. The supernatant was used as sample solution and evaluated according to the criteria of Table 10 below according to Procedure 2 of the U.S. Pharmacopeia. The standard solution was prepared so that the concentration of donepezil hydrochloride standard was 10 ug/mL using a solvent mixture of ethyl acetate:methanol:0.1 N hydrochloric acid=100:675:225 (volume ratio).

[0084] <Procedure 2: Liquid Chromatography Conditions>

[0085] Column: Capcellpak (4.6×250 mm, C18.5 um)

[0086] Mobile phase A: Add 1 mL of phosphoric acid in 1 L of purified water. Adjust with triethylamine to a pH of 6.5. Pass through a filter, remove bubbles, and use as mobile phase.

[0087] Mobile phase B: Acetonitrile

TABLE-US-00010 Time Mobile Mobile (minutes) phase A (%) phase B (%) 0 75 25 10 40 60 40 40 60 41 75 25 50 75 25

[0088] Column temperature: 50° C.

[0089] Flow rate: 1.5 mL/min

[0090] Injection size: 20 uL

[0091] UV wavelength: 286 nm

[0092] Calculation:

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

[0094] Ru: peak response of any individual impurity from the sample solution

[0095] Rs: peak response of donepezil from the standard solution

[0096] Cs: concentration in the standard solution (mg/mL)

[0097] Cu: concentration in the sample solution (mg/mL)

[0098] F: relative correction factor for each impurity

TABLE-US-00011 Relative Relative retention correction Acceptance Impurity time (RRT) factor (F) criteria (%) Desbenzyl donepezil 0.23 1.5 0.15 Donepezil pyridine analog 0.49 1.9 0.15 Donepezil quaternary salt 0.68 0.74 0.15 Donepezil indene analog 1.7 2.2 0.15 Deoxydonepezil 2.1 1.3 0.15 Any individual degradation — 1.0 0.1 product Total impurities — — 1.0

[0099] 2. Impurities Evaluation

[0100] The percutaneous absorption preparations of the examples according to the present invention and comparative examples were subject to short-term stress condition of storage for 48 hours at 70° C., and then tested for donepezil impurities according to Procedure 2. The results are shown in Table 9.

[0101] As seen from Table 9 below, the percutaneous absorption preparation without stabilizer (Comparative Example 1), when analyzed with Procedure 2, produced impurities above criteria from donepezil decomposition at the relative retention time 0.49 (Donepezil pyridine analog), 0.57 (unknown related substances), 1.08 (unknown related substances), and total impurities, showing that stabilizers are necessary for the preparation.

[0102] As for the percutaneous absorption preparations comprising the stabilizers potassium thiocyanate (Comparative Example 2) or monothioglycerol (Comparative Example 3) described in Korean Patent Application No. 2018-0167289 or a mixture of the two (Comparative Example 4), the amount of impurities produced under short-term stress condition (70° C. 48 hour storage) met the criteria of Procedure 2 proposed by the U.S. Pharmacopeia, confirming outstanding stability.

[0103] Comparative Examples 5 through 7 using citric acid, tartaric acid, and benzoic acid, which are the organic acids described in U.S. Pat. No. 6,372,760, were inadequate by Procedure 2 presented in the United States Pharmacopeia. Comparative Examples 8 through 16, which are Comparative Examples 2 through 4 with the above-mentioned stabilizers added, were inadequate by Procedure 2 of the U.S. Pharmacopoeia, even though they met the criteria of Procedure 1.

[0104] In the case of Comparative Examples 17 through 21 using a combination of two stabilizers described in Korean Registered Patent Publication No. 10-1408500 or Korean Registered Patent Publication No. 10-1408454, the impurities did not meet the criteria of Procedure 2 presented in the U.S. Pharmacopeia under short-term stress conditions even though they met the criteria of Procedure 1.

[0105] Comparative Examples 22 through 44, which are percutaneous absorption preparations with stabilizers described in Korean Patent Application Publication No. 10-2009-0086565 and conventionally known stabilizers added, all failed to meet the criteria of Procedure 2, even though some met the criteria of Procedure 1 under short-term stress condition.

[0106] Also, Comparative Examples 45 through 49, which have a mixture of. stabilizers described in Korean Patent Publication No. 10-2009-0086565 and a conventionally known stabilizer also failed to meet the criteria of Procedure 2.

[0107] As for Comparative Examples 50 through 67, which are percutaneous absorption preparations containing potassium thiocyanate, a stabilizer described in Korean Patent Application No. 2018-0167289, and one of the stabilizers described in Korean Patent Application Publication No. 10-2009-0086565, all but Comparative Example 67 (potassium thiocyanate/rutin) failed to meet the criteria of Procedure 2 of the U.S. Pharmacopoeia, even though most met the criteria of Procedure 1 of short-term stress condition.

[0108] As for Comparative Examples 68 through 86, which are percutaneous absorption preparations with stabilizer described in Korean Patent Application No. 2018-0167289 mixed with one of the stabilizers described in Korean Patent Publication No. 10-2009-0086565, even though most of them met the criteria of Procedure 1 for the impurities under short-term stress condition, 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 (monothio Glycerol/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/routine) and comparative example 86 (monothioglycerol/isoascorbic acid) met the criteria of Procedure 2 of the United States Pharmacopeia. Comparative Example 69 (monothioglycerol/cysteine), Comparative Example 71 (monothioglycerol/butylhydroxyanisole), Comparative Example 73 (monothioglycerol/pentaerythryltetra-di-t-butylhydroxyhydrocinnamate), Comparative Example 76 (monothioglycerol/sodium hydroxymethanesulfonate), Comparative Example 77 (monothioglycerol/sodium metabisulfite), Comparative Example 82 (monothioglycerol/(+)-alpha-tocopherol) and Comparative Example 84 (monothioglycerol/benzo-triazole) did not meet the criteria of Procedure 2 presented in the United States Pharmacopeia.

[0109] Also, as for Comparative Examples 87 through 104, percutaneous absorption preparations containing monothioglycerol and potassium thiocyanate (stabilizers described in Korean Patent Application No. 2018-0167289) and one of the stabilizers described in Korean Patent Application Publication No. 10-2009-0086565, all but Comparative Example 104 (monothioglycerol/potassium thiocyanate/rutin) failed to meet the criteria of Procedure 2 of the U.S. Pharmacopoeia, even though most met the criteria of Procedure 1 of short-term stress condition.

[0110] On the other hand, Examples 1 through 13 according to the present invention met the criteria of Procedure 2 suggested by the United States Pharmacopeia under short-term stress conditions in terms of individual impurities, demonstrating outstanding stabilizing effect.

