PERCUTANEOUS ABSORPTION PREPARATION COMPRISING STABILIZED DONEPEZIL

Abstract

A percutaneous absorption preparation including donepezil for the treatment of dementia is disclosed. The percutaneous absorption preparation for the treatment of dementia includes a support layer, a drug-containing layer, and a release layer, wherein the drug-containing layer contains donepezil or a pharmaceutically acceptable salt thereof as an active ingredient; monothioglycerol, thiocyanate metal salt (preferably potassium salt) or dimethylthiourea as a stabilizer; and a pressure-sensitive adhesive. Also disclosed is a percutaneous absorption preparation for the treatment of dementia with reduced the formation of donepezil impurities.

Claims

1. A percutaneous absorption preparation 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, and a stabilizer selected from the group consisting of monothioglycerol, thiocyanate metal salt, and dimethylthiourea.

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

3. A percutaneous absorption preparation according to claim 1, wherein the thiocyanate metal salt used as a stabilizer is potassium thiocyanate.

4. A method of preparing a percutaneous absorption preparation comprising donepezil, wherein the method comprises the steps of: i) dissolving donepezil and monothioglycerol, thiocyanate metal salt, or dimethylthiourea in an organic solvent; ii) applying the solution obtained in step i) onto a release layer and drying to form a drug-containing layer; and iii) laminating the drug-containing layer obtained in step ii) with a support layer.

5. The method of claim 4, wherein the organic solvent is selected from the group consisting of ethyl acetate, toluene, hexane, 2-propanol, methanol, ethanol, methylene chloride, and tetrahydrofuran.

Description

DESCRIPTION OF EMBODIMENTS

[0033] 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 3> Percutaneous Absorption Preparation According to the Present Invention

[0034] Dissolve 16 g of styrene-isoprene-styrene block copolymer, 4.7 g of octyldodecyl myristate, 3 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 of the stabilizer specified in Table 1 in 1 g of methanol and mix it with the ethyl acetate solution from the previous step. Apply this mixture onto a silicone-coated PET film and dry it for 30 minutes in an oven at 80° C. Afterwards, laminate it with a backing film. The obtained results are Examples 1 through 3 of the present invention.

TABLE-US-00001 TABLE 1 Example No. Stabilizer Example 1 monothioglycerol Example 2 potassium thiocyanate Example 3 dimethylthiourea

<Comparative Example 1> Percutaneous Absorption Preparation without Stabilizer

[0035] 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 Example 2> Percutaneous Absorption Preparation with Citric Acid as Stabilizer

[0036] Comparative example 2 is a percutaneous absorption preparation that is identical to example 1 in composition and method of preparation except that it contains citric acid as stabilizer. Citric acid was selected from the stabilizers disclosed in U.S. Pat. No. 6,372,760.

<Comparative Examples 3 Through 15> Percutaneous Absorption Preparations with Various Stabilizers

[0037] Comparative examples 3 through 15 are percutaneous absorption preparations prepared according to the same composition and preparation method as example 1, with the addition of various known stabilizers as specified in Table 2 below.

TABLE-US-00002 TABLE 2 Stabilizer Comparative Example 3 Cysteine Comparative Example 4 Tryptophan Comparative Example 5 Thiomalic acid Comparative Example 6 Catechin Comparative Example 7 Sodium thiosulfate Comparative Example 8 Dibutylhydroxytoluene Comparative Example 9 Butylhydroxyanisole Comparative Example 10 Rutin Comparative Example 11 Ascorbic acid Comparative Example 12 Isoascorbic acid Comparative Example 13 2,6-di-t-butyl-4-methylphenol Comparative Example 14 2-mercaptobenzimidazole Comparative Example 15 Sodium metabisulfite

<Comparative Examples 16 Through 19> Percutaneous Absorption Preparation with Two Stabilizers

[0038] Four pairs of stabilizers were selected from the group of stabilizers disclosed in the Korea Patent Registration No. 10-1408500 that most effectively inhibited the formation of donepezil N-oxide, desbenzyl donepezil, and total impurities.

