WO2025110663A1 - Percutaneous absorption preparation containing donepezil - Google Patents

Abstract

Disclosed is a percutaneous absorption preparation containing donepezil that is a pharmacologically active substance useful in treating Alzheimer's dementia symptoms. This percutaneous absorption preparation suppresses donepezil drug crystallization in the percutaneous absorption preparation even when left at room temperature for a long period of time, can improve a percutaneous permeability degree (cumulative permeation amount and skin permeation rate) of the drug, and in particular, can significantly increase the drug absorption of donepezil despite of a small drug loading amount compared to the currently commercially available Donerion patch.

Description

Transdermal preparation containing donepezil

The present invention relates to a transdermal absorption preparation containing donepezil, and more specifically, to a transdermal absorption preparation capable of suppressing donepezil drug crystallization within the transdermal absorption preparation and improving the transdermal permeation rate (cumulative permeation amount and skin permeation rate) of the drug even when stored at room temperature for a long period of time.

Alzheimer's disease has an unclear cause and no fundamental treatment, so it cannot be completely prevented or treated. Therefore, it has been known that early diagnosis and management to slow its progression are most important.

Most of the Alzheimer's disease treatment drugs are acetylcholinesterase inhibitors, which are enzymes that break down acetylcholine, and include donepezil (Aricept ^TM ), rivastigmine (Exelon ^TM ), and galantamine (Reminyl ^TM ).

Among these, donepezil is the most commonly prescribed ingredient among Alzheimer's disease treatments, and is known to help improve cognitive function by ensuring that acetylcholine, a neurotransmitter that plays an important role in memory and cognitive function in the brain, is maintained normally.

Donepezil is currently the longest-standing treatment for Alzheimer's disease approved by the U.S. Food and Drug Administration (FDA) and is widely prescribed for patients with mild to moderate and severe dementia. According to Ubist, a pharmaceutical market research firm, out of the approximately KRW 290 billion in domestic sales of Alzheimer's disease treatments in 2020, the donepezil component accounts for approximately KRW 230 billion, or 80% of the market size.

Up until now, donepezil has been commercialized only for oral use due to the difficulty in developing a formulation. The currently used donepezil preparation is in tablet form, and is prescribed to Alzheimer's dementia patients through oral administration. However, it is impossible for the oral donepezil preparation to avoid the first pass through the liver, and side effects in the digestive tract have been reported. In addition, when dementia symptoms have significantly progressed, it may be difficult to take it orally. In addition, because tablets have a limitation in dosage, and dementia patients tend to forget to take the medication, a transdermal patch form has been suggested.

In this regard, Korean Patent Publication No. 10-2005-0037405 discloses a transdermal absorption preparation using a synthetic rubber-based polymer of the styrene-isoprene-styrene (SIS) and/or polyisobutylene (PIB) series. However, since the skin permeation rate of donepezil is relatively low, the surface area is manufactured to be larger than necessary to overcome this, and thus, when applying the transdermal absorption preparation to a patient for 1 to 2 days at a time, patient compliance may decrease.

In addition, International Patent Publication No. 2011/049038 discloses a transdermal absorption preparation made by dissolving donepezil, an active ingredient, in an adhesive containing a styrene-isoprene-styrene block copolymer, hydrogenated rosin glycerin ester, liquid paraffin, and an absorption accelerator. However, the transdermal absorption preparation disclosed in International Patent Publication No. 2011/049038 has a problem of unsatisfactory skin irritation, that is, moderate skin irritation. In addition, in order to treat dementia, a chronic disease, the transdermal absorption preparation must be attached to the skin for a long period of time, but there is a problem that moderate skin irritation significantly reduces patient compliance, making it difficult to expect an effective therapeutic effect. In addition, in order to minimize skin irritation, if an irritating substance such as an absorption accelerator is not used, there is a problem that skin permeability decreases rapidly.

Due to these problems, not only global pharmaceutical companies but also domestic pharmaceutical companies are unable to achieve specific results with patches.

[Prior art literature]

[Patent Document]

(Patent Document 1) Korean Publication No. 10-2005-0037405

(Patent Document 2) International Publication No. 2011/049038

The purpose of the present invention is to solve the above problems, and to provide a transdermal absorption preparation containing donepezil which can suppress donepezil drug crystallization in the transdermal absorption preparation and improve the transdermal permeation rate (cumulative permeation amount and skin permeation rate) of the drug even when left at room temperature for a long period of time.

In order to solve the above problem, the present invention discloses the following means.

In one aspect, the present invention discloses a transdermal absorption preparation comprising a drug-containing adhesive layer comprising donepezil or a pharmaceutically acceptable salt thereof as an active ingredient and polyoxyethylene(2) lauryl ether as a transdermal absorption promoter; a support layer; and a peeling layer.

According to the present invention, a transdermal absorption preparation containing donepezil can be provided, which can suppress the drug crystallization phenomenon in the transdermal absorption preparation even when left at room temperature for a long period of time, and improve the transdermal permeation rate (cumulative permeation amount and skin permeation rate) of the drug.

In particular, in the case of the transdermal absorption preparation according to the present invention, although the drug loading amount is significantly lower than that of the currently commercially available Donepezil patch (manufacturer: Celltrion), there is an advantage in that the drug absorption of donepezil in the blood is significantly higher in terms of AUC _(0-72) and C _max .