TABLE-US-00012 TABLE 9 Short-term stress condition of 70° C., 48 hr, Procedure 2 of impurities analysis Content (%) of each impurity according to RRT RRT RRT RRT RRT RRT RRT RRT RRT Example No. Stabilizer 1 Stabilizer 2 Stabilizer 3 0.23.sup.1) 0.49 .sup.2) 0.57 .sup.3) 0.68.sup.4) 1.03.sup.5) 1.08.sup.6) 1.7.sup.7) 2.1.sup.8) TOTAL Example 1 Potassium Tea catechin — 0.04 0.03 0.03 0.00 0.00 0.00 0.00 0.00 0.27 Example 2 thiocyanate (+)-catechin — 0.06 0.03 0.06 0.00 0.00 0.00 0.00 0.00 0.25 Example 3 Epigallocatechin — 0.03 0.04 0.05 0.00 0.00 0.00 0.00 0.00 0.35 gallate Example 4 Ascorbic acid — 0.00 0.05 0.00 0.00 0.00 0.00 0.00 0.00 0.12 Example 5 Isoascorbic acid — 0.00 0.04 0.01 0.00 0.00 0.00 0.00 0.00 0.11 Example 6 Tea catechin 0.03 0.03 0.02 0.00 0.00 0.00 0.00 0.00 0.19 Example 7 (+)-catechin 0.01 0.03 0.04 0.00 0.00 0.00 0.00 0.00 0.16 Example 8 Epigallocatechin Monothioglycerol 0.00 0.04 0.02 0.00 0.00 0.00 0.00 0.00 0.19 gallate Example 9 Ascorbic acid 0.00 0.04 0.00 0.00 0.00 0.00 0.00 0.00 0.12 Example 10 Isoascorbic acid 0.00 0.04 0.01 0.00 0.00 0.00 0.00 0.00 0.10 Example 11 Monothioglycerol Tea catechin — 0.04 0.07 0.01 0.00 0.00 0.00 0.00 0.00 0.20 Example 12 (+)-catechin — 0.01 0.07 0.04 0.00 0.00 0.00 0.00 0.00 0.19 Example 13 Epigallocatechin — 0.01 0.07 0.02 0.00 0.00 0.00 0.00 0.00 0.22 gallate Comparative — — — 0.04 0.48 0.32 0.00 0.00 0.12 0.00 0.00 1.42 Example 1 Comparative Potassium — — 0.01 0.00 0.07 0.00 0.00 0.00 0.00 0.00 0.46 Example 2 thiocyanate Comparative — Monothioglycerol — 0.06 0.04 0.06 0.00 0.00 0.00 0.00 0.00 0.26 Example 3 Comparative Potassium Monothioglycerol — 0.00 0.03 0.09 0.00 0.00 0.00 0.00 0.00 0.22 Example 4 thiocyanate Comparative — Citric acid — 0.00 0.38 0.09 0.00 0.00 0.00 0.00 0.00 0.53 Example 5 Comparative — Tartaric acid — 0.00 0.43 0.12 0.00 0.00 0.00 0.00 0.00 0.56 Example 6 Comparative — Benzoic acid — 0.12 0.54 0.10 0.00 0.00 0.52 0.00 0.00 1.87 Example 7 Comparative Potassium Citric acid — 0.00 0.00 0.11 0.05 0.00 0.00 0.00 0.00 0.27 Example 8 thiocyanate Comparative Tartaric acid — 0.00 0.00 0.11 0.05 0.00 0.00 0.00 0.00 0.27 Example 9 Comparative Benzoic acid — 0.00 0.00 0.11 0.05 0.00 0.00 0.00 0.00 0.35 Example 10 Comparative Monothioglycerol Citric acid — 0.01 0.21 0.08 0.05 0.00 0.08 0.00 0.00 0.58 Example 11 Comparative Tartaric acid — 0.01 0.21 0.07 0.01 0.00 0.09 0.00 0.00 0.56 Example 12 Comparative Benzoic acid — 0.02 0.16 0.11 0.05 0.00 0.05 0.00 0.00 0.73 Example 13 Comparative Potassium Monothioglycerol Citric acid 0.00 0.06 0.10 0.03 0.00 0.00 0.00 0.00 0.21 Example 14 thiocyanate Comparative Monothioglycerol Tartaric acid 0.00 0.05 0.37 0.02 0.00 0.00 0.00 0.00 0.52 Example 15 Comparative Monothioglycerol Benzoic acid 0.00 0.02 0.11 0.05 0.00 0.00 0.00 0.00 0.26 Example 16 Comparative Isoascorbic acid 2- 0.00 0.02 0.11 0.05 0.00 0.00 0.00 0.00 0.35 Example 17 mercapto- benzimidazole Comparative 2-mercaptobenzimidazole 2,6-di-t-butyl- 0.01 0.00 0.16 0.00 2.11 0.00 0.00 0.00 2.41 Example 18 4-methylphenol Comparative 2-mercaptobenzimidazole Rutin 0.01 0.00 0.12 0.00 1.15 0.00 0.00 0.00 1.54 Example 19 Comparative 2,6-di-t-butyl-4- Sodium 0.00 0.01 0.19 0.06 0.73 0.07 0.00 0.00 1.35 Example 20 methylphenol hydroxymethane sulfonate Comparative Ascorbic acid Sodium 0.01 0.25 0.02 0.00 0.00 0.00 0.00 0.00 0.34 Example 21 metabisulfite Comparative Ethylene- — 0.05 0.41 0.27 0.06 0.00 0.14 0.00 0.00 1.15 Example 22 diaminetetraacetic acid (EDTA) Comparative Cysteine — 0.00 0.14 0.12 0.00 0.00 0.00 0.00 0.00 0.28 Example 23 Comparative 2-mercaptobenzimidazole — 0.00 0.00 0.08 0.00 4.48 0.00 0.00 0.00 4.68 Example 24 Comparative Butylhydroxyanisole — 0.65 0.29 0.73 0.00 0.00 2.93 0.00 0.00 4.81 Example 25 Comparative 2,6-di-t-butyl-4- — 0.16 0.24 0.19 0.03 0.00 0.46 0.00 0.00 1.38 Example 26 methylphenol Comparative Pentaerythrityl tetra- — 0.21 0.51 0.43 0.08 0.00 0.48 0.00 0.00 2.15 Example 27 di-t-butyl hydroxyhydrocinnamate Comparative Quercetin dihydrate — 0.00 0.43 0.22 0.00 0.00 0.00 0.00 0.00 0.72 Example 28 Comparative Hydroquinone — 0.00 0.37 0.66 0.06 0.00 1.06 0.00 0.00 5.30 Example 29 Comparative Sodium — 0.19 0.09 0.10 0.00 0.00 0.12 0.00 0.00 1.29 Example 30 hydroxymethane sulfonate Comparative Sodium metabisulfite — 0.04 0.07 0.07 0.00 0.00 0.14 0.00 0.00 0.43 Example 31 Comparative Sodium sulfite — 0.08 0.49 0.25 0.06 0.00 0.16 0.00 0.00 1.36 Example 32 Comparative Sodium thiosulfate — 0.01 0.03 0.12 0.05 0.00 0.04 0.00 0.00 0.37 Example 33 Comparative Propyl gallate — 0.00 0.86 1.97 0.00 0.00 0.03 0.00 0.00 3.00 Example 34 Comparative 1,3-butanediol — 0.09 0.44 0.25 0.10 0.00 0.21 0.00 0.00 1.55 Example 35 Comparative (+)-alpha-tocopherol — 1.72 1.31 7.16 0.00 0.00 11.04 0.00 0.00 22.98 Example 36 Comparative Alpha-tocopherol — 0.10 0.31 0.17 0.08 0.00 0.27 0.00 0.00 1.39 Example 37 acetate Comparative Benzotriazole — 0.08 0.74 0.43 0.00 0.00 0.12 0.00 0.00 2.03 Example 38 Comparative Rutin — 0.01 0.28 0.18 0.00 0.00 0.00 0.00 0.00 0.51 Example 39 Comparative Ascorbic acid — 0.01 0.27 0.02 0.00 0.00 0.00 0.00 0.00 0.47 Example 40 Comparative Isoascorbic acid — 0.01 0.23 0.01 0.00 0.00 0.00 0.00 0.00 0.35 Example 41 Comparative Tea catechin — 0.21 0.23 0.03 0.00 0.00 0.00 0.00 0.00 0.55 Example 42 Comparative (+)-catechin — 0.00 0.23 0.05 0.00 0.00 0.00 0.00 0.00 0.35 Example 43 Comparative Epigallocatechin — 0.03 0.25 0.05 0.00 0.00 0.00 0.00 0.00 0.41 Example 44 gallate Comparative 2,6-di-t-butyl-4- Tea catechin 0.07 0.18 0.06 0.00 0.00 0.00 0.00 0.00 0.38 Example 45 methylphenol Comparative Butylhydroxyanisole Tea catechin 0.10 0.28 0.28 0.00 0.59 5.54 0.00 0.00 6.87 Example 46 Comparative Sodium thiosulfate