Transdermal preparation containing donepezil

Abstract

Disclosed is a transdermal absorption preparation containing donepezil, which is a pharmacologically active substance useful for treating symptoms of Alzheimer's disease. The transdermal absorption preparation can inhibit crystallization of donepezil in the transdermal absorption preparation even when left at room temperature for a long time, and can improve the transdermal permeability (cumulative permeation amount and skin permeation rate) of the drug, particularly, even with a small amount of drug loading, the drug absorption of donepezil can be significantly improved compared with the currently marketed Donerion patch.

Description

Technical Field

[0001] This invention relates to transdermal absorption formulations containing donepezil, and more specifically, to a transdermal absorption formulation that can inhibit donepezil drug crystallization within the transdermal absorption formulation and improve the transdermal permeability (cumulative permeation amount and skin permeation rate) of the drug even when left at room temperature for an extended period. Background Technology

[0002] Because the causes of Alzheimer's disease are unclear and there is no cure, perfect prevention and treatment are impossible. Therefore, it is known to date that management through early diagnosis and slowing its progression is of paramount importance.

[0003] Most Alzheimer's disease treatments are inhibitors of acetylcholinesterase, also known as donepezil. TM Rivastigmin, Exelon TM ), Galantamine (Reminyl) TM ) and others all belong to this category.

[0004] Donepezil is the most prescribed ingredient in Alzheimer's disease treatments. It is known to keep acetylcholine, a neurotransmitter that plays an important role in memory and cognitive function in the brain, at normal levels, thereby helping to improve cognitive function.

[0005] Donepezil is currently the most widely prescribed treatment for Alzheimer's disease approved by the U.S. Food and Drug Administration (FDA), with patients ranging from mild to moderate and severe dementia. According to data from the pharmaceutical market research firm Ubist, in 2020, the domestic sales of Alzheimer's disease treatments in South Korea were approximately 290 billion won, of which donepezil accounted for 80%, with a market size of approximately 230 billion won.

[0006] To date, donepezil has only been commercialized in oral formulations due to difficulties in developing dosage forms. Currently, donepezil is available in tablet form, prescribed orally to patients with Alzheimer's dementia. However, oral donepezil cannot avoid the first-pass effect in the liver, and gastrointestinal side effects have been reported. Furthermore, in cases where dementia symptoms have progressed to a considerable stage, oral administration may become difficult. Tablets also have the disadvantages of dosage limitations and the tendency for dementia patients to forget to take their medication; therefore, a transdermal patch formulation has been proposed.

[0007] Relatedly, Korean Patent Publication No. 10-2005-0037405 discloses a transdermal absorption formulation using styrene-isoprene-styrene (SIS) and / or polyisobutylene (PIB) series synthetic rubber polymers. However, due to the relatively low skin penetration rate of donepezil, to overcome this problem, the patch area is prepared to be larger than actually needed. Therefore, when the transdermal absorption formulation needs to be applied to the patient for 1 to 2 days each time, it leads to a decrease in patient compliance.

[0008] Furthermore, International Patent Publication No. 2011 / 049038 discloses a transdermal absorption formulation, which is prepared by dissolving the active ingredient donepezil in an adhesive containing the following substances: styrene-isoprene-styrene block copolymer, hydrogenated rosin glyceride, liquid paraffin, and an absorption enhancer. However, the transdermal absorption formulation disclosed in International Patent Publication No. 2011 / 049038 suffers from unsatisfactory skin irritation, specifically moderate skin irritation. For the treatment of dementia, a chronic disease, long-term application of transdermal absorption formulations to the skin is necessary, and moderate skin irritation significantly reduces patient compliance, making it difficult to expect effective treatment results. Additionally, when irritating substances such as absorption enhancers are not used to minimize skin irritation, there is a problem of drastically reduced skin permeability.

[0009] Due to these issues, not only global pharmaceutical companies but also domestic South Korean pharmaceutical companies have not yet achieved concrete results with the patch.

[0010] [Existing Technical Documents]

[0011] [Patent Literature]

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

[0013] (Patent Document 2) International Patent No. 2011 / 049038 Summary of the Invention

[0014] The purpose of this invention is to solve the above-mentioned problems, namely, to provide a transdermal absorption formulation containing donepezil that can inhibit the crystallization of donepezil in the transdermal absorption formulation even when placed at room temperature for a long time, and can improve the transdermal permeability of the drug (cumulative permeation amount and skin permeation rate).

