Transdermal absorption preparation containing memantine enanthate for the treatment of dementia

Abstract

The present invention provides a memantine-containing transdermal preparation for treating dementia, which is composed of a support layer, a drug-containing layer, and a release layer, and the drug-containing layer contains memantine enanthate, a solubilizer, and an adhesive. The transdermal preparation for treating dementia according to the present invention is free of crystal precipitation, exhibits high skin permeability, and not only can the clinically usable patch area be easily adjusted, but also can minimize skin irritation caused by the drug by controlling the skin absorption rate through adjustment of the release rate, thereby minimizing drug loss, realizing economic advantages, and preventing drug overdosage.

Description

[Technical field]

[0001] The present invention relates to an improved pharmaceutical salt of memantine, and a transdermal absorption preparation for treating dementia which contains the same and has excellent skin permeability, sustained long-term release, and low skin irritation. [Background technology]

[0002] Alzheimer's dementia is caused by neurodegenerative processes along with cell loss in the cortex or brain regions. This is known to be caused by a decrease in acetylcholine, a neurotransmitter in the brain, or by overactivation of glutamate, another neurotransmitter, which induces neuronal death. In particular, glutamate is a neurotransmitter that plays a very important role in memory and learning. When glutamate continues to stimulate N-Methyl-D-aspartic acid (NMDA) receptors, excess calcium flows into neurons, causing the apoptosis process in which cellular components such as the cytoskeleton, cell membrane, and DNA are degraded, which is known to cause neurodegeneration in the long term.

[0003] Memantine is an NMDA receptor antagonist, and a representative commercially available product is Ebixa (registered trademark), an oral tablet approved by the US Food and Drug Administration in 2003. It has been reported that memantine's NMDA receptor blockade prevents neuronal damage that may occur in dementia patients, restores the physiological function of remaining neurons, and improves symptoms. It is more effective in moderate or severe Alzheimer's patients than in mild Alzheimer's patients, and is used alone or in combination with an acetylcholinesterase inhibitor in moderate to severe Alzheimer's disease when there is no clear improvement in symptoms even with the use of an acetylcholinesterase inhibitor. The initial dose of memantine is 5 mg, and is taken at 5 mg per day in the first week, 10 mg per day (1 / 2 tablet twice a day) in the second week, and 15 mg per day (1 tablet in the morning and 1 / 2 tablet in the evening) in the third week, and from the fourth week, the maintenance dose is 20 mg per day, with 10 mg tablets taken twice a day. Taking memantine oral tablets can cause side effects such as dizziness, headache, constipation, drowsiness, increased blood pressure, and difficulty breathing due to a sudden increase in blood concentration, and this poses problems in terms of ease of administration for elderly patients with reduced swallowing ability.

[0004] In addition, memantine currently available in the market as an oral preparation is in the form of a water-soluble hydrochloride, which is very difficult to dissolve in oil-based adhesives such as acrylic adhesives and rubber adhesives used in transdermal preparations, and there is a problem that memantine hydrochloride crystallizes and precipitates over time, which leads to a decrease in skin permeability and a decrease in adhesive strength, etc. Research has been conducted on transdermal preparations using memantine free base instead of memantine hydrochloride, and although memantine free base has a drug partition coefficient logP of 3.28, which makes it highly lipophilic and easy to permeate through the skin, it induces strong skin irritation and is highly volatile due to its physical properties of a melting point of less than 10°C, which can cause a decrease in the active drug and stability problems during the manufacture and storage of transdermal preparations.

[0005] In order to solve the problems associated with taking memantine-containing drugs, the side effects of the drugs, and the problems caused by the physicochemical properties of memantine salts, various studies have been conducted both domestically and internationally on transdermal preparations for treating dementia containing memantine or its salts. However, due to the low skin permeability and skin irritation of transdermal preparations, as well as problems with physicochemical stability due to crystal precipitation, there are currently no commercially available memantine-containing transdermal preparations.

[0006] Research attempting to overcome the low skin permeability and skin irritation safety issues of memantine-containing transdermal formulations has been disclosed in various prior art documents, such as U.S. Patent Publication No. 2019-0183810, Korean Patent Publication No. 2019-0032551, Korean Registered Patent Publication No. 10-1964295, U.S. Patent Publication No. 8,882,729, and WO2014 / 174564.

[0007] US Patent Publication No. 2019-0183810 relates to a transdermal formulation containing memantine free base, which is a volatile liquid or has a low melting point in an adhesive matrix, and counter anions of glycolate, lactate, alphahydroxybutyrate, pyruvate, acetoacetate and levulinate. The transdermal drug delivery system disclosed includes multiple drug-containing layers to prevent loss of the main component of memantine free base and achieve a therapeutic blood concentration of memantine for about 3 to 7 days, but the maximum skin permeability in human cadaver skin is 10 μg / cm. 2 / hr, which is an insufficient level and does not teach sufficient skin permeability and safety.

[0008] Korean Patent Publication No. 2019-0032551 relates to a multi-layered transdermal drug delivery system containing memantine base produced by reacting memantine hydrochloride with an alkali salt such as sodium bicarbonate or potassium bicarbonate in a drug reservoir layer. The system aims to prevent crystal precipitation due to low solubility, which is a problem that occurs when memantine hydrochloride, which is used as an oral formulation, is applied as a transdermal absorption formulation, and to improve low skin permeability, and to achieve a constant 15μg / cm2 per day on human cadaver skin.2 Although skin permeation was demonstrated at a level of 100 mg / hr, this does not teach about sufficient skin permeation and the safety of drug exposure in the blood and skin irritation.

[0009] Korean Patent Publication No. 10-1964295 relates to a transdermal preparation containing stearates, polymethacrylates, polyvinylpyrrolidone polymers having a molecular weight of 400,000 to 3,000,000, or mixtures thereof as release regulators in order to adjust the release rate for high skin permeation of memantine free base and minimize skin irritation during transdermal administration. This preparation has a skin absorption rate of 20 μg / cm for 24 hours in human cadaver skin. 2 / h level or less, erythema and edema due to human skin irritation are minimized, but there is no teaching about sustained skin permeation and safety of the drug when applied to a transdermal absorption preparation for a long period of time.

[0010] U.S. Patent Publication No. 8,882,729 relates to a transdermal therapeutic system containing memantine or one of its physiologically suitable salts, and discloses a multi-layered transdermal drug delivery system containing memantine free base produced by reacting memantine hydrochloride with an alkali salt such as calcium chloride, sodium ethanolate, etc. in a drug reservoir layer. This prior art discloses that the plasma concentration of memantine can be maintained in a rabbit animal model after 3 days of administration, and through a pharmacokinetic study at a 24-hour administration interval in a clinical trial, a minimum plasma concentration of 65 ng / mL or more was estimated after 300 hours. However, since no experimental data is disclosed in the prior art in relation to skin permeability, this does not teach about sustained skin permeation and safety when a long-term transdermal absorption preparation is actually applied.

[0011] WO2014 / 174564 relates to an adhesive patch drug formulation containing memantine or a pharma- ceutically acceptable salt thereof, the drug-containing layer of which contains an organic acid, such as dicarboxylic acids such as oxalic acid and azelaic acid; hydroxycarboxylic acids such as glycolic acid and lactic acid; aromatic carboxylic acids such as benzoic acid and salicylic acid; caproic acid, caprylic acid, capric acid, undecenoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, oleic acid and isostearic acid. This prior art discloses that the memantine content is maintained by suppressing memantine crystallization and memantine volatilization during patch production or storage, but no experimental data is disclosed in relation to skin permeability, and there is no teaching on sustained skin permeation and safety during actual long-term application of a transdermal preparation.

[0012] Therefore, in order to overcome the problems of memantine-containing transdermal preparations showing low skin permeability or strong skin irritation, the present inventors synthesized various novel salts that can be used pharmacologically for memantine free base, and through solubility evaluation in solubilizers (absorption enhancers or skin permeation enhancers), skin permeability evaluation, crystal precipitation evaluation, skin irritation evaluation in hairless mice and rabbits, and pharmacokinetic evaluation, found that a transdermal preparation containing memantine enanthate can be manufactured that has no crystal precipitation against various solubilizers, shows high skin permeability, and shows a constant release pattern for a long period of time, compared with transdermal preparations containing not only known memantine salts but also other novel salts. In addition, it was found that a transdermal preparation containing memantine free base shows moderate to high skin irritation such as severe erythema and edema, while a transdermal preparation containing memantine enanthate shows weak skin irritation when applied for 7 days, improving skin irritation, and thus the present invention was completed. Summary of the Invention [Problem to be solved by the invention]

[0013] The present invention aims to provide a transdermal absorption preparation containing a salt of memantine which is free from drug crystal precipitation of memantine, exhibits high skin permeability, has a constant release pattern for a long period of time, and has improved safety in terms of skin irritation. [Means for solving the problem]

[0014] The present invention provides an enanthate salt of memantine.

[0015] The memantine used in the drug-containing layer of the present invention is an NMDA receptor antagonist that selectively binds to the NMDA substance, which is a receptor for glutamate, an excitatory neurotransmitter in the brain, and protects against neuronal damage in the brain, and memantine enanthate is used.

[0016] For a memantine salt to meet the objectives of a transdermal formulation, it must satisfy four physicochemical criteria: (1) high solubility in the solubilizing agent, (2) excellent skin permeability, (3) minimal crystal precipitation, and (4) minimal skin irritation.

[0017] As can be seen from the following examples and experimental examples, the memantine enanthate of the present invention has a unique combination of excellent formulation properties that make it particularly suitable for memantine transdermal absorption formulations. That is, the memantine enanthate of the present invention exhibits properties that satisfy all of the above four conditions. However, none of the various salts comparatively tested in the present invention meet all of the above four criteria, and in particular, the commercially available memantine hydrochloride exhibited low solubility in the patch and low skin permeability.

[0018] Thus, the memantine enanthate of the present invention offers a unique combination of excellent solubility, excellent skin permeability, minimal crystal precipitation and minimal skin irritation that is highly suitable for the preparation of memantine-containing transdermal formulations.

[0019] Another aspect of the present invention provides a memantine-containing transdermal preparation for treating dementia, which is composed of a support layer, a drug-containing layer and a release layer, wherein the drug-containing layer contains memantine enanthate, a solubilizing agent and an adhesive.

[0020] The memantine enanthate contained in the drug-containing layer of the present invention can be contained in an amount of 1 to 20% by weight, preferably 1.5 to 15% by weight, and more preferably 2 to 10% by weight, based on the total weight of the drug-containing layer.