[0039] Percutaneous absorption preparations were prepared according to the same composition and preparation method as example 1, with the addition of two stabilizers (0.13 g for each stabilizer) as specified in Table 3 below. The resulting preparations were labeled as comparative examples 16 through 19.

TABLE-US-00003 TABLE 3 Stabilizers Comparative Example 16 isoascorbic acid/2-mercaptobenzimidazole Comparative Example 17 2-mercaptobenzimidazole/2,6-di-t-butyl-4-methylphenol Comparative Example 18 2-mercaptobenzimidazole/Rutin Comparative Example 19 2,6-di-t-butyl-4-methylphenol/Sodium hydroxymethanesulfonate

<Comparative Example 20> Percutaneous Absorption Preparation with Two Stabilizers

[0040] 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 20.

<Experimental Example 1> Impurities Testing with Procedure 1 after 48 Hours of Storage at 70° C.

[0041] Percutaneous absorption preparations of examples and comparative examples were tested for donepezil impurities according to Procedure 1 as below, after 48 hours of storage at 70° C.

[0042] 1. Impurities Analysis by Procedure 1

[0043] Each percutaneous absorption preparation was dissolved in ethyl acetate. Methanol was added and the resulting solution was stirred for 30 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).

[0044] <Procedure 1: Liquid Chromatography Conditions>

[0045] Column: Inertsil octadecylsilane-2 (4.6×150 mm, C18, 5 um)

[0046] 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.

[0047] Column temperature: 35° C.

[0048] Flow rate: 1.4 mL/min

[0049] Injection size: 20 uL

[0050] UV absorptiometer: 271 nm

[0051] Calculation:

Impurity %=(Ru/Rs)×(Cs/Cu)×(1/F)×100 [0052] Ru: peak response of any individual impurity from the sample solution [0053] Rs: peak response of donepezil from the standard solution [0054] Cs: concentration in the standard solution (mg/mL) [0055] Cu: concentration in the sample solution (mg/mL) [0056] F: relative correction factor for each impurity

TABLE-US-00004 Relative retention Relative correction Acceptance criteria Impurity time (RRT) factor (F) (%) 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

[0057] 2. Impurities Analysis by Procedure 1 after 48 Hours of Storage at 70° C.

[0058] The percutaneous absorption preparations of the examples according to the present invention and comparative examples were stored for 48 hours at 70° C., and then tested for impurities according to Procedure 1. The results are shown in Table 4.

[0059] As seen in Table 4 below, a lot of decomposition of donepezil was observed in comparative example 1 without stabilizer, at the relative retention times (RRT) 0.53 (unidentified impurity), 0.7 (donepezil open ring), and 1.2 (donepezil N-oxide), as well as for total impurities—demonstrating the need for stabilizers in percutaneous absorption preparations of donepezil.

[0060] Comparative example 2, which used citric acid (an organic acid disclosed in the U.S. Pat. No. 6,372,760), did not meet the criteria presented by the U.S. Pharmacopoeia at the relative retention time (RRT) 1.2 (donepezil N-oxide).

[0061] As for comparative examples 3 through 15, which are percutaneous absorption preparations with known stabilizers, comparative example 3 (cysteine), comparative example 5 (thiomalic acid), comparative example 7 (sodium thiosulfate), and comparative example 14 (2-mercaptobenzimidazole) did meet the criteria in the U.S. Pharmacopoeia. However, comparative example 6 (catechin), comparative example 11 (ascorbic acid), comparative example 12 (isoascorbic acid), and comparative example 15 (Sodium metabisulfite) produced excessive impurity at RTT 1.2 (Donepezil N-oxide), and comparative example 4 (tryptophan) and comparative example 10 (Rutin) did not meet the criteria for for 1.2 (donepezil N-oxide) like comparative example 2. Comparative example 8 (Dibutylhydroxytoluene), comparative example 9 (Butylhydroxyanisole), and comparative example 13 (2,6-di-t-butyl-4-methylphenol) did not meet the criteria for most of the impurities as well as for total impurities.