[0015] To address the aforementioned technical problems, the present invention discloses the following solution.

[0016] In one aspect, the present invention discloses a transdermal absorption formulation comprising: a drug-containing adhesive layer comprising donepezil or a pharmaceutically acceptable salt thereof as an active ingredient and polyoxyethylene lauryl ether-2 as a transdermal absorption enhancer; a support layer; and a release layer.

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

[0018] In particular, for the transdermal absorption formulation according to the present invention, compared with the currently commercially available Donerion patch (manufacturer: Celltrion), although the drug loading is significantly less, it has a higher AUC in terms of donepezil drug concentration in the blood. (0-72) and C max In terms of absorption, donepezil has the advantage of significantly higher drug absorption.

[0019] The effects of the present invention are not limited to those mentioned above, but may also include various effects within the scope that are obvious to those skilled in the art based on the following description. Attached Figure Description

[0020] Figure 1 These images are used to confirm the inhibition of donepezil drug crystallization in transdermal absorption formulations due to the addition of lactic acid.

[0021] Figure 2 The graph showing the transdermal permeability of the lactic acid-added formulation is presented to illustrate the background of Experimental Example 1.

[0022] Figure 3 This is a graph showing the cumulative permeation of donepezil in the transdermal absorption formulations according to the prescriptions S-21, S-22, S-24, S-25 and S-26 of Experimental Example 2.

[0023] Figure 4 The composition and dosage of the drug are shown according to Experimental Example 3.

[0024] Figure 5 The donepezil blood concentrations of the patch according to Example 3 of the present invention, Example 2, and the commercially available Donerion patch (manufacturer: Celtrion) are shown. Detailed Implementation

[0025] The following is a more detailed description of this instruction manual.

[0026] The specific explanation is as follows. The terminology used in this specification, while considering the function of this invention, has been selected as widely used general terms as possible. However, these terms may differ due to the intent or precedents of those skilled in the art, the emergence of new technologies, etc. Furthermore, in certain cases, terms arbitrarily chosen by the applicant may exist; in such cases, their meanings will be described in detail in the corresponding description of the invention. Therefore, the terminology used in this invention is not merely based on the term's name itself, but should be defined based on the meaning of the term and its content throughout the entire invention.

[0027] Unless otherwise defined, all terms used herein, including technical or scientific terms, shall have the same meaning as commonly understood by one of ordinary skill in the art. Terms as defined in commonly used dictionaries shall also be interpreted as having the same meaning as in the relevant technical context, and shall not be interpreted as having an idealized or overly formal meaning unless expressly defined in this application.

[0028] The numerical range includes the values ​​defined within that range. For all maximum numerical limits given throughout this specification, all lower numerical limits are included because lower numerical limits have been explicitly stated. For all minimum numerical limits given throughout this specification, all higher numerical limits are included because higher numerical limits have been explicitly stated. For all numerical limits given throughout this specification, all better numerical ranges within a wider range are included because narrower numerical limits have been explicitly stated.

[0029] The descriptions and embodiments disclosed herein are applicable to other corresponding descriptions and embodiments. That is, all combinations of the various elements disclosed herein fall within the scope of this invention. Furthermore, the specific descriptions described below should not be construed as limiting the scope of this invention.

[0030] Expressions such as “comprising” as used in this specification should be understood as open-ended terms, which include the possibility of including other embodiments.

[0031] The inventors of this invention have confirmed that, in order to solve the above-mentioned technical problem, drug crystallization occurs when donepezil is formulated into a transdermal absorption formulation, which leads to a decrease in the adhesion of the patch and a decrease in the drug absorption rate.

[0032] Subsequently, it was confirmed that adding lactic acid to donepezil transdermal absorption formulations prevents donepezil crystal formation even during long-term storage. However, while crystallization was inhibited, transdermal absorption (absorption rate) did not reach the desired level. To address this issue, the transdermal penetration degree of donepezil was determined in relation to the content of the transdermal absorption enhancer lauryl polyoxyethylene ether-2, the thickener polyvinylpyrrolidone, and the acrylic adhesive. It was also confirmed that these correlations can improve the transdermal absorption of donepezil.