[0021] The solubilizer of the present invention may be a solubilizer having a solubility of 30 mg / ml or more for memantine enanthate. For example, propylene glycol monocaprylate, propylene glycol monolaurate, diisopropyl adipate, diisopropyl sebacate, oleic acid, isopropyl palmitate, glyceryl monocaprylate, isostearate, cocoyl caprylocaprate, cetyl 2-ethylhexanoate, oleoyl macrogol-6-glyceride, propylene glycol dicaprylocaprate, propylene glycol dicaprylocaprate, propylene glycol dicaprolate / dicaprate, glyceryl monooleate, 1-dodecyl-2-pyrrolidinone, linoleoyl macrogol-6 glyceride, polyglyceryl-3 dicap ... memantine enanthate has a solubility of 30 mg / ml or more, and preferably, one or more of propylene glycol monocaprylate, diisopropyl adipate, diisopropyl sebacate, isopropyl palmitate, isopropyl myristate, oleoyl macrogol-6-glyceride, isopropyl isostearate, and oleyl alcohol can be selected from the group consisting of propylene glycol monocaprylate, diisopropyl adipate, diisopropyl sebacate, isopropyl palmitate, isopropyl myristate, oleoyl macrogol-6-glyceride, isopropyl isostearate, and oleyl alcohol.

[0022] The content of such a solubilizer is from 1 to 40% by weight, preferably from 2 to 30% by weight, more preferably from 3 to 20% by weight, and even more preferably from 5 to 15% by weight, based on the total weight of the drug-containing layer, in order to ensure a sufficient skin permeation enhancing effect of the transdermal absorption preparation.

[0023] The adhesive of the present invention can be selected from styrene-isoprene-styrene block copolymers (SIS), acrylic polymers, or polyisobutylene polymers.

[0024] The acrylic polymer used in the present invention means a polymer that can be obtained by copolymerizing acrylic ester with acrylic acid or its derivative. For example, Duro-Tak 87-9301, Duro-Tak 87-2510, Duro-Tak 87-2287, Duro-Tak 87-4287, Duro-Tak 87-2516, Duro-Tak 87-235A, Duro-Tak 87-2051, etc. are included, but are not limited thereto. The content of such acrylic polymer is 50% by weight or more and 90% by weight or less, preferably 55% by weight or more and 85% by weight or less, more preferably 65% ​​by weight or more and 75% by weight or less, and even more preferably 70% by weight or more and 80% by weight or less, based on the total weight of the drug-containing layer.

[0025] The polyisobutylene polymer used in the present invention is a polymer produced by polymerizing isobutylene, and may have a molecular weight in the range of 500 to 1,000,000 or more. The content of the polyisobutylene polymer is usually 10% by weight or more, preferably 20% by weight or more, more preferably 30% by weight or more, and even more preferably 40% by weight or more, based on the total weight of the drug-containing layer, and usually 90% by weight or less, preferably 80% by weight or less, more preferably 70% by weight or less, and even more preferably 60% by weight or less.

[0026] A particularly preferred adhesive in the present invention is a rubber-based adhesive, a styrene-isoprene-styrene block copolymer. The styrene-isoprene-styrene block copolymer is a thermoplastic elastomer made of styrene and isoprene, and various properties such as melting point and solution viscosity change depending on the styrene content and diblock content in the styrene-isoprene-styrene block copolymer rubber.

[0027] The styrene-isoprene-styrene block copolymer used in the present invention is not particularly limited, but preferably, when the solution viscosity of the styrene-isoprene-styrene block copolymer is measured according to the "Method for measuring viscosity of styrene-isoprene-styrene block copolymer" described in the 2013 edition of the Japanese Pharmaceutical Excipients Standards Collection, the lower limit of the solution viscosity is 0.5 Pa*s or more, preferably 0.7 Pa*s or more, and more preferably 0.9 Pa*s or more, and the upper limit of the solution viscosity is not particularly limited, but is 2.0 Pa s or less, preferably 1.8 Pa s or less.

[0028] If the adhesive content in the drug-containing layer is too low, it is difficult to maintain the shape of the drug-containing layer, and if it is too high, there is a drawback of reduced skin permeability of the drug. Therefore, the content of the styrene-isoprene-styrene block copolymer of the present invention is 10% by weight or more and 70% by weight or less, more preferably 15% by weight or more and 65% by weight or less, even more preferably 20% by weight or more and 60% by weight or less, and particularly preferably 25% by weight or more and 55% by weight or less, based on the total weight of the drug-containing layer.

[0029] The adhesive composition in the transdermal dosage form provided by the present invention can contain a plasticizer. Plasticizers that can be used in the present invention include, but are not limited to, paraffinic process oil, naphthenic process oil, aromatic process oil, olive oil, camellia oil, tall oil, castor oil, isopropyl myristate, hexyl laurate, mineral oil, octyldodecyl myristate, propylene glycol, and propylene glycol monocaprylate. These components may be used in combination of two or more kinds, and the content of such plasticizers is 10% by weight or more and 80% by weight or less, preferably 20% by weight or more and 75% by weight or less, more preferably 25% by weight or more and 70% by weight or less, and even more preferably 30% by weight or more and 65% by weight or less, based on the total weight of the drug-containing layer, in consideration of maintaining sufficient cohesive force of the transdermal preparation.

[0030] A tackifier resin can be added to the drug-containing layer of the present invention to adjust the adhesive strength of the transdermal preparation. Examples of tackifier resins that can be used include rosin derivatives, alicyclic saturated hydrocarbon resins, and aliphatic hydrocarbon resins. In the present invention, terpene resins are typically used, but are not limited to these. However, when a tackifier is contained in the drug-containing layer, the content of the tackifier in the drug-containing layer is preferably 20% by weight or less, preferably 15% by weight or less, more preferably 10% by weight or less, and even more preferably 8% by weight or less, based on the total weight of the drug-containing layer, in order to reduce skin irritation, and the like, and it is most preferable that there is no tackifier. That is, in relation to the skin adhesive strength of the patch, the content of the tackifier can be adjusted according to the type and blending ratio of memantine enanthate, styrene-isoprene-styrene block copolymer, solubilizer, and plasticizer in the drug-containing layer. Also, if sufficient skin adhesive strength is obtained without the addition of a tackifier, a tackifier is not necessary.

[0031] The "support" of the support layer in the present invention is not particularly limited, and can be one commonly used for transdermal absorption preparations. For example, elastic or non-elastic woven or non-woven fabrics such as polyethylene, polypropylene, polyethylene terephthalate, polyesters such as polyethylene terephthalate, polyolefins such as polyethylene and polypropylene, films such as polyurethane, ethylene vinyl acetate copolymer, polyvinyl chloride, or foam supports such as polyolefins and polyolefins. These may be used alone or in combination. In order to prevent static electricity from accumulating in the support, an antistatic agent may be contained in the electrowoven fabric, nonwoven fabric, film, etc. constituting the support. In order to obtain good anchoring properties with the adhesive layer, a nonwoven fabric or a laminate of a film can be used as the support. The thickness of the support is usually 10 μm to 100 μm, preferably 15 μm to 50 μm for films, and usually 50 μm to 2,000 μm, preferably 100 μm to 1,000 μm for porous sheets such as woven fabric, nonwoven fabric, and foam supports.

[0032] The release layer in the present invention may be a general release liner commonly used for transdermal preparations. Examples of the release liner include glassine paper, polyolefins such as polyethylene and polypropylene, polyesters such as polyethylene terephthalate, resin films such as polystyrene, aluminum films, foamed polyethylene films or foamed polypropylene films, and may further include those processed with silicone or fluororesin, embossed, hydrophilic, or hydrophobic. The thickness of the release liner is usually 10 μm to 200 μm, and preferably 15 μm to 150 μm.

[0033] Furthermore, the percutaneous absorption preparation of the present invention may contain additives, solubilizers, percutaneous absorption enhancers, flavoring agents, coloring agents, and the like.

[0034] In the present invention, the method for producing the transdermal preparation includes dissolving or dispersing an adhesive, memantine enanthate, a stabilizer, a plasticizer, etc. in a solvent, combining them, applying the obtained solution or dispersion onto the surface of a release layer, drying it, and then laminating a support. In one embodiment of the present invention, the memantine transdermal preparation can be produced by including the steps of (1) dissolving memantine enanthate and the solubilizer mixture according to the present invention in an organic solvent, (2) applying the solution prepared in the above step onto a release layer and drying it to form a drug-containing layer, and (3) laminating the drug-containing layer with a support layer.

[0035] Examples of the solvent used in the preparation method according to the present invention include ethyl acetate, toluene, hexane, 2-propanol, methanol, ethanol, methylene chloride, and tetrahydrofuran. The temperature at which the adhesive is dissolved or dispersed in the solvent is not particularly limited. However, the higher the temperature, the higher the possibility of the solvent evaporating, and memantine enanthate may be decomposed depending on the temperature to produce a large amount of related substances. Therefore, the temperature is preferably 80° C. or less, more preferably 60° C. or less.

[0036] In addition, the method of applying the solution or dispersion obtained in the above embodiment onto the surface of the release layer, the method of drying, and the method of laminating the support can be produced by the same methods as those for producing conventional transdermal preparations.

[0037] The percutaneous absorption preparation of the present invention can use an antioxidant as necessary. The antioxidant can be a commonly known antioxidant or its derivative, and examples thereof include, but are not limited to, ascorbic acid, its ester derivatives, sodium bisulfite, dibutylhydroxytoluene, butylhydroxyanisole, cysteine, glutathione, tryptophan, methionine, methasulfonic acid, malic acid, citric acid, benzotriazole, monothioglycerin, etc. Effect of the Invention

[0038] The transdermal formulation containing memantine enanthate according to the present invention exhibits high skin permeability without drug crystal precipitation, has a constant release pattern for a long period of time, and minimizes skin irritation, improving safety.

[0039] Therefore, the transdermal preparation according to the present invention can be effectively used in place of conventional oral agents for treating dementia. [Brief description of the drawings]

[0040] [Figure 1] 1 shows the solubility of memantine enanthate and memantine levulinate depending on the type of solubilizer.

[0041] [Diagram 2] 1 shows the skin permeability of a transdermal absorption preparation according to the type of memantine salt.

[0042] [Diagram 3] 1 shows the skin permeability depending on the type of memantine salt with respect to the solubilizer diisopropyl sebacate.

[0043] [Figure 4] 1 shows the skin permeability depending on the type of memantine salt with respect to the solubilizer diisopropyl adipate.

[0044] [Diagram 5] 1 shows the skin permeability depending on the type of memantine salt with respect to the solubilizer isopropyl palmitate.

[0045] [Figure 6] 1 shows the skin permeability depending on the type of memantine salt with respect to the solubilizer isopropyl myristate.

[0046] [Figure 7] 1 shows the skin permeability of different memantine salts relative to the solubilizer oleoyl macrogol-6-glyceride.

[0047] [Figure 8] 1 shows the skin permeability depending on the type of memantine salt with respect to the solubilizer isopropyl isostearate.

[0048] [Figure 9] 1 shows the skin permeability depending on the type of memantine salt with respect to the solubilizer oleyl alcohol.

[0049] [Figure 10] 1 shows the skin permeability of a memantine enanthate transdermal formulation when the amount of solubilizer is reduced and when the adhesive is changed.

