Percutaneous absorption preparation for treating dementia comprising donepezil

Abstract

A percutaneous absorption preparation is disclosed. The percutaneous absorption preparation contains donepezil for treatment of dementia, wherein the preparation includes: (a) donepezil or its pharmaceutically acceptable salt as active component, (b) propylene glycol monocaprylate as solubilizer, and (c) styrene-isoprene-styrene block copolymer (SIS) as adhesive. The percutaneous absorption preparation has low skin irritation and high skin penetration.

Claims

1. A percutaneous absorption preparation for the treatment of dementia comprising a backing layer, a drug-containing layer, and a release liner, wherein the drug-containing layer of the percutaneous absorption preparation comprises (a) donepezil or a pharmaceutically acceptable salt thereof as an active component, (b) a propylene glycol monocaprylate as a solubilizer, (c) a styrene-isoprene-styrene block copolymer as an adhesive, and (d) a plasticizer, wherein a ratio of donepezil or the pharmaceutically acceptable salt thereof: the propylene glycol monocaprylate is not less than 1:1.5 by weight, wherein the styrene-isoprene-styrene block copolymer makes up 10-70 wt % of a total weight of the drug-containing layer, and wherein the plasticizer (d) is selected from the group consisting of paraffin process oil, naphthalene process oil, aromatic process oil, olive oil, camellia oil, tall oil, castor oil, isopropyl myristate, hexyl lauric acid, mineral oil, octyldodecyl myristate, propylene glycol, and a combination thereof.

2. The percutaneous absorption preparation according to claim 1, wherein the donepezil as an active component is donepezil free base.

3. The percutaneous absorption preparation according to claim 1, wherein the propylene glycol monocaprylate makes up 1-40 wt % of the total weight of the drug-containing layer.

4. The percutaneous absorption preparation according to claim 3, wherein the propylene glycol monocaprylate makes up 3-30 wt % of the total weight of the drug-containing layer.

5. The percutaneous absorption preparation according to claim 4, wherein the propylene glycol monocaprylate makes up 5-25 wt % of the total weight of the drug-containing layer.

6. A process for preparing the percutaneous absorption preparation of claim 1, wherein the process comprises the following steps: (a) dissolving propylene glycol monocaprylate, styrene-isoprene-styrene block copolymer and doenpezil free base in an organic solvent; (b) casting the solution obtained in step (a) on a release linear, followed by drying, to form a drug-containing layer; and (c) laminating the drug-containing layer with a backing layer.

7. The percutaneous absorption preparation according to claim 1, wherein the ratio of donepezil or the pharmaceutically acceptable salt thereof: the propylene glycol monocaprylate is 1:1.5-1:4.5 by weight.

Description

DESCRIPTION OF DRAWINGS

(1) The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

(2) FIG. 1 shows the solubility of donepezil in various solubilizers.

(3) FIG. 2 shows the degree of skin penetration according to various solubilizers.

(4) FIG. 3 shows the degree of skin penetration with/without terpene resin.

(5) FIG. 4 shows the degree of skin penetration according to various plasticizers and adhesives.

(6) FIG. 5 shows the degree of skin penetration according to the ratio of donepezil and propylene glycol monocaprylate.

(7) FIG. 6 shows the degree of skin penetration according to the ratio of styrene-isoprene-styrene block copolymer

(8) FIG. 7 shows test results of skin irritation evaluation.

(9) FIG. 8 shows blood concentration level profile of the percutaneous absorption preparation comprising donepezil.

BEST MODE

(10) The present invention is described in more detail hereinafter through embodiments and experimental examples. These examples do not limit the scope of the present invention and is only intended to illustrate the present invention in detail.

<Experimental Example 1> Evaluation of the Solubility of Donepezil in the Solubilizers

(11) The solubility of donepezil in the various solubilizers was evaluated.

