Percutaneous absorption preparation containing donepezil

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

[0001] The present invention relates to a transdermal absorption preparation containing donepezil, and more specifically, to a transdermal absorption preparation that can suppress donepezil drug crystallization within 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.

[0002] The cause of Alzheimer's disease is unclear and there is no fundamental treatment, making complete prevention and treatment impossible. Therefore, early diagnosis and management to slow its progression have been recognized as paramount.

[0003] Most of the treatments for Alzheimer's disease are acetylcholinesterase inhibitors, which are acetylcholinesterase inhibitors, such as Donepezil (Aricept). TM ), rivastigmine (Rivastigmin, Exelon TM ), galantamine (Galantamine, Reminyl) TM ) are included in this.

[0004] Among these, donepezil is the most commonly prescribed ingredient among Alzheimer's dementia 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.

[0005] Donepezil is currently the longest-standing and widely prescribed drug among the Alzheimer's treatment drugs approved by the U.S. Food and Drug Administration (FDA), from mild to moderate and severe dementia patients. According to Ubist, a pharmaceutical market research firm, out of the approximately 290 billion won in domestic sales of Alzheimer's treatment drugs in 2020, the donepezil component accounts for approximately 80%, or approximately 230 billion won, of the market.

[0006] Until now, donepezil has only been commercialized as an oral medication due to difficulties in developing a formulation. The current donepezil formulation is in tablet form, prescribed orally to patients with Alzheimer's disease. However, oral donepezil formulations cannot avoid first-pass hepatic clearance, and gastrointestinal side effects have been reported. Furthermore, oral administration may become difficult in cases where dementia symptoms have progressed significantly. Furthermore, tablets have limited dosages, and dementia patients are prone to forgetting to take their medications. Therefore, a transdermal patch formulation has been proposed.

[0007] 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, because the skin permeation rate of donepezil is relatively low, the preparation is manufactured with an area larger than necessary to overcome this. Therefore, when applying the transdermal absorption preparation to a patient for 1 to 2 days at a time, patient compliance may decrease due to this.

[0008] 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 promoter. 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 promoter is not used, there is a problem that the skin permeability decreases rapidly.

[0009] Due to these problems, not only global pharmaceutical companies but also domestic pharmaceutical companies are unable to achieve concrete results with patches.

[0010] [Prior Art Literature]

[0011] [Patent Document]

[0012] (Patent Document 1) Korean Patent Publication No. 10-2005-0037405

[0013] (Patent Document 2) International Patent Publication No. 2011 / 049038

[0014] The purpose of the present invention is to solve the above problems, and to provide a transdermal absorption preparation containing donepezil that can suppress the drug crystallization phenomenon in the transdermal absorption preparation and improve the drug permeation rate (cumulative permeation amount and skin permeation rate) even when left at room temperature for a long period of time.

[0015] In order to solve the above problem, the present invention discloses the following means.

[0016] 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.

[0017] According to the present invention, a transdermal absorption preparation containing donepezil can be provided, which can suppress the phenomenon of donepezil drug crystallization in the transdermal absorption preparation even when left at room temperature for a long period of time, and can improve the transdermal permeation rate (cumulative permeation amount and skin permeation rate) of the drug.

[0018] In particular, in the case of the transdermal absorption preparation according to the present invention, the drug loading amount is significantly lower than that of the currently commercially available Donepezil patch (manufacturer: Celltrion), but the AUC of the donepezil drug concentration in the blood is (0-72) and C max There is an advantage in that the drug absorption of donepezil is significantly higher.

[0019] The effects of the present invention are not limited to the effects mentioned above, and various effects may be included within a range apparent to those skilled in the art from the contents described below.

[0020] 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.

[0021] Figure 2 is a diagram showing the percutaneous permeability in a prescription with added lactic acid to explain the background in Experimental Example 1.

[0022] 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.

[0023] Figure 4 shows the group composition and administration dose according to Experimental Example 3.

[0024] 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).

[0025] Hereinafter, the present specification will be described in more detail.

[0026] To explain this more specifically, the terms used in this specification are selected from widely used, general terms, taking into account the functions of the present invention. However, these terms may vary depending on the intentions of engineers working in the field, precedents, the emergence of new technologies, etc. Furthermore, in certain cases, terms may be arbitrarily selected by the applicant, and in such cases, their meanings will be described in detail in the description of the relevant invention. Therefore, the terms used in the present invention should not be defined simply as names of terms, but rather based on the meanings of the terms and the overall content of the present invention.