[0050] [Figure 11] The evaluation of skin irritation in rabbits is shown.

[0051] [Figure 12] 1 shows the blood concentration profile of a transdermal formulation containing memantine enanthate in rabbits.

[0052] [Figure 13] 1 shows the blood concentration profile of a transdermal formulation containing memantine enanthate in hairless mice.

[0053] [Figure 14] 1 shows blood concentration profiles according to size and dose of a memantine enanthate-containing transdermal formulation in hairless mice.

[0054] [Figure 15] 1 shows the maximum blood concentration and blood drug concentration-time area under the curve profiles according to size and dose of a transdermal formulation containing memantine enanthate in hairless mice.

[0055] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0056] The present invention will be described in more detail below with reference to examples and experimental examples. These examples and experimental examples are intended to specifically explain the present invention, and the scope of the present invention is not limited by these examples and experimental examples.

[0057] <Production Example 1> Preparation of Memantine Salts

[0058] 1. Preparation of Memantine Enanthate

[0059] 170.0 g of memantine free base was added to the reaction section, followed by 3.4 L of acetonitrile. 124.1 g of enanthic acid was added and stirred at 60°C for 1 hour. The mixture was cooled to room temperature and stirred overnight. The resulting solid was filtered, washed with acetonitrile, and vacuum dried at room temperature overnight to obtain 269.5 g (91%) of the title compound.

[0060] 1H NMR (400MHz, DMSO-d6): 2.07 (m, 3H), 1.44 (t, 2H), 1.42 (s, 1H), 1.22 (m, 10H), 1.06 (d, 1H), 1.02 (d, 1H), 0.84 (t, 3H), 0.79 (s, 6H)

[0061] 2. Manufacturing of Memantine Lactate

[0062] 30.0 g of memantine free base was added to the reaction section, followed by 600 mL of isopropyl ether. 15.2 g of lactic acid was added, followed by stirring at 60°C for 1 hour. After stirring at room temperature for 3 hours, the resulting solid was filtered, washed with isopropyl ether, and vacuum dried at room temperature overnight to obtain 42.2 g (93%) of the title compound.

[0063] 1H NMR (400MHz, DMSO-d6): 3.57 (m, 1H), 2.11 (s, 1H), 1.56 (s, 2H), 1.38 (dd, 2H), 1.08 (m, 6H), 0.82 (s, 6H)

[0064] 3. Manufacturing of Memantine Caprylate

[0065] 3.0 g of memantine free base was added to the reaction section, followed by 30 mL of acetone. 2.7 mL of caprylic acid was added, followed by stirring at 60°C for 30 minutes. The mixture was cooled to room temperature and stirred overnight. The resulting solid was filtered, washed with acetone, and vacuum dried at room temperature overnight to obtain 4.6 g (85%) of the title compound.

[0066] 1H NMR (600MHz, DMSO-d6): 2.05(s, 1H), 2.02(t, 2H), 1.42-1.44(m, 4H), 1.22-1.28(m, 16H), 1.08(dd, 1H), 1.02(dd, 1H), 0.84(t, 3H), 0.79(s, 6H)

[0067] 4. Manufacturing of Memantine Levulinate

[0068] 180.0g of memantine free base was added to the reaction section, followed by 450mL of acetone and 450mL of ethyl acetate. 117.2g of levulinic acid was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and 900mL of n-hexane was added to the concentrated residue. After stirring at room temperature for 3 hours, the solid was filtered, washed with n-hexane, and vacuum dried at room temperature overnight to obtain 277.5g (93%) of the title compound.

[0069] 1H NMR (400MHz, DMSO-d6): 2.49(t, 2H), 2.18(t, 2H), 2.07(s, 4H), 1.49(s, 1H), 1.30(d, 2H), 1.28(s, 2H), 1.24(d, 2H), 1.08(d, 1H), 1.04(d, 1H), 0.80(s, 6H)

[0070] 5. Manufacturing of Memantine Valerate

[0071] 2.0 g of memantine free base was added to the reaction section, and 40 mL of acetonitrile was added to dissolve it. 1.3 g of valeric acid was added, and the mixture was stirred at room temperature for 5 hours. The resulting solid was filtered, washed with a small amount of acetonitrile, and vacuum dried at room temperature overnight to obtain 2.80 g (89%) of the title compound.

[0072] 1H NMR (400MHz, DMSO-d6): 2.05 (s, 1H), 2.00 (t, 2H), 1.41 (m, 2H), 1.28 (d, 2H), 1.25(d, 2H), 1.21(s, 2H), 1.07(d, 1H), 1.03(d, 1H), 0.83(t, 3H), 0.79(s, 6H)

[0073] 6. Preparation of Memantine Xinafoate

[0074] 2.0 g of memantine free base was added to the reaction section, and then 20 mL of methanol was added to dissolve it. 2.3 g of 1-hydroxy-2-naphthoic acid was added and stirred at room temperature for 3 hours. Water (20 mL) was added to the reaction mixture, and then stirred for an additional 2 hours. The resulting solid was filtered, washed with a small amount of water, and vacuum dried at room temperature overnight to obtain 3.94 g (96%) of the title compound.

[0075] 1H NMR (400MHz, DMSO-d6): 8.16(d, 1H), 7.69(dd, 2H), 7.42(t, 1H), 7.35(t, 1H), 7.00(d, 1H), 2.12( s, 1H), 1.60(s, 2H), 1.41(d, 2H), 1.38(d, 2H), 1.26(s, 1H), 1.11(d, 1H), 1.06(d, 1H), 0.81(s, 6H)

[0076] 7. Preparation of memantine (+)-camphorsulfonate

[0077] 2.0 g of memantine free base was added to the reaction section, followed by 10 mL of acetone. 2.9 g of camphorsulfonic acid was added, followed by stirring at room temperature for 3 hours. The resulting solid was filtered, washed with acetone, and then vacuum-dried at room temperature overnight to obtain 4.3 g (93%) of the title compound.

[0078] 1H NMR (400MHz, DMSO-d6): 7.44 (bs, 1H), 3.35 (s, 1H), 2.85 (d, 1H), 2.68 (m, 1H), 2.77 (d, 1H), 2.21 (dd, 1H), 2.15 (m, 1H), 1.93 (t, 1H) , 1.85(m, 1H), 1.80(d, 1H), 1.59(s, 2H), 1.40(q, 4H), 1.28(m, 6H), 1.56(d, 1H), 1.08(d, 1H), 1.03(s, 3H), 0.84(s, 6H), 0.73(s, 3H)

[0079] 8. Preparation of memantine hemiadipate

[0080] 2.0 g of memantine free base was added to the reaction section, and then 60 mL of acetone was added to dissolve it. 0.82 g of adipic acid was added, and the mixture was heated to 60°C and stirred for 1 hour, cooled to room temperature, and stirred for 3 hours. The resulting solid was filtered, washed with 10 mL of acetone, and vacuum dried at room temperature overnight to obtain 2.75 g (76%) of the title compound.

[0081] 1H NMR (400MHz, DMSO-d6): 2.09(m, 2H), 2.04(s, 1H), 1.46(s, 2H), 1.38(s, 2H), 1.21(s, 2H), 1.16(d, 2H), 1.05(d, 1H), 1.02(d, 1H), 0.79(s, 6H)

[0082] 9. Preparation of memantine hemi-edisylate

[0083] 2.0 g of memantine free base was added to the reaction section, and then 60 mL of acetonitrile was added and dissolved. 1.06 g of edisylic acid was added, and the mixture was heated to 60°C and stirred for 1 hour, cooled to room temperature, and stirred for 3 hours. The resulting solid was filtered, washed with 10 mL of acetonitrile, filtered, and vacuum dried at room temperature overnight to obtain 2.50 g (82%) of the title compound.

[0084] 1H NMR (400MHz, DMSO-d6): 7.81 (s, 2H), 2.66 (s, 2H), 2.13 (s, 1H), 1.59 (s, 2H), 1.40(d, 2H), 1.37(d, 2H), 1.27(s, 2H), 1.12(d, 1H), 1.08(d, 1H), 0.83(s, 6H)

[0085] 10. Preparation of Memantine Hemifumarate

[0086] 2.0 g of memantine free base was added to the reaction section, and then 60 mL of acetone was added to dissolve it. 0.65 g of fumaric acid was added, and the mixture was heated to 60°C and stirred for 1 hour, cooled to room temperature, and stirred for 3 hours. The resulting solid was filtered, washed with 10 mL of acetone, and vacuum dried at room temperature overnight to obtain 2.58 g (98%) of the title compound.

[0087] 1H NMR (400MHz, DMSO-d6): 6.29 (s, 1H), 3.33 (s, 1H), 2.08 (s, 1H), 1.47 (s, 2H), 1.28(d, 2H), 1.24(s, 2H), 1.22(d, 2H), 1.08(d, 1H), 1.04(d, 1H), 0.80(s, 2H)

[0088] 11. Manufacturing of Memantine Hemiglutamate

[0089] 2.0 g of memantine free base was added to the reaction section, and then 60 mL of acetone was added to dissolve it. 0.74 g of glutaric acid was added, and the mixture was heated to 60°C and stirred for 1 hour, cooled to room temperature, and stirred for 3 hours. The resulting solid was filtered, washed with 10 mL of acetone, and vacuum dried at room temperature overnight to obtain 2.71 g (99%) of the title compound.

[0090] 1H NMR (400MHz, DMSO-d6): 2.12 (d, 2H), 2.06 (s, 1H), 1.65 (m, 1H), 1.42 (s, 1H), 1.25(d, 2H), 1.24(s, 2H), 1.22(d, 2H), 1.07(d, 1H), 1.03(d, 1H), 0.80(s, 6H)

[0091] 12. Preparation of Memantine Hemimalate

[0092] 2.0 g of memantine free base was added to the reaction section, and then 60 mL of ethyl acetate was added to dissolve it. 0.75 g of L-malic acid was added, and the mixture was heated to 60°C and stirred for 1 hour, cooled to room temperature, and stirred for 3 hours. The resulting solid was filtered, washed with 10 mL of ethyl acetate, and vacuum dried overnight at room temperature to obtain 2.55 g (93%) of the title compound.

[0093] 1H NMR (400MHz, DMSO-d6): 3.80 (d, 0.5H), 2.43 (d, 0.5H), 2.21 (d, 0.5H), 2.08 (s, 1H), 1.4 7(s, 2H), 1.29(d, 2H), 1.24(s, 2H), 1.22(d, 2H), 1.11(d, 1H), 1.09(d, 1H), 0.81(s, 6H)

[0094] 13. Preparation of Memantine Hemimaleate

[0095] 2.0 g of memantine free base was added to the reaction section, and then 60 mL of acetonitrile was added and dissolved. 0.65 g of maleic acid was added, and the mixture was heated to 60°C and stirred for 1 hour, cooled to room temperature, and stirred for 3 hours. The resulting solid was filtered, washed with 10 mL of acetonitrile, and vacuum dried at room temperature overnight to obtain 2.56 g (97%) of the title compound.

