DONEPEZIL EUTECTIC MIXTURE AND USE THEREOF

Abstract

The present invention relates to a donepezil eutectic mixture and a use thereof. A eutectic mixture of the present invention allows increased solubility and skin permeability of donepezil, and a pharmaceutical composition including the same does not generate donepezil crystals and maintains amorphous form even when stored under various conditions, thereby being applicable to various formulations while also having excellent stability and efficacy.

Claims

1. A donepezil eutectic mixture comprising donepezil and coformer, wherein the coformer is dicarboxylic acid or vanilin.

2. The donepezil eutectic mixture of claim 1, wherein the dicarboxylic acid is at least one selected from the group consisting of adipic acid, malic acid, malonic acid, succinic acid, tartaric acid, azelaic acid, glutaric acid, itaconic acid, maleic acid, phthalic acid, pimelic acid, sebacic acid, suberic acid, and a-ketoglutaric acid.

3. The donepezil eutectic mixture of claim 1, wherein the donepezil and the coformer are included in a weight ratio of 100:1 to 1:4.

4. The donepezil eutectic mixture of claim 1, wherein the eutectic mixture is in a fluidized state at −70° C. to 250° C.

5. A pharmaceutical composition for prevention or treatment of Alzheimer's or dementia, the pharmaceutical composition comprising the eutectic mixture of claim 1.

6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is a transdermal preparation.

7. The pharmaceutical composition of claim 6, wherein the transdermal preparation is in a form of a patch or a film.

8. A method of manufacturing a donepezil eutectic mixture, the method comprising mixing donepezil and coformer, wherein the coformer is dicarboxylic acid or vanilin.

9. The method of claim 8, wherein the donepezil and the coformer are mixed in a weight ratio of 10:1 to 1:2.

10. A pharmaceutical composition for prevention or treatment of Alzheimer's or dementia, the pharmaceutical composition comprising the eutectic mixture of claim 2.

11. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is a transdermal preparation.

12. The pharmaceutical composition of claim 11, wherein the transdermal preparation is in a form of a patch or a film.

13. A pharmaceutical composition for prevention or treatment of Alzheimer's or dementia, the pharmaceutical composition comprising the eutectic mixture of claim 3.

14. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition is a transdermal preparation.

15. The pharmaceutical composition of claim 14, wherein the transdermal preparation is in a form of a patch or a film.

16. A pharmaceutical composition for prevention or treatment of Alzheimer's or dementia, the pharmaceutical composition comprising the eutectic mixture of claim 4.

17. The pharmaceutical composition of claim 16, wherein the pharmaceutical composition is a transdermal preparation.

18. The pharmaceutical composition of claim 17, wherein the transdermal preparation is in a form of a patch or a film.

Description

DESCRIPTION OF DRAWINGS

[0037] FIG. 1 shows transdermal preparations prepared including Comparative Example 1 and Example 4, respectively (left: patch of Comparative Example 3, right: patch of Example 23).

[0038] FIG. 2 shows a result of confirming that Examples 2 to 7 of the present invention each exhibit fluidity at room temperature via differential scanning calorimetry analysis.

[0039] FIG. 3 shows a result of confirming that Example 14 to 22 of the present invention each exhibit fluidity at room temperature via differential scanning calorimetry analysis.

[0040] FIG. 4 shows a result of observing the state change of a eutectic mixture of Example 4 according to temperature.

[0041] FIG. 5 shows a result of observing the state change of a eutectic mixture of Example 15 according to temperature.

[0042] FIG. 6 shows a result of measuring skin permeability (i.e., skin permeability depending on types of coformer) of eutectic mixtures of Examples 2 to 7 and Comparative 1.

[0043] FIG. 7 shows a result of measuring skin permeability (i.e., skin permeability depending on types of coformer) of eutectic mixtures of Examples 14 to 22 and Comparative 1.

