WO2024127805A1

WO2024127805A1 - Transdermally absorbable donepezil-containing preparation

Info

Publication number: WO2024127805A1
Application number: PCT/JP2023/037846
Authority: WO
Inventors: 寛青木; やよい中田; 智川上
Original assignee: 帝國製薬株式会社
Priority date: 2022-12-16
Filing date: 2023-10-19
Publication date: 2024-06-20

Abstract

The present invention provides a transdermally absorbable preparation which demonstrates the same level of pharmacokinetics and therapeutic effect as does orally administered donepezil. The present invention specifically provides a transdermally absorbable preparation for treating dementia which has an adhesive layer containing donepezil free base, said adhesive layer containing a styrene-isoprene-styrene block copolymer and 13.75 -55mg of donepezil free base. The preparation is to be administered to a patient once per day.

Description

Donepezil-containing transdermal preparation

The present invention relates to a transdermal absorption preparation comprising a support and an adhesive layer containing an adhesive base and a drug, and in particular to a transdermal absorption preparation of an anti-dementia treatment agent in which the drug contained as an active ingredient is donepezil free form, which is used to treat dementia.

Donepezil has an acetylcholinesterase inhibitory effect and is a drug that is widely used to suppress the progression of dementia symptoms in Alzheimer's dementia, i.e., as a treatment for Alzheimer's disease. In Alzheimer's disease, where damage to the cholinergic nervous system in the brain has been reported, acetylcholinesterase inhibitors such as donepezil increase acetylcholine in the brain and activate the cholinergic nervous system in the brain. Conventionally, the formulations of donepezil that have been used in practice are known to be orally administered in the form of tablets, capsules, syrups, or granules.

However, as symptoms progress, dementia patients face challenges in taking medication, such as difficulty in taking medication due to a decline in swallowing function. Transdermal preparations can be easily administered even when oral treatment is difficult, and because patches have not been approved for use in advanced dementia, their development as a new treatment option is needed.
Patent Document 1 discloses a donepezil-containing transdermal preparation including the transdermal preparation of the present invention, but does not describe the method of use and dosage of the present invention, nor does it show the pharmacokinetic equivalence and therapeutic effect with an oral formulation of donepezil.
Furthermore, Patent Document 2 describes a donepezil transdermal delivery system, but it is essentially a preparation for long-term administration (3 days or more), which differs from the once-daily administration transdermal absorption preparation of the present invention.

International Publication No. 2011/049038 JP 2019-522024 A

Therefore, in order to solve these conventional problems, the objective of the present invention is to provide a transdermal formulation that exhibits pharmacokinetics and therapeutic effects comparable to those of oral formulations of donepezil.

In order to solve these problems, the inventors have conducted extensive research and have found that a transdermal absorption preparation having an adhesive layer containing free donepezil, in which the adhesive layer contains a hydrophobic polymer and 13.75 to 55 mg of free donepezil, can be provided by administering the transdermal absorption preparation to a patient once a day, the transdermal absorption preparation exhibiting pharmacokinetics comparable to those of an oral formulation of donepezil hydrochloride.
In particular, for preparations (hereinafter sometimes abbreviated as "SIS preparations") that use styrene-isoprene-styrene block copolymer (hereinafter sometimes abbreviated as "SIS") as the main base, it has been found that it is preferable to use hydrogenated rosin glycerin ester as a tackifier resin and liquid paraffin as a plasticizer, and this has led to the completion of the present invention.