[0062] Comparative example 16 (ascorbic acid/2-mercaptobenzimidazole), comparative example 17 (2-mercaptobenzimidazole/2,6-di-t-butyl-4-methylphenol), comparative example 18 (2-mercaptobenzimidazole/rutin), comparative example 19 (2,6-di-t-butyl-4-methylphenol/sodium hydroxymethanesulfonate) and comparative example 20 (ascorbic acid/sodium metabisulfite), which used a combination of two stabilizers selected from the stabilizers disclosed in Korea Patent Registration No. 10-1408500 and Korea Patent Registration No. 10-1408454, met the U.S. Pharmacopoeia criteria for all RRT except comparative example 19 for RRT 0.48 (unidentified impurity).

[0063] In contrast, examples 1 through 3 according to the present invention met the criteria presented in the U.S. Pharmacopoeia despite containing only one stabilizer each, demonstrating the outstanding stabilizing effect of monothioglycerol, thiocyanate metal salt (preferably potassium salt) or dimethylthiourea.

TABLE-US-00005 TABLE 4 70° C., 48 hr, Procedure 1 of impurities analysis Content (%) of each impurity (RRT) Stabilizer RRT0.33.sup.1) RRT0.48.sup.2) RRT0.53.sup.3) RRT0.7.sup.4) RRT1.2.sup.5) Total Example 1 monothioglycerol 0.01 0.00 0.06 0.04 0.26 0.39 Example 2 potassium thiocyanate 0.01 0.05 0.17 0.12 0.00 0.40 Example 3 dimethylthiourea 0.02 0.08 0.04 0.04 0.00 0.33 Comparative — 0.02 0.00 0.27 0.25 1.27 1.94 Example 1 Comparative citric acid 0.01 0.00 0.11 0.05 0.83 1.03 Example 2 Comparative cysteine 0.00 0.00 0.08 0.08 0.31 0.51 Example 3 Comparative tryptophan 0.03 0.00 0.15 0.09 0.95 1.27 Example 4 Comparative thiomalic acid 0.05 0.00 0.12 0.07 0.25 0.78 Example 5 Comparative catechin 0.01 0.00 0.04 0.06 0.67 0.77 Example 6 Comparative sodium thiosulfate 0.01 0.00 0.13 0.11 0.27 0.57 Example 7 Comparative dibutylhydroxytoluene 0.02 0.00 0.39 0.40 1.24 2.13 Example 8 Comparative butylhydroxyanisole 0.03 0.00 1.24 2.68 3.04 7.29 Example 9 Comparative rutin 0.01 0.00 0.17 0.07 0.84 1.12 Example 10 Comparative ascorbic acid 0.01 0.00 0.01 0.04 0.79 0.92 Example 11 Comparative isoascorbic acid 0.01 0.00 0.01 0.05 0.85 0.95 Example 12 Comparative 2,6-di-t-butyl-4-methylphenol 0.01 0.00 0.38 0.42 1.27 2.19 Example 13 Comparative 2-mercaptobenzimidazole 0.01 0.00 0.11 0.05 0.00 0.21 Example 14 Comparative sodium metabisulfite 0.01 0.00 0.10 0.10 0.51 0.82 Example 15 Comparative isoascorbic acid/ 0.01 0.00 0.12 0.06 0.00 0.23 Example 16 2-mercaptobenzimidazole Comparative 2-mercaptobenzimidazole/ 0.01 0.00 0.17 0.03 0.00 0.25 Example 17 2,6-di-t-butyl-4-methylphenol Comparative 2-mercaptobenzimidazole/rutin 0.01 0.15 0.09 0.07 0.00 0.44 Example 18 Comparative 2,6-di-t-butyl-4-methylphenol/ 0.01 0.25 0.00 0.04 0.14 0.46 Example 19 Sodium hydroxymethanesulfonate Comparative ascorbic acid/sodium 0.01 0.00 0.01 0.05 0.49 0.62 Example 20 metabisulfite .sup.1)RRT 0.33: Desbenzyldonepezil, within 0.5% .sup.2)RRT 0.48: Unidentified impurity, within 0.2% .sup.3)RRT 0.53: Unidentified impurity, within 0.2% .sup.4)RRT 0.7: Donepezil open ring, within? 0.5% .sup.5)RRT 1.2: Donepezil N-oxdie, within? 0.5%