[0096] 1H NMR (400MHz, DMSO-d6): 6.01(s, 1H), 2.08(s, 1H), 1.44(s, 2H), 1.26(d, 2H), 1.24(s, 2H), 1.22(d, 2H), 1.10(d, 1H), 1.04(d, 1H), 0.80(s, 6H)

[0097] 14. Preparation of Memantine Hemimalonate

[0098] 2.0 g of memantine free base was added to the reaction section, and then 60 mL of acetone was added to dissolve it. 0.58 g of malonic acid was added, and the mixture was heated to 60°C and stirred for 1 hour, cooled to room temperature, and stirred for 3 hours. The resulting solid was filtered, washed with 10 mL of acetone, and vacuum dried at room temperature overnight to obtain 2.57 g (99%) of the title compound.

[0099] 1H NMR (400MHz, DMSO-d6): 2.67(s, 1H), 2.07(s, 1H), 1.44(s, 1H), 1.28(d, 2H), 1.26(s, 2H), 1.23(d, 2H), 1.08(d, 1H), 1.04(d, 1H), 0.80(s, 6H)

[0100] 15. Preparation of memantine hemimucate

[0101] 2.0 g of memantine free base was added to the reaction section, and then 20 mL of dimethyl sulfoxide and 60 mL of acetone were added to dissolve it. 1.17 g of mucic acid was added, and the temperature was raised to 60°C and stirred for 1 hour, and then cooled to room temperature and stirred for 3 hours. The resulting solid was filtered, washed with 10 mL of acetone, and vacuum dried at room temperature overnight to obtain 2.97 g (94%) of the title compound.

[0102] 1H NMR (400MHz, DMSO-d6): 3.72(s, 1H), 3.48(s, 1H), 3.33(br, 2H), 2.10(s, 1H), 1.53( s, 2H), 1.35(d, 2H), 1.31(d, 2H), 1.25(s, 2H), 1.10(d, 1H), 1.06(d, 1H), 0.82(s, 6H)

[0103] 16. Preparation of memantine heminaphthalenedisulfonate

[0104] 2.0 g of memantine free base was added to the reaction section, and then 20 mL of acetone was added to dissolve it. 4.4 g of 1,5-naphthalenedisulfonic acid was added, and then stirred at room temperature for 3 hours. 20 mL of water was added to the reaction mixture, and then stirred for an additional 2 hours. The resulting solid was filtered, washed with a small amount of water, and vacuum dried at room temperature overnight to obtain 2.50 g (48%) of the title compound.

[0105] 1H NMR (400MHz, DMSO-d6): 8.85(d, 1H), 7.93(d, 1H), 7.42(m, 1H), 2.11(s, 1H), 1.56(s , 2H), 1.38(d, 2H), 1.34(d, 2H), 1.25(s, 2H), 1.11(d, 1H), 1.05(d, 1H), 0.81(s, 6H)

[0106] 17. Preparation of Memantine Orotate

[0107] 2.0 g of memantine free base was added to the reaction section, and then 60 mL of acetonitrile was added and dissolved. 1.94 g of orotic acid was added, and the mixture was heated to 60°C and stirred for 1 hour, cooled to room temperature, and stirred for 3 hours. The resulting solid was filtered, washed with 10 mL of acetonitrile, and vacuum dried at room temperature overnight to obtain 2.78 g (71%) of the title compound.

[0108] 1H NMR (400MHz, DMSO-d6): 11.10(s, 1H), 10.15(s, 1H), 8.00(s, 2H), 5.81(s, 1H), 2.13(s, 1H) , 1.60(s, 2H), 1.42(d, 2H), 1.38(d, 2H), 1.27(s, 2H), 1.12(d, 1H), 1,07(d, 1H), 0.82(s, 6H)

[0109] 18. Manufacturing of Memantine Hemioxalate

[0110] 2.0 g of memantine free base was added to the reaction section, and then 60 mL of acetone was added to dissolve it. 0.50 g of oxalic acid was added, and the mixture was heated to 60°C and stirred for 1 hour, cooled to room temperature, and stirred for 3 hours. The resulting solid was filtered, washed with 10 mL of acetone, and vacuum dried at room temperature overnight to obtain 2.40 g (96%) of the title compound.

[0111] 1H NMR (400MHz, DMSO-d6): 2.07(s, 1H), 1.46(s, 1H), 1.30(d, 2H), 1.28(s, 2H), 1.24(d, 2H), 1.08(d, 1H), 1.04(d, 1H), 0.80(s, 6H)

[0112] 19. Preparation of Memantine Hemipimelate

[0113] 2.0 g of memantine free base was added to the reaction section, and then 60 mL of acetone was added to dissolve it. 0.89 g of pimelic acid was added, and the temperature was raised to 60°C and stirred for 1 hour, and then cooled to room temperature and stirred for 3 hours. The resulting solid was filtered, washed with 10 mL of acetone, and vacuum dried at room temperature overnight to obtain 2.85 g (99%) of the title compound.

[0114] 1H NMR (400MHz, DMSO-d6): 2.07 (m, 2H), 2.04 (s, 1H), 1.44 (m, 2H), 1.38 (s, 2H), 1.19 (s, 2H), 1.17 (d, 2H), 1.05 (d, 1H), 1.02 (d, 1H), 0.79 (s, 6H)

[0115] 20. Preparation of Memantine Hemisebacate

[0116] 2.0 g of memantine free base was added to the reaction section, and then 60 mL of acetone was added to dissolve it. 1.13 g of sebacic acid was added, and the mixture was heated to 60°C and stirred for 1 hour, then cooled to room temperature and stirred for 3 hours. The resulting solid was filtered, washed with 10 mL of acetone, and vacuum dried at room temperature overnight to obtain 3.06 g (98%) of the title compound.

[0117] 1H NMR (400MHz, DMSO-d6): 2.07(m, 2H), 20.4(s, 1H), 1.44(m, 2H), 1.38(s, 2H), 1.21(s, 2H), 1.16(d, 2H), 1.05(d, 1H), 1.02(d, 1H), 0.78(s, 6H)

[0118] twenty one. Manufacturing of Memantine Hemisperate

[0119] 2.0 g of memantine free base was added to the reaction section, and then 60 mL of acetone was added to dissolve it. 0.97 g of suberic acid was added, and the temperature was raised to 60°C and stirred for 1 hour, and then cooled to room temperature and stirred for 3 hours. The resulting solid was filtered, washed with 10 mL of acetone, and vacuum dried at room temperature overnight to obtain 2.92 g (98%) of the title compound.

[0120] 1H NMR (400MHz, DMSO-d6): 2.09 (m, 2H), 2.03 (s, 1H), 1.43 (m, 2H), 1.35 (s, 2H), 1.21(s, 2H), 1.18(d, 2H), 1.14(d, 2H), 1.04(d, 1H), 1.02(d, 1H), 0.78(s, 6H)

[0121] twenty two. Preparation of Memantine Hemisuccinate

[0122] 2.0 g of memantine free base was added to the reaction section, and then 60 mL of ethyl acetate was added to dissolve it. 0.66 g of succinic acid was added, and the mixture was heated to 60°C and stirred for 1 hour, cooled to room temperature, and stirred for 3 hours. The resulting solid was filtered, washed with 10 mL of ethyl acetate, and vacuum dried overnight at room temperature to obtain 2.60 g (98%) of the title compound.

[0123] 1H NMR (400MHz, DMSO-d6): 2.21(s, 2H), 2.07(s, 1H), 1.44(s, 1H), 1.28(d, 2H), 1.26(s, 2H), 1.22(d, 2H), 1.08(d, 1H), 1.04(d, 1H), 0.80(s, 6H)

[0124] twenty three. Preparation of Memantine Hemi-L-Tartrate

[0125] 2.0 g of memantine free base was added to the reaction section, and then 60 mL of acetone was added to dissolve it. 0.84 g of L-tartaric acid was added, and the mixture was heated to 60°C and stirred for 1 hour, cooled to room temperature, and stirred for 3 hours. The resulting solid was filtered, washed with 10 mL of acetone, and vacuum dried at room temperature overnight to obtain 2.79 g (98%) of the title compound.

[0126] 1H NMR (400MHz, DMSO-d6): 3.78(s, 1H), 2.10(s, 1H), 1.58(s, 2H), 1.41(d, 2H), 1.36(d, 2H), 1.25(s, 2H), 1.10(d, 1H), 1.07(d, 1H), 0.81(s, 6H)

[0127] twenty four. Manufacturing of Memantine Terephthalate

[0128] 2.0 g of memantine free base was added to the reaction section, and then 20 mL of dimethyl sulfoxide was added and dissolved. 2.0 g of terephthalic acid was added and stirred at room temperature for 3 hours. 20 mL of water was added to the reaction mixture and stirred for an additional 2 hours. The resulting solid was filtered, washed with a small amount of water, and vacuum dried at room temperature overnight to obtain 3.64 g (94%) of the title compound.

[0129] 1H NMR (400MHz, DMSO-d6): 7.90(s, 4H), 2.11(s, 1H), 1.64(s, 2H), 1.48(d, 2H), 1.42(d, 2H), 1.26(s, 2H), 1.11(d, 1H), 1.06(d, 1H), 0.81(s, 6H)

[0130] twenty five. Manufacturing of Memantine L-Aspartate

[0131] 10.0 g of memantine free base was added to the reaction section, followed by 100 mL of methanol. 7.4 g of L-aspartic acid was added, followed by stirring at 60°C for 1 hour. The mixture was cooled to room temperature and stirred overnight. The resulting solid was filtered, washed with methanol, and vacuum dried at room temperature overnight to obtain 9.0 g (52%) of the title compound.

[0132] 1H NMR (600MHz, DMSO-d6): 7.96(br s, 4H), 3.32(t, 1H), 3.15(d, 1H), 2.40(ddd, 1H), 2.15(ddd, 1H), 2.10(s, 1H), 1.54(s, 2H) ), 1.37(dd, 2H), 1.31(dd, 2H), 1.22-1.26(m, 4H), 1.12(dd, 1H), 1.06(dd, 1H), 0.8(s, 6H)

[0133] 26. Preparation of Memantine Hemipamoate

[0134] 5.0g of memantine hydrochloride was added to the reaction vessel, followed by 50mL of ethanol. 9.0g of disodium pamoate was dissolved in 50mL of ethanol and added to the reaction vessel. After stirring at room temperature for 1.5 hours, the mixture was cooled to 5℃ and stirred overnight. The resulting solid was filtered, washed with ethanol, and vacuum dried at room temperature overnight to obtain 1.7g (14%) of the title compound.