[0027] 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 pertains. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and shall not be interpreted in an idealized or overly formal sense unless explicitly defined herein.

[0028] Numerical ranges are inclusive of the numbers defined in the ranges above. Every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if that lower numerical limitation were explicitly stated. Every minimum numerical limitation given throughout this specification includes every higher numerical limitation, as if that higher numerical limitation were explicitly stated. 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 explicitly stated.

[0029] The following descriptions and embodiments disclosed in the present invention may also be applied to other descriptions and embodiments. In other words, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Furthermore, the scope of the present invention should not be considered limited by the specific descriptions described below.

[0030] Expressions such as “comprising” as used herein should be understood as open-ended terms that imply the possibility of including other embodiments.

[0031] In order to solve the above problems, the inventors of the present invention confirmed that when formulating donepezil in the form of a transdermal absorption preparation, a drug crystallization phenomenon occurs, which reduces the adhesiveness of the patch and lowers the drug absorption rate.

[0032] Accordingly, it was confirmed that when lactic acid was added to the donepezil transdermal absorption preparation, donepezil crystals did not form even after long-term storage. However, although crystals could be suppressed, there was a problem that the desired level of transdermal absorption (absorption rate) was not achieved. To solve this problem, 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.

[0033] Accordingly, the inventors of the present invention confirmed that a transdermal absorption preparation in the form of a patch that can increase the concentration of donepezil in the blood despite a small drug loading amount can be manufactured by adopting polyoxyethylene (2) lauryl ether, which is a transdermal absorption promoter, in the donepezil transdermal absorption preparation, thereby completing the present invention.

[0034] Hereinafter, the present invention will be described in detail.

[0035] Unless otherwise specified herein, the term weight percent refers to the mass ratio of a particular component to the entire drug-containing adhesive layer into which it is incorporated.

[0036] Transdermal preparation containing donepezil

[0037] In order to solve the above problem, the present invention discloses the following means.

[0038] 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.

[0039] In the present invention, the transdermal absorption preparation is composed of a single layer (1 layer) of a drug-containing adhesive layer, and has the effect of simplifying the production process and reducing costs compared to a transdermal absorption preparation composed of two layers (2 layers) in which a separate adhesive layer exists in addition to the drug-containing adhesive layer.

[0040] In the present invention, the term "pharmaceutically acceptable salt" includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases. The term "hydrate" refers to 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 refers to donepezil itself.

[0041] 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.

[0042] 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 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, specifically, 50.0 to 60.0 wt%, but is not limited thereto.

[0043] At this time, the term “functional group” means a common atomic group that causes the properties of acrylate polymers with the same chemical properties, for example, an OH group, a COOH group, etc.

[0044] In the present invention, the functional group-free acrylate polymer usable 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.

[0045] In the present invention, the drug-containing adhesive layer includes polyoxyethylene (2) lauryl ether, which is a percutaneous absorption promoter. 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. In this case, among various percutaneous absorption promoters, when an appropriate amount of polyoxyethylene (2) lauryl ether is included, the formation of donepezil drug crystals in the percutaneous absorption preparation can be suppressed while maintaining the desired level, that is, the AUC despite a lower drug loading amount compared to the currently commercially available Donerion patch (manufacturer: Celltrion). (0-72) Wow C max Considering the price, donepezil has the advantage of significantly higher drug absorption, and has the advantage of securing a significantly higher transdermal permeability compared to the transdermal absorption of the Donerion patch (manufacturer: Celltrion).

[0046] Specifically, in the case of the currently commercially available Donerion patch, 1 sheet is 25 cm 2 It contains 87.5 mg of donepezil as a standard, and is known to be administered by attaching it to the back before bedtime twice a week (alternating every 3rd and 4th day), and contains glyceryl monooleate as an additive (percutaneous absorption accelerator). However, in the case of the percutaneous absorption preparation according to the present invention, 25 cm 2 The standard drug loading amount is 26.67 mg, which contains significantly less drug than the Donerion patch (detailed below), and one patch is administered at one-day intervals.