Tea catechin 0.08 0.31 0.31 0.08 0.00 0.10 0.00 0.00 1.16 Example 47 Comparative 2,6-di-t-butyl-4- Isoascorbic 0.01 0.19 0.01 0.00 0.00 0.00 0.00 0.00 0.30 Example 48 methvlphenol acid Comparative Butylhydroxyanisole Isoascorbic 0.01 0.18 0.01 0.00 0.00 0.00 0.00 0.00 0.24 Example 49 acid Comparative Potassium Ethylene- 0.01 0.00 0.15 0.06 0.00 0.00 0.00 0.00 0.27 Example 50 thiocyanate diaminetetraacetic acid (EDTA) Comparative Cysteine 0.00 0.00 0.11 0.01 0.00 0.00 0.00 0.00 0.17 Example 51 Comparative 2-mercaptobenzimidazole 0.00 0.00 0.10 0.03 4.31 0.00 0.00 0.00 4.75 Example 52 Comparative Butylhydroxyanisole 0.04 0.00 1.48 0.05 0.70 6.28 0.00 0.00 8.64 Example 53 Comparative Dibutylhydroxytoluene 0.01 0.00 0.20 0.06 0.00 0.00 0.00 0.00 0.32 Example 54 Comparative Pentaerythrityl tetra- 0.01 0.00 0.22 0.06 0.00 0.04 0.00 0.00 0.39 Example 55 di-t-butyl hydroxyhydrocinnamate Comparative Quercetin dihydrate 0.03 0.00 0.12 0.05 0.00 0.83 0.00 0.00 1.23 Example 56 Comparative Hydroquinone 0.48 0.02 1.62 0.11 0.00 0.14 0.00 0.00 3.99 Example 57 Comparative Sodium 0.02 0.00 0.14 0.00 0.00 0.04 0.00 0.00 0.65 Example 58 hydroxymethane sulfonate Comparative Sodium metabisulfite 0.01 0.00 0.11 0.06 0.00 0.00 0.00 0.00 0.23 Example 59 Comparative Sodium sulfite 0.01 0.00 0.11 0.06 0.00 0.00 0.00 0.00 0.23 Example 60 Comparative Sodium thiosulfate 0.00 0.00 0.11 0.04 0.00 0.00 0.00 0.00 0.17 Example 61 Comparative Propyl gallate 0.02 0.02 1.05 0.00 0.00 0.05 0.00 0.00 4.86 Example 62 Comparative 1,3-butanediol 0.02 0.00 0.18 0.07 0.00 0.00 0.00 0.00 0.31 Example 63 Comparative (+)-alpha-tocopherol 0.25 0.00 12.69 0.26 0.00 0.57 0.00 0.00 13.95 Example 64 Comparative Alpha-tocopherol 0.01 0.00 0.16 0.06 0.00 0.00 0.00 0.00 0.32 Example 65 acetate Comparative Benzotriazole 0.00 0.00 0.15 0.05 0.00 0.00 0.00 0.00 0.24 Example 66 Comparative Rutin 0.00 0.05 0.06 0.00 0.00 0.00 0.00 0.00 0.40 Example 67 Comparative Monothioglycerol Ethylene- 0.00 0.10 0.08 0.03 0.00 0.00 0.00 0.00 0.31 Example 68 diaminetetraacetic acid (EDTA) Comparative Cysteine 0.00 0.12 0.13 0.04 0.00 0.00 0.00 0.00 0.45 Example 69 Comparative 2-mercaptobenzimidazole 0.00 0.00 0.08 0.02 0.00 0.00 0.00 0.00 0.11 Example 70 Comparative Butylhydroxyanisole 0.00 0.10 0.49 0.02 0.68 5.96 0.00 0.00 7.27 Example 71 Comparative Dibutylhydroxyloluene 0.00 0.09 0.09 0.02 0.00 0.03 0.00 0.00 0.30 Example 72 Comparative Pentaerythrityl tetra- 0.00 0.10 0.11 0.02 0.00 0.03 0.00 0.00 0.33 Example 73 di-t-butyl hydroxyhydrocinnamate Comparative Quercetin dihydrate 0.00 0.00 0.07 0.01 0.00 0.00 0.00 0.00 0.11 Example 74 Comparative Hydroquinone 0.11 0.11 0.07 0.00 0.00 0.00 0.00 0.00 0.22 Example 75 Comparative Sodium 0.06 0.07 0.05 0.15 0.00 0.11 0.00 0.00 1.20 Example 76 hydroxymethane sulfonate Comparative Sodium metabisulfite 0.04 0.07 0.07 0.00 0.00 0.14 0.00 0.00 0.43 Example 77 Comparative Sodium sulfite 0.00 0.10 0.08 0.03 0.00 0.00 0.00 0.00 0.28 Example 78 Comparative Sodium thiosulfate 0.00 0.10 0.08 0.03 0.00 0.00 0.00 0.00 0.30 Example 79 Comparative Propyl gallate 0.00 0.13 0.07 0.00 0.00 0.00 0.00 0.00 0.53 Example 80 Comparative 1,3-butanediol 0.00 0.10 0.04 0.02 0.00 0.00 0.00 0.00 0.22 Example 81 Comparative (+)-alpha-tocopherol 0.03 0.11 2.07 0.03 0.00 0.20 0.00 0.00 2.56 Example 82 Comparative Alpha-tocopherol 0.00 0.10 0.07 0.03 0.00 0.00 0.00 0.00 0.25 Example 83 acetate Comparative Benzotriazole 0.00 0.11 0.14 0.03 0.00 0.05 0.00 0.00 0.39 Example 84 Comparative Rutin 0.01 0.11 0.07 0.00 0.00 0.01 0.00 0.00 0.27 Example 85 Comparative Isoascorbic acid 0.00 0.08 0.00 0.00 0.00 0.00 0.00 0.00 0.12 Example 86 Comparative Potassium Ethylene- Monothioglycerol 0.00 0.02 0.12 0.04 0.00 0.00 0.00 0.00 0.25 Example 87 thiocyanate diaminetetraacetic acid (EDTA) Comparative Cysteine 0.00 0.00 0.11 0.02 0.00 0.00 0.00 0.00 0.15 Example 88 Comparative 2-mercaptobenzimidazole 0.00 0.00 0.10 0.04 0.11 0.00 0.00 0.00 0.24 Example 89 Comparative Butylhydroxyanisole 0.02 0.00 0.79 0.04 0.44 3.90 0.00 0.00 5.24 Example 90 Comparative Dibutylhydroxytoluene 0.01 0.00 0.12 0.04 0.00 0.00 0.00 0.00 0.27 Example 91 Comparative Pentaerythrityl tetra- 0.01 0.00 0.12 0.05 0.00 0.00 0.00 0.00 0.33 Example 92 di-t-butyl hydroxyhydrocinnamate Comparative Quercetin dihydrate 0.27 0.00 0.04 0.00 0.00 0.00 0.00 0.00 0.40 Example 93 Comparative Hydroquinone 0.24 0.00 0.95 0.09 0.00 0.05 0.00 0.00 3.77 Example 94 Comparative Sodium 0.00 0.02 0.10 0.08 0.00 0.05 0.00 0.00 0.75 Example 95 hydroxymethane sulfonate Comparative Sodium metabisulfite 0.00 0.00 0.12 0.08 0.00 0.00 0.00 0.00 0.27 Example 96 Comparative Sodium sulfite 0.00 0.01 0.20 0.03 0.00 0.00 0.00 0.00 0.32 Example 97 Comparative Sodium thiosulfate 0.00 0.00 0.14 0.05 0.00 0.00 0.00 0.00 0.25 Example 98 Comparative Propyl gallate 0.00 0.01 0.37 0.00 0.00 0.00 0.00 0.00 0.42 Example 99 Comparative 1,3-butanediol 0.00 0.01 0.12 0.05 0.00 0.00 0.00 0.00 0.20 Example 100 Comparative (+)-alpha- 0.09 0.01 6.22 0.16 0.00 0.21 0.00 0.00 6.70 Example 101 tocopherol Comparative Alpha-tocopherol 0.00 0.01 0.12 0.04 0.00 0.00 0.00 0.00 0.22 Example 102 acetate Comparative Benzotriazole 0.00 0.01 0.13 0.04 0.00 0.00 0.00 0.00 0.18 Example 103 Comparative Rutin 0.00 0.03 0.03 0.00 0.00 0.00 0.00 0.00 0.16 Example 104 .sup.1)RRT 0.23: Desbenzyldonepezil, within 0.15% .sup.2) RRT 0.49: Donepezil pyridine analog, within 0.15% .sup.3) RRT 0.57: Unknown impurities, within 0.1% .sup.4)RRT 0.68: Donepezil quaternary salt, within 0.15% .sup.5)RRT 1.03: Unknown impurities, within 0.1% .sup.6)RRT 1.08: Unknown impurities, within 0.1% .sup.7)RRT 1.7: Donepezil indene analog, within 0.15% .sup.8)RRT 2.1: Deoxydonepezil, within 0.15%