[0044] FIG. 8 shows a result of measuring skin permeability (i.e., skin permeability depending on a ratio of donepezil to malonic acid) of eutectic mixtures of Examples 8 to 13 and Comparative 1.

[0045] FIG. 9 shows a result of measuring skin permeability of transdermal preparations prepared including Comparative Example 1 and Example 4, respectively (DNP raw patch: patch of Comparative Example 3, DNP-MA IL patch: patch of Example 23).

BEST MODES OF THE INVENTION

[0046] Hereinafter, the present invention will be described in detail by examples. However, the following examples are merely illustrative of the present invention, and the present invention is not limited by the following examples.

EXAMPLE 1

Manufacture of Eutectic Mixture of Donepezil-Malonic Acid (1:1)

[0047] 100 mg of Donepezil (from Perrigo) and 100 mg malonic acid were added to a mortar, and then pulverized and mixed using a pestle for 30 minutes, to thereby prepare a composition.

EXAMPLE 2

Manufacture of Eutectic Mixture of Donepezil-Adipic Acid (1:1)

[0048] 100 mg of donepezil (from Perrigo) and 100 mg of adipic acid were added to an ethanol (EtOH) solvent (1 ml) and stirred at 25° C. for about 30 minutes to thereby prepare a mixed solution in which donepezil and adipic acid were dissolved. The solution was dried in an oven at 60° C. for 24 hours to evaporate the solvent, to thereby obtain a eutectic mixture of donepezil-adipic acid (1:1).

EXAMPLE 3

Manufacture of Eutectic Mixture of Donepezil-Malic Acid (1:1)

[0049] 100 mg of donepezil (from Perrigo) and 100 mg of malic acid were added to an ethanol (EtOH) solvent (1 ml) and stirred at 25° C. for about 30 minutes to thereby prepare a mixed solution in which donepezil and malic acid were dissolved. The solution was dried in an oven at 60° C. for 24 hours to evaporate the solvent, to thereby obtain a eutectic mixture of donepezil-malic acid (1:1).

EXAMPLE 4

Manufacture of Eutectic Mixture of Donepezil-Malonic Acid (1:1)

[0050] 100 mg of donepezil (from Perrigo) and 100 mg of malonic acid were added to an ethanol (EtOH) solvent (1 ml) and stirred at 25° C. for about 30 minutes to thereby prepare a mixed solution in which donepezil and malonic acid were dissolved. The solution was dried in an oven at 60° C. for 24 hours to evaporate the solvent, to thereby obtain a eutectic mixture of donepezil-malonic acid (1:1).

EXAMPLE 5

Manufacture of Eutectic Mixture of Donepezil-Succinic Acid (1:1)

[0051] 100 mg of donepezil (from Perrigo) and 100 mg of succinic acid were added to an ethanol (EtOH) solvent (1 ml) and stirred at 25° C. for about 30 minutes to thereby prepare a mixed solution in which donepezil and succinic acid were dissolved. The solution was dried in an oven at 60° C. for 24 hours to evaporate the solvent, to thereby obtain a eutectic mixture of donepezil-succinic acid (1:1).

EXAMPLE 6

Manufacture of Eutectic Mixture of Donepezil-Tartaric Acid (1:1)

[0052] 100 mg of donepezil (from Perrigo) and 100 mg of tartaric acid were added to an ethanol (EtOH) solvent (1 ml) and stirred at 25° C. for about 30 minutes to thereby prepare a mixed solution in which donepezil and tartaric acid were dissolved. The solution was dried in an oven at 60° C. for 24 hours to evaporate the solvent, to thereby obtain a eutectic mixture of donepezil-tartaric acid (1:1).

EXAMPLE 7

Manufacture of Eutectic Mixture of Donepezil-Vanilin (1:1)

[0053] 100 mg of donepezil (from Perrigo) and 100 mg of vanilin were added to an ethanol (EtOH) solvent (1 ml) and stirred at 25° C. for about 30 minutes to thereby prepare a mixed solution in which donepezil and vanilin were dissolved. The solution was dried in an oven at 60° C. for 24 hours to evaporate the solvent, to thereby obtain a eutectic mixture of donepezil-vanilin (1:1).