[0135] 1H NMR (600MHz, DMSO-d6): 8.19(d, 1H), 8.15(s, 1H), 8.02(s, 3H), 7.63(d, 1H), 7.10(dt, 1H), 6.99(dt, 1H), 4.65(s, 1H), 2.15(s, 1H), 1.64(s, 2H), 1.46(dd, 2H), 1.40(dd, 2H), 1.29(s, 4H), 1.15(dd, 1H), 1.09(dd, 1H), 0.84(s, 6H)

[0136] 27. Preparation of Memantine Cypionate

[0137] 2.0 g of memantine free base was added to the reaction section, followed by 15 mL of acetonitrile. 1.8 mL of cypionic acid was added, followed by stirring at room temperature for 3 hours. The resulting solid was filtered, washed with acetonitrile, and then vacuum dried overnight at room temperature to obtain 3.5 g (96%) of the title compound.

[0138] 1H NMR (400MHz, DMSO-d6): 2.08 (m, 3H), 1.67 (m, 3H), 1.55 (m, 3H), 1.45 (s, 3H), 1.40 (s, 2H), 1.22 (m, 6H), 1.06 (m, 4H), 0.79 (s, 6H)

[0139] 28. Manufacturing of Memantine D-Glucuronate

[0140] 2.0 g of memantine free base was added to the reaction section, followed by 60 mL of ethanol. 2.2 g of glucuronic acid was added and stirred at 60°C for 1 hour. After stirring at room temperature for 3 hours, the resulting solid was filtered, washed with ethanol, and vacuum dried at room temperature overnight to obtain 3.9 g (91%) of the title compound.

[0141] 1H NMR (600MHz, DMSO-d6): 6.04(s, 1H), 5.30(bs, 1H), 4.37(bs, 1H), 3.92(s, 1H), 3.76(s, 1H), 3.44(s, 1H), 2.93(d, 1H), 2.79(d, 1H) , 2.14(s, 1H), 1.73(d, 1H), 1.63(d, 1H), 1.56(d, 1H), 1.51(d, 1H), 1.46(d, 1H), 1.41(d, 1H), 1.28(s, 2H), 1.14(q, 2H), 0.84(s, 3H)

[0142] 29. Manufacturing of Memantine Hippurate

[0143] 2.0 g of memantine free base was added to the reaction section, followed by 80 mL of acetonitrile. 2.0 g of hippuric acid was added, followed by stirring at 60°C for 1 hour. After stirring at room temperature for 3 hours, the resulting solid was filtered, washed with acetonitrile, and vacuum dried at room temperature overnight to obtain 3.9 g (98%) of the title compound.

[0144] 1H NMR (400MHz, DMSO-d6): 8.04 (bs, 1H), 7.50 (m, 1H), 7.44 (m, 2H), 3.57 (d, 2H), 2.09 (s, 1H), 1.54(s, 2H), 1.30(d, 2H), 1.28(s, 2H), 1.24(d, 2H), 1.10(d, 1H), 1.04(d, 1H), 0.81(s, 6H)

[0145] 30. Manufacturing of Memantine D-Gluconate

[0146] 10.0 g of memantine free base was added to the reaction section, followed by 100 mL of acetone. 3.4 mL of gluconic acid was added, followed by stirring at 60°C for 1 hour. After stirring at room temperature for 3 hours, the resulting solid was filtered, washed with acetone, and vacuum dried at room temperature overnight to obtain 2.8 g (13%) of the title compound.

[0147] 1H NMR (400MHz, DMSO-d6): 3.74 (d, 1H), 3.58 (d, 1H), 3.57 (d, 1H), 3.46 (s, 1H), 3.40 (d, 1H), 3.32 (m, 2H), 2.12(s, 1H), 1.57(s, 1H), 1.36(d, 2H), 1.27(s, 2H), 1.24(d, 2H), 1.13(d, 1H), 1.06(d, 1H), 0.83(s, 6H)

[0148] 31. Manufacturing of Memantine Laurate

[0149] 1 g of memantine free base was added to the reaction section, followed by 15 mL of n-hexane. 1.12 g of lauric acid was added, followed by stirring at room temperature for 1 hour. The reaction product was concentrated under reduced pressure and then vacuum dried at room temperature overnight to obtain 2.12 g (100%) of the title compound.

[0150] 1H NMR (600MHz, CD3OD): 4.97(s, 2H), 2.24(m, 1H), 2.15(t, 2H), 1.71(s, 2H), 1.59(m, 2H), 1 .52(d, 2H), 1.47(d, 2H), 1.41(s, 4H), 1.24-1.32(m, 17H), 1.19(d, 1H), 0.89-0.92(m, 9H)

[0151] 32. Manufacturing of Memantine Palmitate

[0152] 1 g of memantine free base was added to the reaction section, followed by 15 mL of n-hexane. 1.43 g of palmitic acid was added, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and then vacuum dried at room temperature overnight to obtain 2.43 g (100%) of the title compound.

[0153] 1H NMR (600MHz, CD3OD): 4.96 (s, 2H), 2.24 (m, 1H), 2.15 (t, 2H), 1.71 (s, 2H), 1.59 (m, 2H), 1 .52(d, 2H), 1.46(d, 2H), 1.41(s, 4H), 1.24-1.32(m, 25H), 1.19(d, 1H), 0.89-0.92(m, 9H)

[0154] 33. Preparation of Memantine Decanoate

[0155] 1 g of memantine free base was added to the reaction section, followed by 15 mL of n-hexane. 0.96 g of decanoic acid was added, followed by stirring at room temperature for 1 hour. The reaction product was concentrated under reduced pressure and then vacuum dried at room temperature overnight to obtain 1.96 g (100%) of the title compound.

[0156] 1H NMR (600MHz, CD3OD): 5.01 (s, 2H), 2.24 (m, 1H), 2.15 (t, 2H), 1.71 (s, 2H), 1.60 (m, 2H), 1 .53(d, 2H), 1.47(d, 2H), 1.41(s, 4H), 1.23-1.32(m, 13H), 1.19(d, 1H), 0.89-0.92(m, 9H)

[0157] 34. Manufacturing of Memantine Myristate

[0158] 1g of memantine free base was added to the reaction section, followed by 15mL of n-hexane. 1.27g of myristic acid was added, followed by stirring at room temperature for 1 hour. The reaction product was concentrated under reduced pressure and then vacuum dried at room temperature overnight to obtain 2.27g (100%) of the title compound.

[0159] 1H NMR (600MHz, CD3OD): 4.95(s, 2H), 2.24(m, 1H), 2.15(t, 2H), 1.71(s, 2H), 1.59(m, 2H), 1 .52(d, 2H), 1.46(d, 2H), 1.41(s, 4H), 1.24-1.32(m, 21H), 1.19(d, 1H), 0.89-0.92(m, 9H)

[0160] <Experimental Example 1> Evaluation of solubility for the solubilizer propylene glycol monocaprylate

[0161] The solubilities of various memantine salts produced in 1 to 34 of Production Example 1 in a solubilizing agent were evaluated to select a memantine salt that can be used as a transdermal absorption preparation.

[0162] To evaluate the solubility of memantine salts in solubilizers, solubility evaluation was performed in propylene glycol monocaprylate. For the solubility evaluation, 1 mL of propylene glycol monocaprylate was added to the memantine salts produced in 1 to 34 of Production Example 1 in an amount equivalent to 50 mg of memantine free base, and the mixture was treated in a shaking thermostatic water bath at 25°C for 24 hours, after which the supernatant was separated and centrifuged at 25°C and 13000 rpm for 25 minutes, and the supernatant was passed through a 0.45 μm filter. This filtrate was diluted with ethanol in an appropriate ratio, and 5 mL of the diluent or 5 mL of the standard solution (memantine hydrochloride 1 g / L), 4 mL of 0.015 M FMOC (fluorenylmethoxycarbonyl chloride) solution, and 4 mL of 0.05 M pH 8.5 borate buffer were added to a 50 mL flask and mixed, and a diluent (0.05 M, pH 8.5 borate buffer:acetonitrile = 1:1) was added to make up to 50 mL, and the solution was left at room temperature for 20 minutes.

[0163] The solubility of memantine in this solution was calculated by liquid chromatography, and the range is shown in Table 1.

[0164] <Liquid chromatography conditions>

[0165] Column: Kromasil C18, 4.6 x 150 mm, 5 μm

[0166] Mobile phase: pH 3.0 potassium phosphate buffer:acetonitrile = 20:80

[0167] Column temperature: 30℃

[0168] Flow rate: 2.0mL / min

[0169] Sample injection volume: 20μL

[0170] Ultraviolet absorption photometer: 265nm

[0171] As can be seen from Table 1 below, the solubility evaluation results of the memantine salts produced in 1 to 34 of Production Example 1 in the solubilizer propylene glycol monocaprylate showed that the enanthate, lactate, cypionate, caprylate, laurate, levulinate, palmitate, valerate, decanoate and myristate salts showed high solubilization rates of 30 mg / mL or more, confirming that it is possible to design a transdermal absorption formulation.

[0172] [Table 1]

[0173] <Experimental Example 2> Screening evaluation of oil-phase skin permeability for solubilizers

[0174] Based on the solubility test results of various memantine salts evaluated in Experimental Example 1, memantine salts with a solubility of propylene glycol monocaprylate as a solubilizer of 30 mg / mL or more were selected and an in-vitro permeability evaluation was performed. Phosphate buffer solution of pH 7.4 containing 10% ethanol and 0.02% sodium azide was added as an aqueous solution to the receptor chamber of a Franz diffusion cell for drug permeation experiments, and the temperature was maintained at 32 ± 0.5 ° C. and the mixture was stirred at 600 rpm. Phosphate buffer solution of pH 7.4 was added, and the temperature was maintained at 32 ± 0.5 ° C. and the mixture was stirred at 600 rpm. Human cadaver skin was fixed between the donor chamber and the receptor chamber of the Franz diffusion cell for drug permeation experiments. 200 μl of a 50 mg / mL concentration memantine salt-solubilizer solution was evenly applied onto the skin and allowed to permeate for 7 days, after which the amount of memantine permeated was measured by liquid chromatography. The results are shown in Table 2 below.

[0175] As can be seen from Table 2 below, the oil phase skin permeation rate of each memantine salt dissolved in propylene glycol monocaprylate was evaluated. The results showed that the skin permeation rate of the levulinate, lactate and enanthate salts was about 3000 μg / cm for 7 days. 2 The skin permeation rate for 7 days was 18μg / cm 2 / hr or more, which is 1.4 to 1.7 times higher than that of the free base, whereas caprylate, laurate, palmitate, cypionate, decanoate and myristate showed lower skin permeation rates than the free base. This confirmed that levulinate, lactate and enanthate salts show sufficient skin permeation rates for the design of transdermal formulations, making it possible to design such formulations.