[0111] Of the examples and comparative examples of the present invention, only the Examples of the present invention and Comparative Examples 4 (percutaneous absorption preparation with stabilizer potassium thiocyanate and/or monothioglycerol described in Korean Patent Application No. 2018-0167289 is added), 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) were met the criteria of both Procedure 1 and Procedure 2 of the impurities analysis method presented in the United States Pharmacopeia under short-term stress conditions of 70° C. for 48 hr.

<Experimental Example 3> Impurities Analysis Under Long-Term Accelerated Conditions (Stored for 1 Month Under 40° C., Relative Humidity 75%

[0112] To test the stability of the donepezil percutaneous absorption preparations in 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 met the criteria of Procedure 1 and Procedure 2 of the U.S. Pharmacopoeia) were stored for 1 month under long-term accelerated condition of 40° C. and relative humidity 75%. After 1 month of storage, the preparations were tested with Procedure 1 and Procedure 2 as before. The results are shown in Table 10 and Table 11.

[0113] 1. Impurities Analysis by Procedure 1:

[0114] As seen from Table 10 below, the percutaneous absorption preparation without stabilizer (Comparative Example 1), when analyzed with Procedure 1 under long-term accelerated condition (1 month storage under 40° C. and relative humidity 75%), produced impurities above criteria from donepezil decomposition at the relative retention time 0.53 (unknown impurity), 1.2 (donepezil N-oxide), and total impurities, showing that stabilizers are necessary for the preparation.

[0115] Potassium thiocyanate (Comparative Example 2), the stabilizer described in Korean Patent Application No. 2018-0167289, did not meet the criteria of Procedure 1 under long-term accelerated test condition (40° C. relative humidity 75%, 1 month storage). On the other hand, Comparative Example 4 comprising a combination of monothio-glycerol (Comparative Example 3) and the above two stabilizers (potassium thiocyanate/monothioglycerol) met the criteria of Procedure 1 under long-term accelerated condition (40° C. relative humidity 75%, stored for 1 month).

[0116] Comparative Example 67, which is a percutaneous absorption preparation with combination of potassium thiocyanate, a stabilizer described in Korean Patent Application No. 2018-0167289 and rutin, a stabilizer described in Korean Patent Application Publication No. 10-2009-0086565, met the criteria of Procedure 1 under long-term accelerated test condition (40° C. relative humidity 75%, 1 month storage).

[0117] Comparative Example 75 (monothioglycerol/hydroquinone) and Comparative Example 80 (monothioglycerol/propyl gallate), which is a transdermal absorption preparation with stabilizer described in Korean Patent Application No. 2018-0167289 and one of the stabilizers described in Korean Patent Application Publication No. 10-2009-0086565, met the criteria of Procedure 1 presented in the United States Pharmacopoeia under short-term stress condition but failed to meet the criteria of Procedure 1 the conditions for long-term accelerated test (40° C. relative humidity 75%). 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) met the criteria of Procedure 1 presented in the United States Pharmacopoeia under the long-term accelerated test conditions (40° C. relative humidity 75%, 1 month storage).

[0118] Also, Comparative Example 104, which is a percutaneous absorption preparation with combination of monothioglycerol, a stabilizer described in Korean Patent Application No. 2018-0167289 and potassium thiocyanate, a stabilizer described in Korean Patent Application Publication No. 10-2009-0086565, met the criteria of Procedure 1 under long-term accelerated test condition (40° C. relative humidity 75%, 1 month storage).

[0119] On the other hand, Examples 1 through 13 according to the present invention met the criteria of Procedure 1 presented in the U.S. Pharmacopoeia under long-term accelerated test condition (40° C. relative humidity 75%, stored for 1 month), confirming outstanding stabilizing effect.