EXAMPLES 8 to 13

Manufacture of Eutectic Mixture According to Donepezil-Malonic Acid Ratio

[0054] Donepezil and malonic acid were added to an ethanol (EtOH) solvent (1 ml) at each ratio shown in the following table and stirred at 25° C. for about 30 minutes to thereby prepare a mixed solution in which donepezil and malonic acid were dissolved.

[0055] The solution was dried in an oven at 60° C. for 24 hours to evaporate the solvent, to thereby obtain eutectic mixtures of Examples 8 to 13 in Table 1 below.

TABLE-US-00001 TABLE 1 Category Donepezil (mg) Malonic acid (mg) Example 8 100 109.6 Example 9 100 63.9 Example 10 100 41.0 Example 11 100 27.4 Example 12 100 8.3 Example 13 100 11.7

EXAMPLE 14

Manufacture of Eutectic Mixture of Donepezil (DNP)-Azelaic Acid

[0056] 100 mg of donepezil (from Perrigo) and 100 mg of azelaic acid were added to an ethanol (EtOH) solvent (1 ml) and stirred at 25° C. for about 30 minutes to thereby prepare a mixed solution in which donepezil and azelaic acid were dissolved. The solution was dried in an oven at 60° C. for 24 hours to evaporate the solvent, to thereby obtain a eutectic mixture of donepezil-azelaic acid (1:1).

EXAMPLE 15

Manufacture of Eutectic Mixture of Donepezil-2Lutaric Acid

[0057] 100 mg of donepezil (from Perrigo) and 100 mg of glutaric acid were added to an ethanol (EtOH) solvent (1 ml) and stirred at 25° C. for about 30 minutes to thereby prepare a mixed solution in which donepezil and glutaric acid were dissolved. The solution was dried in an oven at 60° C. for 24 hours to evaporate the solvent, to thereby obtain a eutectic mixture of donepezil-glutaric acid (1:1).

EXAMPLE 16

Manufacture of Eutectic Mixture of Donepezil-Itaconic Acid

[0058] 100 mg of donepezil (from Perrigo) and 100 mg of itaconic acid were added to an ethanol (EtOH) solvent (1 ml) and stirred at 25° C. for about 30 minutes to thereby prepare a mixed solution in which donepezil and itaconic acid were dissolved. The solution was dried in an oven at 60° C. for 24 hours to evaporate the solvent, to thereby obtain a eutectic mixture of donepezil-itaconic acid (1:1).

EXAMPLE 17

Manufacture of Eutectic Mixture of Donepezil-Maleic Acid

[0059] 100 mg of donepezil (from Perrigo) and 100 mg of maleic acid were added to an ethanol (EtOH) solvent (1 ml) and stirred at 25° C. for about 30 minutes to thereby prepare a mixed solution in which donepezil and maleic acid were dissolved. The solution was dried in an oven at 60° C. for 24 hours to evaporate the solvent, to thereby obtain a eutectic mixture of donepezil-maleic acid (1:1).

EXAMPLE 18

Manufacture of Eutectic Mixture of Donepezil-Phthalic Acid

[0060] 100 mg of donepezil (from Perrigo) and 100 mg of phthalic acid were added to an ethanol (EtOH) solvent (1 ml) and stirred at 25° C. for about 30 minutes to thereby prepare a mixed solution in which donepezil and phthalic acid were dissolved. The solution was dried in an oven at 60° C. for 24 hours to evaporate the solvent, to thereby obtain a eutectic mixture of donepezil-phthalic acid (1:1).

