WO2012105715A1 - Novel external preparation - Google Patents
Novel external preparation Download PDFInfo
- Publication number
- WO2012105715A1 WO2012105715A1 PCT/JP2012/052794 JP2012052794W WO2012105715A1 WO 2012105715 A1 WO2012105715 A1 WO 2012105715A1 JP 2012052794 W JP2012052794 W JP 2012052794W WO 2012105715 A1 WO2012105715 A1 WO 2012105715A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- adhesive
- preparation according
- adhesive preparation
- additive
- compound
- Prior art date
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
- A61K9/7061—Polyacrylates
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/24—Antidepressants
Definitions
- the present invention relates to an adhesive preparation for transdermal absorption. Specifically, the present
- invention relates to an adhesive preparation comprising
- compound 1 is a compound useful as an atypical antipsychotic agent, and is disclosed in patent document 1.
- Adhesive preparation for transdermal absorption is one form of a useful preparation, since it can maintain blood drug concentration in a more sustained manner as compared to oral administration, and can lower liver metabolism and/or drug interaction by avoiding first pass effect.
- administration by way of a transdermal absorption preparation has many advantages such as absence of influence of diet, possible administration to patients having difficulty in swallowing, easy confirmation and discontinuation of
- transdermal absorption of antipsychotic agents a transdermal preparation of perospirone (patent document 2), a transdermal preparation of blonanserin (patent document 3) and the like have been reported.
- a transdermal preparation of compound 1 has not been specifically reported.
- the area of adhesion that is, the size of the adhesive preparation for transdermal absorption
- One of the methods to achieve the goal is considered to be the addition of an additive capable of enhancing skin permeation of a drug.
- an additive effective for enhancing the permeation is said to be specific for and vary depending on each target drug (non-patent document 1) .
- non-patent document 1 there are reports on the transdermal absorption preparations of perospirone and blonanserin; however, there is no report on findings relating to a transdermal preparation of compound 1, and an effective means for enhancing skin permeation is completely unclear.
- patent document 1 JP-B-2800953 (US 5532372 A)
- patent document 2 WO2006/025516
- non-patent document 1 Advanced Drug Delivery Reviews 56 (2004) 603-618.
- the present invention aims to provide an adhesive
- the present inventors have intensively studied a
- composition that enhances skin permeation of compound 1 and found the additive series that effectively enhances the skin permeation of compound 1.
- the present invention provides the following.
- An adhesive preparation comprising a support and an
- the adhesive layer formed on one surface of the support, wherein the adhesive layer comprises (i) (3aR, 4S, 7R, 7aS) -2- ⁇ (1R, 2R) -2- [4- (1, 2-benzisothiazol-3-yl) piperazin-1- ylmethyl] cyclohexylmethyl ⁇ hexahydro-4, 7-methano-2H-isoindole- 1,3-dione (compound 1) or a physiologically acceptable acid addition salt thereof, (ii) an adhesive, (iii) lactic acid as the first additive, and (iv) at least one kind of additive selected from the group consisting of alkyl glyceryl ether, polyoxyethylene alkyl ether, fatty acid ester, lecithin, fatty acid, alcohol, soybean oil, methyl isobutyl ketone and
- alkyl glyceryl ether as the second additive comprises a-monoisostearyl glyceryl ether.
- polyoxyethylene alkyl ether as the second additive comprises at least one kind selected from the group consisting of polyoxyethylene behenyl ether and lauromacrogol .
- diisopropyl adipate diisopropyl adipate, diethyl sebacate and propylene glycol esters of fatty acids.
- alcohol as the second additive comprises at least one kind selected from the group consisting of benzyl alcohol, decanol, octyldodecanol and propylene glycol.
- a method for the treatment of schizophrenia and/or a bipolar disorder comprising administering the adhesive preparation of any of the above-mentioned [1] - [25]
- An adhesive preparation comprising a support and an adhesive layer formed on one surface of the support, wherein the adhesive layer comprises (i) compound 1 or a
- physiologically acceptable acid addition salt thereof (ii) an adhesive, and (iii) at least one kind of additive selected from the group consisting of lactic acid, oc-monoisostearyl glyceryl ether, cetyl alcohol, spropylene glycol esters of fatty acids, polyoxyethylene (20) polyoxypropylene (8) cetylether, lipophilic glyceryl monooleate, Beeswax derivatives of
- component (i) at a concentration of 0.1 - 50 wt% in terms of compound 1.
- the adhesive comprises a rubber adhesive.
- the preparation can be downsized and can
- an adhesive preparation means a preparation in general, which can be adhered to the skin, including, for example, tape preparations, patch preparations, cataplasm preparations, plaster preparation and the like.
- the adhesive layer is a layer formed on a support, which comprises a drug.
- adhesive mean wt% when the total weight of the adhesive layer substantially free of solvent and the like by drying and the like is 100 wt%.
- Compound 1 relating to the present invention that is, (3aR, 4S, 7R, 7aS) -2- ⁇ (1R, 2R) -2- [4- (1, 2-benzisothiazol-3- yl ) piperazin-l-ylmethyl] cyclohexylmethyl ⁇ hexahydro-4 , 7- methano-2H-isoindole-l, 3-dione (generic name "lurasidone”) is a compound represented by the following formula:
- Compound 1 or a physiologically acceptable acid addition salt thereof has a pharmacological action as an antipsychotic agent. More specifically, compound 1 or a physiologically acceptable acid addition salt thereof, and a pharmaceutical preparation comprising the same are useful as therapeutic drugs for diseases such as schizophrenia, bipolar disorders and the like.
- Compound 1 may be a free base or a physiologically acceptable acid addition salt thereof.
- an addition salt of organic acid include, but are not limited to, formate, acetate, lactate, adipate, citrate, tartrate, methanesulfonate, fumarate, maleate and the like
- an addition salt of inorganic acid include, but are not limited to,
- hydrochloride hydrochloride, sulfate, nitrate, phosphate and the like.
- compound 1 or a physiologically acceptable acid addition salt thereof may also be a solvate, or a hydrate or non-hydrate .
- compound 1 or a physiologically acceptable acid addition salt thereof may be pulverized as appropriate according to a
- preparation of the present invention is generally about 0.1 - about 50 wt%, preferably about 0.1 - about 40 wt%, more
- the amount of a salt of compound 1 or a hydrate thereof is calculated by converting the weight thereof to the weight of an equimolar amount of compound 1 (free base non-hydrate) .
- Examples of the adhesive of the present invention include polymer adhesives such as silicone adhesives, rubber adhesives, acrylic adhesives and the like.
- silicone adhesive examples include those
- silicone rubber as a main component, such as polydimethyl siloxane, diphenylsiloxane and the like.
- the rubber adhesive include natural rubber,
- polyisopropylene rubber polyisobutylene, styrene-butadiene copolymer, styrene-isopropylene copolymer, styrene-isoprene- styrene block copolymer and the like.
- acrylic adhesive examples include (co) polymers mainly comprising (meth) acrylic acid alkyl ester. Specific examples include polymers mainly comprising acrylic acid alkyl ester, polymers mainly comprising methacrylic acid alkyl ester, copolymers mainly comprising acrylic acid alkyl ester,
- copolymers mainly comprising methacrylic acid alkyl ester and copolymers mainly comprising acrylic acid alkyl ester and methacrylic acid alkyl ester.
- the (co) polymer may be a
- (meth) acrylic acid means “acrylic acid or methacrylic acid”, or “acrylic acid and/or methacrylic acid”
- (co) polymer means “polymer or copolymer”, or
- Examples of the (meth) acrylic acid alkyl ester include those obtained by esterification with straight chain or
- (meth) acrylic acid butyl ester (meth) acrylic acid hexyl ester, (meth) acrylic acid octyl ester, (meth) acrylic acid nonyl ester, (meth) acrylic acid decyl ester and the like.
- the functional monomer include a monomer having a hydroxyl group ( (meth) acrylic acid hydroxyethyl ester etc.), a monomer having a carboxyl group (butyl maleate, crotonic acid etc.), a
- the acrylic adhesive in the present invention may be used singly or in a combination of two or more kinds thereof. In addition, it may be a mixture with other adhesive. Examples of the other adhesive include silicone adhesive, rubber adhesive and the like.
- acrylic adhesive examples include, but are not limited to, acrylic acid-acrylic acid octyl ester copolymer, acrylic acid ester-vinyl acetate
- methacrylate copolymer ethyl acrylate-methyl methacrylate copolymer, acrylic acid-silk fibroin copolymer, methyl
- acrylate-2-ethylhexyl acrylate copolymer and the like examples include commercially available products such as "POLYTHICK 410-SA” manufactured by Sanyo Chemical Industries, Ltd.,
- a curing agent may also be added where necessary.
- the curing agent include commercially available products such as "POLYTHICK SC-75” manufactured by Sanyo Chemical Industries, Ltd., “BHS8515” manufactured by TOYO INK CO., LTD. and the like.
- the amount thereof to be added can be appropriately selected according to the property of the adhesive, which is, for example, about 0.001 - 0.05 part by weight relative to 1 part by weight of the adhesive.
- the amount of the adhesive to be added is a balance after removing compound 1 or a physiologically acceptable acid
- addition salt thereof the following additives, and various components mentioned below, which are added for formulation as necessary, from the adhesive layer, and is the amount
- the amount of the adhesive is about 80 wt%.