The effects of the present invention are not limited to the effects mentioned above, and various effects may be included within a range obvious to those skilled in the art from the contents described below.

Figure 1 is an image for confirming the phenomenon of inhibition of donepezil drug crystal formation in a transdermal absorption preparation due to the addition of lactic acid.

Figure 2 is a diagram showing the percutaneous permeation rate in a prescription with added lactic acid to explain the background in Experimental Example 1.

Figure 3 is a graph showing the cumulative permeation amount of donepezil from the transdermal absorption preparations of S-21, S-22, S-24, S-25, and S-26 according to Experimental Example 2.

Figure 4 shows the group composition and administration dose according to Experimental Example 3.

Figure 5 shows the blood drug concentration of donepezil of the patch of Example 2 of the present invention according to Experimental Example 3 and the commercially available Donepezil patch (manufacturer: Celltrion).

Hereinafter, the present specification will be described in more detail.

This is explained specifically as follows. The terms used in this specification are selected from the most widely used general terms possible while considering the functions in the present invention, but this may vary depending on the intention of engineers engaged in the relevant field, precedents, the emergence of new technologies, etc. In addition, in certain cases, there are terms arbitrarily selected by the applicant, and in this case, the meanings thereof will be described in detail in the description of the relevant invention. Therefore, the terms used in the present invention should be defined based on the meanings of the terms and the overall contents of the present invention, rather than simply the names of the terms.

Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Terms defined in commonly used dictionaries, such as those defined in common usage, should be interpreted as having a meaning consistent with the meaning they have in the context of the relevant art, and will not be interpreted in an idealized or overly formal sense unless expressly defined in this application.

The numerical ranges are inclusive of the numbers defined in the above ranges. Every maximum numerical limitation given throughout this specification will include every lower numerical limitation, as if that lower numerical limitation were expressly written out. Every minimum numerical limitation given throughout this specification will include every higher numerical limitation, as if that higher numerical limitation were expressly written out. Every numerical limitation given throughout this specification will include every better numerical range within that broader numerical range, as if that narrower numerical limitation were expressly written out.

Hereinafter, each description and embodiment disclosed in the present invention can be applied to other descriptions and embodiments for each. That is, all combinations of various elements disclosed in the present invention fall within the scope of the present invention. In addition, the scope of the present invention cannot be considered limited by the specific description described below.

Expressions such as “comprising” as used herein should be understood as open-ended terms implying the possibility of including other embodiments.

In order to solve the above problems, the inventors of the present invention confirmed that when donepezil is formulated in the form of a transdermal absorption preparation, a drug crystal phenomenon occurs, which reduces the adhesiveness of the patch and lowers the drug absorption rate.

Accordingly, it was confirmed that when lactic acid was added to the donepezil transdermal absorption preparation, donepezil crystals were not formed even when stored for a long period of time. However, although the crystals could be suppressed, there was a problem that the desired level of transdermal absorption (absorption rate) was not achieved, and in order to solve this, the degree of transdermal permeation of donepezil was confirmed according to the content of polyoxyethylene (2) lauryl ether as a transdermal absorption accelerator, polyvinyl pyrrolidone as a thickener, and acrylic adhesive, and it was confirmed that the transdermal absorption of donepezil could be increased through the correlation among these.

Accordingly, the inventors of the present invention confirmed that a transdermal absorption preparation in the form of a patch can be manufactured that can increase the concentration of donepezil in the blood despite a small drug loading amount by adopting polyoxyethylene (2) lauryl ether, which is a transdermal absorption accelerator, in the donepezil transdermal absorption preparation, thereby completing the present invention.

Hereinafter, the present invention will be described in detail.

Unless otherwise specified herein, the term weight % means the mass ratio of a particular component to the entire drug-containing adhesive layer into which it is incorporated.

Transdermal preparation containing donepezil

In order to solve the above problem, the present invention discloses the following means.

In one aspect, the present invention discloses a transdermal absorption preparation comprising a drug-containing adhesive layer comprising donepezil or a pharmaceutically acceptable salt thereof as an active ingredient and polyoxyethylene(2) lauryl ether as a transdermal absorption promoter; a support layer; and a peeling layer.

In the present invention, the transdermal absorption preparation comprises a drug-containing adhesive layer as one layer (1 layer), and thus has the effect of simplifying the production process and reducing costs compared to a transdermal absorption preparation comprising two layers (2 layers) in which a separate adhesive layer exists in addition to the drug-containing adhesive layer.

In the present invention, the term "pharmaceutically acceptable salt" includes a salt derived from a pharmaceutically acceptable inorganic acid, organic acid, or base. The term "hydrate" means a compound of the present invention or a pharmaceutically acceptable salt thereof containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. Specifically, the pharmaceutically acceptable salt of donepezil may be donepezil hydrochloride, and the active ingredient in the present invention means donepezil itself.

In the present invention, the content of donepezil or a pharmaceutically acceptable salt thereof may be 10.0 to 20.0 wt% based on the total weight of the entire drug-containing adhesive layer, specifically 13.0 to 18.0 wt%, but is not limited thereto.