EXAMPLE 19

Manufacture of Eutectic Mixture of Donepezil-Pimelic Acid

[0061] 100 mg of donepezil (from Perrigo) and 100 mg of pimelic acid were added to an ethanol (EtOH) solvent (1 ml) and stirred at 25° C. for about 30 minutes to thereby prepare a mixed solution in which donepezil and pimelic acid were dissolved. The solution was dried in an oven at 60° C. for 24 hours to evaporate the solvent, to thereby obtain a eutectic mixture of donepezil-pimelic acid (1:1).

EXAMPLE 20

Manufacture of Eutectic Mixture of Donepezil-Sebacic Acid

[0062] 100 mg of donepezil (from Perrigo) and 100 mg of sebacic acid were added to an ethanol (EtOH) solvent (1 ml) and stirred at 25° C. for about 30 minutes to thereby prepare a mixed solution in which donepezil and sebacic acid were dissolved. The solution was dried in an oven at 60° C. for 24 hours to evaporate the solvent, to thereby obtain a eutectic mixture of donepezil-sebacic acid (1:1).

EXAMPLE 21

Manufacture of Eutectic Mixture of Donepezil-Suberic Acid

[0063] 100 mg of donepezil and 100 mg of suberic acid were added to an ethanol (EtOH) solvent (1 ml) and stirred at 25° C. for about 30 minutes to thereby prepare a mixed solution in which donepezil and suberic acid were dissolved. The solution was dried in an oven at 60° C. for 24 hours to evaporate the solvent, to thereby obtain a eutectic mixture of donepezil-suberic acid (1:1).

EXAMPLE 22

Manufacture of Eutectic Mixture of Donepezil-α-Ketoglutaric Acid

[0064] 100 mg of donepezil and 100 mg of a-ketoglutaric acid were added to an ethanol (EtOH) solvent (1 ml) and stirred at 25° C. for about 30 minutes to thereby prepare a mixed solution in which donepezil and a-ketoglutaric acid were dissolved. The solution was dried in an oven at 60° C. for 24 hours to evaporate the solvent, to thereby obtain a eutectic mixture of donepezil-a-ketoglutaric acid (1:1).

COMPARATIVE EXAMPLE 1

Donepezil Raw Material

[0065] A commercially available donepezil raw material was used as Comparative Example 1.

COMPARATIVE EXAMPLE 2

Donepezil Hydrochloride

[0066] A commercially available donepezil hydrochloride raw material was used as Comparative Example 2.

PREPARATION EXAMPLE 1

Manufacture of Transdermal Preparation

[0067] Comparative Example 3 and Example 23 were prepared as follows.

[0068] Example 23 was prepared by homogeneously mixing components (donepezil, malonic acid, polyisobutylene, butylhydroxytoluen, mineral oil, and hydrocabon resin (Regalite R1100)) according to their amounts shown in Table 2 below, and a patch of Comparative Example 3 was prepared by homogeneously mixing donepezil raw material, polyisobutylene, butylhydroxytoluen, mineral oil, and hydrocabon resin (Regalite R1100) using a mixer. The obtained mixture was left unattended for 6 hours to remove air bubbles, applied to a release liner in an appropriate amount, and then dried at 50° C. for 2 hours and 70° C. for 30 minutes. Afterwards, a backing membrane was adhered thereto to thereby prepare a transdermal preparation.

TABLE-US-00002 TABLE 2 Comparative Example 3 Example 23 Category Component % mg % mg Main component Donepezil 10.0 500 10.0 500 Coformer Malonic acid — — 10.0 500 Stabilizing Butylhydroxy- 0.3 15 0.3 15 agent toluene (BHT) Polymer Oppanol ™ B 22.5 1125 20.85 1042.5 100 (polyiso- butylene, PIB) Oppanol ™ B 15 22.5 1125 20.85 1042.5 Excipient Mineral oil 17.8 890 14.4 720 Tacktifier Regalite R1100 26.9 1345 23.6 1180 (Hydrocarbon Resin) Sum 100 5000 100 5000

[0069] As shown in FIG. 1, the patch of the comparative example using the donepezil raw material was non-uniformly adhered to the surface due to a large amount of air bubbles while showing a turbid color and non-uniform drug distribution, whereas the patch of Example 23 prepared using the donepezil eutectic mixture showed a transparent color and uniform drug distribution, indicating that the patch was well adsorbed on the surface.