[0033] Thus, the inventors of this invention have confirmed that by using lauryl polyoxyethylene ether-2 as a transdermal absorption enhancer in donepezil transdermal absorption formulations, even with a low drug loading, it is possible to prepare transdermal absorption formulations in patch form that can increase the concentration of donepezil in the blood, thereby completing this invention.

[0034] The present invention will now be described in detail.

[0035] Unless otherwise expressly stated in this specification, the term "weight%" means the mass ratio of a particular component relative to the total mass of the drug-containing adhesive layer in which it is incorporated.

[0036] Transdermal formulations containing donepezil

[0037] To address the aforementioned technical problems, the present invention discloses the following solution.

[0038] In one aspect, the present invention discloses a transdermal absorption formulation comprising: a drug-containing adhesive layer comprising donepezil or a pharmaceutically acceptable salt thereof as an active ingredient and lauryl alcohol polyoxyethylene ether-2 as a transdermal absorption enhancer; a support layer; and a release layer.

[0039] In this invention, the transdermal absorption formulation consists of a drug-containing adhesive layer of one layer. Compared with the transdermal absorption formulation consisting of two layers (2 layers) in addition to the drug-containing adhesive layer, it has the effect of simplifying the production process and reducing costs.

[0040] In this invention, the term "pharmaceutically acceptable salt" includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases. The term "hydrate" means a compound of this invention or a pharmaceutically acceptable salt thereof comprising a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. Specifically, a pharmaceutically acceptable salt of donepezil may be donepezil hydrochloride; in this invention, the active ingredient refers to donepezil itself.

[0041] In this invention, based on the total weight of the drug-containing adhesive layer, the content of donepezil or its pharmaceutically acceptable salt can be 10.0 to 20.0% by weight, specifically 13.0 to 18.0% by weight, but is not limited thereto.

[0042] In this invention, the drug-containing adhesive layer includes an adhesive agent. The term "adhesive agent" refers to an agent capable of performing the functions of applying a transdermal absorbent formulation to the skin and acting as a carrier for donepezil or its pharmaceutically acceptable salts. In this case, the drug-containing adhesive layer contains a non-functionalized acrylate polymer, and the content of the adhesive agent can be from 40.0% to 70.0% by weight, specifically from 50.0% to 60.0% by weight, but is not limited thereto, based on the total weight of the entire drug-containing adhesive layer.

[0043] At this point, the term "functional group" refers to the common atomic group that causes the properties of acrylate polymers with the same chemical properties, such as OH group, COOH group, etc.

[0044] In this invention, the non-functional acrylate polymer that can be used as an adhesive can be DURO-TAK 87-4098 (Acrylate copolymer) obtained by synthesizing vinyl acetate monomers and acrylic monomers, or DURO-TAK 87-9301 and GELVA GMS 3083 obtained by synthesizing acrylic monomers.

[0045] In this invention, lauryl polyoxyethylene ether-2, as a transdermal absorption enhancer, is included in the drug-containing adhesive layer. Although the addition of lactic acid can inhibit the formation of donepezil drug crystals in the transdermal absorption formulation, there is a problem that the desired level of transdermal permeability cannot be guaranteed. At this point, when an appropriate amount of lauryl polyoxyethylene ether-2 is included among various transdermal absorption enhancers, the following advantages are achieved: while inhibiting the formation of donepezil drug crystals in the transdermal absorption formulation, the desired level is also achieved, i.e., compared to currently commercially available Donerion patches (manufacturer: Celltrion), although the drug loading is lower, the AUC... (0-72) and C max In terms of values, donepezil has significantly higher drug absorption, thus offering the advantage of achieving significantly higher transdermal penetration than Donerion patches (manufacturer: Celltrion).

[0046] Specifically, for the currently commercially available Donerion patches, it is known that each patch is 25cm in size. 2Based on this, it contains 87.5 mg of donepezil and is administered twice weekly (alternating between 3-day and 4-day intervals) at bedtime, and contains glyceryl monooleate as an additive (transdermal absorption enhancer). However, for the transdermal absorption formulation according to the invention, at a 25 cm... 2 Based on this, the drug loading is 26.67 mg, containing significantly less drug than the Donerion patch (which will be detailed below), and is administered at 1-day intervals between patches.