In the present invention, the drug-containing adhesive layer includes an adhesive, and the term "adhesive" means something that can perform the function of attaching a transdermal absorption agent to the skin and serving as a carrier for donepezil or a pharmaceutically acceptable salt thereof. At this time, the drug-containing adhesive layer includes an acrylate-based polymer without a functional group, and the content of the adhesive may be 40.0 to 70.0 wt% based on the total weight of the entire drug-containing adhesive layer, and specifically, may be 50.0 to 60.0 wt%, but is not limited thereto.

At this time, the term "functional group" means a common atomic group that is the cause of the properties of acrylate polymers with the same chemical properties, for example, an OH group, a COOH group, etc.

In the present invention, the functional group-free acrylate polymer that can be used as an adhesive may be DURO-TAK 87-4098 (Acrylate copolymer) obtained through the synthesis of a vinyl acetate monomer and an acrylic monomer, or DURO-TAK 87-9301 and GELVA GMS 3083 obtained through the synthesis of an acrylic monomer.

In the present invention, the drug-containing adhesive layer contains polyoxyethylene (2) lauryl ether, which is a percutaneous absorption promoter, and although the formation of donepezil drug crystals in the percutaneous absorption preparation can be suppressed when lactic acid is added, there is a problem that the desired level of percutaneous permeation cannot be secured. At this time, when an appropriate amount of polyoxyethylene (2) lauryl ether is included among various percutaneous absorption promoters, the formation of donepezil drug crystals in the percutaneous absorption preparation can be suppressed while maintaining the desired level, that is, compared to the currently commercially available Donerion Patch (manufacturer: Celltrion), despite the smaller drug loading amount, there is an advantage of significantly higher drug absorption of donepezil when considering the AUC _(0-72) and C _max values, so there is an advantage of being able to secure a significant percutaneous permeation rate compared to the percutaneous absorption rate of the Donerion Patch (manufacturer: Celltrion).

Specifically, the currently commercially available Donerion patch contains 87.5 mg of donepezil per 25 ^cm2 , is known to be administered by attaching it twice a week (alternating every 3 and 4 days) before bedtime, and contains glyceryl monooleate as an additive (percutaneous absorption enhancer). However, in the case of the percutaneous absorption preparation according to the present invention, the drug loading amount is 26.67 mg per 25 ^cm2 , which contains significantly less drug than the Donerion patch (this will be described in detail below), and one sheet is administered once a day.

However, the inventors of the present invention conducted research and development to significantly increase the drug absorption of donepezil even if the drug loading amount compared to the donepezil patch is significantly reduced, and adopted polyoxyethylene (2) lauryl ether, which was introduced to solve the problem of lactic acid, and confirmed through animal testing that the drug absorption of donepezil can be significantly increased compared to the commercially available donepezil patch. Therefore, it can be seen that the efficacy and effects are superior among the existing donepezil patches.

In the present invention, the content of the percutaneous absorption accelerator may be 10.0 to 30.0 wt% based on the total weight of the drug-containing adhesive layer, specifically 15.0 to 25.0 wt%, and more specifically 19.0 to 23.0 wt%, but is not limited thereto. If the content of the percutaneous absorption accelerator is less than 19.0 wt% based on the total weight of the drug-containing adhesive layer, there is a problem that the drug is not well permeated, and if it exceeds 23.0 wt%, there is a problem that the stabilization of the drug in the percutaneous absorption preparation is increased, thereby lowering the permeation rate.

In the present invention, the drug-containing adhesive layer may further include a crystal inhibitor, but is not limited thereto.

In the present invention, the decision inhibitor may be lactic acid, but is not limited thereto.

In the present invention, the drug-containing adhesive layer, which is a component of the transdermal absorption preparation, contains lactic acid, which is a crystal inhibitor, in addition to the active ingredient, donepezil or a pharmaceutically acceptable salt thereof. When lactic acid is included, there is an advantage in that it can suppress the crystallization of donepezil in the transdermal absorption preparation even when left at room temperature for a long period of time.

In the present invention, the content of lactic acid, which is the crystal inhibitor, may be 3.0 to 4.5 wt% based on the total weight of the entire drug-containing adhesive layer, specifically, 3.5 to 4.0 wt%, but is not limited thereto.

In the present invention, the support layer may be one selected from the group consisting of a polyester film, a polyethylene (PE) film, a polypropylene (PP) film, an ethylene vinyl acetate (EVA) film, a nylon film, a urethane film, a nonwoven fabric/PET composite, a PET/PE composite, and a PET/EVA composite, but is not limited thereto.

In the present invention, the release layer is silicone-treated, and may be specifically one selected from the group consisting of a polyethylene terephthalate (PET) film, a polyvinyl chloride film, a polyvinylidene chloride film, a polyethylene terephthalate (PET) film, a polyethylene (PE) film, a polyethylene/paper composite, a PET/PE composite, and a PET/EVA composite, but is not limited thereto.

In the present invention, the portion of the peeling layer that comes into direct contact with the drug layer must be thinly coated on a polyethylene terephthalate (PET) film or the like to ensure that the drug layer is easily peeled off. Therefore, it is preferable to use a silicone-treated film for the surface of the peeling layer.

In the present invention, the transdermal absorption agent may be a patch, but is not limited thereto.