TABLE-US-00013 TABLE 10 Procedure 1, long-term accelerated test condition (40° C. relative humidity 75%, stored for 1 month) Content (%) of each impurity according to RRT RRT RRT RRT RRT RRT Stabilizer 1 Stabilizer 2 Stabilizer 3 0.33 .sup.1) 0.48 .sup.2) 0.53 .sup.3) 0.7 .sup.4) 1.2 .sup.5) Total Example 1 Potassium Tea catechin — 0.01 0.00 0.03 0.00 0.10 0.17 Example 2 thiocyanate (+)-catechin — 0.00 0.00 0.03 0.00 0.10 0.16 Example 3 Epigallocatechin — 0.01 0.00 0.05 0.00 0.14 0.27 gallate Example 4 Ascorbic acid — 0.02 0.00 0.00 0.00 0.12 0.16 Example 5 Isoascorbic acid — 0.01 0.02 0.01 0.00 0.12 0.20 Example 6 Tea catechin Monothioglycerol 0.03 0.00 0.02 0.00 0.12 0.18 Example 7 (+)-catechin 0.00 0.00 0.06 0.00 0.09 0.16 Example 8 Epigallocatechin 0.01 0.00 0.03 0.00 0.14 0.19 gallate Example 9 Ascorbic acid 0.01 0.00 0.00 0.00 0.12 0.15 Example 10 Isoascorbic acid 0.00 0.00 0.00 0.00 0.16 0.20 Example 11 Monothioglycerol Tea catechin — 0.01 0.00 0.00 0.00 0.15 0.19 Example 12 (+)-catechin — 0.00 0.00 0.04 0.00 0.20 0.25 Example 13 Epigallocatechin — 0.00 0.00 0.00 0.00 0.16 0.20 gallate Comparative — — — 0.00 0.00 0.36 0.17 1.05 1.68 Example 1 Comparative Potassium — — 0.02 0.00 0.20 0.09 0.07 0.44 Example 2 thiocyanate Comparative — Monothioglycerol — 0.07 0.00 0.11 0.00 0.18 0.41 Example 3 Comparative Potassium Monothioglycerol — 0.03 0.00 0.16 0.09 0.12 0.44 Example 4 thiocyanate Comparative Potassium Rutin — 0.02 0.00 0.19 0.00 0.14 0.40 Example 67 thiocyanate Comparative Monothioglycerol Ethylenediaminetetraacetic — 0.04 0.00 0.17 0.06 0.13 0.40 Example 68 acid (EDTA) Comparative 2-mercaptobenzimidazole — 0.02 0.00 0.10 0.04 0.00 0.15 Example 70 Comparative Dibutylhydroxytoluene — 0.03 0.00 0.16 0.13 0.28 0.60 Example 72 Comparative Quercetin — 0.00 0.05 0.05 0.18 0.15 0.43 Example 74 dihydrate Comparative Hydroquinone — 0.00 0.00 0.31 0.20 0.53 1.33 Example 75 Comparative Sodium sulfite — 0.08 0.00 0.13 0.17 0.33 0.71 Example 78 Comparative Sodium — 0.04 0.00 0.15 0.15 0.26 0.63 Example 79 thiosulfate Comparative Propyl gallate — 0.00 0.03 0.33 0.00 0.24 0.60 Example 80 Comparative 1,3-butanediol — 0.03 0.06 0.17 0.19 0.30 0.70 Example 81 Comparative Alpha-tocopherol — 0.06 0.00 0.016 0.14 0.36 0.71 Example 83 acetate Comparative Rutin — 0.01 0.00 0.06 0.00 0.22 0.38 Example 85 Comparative Isoascorbic acid — 0.02 0.00 0.03 0.00 0.25 0.34 Example 86 Comparative Potassium Rutin Monothioglycerol 0.00 0.00 0.08 0.00 0.13 0.26 Example 104 thiocyanate .sup.1) RRT 0.33: Desbenzyldonepezil, within 0.5% .sup.2) RRT 0.48: Unknown impurities, within 0.2% .sup.3) RRT 0.53: Unknown impurities, within 0.2% .sup.4) RRT 0.7: Donepezil open ring, within 0.5% .sup.5) RRT 1.2: Donenezil N-oxdie, within 0.5%

[0120] 2. Impurities Analysis by Procedure 2:

[0121] As seen from Table 11 below, the percutaneous absorption preparation without stabilizer (Comparative Example 1), when analyzed with Procedure 2 under long-term accelerated test condition (40° C. relative humidity 75%, stored for 1 month), produced impurities above criteria from donepezil decomposition at the relative retention time 0.49 (Donepezil pyridine analog), 0.57 (unknown related substance), 1.08 (unknown related substance), and total impurities, showing that stabilizers are necessary for the preparation.

[0122] Potassium thiocyanate (Comparative Example 2) and monothioglycerol (Comparative Example 3), stabilizers described in Korean Patent Application No. 2018-0167289, did not meet the criteria of Procedure 2 under long-term accelerated test condition (40° C. relative humidity 75%, 1 month storage). On the other hand, Comparative Example 4 comprising a combination of monothioglycerol (Comparative Example 3) and the above two stabilizers (potassium thiocyanate/monothioglycerol) met the criteria of Procedure 2 under long-term accelerated condition (40° C. relative humidity 75%, stored for 1 month).

[0123] Comparative Example 67, which is a percutaneous absorption preparation with combination of potassium thiocyanate, a stabilizer described in Korean Patent Application No. 2018-0167289 and rutin, a stabilizer described in Korean Patent Application Publication No. 10-2009-0086565, met the criteria of Procedure 2 under long-term accelerated test condition but failed to meet the criteria of Procedure 2 under long-term accelerated test condition (40° C. relative humidity 75%, 1 month storage).

[0124] Comparative Example 68 (monothioglycerol/ethylenediaminetetraacetic acid), Comparative Example 70 (monothioglycerol/2-mercaptobenzimidazol), 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 thiosulfite), Comparative Example 80 (monothioglycerol/propyl gallate), Comparative Example 81 (monothioglycerol/1,3-butanediol) and Comparative Examples 83 (monothioglycerol/alpha-tocopherol acetate), which comprise monothioglycerol described in Korean Patent Application No. 2018-0167289 and one of the stabilizers described in Korean Patent Application Publication No. 10-2009-0086565, met the criteria of Procedure 2 presented in the United States Pharmacopoeia under short-term stress condition but failed to meet the criteria of Procedure 2 under long-term accelerated test condition (40° C. relative humidity 75%, 1 month storage). On the other hand, Comparative Example 85 (monothioglycerol/rutin) and Comparative Example 86 (monothioglycerol/isoascorbic acid) met the criteria of Procedure 2 under long-term accelerated test condition (40° C. relative humidity, 75%, 1 month storage).

[0125] Also, Comparative Example 104, which is a percutaneous absorption preparation with combination of monothioglycerol, a stabilizer described in Korean Patent Application No. 2018-0167289 and potassium thiocyanate, a stabilizer described in Korean Patent Application Publication No. 10-2009-0086565, met the criteria of Procedure 2 under long-term accelerated test condition (40° C. relative humidity 75%, 1 month storage).

[0126] On the other hand, Examples 1 through 13 according to the present invention met the criteria of Procedure 2 presented in the U.S. Pharmacopoeia under long-term accelerated test condition (40° C. relative humidity 75%, stored for 1 month), confirming outstanding stabilizing effect.

