PREPARATION FOR PERCUTANEOUS ABSORPTION COMPRISING HIGH DOSE OF DONEPEZIL OR SALT THEREOF

Abstract

A preparation for percutaneous absorption contains a drug-containing matrix layer having a single-layered structure, in which a high dose of donepezil or a pharmaceutically acceptable salt thereof is contained in an amount of 10 to 20 wt % with respect to the total weight of the drug-containing matrix layer, thereby reducing the size of a formulation. The single-layered structure of the preparation allows for easy preparation at a production site and reduced manufacturing costs compared to preparations for percutaneous absorption having multi-layered structures. In addition, despite the high dose of donepezil contained in the preparation, no crystallization of donepezil occurs even during long-term storage, and the preparation continuously exhibits high skin permeability for a long period of time. Above all, due to a high drug dose per unit area, the size of a formulation is reduced compared to that of conventional formulations, and thus patient medication compliance can be remarkably increased.

Claims

1. A preparation for percutaneous absorption, comprising: a support layer, a drug-containing matrix layer and a release layer, wherein the drug-containing matrix layer comprises: (a) 9 to 14 parts by weight of donepezil or a pharmaceutically salt thereof as an active ingredient with respect to a total of 100 parts by weight of the drug-containing matrix layer, (b) 30 to 55 parts by weight of a polyisobutylene mixture of high-molecular weight polyisobutylene having a viscosity average molecular weight of 400,000 to 3,000,000 and low-molecular weight polyisobutylene having a viscosity average molecular weight of 40,000 to 100,000 as an adhesive with respect to a total of 100 parts by weight of the drug-containing matrix layer, and (c) 0.5 to 2.5 parts by weight of a crystallization inhibitor with respect to a total of 100 parts by weight of the drug-containing matrix layer, and wherein a dose per unit area of donepezil or the pharmaceutically acceptable salt thereof in the preparation for percutaneous absorption is 1.0 to 2.0 mg/cm.sup.2.

2. The preparation of claim 1, wherein donepezil or a pharmaceutically acceptable salt thereof is comprised in an amount of 10 to 13 parts by weight with respect to a total of 100 parts by weight of the drug-containing matrix layer.

3. The preparation of claim 1, wherein a dose per unit area of donepezil or the pharmaceutically acceptable salt thereof in the preparation for percutaneous absorption is 1.0 to 1.5 mg/cm.sup.2.

4. The preparation of claim 1, wherein the high-molecular weight polyisobutylene has a viscosity average molecular weight of 800,000 to 2,600,000.

5. The preparation of claim 1, wherein the low-molecular weight polyisobutylene has a viscosity average molecular weight of 40,000 to 85,000.

6. The preparation of claim 1, wherein the adhesive is a mixture of high-molecular weight polyisobutylene having a viscosity average molecular weight of 800,000 to 2,600,000 and low-molecular weight polyisobutylene having a viscosity average molecular weight of 40,000 to 85,000.

7. The preparation of claim 1, wherein a weight ratio of the high-molecular weight polyisobutylene and the low-molecular weight polyisobutylene is 1:0.5 to 1:2.

8. The preparation of claim 1, wherein the adhesive is included in an amount of 35 to 50 parts by weight with respect to a total of 100 parts by weight of the drug-containing matrix layer.

9. The preparation of claim 1, wherein the crystallization inhibitor is polyvinylpyrrolidone.

10. The preparation of claim 1, wherein the crystallization inhibitor is included in an amount of 1.0 to 1.5 parts by weight with respect to a total of 100 parts by weight of the drug-containing matrix layer.

11. The preparation of claim 1, where the donepezil or the pharmaceutically acceptable salt thereof has a skin permeability of 3 to 30 μg/cm.sup.2/hr.

12. The preparation of claim 1, wherein the drug-containing matrix layer further comprises one or more additives selected from the group consisting of a stabilizer, a tackifier, and a softening agent.

Description

DESCRIPTION OF DRAWINGS

[0037] FIGS. 1 and 2 illustrate the results of measuring the skin permeability and permeation amount by applying the preparations for percutaneous absorption of Preparation Examples 2-5 to 2-9 to the skin of hairless mice.

MODES OF THE INVENTION

[0038] Hereinafter, the present invention will be described in detail through Examples and Experimental Examples. However, these Examples and Experimental Examples are provided only for exemplifying the present invention, and the present invention is not limited to these Examples and Experimental Examples.

