Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

• 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.
• acetylcholinesterase inhibitors such as donepezil increase acetylcholine in the brain and activate the cholinergic nervous system in the brain.
• 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.
• 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.
• 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.
• 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.
• 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.
• SIS preparations that use styrene-isoprene-styrene block copolymer (hereinafter sometimes abbreviated as "SIS") as the main base
• SIS styrene-isoprene-styrene block copolymer
• hydrogenated rosin glycerin ester as a tackifier resin and liquid paraffin as a plasticizer
• 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.
• a method for treating dementia comprising administering the transdermal preparation according to any one of [1] to [12] to a patient.
• 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%.
• 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.
• 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.
• the transdermal preparation provided by the present invention contains donepezil free form dissolved in an adhesive composition.
• 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.
• 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.
• 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.
• rubber-based polymers examples 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.
• PIB polyisobutylene
• SBS styrene-butadiene-styrene block copolymers
• SBR styrene-butadiene rubber
• 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.
• at least one (meth)acrylic acid derivative such as 2-ethylhexyl acrylate, methyl acrylate, butyl acrylate, hydroxyethyl acrylate, or 2-ethylhexyl methacrylate.
• 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.
• acrylic acid/octyl acrylate copolymer 2-ethylhexyl acrylate/vinylpyrrolidone copolymer
• hydrophobic polymers 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.
• an absorption enhancer examples 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
• fatty alcohols e.g., lauryl alcohol, stearyl alcohol, isostearyl alcohol, myristyl alcohol, oleyl alcohol, etc.
• 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.
• 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
• 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.
• tackifier resins 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.
• tackifying resins examples 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• keeping the amount of liquid paraffin low leads to a decrease in adhesive properties.
• an antioxidant 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.
• an antioxidant tocopherol and its ester derivatives, ascorbic acid, ascorbic acid stearate, nordihydroguaiaretic acid, dibutylhydroxytoluene (hereinafter abbreviated as BHT), butylhydroxyanisole, etc. are preferable.
• BHT dibutylhydroxytoluene
• 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.
• a thermosetting resin such as an amino resin, a phenol resin, an epoxy resin, an alkyd resin, or an unsaturated polyester
• an isocyanate compound such as an epoxy resin, an alkyd resin, or an unsaturated polyester
• an isocyanate compound such as an epoxy resin, an alkyd resin, or an unsaturated polyester
• an isocyanate compound such as an epoxy resin, an alkyd resin, or an unsaturated polyester
• an isocyanate compound such as an epoxy resin, an alkyd resin, or an unsaturated polyester
• an isocyanate compound such as an epoxy resin, an alkyd resin, or an unsaturated polyester
• UV 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.
• antioxidants 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).
• dementia e.g., Alzheimer's disease and Lewy body dementia.
• 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.
• 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.
• 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
• 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.
• a stretchable or non-stretchable support can be used as the support for the transdermal preparation of the present invention.
• 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.
• 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 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.
• 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.
• the results are shown in Table 2.
• 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.
• 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.
• the tape preparation of the present invention can obtain stable effects by maintaining high blood concentrations while keeping the risk of side effects low.
• results are shown in Tables 3 and 4.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• the mean ⁇ standard deviation of the changes from 24 weeks in the ABC dementia scale 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 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 also showed scores similar to those of the TDD.
• 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.
• 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.
• Test Example 7 In vitro skin permeability test
• 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 active ingredient free donepezil
• 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.
• 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.

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  • 2023-10-19 JP JP2024564189A patent/JPWO2024127805A1/ja active Pending
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