[0176] [Table 2]

[0177] <Experimental Example 3> Evaluation of the solubility of memantine using different solubilizers

[0178] In order to design a transdermal formulation of memantine enanthate selected in Experimental Example 2, solubility evaluation was performed for various solubilizers. In addition, although it was evaluated in Experimental Example 2 that a transdermal formulation could be designed, levulinate, which is known in the prior art, was used as a comparative experimental group. The solubility evaluation was performed by adding an excess amount of memantine enanthate and memantine levulinate to 1 mL of each solubilizer, treating the mixture in a shaking thermostatic bath at 25°C for 24 hours, separating the supernatant, centrifuging the mixture at 25°C and 13,000 rpm for 25 minutes, and then passing the supernatant through a 0.45 μm filter. The filtrate was diluted with ethanol in an appropriate ratio, and 5 mL of the diluent or 5 mL of the standard solution (1 g / L memantine hydrochloride), 4 mL of 0.015 M FMOC solution, and 4 mL of 0.05 M pH 8.5 borate buffer were placed in a 50 mL flask and mixed, and diluent (0.05 M pH 8.5 borate buffer:acetonitrile = 1:1) was added to make up to 50 mL, and the mixture was allowed to stand at room temperature for 20 minutes.

[0179] The solubility of memantine in this solution was measured by liquid chromatography and is shown in FIG.

[0180] As can be seen from Figure 1, the results of the solubility evaluation showed that memantine enanthate generally had a higher solubility in the solubilizer than memantine levulinate. In general, in a transdermal preparation, when the solubility of a drug in a solubilizer is low, there is a risk of the drug not being sufficiently released due to crystal precipitation, and when a large amount of solubilizer is used to sufficiently dissolve the drug, the properties of the preparation may not be suitable. Therefore, it can be said that a transdermal preparation containing memantine enanthate, which has a high solubility in a solubilizer, has the advantage that the preparation can be easily designed.

[0181] Furthermore, in order to compare the transdermal permeability of memantine enanthate, the free base, and other salts, eight solubilizers with various solubilities were selected to prepare transdermal preparations containing memantine and its salts in the following Examples and Comparative Examples.

[0182] <Example 1> Preparation of memantine transdermal formulation according to the present invention

[0183] A transdermal absorption preparation containing memantine enanthate of the present invention was prepared as Example 1 as follows. 17.6 g of styrene-isoprene-styrene block copolymer, 7 g of octyldodecyl myristate, and 6.5 g of propylene glycol monocaprylate were dissolved in 32 g of ethyl acetate according to the composition shown in Table 3 below, and then 3.45 g of memantine enanthate was added and dissolved uniformly. The obtained solution was applied to a silicone-coated PET film so that the drug content per unit area was 3.0 mg / cm2 in terms of memantine. 2 The mixture was dried in an oven at 80° C. for 30 minutes, and then laminated with a backing film to prepare a transdermal absorption preparation.

[0184] [Table 3]

[0185] <Examples 2 to 8> Manufacturing of memantine transdermal formulations by type of solubilizer

[0186] As described in the above Experimental Example 3, eight solubilizers having various memantine solubilities were selected based on the solubility results. For Examples 2 to 8, which differ from Example 1 only in the solubilizer, memantine-containing transdermal preparations were produced in the same manner as in Example 1 with the compositions shown in Table 4 below.

[0187] [Table 4]

[0188] <Examples 9 to 11> Preparation of memantine percutaneous absorption preparation by reducing the amount of solubilizer and changing the adhesive of the present invention

[0189] Memantine-containing transdermal absorption preparations were produced in the same manner as in Example 1 with the compositions shown in Table 5 below, with Example 9 being different in the amount of solubilizer from Example 1 of the present invention, Example 10 being different in the amount of solubilizer from Example 3, and Example 11 being different in the adhesive from Example 3.

[0190] [Table 5]

[0191] <Example 12> Preparation of memantine percutaneous absorption preparation by changing the solubilizer and adhesive of the present invention

[0192] As an example described in U.S. Patent Publication No. 2019-0183810, memantine enanthate was added instead of memantine levulinate, and the ingredients and contents were prepared as shown in Table 6 below.

[0193] 5.61g of memantine enanthate and 3g of propylene glycol were dissolved in 26.9g of toluene and 0.6g of isopropyl alcohol, and 1.75g ​​of fumed silica was added and dispersed, and then 24.8g of polyisobutylene (14.9g as solid) was added and stirred to prepare a drug mixture. The obtained solution was applied to a silicone-coated PET film and dried in an oven at 60°C for 30 minutes, and then laminated with a backing film to prepare a drug layer. The adhesive layer mixture was prepared in the same manner, and then applied to a silicone-coated PET film and dried, and the drug layer, from which the PET film had been removed, was laminated on the adhesive layer to prepare Example 12.

[0194] [Table 6]

[0195] <Comparative Examples 1 to 4> Preparation of memantine free base and modified salt transdermal formulations

[0196] In order to compare the characteristics of memantine enanthate with other salts, memantine free base, memantine hydrochloride used in commercial products, and memantine levulinate and memantine lactate, which were evaluated as being capable of being designed as the transdermal absorption preparations in Experimental Example 2, were prepared into transdermal absorption preparations in the same manner as in Example 1 with the compositions shown in Table 7 below, and were designated Comparative Examples 1 to 4. Furthermore, the compositions were the same as in Comparative Example 1, but the amount of active ingredient was different (2 mg / cm 2 ) A transdermal absorption preparation was produced and designated as Comparative Example 1-1.

[0197] [Table 7]

[0198] <Comparative Example 5> Preparation of transdermal formulations containing memantine free base and levulinic acid

[0199] As an example described in US Patent Publication No. 2019-0183810, a patch in which levulinic acid was added to memantine free base to form a salt was prepared with the ingredients and contents in Table 8 below. Specifically, Comparative Example 5 was prepared as follows. 3.25 g of memantine free base, 2.1 g of levulinic acid, and 3 g of propylene glycol were dissolved in 26.9 g of toluene and 0.6 g of isopropyl alcohol, and 1.75 g of fumed silica was added and dispersed, and then 24.8 g of polyisobutylene (14.9 as a solid) was added and stirred to prepare a drug mixture. The resulting solution was applied to a silicone-coated PET film and dried in an oven at 60 ° C. for 30 minutes, and then laminated with a backing film to prepare a drug layer. An adhesive layer mixture was prepared in the same manner, applied to a silicone-coated PET film and dried, and then the drug layer from which the PET film had been removed was laminated on the adhesive layer to prepare Comparative Example 5.

[0200] [Table 8]

[0201] <Comparative Example 6> Preparation of a bilayer in-situ transdermal formulation containing memantine hydrochloride and sodium bicarbonate

[0202] As an example described in Korean Patent Publication No. 2019-0032551, a memantine hydrochloride in-situ transdermal formulation was prepared with the components and contents shown in Table 9 below, and used as Comparative Example 6. Specifically, 3 g of octyldodecanol and 3 g of glycerol were dissolved in 44 g of ethyl acetate and 2.79 g of isopropyl alcohol, and 7.5 g of memantine hydrochloride and 2.9 g of sodium bicarbonate were added and stirred, and then 4.5 g of Kollidone CL-M was added and dispersed, and 23.3 g of Durotak 87-4287 (9.1 g as solid) was added and stirred to prepare a drug mixture. The obtained solution was applied to a silicone-coated PET film and dried in an oven at 60 ° C for 30 minutes, and then laminated with a backing film to prepare a drug layer. The adhesive layer mixture was prepared in the same manner, and then coated on a silicone-coated PET film and dried. The drug layer, from which the PET film had been removed, was then laminated on the adhesive layer to prepare Comparative Example 6.

[0203] [Table 9]

[0204] <Comparative Example 7> Preparation of memantine free base transdermal formulations containing release modifiers

[0205] As an example described in Korean Patent Publication No. 10-1964295, a memantine free base-containing patch containing a release regulator was prepared with the ingredients and contents shown in Table 10 below. Specifically, Comparative Example 7 was prepared as follows. 0.02 g of dibutylhydroxytoluene, 1 g of PVP90F, and 1 g of stearic acid were dissolved in 2 g of ethanol, and 2 g of memantine free base and 43.78 g of acrylate polymer (87-9301) (amount of mixture equivalent to 15.98 g as solid) were added to prepare an adhesive acrylate drug mixture. The obtained solution was applied to a silicone-coated PET film, dried at room temperature for 10 minutes, dried in an oven at 70°C for 20 minutes, and then laminated with a backing film to prepare a drug layer. A release-regulating layer mixture was prepared in the same manner, applied to a silicone-coated PET film, dried, and then a drug layer was laminated on the release-regulating layer with the PET film removed, to prepare Comparative Example 7.

[0206] [Table 10]

[0207] <Comparative Example 8> Preparation of a Single-Layer In-Situ Transdermal Preparation Containing Memantine Hydrochloride and Sodium Ethanolate

[0208] As an example described in U.S. Patent Publication No. 8,882,729, an in-situ memantine hydrochloride transdermal formulation was prepared with the ingredients and contents shown in Table 11 below, and designated as Comparative Example 8. Specifically, 2 g of memantine hydrochloride was suspended in 0.66 g of ethyl acetate, 41 g of Durotak 87-2516 (16.6 g as solid) was added and stirred, and then 1.4 g of sodium ethanolate was added and stirred to prepare a drug mixture. The obtained solution was applied to a silicone-coated PET film, dried in an oven at 80°C for 30 minutes, and then laminated with a backing film to prepare Comparative Example 8.

[0209] [Table 11]

[0210] <Comparative Example 9> Manufacture of memantine caprylate and acrylic adhesive transdermal formulation

[0211] As an example described in WO2014 / 174564, a transdermal formulation containing memantine caprylate was prepared with the ingredients and contents shown in Table 12 below, and designated as Comparative Example 9. Specifically, 0.46 g of NaOH was dissolved in 7.71 mL of methanol, 2.5 g of memantine hydrochloride was added and mixed, 2.00 g of caprylic acid was added and mixed, 17.5 g of toluene and 51.39 g of Durotak 87-4287 (20.04 g as solid) were added and stirred, and the mixture was applied to a silicone-coated PET film, dried in an oven at 80°C for 30 minutes, and then laminated with a backing film to prepare Comparative Example 9.

[0212] [Table 12]

[0213] <Comparative Examples 10 to 15> Preparation of transdermal formulations of memantine free base and salts modified with the solubilizing agents diisopropyl sebacate and diisopropyl adipate.

[0214] In order to compare the characteristics of memantine enanthate with other salts, transdermal preparations were produced in Comparative Examples 10 to 12 in which the salt of the active ingredient was different from that in Example 2 of the present invention, and in Comparative Examples 13 to 15 in which the salt of the active ingredient was different from that in Example 3, using the compositions shown in Table 13 below in the same manner as in Example 1.

[0215] [Table 13]

[0216] <Comparative Examples 16 to 21> Preparation of transdermal formulations of memantine free base and salts modified with the solubilizing agents isopropyl palmitate and isopropyl myristate.