TABLE-US-00014 TABLE 11 Long-term accelerated test condition (40° C. relative humidity 75%, 1 month storage) Procedure 2 Content (%) of each impurity according to RRT RRT RRT RRT RRT RRT RRT RRT RRT Stabilizer1 Stabilizer2 Stabilizer3 0.23.sup.1) 0.49.sup.2) 0.57.sup.3) 0.68.sup.4) 1.03.sup.5) 1.08.sup.6) 1.7.sup.7) 2.1.sup.8) TOTAL Example 1 Potassium Tea — 0.00 0.06 0.04 0.00 0.00 0.00 0.00 0.00 0.21 thiocyanate catechin Example 2 (+)- — 0.09 0.05 0.06 0.00 0.00 0.00 0.00 0.00 0.31 catechin Example 3 Epigallocatechin — 0.00 0.07 0.05 0.02 0.00 0.00 0.00 0.00 0.26 gallate Example 4 Ascorbic — 0.00 0.06 0.00 0.00 0.00 0.00 0.00 0.00 0.12 acid Example 5 Isoascorbic — 0.00 0.07 0.00 0.00 0.00 0.00 0.00 0.00 0.15 acid Example 6 tea Monothioglycerol 0.00 0.06 0.02 0.00 0.00 0.00 0.00 0.00 0.20 catechin Example 7 (+)- 0.00 0.05 0.06 0.00 0.00 0.00 0.00 0.00 0.21 catechin Example 8 Epigallocatechin 0.00 0.08 0.04 0.00 0.00 0.00 0.00 0.00 0.22 gallate Example 9 Ascorbic 0.00 0.06 0.00 0.00 0.00 0.00 0.00 0.00 0.15 acid Example 10 Isoascorbic 0.00 0.09 0.00 0.00 0.00 0.00 0.00 0.00 0.18 acid Example 11 Monothioglycerol tea — 0.03 0.08 0.01 0.03 0.00 0.00 0.00 0.00 0.21 catechin Example 12 (+)- — 0.00 0.10 0.05 0.00 0.00 0.00 0.00 0.00 0.25 catechin Example 13 Epigallocatechin — 0.00 0.10 0.02 0.00 0.00 0.00 0.00 0.00 0.22 gallate Comparative — — — 0.05 0.52 0.63 0.05 0.00 0.05 0.00 0.00 1.45 Example 1 Comparative Potassium — — 0.02 0.01 0.33 0.00 0.00 0.00 0.00 0.00 0.49 Example 2 thiocyanate Comparative — Monothioglycerol — 0.00 0.09 0.14 0.00 0.00 0.00 0.00 0.00 0.46 Example 3 Comparative Potassium Monothioglycerol — 0.03 0.06 0.09 0.00 0.00 0.00 0.00 0.00 0.41 Example 4 thiocyanate Comparative Potassium Rutin — 0.00 0.08 0.28 0.03 0.00 0.00 0.00 0.00 0.48 Example 67 thiocyanate Comparative Monothioglycerol Ethylenediaminetetraacetic — 0.02 0.05 0.29 0.00 0.00 0.04 0.00 0.00 0.40 Example 68 acid (EDTA) Comparative 2- — 0.00 0.00 0.15 0.05 0.00 0.00 0.00 0.00 0.20 Example 70 mercaptobenzoimidazol Comparative dibutylhydroxytoluene — 0.04 0.04 0.28 0.00 0.00 0.18 0.00 0.00 0.54 Example 72 Comparative Quercetin — 0.00 0.18 0.11 0.00 0.00 0.00 0.00 0.00 0.29 Example 74 dihydrate Comparative Hydroquinone — 0.04 0.13 0.47 0.44 0.00 0.16 0.00 0.00 1.47 Example 75 Comparative Sodium — 0.05 0.05 0.27 0.00 0.00 0.14 0.00 0.00 0.51 Example 78 sulfite Comparative Sodium — 0.05 0.05 0.26 0.00 0.00 0.13 0.00 0.00 0.49 Example 79 thiosulfate Comparative Propyl — 0.03 0.07 0.50 0.00 0.00 0.00 0.00 0.00 0.76 Example 80 gallate Comparative 1,3- — 0.07 0.11 0.27 0.00 0.00 0.18 0.00 0.00 0.62 Example 81 Butanediol Comparative alpha- — 0.05 0.09 0.26 0.00 0.00 0.15 0.00 0.00 0.55 Example 83 tocopherol acetate Comparative Rutin — 0.00 0.12 0.08 0.00 0.00 0.00 0.00 0.00 0.29 Example 85 Comparative Isoascorbic — 0.00 0.14 0.02 0.00 0.00 0.00 0.00 0.00 0.26 Example 86 acid Comparative Potassium Rutin — 0.00 0.08 0.09 0.00 0.00 0.01 0.00 0.00 0.24 Example 104 thiocyanate .sup.1)RRT 0.23: Desbenzyldonepezil, within 0.15% .sup.2)RRT 0.49: Donepezil pyridine analog, within 0.15% .sup.3)RRT 0.57: Unknown impurities, within 0.1% .sup.4)RRT 0.68: Donepezil quaternary salt, within 0.15% .sup.5)RRT 1.03: Unknown impurities, within 0.1% .sup.6)RRT 1.08: Unknown impurities, within 0.1% .sup.7)RRT 1.7: Donepezil indene analog, within 0.15% .sup.8)RRT 2.1: Deoxydonepezil, within 0.15%

<Experimental Example 4> Impurities Analysis Under Long-Term Accelerated Conditions (Stored for 3 Month Under 40° c., Relative Humidity 75%

[0127] To test the stability of the donepezil percutaneous absorption preparations in long-term storage, Examples 1 through 13 and Comparative Examples 4, 85, 86, and 104, which met the criteria of Procedure 1 and Procedure 2 of the U.S. Pharmacopoeia under long-term accelerated test condition (40° C. relative humidity 75%, 1 month storage) in Experimental Example 3, were stored for 3 months under long-term accelerated condition of 40° C. and relative humidity 75%. Afterwards, the preparations were tested with Procedure 1 and Procedure 2 in the same way as Experimental Experiment 1 above. The results are shown in Table 12 and Table 13.

[0128] 1. Impurities Analysis by Procedure 1:

[0129] As seen from Table 12 below, the percutaneous absorption preparation without stabilizer (Comparative Example 1), when analyzed with Procedure 1 under long-term accelerated condition (3 month storage under 40° C. and relative humidity 75%), produced impurities above criteria from donepezil decomposition at the relative retention time 0.53 (unknown impurity), 1.2 (donepezil N-oxide), and total impurities, showing that stabilizers are necessary for the preparation.

[0130] Percutaneous absorption preparation (Comparative Example 4) comprising both potassium thiocyanate and monothioglycerol, which are the stabilizers described in Korean Patent Application No. 2018-0167289 did not meet the criteria of Procedure 1 of the U.S. Pharmacopoeia under long-term accelerated test conditions (40° C. relative humidity 75%, storage for 3 months).

[0131] Of the percutaneous absorption preparations comprising monothioglycerol, a stabilizer described in Korean Patent Application No. 2018-0167289, and one of the stabilizers described in Korean Patent Application Publication No. 10-2009-0086565, Comparative Example 86 (monothioglycerol/isoascorbic acid) met the criteria of Procedure 1 of the U.S. Pharmacopoeia under long-term accelerated test condition (40° C. relative humidity 75%, 3 month storage), whereas Comparative Example 85 (monothioglycerol/rutin) did not meet the criteria.

[0132] Also, Comparative Example 104, which is a percutaneous absorption preparation with a combination of monothioglycerol and potassium thiocyanate, which are described in Korean Patent Application 2018-0167289, and rutin, which is described in Korean Patent Application Publication No. 10-2009-0086565, also failed to meet the criteria of Procedure 1 presented in the United States Pharmacopeia.

[0133] On the other hand, Examples 1 through 13 according to the present invention met the criteria of Procedure 1 presented in the U.S. Pharmacopoeia under long-term accelerated test condition (40° C. relative humidity 75%, stored for 3 month), confirming outstanding stabilizing effect.