<Experimental Example 2> Impurities Analysis by Procedure 2 after 48 Hours of Storage at 70° C.

[0064] To test for donepezil impurities, percutaneous absorption preparation of the examples and comparative examples were stored for 48 hours at 70° C. and analyzed for impurities according to Procedure 2 as described below.

[0065] 1. Impurities Analysis by Procedure 2

[0066] Each percutaneous absorption preparation was dissolved in ethyl acetate. Then, a solution mixture of 0.1 N hydrochloric acid and methanol at a 25:75 ratio was added and the resulting mixture was stirred for 30 minutes and centrifuged for 5 minutes. The resulting supernatant was used as the sample solution for Procedure 2 of the U.S. Pharmacopoeia. The standard solution was prepare 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).

[0067] <Procedure 2: Liquid Chromatography Conditions>

[0068] Column: CAPCELLPAK™ (4.6×250 mm, C18.5 um)

[0069] 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.

TABLE-US-00006 Mobile phase B: acetonitrile Time (mm) Mobile phase A (%) Mobile phase B (%) 0 75 25 10 40 60 40 40 60 41 75 25 50 75 25

[0070] Column temperature: 50° C.

[0071] Flow rate: 1.5 mL/min

[0072] Injection size: 20 uL

[0073] UV absorptiometer: 286 nm

[0074] Calculation:

Impurity %=(Ru/Rs)×(Cs/Cu)×(1/F)×100 [0075] Ru: peak response of any individual impurity from the sample solution [0076] Rs: peak response of donepezil from the standard solution [0077] Cs: concentration in the standard solution (mg/mL) [0078] Cu: concentration in the sample solution (mg/mL) [0079] F: relative correction factor for each impurity

TABLE-US-00007 Relative retention Relative correction Acceptance criteria Impurity time (RRT) factor (F) ( %) 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 product — 1.0 0.1 Total impurities — — 1.0

[0080] 2. Impurities Analysis by Procedure 2 after 48 Hours of Storage at 70° C.

[0081] The percutaneous absorption preparations of the examples according to the present invention and comparative examples were stored for 48 hours at 70° C., and then tested for impurities according to Procedure 2. The results are shown in Table 5.

[0082] As seen in Table 5 below, a lot of decomposition of donepezil was observed in comparative example 1 without a stabilizer with Procedure 2, at relative retention times (RRT) 0.49 (donepezil pyridine analog), 0.57 (unidentified impurity), and total impurities—demonstrating the need for stabilizers in percutaneous absorption preparations of donepezil.

[0083] As for comparative example 2, which used citric acid (an organic acid disclosed in the U.S. Pat. No. 6,372,760), the RTT 0.49 (donepezil pyridine analog) and 0.57 (unidentified impurity) did not meet the criteria presented by the U.S. Pharmacopoeia.