[0070] The above result indicates that, compared to conventional patches, the transdermal preparation including the donepezil eutectic mixture of the present invention maintains the amorphous form of the drug while crystals are not generated over time, has excellent stability and maintains initial release characteristics, by maintaining the amorphous form, and increases drug delivery effect by being well adhered to the surface.

EXPERIMENTAL EXAMPLE 1

Differential Scanning Calorimetry Analysis

[0071] A differential scanning calorimeter (DSC auto Q2000, TA instrument, New castle, USA) was used to identify thermal behavior of samples. Specifically, 3 mg to 6 mg of all samples were accurately weighed and sealed in an aluminum pan. Measurements were made at a heating rate of 10° C./min and a nitrogen flow rate of 40 ml/min, and a temperature range was appropriately selected from -70° C. to 250° C. for each material.

[0072] As a result of the measurements, it was conformed that Examples 2 to 7 and Examples 14 to 22 each had a glass transition temperature (Tg) below room temperature, which means that they have fluidity in a paste state or a liquid state (Table 3 and FIGS. 2 and 3).

TABLE-US-00003 TABLE 3 Sample name Tg (° C.) Example 2 DNP-ADI −20.68 Example 3 DNP-MA −24.38 Example 4 DNP-ML −21.41 Example 5 DNP-SUC −21.41 Example 6 DNP-TAR −14.18 Example 7 DNP-VN 3.62 Example 14 DNP-Azelaic acid −22.77 Example 15 DNP-Glutaric acid −27.50 Example 16 DNP-Itaconic acid −20.51 Example 17 DNP-Maleic acid −18.23 Example 18 DNP-Phthalic acid −11.08 Example 19 DNP-Pimelic acid −29.34 Example 20 DNP-Sebacic acid −15.40 Example 21 DNP-Suberic acid −17.52 Example 22 DNP-α-ketoglutaric −12.94 acid

EXPERIMENTAL EXAMPLE 2

Checking of State Change According to Temperature

[0073] In order to check the state change according to temperature, observation was made using a hot state microscopy capable of controlling temperature of samples. The model used was an Axio scope (A1,Carl zeiss, Oberkochen, Germany) and was performed at magnification of 200 times using a microscope camera (Axio cam MRc, Carl zeiss,Oberkochen Germany). When temperature control is required, the temperature was controlled at a heating rate of 5° C./min.

[0074] Specifically, the state change of the eutectic mixture of Example 4 according to temperature was identified, and was measured at each temperature of 32° C. (a), 50° C. (b), 75° C. (c), 100° C. (d), 122.5° C. (e), and 140° C. (f).

[0075] As a result, as shown in FIG. 4, it was observed that, since 32° C. (a), the eutectic mixture had already been in a liquid state or in a paste state having fluidity, which means that there was no significant difference from the state at 94° C. to 99° C., which is the melting point of donepezil, and at 135° C. to 140° C., which is the melting point of malonic acid.

[0076] This implies that the eutectic mixture of the present invention may prevent deformation of an active ingredient of drugs by obtaining a liquid property for improving drug absorption even when a high temperature is applied to donepezil or an organic solvent is not added.

[0077] Also, the state change of the eutectic mixture of Example 15 according to temperature was identified, and was observed at each temperature of 25° C. (a), 50° C. (b), 70° C. (c), 90° C. (d), 100° C. (e), and 110° C. (f).

[0078] As a result, as shown in FIG. 5, it was confirmed that, since 25° C. (a), the eutectic mixture had already been in a liquid state or in a paste state having fluidity, which means that there was no significant difference from the state at 94° C. to 99° C., which is the melting point of donepezil, and at 95° C. to 98° C., which is the melting point of glutaric acid.