That is, the present invention relates to the following.
[1]
A transdermal absorption preparation for treating dementia, comprising an adhesive layer containing donepezil free form,
the adhesive layer contains a styrene-isoprene-styrene block copolymer and 13.75 mg to 55 mg of donepezil free form;
Administered to patients once daily,
Transdermal absorption preparation.
[2]
The transdermal absorption preparation according to [1], wherein the adhesive layer further contains hydrogenated rosin glycerin ester, liquid paraffin, and an absorption enhancer.
[3]
The transdermal absorption preparation according to [2], wherein the blending amount of the styrene-isoprene-styrene block copolymer is 5 to 70% by weight, the blending amount of the hydrogenated rosin glycerin ester is 5 to 70% by weight, the blending amount of the liquid paraffin is 10 to 70% by weight, and the blending amount of the absorption enhancer is 0.01 to 30% by weight, relative to the weight of the adhesive layer.
[4]
The transdermal absorption preparation according to [2], wherein the blending amount of the styrene-isoprene-styrene block copolymer is 10 to 50% by weight, the blending amount of the hydrogenated rosin glycerin ester is 10 to 60% by weight, the blending amount of the liquid paraffin is 10 to 50% by weight, and the blending amount of the absorption enhancer is 1 to 10% by weight, relative to the weight of the adhesive layer.
[5]
The transdermal absorption preparation according to [2], wherein the blending amount of the styrene-isoprene-styrene block copolymer is 20 to 30% by weight, the blending amount of the hydrogenated rosin glycerin ester is 30 to 50% by weight, the blending amount of the liquid paraffin is 15 to 30% by weight, and the blending amount of the absorption enhancer is 3 to 8% by weight, relative to the weight of the adhesive layer.
[6]
The transdermal absorption preparation according to any one of [1] to [5], wherein the weight ratio of the hydrogenated rosin glycerin ester to the donepezil free form is hydrogenated rosin glycerin ester/donepezil free form=1.5 to 8, and the weight ratio of the styrene-isoprene-styrene block copolymer to liquid paraffin is styrene-isoprene-styrene block copolymer/liquid paraffin=0.7 to 1.8.
[7]
The transdermal absorption preparation according to any one of [1] to [5], wherein the weight ratio of the hydrogenated rosin glycerin ester to the donepezil free form is hydrogenated rosin glycerin ester/donepezil free form=4 to 7, and the weight ratio of the styrene-isoprene-styrene block copolymer to liquid paraffin is styrene-isoprene-styrene block copolymer/liquid paraffin=0.8 to 1.6.
[8]
The transdermal absorption preparation according to any one of [1] to [5], which contains 13.75 mg, 27.5 mg, or 55 mg of donepezil free form.
[9]
The transdermal absorption preparation according to [6], comprising 13.75 mg, 27.5 mg, or 55 mg of donepezil free form.
[10]
The transdermal absorption preparation according to [7], comprising 13.75 mg, 27.5 mg, or 55 mg of donepezil free form.
[11]
The percutaneous absorption preparation according to any one of [1] to [10], wherein the absorption enhancer is an aliphatic alcohol.
[12]
The transdermal absorption preparation according to any one of [1] to [5], wherein the surface area of the adhesive layer containing the donepezil free form that comes into contact with the skin is 10 to ¹⁰⁰ cm2.
[13]
A method for treating dementia, comprising administering the transdermal preparation according to any one of [1] to [12] to a patient.
[14]
The percutaneous absorption preparation according to any one of [1] to [12] for use in the treatment of dementia.
[15]
Use of the transdermal preparation according to any one of [1] to [12] in the manufacture of a medicament for treating dementia.
[16]
Use of the transdermal preparation according to any one of [1] to [12] in the treatment of dementia.
[17]
The percutaneous absorption preparation according to any one of [1] to [12], wherein in a release test, the drug release rate from the preparation after 3 hours is 10 to 50%.
[18]
The percutaneous absorption preparation according to any one of [1] to [12], wherein in a release test, the drug release rate from the preparation after 6 hours is 30 to 70%.
[19]
The percutaneous absorption preparation according to any one of [1] to [12], wherein in a release test, the drug release rate from the preparation after 9 hours is 40% or more.

The present invention provides a transdermal formulation that exhibits pharmacokinetics and therapeutic effects comparable to those of an oral formulation of donepezil.

The donepezil-containing transdermal formulation provided by the present invention enables free donepezil to be efficiently absorbed into the circulating blood via the skin, and can provide therapeutic effects equivalent to those of oral formulations.
Therefore, the present invention not only provides a new option for patients with advanced symptoms, but is also expected to improve medication compliance for patients with impaired swallowing function due to its ease of administration and visibility, and to reduce the burden on caregivers.

The donepezil-containing transdermal formulation provided by the present invention will be described in more detail below.

In this specification, "contain" or "include" may be used interchangeably with "blended." Also, in this specification, "content" and "blended amount" may be used interchangeably.

The transdermal preparation of the present invention refers to a patch that contains at least a support and an adhesive layer (also called an adhesive composition), and includes reservoir-type external patches that have a drug storage layer, and single-layer matrix-type external patches.

Matrix-type topical patches have superior adhesion and drug absorption compared to reservoir-type topical patches because the adhesive composition having self-adhesive properties and active ingredients adheres directly to the skin.
Therefore, the following description of the percutaneous absorption preparation of the present invention will be given mainly with reference to a matrix-type patch, but the present invention is not limited to this.

The transdermal preparation provided by the present invention contains donepezil free form dissolved in an adhesive composition.
Typically, it is in the form of an adhesive layer containing the drug (donepezil free form) and a backing layer laminated on the back of the adhesive layer. It is preferable that the adhesive layer has a self-adhesive strength that allows it to be attached to the skin surface for 24 hours or more with an effective area that does not cause any problems in terms of treatment, but if this is difficult, it is also possible to use a sheet-like cover that has an area larger than the drug-containing layer and has adhesive strength.

Donepezil can form a salt, but the transdermal preparation of the present invention uses free donepezil (ie, donepezil in the free form without forming a salt).
The transdermal preparation of the present invention enables stable drug supply without problems in adhesion by dissolving free donepezil in the adhesive composition.
The amount of the donepezil in the percutaneous absorption preparation of the present invention is preferably 5 to 8% by weight, more preferably 6 to 7% by weight, based on the total weight of the adhesive composition. More preferably, the percutaneous absorption preparation of the present invention is produced so as to contain 13.75 mg, 27.5 mg, or 55 mg of donepezil free form.
Since the release of donepezil in the percutaneous absorption preparation of the present invention is also affected by the base component, the amount of donepezil to be incorporated can also be determined by a drug release test. A preferred drug release test is a method for measuring the release rate in water. For example, when the test is performed with 1000 mL of test liquid, a test liquid temperature of 32±0.5° C., and a cylinder rotation speed of 50 rpm, it is preferred that the release rate in water after 3 hours from the start of the test is 10-50%, after 6 hours it is 30-70%, and after 9 hours it is 40% or more.