[0047] However, in order to significantly improve donepezil absorption even with a significantly reduced drug loading compared to Donerion patches, the inventors of this invention conducted research and development using lauryl polyoxyethylene ether-2, which was introduced to solve the lactic acid problem. Animal experiments confirmed that it can significantly improve donepezil absorption compared to commercially available Donerion patches. Therefore, it can be considered that its efficacy is superior even among existing Donerion patches.

[0048] In this invention, based on the total weight of the drug-containing adhesive layer, the content of the transdermal absorption enhancer can be from 10.0% to 30.0% by weight, specifically from 15.0% to 25.0% by weight, and more specifically from 19.0% to 23.0% by weight, but is not limited thereto. Based on the total weight of the drug-containing adhesive layer, when the content of the transdermal absorption enhancer is less than 19.0% by weight, there is a problem of poor drug penetration; when it exceeds 23.0% by weight, there is a problem of increased drug stability within the transdermal absorption formulation, thus reducing the penetration rate.

[0049] In this invention, the drug-containing adhesive layer may also contain a crystallization inhibitor, but is not limited thereto.

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

[0051] In this invention, the drug-containing adhesive layer constituting a transdermal absorption formulation contains, in addition to the active ingredient donepezil or a pharmaceutically acceptable salt thereof, lactic acid as a crystallization inhibitor. The inclusion of lactic acid has the advantage of inhibiting donepezil drug crystallization within the transdermal absorption formulation even after prolonged exposure to room temperature.

[0052] In this invention, based on the total weight of the drug-containing adhesive layer, the content of lactic acid as a crystallization inhibitor can be 3.0 to 4.5% by weight, specifically 3.5 to 4.0% by weight, but not limited thereto.

[0053] In this invention, the support layer may be selected from the group consisting of polyester film, polyethylene (PE) film, polypropylene (PP) film, ethylene-vinyl acetate (EVA) film, nylon film, polyurethane film, nonwoven / PET composite material, PET / PE composite material and PET / EVA composite material, but is not limited thereto.

[0054] In this invention, the release layer is a silicon-treated layer, specifically selected from the group consisting of polyethylene terephthalate (PET) film, polyvinyl chloride film, polyvinylidene chloride film, polyethylene terephthalate (PET) film, polyethylene (PE) film, polyethylene / paper composite material, PET / PE composite material, and PET / EVA composite material, but not limited thereto.

[0055] In this invention, the release layer portion that is in direct contact with the drug layer should be treated with a thin coating on a polyethylene terephthalate (PET) film or the like so that the drug layer can be easily peeled off. Therefore, a silicone-treated film is preferably used on the surface of the release layer.

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

[0057] In this invention, the loading dose of donepezil or its pharmaceutically acceptable salt in each transdermal formulation varies depending on the size of the transdermal formulation. Specifically, when the size of the transdermal formulation is 5 cm... 2 10cm 2 20cm 2 30cm 2 40cm 2 At that time, the loading doses of donepezil or its pharmaceutically acceptable salts were 6.668 mg, 13.335 mg, 26.67 mg, 40.00 mg, and 53.34 mg, respectively.

[0058] In this invention, the administration of the transdermal absorption formulation may be to apply one patch daily to patients with Alzheimer's dementia symptoms to administer donepezil, but is not limited to this method.

[0059] The present invention will now be described in detail with reference to embodiments and comparative examples. It should be noted that the following embodiments and comparative examples are only for illustrative purposes and the scope of the present invention is not limited thereto.

[0060] Examples and Comparative Examples

[0061] Examples 1-4 and Comparative Examples 1-2: Preparation of transdermal absorption formulations (patches) containing donepezil

[0062] Example 1

[0063] Based on the prescriptions described in Table 1 below, a transdermal absorption formulation (patch) containing donepezil according to Example 1 was prepared in the order described below.

[0064] Preparation method

[0065] 1. Mix ethanol and ethyl acetate to prepare solution 1.

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

[0067] 3. Dissolve lauryl alcohol polyoxyethylene ether-2 (product name: MONOPOL LAE2 BL-2), lactic acid (product name: Lacticacid), and butylated hydroxytoluene (product name: BHT (Butylated Hydroxytoluene)) in the above solution 2 to prepare solution 3.