EXAMPLES

Preparation Examples 1 to 4

[0039] Preparations for percutaneous absorption were prepared according to the ingredients and contents in the following Table 1. Hereinafter, the numerical values in the table associated with the Production Examples indicate the weight (mg) of the raw material contained per preparation for percutaneous absorption having a size of about 47.6 cm.sup.2. Specifically, a donepezil free base, polyisobutylene having a viscosity average molecular weight of about 1,110,000 [g/mol] (Oppanol™ N100, BASF, Germany) and polyisobutylene having a viscosity average molecular weight of about 55,000 [g/mol] (Oppanol™ B12, BASF, Germany), polyvinylpyrrolidone (Povidone K-30, K-25, K-90) or copovidone, isopropanol, toluene, a mineral oil, and a hydrocarbon resin (Pinecrystal KE-311,) were homogeneously mixed using a roller mixer. After air bubbles were removed from the obtained mixture, the mixture was applied to a release liner coated with silicone and dried. A preparation for percutaneous absorption containing donepezil was prepared by laminating a polyethylene film to form a backing membrane.

TABLE-US-00001 TABLE 1 Preparation Preparation Preparation Preparation Name of raw material Example 1 Example 2 Example 3 Example 4 Donepezil 54 54 54 54 Ascorbyl palmitate 0.1 0.1 0.1 0.1 Toluene (preparation solvent) 200.0 200.0 200.0 200.0 Hydrocarbon resin 134.0 134.0 134.0 134.0 Toluene (tackifier solvent) 89.0 89.0 89.0 89.0 Povidone K25 (PVP K25) 5.6 — — — Povidone K30 (PVP K30) — 5.6 — — Povidone K90 (PVP K90) — — 5.6 — Copovidone — — — 5.6 Isopropanol 39.2 39.2 39.2 39.2 Paraffin liquid (Mineral oil) 86.8 86.8 86.8 86.8 Polyisobutylene pressure adhesive 968.3 968.3 968.3 968.3 (hereinafter, Duro-Tak 87-6919) Sub-Total (Wet basis) 1577 1577 1577 1577 Sub-Total (Dried basis) 503.2 503.2 503.2 503.2

Experimental Example 1: Evaluation of Stability in Preparation Examples 1 to 4

[0040] After room temperature, acceleration, open acceleration, and freeze-thaw tests (storage at −20° C./room temperature for 24 hours repeated three times) were performed on the prepared preparations for percutaneous absorption, preparation stability was evaluated by allowing the preparations to stand under open acceleration conditions for 4 weeks.

TABLE-US-00002 TABLE 2 Stability Freeze thaw Preparation Room Open open Example temperature Acceleration acceleration acceleration Preparation X ◯ ◯ ◯ Example 1 (week 2) (week 4) (week 4) Preparation X ◯ X ◯ Example 2 (week 4) (week 4) Preparation X X ◯ ◯ Example 3 (week 4) (week 4) Preparation X X X X Example 4

[0041] As can be seen in Table 2, in the case of Preparation Example 1, crystals were formed in the preparation for percutaneous absorption at week 2 under the accelerated conditions, so it was evaluated that the compositions of Preparation Examples 2 to 4 were more preferable than Preparation Example 1. In particular, in the case of Preparation Example 2, almost no crystal generation was observed, so an additional experiment was performed based on the composition of Preparation Example 2.

Preparation Examples 2-1 to 2-4

[0042] An attempt was made to test how preparation stability changes by adjusting the content of crystallization inhibitor in the composition of Preparation Example 2. Thus, Preparation Examples 2-1 to 2-4 were prepared by equally maintaining the content of the drug and the content of the other excipients and differently adjusting only the content of the crystallization inhibitor in the composition of Preparation Example 2.

TABLE-US-00003 TABLE 3 Preparation Preparation Preparation Preparation Name of raw material Example 2-1 Example 2-2 Example 2-3 Example 2-4 Donepezil 54 54 54 54 Ascorbyl palmitate 0.1 0.1 0.1 0.1 Toluene (preparation solvent) 200.0 200.0 200.0 200.0 Hydrocarbon resin 134.0 134.0 134.0 134.0 Toluene (tackifier solvent) 89.0 89.0 89.0 89.0 Povidone K30 (PVP K30) 2.5 4.0 5.6 7.6 Isopropanol 39.2 39.2 39.2 39.2 Paraffin liquid (Mineral oil) 86.8 86.8 86.8 86.8 Polyisobutylene pressure adhesive 968.3 968.3 968.3 968.3 (hereinafter, Duro-Tak 87-6919) Sub-Total (Wet basis) 1573.9 1575.4 1577 1579 Sub-Total (Dried basis) 500.1 501.6 503.2 505.2

Experimental Example 2: Evaluation of Stability of Preparation Examples 2-1 to 2-4

[0043] The stability of Preparation Examples 2-1 to 2-4 was evaluated under the same conditions as in Experimental Example 1 for 4 weeks, and the results are shown in the following Table 4.