(12) The solubility was evaluated by adding a large excess of donepezil in 5 mL of each solubilizer, maintaining them for 24 hours in a 25? C. constant-temperature shaking water bath, and filtered the supernatant through 0.45 um filter. The filtrate was used to calculate the solubility of donepezil by liquid chromatography. The solubility is shown in FIG. 1.

(13) <High Performance Liquid Chromatography Conditions>

(14) Column: Capcellpak C18, 4.6?150 mm, 5 um

(15) Mobile phase: 2.5 g of sodium decanesulfonate was dissolved in 650 mL of water. Then 1 mL of 70% perchloric acid and 350 mL of acetonitrile solution were added to the solution. The solution was filtered and bubbles within were removed using an ultrasonic washing machine. The resulting solution was used as the mobile phase.

(16) Column temperature: 35? C.

(17) Flow rate: 1.4 mL/min

(18) Injection volume: 20 uL

(19) Ultraviolet wavelength: 271 nm

(20) As shown in FIG. 1, the solubility evaluation shows that the solubility of donepezil was the highest in oleic acid. Nine solubilizers that donepezil showed high solubility in, based on the solubility evaluation, were used to make the percutaneous absorption preparations comprising donepezil of the below embodiments and comparative examples.

<Embodiment 1> Formulation of the Percutaneous Absorption Preparation According to the Present Invention (1)

(21) 4.5 g of propylene glycol monocaprylate, 5.2 g of styrene-isoprene-styrene block copolymer, 8.2 g of octyldodecyl myristate, and 4.5 g of propylene glycol monocaprylate were dissolved in 15 g of ethylacetate and then added to 1 g of donepezil and dissolved thoroughly, like the composition disclosed in the table 1 below. The percutaneous absorption preparation was formulated by spreading the resulting solution on the silicon coated PET film and then drying it for 30 minutes in 80? C. oven and attaching it to backing film.

<Embodiment 2> Formulation of the Percutaneous Absorption Preparation According to the Present Invention (2)

(22) To test the degree of skin penetration and crystal precipitation contingent upon the terpene resin, the percutaneous absorption preparation was formulated with the components disclosed in table 1 below through the same process as the embodiment 1 above.

(23) TABLE-US-00001 TABLE 1 Embodi- Embodi- Category Ingredient (g) ment 1 ment 2 Active Donepezil 1 1 component Base polymer Styrene-isoprene-styrene block 5.2 5.2 for adhesive copolymer Tackifier Terpene resin 1.3 Solubilizer Propylene glycol monocaprylate 4.5 4.5 Solubilizer Octyldodecyl myristate 8.2 8.2 Total 18.9 20.2

<Embodiment 3 and 4> Formulation of the Percutaneous Absorption Preparation According to the Present Invention (3)

(24) With the components disclosed in table 2 below, the percutaneous absorption preparations of embodiment 3, with the same components as the embodiment 1 but in different amounts, and embodiment 4, with different plasticizer from embodiment 1, were formulated through the same process as the embodiment 1 above.

(25) TABLE-US-00002 TABLE 2 Embodi- Embodi- Category Ingredient (g) ment 3 ment 4 Active Donepezil 1 1 component Base polymer Styrene-isoprene-styrene block 12 12 for adhesive copolymer Solubilizer Propylene glycol monocaprylate 3 3 Plasticizer Octyldodecyl myristate 6 Mineral oil 6 Total 22 22

<Embodiment 5> Formulation of the Percutaneous Absorption Preparation with Various Amounts of Solubilizer According to the Present Invention (4)

(26) To select the optimum ratio of donepezil to propylene glycol monocaprylate of the present invention, the amounts of solubilizer of the percutaneous absorption preparations of embodiment 5-1 through 5-3 were changed to differ from that of embodiment 2 and were formulated with components disclosed in table 3 below through the same process as embodiment 2.