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

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

[0070] 6. Using the solution 5, apply / dry / bond the patch under the following conditions to prepare the patch (patch size: 20cm). 2 ).

[0071] ① Coating / Drying: Solution 5 is uniformly coated onto a polyethylene terephthalate film (PET film, manufacturer: Kiseunginc.co) as a release layer (also known as a cover layer), with a thickness of approximately 185-195 μm, and dried in a 90°C chamber for 2 minutes and 30 seconds to prepare a drug-containing adhesive layer.

[0072] ② Lamination: Then, a polyester film (PE film, tentative name, manufacturer: 3M) is laminated onto the coated medicated adhesive layer, and then cut after pressing with a pressure roller to prepare the patch.

[0073] Example 1 Prescription

[0074] Table 1

[0075] Example 2

[0076] Based on the prescriptions described in Table 2 below, a transdermal absorption formulation (patch) containing donepezil according to Example 2 was prepared using the method described in Example 1 above.

[0077] Example 2 Prescription

[0078] Table 2

[0079] Example 3

[0080] Based on the prescriptions listed in Table 3 below, transdermal absorption formulations (patches) containing donepezil were prepared in the order described below.

[0081] Preparation method

[0082] 1. Mix ethanol and ethyl acetate to prepare solution 1.

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

[0084] 3. Dissolve lauryl alcohol polyoxyethylene ether-2 (product name: MONOPOL LAE2), lactic acid (product name: Lacticacid), and butylated hydroxytoluene (product name: BHT (Butylated Hydroxytoluene)) in the above solution 2 to prepare solution 3.

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

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

[0087] 6. Using the solution 5, apply / dry / bond the patch under the following conditions to prepare the patch (patch size: 30cm). 2 ).

[0088] ① Coating / Drying: Solution 5 is uniformly coated onto a polyethylene terephthalate film (PET film, manufacturer: Kiseunginc.co) as a release layer (also known as a cover layer), with a thickness of approximately 185-195 μm, and dried in a 90°C chamber for 2 minutes and 30 seconds to prepare a drug-containing adhesive layer.

[0089] ② Lamination: Then, a polyester film (PE film, tentative name, manufacturer: 3M) is laminated onto the coated medicated adhesive layer, and then cut after pressing with a pressure roller to prepare the patch.

[0090] Example 3 Prescription

[0091] Table 3

[0092] Example 4

[0093] Based on the prescriptions described in Table 4 below, a transdermal absorption formulation (patch) containing donepezil according to Example 4 was prepared using the method described in Example 3 above.

[0094] Example 4 Prescription

[0095] Table 4

[0096] Comparative Example 1

[0097] Based on the prescriptions recorded in Table 5 below, a transdermal absorption formulation (patch) containing donepezil according to Comparative Example 1 was prepared using the method described in Example 1 above.

[0098] Comparative Example 1 Prescription

[0099] Table 5

[0100] Comparative Example 2

[0101] Based on the prescriptions described in Table 6 below, a transdermal absorption formulation (patch) containing donepezil according to Comparative Example 2 was prepared using the method described in Example 3 above.

[0102] Comparative Example 2 Prescription

[0103] Table 6

[0104] The present invention will now be described in detail based on experimental examples. It should be noted that the following experimental examples are for illustrative purposes only, and the scope of the present invention is not limited thereto.

[0105] Experimental Example

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

[0107] 1. Experimental Methods

[0108] For donepezil, the following problem exists when formulating it into a patch: drug crystallization occurs. As crystals form, the adhesion of the transdermal absorption formulation decreases, leading to a reduction in drug absorption rate. Therefore, it was investigated whether lactic acid could be used to inhibit drug crystallization.

[0109] Specifically, Table 7 below shows the formulations used to confirm the effects of adding lactic acid. After preparing transdermal absorption formulation samples according to the following formulations, they were stored at room temperature (20–25°C) for 5 months. The surface of the drug-containing adhesive layer in the transdermal absorption formulation samples was then compared and evaluated using both naked-eye observation and an optical microscope (OLYMPUS-CX41, x100 (100x magnification), x200 (200x magnification)). The results are shown in Table 7. Figure 1 .