TABLE-US-00004 TABLE 4 Stability Freeze thaw Preparation Room Open open of patch temperature Acceleration acceleration acceleration Preparation X ◯ ◯ ◯ Example 2-1 (week 4) (week 2) (week 2) Preparation X X X ◯ Example 2-2 (week 4) Preparation X ◯ X ◯ Example 2-3 (week 4) (week 4) Preparation X X ◯ ◯ Example 2-4 (week 2) (week 4)

[0044] As can be seen in Table 4, all of Preparation Examples 2-1 to 2-4 show generally good preparation stability.

Preparation Examples 2-5 to 2-9

[0045] An attempt was made to test how preparation stability changed when the amount of drug loaded was changed in the composition of Preparation Example 2. Thus, Preparation Examples 2-5 to 2-9 were prepared by equally maintaining the content of the excipients and differently adjusting only the content of the drug as shown in the following Table 5 in the composition of Preparation Example 2.

TABLE-US-00005 TABLE 5 Preparation Preparation Preparation Preparation Preparation Name of raw material Example 2-5 Example 2-6 Example 2-7 Example 2-8 Example 2-9 Donepezil 45.30 54.0 61.0 71.0 81.0 Ascorbyl palmitate 0.1 0.1 0.1 0.1 0.1 Toluene (preparation solvent) 200.0 200.0 200.0 200.0 200.0 Hydrocarbon resin 134.0 134.0 134.0 134.0 134.0 Toluene (tackifier solvent) 89.0 89.0 89.0 89.0 89.0 Povidone K30 (PVP K30) 5.6 5.6 5.6 5.6 5.6 Isopropanol 39.2 39.2 39.2 39.2 39.2 Paraffin liquid (Mineral oil) 86.8 86.8 86.8 86.8 86.8 Polyisobutylene adhesive 968.3 968.3 968.3 968.3 968.3 (hereinafter, Duro-Tak 87-6919) Sub-Total (Wet basis) 1568.3 1577 1584 1594 1604 Sub-Total (Dried basis) 494.5 503.2 510.2 520.2 530.2

Experimental Example 3: Evaluation of Stability of Preparation Examples 2-5 to 2-9

[0046] The stability of Preparation Examples 2-5 to 2-9 was evaluated under the same conditions as in Experimental Example 1 for 4 weeks, and the results are shown in the following Table 6.

TABLE-US-00006 TABLE 6 Stability Freeze thaw Preparation Room Open open of patch temperature Acceleration acceleration acceleration Preparation X X X X Example 2-5 Preparation X ◯ X ◯ Example 2-6 (week 4) (week 4) Preparation X ◯ X ◯ Example 2-7 (week 4) (week 4) Preparation X X ◯ X Example 2-8 (week 4) Preparation X X ◯ ◯ Example 2-9 (week 4) (week 4)

[0047] In Preparation Examples 2-8 and 2-9, crystal generation was conspicuous, indicating poor preparation stability. Other Preparation Examples 2-5 to 2-7 showed relatively good stability.

Preparation Examples 2-10 to 2-13

[0048] During a preliminary experiment, it was revealed that the change in co-solvent of the crystallization inhibitor at the time of preparation of the preparation for percutaneous absorption affects preparation stability. Thus, an attempt was made to test how preparation stability changed when the type of co-solvent was varied in the composition of Preparation Example 2. Thus, Preparation Examples 2-10 to 2-13 were prepared by equally maintaining the contents of the drug and the excipients and using only different types of co-solvent during the preparation of the crystallization inhibitor solution as shown in the following Table 7 in the composition of Preparation Example 2.