(27) TABLE-US-00003 TABLE 3 Embodi- Embodi Embodi- Category Ingredient (g) ment 5-1 ment 5-2 ment 5-3 Active Donepezil 1.0 1.0 1.0 component Base Styrene-isoprene-styrene 5.2 5.2 5.2 polymer block copolymer for adhesive Tackifier Terpene resin 1.3 1.3 1.3 Solubilizer Propylene glycol 4.5 3 1.5 monocaprylate Plasticizer Octyldodecyl myristate 8.2 8.2 8.2 Total 20.2 18.7 17.2

<Embodiment 6> Formulation of the Percutaneous Absorption Preparation with Various Amounts of Adhesive According to the Present Invention (5)

(28) To select the optimum ratio of styrene-isoprene-styrene block copolymer of the present invention, the amounts of base polymer for adhesive of the percutaneous absorption preparations of embodiment 6-1 through 6-6 were changed to differ from that of embodiment 2 and were formulated with components disclosed in table 4 below through the same process as embodiment 2.

(29) TABLE-US-00004 TABLE 4 (unit: g) Embodiment Embodiment Embodiment Embodiment Embodiment Embodiment Category Ingredient (wt %) 6-1 6-2 6-3 6-4 6-5 6-6 Active Donepezil 1 1 1 1 1 1 component (5.3%) (4.9%) (4.5%) (4.0%) (3.6%) (2.5%) Base Styrene-isoprene- 3 4.5 6 9 12 24 polymer for styrene block (15.8%) (22.0%) (27.3%) (36.0%) (42.9%) (60.0%) adhesive copolymer Tackifier Terpene resin 3 3 3 3 3 3 (15.8%) (14.6%) (13.6%) (12.0%) (10.7%) (7.5%) Solubilizer Propylene glycol 3 3 3 3 3 3 monocaprylate (15.8%) (14.6%) (13.6%) (12.0%) (10.7%) (7.5%) Plasticizer Octyldodecyl 9 9 9 9 9 9 myristate (47.3%) (43.9%) (41.0%) (36.0%) (32.1%) (22.5%) Total 19 20.5 22 25 28 40 (100%) (100%) (100%) (100%) (100%) (100%)

<Comparative Example 1 Through 9> Formulation of the Percutaneous Absorption Preparation Comprising Donepezil with Different Solubilizers

(30) Based on the evaluation of solubility in experimental example 1, eight solubilizers that donepezil showed high solubility in were selected. Comparative example 1 through 8 were formulated with components disclosed in table 5 below through the same process as embodiment 2, comprising each of the solubilizers mentioned above and the same components of embodiment 2, except for the solubilizer. Comparative example 9 was formulated without a solubilizer.

(31) TABLE-US-00005 TABLE 5 (unit: g) Comparative example Ingredient 1 2 3 4 5 6 7 8 9 Donepezil 1 1 1 1 1 1 1 1 1 Styrene-isoprene-styrene 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 block copolymer Terpene resin 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 Solubilizer Polyethylene glycol 4.5 hexadecyl ester Tetraglycol 4.5 Triacetin 4.5 Diethylene glycol 4.5 monoethyl ether Polyethylene glycol 4.5 400 Polyethylene glycol 4.5 200 oleyl alcohol 4.5 oleic acid 4.5 Octyldodecyl myristate 8.2 8.2 8.2 8.2 8.2 8.2 8.2 8.2 8.2 Total 20.2 20.2 20.2 20.2 20.2 20.2 20.2 20.2 15.7

<Comparative Example 10 Through 12> Formulation of the Percutaneous Absorption Preparation Comprising Donepezil with Different Adhesives

(32) Comparative examples 10 through 12 were formulated with components disclosed in table 6 below through the same process as embodiment 1, comprising different adhesives from embodiment 1. Comparative example 10 through 12 each used polyethylene vinyl acetate (containing 40% vinyl acetate), an EVA adhesive, acrylic adhesive Duro-Tak? 87-9301, and polyisobutylene adhesive, respectively. When polyisobutylene was used as a base polymer for adhesive, hexane was used as an organic solvent.