- the adhesiveness of the adhesive to be used here is of the level employed for medical adhesive preparations, and intended to mean adhesiveness of the level permitting easy adhesion to the skin and causing no particular problem in peeling off.
- adhesive preparation of the present invention is generally about 0.01 - about 50 wt%, preferably about 0.1 - about 40 wt%, more preferably about 0.3 - about 40 wt%, of the adhesive layer as 100 wt%.
- the additive in the present invention may be used singly or in a combination of two or more kinds thereof. It is
- lactic acid selected from lactic acid, cc-monoisostearyl glyceryl ether, cetyl alcohol, propylene glycol esters of fatty acids,
- lactate oleyl oleate, octyldodecanol (2-octyldodecan-l-ol;
- octyldodecyl myristate soybean lecithin, triethanolamine, polyethylene glycol mono-p-isooctylphenylether, polyethylene glycol #200, squalane, isopropyl myristate, diethyl sebacate, cetyl 2-ethylhexanoate, cetanol-polyethylene glycol
- monostearate mixed wax and liquid lanolin and, particularly preferably, it is selected from lactic acid, a-monoisostearyl glyceryl ether, cetyl alcohol, spropylene glycol esters of fatty acids, polyoxyethylene (20) polyoxypropylene (8) cetylether, lipophilic glyceryl monooleate, Beeswax derivatives of
- lauromacrogol cetyl lactate and oleyl oleate, more preferably, lactic acid and a-monoisostearyl glyceryl ether.
- the skin permeability of compound 1 can be more remarkably enhanced by adding a particular additive (the second additive) other than lactic acid to the adhesive layer comprising lactic acid as the first additive.
- a particular additive the second additive
- an adhesive preparation it has been found that an adhesive preparation
- the second additive in the present invention is a
- alkyl glyceryl ether selected from the group consisting of alkyl glyceryl ether, polyoxyethylene alkyl ether, fatty acid ester, lecithin, fatty acid, alcohol and soybean oil.
- alkyl glyceryl ether include ⁇ -monoisostearyl glyceryl ether, cetyl glyceryl ether, oleyl glyceryl ether, lauryl glyceryl ether and the like.
- polyoxyethylene alkyl ether include polyoxyethylene behenyl ether, lauromacrogol, polyoxyethylene (20) cetyl ether and the like.
- ester of fatty acid having a carbon number of 12 - 18 (higher fatty acid) and ester of dicarboxylic acid having a carbon number of 6 - 10 are preferable.
- examples thereof include diisopropyl adipate, diethyl sebacate, propylene glycol esters of fatty acids, octyldodecyl myristate, sorbitan monostearate, propyleneglycol monostearate, isopropyl myristate, polyethylene glycol
- the lecithin examples include egg-yolk lecithin, soybean lecithin and the like and, as the fatty acid, fatty acid having a carbon number of 12 - 18 is preferable and, for example, isostearic acid, oleic acid and the like can be mentioned.
- the alcohol examples include benzyl alcohol, decanol, octyldodecanol, propylene glycol, cetyl alcohol, lauryl alcohol, polyethylene glycol #200 and the like. The combination of the above
- the second additive in the present invention may be a combination of one or more kinds of additives selected from methyl isobutyl ketone, crotamiton, propylene carbonate, purified microcrystalline wax, polybutylene, squalane, 1- menthol, triacetine, liquid paraffin, polyoxyethylene
- Preferable examples of the second additive in the present invention include a-monoisostearyl glyceryl ether,
- octyldodecanol propylene glycol, cetyl alcohol, soybean oil, methyl isobutyl ketone, crotamiton, squalane, triacetine, purified microcrystalline wax, and a combination of plural additives selected therefrom.
- More preferable examples of the second additive in the present invention include ⁇ -monoisostearyl glyceryl ether, polyoxyethylene behenyl ether, lauromacrogol, diisopropyl adipate, diethyl sebacate, propylene glycol esters of fatty acids, egg-yolk lecithin, isostearic acid, oleic acid, benzyl alcohol, decanol, octyldodecanol, propylene glycol, soybean oil, methyl isobutyl ketone, crotamiton, and a combination of plural additives selected therefrom.
- the amount of the second additive to be combined with lactic acid is generally 0.1-fold- to 9-fold, preferably 0.1- to 7-fold, more preferably 0.3- to - 3-fold, in weight ratio, of lactic acid.
- the lactic acid may be a DL-lactic acid (racemate) , and may also be L-lactic acid or D-lactic acid (optically active forms) .
- the lactic acid in the present specification may be either of them.
- the amount of lactic acid to be comprised in an adhesive preparation comprising lactic acid and the second additive is generally about 0.01 - about 30 wt%, preferably about 0.1 - about 20 wt%, more preferably about 0.1 - about 15 wt%, in the adhesive layer as 100 wt%.
- the total amount (lactic acid + the second additive) of the additive to be comprised in the adhesive preparation comprising lactic acid and the second additive is generally about 0.1 - about 60 wt%, preferably about 0.1 - about 40 wt%, more preferably about 0.3 - about 40 wt%, in the adhesive layer as 100 wt%.
- the adhesive layer in the adhesive preparation of the present invention may comprise, as long as no particular problem is caused, a pharmaceutically acceptable component used for formulating an adhesive preparation.
- a pharmaceutically acceptable component used for formulating an adhesive preparation.
- any component can be used as long as its
- the stabilizer examples include, but are not limited to, ascorbic acid, sodium alginate, propyleneglycol alginate, dibutylhydroxytoluene, butylhydroxyanisole, tocopherol acetate, tocopherol, propyl gallate, ethyl p-hydroxybenzoate, butyl p- hydroxybenzoate, propyl p-hydroxybenzoate, methyl p- hydroxybenzoate, 2-mercaptobenzimidazole and the like.
- tackifier examples include, but are not limited to, ester gum, glycerol, glycerol ester of hydrogenated rosin, petroleum resin, rosin, polybutene and the like can be
- plasticizer examples include, but are not limited to, polybutene, liquid paraffin, glycerol, glycerin fatty acid ester and the like.
- flavor examples include, but are not limited to, dl-menthol, orange oil, peppermint oil, lemon oil, rose oil and the like.
- filler examples include, but are not limited to, titanium oxide, zinc oxide, acrylic acid starch 100 and the like.
- thickener examples include, but are not limited to, carboxymethylcellulose, carageenan, pectin, poly(N- vinylacetamide) , N-vinylacetamide-sodium acrylate copolymer and the like.
- the pharmaceutically active ingredient in the adhesive layer may comprise other pharmaceutically active ingredients other than compound 1.
- antipsychotics such as haloperidol, clozapine, risperidone, olanzapine,
- quetiapine, ziprasidone, aripiprazole, asenapine, amisulpride, iloperidone, cariprazine, sertindole, zotepine, paliperidone, bifeprunox and the like (which may be in a free form or in the form of a physiologically acceptable salt) , a therapeutic drug for mania such as lithium preparation (lithium carbonate etc.), valproic acid or a derivative thereof (Divalproex sodium etc.) etc., and the like may be comprised therein.
- the release liner is peeled off and the adhesive layer of the adhesive
- a systemic action type external preparation expected to provide efficacy by delivering the transdermally absorbed active ingredient to the systemic blood flow
- a topical action type external preparation aiming to deliver the active ingredient to adhesion site or the affected part nearby.
- the support is not particularly limited as long as it is made of a material impermeable to drugs or hardly permeable to drugs, and uninfluential on drug release or hardly influential on drug release, and may be stretchable or nonstretchable .
- resin film such as ethylcellulose, nylon, polyethylene terephthalate
- PET PET
- polyester polyester
- polypropylene polypropylene
- non-woven fabric such as PET and the like may be formed on one side of a support on which an adhesive layer is not formed.
- a support may be a support with a single layer structure or a structure of a laminate of plural materials.
- the support may be colorless and transparent, may be colored white or flesh color and the like.
- the support colored white or flesh color and the like may have a surface of the support coated with a dye or may have a support containing dye, pigment and the like uniformly kneaded therein.
- the support surface on which an adhesive layer is formed is preferably subjected to, for example, a surface treatment such as corona discharge treatment, plasma treatment,
- the adhesive preparation of the present invention can be produced by a conventional method.
- the adhesive preparation of the present invention can be produced by a conventional method.
- a general production method of adhesive tapes can be applied to form an adhesive layer.
- Representative example thereof is a solvent coating method.
- a hot-melt coating method, an electron beam cured emulsion coating method and the like can be used.
- an adhesive layer mixture is prepared by mixing compound 1 or an acid addition salt thereof, a mixture comprising an acrylic adhesive and, where necessary, a
- the thickness of the obtained adhesive layer is within the range of about 10 - about 400 jam, preferably about 20 - about 200 um. However, the thickness of the adhesive layer is not limited to these ranges, and any thickness greater or smaller than these ranges is within the scope of the present invention.
- the release liner to cover the surface of the adhesive layer is appropriately selected.
- the release liner include, but are not limited to, a release liner having a release layer having detachability on the surface thereof, such as a paper liner treated with a silicone resin and the like, a plastic film and the like.
- An adhesive preparation with such size may be a tape having a size larger than the size to be actually
- the part of the body to which the preparation is applied is not particularly limited, for example, arm,
- the adhesive preparation of the present invention is packed with a written matter containing information relating to the adhesive preparation and distributed.