[0047] However, the inventors of the present invention have researched and developed a method to significantly increase the drug absorption of donepezil even if the drug loading amount is significantly reduced compared to the donepezil patch, and have confirmed through animal experiments that the drug absorption of donepezil can be significantly increased compared to the commercially available donepezil patch by adopting polyoxyethylene(2) lauryl ether, which was introduced to solve the problem of lactic acid. Therefore, it can be said that the efficacy and effect are superior among the existing donepezil patches.

[0048] 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 drug stabilization in the percutaneous absorption preparation is increased, thereby lowering the permeation rate.

[0049] In the present invention, the drug-containing adhesive layer may further include a crystal inhibitor, but is not limited thereto.

[0050] In the present invention, the decision inhibitor may be lactic acid, but is not limited thereto.

[0051] In the present invention, the drug-containing adhesive layer, which is a component of the transdermal absorption preparation, contains lactic acid, a crystal-inhibiting agent, in addition to the active ingredient, donepezil or a pharmaceutically acceptable salt thereof. The inclusion of lactic acid has the advantage of inhibiting donepezil drug crystallization within the transdermal absorption preparation even when stored at room temperature for extended periods.

[0052] 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, and specifically, may be 3.5 to 4.0 wt%, but is not limited thereto.

[0053] 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 / PET composite, a PET / PE composite, and a PET / EVA composite, but is not limited thereto.

[0054] 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.

[0055] 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 can be peeled off easily. Therefore, it is preferable to use a silicone-treated film for the surface of the peeling layer.

[0056] In the present invention, the transdermal absorption agent may be a patch, but is not limited thereto.

[0057] In the present invention, the loading dose of donepezil or a pharmaceutically acceptable salt thereof in one sheet of transdermal absorption preparation may vary depending on the size of the transdermal absorption preparation, and specifically, the size of the transdermal absorption preparation is 5 cm. 2 , 10 cm 2 , 20 cm 2, 30 cm 2 , 40 cm 2 In this case, the loading dose of donepezil or its pharmaceutically acceptable salt is 6.668 mg, 13.335 mg, 26.67 mg, 40.00 mg, and 53.34 mg, respectively.

[0058] 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.

[0059] Hereinafter, the present invention will be described in detail based on examples and comparative examples. However, the following examples and comparative examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention.

[0060] Examples and Comparative Examples

[0061] Examples 1 to 4 and Comparative Examples 1 to 2. Preparation of transdermal absorption preparations (patches) containing donepezil

[0062] Example 1.

[0063] 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.

[0064] Manufacturing method

[0065] 1. Prepare solution 1 by mixing ethanol and ethyl acetate.

[0066] 2. Dissolve hydroxypropyl cellulose (product name: HPC A) in the above solution 1 to prepare solution 2.

[0067] 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.

[0068] 4. Add donepezil to the above solution 3 and dissolve it to prepare solution 4.

[0069] 5. Add acrylic adhesive (product name: Duro-tak 87-9301) to the above solution 4 and mix evenly to prepare solution 5.

[0070] 6. Apply / dry / combine the above 5 solutions according to the following conditions to produce a patch (patch size: 20 cm) 2 ).

[0071] ① Application / Drying: Apply solution 5 evenly to a polyethylene terephthalate film (PET film, manufacturer: Kisung Industry), which is the peeling 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.

[0072] ② Lamination: Afterwards, a polyester film (PE film, tentative name, manufacturer: 3M) is laminated on top of the drug-containing adhesive layer applied, and then pressed using a pressing roller and then cut to produce a patch.

[0073] Example 1 Prescription

[0074] Mixing purposeIngredient nameOriginal drug content (mg / 1 Patch)After drying (unit: mg)After drying weight %Active ingredientDonepezil 26.6726.6716.07AdhesiveAcrylic adhesive (Duro-tak 87-9301) 266.6797.3358.64Crystallization inhibitorLactic acid 6.336.333.81Percutaneous absorption promoterPolyoxyethylene (2) lauryl ether (Product name: MONOPOL LAE2) 35.2535.2521.24ThickenerHydroxypropyl cellulose (Product name: HPC) A) 0.330.330.20 Antioxidant Butylhydroxytoluene 0.070.070.04 Solvent Ethyl Acetate 13.330.000.00 Solvent Ethanol 26.670.000.00 Total 375.31165.98100.00

[0075] Example 2.

[0076] 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.