In the present invention, the loading dose of donepezil or a pharmaceutically acceptable salt thereof in one sheet of a transdermal absorption preparation may vary depending on the size of the transdermal absorption preparation. Specifically, when the sizes of the transdermal absorption preparation are 5 cm ² , 10 cm ² , 20 cm ² , 30 cm ² , and 40 cm ² , the loading dose of donepezil or a pharmaceutically acceptable salt thereof is 6.668 mg, 13.335 mg, 26.67 mg, 40.00 mg, and 53.34 mg, respectively.

In the present invention, the administration method of the transdermal absorption agent may be to administer donepezil to a patient with Alzheimer's dementia symptoms by attaching one sheet per day, but is not limited thereto.

Hereinafter, the present invention will be described in detail based on examples and comparative examples. However, the following examples and comparative examples are only intended to illustrate the present invention, and the scope of the present invention is not limited thereto.

Examples and Comparative Examples

Examples 1 to 4 and Comparative Examples 1 to 2. Preparation of transdermal absorption preparation (patch) containing donepezil

Example 1.

A transdermal absorption preparation (patch) containing donepezil according to Example 1 was manufactured in the order described below based on the prescription described in Table 1 below.

Manufacturing method

1. Prepare solution 1 by mixing ethanol and ethyl acetate.

2. Dissolve hydroxypropyl cellulose (product name: HPC A) in the above solution 1 to prepare solution 2.

3. Prepare solution 3 by dissolving polyoxyethylene(2) lauryl ether (product name: MONOPOL LAE2 BL-2), lactic acid (product name: Lactic acid), and butylated hydroxytoluene (product name: BHT (Butylated Hydroxytoluene)) in the above solution 2.

4. Add donepezil to the above solution 3 and dissolve it to prepare solution 4.

5. Add acrylic adhesive (product name: Duro-tak 87-9301) to the above solution 4 and mix evenly to prepare solution 5.

6. Apply/dry/laminate the above 5 solutions according to the following conditions to produce a patch (patch size: 20 cm ² ).

① Application/Drying: Apply solution 5 evenly to a polyethylene terephthalate film (PET film, manufacturer: Kisung Industry), which is the release layer (also called the covering layer), with a thickness of approximately 185 to 195 um and dry in a 90℃ chamber for 2 minutes and 30 seconds to produce a drug-containing adhesive layer.

② Lamination: Afterwards, a polyester film (PE film, tentative name, manufacturer: 3M) is laminated on top of the drug-containing adhesive layer applied, pressed using a pressing roller, and then cut to produce a patch.

Example 1 Prescription

Mixing purpose Ingredient name Original dosage
(mg/1 Patch) After drying
(Unit: mg) After drying
weight% Active ingredient Donepezil 26.67 26.67 16.07 adhesive Acrylic adhesive
(Duration 87-9301) 266.67 97.33 58.64 Decision inhibitor Lactic acid 6.33 6.33 3.81 Transdermal absorption enhancer Polyoxyethylene(2) lauryl ether
(Product name: MONOPOL LAE2) 35.25 35.25 21.24 Thickener Hydroxypropyl cellulose
(Product name: HPC A) 0.33 0.33 0.20 Antioxidant Butylated hydroxytoluene 0.07 0.07 0.04 menstruum Ethyl acetate 13.33 0.00 0.00 menstruum Ethanol 26.67 0.00 0.00 total 375.31 165.98 100.00

Example 2.

A transdermal absorption preparation (patch) containing donepezil according to Example 2 was prepared using the method described in Example 1 based on the prescription described in Table 2 below.

Example 2 Prescription

Mixing purpose Ingredient name Original dosage
(mg/1 Patch) After drying
(Unit: mg) After drying
weight% Active ingredient Donepezil 26.67 26.67 16.07 adhesive Acrylic adhesive
(Duration 87-9301) 266.67 97.33 58.64 Decision inhibitor Lactic acid 6.33 6.33 3.81 Transdermal absorption enhancer Polyoxyethylene(2) lauryl ether
(Product name: MONOPOL LAE2) 35.25 35.25 21.24 Thickener Hydroxypropyl cellulose
(Product name: HPC B) 0.33 0.33 0.20 Antioxidant Butylated hydroxytoluene 0.07 0.07 0.04 menstruum Ethyl acetate 13.33 0.00 0.00 menstruum Ethanol 26.67 0.00 0.00 total 375.31 165.98 100.00

Example 3.

A transdermal absorption preparation (patch) containing donepezil was manufactured in the following order based on the prescription described in Table 3 below.

Manufacturing method

1. Prepare solution 1 by mixing ethanol and ethyl acetate.

2. Dissolve hydroxypropyl cellulose (product name: HPC A) in the above solution 1 to prepare solution 2.

3. Prepare solution 3 by dissolving polyoxyethylene (2) lauryl ether (product name: MONOPOL LAE2), lactic acid (product name: Lactic acid), and butylated hydroxytoluene (product name: BHT (Butylated Hydroxytoluene)) in the above solution 2.

4. Add donepezil to the above solution 3 and dissolve it to prepare solution 4.

5. Add acrylic adhesive (product name: Duro-tak 87-9301) to the above solution 4 and mix evenly to prepare solution 5.

6. Apply/dry/laminate the above 5 solutions according to the following conditions to produce a patch (patch size: 30 cm ² ).

① Application/Drying: Apply solution 5 evenly to a polyethylene terephthalate film (PET film, manufacturer: Kisung Industry), which is the release layer (also called the covering layer), with a thickness of approximately 185 to 195 um and dry in a 90℃ chamber for 2 minutes and 30 seconds to produce a drug-containing adhesive layer.