[0110] Table 7

[0111] 2. Experimental Results

[0112] Reference Figure 1 It can be seen that for transdermal absorption formulations containing lactic acid, even after 5 months at room temperature, no crystals formed on the surface of the drug-containing adhesive layer, which remained smooth and uniform.

[0113] However, for transdermal absorption formulations without added lactic acid, crystals formed in the drug-containing adhesive layer after 5 months at room temperature, and the surface of the drug-containing adhesive layer was found to be uneven by visual inspection and microscopy.

[0114] Therefore, it was confirmed that adding lactic acid can inhibit the formation of donepezil drug crystals in transdermal absorption formulations.

[0115] Experimental Example 2: Confirming the effect of additives on transdermal penetration

[0116] 1. Background and Experimental Methods

[0117] <Background>

[0118] It was confirmed that while adding lactic acid (according to the formulation in Table 8 below) can inhibit the formation of donepezil drug crystals in transdermal absorption formulations, it cannot guarantee the desired level of transdermal penetration (see Table 9 and...). Figure 2 The percutaneous permeability test was performed in the same manner as described below.

[0119] - The original dosage of added lactic acid

[0120] Table 8

[0121] - Transdermal penetration (ug / cm) in human cadaver skin when lactic acid is added 2 )

[0122] Table 9

[0123] Accordingly, it was confirmed whether transdermal penetration could be improved by adjusting the content of lauryl alcohol polyoxyethylene ether-2 (product name: NIKKOL BL-2) as a transdermal absorption enhancer, polyvinylpyrrolidone (product name: PVP 90) as a thickener, and acrylic adhesives.

[0124] <Experimental Methods>

[0125] Specifically, using the formulations S-21, S-22, S-24, S-25, and S-26 listed in Table 10 below, transdermal absorption formulation (patch) samples were prepared using the method described in Example 1. Human cadaver skin (Human epidermis, 3×3cm) was then used. 2 The drug absorption of transdermal formulations prepared according to formulations S-21, S-22, S-24, S-25, and S-26 was evaluated. Skin permeability testing was performed using a 1.77 cm² skin membrane. 2 The diffusion was performed using a Franz-type diffusion cell in the diffusion area. The receiving chamber solution volume was 12.5 ml. Transdermal absorption formulations (patches) prepared according to formulations S-21, S-22, S-24, S-25, and S-26 were pressed firmly against the skin of cadavers, with the skin / patch layer facing the receiving chamber solution. The donor and receiving chambers of the Franz cell were fixed together using clamps. Phosphate buffer (pH 6.0) was added to the receiving chamber of the Franz cell, and the diffusion apparatus temperature was maintained at 32°C. The receiving chamber buffer was stirred at a constant speed of 600 rpm, and 0.2 ml samples were taken from the receiving chamber at sampling points of 4, 8, 12, 16, 20, and 24 hours. To maintain sink conditions, the same volume of fresh phosphate buffer was added. The cumulative release of donepezil through skin penetration was analyzed by HPLC and shown in the figure. Figure 3 The skin penetration rate is shown in Table 11.

[0126] HPLC conditions

[0127] Chromatographic column: 15cm × 4.6mm, C18, 5μm particle size

[0128] Mobile phase: Acetonitrile / buffer solution (35:65), adjusted to pH 1.8 with perchloric acid. Buffer solution: The solution obtained by dissolving 3.9 g of sodium 1-decanesulfonate in 1 L of water. Detection wavelength: 271nm Flow rate: 1.4 mL / min Injection volume: 20 μl Column temperature: 35℃ Table 10

[0129] 2. Experimental Results

[0130] The cumulative value of donepezil present in the sample at each sampling time point corresponds to the amount of donepezil permeating the membrane in the transdermal absorption formulation.

[0131] Reference Figure 3 As shown in Table 11, excessive addition of lauryl alcohol polyoxyethylene ether-2 (product name: MONOPOL LAE2), a transdermal absorption enhancer, actually leads to a decrease in penetration rate (Formula S-21). The reason given is that adding more than a certain amount increases the stability of the drug within the transdermal absorption formulation, thereby reducing the penetration rate.