[0084] Unlike with Procedure 1, none of comparative examples 3 through 15, which are percutaneous absorption preparations with known stabilizers met the criteria of the U.S. Pharmacopoeia at all with Procedure 2. That is, comparative example 6 (catechin), comparative example 11 (ascorbic acid) and comparative example 12 (isoascorbic acid) produced excess impurity at RRT 0.49 (donepezil pyridine analog). Comparative example 5 (thiomalic acid) and comparative example 7 (sodium thiosulfate) produced excess impurity at RRT 0.57 (unidentified impurity). Comparative example 8 (dibutylhydroxytoluene), comparative example 9 (butylhydroxyanisole), comparative example 13 (2,6-di-t-butyl-4-methylphenol) and comparative example 14 (2-mercaptobenzimidazole) did not meet the criteria for 1-3 impurities as well as total impurities.

[0085] Comparative example 16 (ascorbic acid/2-mercaptobenzimidazole), comparative example 17 (2-mercaptobenzimidazole/2,6-di-t-butyl-4-methylphenol), comparative example 18 (2-mercaptobenzimidazole/Rutin) and comparative example 19 (2,6-di-t-butyl-4-methylphenol/Sodium hydroxymethanesulfonate), which used a combination of two stabilizers selected from the stabilizers disclosed in Korea Patent Registration No 10-1408500, did not meet the U.S. Pharmacopoeia criteria. Comparative examples 16 through 18 also failed to meet the criteria for total impurities.

[0086] Comparative example 20 (ascorbic acid/Sodium metabisulfite), which used a combination of two stabilizers selected from the stabilizers disclosed in Korea Patent Registration No. 10-140854, did not meet the U.S. Pharmacopoeia criteria for RRT 0.49 (donepezil pyridine analog).

[0087] In contrast, examples 1 through 3 according to the present invention successfully met the criteria presented in the U.S. Pharmacopoeia despite each containing only one stabilizer—thus demonstrating the outstanding stabilizing effect of monothioglycerol, thiocyanate metal salt (preferably potassium salt) or dimethylthiourea.

TABLE-US-00008 TABLE 5 70° C., 48 hr, Procedure 2 of impurities analysis Content (%) of each impurity (RRT) RRT RRT RRT RRT RRT RRT RRT Stabilizer 0.23.sup.1) 0.49.sup.2) 0.57.sup.3) 0.68.sup.4) 1.03.sup.5) 1.7.sup.6) 2.1.sup.7) TOTAL Example 1 monothioglycerol 0.11 0.12 0.08 0.00 0.00 0.00 0.00 0.53 Example 2 potassium thiocyanate 0.02 0.00 0.08 0.02 0.00 0.00 0.00 0.56 Example 3 dimethylthiourea 0.05 0.02 0.06 0.00 0.00 0.00 0.00 0.49 Comparative — 0.07 0.69 0.43 0.08 0.00 0.00 0.00 1.62 Example 1 Comparative citric acid 0.01 0.44 0.16 0.02 0.00 0.00 0.00 0.71 Example 2 Comparative cysteine 0.01 0.24 0.13 0.00 0.00 0.00 0.00 0.40 Example 3 Comparative tryptophan 0.02 0.50 0.24 0.02 0.00 0.00 0.00 0.89 Example 4 Comparative thiomalic acid 0.12 0.14 0.18 0.05 0.00 0.00 0.00 0.80 Example 5 Comparative catechin 0.02 0.38 0.06 0.00 0.00 0.00 0.00 0.52 Example 6 Comparative sodium thiosulfate 0.02 0.14 0.18 0.02 0.00 0.00 0.00 0.48 Example 7 Comparative Dibutylhydroxytoluene 0.10 0.60 0.60 0.04 0.00 0.00 0.00 1.76 Example 8 Comparative Butylhydroxyanisole 0.62 0.83 1.88 0.04 0.00 0.00 0.00 3.75 Example 9 Comparative Rutin 0.01 0.46 0.26 0.02 0.00 0.00 0.00 0.88 Example 10 Comparative ascorbic acid 0.02 0.45 0.01 0.02 0.00 0.00 0.00 0.59 Example 11 Comparative isoascorbic acid 0.01 0.47 0.01 0.00 0.00 0.00 0.00 0.56 Example 12 Comparative 2,6-di-t-butyl-4- 0.09 0.59 0.58 0.00 0.00 0.00 0.00 1.62 Example 13 methylphenol Comparative 2-mercaptobenzimidazole 0.00 0.00 0.17 0.11 5.60 0.00 0.00 6.19 Example 14 Comparative Sodium metabisulfite 0.03 0.27 0.17 0.03 0.00 0.00 0.00 0.70 Example 15 Comparative 2-isoascorbic acid/ 0.00 0.01 0.17 0.10 5.83 0.00 0.00 6.45 Example 16 mercaptobenzimidazole Comparative 2-mercaptobenzimidazole/ 0.00 0.01 0.25 0.06 5.40 0.00 0.00 5.98 Example 17 2,6-d i-t-buty1-4- methylphenol Comparative 2-mercaptobenzimidazole/ 0.00 0.00 0.31 0.11 3.52 0.00 0.00 4.37 Example 18 Rutin Comparative 2,6-di-t-butyl-4- 0.00 0.11 0.28 0.00 0.00 0.00 0.00 0.48 Example 19 methylphenol/Sodium hydroxymethanesulfonate Comparative ascorbic acid/ 0.01 0.39 0.00 0.01 0.00 0.00 0.00 0.51 Example 20 Sodium metabisulfite .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: Unidentified impurity, within 0.1% .sup.4)RRT 0.68: Donepezil quaternary salt, within 0.15% .sup.5)RRT 1.03: Unidentified impurity, within 0.1% .sup.6)RRT 1.7: Donepezil indene analog, within 0.15% .sup.7)RRT 2.1: Deoxydonepezil, within 0.15%