[0077] Example 2 Prescription

[0078] Mixing purposeIngredient nameOriginal drug content (mg / 1 Patch)After drying (unit: mg)After drying weight %Active ingredientDonepezil 26.6726.6716.07AdhesiveAcrylic adhesive (Duro-tak 87-9301) 266.6797.3358.64Crystallization inhibitorLactic acid 6.336.333.81Percutaneous absorption promoterPolyoxyethylene (2) lauryl ether (Product name: MONOPOL LAE2) 35.2535.2521.24ThickenerHydroxypropyl cellulose (Product name: HPC) B) 0.330.330.20 Antioxidant Butylhydroxytoluene 0.070.070.04 Solvent Ethyl Acetate 13.330.000.00 Solvent Ethanol 26.670.000.00 Total 375.31165.98100.00

[0079] Example 3.

[0080] A transdermal absorption preparation (patch) containing donepezil was manufactured in the order described below based on the prescription described in Table 3 below.

[0081] Manufacturing method

[0082] 1. Prepare solution 1 by mixing ethanol and ethyl acetate.

[0083] 2. Dissolve hydroxypropyl cellulose (product name: HPC A) in the above solution 1 to prepare solution 2.

[0084] 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.

[0085] 4. Add donepezil to the above solution 3 and dissolve it to prepare solution 4.

[0086] 5. Add acrylic adhesive (product name: Duro-tak 87-9301) to the above solution 4 and mix evenly to prepare solution 5.

[0087] 6. Apply / dry / combine the above 5 solutions according to the following conditions to produce a patch (patch size: 30 cm) 2 ).

[0088] ① Application / Drying: Apply solution 5 evenly to a polyethylene terephthalate film (PET film, manufacturer: Kisung Industry), which is the peeling 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.

[0089] ② Lamination: Afterwards, a polyester film (PE film, tentative name, manufacturer: 3M) is laminated on top of the drug-containing adhesive layer applied, and then pressed using a pressing roller and then cut to produce a patch.

[0090] Example 3 Prescription

[0091] Mixing purposeIngredient nameOriginal drug content (mg / 1 Patch)After drying (unit: mg)After drying weight %Active ingredientDonepezil 40.0040.0016.07AdhesiveAcrylic adhesive (Duro-tak 87-9301) 400.00146.0058.64Crystallization inhibitorLactic acid 9.499.493.81Percutaneous absorption promoterPolyoxyethylene (2) lauryl ether (Product name: MONOPOL LAE2) 52.8852.8821.24ThickenerHydroxypropyl cellulose (Product name: HPC) A) 0.500.500.20 Antioxidant Butylhydroxytoluene 0.100.100.04 Solvent Ethyl Acetate 20.000.000.00 Solvent Ethanol 40.000.000.00 Total 562.97248.97100.00

[0092] Example 4.

[0093] 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.

[0094] Example 4 Prescription

[0095] Mixing purposeIngredient nameOriginal drug content (mg / 1 Patch)After drying (unit: mg)After drying weight %Active ingredientDonepezil 40.0040.0016.07AdhesiveAcrylic adhesive (Duro-tak 87-9301) 400.00146.0058.64Crystallization inhibitorLactic acid 9.499.493.81Percutaneous absorption promoterPolyoxyethylene (2) lauryl ether (Product name: MONOPOL LAE 252.8852.8821.24ThickenerHydroxypropyl cellulose (Product name: HPC) B) 0.500.500.20 Antioxidant Butylhydroxytoluene 0.100.100.04 Solvent Ethyl Acetate 20.000.000.00 Solvent Ethanol 40.000.000.00 Total 562.97248.97100.00

[0096] Comparative Example 1.

[0097] 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.

[0098] Comparative Example 1 Prescription

[0099] Mixing purposeIngredient nameOriginal drug content (mg / 1 Patch)After drying (unit: mg)After drying weight %Active ingredientDonepezil 26.6726.6717.26AdhesiveAcrylic adhesive (Duro-tak 87-9301) 266.6797.33362.98Crystallization inhibitorLactic acid 6.336.334.10Percutaneous absorption promoterPolyoxyethylene (2) lauryl ether (Product name: MONOPOL LAE2) 23.3323.3315.10ThickenerHydroxypropyl cellulose (Product name: HPC) F) 0.67 0.67 0.43 Antioxidant Butyl hydroxytoluene 0.200 200 13 Solvent Ethyl acetate 13.33 0.000 00 Solvent Ethanol 26.67 0.000 00 Total 363.86 154.53 100 00

[0100] Comparative Example 2.