The adhesive composition of the present invention contains a hydrophobic polymer as an adhesive composition having self-adhesive strength.
The hydrophobic polymer is not particularly limited, but a rubber-based polymer, an acrylic-based polymer, or a silicone-based polymer is preferably used.
Examples of rubber-based polymers include styrene-isoprene-styrene block copolymers, isoprene, polyisobutylene (hereinafter abbreviated as "PIB"), styrene-butadiene-styrene block copolymers (hereinafter abbreviated as "SBS"), and styrene-butadiene rubber (hereinafter abbreviated as "SBR"), and among these, SIS is preferable.

The acrylic polymer is not particularly limited as long as it is a copolymer containing at least one (meth)acrylic acid derivative, such as 2-ethylhexyl acrylate, methyl acrylate, butyl acrylate, hydroxyethyl acrylate, or 2-ethylhexyl methacrylate.
Specifically, for example, adhesives such as acrylic acid/octyl acrylate copolymer, 2-ethylhexyl acrylate/vinylpyrrolidone copolymer solution, acrylic ester/vinyl acetate copolymer, 2-ethylhexyl acrylate/2-ethylhexyl methacrylate/dodecyl methacrylate copolymer, methyl acrylate/2-ethylhexyl acrylate copolymer resin emulsion, and acrylic polymers contained in acrylic resin alkanolamine liquid, which are listed as adhesives in the Dictionary of Pharmaceutical Additives 2007 (edited by the Japan Pharmaceutical Additives Association), DURO-TAK acrylic adhesive series (manufactured by Henkel), and Eudragit series (Higuchi Shokai), can be used.

Specific examples of silicon-based polymers include silicone rubbers such as polyorganosiloxane.

Two or more of such hydrophobic polymers may be used in combination, and the amount of these polymers based on the weight of the entire composition is 5 to 70% by weight, preferably 10 to 50% by weight, and more preferably 20 to 30% by weight, taking into consideration the formation of an adhesive layer and sufficient permeability.

In the adhesive composition of the transdermal absorption preparation provided by the present invention, it is preferable to contain an absorption enhancer. Examples of the absorption enhancer that can be used include fatty acid esters, fatty alcohols, surfactants, etc.
Specifically, methyl laurate, hexyl laurate, triethyl citrate, isopropyl myristate (hereinafter abbreviated as IPM), myristyl myristate, octyldodecyl myristate, cetyl palmitate, triacetin, cetyl lactate, lauryl lactate, methyl salicylate, glycol salicylate, ethylene glycol salicylate, diethyl sebacate, diisopropyl sebacate, medium-chain triglyceride, lauryl alcohol, stearyl alcohol, isostearyl alcohol, myristyl alcohol, oleyl alcohol, cetanol, glycerin monocaprylate, glycerin monocaprate, glycerin monolaurate, glycerin monooleate, Examples of the laurate include sorbitan monolaurate, sorbitan monooleate, sucrose monolaurate, polysorbate 20, propylene glycol monolaurate, polyethylene glycol monolaurate, polyethylene glycol monostearate, lauromacrogol, HCO-60, lauric acid diethanolamide, N-methyl-2-pyrrolidone, crotamiton, and dimethyl sulfoxide, and preferred examples include triethyl citrate, isopropyl myristate, cetyl lactate, oleyl alcohol, sorbitan monooleate, polyethylene glycol monostearate, lauromacrogol, N-methyl-2-pyrrolidone, and triacetin.

Among these, it is preferable to blend one or more selected from fatty alcohols (e.g., lauryl alcohol, stearyl alcohol, isostearyl alcohol, myristyl alcohol, oleyl alcohol, etc.).

In consideration of sufficient permeability of the active ingredient as a patch preparation and skin irritation such as redness and edema, the absorption enhancer is preferably blended in an amount of about 0.01 to 30% by weight, more preferably 1 to 10% by weight, and even more preferably 3 to 8% by weight, based on the weight of the total composition of the adhesive layer.

The adhesive composition in the transdermal preparation provided by the present invention may contain a plasticizer. Examples of plasticizers that can be used include petroleum-based oils (e.g., paraffin-based process oils, naphthenic process oils, aromatic process oils, etc.), squalane, squalene, vegetable oils (e.g., olive oil, camellia oil, tall oil, peanut oil, castor oil), silicone oils, dibasic acid esters (e.g., dibutyl phthalate, dioctyl phthalate, etc.), liquid rubbers (e.g., polybutene, liquid isoprene rubber), liquid fatty acid esters (isopropyl myristate, hexyl laurate, diethyl sebacate, diisopropyl sebacate), diethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, etc. Liquid paraffin, liquid polybutene, or silicone oil is particularly preferred. Liquid paraffin is the most preferred.