<Experimental Example 3> Impurities Analysis by Procedures 1 and 2 after 24 Hours of Storage at 80° C.

[0088] Percutaneous absorption preparations of examples and comparative examples were tested for donepezil impurities according to Procedure 1 and Procedure 2 after 24 hours of storage at 80° C.

[0089] 1. Impurities Analysis by Procedure 1 after 24 Hours of Storage at 80° C.

TABLE-US-00009 TABLE 6 80° C., 24 hr, Procedure 1 Content (%) of each impurity (RRT) stabilizer RRT0.33.sup.1) RRT0.48.sup.2) RRT0.53.sup.3) RRT0.7.sup.4) RRT1.2.sup.5) Total Example 1 monothioglycerol 0.02 0.00 0.05 0.06 0.09 0.24 Example 2 potassium thiocyanate 0.00 0.03 0.14 0.02 0.00 0.22 Example 3 dimethylthiourea 0.03 0.09 0.06 0.04 0.00 0.24 Comparative — 0.03 0.00 0.19 0.22 1.00 1.62 Example 1 Comparative citric acid 0.01 0.00 0.09 0.05 0.65 0.83 Example 2 Comparative cysteine 0.02 0.00 0.06 0.06 0.18 0.35 Example 3 Comparative tryptophan 0.02 0.00 0.12 0.07 0.78 1.00 Example 4 Comparative thiomalic acid 0.04 0.00 0.11 0.04 0.15 0.57 Example 5 Comparative catechin 0.01 0.00 0.05 0.05 0.41 0.52 Example 6 Comparative sodium thiosulfate 0.04 0.00 0.13 0.11 0.44 0.77 Example 7 Comparative Dibutylhydroxytoluene 0.02 0.00 0.37 0.48 1.12 2.08 Example 8 Comparative Butylhydroxyanisole 0.03 0.00 1.34 2.90 3.25 8.26 Example 9 Comparative Rutin 0.01 0.00 0.14 0.05 0.59 0.87 Example 10 Comparative ascorbic acid 0.01 0.00 0.00 0.04 0.50 0.62 Example 11 Comparative isoascorbic acid 0.01 0.00 0.00 0.05 0.69 0.80 Example 12 Comparative 2,6-di-t-butyl-4-methylphenol 0.01 0.00 0.33 0.46 1.02 2.00 Example 13 Comparative 2-mercaptobenzimidazole 0.02 0.00 0.09 0.08 0.00 0.25 Example 14 Comparative Sodium metabsulfitei 0.01 0.00 0.52 0.11 0.52 0.95 Example 15 Comparative isoascorbic acid/ 0.02 0.00 0.10 0.04 0.00 0.19 Example 16 2-mercaptobenzimidazole Comparative 2-mercaptobenzimidazole/ 0.02 0.00 0.16 0.07 0.00 0.29 Example 17 2,6-di-t-butyl-4-methylphenol Comparative 2-mercaptobenzimidazole/ 0.00 0.22 0.09 0.05 0.00 0.50 Example 18 Rutin Comparative 2,6-di-t-butyl-4-methylphenol/ 0.01 0.23 0.00 0.05 0.13 0.51 Example 19 Sodium hydroxymethanesulfonate Comparative ascorbic acid/ 0.01 0.00 0.01 0.05 0.48 0.77 Example 20 Sodium metabisulfite .sup.1)RRT 0.33: Desbenzyldonepezil, within 0.5% .sup.2)RRT 0.48: unidentified impurity, within 0.2% .sup.3)RRT 0.53: unidentified impurity, within 0.2% .sup.4)RRT 0.7: Donepezil open ring, within 0.5% .sup.5)RRT 1.2: Donepezil N-oxdie, within 0.5%