[0217] In order to compare the characteristics of memantine enanthate with other salts, transdermal preparations were produced in the same manner as in Example 1 with the compositions shown in Table 14 below to produce Comparative Examples 16 to 18 in which the salt of the active ingredient was different from that in Example 4 of the present invention, and Comparative Examples 19 to 21 in which the salt of the active ingredient was different from that in Example 5 of the present invention.

[0218] [Table 14]

[0219] <Comparative Examples 22 to 27> Preparation of transdermal formulations of memantine free base and salts modified with solubilizers oleoyl macrogol-6-glyceride and isopropyl isostearate

[0220] In order to compare the characteristics of memantine enanthate with other salts, transdermal preparations were produced in the same manner as in Example 1 with the compositions shown in Table 15 below to produce Comparative Examples 22 to 24 in which the salt of the active ingredient was different from that in Example 6 of the present invention, and Comparative Examples 25 to 27 in which the salt of the active ingredient was different from that in Example 7.

[0221] [Table 15]

[0222] <Comparative Examples 28 to 30> Preparation of memantine free base and salt-modified transdermal formulations with oleyl alcohol as solubilizer

[0223] In order to compare the characteristics of memantine enanthate with other salts, transdermal preparations were produced in Comparative Examples 28 to 30 using different salts of the active ingredient from Example 8 of the present invention, with the compositions shown in Table 16 below, in the same manner as in Example 1.

[0224] [Table 16]

[0225] <Experimental Example 5> Evaluation of skin permeability of memantine transdermal formulation

[0226] The in-vitro permeability evaluation of each transdermal preparation prepared in Examples 1-10 and Comparative Examples 1-30 was carried out using a Franz diffusion cell for drug permeation experiments. Phosphate buffer solution of pH 7.4 containing 10% ethanol and 0.02% sodium azide was added as an aqueous solution in the receptor chamber, and the temperature was maintained at 32±0.5°C and stirred at 600 rpm. Human cadaver skin was fixed between the donor chamber and the receptor chamber in the diffusion cell for drug permeation experiments. Each transdermal preparation prepared in Examples 1-10 and Comparative Examples 1-30 was cut to the size of the donor cell and applied to the skin, and the amount of memantine permeated over time was measured by liquid chromatography. The drug release patterns over time of the patches prepared in Examples 1-10 and Comparative Examples 1-30 are shown in Figures 2 to 10.

[0227] 1. Comparative evaluation of skin permeability of transdermal preparations using different memantine salts

[0228] As shown in FIG. 2, Comparative Example 2 containing memantine hydrochloride had a skin permeability of 199.3 μg / cm for 7 days. 2 Comparative Example 3 containing memantine levulinate and Comparative Example 4 containing memantine lactate had higher skin permeability than Comparative Example 2, but the 7-day skin permeability was 1217.9 μg / cm 2 , 711.1 μg / cm 2 It was confirmed that the content was less than half of the content, and compared with Comparative Examples 5 to 9 described as examples of the prior art, Example 1 of the present invention showed a skin permeability that was at least 1.56 times higher, which was still a high result.

[0229] On the other hand, Example 1, which contains memantine enanthate, had a skin permeability of 1972.6 μg / cm for 7 days. 2 The skin permeability was found to be significantly higher since it was 1.6 to 9.9 times higher than those of Comparative Examples 2 to 4.

[0230] In addition, Comparative Example 1, which contains memantine free base, had a skin permeability of 1814.8 μg / cm 2 However, there is a problem that it may cause severe skin irritation due to rapid skin permeation in a short period of time. In contrast, Example 1 containing memantine enanthate showed a constant skin permeation release pattern for a long period of time.

[0231] Therefore, it was found that the transdermal absorption preparation using memantine enanthate of the present invention not only allows easy design of a sustained release dosage form, but also has the advantage of being able to minimize skin irritation in humans.

[0232] 2. Evaluation of solubilizer solubility and skin permeation rate of memantine salts for transdermal formulations

[0233] As described in the solubility test results of Experimental Example 3, in order to confirm that the memantine enanthate-containing transdermal formulation exhibits high skin permeability and a consistent release pattern regardless of the solubility of the solubilizer, the skin permeability of Examples and Comparative Examples prepared by adding solubilizers having various solubilities was evaluated.

[0234] The solubilizers selected were diisopropyl sebacate, diisopropyl adipate, isopropyl palmitate, isopropyl myristate, isopropyl isostearate, and oleyl alcohol, and those with a solubility of 50 mg / g or more were selected.

[0235] As shown in Figure 3, Example 2, in which diisopropyl sebacate was added as a solubilizer, showed the same skin permeation results as Example 1, in which propylene glycol monocaprylate was added as a solubilizer, and maintained a higher skin permeation rate than Comparative Example 11 (containing memantine hydrochloride) and Comparative Example 12 (containing memantine levulinate). Moreover, Example 2 showed a constant skin permeation release pattern for a long period of time compared to Comparative Example 10 (containing memantine free base), which was found to have the same tendency as the results in Figure 2.

[0236] As shown in Figure 4, Example 3, in which diisopropyl adipate was added as a solubilizer, showed the same skin permeation results as Example 1, and maintained a higher skin permeation rate than Comparative Example 14 (containing memantine hydrochloride) and Comparative Example 15 (containing memantine levulinate). Moreover, Example 3 showed a constant skin permeation release pattern for a long period of time compared to Comparative Example 13 (containing memantine free base).

[0237] As shown in Figure 5, Example 4, which contains isopropyl palmitate as a solubilizer, showed the same skin permeability results as Example 1, and maintained a higher skin permeability than Comparative Example 17 (containing memantine hydrochloride) and Comparative Example 18 (containing memantine levulinate). Moreover, Example 4 showed a constant skin permeation release pattern for a long period of time compared to Comparative Example 16 (containing memantine free base).

[0238] As shown in Figure 6, Example 5, which contained isopropyl myristate as a solubilizer, showed the same skin permeation results as Example 1, and maintained a higher skin permeation rate than Comparative Example 20 (containing memantine hydrochloride) and Comparative Example 21 (containing memantine levulinate). Moreover, Example 5 showed a longer, more constant skin permeation release pattern than Comparative Example 19 (containing memantine free base).

[0239] As shown in Figure 7, Example 6, in which oleoyl macrogol-6-glyceride was added as a solubilizer, showed the same skin permeation results as Example 1, and maintained a higher skin permeation rate than Comparative Example 23 (containing memantine hydrochloride) and Comparative Example 24 (containing memantine levulinate). Moreover, Example 6 showed a constant skin permeation release pattern for a long period of time compared to Comparative Example 22 (containing memantine free base).

[0240] As shown in Figure 8, Example 7, which contained isopropyl isostearate as a solubilizer, showed the same skin permeability results as Example 1, and maintained a higher skin permeability than Comparative Example 26 (containing memantine hydrochloride) and Comparative Example 27 (containing memantine levulinate). Moreover, Example 7 showed a constant skin permeation release pattern for a long period of time compared to Comparative Example 25 (containing memantine free base).

[0241] 9, Example 8, which contained oleyl alcohol as a solubilizer, showed the same skin permeation results as Example 1, and maintained a higher skin permeation rate than Comparative Example 29 (containing memantine hydrochloride) and Comparative Example 30 (containing memantine levulinate). Moreover, Example 8 showed a longer, more constant skin permeation release pattern than Comparative Example 28 (containing memantine free base).

[0242] 3. Evaluation of skin permeation rate of memantine enanthate transdermal formulations by reducing the amount of solubilizer and changing the adhesive

[0243] As shown in FIG. 10, Examples 9 and 10, which were prepared by reducing the amount of the solubilizers propylene glycol monocaprylate and diisopropyl adipate in Examples 1 and 3, showed the same skin permeability as Examples 1 and 3, regardless of the reduction in the amount of the solubilizer. Example 11, in which the adhesive composition of Example 3 was changed to an acrylic adhesive, also showed the same skin permeability as Examples 1 and 3, regardless of the change in adhesive. In addition, Example 12, which has the same composition as the composition described in the prior art example and only the active ingredient was changed to memantine enanthate, showed the same skin permeability results as Examples 1 and 3, despite the use of a polyisobutylene adhesive, and showed a skin permeability result 1.85 times higher than Comparative Example 5, which contained memantine levulinate in the same composition. This confirmed that even when the amount of the solubilizer was reduced and various adhesives were changed, the transdermal preparation containing memantine enanthate still showed skin permeability.

[0244] <Experimental Example 6> Drug crystallization studies

[0245] The percutaneous absorption preparations produced in Examples 1 to 10 and Comparative Example 2 were evaluated for the presence or absence of drug crystal precipitation. The percutaneous absorption preparations produced in Examples 1 to 10 were stored at 25°C and 60% RH for one month, and then the formation of crystals was observed under a microscope. The results are shown in Table 17 below.

[0246] [Table 17]

[0247] As shown in Table 17, the crystal formation by solubilizer type in Examples 1 to 8 was confirmed to be absent, whereas crystal precipitation was confirmed in Comparative Example 2 containing memantine hydrochloride. In addition, it was confirmed that no crystal precipitation occurred even when memantine enanthate was added to the solubilizers of Examples 9 and 10, propylene glycol monocaprylate and diisopropyl adipate, in a 1:1 ratio.

[0248] <Experimental Example 7> Skin irritation assessment

[0249] The degree of skin irritation of the memantine transdermal preparation according to the present invention was evaluated. For the above evaluation, Comparative Example 1, which contained the same dose of memantine free base as Example 9 and Example 10, which contained memantine enanthate according to the present invention, Comparative Example 1-1, in which the dose of memantine free base was reduced to a 70% level, Comparative Examples 3 and 5, which contained the same dose of memantine levulinate when converted into free base, and Comparative Example 6, which contained memantine hydrochloric acid, were compared and evaluated.

[0250] 1. Evaluation of skin irritation in rabbits

[0251] The test method was as follows: Five white rabbits were used, the hair of which was thoroughly removed, and then Examples 9 to 10, Comparative Example 1-1, Comparative Example 3, Comparative Example 5 and Comparative Example 6 were applied to the rabbits at a distance of 5 cm. 2The patch was cut and removed 7 days later. The skin reactions were visually observed immediately after and 48 hours after removal to evaluate the presence or absence of erythema and edema at the site of transdermal preparation application, and were scored according to the method shown in Table 18. The primary irritation index (PII) was evaluated according to Table 19. The results are shown in Table 20 and Figure 11.

[0252] 2. Evaluation of skin irritation in hairless mice

[0253] The test method was as follows: four hairless mice were used, the hair of which was completely removed, and then the samples of Examples 9 and 10, Comparative Example 1, Comparative Example 3, Comparative Example 5 and Comparative Example 6 were placed at 1 cm 2 The patch was cut and removed 7 days later. The skin reactions were visually observed immediately after and 48 hours after removal to evaluate the presence or absence of erythema and edema at the site of transdermal preparation application, and were scored according to the method shown in Table 18. The skin irritation index (PII, primary irritation index) was evaluated according to Table 19, and the results are shown in Table 20.