Two or more of these components may be mixed and used, and the amount of such plasticizer based on the entire composition of the adhesive layer is 10-70% by weight, preferably 10-50% by weight, and more preferably 15-30% by weight, in total, taking into consideration sufficient skin permeability and maintaining sufficient cohesive strength as a patch preparation.

In order to adjust the adhesive strength of the preparation, it is desirable to incorporate a tackifier resin into the adhesive layer of the present invention. Some tackifier resins also have the effect of dissolving donepezil free form, and are also used to adjust the solubility of donepezil free form in the patch.
Examples of tackifying resins that can be used include rosin derivatives (e.g., rosin, rosin glycerin ester, hydrogenated rosin, hydrogenated rosin glycerin ester, pentaerythritol ester of rosin, etc.), alicyclic saturated hydrocarbon resins (e.g., Alcon P100, manufactured by Arakawa Chemical Industries, Ltd.), aliphatic hydrocarbon resins (e.g., Quinton B170, manufactured by Zeon Corporation), terpene resins (e.g., Clearon P-125, manufactured by Yasuhara Chemical Co., Ltd.), maleic acid resins, and the like. In consideration of the adhesion of the formulation and the solubility of donepezil free form in the formulation, hydrogenated rosin glycerin ester is particularly preferred.

The amount of such a tackifier resin based on the overall composition of the adhesive composition can be 5 to 70% by weight, preferably 10 to 60% by weight, and more preferably 30 to 50% by weight, taking into consideration sufficient adhesive strength as a patch preparation and skin irritation upon removal.

The donepezil-containing transdermal formulation provided by the present invention is a systemically acting transdermal formulation, and therefore crystallization of the active ingredient during storage is undesirable as it leads to a decrease in the blood concentration of donepezil free at the time of application. Therefore, it is desirable that crystals of donepezil free are not formed in the formulation even under long-term storage conditions. However, since the present invention is a formulation that contains a transdermal absorption enhancer, it is difficult to maintain the uniformity of the base in long-term storage products, and there is concern that the active ingredient may crystallize due to non-uniformity of the base.

For this reason, in SIS formulations, hydrogenated rosin glycerin ester functions not only as a tackifying resin but also as a dissolving agent for donepezil free form, in an attempt to increase the solubility of donepezil free form. However, when hydrogenated rosin glycerin ester is added in amounts greater than a certain level, the solubility of donepezil free form increases too much, resulting in a decrease in the release of the active ingredient. Therefore, it is necessary to mix hydrogenated rosin glycerin ester and donepezil free form in an appropriate weight ratio.

According to the studies of the present inventors, it has been found that the preferred weight ratio of hydrogenated rosin glycerin ester to donepezil free form in the donepezil-containing transdermal formulation of the present invention is hydrogenated rosin glycerin ester/donepezil free form = 1.5 to 8, more preferably 4 to 7, and even more preferably 6 to 7. In other words, if the hydrogenated rosin glycerin ester/donepezil free form is less than 1.5, the solubility of the donepezil free form in the formulation is low, raising concerns about crystallization of the active ingredient in the formulation during storage, and if it is more than 8, the release of the active ingredient will decrease.

Furthermore, it was found that in SIS formulations, there is a correlation between the amount of SIS and the crystallization of donepezil free. In other words, by adding SIS, the mobility of donepezil free in the formulation is suppressed, and as a result, the crystallization of the active ingredient can be suppressed. However, if a large amount of SIS is added, it may cause a decrease in the adhesiveness of the formulation.
On the other hand, the incorporation of liquid paraffin promotes the crystallization of donepezil free form. In other words, the incorporation of liquid paraffin not only promotes the mobility of donepezil free form in the formulation, but also reduces the solubility of donepezil free form in the formulation as a whole, since liquid paraffin itself has low solubility in donepezil free form. However, keeping the amount of liquid paraffin low leads to a decrease in adhesive properties.

In light of these circumstances, in the present invention, by optimizing the weight ratio of liquid paraffin to SIS, it is possible to suppress crystallization of donepezil free form without impairing its adhesive properties.
That is, the weight ratio of SIS to liquid paraffin in the present invention is SIS/liquid paraffin = 0.7 to 1.8, preferably 0.8 to 1.6, and more preferably 1 to 1.5. If the SIS/liquid paraffin ratio is less than 0.7, the amount of liquid paraffin blended becomes excessive, and there is a concern that the free donepezil may crystallize in the long-term storage preparation. On the other hand, if it is more than 1.8, the SIS content is too high, which causes a decrease in adhesive strength.