- the written matter may be placed on a package or contained in a package as an instruction sheet.
- Examples of the "information relating to the adhesive preparation" here include information stating that the preparation can or should be used for the treatment of schizophrenia and/or a bipolar disorder.
- a 25 ⁇ polyethylene terephthalate film manufactured by FUJIMORI KOGYO CO., LTD. was used as a support.
- the skin permeability of compound 1 in the tape preparations obtained in Examples 1 - 24 and Comparative Example 1 through the abdominal skin of hairless rats was measured. That is, the skin of hairless rat was set on an in vitro diffusion cell with permeation area 1.13 cm 2 and using, as a receiver fluid, 0.75 mL of a 3:1 mixture of propylene glycol and phosphate buffer, each
- the receiver fluid was stirred for 24 hr while keeping at 37°C, the concentration of compound 1 in the receiver fluid was measured by high performance liquid chromatography (column: SymmetryTM C18 3.5 urn 4.6x50 mm; Waters), mobile phase: 5 mM monosodium phosphate (adjusted to pH 7.0 with
- Tape preparation was produced using cetyl lactate instead of ⁇ -monoisostearyl glyceryl ether in Example 25.
- the permeation amount of compound 1 from the preparation added with lactic acid 5% and the second additive 5% in combination remarkably increased as compared to the average of the permeation amount of compound 1 from the preparation added with lactic acid 10% alone and that from the preparation added with the second additive 10% alone ((c) ⁇ [average of (a) and (b)]»l).
- Tape preparation was produced using lactic acid 20% alone instead of the addition of both lactic acid and a- monoisostearyl glyceryl ether in Examples 41 - 47.
- Tape preparation was produced using a-monoisostearyl glyceryl ether instead of lactic acid in Example 48.
- Experimental Example 3 reveals that in a preparation comprising lactic acid and -monoisostearyl glyceryl ether, content ratio (weight ratio) of ⁇ -monoisostearyl glyceryl ether to lactic acid is at least 0.1-fold to 7-fold, a remarkable synergistic effect of the combination of lactic acid and ⁇ -monoisostearyl glyceryl ether on skin permeation of compound 1 as compared to a preparation comprising lactic acid alone or ⁇ -monoisostearyl glyceryl ether alone was confirmed.
- Preferable content ratio of ⁇ -monoisostearyl glyceryl ether to lactic acid was 0.3-fold to 3-fold.
- the content ratio (weight ratio) of the second additive to lactic acid was preferably 0.1-fold to 7-fold, more preferably 0.3- fold to 3-fold.
- a styrene-isoprene-styrene block copolymer (Quintac 3421, manufactured by ZEON CORPORATION) (0.4 g) , liquid paraffin (0.4 g) , polybutene (HV-300, manufactured by Nippon Petroleum Refining Corporation) (0.3 g) , alicyclic saturated hydrocarbon resin (ARKON P-100, manufactured by Arakawa Chemical
- the adhesive preparation of the present invention suppresses metabolites production, and maintains the blood drug concentration of compound 1 in a sustained manner.
- the adhesive preparation of the present invention can remarkably enhance the skin permeability of compound 1 by adding particular additives to the adhesive layer, and
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Abstract
The present invention provides an adhesive preparation comprising (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione (hereinafter to be referred to as "compound 1"), which suppresses metabolites production and is superior in skin permeability. The adhesive preparation of the present invention containing a support and an adhesive layer formed on one surface of the support, wherein the adhesive layer comprises (i) compound 1 or a physiologically acceptable acid addition salt thereof, (ii) an adhesive, and (iii) an additive comprising a particular skin permeation enhancer, can remarkably enhance the skin permeability of compound 1.
Description
DESCRIPTION
NOVEL EXTERNAL PREPARATION
Technical Field
[0001]
The present invention relates to an adhesive preparation for transdermal absorption. Specifically, the present
invention relates to an adhesive preparation comprising
(3aR, 4S, 7R,7aS) -2-{ (1R,2R) -2- [4- (1, 2-benzisothiazol-3- yl) piperazin-l-ylmethyl] cyclohexylmethyl }hexahydro-4 , 7- methano-2H-isoindole-l, 3-dione (hereinafter to be also referred to as "compound 1" in the present specification) , or a physiologically acceptable acid addition salt thereof as an active ingredient, which shows enhanced skin permeability of the active ingredient when adhered to a skin surface.
Background Art
[0002]
(3aR, 4S, 7R, 7aS) -2-{ (1R, 2R) -2- [4- (1, 2-benzisothiazol-3- yl) piperazin-l-ylmethyl] cyclohexylmethyl }hexahydro-4, 7- methano-2H-isoindole-l, 3-dione (compound 1) is a compound useful as an atypical antipsychotic agent, and is disclosed in patent document 1.
[0003]
Adhesive preparation for transdermal absorption is one form of a useful preparation, since it can maintain blood drug concentration in a more sustained manner as compared to oral administration, and can lower liver metabolism and/or drug interaction by avoiding first pass effect. In addition, administration by way of a transdermal absorption preparation has many advantages such as absence of influence of diet, possible administration to patients having difficulty in swallowing, easy confirmation and discontinuation of
medication and the like.
[0004]
Conventionally, as an adhesive preparation for
transdermal absorption of antipsychotic agents, a transdermal
preparation of perospirone (patent document 2), a transdermal preparation of blonanserin (patent document 3) and the like have been reported. However, a transdermal preparation of compound 1 has not been specifically reported.
[0005]
In terms of actual medical treatments, that is, for the significance of improving the quality-of-life (QOL) of patients, reduction of foreign-body feeling and uncomfortable feeling caused by the adhesion of a transdermal absorption adhesive preparation to a skin surface is very important.
Accordingly, the area of adhesion, that is, the size of the adhesive preparation for transdermal absorption, is desired to be as small as possible. One of the methods to achieve the goal is considered to be the addition of an additive capable of enhancing skin permeation of a drug. However, an additive effective for enhancing the permeation is said to be specific for and vary depending on each target drug (non-patent document 1) . As mentioned above, there are reports on the transdermal absorption preparations of perospirone and blonanserin; however, there is no report on findings relating to a transdermal preparation of compound 1, and an effective means for enhancing skin permeation is completely unclear.
[Document List]
[patent documents]
[0006]
patent document 1: JP-B-2800953 (US 5532372 A)
patent document 2: WO2006/025516
patent document 3: WO2007/142295
[non-patent document]
[0007]
non-patent document 1: Advanced Drug Delivery Reviews 56 (2004) 603-618.
[SUMMARY OF HE INVENTION]
Problems to be Solved by the Invention
[0008]
The present invention aims to provide an adhesive
preparation for transdermal administration, which shows enhanced skin permeability of compound 1.
Means of Solving the Problems
[0009]
The present inventors have intensively studied a
composition that enhances skin permeation of compound 1 and found the additive series that effectively enhances the skin permeation of compound 1.
Accordingly, the present invention provides the following.
[0010]
[1] An adhesive preparation comprising a support and an
adhesive layer formed on one surface of the support, wherein the adhesive layer comprises (i) (3aR, 4S, 7R, 7aS) -2-{ (1R, 2R) -2- [4- (1, 2-benzisothiazol-3-yl) piperazin-1- ylmethyl] cyclohexylmethyl }hexahydro-4, 7-methano-2H-isoindole- 1,3-dione (compound 1) or a physiologically acceptable acid addition salt thereof, (ii) an adhesive, (iii) lactic acid as the first additive, and (iv) at least one kind of additive selected from the group consisting of alkyl glyceryl ether, polyoxyethylene alkyl ether, fatty acid ester, lecithin, fatty acid, alcohol, soybean oil, methyl isobutyl ketone and
crotamiton as the second additive.
[2] The adhesive preparation of the above-mentioned [1], wherein alkyl glyceryl ether as the second additive comprises a-monoisostearyl glyceryl ether.
[3] The adhesive preparation of the above-mentioned [1], wherein polyoxyethylene alkyl ether as the second additive comprises at least one kind selected from the group consisting of polyoxyethylene behenyl ether and lauromacrogol .
[4] The adhesive preparation of the above-mentioned [3] , wherein the second additive comprises polyoxyethylene behenyl ether.
[5] The adhesive preparation of the above-mentioned [3] , wherein the second additive comprises lauromacrogol.
[6] The adhesive preparation of the above-mentioned [1], wherein fatty acid ester as the second additive comprises an ester of fatty acid having a carbon number of 12 - 18 (higher fatty acid) or an ester of dicarboxylic acid having a carbon number of 6 - 10.
[7] The adhesive preparation of the above-mentioned [1], wherein fatty acid ester as the second additive comprises at least one kind selected from the group consisting of
diisopropyl adipate, diethyl sebacate and propylene glycol esters of fatty acids.
[8] The adhesive preparation of the above-mentioned [7], wherein the second additive comprises diisopropyl adipate.
[9] The adhesive preparation of the above-mentioned [7], wherein the second additive comprises diethyl sebacate.
[10] The adhesive preparation of the above-mentioned [7], wherein the second additive comprises propylene glycol esters of fatty acids .
[11] The adhesive preparation of the above-mentioned [1], wherein lecithin as the second additive comprises egg-yolk lecithin.
[12] The adhesive preparation of the above-mentioned [1], wherein fatty acid as the second additive comprises fatty acid having a carbon number of 12 - 18.