[0090] 2. Impurities Analysis by Procedure 2 after 24 Hours of Storage at 80° C.

TABLE-US-00010 TABLE 7 80° C., 24 hr, Procedure 2 Content (%) of each impurity (RRT) RRT RRT RRT RRT RRT RRT RRT stabilizer 0.23.sup.1) 0.49.sup.2) 0.57.sup.3) 0.68.sup.4) 1.03.sup.5) 1.7.sup.6) 2.1.sup.7) TOTAL Example 1 monothioglycerol 0.10 0.08 0.07 0.11 0.00 0.00 0.00 0.60 Example 2 potassium thiocyanate 0.01 0.00 0.06 0.00 0.00 0.00 0.00 0.51 Example 3 dimethyl thiourea 0.04 0.01 0.07 0.00 0.00 0.00 0.00 0.44 Comparative — 0.05 0.50 0.32 0.06 0.06 0.00 0.00 1.31 Example 1 Comparative citric acid 0.01 0.36 0.14 0.00 0.00 0.00 0.00 0.59 Example 2 Comparative cysteine 0.01 0.20 0.13 0.00 0.00 0.00 0.00 0.35 Example 3 Comparative tryptophan 0.01 0.24 0.15 0.00 0.00 0.00 0.00 0.47 Example 4 Comparative thiomalic acid 0.19 0.08 0.27 0.07 0.00 0.00 0.00 1.10 Example 5 Comparative catechin 0.10 0.28 0.21 0.00 0.00 0.00 0.00 0.76 Example 6 Comparative sodium thiosulfate 0.02 0.24 0.22 0.00 0.00 0.00 0.00 0.60 Example 7 Comparative Dibutylhydroxytoluene 0.10 0.50 0.57 0.00 0.15 0.00 0.00 1.64 Example 8 Comparative Butylhydroxyanisole 0.87 0.93 2.09 0.00 0.13 0.00 0.00 4.28 Example 9 Comparative Rutin 0.03 0.24 0.30 0.00 0.00 0.00 0.00 0.61 Example 10 Comparative ascorbic acid 0.00 0.30 0.03 0.00 0.00 0.00 0.00 0.45 Example 11 Comparative isoascorbic acid 0.00 0.26 0.02 0.00 0.00 0.00 0.00 0.38 Example 12 Comparative 2,6-di-t-buty1-4-methyl phenol 0.08 0.25 0.48 0.00 0.00 0.00 0.00 1.47 Example 13 Comparative 2-mercaptobenzimidazole 0.00 0.00 0.10 0.05 4.97 0.00 0.00 5.72 Example 14 Comparative Sodium metabisulfite 0.03 0.28 0.20 0.00 0.00 0.00 0.00 0.72 Example 15 Comparative isoascorbic acid/ 0.01 0.06 0.09 0.24 4.21 0.00 0.00 5.24 Example 16 2-mercaptobenzimidazole Comparative 2-mercaptobenzimidazole/ 0.01 0.01 0.15 0.04 5.40 0.00 0.00 6.27 Example 17 2,6-di-t-buty1-4-methylphenol Comparative 2-mercaptobenzimidazole/ 0.01 0.00 0.23 0.03 3.31 0.00 0.00 4.67 Example 18 Rutin Comparative 2,6-di-t-butyl-4- 0.05 0.11 0.17 0.00 0.00 0.00 0.00 0.42 Example 19 methylphenol/Sodium hydroxymethanesulfonate Comparative ascorbic acid/ 0.00 0.21 0.00 0.00 0.00 0.00 0.00 0.30 Example 20 Sodium metabisulfite .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: Unidentified impurity, within 0.1% .sup.4)RRT 0.68: Donepezil quaternary salt, within 0.15% .sup.5)RRT 1.03: Unidentified impurity, within 0.1% .sup.6)RRT 1.7: Donepezil indene analog, within 0.15% .sup.7)RRT 2.1: Deoxydonepezil, within 0.15%