[0254] [Table 18]

[0255] [Table 19]

[0256] [Table 20]

[0257] As shown in Table 20 and Figure 11, the skin irritation evaluation results in rabbits showed that Examples 9 and 10 containing the memantine enanthate of the present invention had skin irritation indices of 0.6 and 1.5, respectively, indicating that they were weak irritants, and the remaining amounts were confirmed to be 19.1% and 1.9%, respectively, indicating sufficient dermal absorption of memantine. In contrast, Comparative Example 1-1 containing memantine free base had a skin irritation index of 2.1, indicating that it was a moderate irritant due to obvious erythema and edema despite the reduced dose of memantine free base, and no remaining amount remained. In addition, Comparative Examples 3 and 5 containing memantine levulinate and Comparative Example 6 containing memantine hydrochloride had skin irritation indices of 1 or less, indicating that they were non-irritants or weak irritants, and the remaining amounts were confirmed to be at the level of 31.8% to 72.9%, indicating that they had lower dermal absorption than memantine enanthate.

[0258] As shown in Table 20, the skin irritation evaluation results in hairless mice showed that Examples 9 and 10 containing the memantine enanthate of the present invention had skin irritation indices of 0.75 and 0.38, respectively, indicating that they were weakly irritating or non-irritating substances, and the remaining amounts were confirmed to be 15.2% and 17.4%, respectively, indicating sufficient dermal absorption of memantine. In contrast, Comparative Example 1 containing memantine free base had a skin irritation index of 5.25, indicating that it was a strong irritant due to severe erythema and crusts and severe edema, and the remaining amount was confirmed to be less than 1.5%. In addition, Comparative Examples 3 and 5 containing memantine levulinate and Comparative Example 6 containing memantine hydrochloride had skin irritation indices of 1 or less, indicating that they were non-irritating or weakly irritating substances, and the remaining amount was at a level of 66.5% to 78.9%, indicating low dermal absorption of memantine.

[0259] This shows that the transdermal absorption preparation containing memantine enanthate of the present invention exhibits sufficient dermal absorption compared to transdermal absorption preparations containing memantine levulinate and memantine hydrochloride, while showing significantly lower skin irritation compared to transdermal absorption preparations containing memantine free base.

[0260] <Experimental Example 8> Pharmacokinetic evaluation

[0261] The memantine percutaneous absorption preparation according to the present invention was subjected to a pharmacokinetic evaluation. For the evaluation, Example 10 containing the memantine enanthate of the present invention, Comparative Example 3 containing memantine levulinate, and Reference Example 1 as an oral preparation (Ebixa (registered trademark), which is an oral preparation containing 10 mg of memantine hydrochloride, containing 8.3 mg of free base) were compared and evaluated.

[0262] 1. Pharmacokinetic evaluation in rabbits

[0263] In Example 10, the transdermal preparations were molded to a size containing 106 mg and 160 mg of free base, respectively, and in Comparative Example 3, the transdermal preparations had the same composition except for memantine levulinate, and were molded to a size containing 140 mg of free base, which were attached to rabbits, and the patch was removed after 7 days, and blood was collected at 0, 4, 8, 24, 30, 48, 72, 96, 144, and 168 hours after patch attachment to measure the amount of memantine in plasma. In Reference Example 1, one tablet of Ebixa (registered trademark) was suspended in 2 mL of 0.5% carboxymethylcellulose (CMC) solution, and 2 mL of the suspension was orally administered, and blood was collected at 0, 0.5, 1, 2, 4, 6, and 24 hours after administration to measure the amount of memantine in plasma.

[0264] [Table 21]

[0265] As can be seen from Table 21, in a pharmacokinetic comparison in rabbits between Example 10 containing memantine enanthate of the present invention, Comparative Example 3 containing memantine levulinate and 10 mg oral administration of Ebixa® tablets, the AUC was 10518.1 ng*hr / mL in the case of 106 mg patch attachment in Example 10, the AUC was 3381.2 ng*hr / mL in the case of 140 mg patch attachment in Comparative Example 3, and the AUC of the daily oral administration dose in Reference Example 1 was 148.8 ng*hr / mL. This indicates that, when calculated in terms of the same drug administration dose, the AUC of Example 10 is improved by about 550% and that of Comparative Example 3 is improved by 130% compared to Reference Example 1, and it was confirmed that the transdermal preparation containing memantine enanthate according to the present invention achieves a significantly higher drug blood concentration than the oral administration containing memantine hydrochloride and Comparative Example 3 containing memantine levulinate. In addition, the size of the patch was molded according to the administered dose in Example 10 and evaluated. As a result, it was found that the blood concentration increased by increasing the area of ​​the transdermal absorption preparation, demonstrating that it is easy to adjust the dose of the transdermal absorption preparation by adjusting the size of the patch.

[0266] 2. Pharmacokinetic evaluation in hairless mice

[0267] In Example 10, the transdermal absorption preparation was molded into a size containing 10 mg, 20 mg, and 30 mg of the free base, and in Comparative Example 3, the preparation was molded into a size containing 9 mg of the free base. After administration of Reference Example 1 in the same manner as in 1. Pharmacokinetic evaluation in rabbits, blood samples were taken at 0, 0.5, 1, 2, 4, 6, and 24 hours after administration to measure the amount of memantine in the plasma.

[0268] [Table 22]

[0269] As can be seen from Table 22, in a pharmacokinetic comparison between Example 10 containing memantine enanthate of the present invention, Comparative Example 3 containing memantine levulinate, and Reference Example 1, 10 mg oral administration of Ebixa® tablets, in hairless mice, the AUC was 6374.7 ng*hr / mL in the case of 10 mg patch attachment in Example 10, the AUC was 3999.0 ng*hr / mL in the case of 9 mg patch attachment in Comparative Example 3, and the AUC of Reference Example 1, 2862.2 ng*hr / mL. This indicates that, when calculated in terms of the same drug administration dose, the AUC of Example 10 was improved by about 185% compared to Reference Example 1, and the AUC of Comparative Example 3 was improved by 130%, confirming that the transdermal preparation containing memantine enanthate according to the present invention achieves a higher drug blood concentration than the oral administration containing memantine hydrochloride and Comparative Example 3 containing memantine levulinate.

[0270] [Table 23]

[0271] As can be seen from Table 23 and Figure 15, the patch area of ​​Example 10 was increased to sizes containing 10 mg, 20 mg, and 30 mg, and evaluated. As a result, it was found that the maximum blood concentration and the area under the blood drug concentration-time curve increased proportionally by increasing the area of ​​the transdermal preparation, indicating that it is easy to adjust the dose of the transdermal preparation by adjusting the patch size.

[0272] The present invention, which summarizes the above results, has the characteristic that the transdermal preparation containing memantine enanthate does not crystallize and shows high skin permeability compared to transdermal preparations containing other salts of memantine. This shows that the blood exposure is dose-proportional, which has the advantage of not only easily adjusting the clinically usable patch area but also reducing the area. At the same time, it has the advantage of minimizing skin irritation caused by the drug by controlling the skin absorption rate by adjusting the release rate. In addition, it was confirmed that the amount of the drug remaining in the patch after administration was about 20% by weight or less compared to the content of the drug before administration. This has the advantage of minimizing the loss of the remaining drug, realizing economic benefits, and preventing overdosing of the drug.

Claims

1. A memantine-containing transdermal formulation comprising a support layer, a drug-containing layer and a release layer, The drug-containing layer comprises memantine enanthate, a solubilizing agent, and an adhesive,

2. 2. The transdermal formulation for treating dementia according to claim 1, wherein the memantine enanthate is contained in an amount of 1 to 20% by weight based on the total weight of the drug-containing layer.

3. 2. The transdermal formulation for treating dementia according to claim 1, wherein the solubilizer has a solubility of the memantine enanthate of 30 mg / ml or more.

4. The solubilizing agent is selected from one or more of propylene glycol monocaprylate, propylene glycol monolaurate, diisopropyl adipate, diisopropyl sebacate, oleic acid, isopropyl palmitate, glyceryl monocaprylate, isostearate, cocoyl caprylocaprate, cetyl 2-ethylhexanoate, oleoyl macrogol-6-glyceride, propylene glycol dicaprylocaprate, propylene glycol dicaprylocaprate, propylene glycol dicaprolate / dicaprate, glyceryl monooleate, 1-dodecyl-2-pyrrolidinone, linoleoyl macrogol-6 glyceride, polyglyceryl-3 dioleate, ethyl oleate, isopropyl isostearate, isopropyl myristate, medium chain triglyceride, isocetyl myristate, isostearyl alcohol, oleyl alcohol, peanut oil, and diethylene glycol monoethyl ether. The transdermal formulation for treating dementia according to claim 3.

5. The transdermal formulation for treating dementia according to claim 4, characterized in that the solubilizing agent is at least one selected from the group consisting of propylene glycol monocaprylate, diisopropyl adipate, diisopropyl sebacate, isopropyl palmitate, isopropyl myristate, oleoyl macrogol-6-glyceride, isopropyl isostearate, and oleyl alcohol.

6. The transdermal formulation for treating dementia according to claim 1, wherein the solubilizer is present in an amount of 1 to 40% by weight based on the total weight of the drug-containing layer.

7. The transdermal formulation for treating dementia according to claim 1, wherein the adhesive is selected from the group consisting of styrene-isoprene-styrene block copolymer (SIS), acrylic polymer, and polyisobutylene polymer.

8. The transdermal formulation for treating dementia according to claim 7, wherein the adhesive is a styrene-isoprene-styrene block copolymer.

9. The transdermal formulation for treating dementia according to claim 8, wherein the styrene-isoprene-styrene block copolymer is contained in an amount of 10 to 70% by weight based on the total weight of the drug-containing layer.

10. The transdermal formulation for treating dementia according to claim 7, wherein the adhesive is an acrylic polymer.

11. The transdermal formulation for treating dementia according to claim 10, characterized in that the acrylic polymer is contained in an amount of 50 to 90% by weight based on the total weight of the drug-containing layer.

12. The transdermal formulation for treating dementia according to claim 7, wherein the adhesive is a polyisobutylene polymer.

13. The transdermal formulation for treating dementia according to claim 12, wherein the polyisobutylene polymer is contained in an amount of 10 to 90% by weight based on the total weight of the drug-containing layer.

14. The transdermal absorption preparation according to claim 1, wherein the drug-containing layer further contains a plasticizer.

15. (a) dissolving a solubilizing agent, an adhesive and memantine enanthate in an organic solvent; (b) applying the solution prepared in step (a) onto the release layer and drying it to form a drug-containing layer; (c) laminating the drug-containing layer with a support layer.

16. The method for producing a transdermal preparation according to claim 15, wherein the organic solvent is selected from the group consisting of ethyl acetate, toluene, hexane, 2-propanol, methanol, ethanol, methylene chloride, and tetrahydrofuran.

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