[13] The adhesive preparation of the above-mentioned [1], wherein fatty acid as the second additive comprises isostearic acid.
[14] The adhesive preparation of the above-mentioned [1], wherein alcohol as the second additive comprises at least one kind selected from the group consisting of benzyl alcohol, decanol, octyldodecanol and propylene glycol.
[15] The adhesive preparation of the above-mentioned [1], wherein the second additive comprises soybean oil.
[16] The adhesive preparation of the above-mentioned [1], wherein the weight ratio of the second additive is 0.1-fold to 9-fold relative to lactic acid.
[17] The adhesive preparation of any of the above-mentioned [1] - [16], wherein the content of lactic acid in the adhesive layer is 0.01 - 30 wt%.
[18] The adhesive preparation of any of the above-mentioned [1] - [17], wherein the adhesive layer comprises component (i) at a concentration of 0.1 - 50 wt% in terms of compound 1.
[19] The adhesive preparation of any of the above-mentioned [1] - [18], wherein the adhesive is at least one kind selected from the group consisting of an acrylic adhesive, a rubber adhesive, and a silicone adhesive.
[20] The adhesive preparation of the above-mentioned [19] , wherein the adhesive comprises an acrylic adhesive.
[21] The adhesive preparation of the above-mentioned [20] , wherein the acrylic adhesive is at least one kind selected from the group consisting of a (co) polymer mainly comprising (meth) acrylic acid alkyl ester, and a copolymer of
(meth) acrylic acid alkyl ester and a functional monomer.
[22] The adhesive preparation of the above-mentioned [19] or [20], wherein the adhesive comprises a rubber adhesive.
[23] The adhesive preparation of the above-mentioned [22], wherein the rubber adhesive is at least one kind selected from the group consisting of a styrene-isoprene-styrene block copolymer and polyisobutylene .
[24] The adhesive preparation of any of the above-mentioned [1] - [23] , which is in the form of a tape preparation.
[25] The adhesive preparation of any of the above-mentioned [1] - [24], which is a therapeutic agent for schizophrenia and/or a bipolar disorder.
[26] A method for the treatment of schizophrenia and/or a bipolar disorder, comprising administering the adhesive preparation of any of the above-mentioned [1] - [25]
comprising an effective amount of compound 1 or a
physiologically acceptable acid addition salt thereof.
[27] An adhesive preparation comprising a support and an adhesive layer formed on one surface of the support, wherein
the adhesive layer comprises (i) compound 1 or a
physiologically acceptable acid addition salt thereof, (ii) an adhesive, and (iii) at least one kind of additive selected from the group consisting of lactic acid, oc-monoisostearyl glyceryl ether, cetyl alcohol, spropylene glycol esters of fatty acids, polyoxyethylene (20) polyoxypropylene (8) cetylether, lipophilic glyceryl monooleate, Beeswax derivatives of
polyoxyethylene sorbitol, lauryl alcohol, decanol,
lauromacrogol, cetyl lactate, oleyl oleate, octyldodecanol, octyldodecyl myristate, soybean lecithin, egg-yolk lecithin, triethanolamine, polyethylene glycol mono-p- isooctylphenylether, polyethylene glycol #200, squalane, isopropyl myristate, diethyl sebacate, cetyl 2-ethylhexanoate, cetanol - polyethylene glycol monostearate mixed wax, and liquid lanolin.
[28] The adhesive preparation of the above-mentioned [27], wherein the adhesive layer comprises the aforementioned
component (i) at a concentration of 0.1 - 50 wt% in terms of compound 1.
[29] The adhesive preparation of the above-mentioned [27] or [28], wherein the adhesive is at least one kind selected from the group consisting of an acrylic adhesive, a rubber adhesive, and a silicone adhesive.
[30] The adhesive preparation of the above-mentioned [29] , wherein the adhesive comprises an acrylic adhesive.
[31] The adhesive preparation of the above-mentioned [30] , wherein the acrylic adhesive is at least one kind selected from the group consisting of a (co) polymer mainly comprising (meth) acrylic acid alkyl ester, and a copolymer of
(meth) acrylic acid alkyl ester and a functional monomer.
[32] The adhesive preparation of the above-mentioned [29] or
[30], wherein the adhesive comprises a rubber adhesive.
[33] The adhesive preparation of the above-mentioned [32], wherein the rubber adhesive is at least one kind selected from the group consisting of a styrene-isoprene-styrene block
copolymer and polyisobutylene .
[34] The adhesive preparation of any of the above-mentioned [27] - [33], which is a therapeutic agent for schizophrenia and/or a bipolar disorder.
Effect of the Invention
[0011]
An adhesive preparation of the present invention
comprising compound 1 as an active ingredient is superior in skin permeability, and provides options for drug therapy, which are useful for satisfying the medical needs of patients with schizophrenia and the like. With the high skin
permeability, the preparation can be downsized and can
contribute to the improvement of usability in medical care and economic efficiency.
[Description of Embodiments]
[0012]
Preferable embodiments of the present invention are explained in detail in the following.
[0013]
In the present invention, an adhesive preparation means a preparation in general, which can be adhered to the skin, including, for example, tape preparations, patch preparations, cataplasm preparations, plaster preparation and the like.
[0014]
In the present claims and the present specification, the adhesive layer is a layer formed on a support, which comprises a drug.
[0015]
In the present claims and the present specification, those simply shown by "wt%" in the adhesive layer, and those indicated to be "content percentages (amounts) in the
adhesive" mean wt% when the total weight of the adhesive layer substantially free of solvent and the like by drying and the like is 100 wt%.
[0016]
(i) Compound 1 or a physiologically acceptable acid addition salt thereof
Compound 1 relating to the present invention, that is, (3aR, 4S, 7R, 7aS) -2-{ (1R, 2R) -2- [4- (1, 2-benzisothiazol-3- yl ) piperazin-l-ylmethyl] cyclohexylmethyl }hexahydro-4 , 7- methano-2H-isoindole-l, 3-dione (generic name "lurasidone") is a compound represented by the following formula:
[0017]
Compound 1 or a physiologically acceptable acid addition salt thereof has a pharmacological action as an antipsychotic agent. More specifically, compound 1 or a physiologically acceptable acid addition salt thereof, and a pharmaceutical preparation comprising the same are useful as therapeutic drugs for diseases such as schizophrenia, bipolar disorders and the like.
[0019]
Compound 1 may be a free base or a physiologically acceptable acid addition salt thereof. Examples of an addition salt of organic acid include, but are not limited to, formate, acetate, lactate, adipate, citrate, tartrate, methanesulfonate, fumarate, maleate and the like, and examples of an addition salt of inorganic acid include, but are not limited to,
hydrochloride, sulfate, nitrate, phosphate and the like.
Furthermore, compound 1 or a physiologically acceptable acid addition salt thereof may also be a solvate, or a hydrate or
non-hydrate .
[0020]
The above-mentioned compound 1 or a physiologically acceptable acid addition salt thereof can be produced
according to, for example, the method described in patent document 1 or a method analogous thereto. The produced
compound 1 or a physiologically acceptable acid addition salt thereof may be pulverized as appropriate according to a
conventional method.
[0021]
The amount of "compound 1 or a physiologically acceptable acid addition salt thereof" contained in the adhesive
preparation of the present invention is generally about 0.1 - about 50 wt%, preferably about 0.1 - about 40 wt%, more
preferably about 0.1 - about 30 wt%, in terms of compound 1, of an adhesive layer as 100 wt%, though subject to change depending on the area of the adhesive preparation. In addition, it is preferably about 0.5 - about 50 wt%, more preferably about 0.5 - about 40 wt%, still more preferably about 0.5 - about 30 wt%. Here, "in terms of compound 1" means that the amount corresponding to a salt and crystal water is not
contained in the weight of component (1), even when compound 1 takes the form of a salt of compound 1 or contains crystal water. In other words, it means that the amount of a salt of compound 1 or a hydrate thereof is calculated by converting the weight thereof to the weight of an equimolar amount of compound 1 (free base non-hydrate) .
[0022]
(ii) Adhesive
Examples of the adhesive of the present invention include polymer adhesives such as silicone adhesives, rubber adhesives, acrylic adhesives and the like.
[0023]
Examples of the silicone adhesive include those
containing silicone rubber as a main component, such as
polydimethyl siloxane, diphenylsiloxane and the like. Examples of the rubber adhesive include natural rubber,
polyisopropylene rubber, polyisobutylene, styrene-butadiene copolymer, styrene-isopropylene copolymer, styrene-isoprene- styrene block copolymer and the like.
Examples of the acrylic adhesive include (co) polymers mainly comprising (meth) acrylic acid alkyl ester. Specific examples include polymers mainly comprising acrylic acid alkyl ester, polymers mainly comprising methacrylic acid alkyl ester, copolymers mainly comprising acrylic acid alkyl ester,
copolymers mainly comprising methacrylic acid alkyl ester, and copolymers mainly comprising acrylic acid alkyl ester and methacrylic acid alkyl ester. The (co) polymer may be a
copolymer of two or more kinds of (meth) acrylic acid alkyl ester as mentioned above, or may be a copolymer of
(meth) acrylic acid alkyl ester and (a) functional monomer (s) capable of copolymerizing with (meth) acrylic acid alkyl ester.