In the percutaneous absorption preparation of the present invention, an antioxidant, a filler, a crosslinking agent, a preservative, and an ultraviolet absorbing agent can be used as necessary.
As the antioxidant, tocopherol and its ester derivatives, ascorbic acid, ascorbic acid stearate, nordihydroguaiaretic acid, dibutylhydroxytoluene (hereinafter abbreviated as BHT), butylhydroxyanisole, etc. are preferable.
As the filler, calcium carbonate, magnesium carbonate, silicates (for example, aluminum silicate, magnesium silicate, etc.), silicic acid, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide, silicon dioxide, etc. are preferable.

The crosslinking agent is preferably a thermosetting resin such as an amino resin, a phenol resin, an epoxy resin, an alkyd resin, or an unsaturated polyester; an isocyanate compound, a blocked isocyanate compound, an organic crosslinking agent; or an inorganic crosslinking agent such as a metal or a metal compound.
As the preservative, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, etc. are preferable.
As the ultraviolet absorber, p-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, amino acid compounds, dioxane derivatives, coumarin derivatives, imidazoline derivatives, pyrimidine derivatives, etc. are preferable.

Such antioxidants, fillers, crosslinking agents, preservatives, UV absorbers, etc., can be blended in amounts of preferably 10% by weight or less, more preferably 5% by weight or less, and particularly preferably 2% by weight or less, based on the weight of the entire composition of the adhesive layer of the formulation.

The transdermal formulation of the present invention can be used to treat dementia (e.g., Alzheimer's disease and Lewy body dementia).

In the present invention, "treatment" refers to the act of administering the transdermal preparation of the present invention to an individual who has already developed a disease or symptoms. Therefore, administering to an individual who has already developed a disease or symptoms to prevent the worsening of symptoms, prevent attacks, or prevent recurrence is one aspect of "treatment".

The transdermal preparation of the present invention is usually administered to a patient suffering from or at risk of dementia, such as a human or animal, preferably a human. The number of administrations may vary depending on conditions such as the severity of the disease or symptoms, the age, weight, and sex of the patient, and the amount of donepezil free in the transdermal preparation. When administered to humans, the transdermal preparation of the present invention is usually administered once a day.

The transdermal preparation of the present invention having the above-mentioned composition can be manufactured by any method. For example, the method generally called the hot melt method involves heat-melting a base composition containing a drug, applying it to a release film or support, and then laminating the support or release film to obtain the desired drug, or the method generally called the solvent method involves dissolving a base component containing a drug in a solvent such as toluene, hexane, or ethyl acetate, spreading it on a release film or support, drying and removing the solvent, and then laminating the support or release film to obtain the desired drug.

As the support for the transdermal preparation of the present invention, a stretchable or non-stretchable support can be used. For example, the support can be selected from cloth, nonwoven fabric, polyurethane, polyester, polyvinyl acetate, polyvinylidene chloride, polyethylene, polyethylene terephthalate (hereinafter abbreviated as "PET"), aluminum sheet, etc., or a composite material thereof.

The release film is not particularly limited as long as it protects the adhesive layer until the transdermal absorption preparation is applied to the skin, does not cause the anti-dementia agent, donepezil free form, to deteriorate, and is silicone-coated to allow easy peeling.
Specific examples of such a film include a polyethylene film, a polyethylene terephthalate film, and a polypropylene film coated with silicone.

Although the adhesive layer of the percutaneously absorbable preparation of the present invention has adhesive power, a fixing sheet may be used to reinforce adhesion to the skin when applied to the skin. The preparation area of the percutaneously absorbable preparation of the present invention is 10 to 100 ^cm2 , preferably 20 to 90 ^cm2 , and the preparation shape is not important, but the area of the adhesive surface of the fixing sheet is not included in the preparation area defined here.

The transdermal formulation of the present invention prepared in the above manner contains the active ingredient, donepezil free form, dissolved in a patch base containing a hydrophobic polymer, an absorption enhancer, and the various additives mentioned above, and as a result exhibits the excellent effects of rapidly increasing the blood concentration of donepezil free form after administration and maintaining an effective blood concentration for a long period of time.

The present invention will be explained in more detail below by showing examples of the present invention, but the present invention is not limited to these examples, and various modifications are possible within the scope of the technical concept of the present invention.

Example :
Donepezil free form was dissolved in a mixture of aliphatic alcohol and toluene in advance, and then mixed with the remaining components dissolved in toluene. The mixture was coated on a release film, the toluene was dried to remove, and the film was laminated with a PET film support and cut to a preparation area of 22 ^cm2 (13.75 mg preparation), 44 ^cm2 (27.5 mg preparation), and 88 ^cm2 (55 mg preparation), to obtain the percutaneous absorption preparation of the present invention.

Next, the effect of the transdermal absorption preparation of the present invention will be shown in the following test examples. In the following test examples, the tape preparation of the present invention refers to the transdermal absorption preparation of the present invention having the configuration of the example.