(33) TABLE-US-00006 TABLE 6 Compara- Compara- Compara- tive exam- tive exam- tive exam- Ingredient (g) ple 10 ple 11 ple 12 Active Donepezil 1 1 1 component Adhesive Polyethylene vinyl 12 acetate Duro-Tak? 87-9301 12 Polyisobutylene 12 Solubilizer Propylene glycol 3 3 3 monocaprylate Plasticizer Octyldodecyl 6 6 6 myristate Total 22 22 22

<Comparative Example 13> Formulation of the Percutaneous Absorption Preparation Comprising Donepezil

(34) To select the optimum ratio of donepezil to propylene glycol monocaprylate of the present invention, the amounts of solubilizer of the percutaneous absorption preparations of comparative example 13 were changed to differ from that of embodiment 2 and were formulated with components disclosed in table 7 below through the same process as embodiment 2.

(35) TABLE-US-00007 TABLE 7 Comparative Category Ingredient (g) example 13 Active component Donepezil 1.0 Base polymer for Styrene-isoprene-styrene 5.2 adhesive block copolymer Tackifier Terpene resin 1.3 Solubilizer Propylene glycol mono- 0.75 caprylate Plasticizer Octyldodecyl myristate 8.2 Total 16.45

<Experimental Example 2> Evaluation of the Degree of Skin Penetration Using Hairless Rat's Skin

(36) The in-vitro permeability of the percutaneous absorption preparations prepared in examples 1 to 6 and comparative examples 1 to 13 was evaluated by using a Franz diffusion cell. The receptor chamber was filled with physiological saline containing 10% ethanol and 0.02% sodium azide as a receptor solution, and the temperature was maintained at 32?0.5? C. Each of the percutaneous absorption preparations prepared in Examples 1 to 6 and Comparative Examples 1 to 13 was cut and applied to the donor cell size using a hairless rat skin. The penetrated amount of donepezil in the receptor solution was measured over time using liquid chromatography. FIG. 2 through 6 shows patterns of drug release over time of patches made in embodiment 1 through 6 and comparative example 1 through 13.

(37) (1) Evaluation of the Degree of Skin Penetration According to Various Absorption Enhancers

(38) As shown in FIG. 2, comparative example 9 without solubilizer induce little penetration of donepezil. Also, oleic acid (comparative example 8), which showed high solubility of donepezil, also showed very low level of penetration. However it can be seen that embodiment with propylene glycol monocaprylate as the solubilizer showed significant increase of degree of skin penetration. This shows the degree of skin penetration of propylene glycol monocaprylate is great.

(39) (2) Evaluation of the Degree of Skin Penetration with/without Terpene Resin

(40) As shown in FIG. 3, embodiment 1 with terpene resin and embodiment 2 without terpene resin showed no difference in the degree of skin penetration.

(41) (3) Evaluation of the Degree of Skin Penetration Contingent Upon Change of Plasticizer and Adhesive

(42) As shown in FIG. 4, embodiment 3 through 4, wherein octyldodecyl myristate is changed to mineral oil as the plasticizer, showed no change in the degree of skin penetration. On the contrary, comparative example 10 through 12, wherein adhesive is changed, showed significant decrease in the degree of skin penetration compared to when styrene-isoprene-styrene block copolymer is used as the base polymer for adhesive.

(43) (4) Evaluation of the Degree of Skin Penetration According to the Ratio of Donepezil to Propylene Glycol Monocaprylate

(44) The percutaneous absorption preparation formulated according to embodiment 5 and comparative example 13 was evaluated using experimental franz diffusion cell. The results show that when the ratio is below 1:0.75 (comparative example 13) drug precipitates formed thereby significantly decreasing the degree of skin penetration, and that when the ratio is between 1:1.5 and 1:4.5, the degree of skin penetration was great without drug crystal precipitation (FIG. 5).