Here, the " (meth) acrylic acid" means "acrylic acid or methacrylic acid", or "acrylic acid and/or methacrylic acid", and the " (co) polymer" means "polymer or copolymer", or
"polymer and/or copolymer".
[0024]
Examples of the (meth) acrylic acid alkyl ester include those obtained by esterification with straight chain or
branched chain alkyl having a carbon number of 1 - 18, and specifically include (meth) acrylic acid methyl ester,
(meth) acrylic acid butyl ester, (meth) acrylic acid hexyl ester, (meth) acrylic acid octyl ester, (meth) acrylic acid nonyl ester, (meth) acrylic acid decyl ester and the like. Examples of the functional monomer include a monomer having a hydroxyl group ( (meth) acrylic acid hydroxyethyl ester etc.), a monomer having a carboxyl group (butyl maleate, crotonic acid etc.), a
monomer having an amido group ( (meth) acrylamide etc.), a
monomer having an amino group (dimethylaminoacrylic acid ester etc.), a monomer having a pyrrolidone ring (N-vinyl-2-
pyrrolidone etc.) and the like.
[0025]
The acrylic adhesive in the present invention may be used singly or in a combination of two or more kinds thereof. In addition, it may be a mixture with other adhesive. Examples of the other adhesive include silicone adhesive, rubber adhesive and the like.
[0026]
Specific preferable examples of the acrylic adhesive include, but are not limited to, acrylic acid-acrylic acid octyl ester copolymer, acrylic acid ester-vinyl acetate
copolymer, 2-ethylhexyl acrylate-vinylpyrrolidone copolymer, 2-ethylhexyl acrylate-2-ethylhexyl methacrylate-dodecyl
methacrylate copolymer, ethyl acrylate-methyl methacrylate copolymer, acrylic acid-silk fibroin copolymer, methyl
acrylate-2-ethylhexyl acrylate copolymer and the like, and include commercially available products such as "POLYTHICK 410-SA" manufactured by Sanyo Chemical Industries, Ltd.,
"Oribain BPS-4849-40" manufactured by TOYO INK CO., LTD.,
"DURO-TAK 87-2194 (registered trade mark)" and "DURO-TAK387- 2516 (registered trade mark)" manufactured by National Starch and Chemical Corp., "MAS811", "MAS683" and "MAS955"
manufactured by CosMED Pharmaceutical Co. Ltd. and the like.
[0027]
To afford appropriate adhesiveness to the skin, moreover, a curing agent may also be added where necessary. Examples of the curing agent include commercially available products such as "POLYTHICK SC-75" manufactured by Sanyo Chemical Industries, Ltd., "BHS8515" manufactured by TOYO INK CO., LTD. and the like. The amount thereof to be added can be appropriately selected according to the property of the adhesive, which is, for example, about 0.001 - 0.05 part by weight relative to 1 part by weight of the adhesive.
[0028]
The amount of the adhesive to be added is a balance after
removing compound 1 or a physiologically acceptable acid
addition salt thereof, the following additives, and various components mentioned below, which are added for formulation as necessary, from the adhesive layer, and is the amount
necessary for completing the adhesive layer. Thus, for example, when the adhesive layer comprises 10 wt% of compound 1 and 10 wt% of an additive, the amount of the adhesive is about 80 wt%.
[0029]
The adhesiveness of the adhesive to be used here is of the level employed for medical adhesive preparations, and intended to mean adhesiveness of the level permitting easy adhesion to the skin and causing no particular problem in peeling off.
[0030]
Additive
The amount of the additive to be comprised in the
adhesive preparation of the present invention is generally about 0.01 - about 50 wt%, preferably about 0.1 - about 40 wt%, more preferably about 0.3 - about 40 wt%, of the adhesive layer as 100 wt%.
[0031]
The additive in the present invention may be used singly or in a combination of two or more kinds thereof. It is
selected from lactic acid, cc-monoisostearyl glyceryl ether, cetyl alcohol, propylene glycol esters of fatty acids,
polyoxyethylene (20) polyoxypropylene (8) cetylether, lipophilic glyceryl monooleate, Beeswax derivatives of polyoxyethylene sorbitol, lauryl alcohol, decanol, lauromacrogol, cetyl
lactate, oleyl oleate, octyldodecanol (2-octyldodecan-l-ol;
hereinafter the same in the present specification) ,
octyldodecyl myristate, soybean lecithin, triethanolamine, polyethylene glycol mono-p-isooctylphenylether, polyethylene glycol #200, squalane, isopropyl myristate, diethyl sebacate, cetyl 2-ethylhexanoate, cetanol-polyethylene glycol
monostearate mixed wax and liquid lanolin and, particularly
preferably, it is selected from lactic acid, a-monoisostearyl glyceryl ether, cetyl alcohol, spropylene glycol esters of fatty acids, polyoxyethylene (20) polyoxypropylene (8) cetylether, lipophilic glyceryl monooleate, Beeswax derivatives of
polyoxyethylene sorbitol, lauryl alcohol, decanol,
lauromacrogol, cetyl lactate and oleyl oleate, more preferably, lactic acid and a-monoisostearyl glyceryl ether.
[0032]
In addition, it has been surprisingly found in the present invention that the skin permeability of compound 1 can be more remarkably enhanced by adding a particular additive (the second additive) other than lactic acid to the adhesive layer comprising lactic acid as the first additive. To be specific, it has been found that an adhesive preparation
comprising lactic acid and the second additive shows
remarkably enhanced skin permeability as compared to an
adhesive preparation showing good permeability, which
comprises compound 1 added with lactic acid alone in an amount equivalent to the total amount of lactic acid and the second additive.
[0033]
The second additive in the present invention is a
combination of one or more kinds of additives selected from the group consisting of alkyl glyceryl ether, polyoxyethylene alkyl ether, fatty acid ester, lecithin, fatty acid, alcohol and soybean oil. While the additive is not limited to the following, specific examples of alkyl glyceryl ether include α-monoisostearyl glyceryl ether, cetyl glyceryl ether, oleyl glyceryl ether, lauryl glyceryl ether and the like. Examples of the polyoxyethylene alkyl ether include polyoxyethylene behenyl ether, lauromacrogol, polyoxyethylene (20) cetyl ether and the like. As the fatty acid ester, ester of fatty acid having a carbon number of 12 - 18 (higher fatty acid) and ester of dicarboxylic acid having a carbon number of 6 - 10 are preferable. Examples thereof include diisopropyl adipate,
diethyl sebacate, propylene glycol esters of fatty acids, octyldodecyl myristate, sorbitan monostearate, propyleneglycol monostearate, isopropyl myristate, polyethylene glycol
monolaurate, sorbitan sesquioleate and the like. Examples of the lecithin include egg-yolk lecithin, soybean lecithin and the like and, as the fatty acid, fatty acid having a carbon number of 12 - 18 is preferable and, for example, isostearic acid, oleic acid and the like can be mentioned. Examples of the alcohol include benzyl alcohol, decanol, octyldodecanol, propylene glycol, cetyl alcohol, lauryl alcohol, polyethylene glycol #200 and the like. The combination of the above
mentioned additives can also be mentioned. In addition to the above, the second additive in the present invention may be a combination of one or more kinds of additives selected from methyl isobutyl ketone, crotamiton, propylene carbonate, purified microcrystalline wax, polybutylene, squalane, 1- menthol, triacetine, liquid paraffin, polyoxyethylene
hydrogenated castor oil 10, acetic acid and N-methyl-2- pyrrolidone .
[0034]
Preferable examples of the second additive in the present invention include a-monoisostearyl glyceryl ether,
polyoxyethylene behenyl ether, lauromacrogol,
polyoxyethylene (20) cetyl ether, diisopropyl adipate, diethyl sebacate, propylene glycol esters of fatty acids , propylene glycol monostearate, isopropyl myristate, egg-yolk lecithin, isostearic acid, oleic acid, benzyl alcohol, decanol,
octyldodecanol, propylene glycol, cetyl alcohol, soybean oil, methyl isobutyl ketone, crotamiton, squalane, triacetine, purified microcrystalline wax, and a combination of plural additives selected therefrom.
[0035]
More preferable examples of the second additive in the present invention include α-monoisostearyl glyceryl ether, polyoxyethylene behenyl ether, lauromacrogol, diisopropyl
adipate, diethyl sebacate, propylene glycol esters of fatty acids, egg-yolk lecithin, isostearic acid, oleic acid, benzyl alcohol, decanol, octyldodecanol, propylene glycol, soybean oil, methyl isobutyl ketone, crotamiton, and a combination of plural additives selected therefrom.
[0036]
The amount of the second additive to be combined with lactic acid is generally 0.1-fold- to 9-fold, preferably 0.1- to 7-fold, more preferably 0.3- to - 3-fold, in weight ratio, of lactic acid.
[0037]
The lactic acid may be a DL-lactic acid (racemate) , and may also be L-lactic acid or D-lactic acid (optically active forms) . The lactic acid in the present specification may be either of them.
[0038]
In the present invention, the amount of lactic acid to be comprised in an adhesive preparation comprising lactic acid and the second additive is generally about 0.01 - about 30 wt%, preferably about 0.1 - about 20 wt%, more preferably about 0.1 - about 15 wt%, in the adhesive layer as 100 wt%.