② Lamination: Afterwards, a polyester film (PE film, tentative name, manufacturer: 3M) is laminated on top of the drug-containing adhesive layer applied, pressed using a pressing roller, and then cut to produce a patch.

Example 3 Prescription

Mixing purpose Ingredient name Original dosage
(mg/1 Patch) After drying
(Unit: mg) After drying
weight% Active ingredient Donepezil 40.00 40.00 16.07 adhesive Acrylic adhesive
(Duration 87-9301) 400.00 146.00 58.64 Decision inhibitor Lactic acid 9.49 9.49 3.81 Transdermal absorption enhancer Polyoxyethylene(2) lauryl ether
(Product name: MONOPOL LAE2) 52.88 52.88 21.24 Thickener Hydroxypropyl cellulose
(Product name: HPC A) 0.50 0.50 0.20 Antioxidant Butylated hydroxytoluene 0.10 0.10 0.04 menstruum Ethyl acetate 20.00 0.00 0.00 menstruum Ethanol 40.00 0.00 0.00 total 562.97 248.97 100.00

Example 4.

A transdermal absorption preparation (patch) containing donepezil according to Example 4 was prepared using the method described in Example 3 based on the prescription described in Table 4 below.

Example 4 Prescription

Mixing purpose Ingredient name Original dosage
(mg/1 Patch) After drying
(Unit: mg) After drying
weight% Active ingredient Donepezil 40.00 40.00 16.07 adhesive Acrylic adhesive
(Duration 87-9301) 400.00 146.00 58.64 Decision inhibitor Lactic acid 9.49 9.49 3.81 Transdermal absorption enhancer Polyoxyethylene(2) lauryl ether
(Product name: MONOPOL LAE2 52.88 52.88 21.24 Thickener Hydroxypropyl cellulose
(Product name: HPC B) 0.50 0.50 0.20 Antioxidant Butylated hydroxytoluene 0.10 0.10 0.04 menstruum Ethyl acetate 20.00 0.00 0.00 menstruum Ethanol 40.00 0.00 0.00 total 562.97 248.97 100.00

Comparative example 1.

A transdermal absorption preparation (patch) containing donepezil according to Comparative Example 1 was manufactured using the method described in Example 1 based on the prescription described in Table 5 below.

Comparative Example 1 Prescription

Mixing purpose Ingredient name Original dosage
(mg/1 Patch) After drying
(Unit: mg) After drying
weight% Active ingredient Donepezil 26.67 26.67 17.26 adhesive Acrylic adhesive
(Duration 87-9301) 266.67 97.333 62.98 Decision inhibitor Lactic acid 6.33 6.33 4.10 Transdermal absorption enhancer Polyoxyethylene(2) lauryl ether
(Product name: MONOPOL LAE2) 23.33 23.33 15.10 Thickener Hydroxypropyl cellulose
(Product name: HPC F) 0.67 0.67 0.43 Antioxidant Butylated hydroxytoluene 0.20 0.20 0.13 menstruum Ethyl acetate 13.33 0.00 0.00 menstruum Ethanol 26.67 0.00 0.00 total 363.86 154.53 100.00

Comparative example 2.

A transdermal absorption preparation (patch) containing donepezil according to Comparative Example 2 was manufactured using the method described in Example 3 based on the prescription described in Table 6 below.

Comparative Example 2 Prescription

Mixing purpose Ingredient name Original dosage
(mg/1 Patch) After drying
(Unit: mg) After drying
weight% Active ingredient Donepezil 40.00 40.00 17.26 adhesive Acrylic adhesive
(Duration 87-9301) 400.00 146.00 62.99 Decision inhibitor Lactic acid 9.49 9.49 4.09 Transdermal absorption enhancer Polyoxyethylene(2) lauryl ether
(Product name: MONOPOL LAE2) 35.00 35.00 15.10 Thickener Hydroxypropyl cellulose
(Product name: HPC F) 1.00 1.00 0.43 Antioxidant Butylated hydroxytoluene 0.30 0.30 0.13 menstruum Ethyl acetate 20.00 0.00 0.00 menstruum Ethanol 40.00 0.00 0.00 total 545.79 231.79 100.00

Hereinafter, the present invention will be described in detail based on experimental examples. However, the following experimental examples are only intended to illustrate the present invention, and the scope of the present invention is not limited thereto.

Experimental example

Experimental Example 1. Confirmation of the phenomenon of inhibition of donepezil drug crystals in transdermal absorption preparations by addition of lactic acid

1. Experimental method

In the case of donepezil, when formulated as a patch, drug crystallization occurs, and as crystals are formed, the adhesiveness of the transdermal absorption agent decreases, and there is a problem that the drug absorption rate decreases. Accordingly, it was confirmed whether drug crystallization can be suppressed by using lactic acid.

Specifically, Table 7 below is a prescription for confirming the effect according to the addition of lactic acid. A transdermal absorption preparation sample was manufactured according to the prescription below, and after 5 months at room temperature (20 to 25°C), the surface of the drug-containing adhesive layer included in the transdermal absorption preparation sample was compared and evaluated by visual observation and an optical microscope (OLYMPUS-CX41, x100 (100x magnification), x200 (200x magnification)). The results are shown in Fig. 1.