[0091] As seen in Table 6 and Table 7 above, the impurity content result of experimental example 3 was similar to the result of experimental examples 1 and 2, even with differing conditions.

[0092] In the above results, only a subset of percutaneous absorption preparations of donepezil containing a previously known stabilizers were found to be acceptable according to Procedure 1, and none of them met the acceptance criteria of Procedure 2. Furthermore, comparative example 2, 16 through 20 (which are prior art examples) were mostly acceptable according to Procedure 1 but not acceptable according to Procedure 2.

[0093] In contrast, examples 1 through 3 according to the present invention met the acceptance criteria of both Procedure 1 and Procedure 2 presented in the U.S. Pharmacopoeia, despite containing only one stabilizer each—demonstrating that adding monothioglycerol, thiocyanate metal salt (preferably potassium salt) or dimethylthiourea, unlike prior art, can successfully reduce the amount of impurities formed from decomposition of donepezil in percutaneous absorption preparations.

[0094] Of the impurities of donepezil disclosed in the U.S. Pharmacopoeia, three can be identified using Procedure 1 and five can be identified with Procedure 2. Only one impurity, desbenzyl donepezil, is identified by both Procedure 1 and Procedure 2. The rest of the impurities identified by Procedures 1 and 2 do not overlap with each other. The acceptance criteria for controlling these impurities are set based on the toxicity of each impurity.

[0095] The inventors of the present invention found that employing only one of the two methods (Procedures 1 and 2) of donepezil impurity analysis cannot successfully test for all of the various impurities that are formed from decomposition of donepezil. Indeed, comparative example 16 met all of the acceptance criteria of Procedure 1 while exceeding the limit for an unidentified impurity with Procedure 2. Administering a donepezil formulation containing such an unidentified impurity may result in problems that arise from the potential toxicity of the unidentified impurity.

[0096] Therefore, the inventors of the present invention recognized the need for a stabilizer that can effectively reduce all of the impurities of donepezil tested for by both Procedure 1 and Procedure 2. The present inventors have found that adding monothioglycerol, thiocyanate metal salt (preferably potassium salt), or dimethylthiourea as a stabilizer, as in Examples 1 through 3, can successfully and effectively inhibit the formation of donepezil impurities covered by both Procedure 1 and Procedure 2.