(45) (5) Evaluation of the Degree of Skin Penetration According to the Ratio of Styrene-Isoprene-Styrene Block Copolymer

(46) To determine the optimum ratio of styrene-isoprene-styrene block copolymer in the drug-containing layer, the percutaneous absorption preparation prepared according to Example 6 was evaluated using a franz diffusion cell.

(47) As a result, skin permeability tended to decrease as the weight % of styrene-isoprene-styrene block copolymer for adhesive in the drug-containing layer was increased. On the other hand, as the weight % of the styrene-isoprene-styrene block copolymer in the drug-containing layer decreased, the gel cohesion of the drug-containing layer became weaker. In Example 6-1, the gel cohesive force weakened and the part of the drug-containing layer remained on the surface of the skin when the percutaneous absorption preparation was removed after skin permeability study. Based on the results, for the styrene-isoprene-styrene block copolymer in the drug-containing layer to have sufficient gel cohesion and skin permeability, the amount of the styrene-isoprene-styrene block copolymer in the drug-containing layer needed is 10 wt % to 70 wt %, more preferably 20 wt % to 60% by weight.

<Experimental Example 3> Evaluation of Drug Crystal Precipitation

(48) The percutaneous absorption preparations according to embodiment 1 through 6 were evaluated for the presence of drug crystal precipitation. The appearance of crystal precipitation was observed with microscopes for crystal formations after storing the percutaneous absorption preparations according to embodiment 1 through 6 under 25? C. 60% RH for 1 month. Table 8 below shows the results.

(49) TABLE-US-00008 TABLE 8 Embodi- Embodi- Embodi- Embodi- Embodi- Embodi- Embodi- Embodi- Embodi- Embodi- Embodi- Embodi- ment 1 ment2 ment 3 ment 4 ment 5-1 ment 5-2 ment 5-3 ment 6-2 ment 6-3 ment 6-4 ment 6-5 ment 6-6 Crystal X X X X X X X X X X X X precipitation (No) (No) (No) (No) (No) (No) (No) (No) (No) (No) (No) (No)

(50) As shown in table 8, when donepezil:propylene glycol monocaprylate used is 1:1.5, it was found that crystal precipitates do not form because of high solubility of donepezil in propylene glycol monocaprylate. Also, embodiment 1 and 2 showed no appearance of crystal precipitates irrespectively to the addition of terpene resin.

<Experimental Example 4> Evaluation of Skin Irritation

(51) The degree of skin irritation of the percutaneous absorption preparation according to the present invention was evaluated. Marketed product Exelon 5 mg patch was used as comparative example for the above evaluation of the percutaneous absorption preparation according to embodiment 6-5 of the present invention.

(52) Four shaved, white rabbits were used for the evaluation. Embodiment 6-5 and marketed preparation Exelon were cut to 5 cm.sup.2. They were attached for 24 hours before being detached. The red spots and edema formation on the attachment area of the percutaneous absorption preparation after 24 hours and 74 hours were observed with bare eyes and evaluated with method disclosed in table 9. The results are shown in table 10 and FIG. 7.

(53) TABLE-US-00009 TABLE 9 Red spots and incrustation Edema formation Point(s) Point(s) No red spot 0 No edema 0 Very light red spot 1 Very light edema (barely 1 (barely distinguished distinguished with bare eyes) with bare eyes) Clear red spot 2 Light edema (clearly swollen that the edges can 2 be clearly distinguished) Slightly severe red 3 Average edema (swollen 3 spot to approx. 1 mm) Severe red spot (red 4 Severe edema (swollen 4 flare) and light more than 1 mm and extended incrustation beyond the attached area) Severest 4 Severest 4

(54) TABLE-US-00010 TABLE 10 Skin Observation Category reaction period Individual 1 Individual 2 Individual 3 Individual 4 Average Embodiment Red spot 24 hr 1 1 0 1 0.75 6-5 72 hr 1 1 1 0 0.75 Edema 24 hr 0 0 0 0 0 72 hr 0 0 0 0 0 Exelon patch Red spot 24 hr 3 3 2 2 2.5 72 hr 3 2 2 1 2 Edema 24 hr 0 0 0 0 0 72 hr 0 0 0 0 0

(55) As shown in table 10 and FIG. 7, embodiment 6-5 of the present invention induced no edema and induced light red spot with 0.75 point, whereas, marketed Exelon? patch induced no edema but induced 2.5 (24 hr) and 2.0 (74 hr) of severe red spot.