Raw material name No lactic acid added
1 sheet (mg/1 Patch) Added lactic acid
1 sheet (mg/1 Patch) Donepezil 30.00 30.00 Acrylic adhesive
(Product name: Duro-tak 87-9301) 314.00 314.00 Laroglycol 90 30.00 30.00 Lactic acid - 7.12
(Amount equivalent to 1 equivalent of donepezil) Butylated hydroxytoluene 0.1 0.1 Ethyl acetate 60.00 60.00

B. Experimental results

Referring to Figure 1, in the case of a sample of a transdermal absorption preparation with added lactic acid, it was confirmed that no crystals were formed on the surface of the drug-containing adhesive layer even after 5 months at room temperature, and that it was smooth and uniform.

However, in the case of a sample of a transdermal absorption preparation without added lactic acid, it was confirmed visually and microscopically that crystals were formed in the drug-containing adhesive layer after 5 months at room temperature, and the surface of the drug-containing adhesive layer was uneven.

Therefore, it was confirmed that the formation of donepezil drug crystals in a transdermal absorption formulation can be inhibited by adding lactic acid.

Experimental Example 2. Confirmation of the effect of additives on percutaneous penetration

1. Background and experimental method

<Background>

It was confirmed that the formation of donepezil drug crystals in the transdermal absorption preparation could be suppressed when lactic acid was added (prescription according to Table 8 below), but the desired level of transdermal permeability could not be secured (see Table 9 and Figure 2, the experiment on transdermal permeability was conducted in the same manner as described below).

- Amount of raw material added with lactic acid

Raw material name Added lactic acid
1 sheet (mg/1 Patch) Donepezil 30.00 Acrylic adhesive
(Product name: Duro-tak 87-9301) 314.00 Lactic acid 30.00 Butylated hydroxytoluene 0.3 Ethyl acetate 60.00

- Percutaneous permeation rate in human cadaer skin with lactic acid added (ug/cm ² )

Raw material name Cumulative Emission (ug/cm ² ) 0 0 2 0.24 4 0.52 6 0.62 8 0.78 24 2.10

Accordingly, it was confirmed whether the percutaneous permeation rate could be improved depending on the content of polyoxyethylene (2) lauryl ether (product name: NIKKOL BL-2), a percutaneous absorption accelerator, polyvinyl pyrrolidone (product name: PVP 90), a thickener, and an acrylic adhesive.

<Test method>

Specifically, percutaneous absorption preparation (patch) samples were manufactured by the method described in Example 1 using the S-21, S-22, S-24, S-25 and S-26 formulations described in Table 10 below, and then the drug absorption of the percutaneous absorption preparations manufactured with the S-21, S-22, S-24, S-25 and S-26 formulations was evaluated using human cadaver skin (human epidermis, 3 × 3 cm2). The skin permeation test was performed using a Franz type diffusion cell having a diffusion area of 1.77 cm2. The volume of the solution in the receiving chamber was 12.5 ml. Transdermal absorption drugs (patches) manufactured with the S-21, S-22, S-24, S-25, and S-26 prescriptions were pressed against the human cadaver skin, and the skin/patch laminate was clamped between the supply chamber and the receiving chamber of the Franz cell with the skin side facing the receiving chamber solution. The receiving chamber of the Franz cell was filled with a phosphate buffer solution (pH 6.0), and the temperature of the diffusion apparatus was maintained at 32°C. The buffer solution in the receiving chamber was stirred at a constant speed of 600 rpm, and 0.2 ml of a sample was collected from the receiving chamber at 4, 8, 12, 16, 20, and 24 hours, and the same volume of fresh phosphate buffer solution was added to maintain sink conditions. The cumulative release of donepezil permeated through the skin was analyzed under HPLC conditions and is shown in Fig. 3, and its skin permeation rate is shown in Table 11.

HPLC Conditions

Column: 15 cm × 4.6 mm, C18, 5 μm particles

Mobile phase: Acetonitrile/buffer (35:65) adjusted to pH 1.8 with perchloric acid

*Buffer: Solution of 3.9 g of sodium 1-decane sulfonate dissolved in 1 L of water

Detection wavelength: 271 nm

Flow rate: 1.4 mL/min

Injection volume: 20 μl

Column temperature: 35 ℃

Raw material name S-21
(mg/1 Patch) S-22
(mg/1 Patch) S-24
(mg/1 Patch) S-25
(mg/1 Patch) S-26
(mg/1 Patch) Donepezil 40.00 40.00 40.00 40.00 40.00 Acrylic adhesive
(Duration 87-9301) 314.00 314.00 314.00 345.40 314.00 Lactic acid 9.49 9.49 9.49 9.49 9.49 PVP 90 5.00 - - - 2.00 MONOPOL LAE2 87.50 52.88 70.19 52.88 87.50 Butylated hydroxytoluene 0.30 0.30 0.30 0.30 0.30 Ethyl acetate 60.00 60.00 60.00 60.00 60.00 aggregate 516.3 476.7 494.0 508.1 513.3

2. Experimental Results

The cumulative value of the amount of donepezil present in the sample at each collection time corresponds to the amount of donepezil in the transdermal absorption preparation that has permeated the membrane (cumulative dermal absorption).