[0132] Furthermore, it was confirmed that the higher the concentration of lauryl alcohol polyoxyethylene ether-2 (product name: MONOPOLLAE2), which acts as a transdermal absorption enhancer (S-22 vs S-24), and the lower the PVP concentration (S-21 vs S-26), the higher the penetration rate.

[0133] In addition, it can be confirmed that the amount of acrylic adhesive used does not significantly affect the penetration rate.

[0134] The above results confirm that, for the problems caused by the addition of lactic acid, the use of an appropriate amount of lauryl alcohol polyoxyethylene ether-2 (product name: MONOPOL LAE2) as a transdermal absorption enhancer can both inhibit the formation of donepezil drug crystals in transdermal absorption formulations and ensure the desired level of transdermal absorption.

[0135] Table 11

[0136] Experimental Example 3: Comparison of donepezil blood concentrations with commercially available Donerion patches (manufacturer: Celtran)

[0137] Experimental Example 2 above confirmed that by using an appropriate amount of lauryl polyoxyethylene ether-2 (product name: MONOPOL LAE2) as a transdermal absorption enhancer, the desired level of transdermal absorption can be ensured while inhibiting the formation of donepezil drug crystals in the transdermal absorption formulation. Therefore, in the formulation of the embodiments of the present invention, in particular, a comparative analysis of donepezil blood concentrations between the patch according to Example 2 and the currently commercially available Donerion patch (manufacturer: Celltrion) was conducted through animal experiments.

[0138] 1. Test Methods

[0139] (1) Animal species / strain

[0140] Specific Pathogen Free Rats / Hairless Wistar Yagi / Slc Rats

[0141] (2) Animal information

[0142] Animal information is shown in Table 12 below.

[0143] Table 12

[0144] (3) Administration method

[0145] After securing the experimental animal, disinfect the area around the patch application site with rubbing alcohol. Apply the patch to the back, and to prevent damage, cover and secure the patch with a Tegaderm film (#1624W, 3M, USA) to stabilize the animal.

[0146] (4) Composition and dosage

[0147] The composition and dosage are shown in Table 13 below. Figure 4 As shown.

[0148] Table 13

[0149] (5) Sample collection time

[0150] 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 18, 24, 36, 48, 60, 72 hours

[0151] (6) Sample removal

[0152] The sample was peeled off the skin 24 hours after administration. Blood was collected 72 hours after peeling.

[0153] (7) Blood collection and separation of plasma samples

[0154] Blood was drawn from all surviving animals (including those scheduled for dissection), after which the animals were fasted for at least 16 hours (water was provided). After securing the animals, blood was drawn via the jugular vein using a sterile syringe (26G needle, Korean Vaccine, made in Korea), with approximately 200-300 μL of blood collected each time. The collected blood was immediately transferred to a 0.5 mL K2 EDTA tube (#365974, BD, made in the USA) containing anticoagulant, and thoroughly mixed with the anticoagulant using a roller mixer (208RM, HST, made in China). The collected blood was then centrifuged for 15 minutes at 4°C and 3,000 rpm using a refrigerated centrifuge (Combi R515, Hanil Scientific, made in Korea) within 30 minutes to separate the plasma. The separated plasma was aliquoted into 1.7 mL microcentrifuge tubes (MCT-175-C, Axygen, USA) in portions of approximately 100 μL each, stored in an ultra-low temperature freezer (NU-9483GC, NuAire, USA) at -70±10℃, and subjected to PK analysis after the experiment.

[0155] (8) Plasma analysis

[0156] Donepezil hydrochloride standard was dissolved in methanol to prepare a 1 mg / mL donepezil hydrochloride stock solution, which was stored at -20 to -10°C. Donepezil hydrochloride-d7 standard (used as an internal standard) was dissolved in methanol to prepare a 1 mg / mL internal standard stock solution, which was also stored at -20 to -10°C. Blank plasma from rats was mixed with the corresponding standard solution (blank plasma: standard solution = 19:1). 50 μL of plasma sample was added, along with 50 μL of the internal standard diluted in 50% methanol (10 ng / mL) and 950 μL of methyl tert-Butyl Ether. The sample was extracted for 5 minutes using an Automatic Fine Vortex mixer (SH2000, FINEPCR, Korea), and then centrifuged for 3 minutes using a Smart R17 Plus centrifuge (HANIL, Korea) to precipitate the sample. Take 850 μL of the separated supernatant, dry it with N2 gas at 40 °C, add 400 μL of mobile phase (10 mM ammonium formate (0.1% formic acid): methanol = 40:60 (v / v)) to the residue for redissolution, centrifuge for 2 minutes, and inject 4 μL of supernatant into LC-MS / MS.