Test Example 1
Test method:
A four-group, two-period crossover study was conducted on 48 healthy elderly male subjects. In Period I, 27.5 mg of the tape preparation of the present invention was administered to the back once a day for 17 days, and in Period II, 5 mg of the donepezil hydrochloride oral preparation was administered once a day for 21 days. The blood concentration of donepezil was measured at each time point. Based on the blood concentration values obtained, the parameters of Period I and Period II were compared.
The blood sampling times are as follows:
The tape preparation of the present invention: applied to the backs of 48 healthy elderly males. Just before application, and 2, 4, 6, 8, 12, 24, 48, 96, 144, 146, 148, 150, 152, 156, 168, 216, 264, 312, 336, 384, 386, 388, 390, 392, 396, 408, 420, 432, 456, 504, 552, 624, and 696 hours after the first application. Donepezil hydrochloride oral preparation: The drug was administered orally to six subjects, immediately before administration, and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408, 432, 456, 480, 480.5, 481, 482, 483, 484, 486, 488, 492, 504, 528, 552, 576, 600, 648, and 744 hours after the first administration.

result:
The results are shown in Table 2.
Regarding the pharmacokinetics of the 27.5 mg tape preparation of the present invention, the geometric mean ratio of AUC _0-24h on the final administration day in Period I to Period II was 0.956, with a 90% confidence interval that included 1, indicating that repeated application of the tape preparation of the present invention for 17 days provides an exposure level equivalent to that of repeated oral administration of a donepezil hydrochloride oral preparation for 21 days. Similarly, the 90% confidence interval for the geometric mean ratio of C _trough included 1, indicating that the tape preparation of the present invention and a donepezil hydrochloride oral preparation provide an exposure level equivalent to that of the donepezil hydrochloride oral preparation.
Generally, the higher the blood concentration peak, the higher the incidence of side effects, but the geometric mean value of _Cmax on the final administration day was lower in Period I than in Period II. On the other hand, the geometric mean value of _Ctrough on the final administration day was higher in Period I than in Period II. From the above, it was suggested that the tape preparation of the present invention can obtain stable effects by maintaining high blood concentrations while keeping the risk of side effects low.

Test Example 2
Test Method The test was carried out using 13.75 mg of the tape preparation of the present invention, 27.5 mg of the tape preparation of the present invention, and 55 mg of the tape preparation of the present invention.
Thirty-six healthy elderly male subjects (12 subjects in each of the three groups) were administered the drug repeatedly to the back once a day for 17 days in each period in a three-group, three-period crossover study. The blood concentration of donepezil was measured at each time point. Based on the blood concentration values obtained, the pharmacokinetics at steady state and C _max and AUC _0-24 of each dose were compared.
Blood sampling times for each period were as follows:
Immediately before application, 2, 4, 6, 8, 12, 24, 72, 120, 168, 216, 264, 312, 336, 360, 384, 386, 388, 390, 392, 396, 408, 420, 432, 456, 504, 552, 624, 696 hours after first application

Results The results are shown in Tables 3 and 4.
On Day 17, the geometric mean values of _Cmax were 12.317 ng/mL for the 13.75 mg tape preparation of the present invention, 23.354 ng/mL for the 27.5 mg tape preparation of the present invention, and 49.452 ng/mL for the 55 mg tape preparation of the present invention. The geometric mean values of AUC0-24h were 268.10 ng·h/mL (57.17%), 508.11 ng·h/mL, and 1077.02 ng·h/mL, respectively, and it was observed that _Cmax and _AUC0-24h tended to increase with increasing dose.
The linearity of the pharmacokinetic parameters on Day 17 was evaluated using a power model. The point estimates (95% confidence intervals) of the slopes of the regression lines for C _max and AUC _0-24h were both 1.00 (0.96 to 1.04), and the 95% confidence intervals included 1, indicating that C _max and AUC _0-24h increased linearly in proportion to the dose.

Test Example 3
(1) Non-inferiority: double-blind phase
Test method: A test was conducted on 339 patients with mild to moderate Alzheimer's dementia (173 patients receiving the 27.5 mg tape preparation of the present invention, and 166 patients receiving the donepezil oral preparation (containing 5 mg donepezil hydrochloride)) once daily for 24 weeks. The tape preparation of the present invention was applied to the back. The change in ADAS-Jcog score from baseline to 24 weeks was examined to determine non-inferiority to the oral preparation. The change in DAD and ABC dementia scale scores from baseline to 24 weeks was also evaluated.

Results The results are shown in Tables 5 and 6.
The least squares mean ± standard error of the change from baseline in ADAS-Jcog at 24 weeks was -0.7 ± 0.4 for the tape preparation group of the present invention and 0.2 ± 0.4 for the donepezil hydrochloride oral formulation group. The least squares mean difference (95% confidence interval) between the tape preparation group of the present invention and the donepezil hydrochloride oral formulation group was -0.9 (-2.01 to 0.14), and the upper limit of the 95% confidence interval of the difference between the groups was below the pre-established non-inferiority limit of 2.15, verifying the non-inferiority of the tape preparation group of the present invention to the donepezil hydrochloride oral formulation group.
In addition, the changes from baseline to 24 weeks in each domain of the DAD and ABC dementia scale for the tape preparation group of the present invention and the donepezil hydrochloride oral formulation group, respectively, were -2.2±12.3 and -3.5±10.9 for DAD, -0.5±4.5 and -0.5±3.8 for ADL, -0.4±2.6 and -0.3±2.5 for BPSD, -0.6±3.7 and -0.8±3.5 for cognitive function, and -0.8±4.7 and -0.8±4.1 for TDD.