Referring to Figure 3 and Table 11, it was confirmed that when polyoxyethylene (2) lauryl ether (product name: MONOPOL LAE2), a percutaneous absorption accelerator, was added in excessive amounts, the permeation rate actually decreased (S-21 prescription). This is thought to be because adding a certain amount or more increases the stabilization of the drug in the percutaneous absorption preparation, thereby decreasing the permeation rate.

In addition, it was confirmed that the permeation rate improved as the concentration of polyoxyethylene (2) lauryl ether (product name: MONOPOL LAE2), a percutaneous absorption promoter, increased (S-22 vs S-24) and as the concentration of PVP decreased (S-21 vs S-26).

In addition, it was confirmed that the change in penetration rate according to the amount of acrylic adhesive was not large.

Through these results, it was confirmed that the problem caused by adding lactic acid can be solved by using an appropriate amount of polyoxyethylene (2) lauryl ether (product name: MONOPOL LAE2), a percutaneous absorption promoter, to suppress the formation of donepezil drug crystals in the percutaneous absorption preparation while securing the desired level of percutaneous absorption.

division S-21 S-22 S-24 S-25 S-26 Skin penetration rate
(㎍/㎠/hr) 11.49 15.86 21.76 18.61 20.02

Experimental Example 3. Comparison of blood drug concentrations of donepezil with commercially available Donerion Patch (manufacturer: Celltrion)

Through the above Experimental Example 2, it was confirmed that by using an appropriate amount of polyoxyethylene (2) lauryl ether (product name: MONOPOL LAE2), which is a percutaneous absorption promoter, the formation of donepezil drug crystals in a percutaneous absorption preparation can be suppressed while securing a desired level of percutaneous absorption, and therefore, among the example prescriptions of the present invention, the blood drug concentration of donepezil between the patch according to Example 2 in particular and the currently commercially available Donerion patch (manufacturer: Celltrion) was compared and analyzed through animal testing.

1. Test method

A. Animal species/phylum

Specific Pathogen Free Rat/Hairless Wistar Yagi/Slc Rat

B. Animal information

Animal information is as shown in Table 12 below.

gender Male Number of animals (age) at time of acquisition 12 (6 weeks old) Number of animals (age) at time of administration 12 (7 weeks old) Weight range upon acquisition 155~176g Weight range at time of administration 170~195g

D. Method of administration

The experimental animals were calibrated and the area around the patch attachment site was disinfected with alcohol for disinfection. The patch was attached to the back, and the patch was covered and fixed with Tegaderm film (#1624W, 3M, USA) to prevent damage to the patch, and the animal was stabilized.

A. Military composition and dosage

The composition and dosage of the group are as shown in Table 13 below and Figure 4.

Test group Drug administration Drug loading amount number Donerion Patch 8.75mg/ ^2.5cm2 1 Patch according to Example 2 2.667mg/ ^2cm2 1

B. Sampling time

0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 18, 24, 36, 48, 60, 72 hours

B. Sample removal

The sample was removed from the skin 24 hours after administration. Blood samples were collected for up to 72 hours after removal.

4. Blood collection and separation of plasma samples

Blood collection was performed on all surviving animals (including animals subjected to planned necropsy), and the animals were fasted for more than 16 h (drinking water was provided) before blood collection. The animals were calibrated, and approximately 200–300 μL of blood was collected at a time through the jugular vein route using a sterile syringe (26G needle, Korea Vaccine, KOR). The collected blood was immediately placed in a 0.5 mL K2 EDTA Tube (#365974, BD, USA) containing an anticoagulant, and a Roll-mixer (208RM, HST, CHN) was used to evenly mix the blood and anticoagulant. The collected blood was centrifuged at 4℃ and 3,000 rpm for 15 minutes to separate the plasma using a refrigerated centrifuge (Combi R515, Hanil Scientific, KOR) within 30 minutes. Approximately 100 μL of the separated plasma was placed in a 1.7 mL microtube (MCT-175-C, Axygen, USA) and stored in an ultra-low temperature freezer (NU-9483GC, NuAire, USA) at -70±10℃. PK analysis was performed after the experiment.

Ah. Plasma analysis method

Donepezil Hydrochloride standard substance was dissolved in methanol to prepare a 1 mg/mL donepezil hydrochloride standard stock solution and stored in a -20 to -10°C freezer. Donepezil-d7 Hydrochloride standard substance, as an internal standard substance, was dissolved in methanol to prepare a 1 mg/mL internal standard stock solution and stored in a -20 to -10°C freezer. To 50 μL of plasma sample mixed with the corresponding standard solution in the blood plasma of an experimental rat (blood plasma: standard solution = 19:1), 50 μL of the internal standard substance (10 ng/mL) diluted with 50% methanol solution and 950 μL of Methyl tert-Butyl Ether were added. The sample was extracted for 5 minutes using an Automatic Fine Vortex (SH2000, FINEPCR, KOR) and precipitated for 3 minutes using a Centrifuge (Smart R17 Plus, HANIL, KOR). After drying the separated supernatant (850 μL) using N2 gas at 40°C, 400 μL of mobile phase (10 mM ammonium formate (0.1% formic acid) : methanol = 40:60 (v/v)) was added to the residue to reconstitute, and after centrifugation for 2 minutes, 4 μL of the supernatant was injected into LC-MS/MS.