[0157] (9) Processing of plasma samples

[0158] Plasma samples collected from all experimental animals at various time points and stored in an ultra-low temperature freezer (-70±10℃) were thawed at room temperature, and 50 μL of each sample was pretreated using the same method as for the calibration curve and injected into the LC / MS / MS system.

[0159] (10) Calculation of plasma concentration

[0160] The ratio of the peak area of ​​the analyte to the peak area of ​​the internal standard was determined from the obtained chromatogram, and the concentration of the analyte in the plasma (ng / mL) was calculated from the pre-prepared calibration curve.

[0161] (11) Statistical processing of analysis results

[0162] Statistical analysis was performed using the Phoenix WinNonlin (version 6.4, CERTARA, USA) program based on the plasma drug concentration-time curve.

[0163] 2. Experimental Results

[0164] (1) Average and deviation of donepezil concentration in blood

[0165] The average and deviation of donepezil concentration in the blood are shown in Table 14 below.

[0166] Table 14

[0167] (2) Donepezil blood concentration

[0168] Donepezil blood concentrations are shown as follows Figure 5 .

[0169] (3) Pharmacokinetic characteristics of donepezil after administration

[0170] The pharmacokinetic characteristics of donepezil after administration are shown in Table 15 below.

[0171] Table 15

[0172] (4) AUC between the Donerion patch and the patch according to Example 2 (0-72) C max Ratio comparison

[0173] The AUC between the Donerion patch and the patch according to Example 2 (0-72) C max The ratios are shown in Table 16 below.

[0174] Table 16

[0175] (5) Conclusion and Investigation

[0176] - Donerion patch and the patch according to Example 2 showed that the AUC of the Donerion patch was lower than that of the patch in animals (~72 hours). (0-72) It is 256.15 ng·h / mL, C max The AUC of the patch according to Example 2 was 14.93 ng / mL. (0-72) It is 1197.02 ng·h / mL, C max It was 97.54 ng / mL.

[0177] - Compare the AUC between the two patches (0-72) and C max The ratio results showed that, according to Example 2, the patch had an AUC 461% higher than the Donerion patch, and C... max The absorption rate was 592.8%. This confirms that, according to Example 2, the donepezil absorption was significantly higher than that of the Donerion patch.

[0178] This result can be attributed to the inclusion of lauryl alcohol polyoxyethylene ether-2, which acts as a transdermal absorption enhancer, in the drug-containing adhesive layer of the transdermal absorption formulation.

[0179] The foregoing has described specific aspects of the present invention in detail. These specific techniques will be recognized by those skilled in the art as preferred embodiments only, and it is clear that the scope of the present invention is not limited thereto. Therefore, the essential scope of the present invention should be defined by the appended claims and their equivalents.

Claims

1. A transdermal absorption formulation, comprising: The drug-containing adhesive layer comprises donepezil or a pharmaceutically acceptable salt thereof as the active ingredient and lauryl alcohol polyoxyethylene ether-2 as a transdermal absorption enhancer; Support layer; and Peel-off layer.

2. The transdermal absorption formulation according to claim 1, characterized in that, Based on the total weight of the drug-containing adhesive layer, it contains 10.0 to 20.0% by weight of donepezil or a pharmaceutically acceptable salt thereof as the active ingredient.

3. The transdermal absorption formulation according to claim 1, characterized in that, Based on the total weight of the drug-containing adhesive layer, the content of the transdermal absorption enhancer is 10.0 to 30.0% by weight.

4. The transdermal absorption formulation according to claim 1, characterized in that, The drug-containing adhesive layer also contains a crystallization inhibitor.

5. The transdermal absorption formulation according to claim 4, characterized in that, The crystallization inhibitor is lactic acid.

6. The transdermal absorption formulation according to claim 4, characterized in that, Based on the total weight of the drug-containing adhesive layer, the content of lactic acid, which is the crystallization inhibitor, is 3.0 to 4.5% by weight.

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