[0079] This means that the eutectic mixture including donepezil and coformer of the present invention may obtain a liquid property for improving drug absorption even when a high temperature is applied or an organic solvent is not added, and implies that crystal precipitation of a main component may be prevented when transdermal patches are prepared.

EXPERIMENTAL EXAMPLE 3

Solubility Test

[0080] A solubility test was performed on the donepezil eutectic mixtures obtained in Examples 2 to 7 and Examples 14 to 22 and Comparative Example (donepezil raw material). Specifically, 100 mg of a sample corresponding to 50 mg of donepezil (50 mg of the donepezil raw material) was added to 0.5 ml of distilled water (at a concentration of 100 mg/mL) and stirred at a rate of 50 rpm at room temperature for 24 hours using a rotator (CRT-350, Lab companion). An additional 100 mg of a sample was added to a sample which was checked every 2 hours and was already transparently dissolved. In the case of melting greater than or equal to 1:1, the experiment was no longer conducted.

[0081] Solubility results were classified according to the solubility reference table of the following U.S. Pharmacopoeia.

TABLE-US-00004 TABLE 4 Solubility criteria Description (Parts of solvent required for one part of solute) Very soluble   <1 Freely soluble 1-10 Soluble 10-30  Sparingly soluble 30-100 Slightly soluble 100-1000 Very slightly soluble 1000-10000 Insoluble >10000

[0082] The solubility test results according to the solubility reference table of the U.S.

[0083] Pharmacopoeia are shown in Table 5 below.

TABLE-US-00005 TABLE 5 Solubility at room temperature U.S. Pharmacopeia Category Sample name mg/mL reference Comparative DNP 0.07 (74.55 Insoluble Example 1 μg/mL) Comparative DNP-HCl 29.86 Sparingly soluble Example 2 Example 2 DNP-ADI 137.11 Freely soluble Example 3 DNP-MA Very soluble Example 4 DNP-ML Very soluble Example 5 DNP-SUC 276.81 Freely soluble Example 6 DNP-TAR Very soluble Example 7 DNP-VN 4.40 Slightly soluble Example 14 DNP-Azelaic acid 7.01 Slightly soluble Example 15 DNP-Glutaric acid 90.38 Soluble Example 16 DNP-Itaconic acid Very soluble Example 17 DNP-Maleic acid Very soluble Example 18 DNP-Phthalic acid 3.64 Slightly soluble Example 19 DNP-Pimelic acid Very soluble Example 20 DNP-Sebacic acid 9.93 Slightly soluble Example 21 DNP-Suberic acid 20.79 Sparingly soluble Example 22 DNP-α-ketoglutaric Very soluble acid

[0084] As shown in Table 5, the donepezil raw material (solubility: 74.55 μg/mL) of Comparative Example 1 was found to be insoluble, whereas Examples 2 to 7 were found to have higher solubility than that of Comparative Example 1 by a factor of at least 60. Meanwhile, Examples 14 to 22 were found to have higher solubility than that of Comparative Example 1 by a factor of at least 50.

[0085] Particularly, Examples 2 to 6 were found to have superior solubility to that of donepezil hydrochloride of Comparative Example 2, which is a component of commercially available products. It was confirmed that Examples 3, 4, and 6 among them had solubility of at least 1 /mL and corresponded to “Very soluble” (Korean Pharmacopoeia) or “Very soluble” (USP).