(56) This shows that the percutaneous absorption preparation comprising donepezil of the present invention induces significantly low degree of skin irritation compared to the market Exelon?.

<Experimental Example 5> Evaluation of Rat PK

(57) The pharmacokinetics of the percutaneous absorption preparations according to embodiment 1 and 6-5 of the present invention were evaluated using hairless rat and the results are shown in table 11. For comparison, comparative example 3 (triacetin as the solubilizer), with the highest degree of skin penetration based on the in-vitro evaluation of the degree of skin penetration of the comparative examples, and oral preparation of reference example 1 (oral composition comprising 5 mg donepezil) were evaluated as well.

(58) Embodiment 1 and comparative example 3, which comprise the same component except for the solubilizers, were cut into 2.5 cm.sup.2. Embodiment 6-5 was cut into 4 cm.sup.2 and 8 cm.sup.2. They were attached to hairless rats for 7 days before being detached. Blood was drawn 0, 4, 8, 24, 30, 48, 72, 96, 144, 168 hours after patch attachment and the blood level of donepezil was measured. In reference example 1, donepezil was dissolved at 2.5 mg/mL in distilled water, and 2 mL of the donepezil solution was orally administrated. The blood was drawn 0, 0.5, 1, 2, 4, 6, 24 hours later and the amount of donepezil in blood was measured.

(59) TABLE-US-00011 TABLE 11 Com- para- Refer- Embodi- Embodi- Embodi- tive ence ment 1 ment 6-5 ment 6-5 exam- exam- (2.5 cm.sup.2) (4 cm.sup.2) (8 cm.sup.2) ple 3 ple 1 Content of drug in 4 5 10 4 5 patch (mg/sheet) Residual amount 6.6 9.5 15.3 34.6 of drug after 7 days of attachment (%) Degree of skin 93.4 90.5 84.7 65.4 penetration (%) AUC.sub.inf (ng * hr/mL) 3241.2 3913.9 8439.4 2308.0 1167.4 Cmax (ng/mL) 97.1 109.8 228.1 49.7 95.8 Tmax (hr) 24 24 24 24 2

(60) As shown in table 11 above, the residual amount of drug in patch after 7 days of attachment of embodiment 1 of the present invention was 6.6%, indicating 93.4% of the drug penetrated the skin, whereas, the residual amount of drug in patch after 7 days of attachment of comparative example 3 was 34.6% and thereby only 65.4% of the drug penetrated the skin.

(61) The results of the in-vivo evaluation of the degree of skin penetration of the above experimental example 6 conform with the results of in-vitro evaluation of the degree of skin penetration of the above experimental example 2 (1). This shows that the percutaneous absorption preparation comprising propylene glycol monocaprylate as the solubilizer according to the present invention induce great degree of drug penetration.

(62) Also, the evaluation of blood level of donepezil of embodiment 6-5 with patch area of 4 cm.sup.2 and 8 cm.sup.2 shows that the blood concentration level proportionally increases as the area of the percutaneous absorption preparation increases. Particularly when embodiment 6-5 in 4 cm.sup.2 and oral administration of reference example 1 with 5 mg donepezil are compared, AUC of percutaneous administration increased approximately 335% to 3913.9 ng*hr/ml compared to 1167.4 ng*hr/ml of the oral administration. This shows that the percutaneous absorption preparation according to the present invention can achieve significantly higher blood concentration level compared to the oral administration with the same drug dosage.