[0101] 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.

[0102] Comparative Example 2 Prescription

[0103] Mixing purposeIngredient nameOriginal drug content (mg / 1 Patch)After drying (unit: mg)After drying weight %Active ingredientDonepezil 40.0040.0017.26AdhesiveAcrylic adhesive (Duro-tak 87-9301) 400.00146.0062.99Crystallization inhibitorLactic acid 9.499.494.09Percutaneous absorption promoterPolyoxyethylene (2) lauryl ether (Product name: MONOPOL LAE2) 35.0035.0015.10ThickenerHydroxypropyl cellulose (Product name: HPC) F)1.001.000.43 Antioxidant Butylhydroxytoluene 0.300.300.13 Solvent Ethyl Acetate 20.000.000.00 Solvent Ethanol 40.000.000.00 Total 545.79231.79100.00

[0104] Hereinafter, the present invention will be described in detail based on experimental examples. However, the following experimental examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention.

[0105] Experimental example

[0106] Experimental Example 1. Confirmation of the phenomenon of inhibition of donepezil drug crystallization in a transdermal absorption preparation due to the addition of lactic acid.

[0107] 1. Experimental method

[0108] When formulated as a patch, donepezil can form crystals. This crystal formation reduces the adhesive strength of the transdermal preparation and reduces drug absorption. Therefore, we investigated whether the use of lactic acid could suppress crystallization.

[0109] 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 (20-25°C), the surface of the drug-containing adhesive layer included in the transdermal absorption preparation sample was compared and evaluated with the naked eye and an optical microscope (OLYMPUS-CX41, x100 (100x magnification), x200 (200x magnification) observation), and the results are shown in Fig. 1.

[0110] Ingredients: Lactic acid not added, 1 sheet (mg / 1 Patch) Lactic acid added, 1 sheet (mg / 1 Patch) Donepezil 30.00 30.00 Acrylic adhesive (Product name: Duro-tak 87-9301) 314.00 314.00 Laroglycol 9030.00 30.00 Lactic acid-7.12 (amount equivalent to 1 equivalent of donepezil) Butylhydroxytoluene 0.10.1 Ethyl acetate 60.00 60.00

[0111] B. Experimental results

[0112] 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.

[0113] However, in the case of a sample of a transdermal absorption preparation without added lactic acid, it was confirmed with the naked eye and under a microscope 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.

[0114] Therefore, it was confirmed that the formation of donepezil drug crystals in a transdermal absorption preparation can be inhibited by adding lactic acid.

[0115] Experimental Example 2. Confirmation of the effect of additives on percutaneous penetration.

[0116] 1. Background and experimental methods

[0117] Background

[0118] It was confirmed that the formation of donepezil drug crystals in the transdermal absorption preparation could be suppressed by adding lactic acid (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).

[0119] - Amount of raw material with added lactic acid

[0120] Raw material name: Lactic acid added 1 sheet (mg / 1 Patch) Donepezil 30.00 Acrylic adhesive (Product name: Duro-tak 87-9301) 314.00 Lactic acid 30.00 Butylhydroxytoluene 0.3 Ethyl acetate 60.00

[0121] - Percutaneous permeability in human cadaer skin when lactic acid was added (ug / cm) 2 )

[0122] Raw material name Cumulative emission amount (ug / cm) 2 )0020.2440.5260.6280.78242.10

[0123] Accordingly, it was confirmed whether the percutaneous permeability could be improved depending on the content of polyoxyethylene (2) lauryl ether (product name: NIKKOL BL-2), a percutaneous absorption promoter, polyvinyl pyrrolidone (product name: PVP 90), a thickener, and an acrylic adhesive.

[0124] <Test method>

[0125] Specifically, transdermal absorption preparations (patches) samples were prepared using 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 transdermal absorption preparations prepared 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 permeability test was performed using a Franz type diffusion cell with a diffusion area of ​​1.77 cm2. The volume of the solution in the receiving chamber was 12.5 ml. Transdermal absorption agents (patches) manufactured with the S-21, S-22, S-24, S-25, and S-26 formulations were pressed against the human cadaver skin, and the skin / patch laminate was clamped between the supply and receiving chambers 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 samples were 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 the sink condition. The cumulative release of donepezil permeated through the skin was analyzed under HPLC conditions and is shown in Figure 3, and its skin permeation rate is shown in Table 11.