TABLE-US-00015 TABLE 12 Long-term accelerated test condition (40° C. relative humidity 75%, 3 month storage) Procedure 1 Content (%) of each impurity according to RRT RRT RRT RRT RRT RRT Stabilizer 1 Stabilizer 2 Stabilizer 3 0.33.sup.1) 0.48.sup.2) 0.53.sup.3) 0.7.sup.4) 1.2.sup.5) Total Example 1 Potassium tea catechin — 0.00 0.00 0.12 0.02 0.12 0.31 Example 2 thiocyanate (+)-catechin — 0.00 0.00 0.13 0.04 0.08 0.30 Example 3 Epigallocatechin — 0.00 0.02 0.13 0.05 0.12 0.36 gallate Example 4 Ascorbic acid — 0.00 0.00 0.17 0.06 0.24 0.57 Example 5 Isoascorbic acid — 0.01 0.00 0.14 0.05 0.25 0.51 Example 6 tea catechin 0.02 0.01 0.11 0.06 0.13 0.41 Example 7 (+)-catechin 0.00 0.00 0.16 0.00 0.03 0.32 Example 8 Epigallocatechin Monothioglycerol 0.00 0.00 0.12 0.02 0.12 0.29 gallate Example 9 Ascorbic acid 0.00 0.03 0.15 0.06 0.23 0.54 Example 10 Isoascorbic acid 0.00 0.00 0.14 0.09 0.19 0.48 Example 11 Monothioglycerol tea catechin — 0.01 0.02 0.05 0.04 0.24 0.39 Example 12 (+)-catechin — 0.00 0.00 0.16 0.09 0.39 0.76 Example 13 Epigallocatechin — 0.03 0.00 0.13 0.06 0.32 0.57 gallate Comparative — — — 0.00 0.00 0.71 0.29 1.84 3.04 Example 1 Comparative Potassium Monothioglycerol — 0.00 0.03 0.37 0.24 0.15 0.92 Example 4 thiocyanate Comparative Monothioglycerol Rutin — 0.00 0.00 0.27 0.12 0.41 0.94 Example 85 Comparative Monothioglycerol Isoascorbic acid — 0.02 0.00 0.09 0.08 0.35 0.61 Example 86 Comparative Potassium Rutin Monothioglycerol 0.00 0.00 0.23 0.05 0.19 0.53 Example 104 thiocyanate .sup.1)RRT 0.33: Desbenzyldonepezil, within 0.5% .sup.2)RRT 0.48: Unknown impurities, within 0.2% .sup.3)RRT 0.53: Unknown impurities, within 0.2% .sup.4)RRT 0.7: Donepezil open ring, within 0.5% .sup.5)RRT 1.2: Donepezil N-oxides, within 0.5%

[0134] 2. Impurities Analysis by Procedure 2:

[0135] As seen from Table 13 below, the percutaneous absorption preparation without stabilizer (Comparative Example 1), when analyzed with Procedure 2 under long-term accelerated test condition (40° C. relative humidity 75%, stored for 3 months), produced impurities above criteria from donepezil decomposition at the relative retention time 0.49 (Donepezil pyridine analog), 0.57 (unknown related substance), 1.08 (unknown related substance), and total impurities, showing that stabilizers are necessary for the preparation.

[0136] Percutaneous absorption preparation (Comparative Example 4) comprising both potassium thiocyanate and monothioglycerol, which are the stabilizers described in Korean Patent Application No. 2018-0167289, did not meet the criteria of Procedure 2 of the U.S. Pharmacopoeia under the condition of 40° C. relative humidity 75%, storage for 3 months due to production of impurities over the criteria.

[0137] Also, Comparative Example 104, which is a percutaneous absorption preparation with a combination of monothioglycerol and potassium thiocyanate, which are described in Korean Patent Application 2018-0167289, and rutin, which is described in Korean Patent Application Publication No. 10-2009-0086565, also failed to meet the criteria of Procedure 2 presented in the United States Pharmacopeia under long-term accelerated test condition (40° C., relative humidity 75%, 3 month storage).

[0138] On the other hand, Examples 1 through 13 according to the present invention met the criteria of Procedure 2 presented in the U.S. Pharmacopoeia under long-term accelerated test condition (40° C. relative humidity 75%, stored for 3 month), confirming outstanding stabilizing effect.

TABLE-US-00016 TABLE 13 Long-term accelerated test condition (40° C. relative humidity 75%, 3 month storage) Procedure 2 Content (%) of each impurity according to RRT RRT RRT RRT RRT RRT RRT RRT RRT Stabilizer1 Stabilizer2 Stabilizer3 0.23.sup.1) 0.49.sup.2) 0.57.sup.3) 0.68.sup.4) 1.03.sup.5) 1.08.sup.6) 1.7.sup.7) 2.1.sup.8) Total Example1 Potassium tea catechin — 0.06 0.06 0.08 0.00 0.00 0.00 0.00 0.00 0.25 Example2 thiocyanate (+)-catechin — 0.02 0.12 0.09 0.00 0.00 0.00 0.00 0.00 0.26 Example3 Epigallocate — 0.02 0.08 0.09 0.00 0.00 0.00 0.00 0.00 0.30 chin gallate Example4 Ascorbic — 0.01 0.07 0.00 0.00 0.00 0.00 0.00 0.00 0.16 acid Example5 Isoascorbic — 0.01 0.05 0.02 0.00 0.00 0.00 0.00 0.00 0.15 acid Example6 tea catechin 0.03 0.11 0.06 0.00 0.00 0.00 0.00 0.00 0.23 Example7 (+)-catechin 0.04 0.04 0.08 0.00 0.00 0.00 0.00 0.00 0.39 Example8 Epigallocate Monothioglycerol 0.02 0.07 0.08 0.00 0.00 0.00 0.00 0.00 0.27 chin gallate Example9 Ascorbic 0.00 0.07 0.03 0.00 0.00 0.00 0.00 0.00 0.19 acid Example10 Isoascorbic 0.00 0.07 0.06 0.00 0.00 0.00 0.00 0.00 0.20 acid Example11 Monothioglycerol tea catechin — 0.10 0.09 0.05 0.00 0.00 0.01 0.00 0.00 0.25 Example12 (+)-catechin — 0.05 0.07 0.07 0.00 0.00 0.00 0.00 0.00 0.24 Example13 Epigallocate — 0.05 0.04 0.08 0.00 0.00 0.00 0.00 0.00 0.27 chin gallate Comparative — — — 0.10 0.91 0.92 0.01 0.00 0.06 0.00 0.00 2.38 Example 1 Comparative Potassium Monothioglycerol — 0.07 0.04 0.43 0.00 0.00 0.04 0.00 0.00 0.71 Example 4 thiocyanate Comparative Monothioglycerol Rutin — 0.01 0.15 0.17 0.00 0.00 0.00 0.00 0.00 0.37 Example 85 Comparative Monothioglycerol Isoascorbic — 0.01 0.16 0.11 0.00 0.00 0.00 0.00 0.00 0.33 Example 86 acid Comparative Potassium Rutin — 0.01 0.09 0.37 0.00 0.00 0.00 0.00 0.00 0.57 Example 104 thiocyanate .sup.1)RRT 0.23: Desbenzyldonepezil, within 0.15% .sup.2)RRT 0.49: Donepezil pyridine analog, within 0.15% .sup.3)RRT 0.57: Unknown impurities, within 0.1% .sup.4)RRT 0.68: Donepezil quaternary salt, within 0.15% .sup.5)RRT 1.03: Unknown impurities, within 0.1% .sup.6)RRT 1.08: Unknown impurities, within 0.1% .sup.7)RRT 1.7: Donepezil indene analog, within 0.15% .sup.8)RRT 2.1: Deoxydonepezil, within 0.15%

[0139] The above experiment results show that the storage stability of donepezil cannot be confirmed using only Procedure 1 or only Procedure 2 of the donepezil impurity analysis.