(2) Continuation: Open-label period
Test method: 301 patients with mild to moderate Alzheimer's disease who had completed 24 weeks of repeated administration in a non-inferiority test (double-blind period) were asked to apply 27.5 mg of the tape preparation of the present invention once daily to the back, upper arm, or chest for 28 consecutive weeks (52 weeks in total from the double-blind period), and the changes in the ADAS-Jcog and ABC dementia scale total scores at baseline and from 24 weeks to 52 weeks were evaluated.

Results The results are shown in Tables 7 and 8.
The mean ± standard deviation of the change in ADAS-Jcog score from 24 weeks in the tape preparation group of the present invention was 0.5 ± 4.3 at 28 weeks, 0.8 ± 5.1 at 36 weeks, and 1.2 ± 5.2 at 52 weeks. In the donepezil hydrochloride oral preparation group (switched to the tape preparation of the present invention after 28 weeks), the mean ± standard deviation was 1.5 ± 4.5 at 28 weeks, 1.4 ± 4.5 at 36 weeks, and 1.9 ± 5.4 at 52 weeks.
In addition, the mean ± standard deviation of the changes from 24 weeks in the ABC dementia scale (total score) was -1.0 ± 4.3 at 28 weeks, -1.1 ± 5.1 at 36 weeks, and -2.6 ± 6.8 at 52 weeks in the tape preparation group of the present invention, and -0.1 ± 4.4 at 28 weeks, -1.0 ± 4.9 at 36 weeks, and -2.8 ± 6.6 at 52 weeks in the switching group.

Test Example 4
Test Method: This test was carried out using 55 mg of the tape preparation of the present invention.
This open-label, uncontrolled study involved 64 patients with severe Alzheimer's disease in which the device was applied to the back, upper arm, or chest once daily for 52 weeks, and the changes from baseline to week 52 in MMSE and ABC dementia scale scores were evaluated.

Results The results are shown in Tables 9 and 10.
The mean ± standard deviation change from baseline in MMSE was 0.0 ± 2.7 at 12 weeks, −0.2 ± 3.0 at 24 weeks, and −1.1 ± 3.4 at 52 weeks, with baseline scores maintained up to 24 weeks.
The mean ± standard deviation of the change from baseline in the ABC Dementia Scale (TDD) was 1.0 ± 5.3 at screening, -0.2 ± 5.3 at week 12, -2.2 ± 6.2 at week 24, and -4.3 ± 6.9 at week 52. The total score of the ABC Dementia Scale and each domain (ADL, BPSD, cognitive function) also showed scores similar to those of the TDD.

Furthermore, by repeatedly applying 27.5 mg of the tape preparation of the present invention to the back, upper arm, or chest of a human, the steady-state AUC _0-24h became equivalent to that of a 5 mg oral preparation of donepezil hydrochloride.

Test Example 5
Test Method: This test was carried out using 13.75 mg of the tape preparation of the present invention.
A four-group, two-period crossover study was conducted on 64 healthy elderly male subjects (groups A to D: 16 subjects each). The drug was administered once daily for 17 days in each period to the back, upper arm, or chest, and the blood concentration of donepezil was measured at each time point. The pharmacokinetic equivalence between application sites was examined based on the obtained blood concentrations.
Blood sampling times for each period were as follows:
Immediately before application, 2, 4, 6, 8, 12, 24, 72, 120, 168, 216, 264, 312, 336, 360, 384, 386, 388, 390, 392, 396, 408, 420, 432, 456, 504, 552, 624, 696 hours after first application

Results The results are shown in Table 11.
The geometric mean differences (90% confidence interval) of C _max and AUC _0-24h between the back and upper arm applications on Day 17 were 1.03 (0.96-1.11) and 1.08 (1.03-1.14), respectively.
The geometric mean differences (90% confidence interval) of C _max and AUC _0-24h between the back and chest applications on Day 17 were 1.03 (0.96-1.11) and 1.04 (0.97-1.12), respectively.
The ratios of the geometric means when the drug was applied to the back and the upper arm, and when it was applied to the back and the chest, were all close to 1, and the 90% confidence interval for the difference in the mean logarithmic values was within the range of log(0.80) to log(1.25), which is the criterion for determining bioequivalence. This confirmed that the pharmacokinetics when the drug was applied to the back, the upper arm, and the chest were equivalent.

Test Example 6 Release Test
Test method: Drug release from the test preparations (27.5 mg and 55 mg of the tape preparation of the present invention) was tested by the rotating cylinder method described in the Japanese Pharmacopoeia Release Test Method. The test conditions are shown in Table 12.