[0126] HPLC conditions

[0127] Column: 15 cm × 4.6 mm, C18, 5 μm particles

[0128] Mobile phase: Acetonitrile / buffer (35:65) adjusted to pH 1.8 with perchloric acid

[0129] *Buffer: A solution of 3.9 g of sodium 1-decane sulfonate dissolved in 1 L of water.

[0130] Detection wavelength: 271 nm

[0131] Flow rate: 1.4 mL / min

[0132] Injection volume: 20 μl

[0133] Column temperature: 35 ℃

[0134] 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 40.00 Acrylic adhesive (Duro-tak 87-9301) 314.00 314.00 314.00 345.40 314.00 Lactic acid 9.499.499.499.499.49 PVP 905.00---2.00 MONOPOL LAE 287.50 52.8870.19 52.8887.50 Butylhydroxytoluene 0.300.300.300.300.30 Ethyl acetate 60.0060.0060.0060.0060.00 Total 516.3476.7494.0508.1513.3

[0135] 2. Experimental results

[0136] The cumulative value of the amount of donepezil present in the sample at each collection point corresponds to the amount of donepezil in the transdermal absorption preparation that has permeated the membrane (cumulative dermal absorption).

[0137] Referring to Figure 3 and Table 11, it was confirmed that when polyoxyethylene(2) lauryl ether (product name: MONOPOL LAE2), a percutaneous absorption promoter, was added in excessive amounts, the permeation rate actually decreased (S-21 formulation). This is thought to be because adding a certain amount or more increases drug stabilization within the percutaneous absorption preparation, thereby lowering the permeation rate.

[0138] 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).

[0139] In addition, it was confirmed that the change in penetration rate according to the amount of acrylic adhesive was not large.

[0140] Through these results, it was confirmed that the problem that occurs due to the addition of 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.

[0141] Category S-21S-22S-24S-25S-26Skin penetration rate (㎍ / ㎠ / hr) 11.49 15.86 21.76 18.6 120.02

[0142] Experimental Example 3. Comparison of Donepezil blood drug concentrations with the commercially available Donerion patch (manufacturer: Celltrion)

[0143] 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. Accordingly, among the example prescriptions of the present invention, the blood drug concentration of donepezil between the patch according to Example 2 and the currently commercially available Donerion patch (manufacturer: Celltrion) was compared and analyzed through animal testing.

[0144] 1. Test method

[0145] a. Animal species / phylum

[0146] Specific Pathogen Free Rat / Hairless Wistar Yagi / Slc Rat

[0147] B. Animal information

[0148] Animal information is as shown in Table 12 below.

[0149] Gender: Male Number of animals (weeks old) at time of acquisition: 12 (6 weeks old) Number of animals (weeks old) at time of administration: 12 (7 weeks old) Weight range at time of acquisition: 155-176g Weight range at time of administration: 170-195g

[0150] D. Method of administration

[0151] The experimental animals were calibrated and the area around the patch was disinfected with alcohol. The patch was applied to the back and secured with Tegaderm film (#1624W, 3M, USA) to prevent damage to the patch. The animals were then stabilized.

[0152] A. Military composition and dosage

[0153] The composition and dosage of the group are as shown in Table 13 and Figure 4 below.

[0154] Test group, drug administration, drug loading amount, number of times, Nerion patch 8.75 mg / 2.5 cm 2 1. Patch according to Example 2 2.667 mg / 2 cm 2 1

[0155] Ma. Sampling time

[0156] 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 18, 24, 36, 48, 60, 72 hours

[0157] Bar. Sample removal

[0158] The sample was removed from the skin 24 hours after administration. Blood samples were collected for up to 72 hours after removal.

[0159] 4. Blood collection and separation of plasma samples

[0160] Blood collection was performed on all surviving animals (including those subjected to necropsy), which were fasted for at least 16 hours (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 using a sterile syringe (26G needle, Korea Vaccine, KOR). The collected blood was immediately transferred to a 0.5 mL K2 EDTA tube (#365974, BD, USA) containing an anticoagulant and mixed evenly with the blood using a roll-mixer (208RM, HST, CHN). The collected blood was centrifuged at 4°C 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.