In the present invention, the total amount (lactic acid + the second additive) of the additive to be comprised in the adhesive preparation comprising lactic acid and the second additive is generally about 0.1 - about 60 wt%, preferably about 0.1 - about 40 wt%, more preferably about 0.3 - about 40 wt%, in the adhesive layer as 100 wt%.
[0039]
Adhesive layer
Where necessary, the adhesive layer in the adhesive preparation of the present invention may comprise, as long as no particular problem is caused, a pharmaceutically acceptable component used for formulating an adhesive preparation. As such component, any component can be used as long as its
addition does not cause any particular problem and the
addition is necessary, and, for example, stabilizer, tackifier, plasticizer, flavor, filler, thickener and the like can be mentioned.
[0040]
Examples of the stabilizer include, but are not limited to, ascorbic acid, sodium alginate, propyleneglycol alginate, dibutylhydroxytoluene, butylhydroxyanisole, tocopherol acetate, tocopherol, propyl gallate, ethyl p-hydroxybenzoate, butyl p- hydroxybenzoate, propyl p-hydroxybenzoate, methyl p- hydroxybenzoate, 2-mercaptobenzimidazole and the like.
[0041]
Examples of the tackifier include, but are not limited to, ester gum, glycerol, glycerol ester of hydrogenated rosin, petroleum resin, rosin, polybutene and the like can be
mentioned. Examples of the plasticizer include, but are not limited to, polybutene, liquid paraffin, glycerol, glycerin fatty acid ester and the like. Examples of the flavor include, but are not limited to, dl-menthol, orange oil, peppermint oil, lemon oil, rose oil and the like. Examples of the filler include, but are not limited to, titanium oxide, zinc oxide, acrylic acid starch 100 and the like.
[0042]
Examples of the thickener include, but are not limited to, carboxymethylcellulose, carageenan, pectin, poly(N- vinylacetamide) , N-vinylacetamide-sodium acrylate copolymer and the like.
[0043]
In addition, the pharmaceutically active ingredient in the adhesive layer may comprise other pharmaceutically active ingredients other than compound 1. For example, antipsychotics such as haloperidol, clozapine, risperidone, olanzapine,
quetiapine, ziprasidone, aripiprazole, asenapine, amisulpride, iloperidone, cariprazine, sertindole, zotepine, paliperidone, bifeprunox and the like (which may be in a free form or in the form of a physiologically acceptable salt) , a therapeutic drug
for mania such as lithium preparation (lithium carbonate etc.), valproic acid or a derivative thereof (Divalproex sodium etc.) etc., and the like may be comprised therein.
[0044]
Adhesive preparation of the present invention
The adhesive preparation of the present invention
comprises a support, the aforementioned adhesive layer formed on one surface (one side) of the support, and a release liner as appropriate on the other surface free of contact with the support of the adhesive layer. When in use, the release liner is peeled off and the adhesive layer of the adhesive
preparation is adhered to the skin, whereby transdermal
administration is performed.
[0045]
The adhesive preparation of the present invention
includes both (1) a systemic action type external preparation expected to provide efficacy by delivering the transdermally absorbed active ingredient to the systemic blood flow, and (2) a topical action type external preparation aiming to deliver the active ingredient to adhesion site or the affected part nearby.
[0046]
The adhesive preparation of the present invention
includes tape preparation, patch preparation, cataplasm
preparation, plaster preparation and the like, as mentioned above, with preference given to tape preparation and patch preparation.
[0047]
The support is not particularly limited as long as it is made of a material impermeable to drugs or hardly permeable to drugs, and uninfluential on drug release or hardly influential on drug release, and may be stretchable or nonstretchable .
Examples thereof include, but are not limited to, resin film such as ethylcellulose, nylon, polyethylene terephthalate
(PET), polyester, polypropylene and the like, and a
combination thereof. In addition, non-woven fabric such as PET and the like may be formed on one side of a support on which an adhesive layer is not formed. Furthermore, it may be a support with a single layer structure or a structure of a laminate of plural materials. The support may be colorless and transparent, may be colored white or flesh color and the like. The support colored white or flesh color and the like may have a surface of the support coated with a dye or may have a support containing dye, pigment and the like uniformly kneaded therein.
[0048]
The support surface on which an adhesive layer is formed is preferably subjected to, for example, a surface treatment such as corona discharge treatment, plasma treatment,
oxidation treatment, hairline processing, sand mat processing and the like.
[0049]
The adhesive preparation of the present invention can be produced by a conventional method. For example, the
preparation can be produced according to the section relating to the production of a plaster preparation described in
"Manual for the development of transdermal formulation" Edited by Mitsuo Matsumoto (1985) and the like. In addition, for example, the preparation can be produced by using the
apparatus, method and the like described in "Development of Apparatus for Producing Adhesive Preparation for Transdermal Treatment System (MEMBRANE, 32(2), 116-119 (2007))".
[0050]
To be specific, in the adhesive preparation of the present invention, particularly manufacture of a tape
preparation, a general production method of adhesive tapes can be applied to form an adhesive layer. Representative example thereof is a solvent coating method. Besides this, a hot-melt coating method, an electron beam cured emulsion coating method and the like can be used.
[0051]
When an adhesive layer is formed by a solvent coating method, for example, an adhesive layer mixture is prepared by mixing compound 1 or an acid addition salt thereof, a mixture comprising an acrylic adhesive and, where necessary, a
formulation component such as permeation enhancer, curing agent and the like, and an organic solvent, the mixture is applied onto one surface of a support or a release liner, the organic solvent is removed by drying, and a release liner or a support is adhered at a certain timing before or after drying. The thickness of the obtained adhesive layer is within the range of about 10 - about 400 jam, preferably about 20 - about 200 um. However, the thickness of the adhesive layer is not limited to these ranges, and any thickness greater or smaller than these ranges is within the scope of the present invention.
[0052]
The release liner to cover the surface of the adhesive layer is appropriately selected. Examples of the release liner include, but are not limited to, a release liner having a release layer having detachability on the surface thereof, such as a paper liner treated with a silicone resin and the like, a plastic film and the like.
[0053]
The thus-obtained adhesive preparation of the present invention may be produced to have a suitable size in
consideration of the factors such as dose and the like, or cut into such form. An adhesive preparation with such size may be a tape having a size larger than the size to be actually
adhered, or conversely smaller, and may be cut as appropriate when in use or a suitable number thereof may be adhered in a row. While the part of the body to which the preparation is applied is not particularly limited, for example, arm,
shoulder, cervical part, back, waist, abdomen, thorax, hip, leg and the like can be mentioned. The adhesive preparation of the present invention is packed with a written matter
containing information relating to the adhesive preparation and distributed. The written matter may be placed on a package or contained in a package as an instruction sheet. Examples of the "information relating to the adhesive preparation" here include information stating that the preparation can or should be used for the treatment of schizophrenia and/or a bipolar disorder.
Examples
[0054]
The present invention is explained in more detail in the following by referring to Examples, Comparative Examples, Experimental Examples and the like, which are not to be construed as limitative. In the following Examples and the like, "%" means "wt%".
[0055]
In the following Experimental Examples, the "permeation amount of compound 1" shows that based on a free base form of compound 1.
[0056]
As a support, a 25 μπι polyethylene terephthalate film manufactured by FUJIMORI KOGYO CO., LTD. was used. As a
release liner, a Bynasheet 64S-018B manufactured by FUJIMORI KOGYO CO., LTD. was used.
[0057]
Example 1
An acrylic adhesive (POLYTHICK 410-SA, manufactured by Sanyo Chemical Industries, Ltd., solid content 38%) (4.16 g) , a curing agent (POLYTHICK SC-75, manufactured by Sanyo
Chemical Industries, Ltd., solid content 75%) (25 mg) , ethyl acetate (1.2 mL) , and a-monoisostearyl glyceryl ether (0.2 g) to a content percentage of 10% in an adhesive layer were mixed. To the mixture was added 0.2 g of compound 1 such that its content percentage in the adhesive layer was 10%, and the mixture was sufficiently stirred. The obtained mixture was spread on the support such that the thickness of the adhesive
layer after drying was about 60 μτη, and the layer was dried at room temperature for one day. Then, a release liner was adhered to the adhesive layer to give a tape preparation.
[0058]
Example 2 - 24
Tape preparations were produced using various additives shown in Table 1 instead of cc-monoisostearyl glyceryl ether in Example 1.
[0059]
Comparative Example 1
An acrylic adhesive (POLYTHICK 410-SA, manufactured by Sanyo Chemical Industries, Ltd., solid content 38%) (4.68 g) , a curing agent (POLYTHICK SC-75, manufactured by Sanyo
Chemical Industries, Ltd., solid content 75%) (28 mg) and ethyl acetate (1.2 mL) were mixed. To the mixture was added 0.2 g of compound 1 such that its content percentage in the adhesive layer was 10%, and the mixture was sufficiently stirred. The obtained mixture was spread on the support such that the thickness of the adhesive layer after drying was about 60 μτ, and the layer was dried at room temperature for one day. Then, a release liner was adhered to the adhesive layer to give a tape preparation.
[0060]
Experimental Example 1
Hairless rat skin permeation experiment
Using an in vitro diffusion cell, the skin permeability of compound 1 in the tape preparations obtained in Examples 1 - 24 and Comparative Example 1 through the abdominal skin of hairless rats was measured. That is, the skin of hairless rat was set on an in vitro diffusion cell with permeation area 1.13 cm2 and using, as a receiver fluid, 0.75 mL of a 3:1 mixture of propylene glycol and phosphate buffer, each
preparation was adhered to the skin on the donor side (n=4) .