The results are shown in Tables 13-1 and 13-2. The release rate of the 27.5 mg formulation was 27.9±0.9% after 3 hours, 45.6±0.5% after 6 hours, and 59.5±1.0% after 9 hours. The release rate of the 55 mg formulation was 21.6±0.1% after 3 hours, 33.0±0.2% after 6 hours, and 42.5±0.8% after 9 hours.

Formulation Examples According to the blending amounts in Table 14, percutaneous absorption preparations of Formulation Examples 1 to 4 were obtained in the same manner as in the Examples.

Test Example 7
In vitro skin permeability test For the percutaneous absorption preparations of the Examples and Formulation Examples 1 to 4, an in vitro hairless rat skin permeability test was performed. The abdominal skin of male hairless rats (HWY, 7 weeks old) was excised and set in a Franz diffusion cell, the dermis side was set as the receptor side, the inside was filled with phosphate buffered saline, and 37°C warm water was refluxed in the water jacket. Each patch was punched out into a circle (1.54 cm ² ) and applied to the excised skin, and the receptor liquid was sampled 24 hours after the start of the test, and the skin permeation amount of the drug was measured by high performance liquid chromatography. The cumulative permeation amount of Formulation Examples 1 to 4 relative to the cumulative permeation amount of the Examples is shown in Table 14.

The formulations of Formulation Examples 1 to 4 exhibited the same level of permeability as the Examples, suggesting that it is possible to provide a transdermal formulation that exhibits the same level of pharmacokinetics as the donepezil hydrochloride oral formulation, just like the Examples.

According to the donepezil-containing transdermal formulation provided by the present invention, the active ingredient, free donepezil, can be efficiently absorbed into the circulating blood via the skin, and can provide therapeutic effects equivalent to those of oral formulations.
Therefore, the present invention provides a new treatment option for patients with advanced symptoms, and is expected to improve compliance for patients with impaired swallowing function due to its ease of administration and visibility, and to reduce the burden on caregivers. In addition, the present invention is particularly effective as a transdermal absorption preparation for long-term administration of donepezil free form, and offers hope for the treatment of dementia diseases.

Claims

A transdermal absorption preparation for treating dementia, comprising an adhesive layer containing donepezil free form,
the adhesive layer contains a styrene-isoprene-styrene block copolymer and 13.75 mg to 55 mg of donepezil free form;
Administered to patients once daily,
Transdermal absorption preparation.
The transdermal preparation according to claim 1, further comprising hydrogenated rosin glycerin ester, liquid paraffin, and an absorption enhancer in the adhesive layer.
The transdermal preparation according to claim 2, in which the amount of styrene-isoprene-styrene block copolymer is 5-70% by weight, the amount of hydrogenated rosin glycerin ester is 5-70% by weight, the amount of liquid paraffin is 10-70% by weight, and the amount of absorption enhancer is 0.01-30% by weight, relative to the weight of the adhesive layer.
The transdermal preparation according to claim 2, in which the amount of styrene-isoprene-styrene block copolymer is 10-50% by weight, the amount of hydrogenated rosin glycerin ester is 10-60% by weight, the amount of liquid paraffin is 10-50% by weight, and the amount of absorption enhancer is 1-10% by weight, relative to the weight of the adhesive layer.
The transdermal preparation according to claim 2, in which the amount of styrene-isoprene-styrene block copolymer is 20-30% by weight, the amount of hydrogenated rosin glycerin ester is 30-50% by weight, the amount of liquid paraffin is 15-30% by weight, and the amount of absorption enhancer is 3-8% by weight, relative to the weight of the adhesive layer.
The transdermal absorption preparation according to any one of claims 1 to 5, wherein a weight ratio of the hydrogenated rosin glycerin ester to the donepezil free form is hydrogenated rosin glycerin ester/donepezil free form=1.5 to 8, and a weight ratio of the styrene-isoprene-styrene block copolymer to liquid paraffin is styrene-isoprene-styrene block copolymer/liquid paraffin=0.7 to 1.8.
The transdermal absorption preparation according to any one of claims 1 to 5, wherein a weight ratio of the hydrogenated rosin glycerin ester to the donepezil free form is hydrogenated rosin glycerin ester/donepezil free form=4 to 7, and a weight ratio of the styrene-isoprene-styrene block copolymer to liquid paraffin is styrene-isoprene-styrene block copolymer/liquid paraffin=0.8 to 1.6.
The transdermal preparation according to any one of claims 1 to 5, containing 13.75 mg, 27.5 mg, or 55 mg of donepezil free form.
The transdermal preparation according to claim 6, which contains 13.75 mg, 27.5 mg, or 55 mg of donepezil free form.
The transdermal preparation according to claim 7, which contains 13.75 mg, 27.5 mg, or 55 mg of donepezil free form.
The percutaneous absorption preparation according to any one of claims 1 to 5, wherein the surface area of the adhesive layer containing the free donepezil that comes into contact with the skin is 10 to 100 cm2.