[0161] Ah. Plasma analysis method

[0162] Donepezil Hydrochloride standard 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, an internal standard, was dissolved in methanol to prepare a 1 mg / mL internal standard stock solution and stored in a -20 to -10°C freezer. 50 μL of the internal standard (10 ng / mL) diluted with 50% methanol solution and 950 μL of methyl tert-butyl ether were added 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). 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 850 μL of the separated supernatant 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.

[0163] Now, processing the plasma sample.

[0164] 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 the calibration curve preparation method and injected into the LC / MS / MS system.

[0165] Tea. Plasma concentration calculation

[0166] 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.

[0167] TA. Statistical processing of analysis results

[0168] The Phoenix WinNonlin (ver. 6.4, CERTARA, USA) program was used to obtain drug concentration-time curves in plasma.

[0169] 2. Test results

[0170] A. Mean and deviation of blood donepezil concentration

[0171] The mean and deviation of blood donepezil concentrations are shown in Table 14 below.

[0172] Donepezil Patch Example 2 Patch Blood collection time (hours) Mean blood concentration of donepezil (n=3) Deviation Mean blood concentration of donepezil (n=3) Deviation 00.000.000.000.000.250.000.000.000.000.50.000.000.000.0010.000.000.000.0020.000.000.000.0040.130.230.590.1161.390.443.830.9181.971.298.571.40104.991.971 6.316.29127.493.7120.917.181610.813.5622.197.591810.612.0222.927.412414.934.7497. 5451.53362.020.1813.769.49480.590.243.140.46600.300.531.700.42720.150.260.760.11T max 24.000.0024.000.00C max 14.934.7497.5451.53AUC last 256.1569.921197.02386.26

[0173] B. Donepezil blood drug concentration

[0174] The blood drug concentration of donepezil is shown in Figure 5.

[0175] D. Pharmacokinetic characteristics of donepezil after administration

[0176] The pharmacokinetic characteristics of donepezil after administration are shown in Table 15 below.

[0177] Pharmacokinetic properties of 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±69.921197.02±386.26Highest blood concentration (C max )(ng / mL)14.93±4.7497.54±51.53Time to reach maximum blood concentration (T max )(hour)21.33±4.6224.00±0.00

[0178] AUC between the Donerion patch and the patch according to Example 2 (0-72) , C max Comparing ratio values

[0179] AUC between the Donerion patch and the patch according to Example 2 (0-72) , C max The ratio values ​​are shown in Table 16 below.

[0180] Pharmacokinetic characteristics Area under the blood (drug) concentration curve (AUC) (0-72) ) Peak blood concentration (C max )(ng / mL) Donerion Patch ÷ Patch Ratio according to Example 2 (%)461.21%592.82%

[0181] B. Conclusion and Discussion

[0182] - Results of blood drug concentration measurements of donepezil in animals using the Donerion patch and the patch according to Example 2 (~72 hours) Donerion patch AUC (0-72) 256.15 ng·h / mL, C max 14.93 ng / mL, AUC of the patch according to Example 2 (0-72) 1197.02 ng·h / mL, C max The result showed a value of 97.54 ng / mL.

[0183] - AUC between two patches (0-72) Wow C max As a result of comparing the ratio of values, the patch according to Example 2 had an AUC of 461% compared to the Donerion patch, C maxshowed a result value that was 592.8% higher. Accordingly, it was confirmed that the patch according to Example 2 had significantly higher drug absorption of donepezil compared to the Donerion patch.

[0184] 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.

[0185] While specific aspects of the present invention have been described in detail above, it should be apparent to those skilled in the relevant technical field that these specific descriptions are merely preferred embodiments and do not limit the scope of the present invention. Therefore, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims

1. 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.

2. A transdermal absorption preparation according to claim 1, characterized in that 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.

3. A percutaneous absorption preparation according to claim 1, characterized in that 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.

4. A percutaneous absorption preparation according to claim 1, characterized in that the drug-containing adhesive layer further contains a crystal inhibitor.

5. A percutaneous absorption preparation according to claim 4, characterized in that the decision inhibitor is lactic acid.

6. A percutaneous absorption preparation, characterized in that in paragraph 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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