TABLE-US-00007 TABLE 7 Preparation Preparation Preparation Preparation Name of raw material Example 2-10 Example 2-11 Example 2-12 Example 2-13 Donepezil 54 54 54 54 Ascorbyl palmitate 0.1 0.1 0.1 0.1 Toluene (preparation solvent) 200.0 200.0 200.0 200.0 Hydrocarbon resin 134.0 134.0 134.0 134.0 Toluene (tackifier solvent) 89.0 89.0 89.0 89.0 Povidone K30 (PVP K30) 5.6 5.6 5.6 5.6 Ethanol 39.2 — — — Butanol — 39.2 — — Isopropanol — — 39.2 — Propanol — — — 39.2 Paraffin liquid (Mineral oil) 86.8 86.8 86.8 86.8 Polyisobutylene adhesive 968.3 968.3 968.3 968.3 (Hereinafter, Duro-Tak 87-6919) Sub-Total (Wet basis) 1577 1577 1577 1577 Sub-Total (Dried basis) 503.2 503.2 503.2 503.2

Experimental Example 4: Evaluation of Stability of Preparation Examples 2-10 to 2-13

[0049] The stability of Preparation Examples 2-10 to 2-13 was evaluated under the same conditions as in Experimental Example 1 for 4 weeks, and the results are shown in the following Table 8.

TABLE-US-00008 TABLE 8 Stability Freeze thaw Preparation Room Open open of patch temperature Acceleration acceleration acceleration Preparation X ◯ ◯ ◯ Example 2-10 (week 2) (week 2) (week 2) Preparation X ◯ ◯ ◯ Example 2-11 (week 4) (week 2) (week 2) Preparation X ◯ X ◯ Example 2-12 (week 4) (week 4) Preparation X ◯ ◯ ◯ Example 2-13 (week 4) (week 4) (week 4)

[0050] As a result of the experiment, the crystal generation of Preparation Example 2-12 using isopropanol as a co-solvent was the least compared to other solvents.

Preparation Examples 2-14 to 2-16

[0051] In order to confirm whether the content of co-solvent affected preparation stability when the preparation for percutaneous absorption was prepared, an attempt was made to test how preparation stability changed when the content of co-solvent in the composition of Preparation Example 2-12 was varied. Thus, Preparation Examples 2-14 to 2-16 were prepared by equally maintaining the contents of the drug and the excipients and using only different contents of co-solvent during the preparation of the crystallization inhibitor solution as shown in the following Table 9 in the composition of Preparation Example 2-12.

TABLE-US-00009 TABLE 9 Preparation Preparation Preparation Name of raw material Example 2-14 Example 2-15 Example 2-16 Donepezil 54 54 54 Ascorbyl palmitate 0.1 0.1 0.1 Toluene (preparation solvent) 200.0 200.0 200.0 Hydrocarbon resin 134.0 134.0 134.0 Toluene (tackifier solvent) 89.0 89.0 89.0 Povidone K30 (PVP K30) 5.6 5.6 5.6 Isopropanol 16.8 39.2 84 Paraffin liquid (Mineral oil) 86.8 86.8 86.8 Polyisobutylene pressure adhesive 968.3 968.3 968.3 (hereinafter, Duro-Tak 87-6919) Sub-Total (Wet basis) 1554.6 1577 1621.8 Sub-Total (Dried basis) 503.2 503.2 503.2

Experimental Example 5: Evaluation of Stability of Preparation Examples 2-14 to 2-16

[0052] The stability of Preparation Examples 2-14 to 2-16 was evaluated under the same conditions as in Experimental Example 1 for 4 weeks, and the results are shown in the following Table 10.

TABLE-US-00010 TABLE 10 Stability Freeze thaw Preparation Room Open open of patch temperature Acceleration acceleration acceleration Preparation X ◯ ◯ ◯ Example 2-14 (week 4) (week 4) (week 2) Preparation X ◯ X ◯ Example 2-15 (week 4) (week 4) Preparation ◯ (precipitation of crystals Example 2-16 immediately after preparation of patch)

[0053] As a result of the experiment, in Preparation Example 2-16, crystals were precipitated immediately after the preparation of a patch so a stable preparation could not be obtained. It was observed that the stability of the preparation stability was secured in Preparation Examples 2-14 and 2-15.

Experimental Example 6: Percutaneous Dissolution Test

[0054] The skin permeability and permeation amount were measured by applying the preparations for percutaneous absorption of Preparation Examples 2-5 to 2-9 to the skin of hairless mice.

[0055] Specifically, after each preparation for percutaneous absorption was adhered to the skin of hairless mice (6 to 8 weeks old) by removing the skin immediately before the test, the skin was fixed with a clamp in a flow-through diffusion cell, an isotonic phosphate buffer solution (pH 7.4) was put into a receptor and maintained at 32.5° C., and a sample was collected at 0, 3, 6, 9, 12, 24, 36, and 48 hours while stirring the solution at 600 rpm with a magnetic stirrer. The obtained sample was quantified using high performance liquid chromatography and an ultraviolet absorptiometer under the following analytical conditions.