[0140] Donepezil is a dementia treatment that is taken over a long period of time by increasing the dose in a stepwise manner. If a preparation comprising impurities is administered continuously, there is a possibility of a potential risk from toxicity of the unknown impurities. For the long-term storage stability of donepezil percutaneous absorption preparation, the tolerance criteria for impurities should be set and managed.

[0141] As for the impurities related to donepezil that are published in the United States Pharmacopoeia, Procedure 1 can identify 3 types of impurities, and Procedure 2 can identify 5 types of impurities. Other than desbenzyl donepezil, which can be identified by either procedure, no other impurities overlap between the two procedures. There are criteria of acceptable limits of these impurities in the preparation in consideration of toxicity.

[0142] The present invention provides a percutaneous absorption preparation comprising donepezil that meets Procedure 1 and Procedure 2 criteria by comprising potassium thiocyanate or monothioglycerol, the stabilizers disclosed in Korean Patent Application No. 2018-0167289. The change in impurities over time was confirmed by short-term stress test (stored at 70° C. for 48 hours), long-term accelerated test 1 (stored at 40° C. relative humidity 75% for 1 month) and long-term accelerated test 2 (stored at 40° C. relative humidity 75% for 3 months).

[0143] Under short-term stress conditions of 70° C. or 48 hours, all Examples of the present invention, Comparative Examples 2 through 4 (potassium thiocyanate and/or monothioglycerol), Comparative Example 67 (potassium thiocyanate/rutin), and Comparative Example 104 (monothioglycerol/potassium thiocyanate/rutin) met the criteria of both Procedure 1 and Procedure 2 of impurities analysis methods presented in the United States Pharmacopeia.

[0144] The first type and second type stabilizers disclosed in the examples of Korean Patent Application Publication No. 10-2009-0086565 did not meet the criteria of Procedure 1 and/or Procedure 2 of the United States Pharmacopoeia under short-term stress condition of 70° C. for 48 hours. But among percutaneous preparations comprising 3-mercapto-1,2-propanediol (also known as monothioglycerol) and other stabilizers, which are Comparative Example 68 (monothioglycerol/ethylenediaminetetraacetic acid), Comparative Example 70 (monothioglycerol/2-mercaptobenzimidazole), Comparative Example 72 (monothioglycerol/dibutylhydride), 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), a percutaneous absorption preparation prepared in Comparative Example 86 (monothioglycerol/isoascorbic acid) all met the criteria of both Procedure 1 and Procedure 2 presented in the United States Pharmacopoeia under short-term stress condition of 70° C. for 48 hours.

[0145] In Experimental Example 3 described in the present invention, to test the stability of the donepezil percutaneous absorption preparations in long-term storage, 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 met the criteria of Procedure 1 and Procedure 2 of the U.S. Pharmacopoeia under short-term stress test of Experimental Examples 1 and 2) were stored for 1 month under long-term accelerated condition of 40° C. and relative humidity 75%. Afterwards, the preparations were tested for impurities.

[0146] In Experimental Example 3 described in the present invention, only Comparative Example 4, a percutaneous 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 Pharmacopeia. Comparative Example 2 (potassium thiocyanate) and Comparative Example 3 (monothioglycerol) did not meet the criteria under long-term accelerated test under condition of 1 month storage in relative humidity 75%. Also, Comparative Example 104, which is a percutaneous absorption preparation with a combination of monothioglycerol and potassium thiocyanate, which are described in Korean Patent Application 2018-0167289, and rutin, which is described in Korean Patent Application Publication No. 10-2009-0086565, met the criteria of Procedure 1 and Procedure 2 presented in the United States Pharmacopeia under long-term accelerated condition (40° C. relative humidity 75%, 1 month storage).

[0147] However, among percutaneous absorption preparations comprising a combination of monothioglycerol described in Korean Patent Application No. 2018-0167289 (which is the same as 3-mercapto-1,2-propanediol described in Korean Patent Application Publication No. 10-2009-0086565) and a 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 long-term accelerated test condition (40° C. relative humidity 75%, stored for 1 month), whereas Comparative Examples 68, 70, 72, 74, 75, 78, 79, 80, 81 and 83 did not meet the criteria of Procedure 1 and Procedure 2 under long-term accelerated test condition (40° C., relative humidity 75%, 1 month storage).

[0148] In Experimental Example 4, the Examples of the present invention and Comparative Examples 4, 85, 86, and 104, which had met the criteria for impurities presented in the U.S. Pharmacopoeia under 1 month long-term accelerated condition at 40° C. and relative humidity 75%, were subject to accelerated test of 3 month storage at 40° C. and relative humidity 75% and analyzed for impurities by the methods presented in the U.S. Pharmacopoeia to see the change in impurities over time.

[0149] In Experimental Example 4, Comparative Example 4 (potassium thiocyanate/monothioglycerol), which is a percutaneous absorption preparation comprising both potassium thiocyanate and monothioglycerol described in Korean Patent Application No. 2018-0167289, and Comparative Example 104 (potassium thiocyanate/monothioglycerol/rutin), which is a percutaneous absorption preparation comprising mono glycerol and potassium thiocyanate described in Korean Patent Application No. 2018-0167289 and rutin described in Korean Patent Publication No. 10-2009-0086565, increased in impurities production after 1 month at 40° C. and relative humidity 75%, failing to meet the criteria of Procedure 1 and Procedure 2 presented in the U.S. Pharmacopoeia for 3 month storage.

[0150] However, among percutaneous absorption preparations made to comprise a combination of monothioglycerol, a stabilizer described in Korean Patent Application No. 2018-0167289 (which is the same as 3-mercapto-1,2-propanediol described in Korean Patent Application Publication No. 10-2009-0086565) and a stabilizer described in Korean Patent Publication No. 10-2009-0086565. Comparative Example 85 (monothioglycerol/rutin) did not meet the criteria for impurities of Procedure 1 and Procedure 2 presented in the U.S. Pharmacopoeia. Comparative Example 86 (monothioglycerol/isoascorbic acid) met the criteria of Procedure 1 but failed to meet the criteria of Procedure 2.

[0151] Therefore, the present invention provides a percutaneous absorption preparation comprising donepezil that meet the criteria of Procedure 1 and Procedure 2 presented in the U.S. Pharmacopoeia in short-term stress test (70° C. 48 hours storage), long-term accelerated test 1 (40° C. relative humidity 75% 1 month storage), and long-term accelerated test 2 (40° C. relative humidity 75% 3 months storage). The donepezil-containing percutaneous absorption preparation reduces the production of impurities by inhibiting decomposition of donepezil, thereby making it possible to make a percutaneous absorption preparation comprising donepezil with improved stability for long-term preservation.