EXPERIMENTAL EXAMPLE 4

Skin Permeability Measurement

[0086] 4-1. Skin Permeability Measurement According to Types of Coformer

[0087] A skin permeability test was performed on the eutectic mixtures of Examples 2 to 7 and Comparative Example 1 (donepezil raw material) respectively synthesized by different types of coformer. Specifically, each eutectic mixture was applied to a release liner of 1×1 cm in an appropriate amount and then adhered to an artificial skin, which was then fixed to a Franz cell using a clamp. In the case of using a transdermal preparation, it was cut into a size of 1×1 cm and then used by being adhered to a skin. Isotonic phosphate buffer (pH 7.4) was added to a receptor, maintained at 32.5° C., and then stirred at 300 rpm using a magnetic stirrer, 1 ml of a sample was collected at 0, 2, 4, 8, 12, and 24 hours (collection was made at 0, 2, 6, 12, 24, 48, 72, 96, 120, 144, and 168 hours in case of a test of skin permeability of a patch), and isotonic phosphate buffer was added again thereto. The obtained sample was quantified using high-speed liquid chromatography and an ultraviolet absorption spectrophotometer under the following analysis condition. The analysis condition is as follows.

[0088] <Analysis Condition>

[0089] Column: Phenomenex, 250*4.6*5, C18 column

[0090] Mobile phase: 0.1M PBS pH 2.7 solution:Acetonitrile:Methanol=50:20:30

[0091] Temperature: 25° C.

[0092] Amount of sample injected: 20 μL

[0093] UV absorption wavelength: 268 nm

[0094] Analysis time period: 7 minutes

[0095] As a result, as shown in FIG. 6, Comparative Example 1 showed little skin permeability over 24 hours, whereas the eutectic mixtures of Examples 2 to 7 showed higher skin permeability than that of Comparative Example 1 by a factor of at least 8 after 24 hours.

[0096] Particularly, Example 4 showed a skin permeability of 1,509 μg/cm2 in 12 hours, which is higher than that of Comparative Example 1 by a factor of about at least 14 in that same time.

[0097] Also, as shown in FIG. 7, Comparative Example 1 showed little skin permeability over 24 hours, whereas the eutectic mixtures of Examples 14 to 22 showed improved skin permeability compared to that of Comparative Example 1.

[0098] Particularly, Example 15 showed a skin permeability of 1,475 μg/cm2 for 24 hours, which is higher than that of Comparative Example 1 by a factor of about at least 8 in that same time.

[0099] The above results indicate that the eutectic mixture of the present invention exhibits excellent skin permeability, indicating that a transdermal drug administration, which is not applicable in Comparative Example 1, may be applied to the eutectic mixture of the present invention.

[0100] 4-2. Measurement of Skin Permeability of Eutectic Mixtures with different Ratios of Donepezil to Malonic Acid

[0101] Skin permeability was measured with respect to the eutectic mixtures respectively prepared in Examples 8 to 13 and Comparative Example 1 (donepezil raw material). A specific skin permeability test was performed in the same manner as in the method described in 4-1.

[0102] As a result, as shown in FIG. 8, it was confirmed that even when a proportion of malonic acid varied, all groups of Examples 8 to 13 showed superior skin permeability to that of Comparative Example 1. Particularly, it was confirmed that as the proportion of malonic acid increased, skin permeability increased.

[0103] Skin permeability of the “transdermal preparation of Comparative Example 3” and the “transdermal preparation of Example 23”, which were prepared via Preparation Example 1, was measured. A specific skin permeability test was performed in the same manner as in the method described in 4-1.

[0104] As a result, as shown in FIG. 9, it was confirmed that skin permeability of the transdermal preparation of Example 23 including the eutectic mixture was higher than that of the transdermal preparation of Comparative Example 3 by a factor of about at least 6, and it was confirmed that excellent skin permeability may be exhibited even when the eutectic mixture is applied to a transdermal preparation in a patch formulation.

[0105] The above description of the present invention is provided for the purpose of illustration, and it would be understood by those skilled in the art that various changes may be made without changing technical spirit and essential features of the present invention.

[0106] Therefore, it should be understood that the embodiments described above are illustrative and non-limiting in all respects. For example, each component described as a single type may be implemented in a distributed manner, and similarly, components described as being distributed may also be implemented in a combined form.

[0107] The scope of the present invention is defined by the following claims, and it shall be understood that all modifications or modified embodiments conceived from the meaning and scope of the claims and their equivalents are included in the scope of the present invention.