[0056] <Analytical Conditions>

[0057] Column: Capcellpak MG C18, 4.6×150 mm, 5 μm

[0058] Mobile phase: after 2.12 g of sodium decanesulfonate was completely dissolved in 550 mL of water, 1 mL of 70% perchloric acid and 450 mL of an acetonitrile solution were added thereto. After the obtained solution was filtered, air bubbles were removed for 10 minutes using an ultrasonic cleaner and the resulting product was used as a mobile phase.

[0059] Column temperature: 35° C.

[0060] Amount of sample injected: 5 μl

[0061] Ultraviolet absorptiometer: 271 nm

[0062] Flow rate: 1.0 mL/min

[0063] As a result of a percutaneous dissolution test of the preparations for percutaneous absorption of Preparation Examples 2-5 to 2-9, the permeability (μg/cm.sup.2/hr) is shown in the following Table 11 and FIG. 1.

TABLE-US-00011 TABLE 11 Preparation Time (hr) Example 0 3 6 9 12 24 36 48 Preparation average 0 8.1 8.6 10.5 11.2 14.9 15.4 14.8 Example 2-5 STDEV 0 7.9 7.0 7.8 7.1 6.8 5.8 3.9 Preparation average 0 8.6 8.8 12.4 14.3 20.5 21.3 20.6 Example 2-6 STDEV 0 5.6 4.3 5.3 5.3 5.2 3.8 3.3 Preparation average 0 5.8 6.7 8.5 11.9 21.9 22.2 20.8 Example 2-7 STDEV 0 1.9 5.4 5.8 5.9 3.7 3.1 3.1 Preparation average 0 15.5 14.7 18.7 22.6 28.0 27.7 26.6 Example 2-8 STDEV 0 1.7 6.7 3.9 5.7 1.3 0.8 0.9 Preparation average 0 10.9 7.2 20.9 22.1 27.5 29.7 28.9 Example 2-9 STDEV 0 1.4 3.1 1.9 4.4 2.8 1.0 1.2

[0064] Further, the permeation amount (μg/cm.sup.2) by content of donepezil is shown in Table 12 and FIG. 2.

TABLE-US-00012 TABLE 12 Sample Time (hr) (content) 0 3 6 9 12 24 36 48 Preparation average 0 24.2 51.5 94.8 134.8 357.8 555.9 711.7 Example 2-5 STDEV 0 23.8 41.9 70.4 85.8 164.2 209.1 187.4 Preparation average 0 25.8 52.6 111.3 172.0 490.8 768.4 988.3 Example 2-6 STDEV 0 16.8 25.7 48.1 63.3 124.8 138.3 158.2 Preparation average 0 17.3 40.3 76.4 143.4 526.5 798.9 997.2 Example 2-7 STDEV 0 5.7 32.4 52.5 71.0 87.9 109.8 147.2 Preparation average 0 46.4 88.2 168.3 270.8 672.8 996.2 1277.4 Example 2-8 STDEV 0 5.1 40.0 35.0 68.7 30.9 29.0 43.2 Preparation average 0 32.7 43.3 188.5 264.8 659.3 1069.8 1389.4 Example 2-9 STDEV 0 4.2 18.6 17.0 53.3 68.4 34.8 56.6

Experimental Example 7: Observation of Related Substances Formation

[0065] In order to confirm the safety of the preparation for percutaneous absorption of Preparation Example 2-6, the contents of donepezil and a related substances thereof were quantified at a time point when 4 months after the production of the preparation had elapsed. As a result, the contents of donepezil and the related substances in the preparation for percutaneous absorption of Preparation Example 2-6 containing 54 mg of donepezil were measured as follows, and were confirmed to be included at reference amount levels.

TABLE-US-00013 TABLE 13 4 months passed at Item Reference Initial room temperature Donepezil 95 to 105% 103.4% 101.5% BDNPZ* NMT 0.2% ND ND DDIMP** NMT 0.2% ND ND N-oxide NMT 0.5% 0.08% 0.06% Individual related NMT 0.2% 0.04% 0.06% substances Total related NMT 1.2% 0.11% 0.13% substances *BDNPZ: N-dibenzyl-4-[(dimethoxyindanon)-2-methyl]piperidine chloride **DDIMP: 4-[(dimethoxyindanone)-2-methyl]piperidine