The receiver fluid was stirred for 24 hr while keeping at 37°C, the concentration of compound 1 in the receiver fluid was
measured by high performance liquid chromatography (column: Symmetry™ C18 3.5 urn 4.6x50 mm; Waters), mobile phase: 5 mM monosodium phosphate (adjusted to pH 7.0 with
triethylamine) /methanol (1:4), column temperature: 30°C, flow rate: 0.9 mL/min) , and the permeation amount of each
preparation was determined. The results are shown in Table 1.
[0061]
Table 1
[0062]
Experimental Example 1 has revealed that respective tape
preparations produced in Examples 1 - 24, which comprise particular additives, show very high skin permeability of compound 1, as compared to the tape preparation produced in Comparative Example 1, which is free of additive.
[0063]
Example 25
An acrylic adhesive (POLYTHICK 410-SA, manufactured by Sanyo Chemical Industries, Ltd., solid content 38%) (4.16 g) , a curing agent (POLYTHICK SC-75, manufactured by Sanyo
Chemical Industries, Ltd., solid content 75%) (25 mg) , ethyl acetate (1.2 mL) , lactic acid (0.1 g) to a content percentage of 5% in an adhesive layer and a-monoisostearyl glyceryl ether (0.1 g) to a content percentage of 5% in an adhesive layer were mixed. To the mixture was added 0.2 g of compound 1 such that its content percentage in the adhesive layer was 10%, and the mixture was sufficiently stirred. The obtained mixture was spread on the support such that the thickness of the adhesive layer after drying was about 60 urn, and the layer was dried at room temperature for one day. Then, a release liner was adhered to the adhesive layer to give a tape preparation.
[0064]
Examples 26 - 40
Tape preparations were produced using various additives shown in Table 2 instead of a-monoisostearyl glyceryl ether in Example 25.
[0065]
Reference Examples 1 - 10
In the same manner as in Example 1, tape preparations were produced using several additives shown in Table 2 instead of α-monoisostearyl glyceryl ether.
[0066]
Comparative Example 2
Tape preparation was produced using cetyl lactate instead of α-monoisostearyl glyceryl ether in Example 25.
[0067]
Experimental Example 2
Hairless rat skin permeation experiment
In the same manner as in Experimental Example 1 and using an in vitro diffusion cell, the skin permeability of compound 1 in the tape preparations obtained in Examples 25 - 40,
Reference Example 1 - 10 and Comparative Example 2 through the abdominal skin of hairless rats was measured. The results are shown in Table 2.
[0068]
Table 2
(note) The "synergistic effect on permeability by combination of
lactic acid and second additive" is shown by "permeation amount (c) of compound 1 in preparation added with lactic acid 5% and second additive 5%" divided by "average of "permeation amount (a) of compound 1 in preparation added with lactic acid 10% alone" and "permeation amount (b) of compound 1 in preparation added with second additive 10% alone"", i.e., an index of (c)÷ [average of (a) and (b)](=(c)÷ [ { (a) + (b) }/2] ) . When the index is larger than 1, the effect on permeability is considered to be synergistic. Particularly preferred is a combination of 2 or more of the indices in Table 2.
[0069]
As is clear from the results of Experimental Example 2, as compared to the preparation added with lactic acid 10% alone, a preparation wherein 5% of lactic acid 10% is
substituted by a particular second additive showed remarkably enhanced skin permeability of compound 1. Thus, the superior feature of the preparation of the present invention that a combination of lactic acid and the second additive enhances the skin permeability of compound 1 has been demonstrated.
[0070]
By comparison of the obtained permeability data, the permeation amount of compound 1 from the preparation added with lactic acid 5% and the second additive 5% in combination remarkably increased as compared to the average of the permeation amount of compound 1 from the preparation added with lactic acid 10% alone and that from the preparation added with the second additive 10% alone ((c)÷ [average of (a) and (b)]»l). This exhibits the superior feature of the present invention that a combination of lactic acid and the second additive synergistically enhances the skin permeability of compound 1.
[0071]
Examples 41 - 47
In the same manner as in Example 25, respective tape preparations were produced using an acrylic adhesive
(POLYTHICK 410-SA, manufactured by Sanyo Chemical Industries,
Ltd., solid content 38%) (3.64 g) , a curing agent (POLYTHICK
SC-75, manufactured by Sanyo Chemical Industries, Ltd., solid content 75%) (22 mg) , ethyl acetate (1.2 mL) , and lactic acid and a-monoisostearyl glyceryl ether to meet the compositions shown in Table 3.
[0072]
Example 48
Tape preparation was produced using lactic acid 20% alone instead of the addition of both lactic acid and a- monoisostearyl glyceryl ether in Examples 41 - 47.
[0073]
Example 49
Tape preparation was produced using a-monoisostearyl glyceryl ether instead of lactic acid in Example 48.
[0074]
Experimental Example 3
Hairless rat skin permeation experiment
In the same manner as in Experimental Example 1 and using an in vitro diffusion cell, the skin permeability of compound 1 in the tape preparations obtained in Examples 41 - 49 through the abdominal skin of hairless rats was measured. The results are shown in Table 3.
[0075]
Table 3
[0076]
Experimental Example 3 reveals that in a preparation comprising lactic acid and -monoisostearyl glyceryl ether, content ratio (weight ratio) of α-monoisostearyl glyceryl ether to lactic acid is at least 0.1-fold to 7-fold, a remarkable synergistic effect of the combination of lactic acid and α-monoisostearyl glyceryl ether on skin permeation of compound 1 as compared to a preparation comprising lactic acid alone or α-monoisostearyl glyceryl ether alone was confirmed. Preferable content ratio of α-monoisostearyl glyceryl ether to lactic acid was 0.3-fold to 3-fold.
[0077]
Even when an additive other than a-monoisostearyl glyceryl ether was selected as the second additive, the content ratio (weight ratio) of the second additive to lactic
acid was preferably 0.1-fold to 7-fold, more preferably 0.3- fold to 3-fold.
[0078]
Examples 50 - 55
Using the starting materials shown in Table 4, and in the same manner as in Example 25, tape preparations were produced.
[0079]
Table 4
In Table 4, POLYTHICK 410-SA (manufactured by Sanyo
Chemical Industries, Ltd., solid content 38%) was used as the acrylic adhesive, and POLYTHICK SC-75 (manufactured by Sanyo Chemical Industries, Ltd., solid content 75%) was used as the curing agent. Acrylic adhesive, curing agent, and ethyl acetate are each shown in the charged amount. The "content percentage (%) in the adhesive" of lactic acid, a-monostearyl glyceryl ether, and compound 1 shows each content percentage (wt%) in the adhesive in the produced tape preparation.
[0081]
Example 56
An acrylic adhesive (DURO-TAK 387-2516 registered trade mark, manufactured by National Starch & Chemical Ltd., solid content 41.5%) (3.86 g) , ethyl acetate (1.2 mL) , and a- monoisostearyl glyceryl ether (0.1 g) and lactic acid (0.1 g) each to a content percentage of 5% in an adhesive layer were mixed. To the mixture was added 0.2 g of compound 1 such that its content percentage in the adhesive layer was 10%, and the mixture was sufficiently stirred. The obtained mixture was
spread on the support such that the thickness of the adhesive layer after drying was about 60 um, and the layer was dried at room temperature for one day. Then, a release liner was adhered to the adhesive layer to give a tape preparation.
[0082]
Example 57
An acrylic adhesive (MAS683, manufactured by Cos ED Pharmaceutical Co. Ltd., solid content 36.5%) (4.38 g) , ethyl acetate (1.2 mL) , and a-monoisostearyl glyceryl ether (0.1 g) and lactic acid (0.1 g) each to a content percentage of 5% in an adhesive layer were mixed. To the mixture was added 0.2 g of compound 1 such that its content percentage in the adhesive layer was 10%, and the mixture was sufficiently stirred. The obtained mixture was spread on the support such that the thickness of the adhesive layer after drying was about 60 μιη, and the layer was dried at room temperature for one day. Then, a release liner was adhered to the adhesive layer to give a tape preparation.
[0083]
Example 58
A styrene-isoprene-styrene block copolymer (Quintac 3421, manufactured by ZEON CORPORATION) (0.4 g) , liquid paraffin (0.4 g) , polybutene (HV-300, manufactured by Nippon Petroleum Refining Corporation) (0.3 g) , alicyclic saturated hydrocarbon resin (ARKON P-100, manufactured by Arakawa Chemical
Industries, Ltd.) (0.5 g) , ethyl acetate (3.0 mL) , and oc- monoisostearyl glyceryl ether (0.1 g) and lactic acid (0.1 g) each to a content percentage of 5% in an adhesive layer were mixed. To the mixture was added 0.2 g of compound 1 such that its content percentage in the adhesive layer was 10%, and the mixture was sufficiently stirred. The obtained mixture was spread on the support such that the thickness of the adhesive layer after drying was about 60 μιτι, and the layer was dried at room temperature for one day. Then, a release liner was adhered to the adhesive layer to give a tape preparation.