Okay. Processing of plasma samples

Plasma samples were collected from all experimental animals at each time point and stored in an ultra-low temperature freezer (-70±10℃). After thawing at room temperature, 50 μL was pretreated using the same method as for preparing the calibration curve and injected into the LC/MS/MS system.

Tea. Calculation of plasma concentration

From the obtained chromatogram, the ratio of the peak area of the analyte to the peak area of the internal standard was obtained, and the concentration of the analyte in plasma (ng/mL) was calculated from a previously prepared calibration curve.

TA. Statistical processing of analysis results

The Phoenix WinNonlin (ver. 6.4, CERTARA, USA) program was used to obtain drug concentration-time curves in plasma.

2. Test results

A. Mean and deviation of blood donepezil concentration

The mean and deviation of blood donepezil concentrations are shown in Table 14 below.

division Donerion Patch Patch according to Example 2 Blood collection time
(hours) Mean blood donepezil concentration (n=3) Deviation Mean blood donepezil concentration (n=3) Deviation 0 0.00 0.00 0.00 0.00 0.25 0.00 0.00 0.00 0.00 0.5 0.00 0.00 0.00 0.00 1 0.00 0.00 0.00 0.00 2 0.00 0.00 0.00 0.00 4 0.13 0.23 0.59 0.11 6 1.39 0.44 3.83 0.91 8 1.97 1.29 8.57 1.40 10 4.99 1.97 16.31 6.29 12 7.49 3.71 20.91 7.18 16 10.81 3.56 22.19 7.59 18 10.61 2.02 22.92 7.41 24 14.93 4.74 97.54 51.53 36 2.02 0.18 13.76 9.49 48 0.59 0.24 3.14 0.46 60 0.30 0.53 1.70 0.42 72 0.15 0.26 0.76 0.11 T _max 24.00 0.00 24.00 0.00 C _max 14.93 4.74 97.54 51.53 AUC _last 256.15 69.92 1197.02 386.26

B. Donepezil blood drug concentration

The blood drug concentration of donepezil is shown in Figure 5.

D. Pharmacokinetic characteristics of donepezil after administration

The pharmacokinetic characteristics of donepezil after administration are shown in Table 15 below.

Pharmacokinetic properties Donerion Patch
(Mean ± Deviation) Patch according to Example 2
(Mean ± Deviation) Area under the blood (drug) concentration curve (AUC _(0-72) )(ng·h/mL) 256.15±69.92 1197.02±386.26 Peak blood concentration (C _max )(ng/mL) 14.93±4.74 97.54±51.53 Time to reach maximum blood concentration (T _max ) (hour) 21.33±4.62 24.00±0.00

Ra. Comparison of AUC _(0-72) and C _max Ratio values between the Donerion patch and the patch according to Example 2

The AUC _(0-72) and C _max Ratio values between the Donerion patch and the patch according to Example 2 are shown in Table 16 below.

Pharmacokinetic properties Area under the blood (drug) concentration curve (AUC _(0-72) ) Maximum blood concentration (C _max )
(ng/mL) Donerion Patch ÷ Patch Ratio according to Example 2 (%) 461.21% 592.82%

B. Conclusion and Discussion

- The results of measuring the blood drug concentration of donepezil in animals (~72 hours) after applying the Donerion patch and the patch according to Example 2 showed AUC _(0-72) 256.15 ng·h/mL, C _max 14.93 ng/mL, and the patch according to Example 2 showed AUC _(0-72) 1197.02 ng·h/mL, C _max 97.54 ng/mL.

- As a result of comparing the ratio of AUC _(0-72) and C _max values between the two patches, the patch according to Example 2 showed 461% higher AUC and 592.8% higher C _max than the Donerion patch. Accordingly, it was confirmed that the patch according to Example 2 showed significantly higher drug absorption of donepezil than the Donerion patch.

These results can be seen as a result of including polyoxyethylene (2) lauryl ether, a percutaneous absorption accelerator, in the drug absorption adhesive layer within the percutaneous absorption preparation.

While the specific parts of the present invention have been described in detail above, it is obvious to those skilled in the art that these specific descriptions are merely preferred embodiments and that the scope of the present invention is not limited thereto. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (6)

A drug-containing adhesive layer comprising donepezil or a pharmaceutically acceptable salt thereof as an active ingredient and polyoxyethylene (2) lauryl ether as a percutaneous absorption promoter; support base; and A transdermal preparation comprising a peeling layer. A transdermal absorption preparation, characterized in that in claim 1, the effective ingredient, donepezil or a pharmaceutically acceptable salt thereof, is contained in an amount of 10.0 to 20.0 wt% based on the total weight of the entire drug-containing adhesive layer. A percutaneous absorption preparation, characterized in that in claim 1, the content of the percutaneous absorption accelerator is 10.0 to 30.0 wt% based on the total weight of the drug-containing adhesive layer. A transdermal absorption preparation according to claim 1, characterized in that the drug-containing adhesive layer further comprises a crystal inhibitor. A percutaneous absorption preparation, characterized in that in claim 4, the decision inhibitor is lactic acid. A percutaneous absorption preparation, characterized in that in claim 4, the content of lactic acid, which is the decision inhibitor, is 3.0 to 4.5 wt% based on the total weight of the entire drug-containing adhesive layer.

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