[0084]
Example 59
An acrylic adhesive (POLYTHICK 410-SA, manufactured by Sanyo Chemical Industries, Ltd., solid content 38%) (4.12 g) , a curing agent (POLYTHICK SC-75, manufactured by Sanyo
Chemical Industries, Ltd., solid content 75%) (25 mg) , ethyl acetate (1.2 mL) , and a-monoisostearyl glyceryl ether (0.1 g) and lactic acid (0.1 g) each to a content percentage of 5% in an adhesive layer were mixed. To the mixture was added 0.215 g of compound 1 hydrochloride (10% as free base of compound 1) such that its content percentage in the adhesive layer was 10.74%, and the mixture was sufficiently stirred. The obtained mixture was spread on the support such that the thickness of the adhesive layer after drying was about 60 μπι, and the layer was dried at room temperature for one day. Then, a release liner was adhered to the adhesive layer to give a tape
preparation .
[0085]
Example 60
To N-vinylacetamide-sodium acrylate copolymer (adHERO GE-
167, manufactured by Showa Denko K. K. ) (30 mg) was added methanol (0.6 mL) and the mixture was left standing for one day. The solution was mixed with an acrylic adhesive (MAS683, manufactured by CosMED Pharmaceutical Co. Ltd., solid content 36.5%) (4.30 g) , methanol (0.6 mL) , and lactic acid (0.1 g) and lauromacrogol (0.1 g) each to a content percentage of 5% in an adhesive layer. To the mixture was added 0.2 g of compound 1 such that its content percentage in the adhesive layer was 10%, and the mixture was sufficiently stirred. The obtained mixture was spread on the support such that the thickness of the adhesive layer after drying was about 60 μπι, and the layer was dried at room temperature for one day. Then, a release liner was adhered to the adhesive layer to give a tape preparation.
Industrial Applicability
[0086]
The adhesive preparation of the present invention suppresses metabolites production, and maintains the blood drug concentration of compound 1 in a sustained manner. In addition, the adhesive preparation of the present invention can remarkably enhance the skin permeability of compound 1 by adding particular additives to the adhesive layer, and
therefore, can provide a practically preferable adhesive preparation superior in the usability and economic efficiency.
[0087]
While some of the embodiments of the present invention have been described in detail in the above, it is, however, possible for those of ordinary skill in the art to make various modifications and changes to the particular embodiments shown without substantially departing from the teaching and advantages of the present invention. Such modifications and changes are encompassed in the spirit and scope of the present invention as set forth in the appended claims .
[0088]
This application is based on US provisional patent application No. 61/438,787 and the contents disclosed therein are hereby entirely incorporated.
Claims
1. An adhesive preparation comprising a support and an
adhesive layer formed on one surface of the support, wherein the adhesive layer comprises (i) (3aR, 4S, 7R, 7aS) -2-{ (1R, 2R) -2- [4- (1, 2-benzisothiazol-3-yl) piperazin-1- ylmethyl] cyclohexylmethyl }hexahydro-4, 7-methano-2H-isoindole- 1,3-dione (hereinafter to be referred to as "compound 1") or a physiologically acceptable acid addition salt thereof, (ii) an adhesive, (iii) lactic acid as the first additive, and (iv) at least one kind of additive selected from the group consisting of alkyl glyceryl ether, polyoxyethylene alkyl ether, fatty acid ester, lecithin, fatty acid, alcohol, soybean oil, methyl isobutyl ketone and crotamiton as the second additive.
2. The adhesive preparation according to claim 1, wherein alkyl glyceryl ether as the second additive comprises a- monoisostearyl glyceryl ether.
3. The adhesive preparation according to claim 1, wherein polyoxyethylene alkyl ether as the second additive comprises at least one kind selected from the group consisting of
polyoxyethylene behenyl ether and lauromacrogol .
4. The adhesive preparation according to claim 1, wherein fatty acid ester as the second additive comprises at least one kind selected from the group consisting of diisopropyl adipate, diethyl sebacate and propylene glycol esters of fatty acids.
5. The adhesive preparation according to claim 1, wherein lecithin as the second additive comprises egg-yolk lecithin.
6. The adhesive preparation according to claim 1, wherein fatty acid as the second additive comprises isostearic acid.
7. The adhesive preparation according to claim 1, wherein alcohol as the second additive comprises at least one kind selected from the group consisting of benzyl alcohol, decanol, octyldodecanol and propylene glycol.
5
8. The adhesive preparation according to claim 1, wherein the second additive comprises soybean oil.
9. The adhesive preparation according to any one of claims 1 10 to 8, wherein the weight ratio of the second additive is 0.1- fold to 9-fold relative to lactic acid.
10. The adhesive preparation according to any one of claims 1 to 9, wherein the content of lactic acid in the adhesive layer
15 is 0.01 - 30 wt%.
11. The adhesive preparation according to any one of claims 1 to 10, wherein the adhesive layer comprises component (i) at a concentration of 0.1 - 50 wt% in terms of compound 1.
20
12. The adhesive preparation according to any one of claims 1 to 11, wherein the adhesive is at least one kind selected from the group consisting of an acrylic adhesive, a rubber adhesive, and a silicone adhesive.
25
13. The adhesive preparation according to claim 12, wherein the adhesive comprises an acrylic adhesive.
14. The adhesive preparation according to claim 13, wherein 30 the acrylic adhesive is at least one kind selected from the
group consisting of a (co) polymer mainly comprising
(meth) acrylic acid alkyl ester, and a copolymer of
(meth) acrylic acid alkyl ester and a functional monomer.
35 15. The adhesive preparation according to claim 12 or 13, wherein the adhesive comprises a rubber adhesive.
16. The adhesive preparation according to claim 15, wherein the rubber adhesive is at least one kind selected from the group consisting of a styrene-isoprene-styrene block copolymer and polyisobutylene .
17. The adhesive preparation according to any one of claims 1 to 16, which is in the form of a tape preparation.
18. The adhesive preparation according to any one of claims 1 - 17, which is a therapeutic agent for schizophrenia and/or a bipolar disorder.
19. A method for the treatment of schizophrenia and/or a bipolar disorder, comprising administering the adhesive preparation according to any of claims 1 to 18 comprising an effective amount of compound 1 or a physiologically acceptable acid addition salt thereof.
20. An adhesive preparation comprising a support and an adhesive layer formed on one surface of the support, wherein the adhesive layer comprises (i) compound 1 or a
physiologically acceptable acid addition salt thereof, (ii) an adhesive, and (iii) at least one kind of additive selected from the group consisting of lactic acid, oc-monoisostearyl glyceryl ether, cetyl alcohol, propylene glycol esters of fatty acids, polyoxyethylene (20) polyoxypropylene (8) cetylether, lipophilic glycerylmonooleate, Beeswax derivatives of
polyoxyethylene sorbitol, lauryl alcohol, decanol,
lauromacrogol, cetyl lactate, oleyl oleate, octyldodecanol, octyldodecyl myristate, soybean lecithin, egg-yolk lecithin, triethanolamine, polyethylene glycol mono-p- isooctylphenylether, polyethylene glycol #200, squalane, isopropyl myristate, diethyl sebacate, cetyl 2-ethylhexanoate, cetanol - polyethylene glycol monostearate mixed wax, and liquid lanolin.
21. The adhesive preparation according to claim 20, wherein
5 the adhesive layer comprises the aforementioned component (i) at a concentration of 0.1 - 50 wt% in terms of compound 1.
22. The adhesive preparation according to claim 20 or 21, wherein the adhesive is at least one kind selected from the
10 group consisting of an acrylic adhesive, a rubber adhesive, and a silicone adhesive.
23. The adhesive preparation according to claim 22, wherein the adhesive comprises an acrylic adhesive.
15
24. The adhesive preparation according to claim 23, wherein the acrylic adhesive is at least one kind selected from the group consisting of a (co) polymer mainly comprising
(meth) acrylic acid alkyl ester, and a copolymer of
20 (meth) acrylic acid alkyl ester and a functional monomer.
25. The adhesive preparation according to claim 22 or 23, wherein the adhesive comprises a rubber adhesive.
25 26. The adhesive preparation according to claim 25, wherein the rubber adhesive is at least one kind selected from the group consisting of a styrene-isoprene-styrene block copolymer and polyisobutylene .
30 27. The adhesive preparation according to any one of claims 20 to 26, which is a therapeutic agent for schizophrenia and/or a bipolar disorder.
Priority Applications (1)
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JP2013534873A JP5913335B2 (en) | 2011-02-02 | 2012-02-01 | New topical preparation |
Applications Claiming Priority (4)
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US201161438787P | 2011-02-02 | 2011-02-02 | |
JP2011-021204 | 2011-02-02 | ||
US61/438,787 | 2011-02-02 | ||
JP2011021204 | 2011-02-02 |
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PCT/JP2012/052794 WO2012105715A1 (en) | 2011-02-02 | 2012-02-01 | Novel external preparation |
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JP (1) | JP5913335B2 (en) |
WO (1) | WO2012105715A1 (en) |
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WO2006134864A1 (en) * | 2005-06-13 | 2006-12-21 | Dainippon Sumitomo Pharma Co., Ltd. | Solubilization preparation |
CA2653827A1 (en) * | 2006-06-09 | 2007-12-13 | Dainippon Sumitomo Pharma Co., Ltd. | Novel blonanserin tape preparation |
JP2008169145A (en) * | 2007-01-11 | 2008-07-24 | Kotobuki Seiyaku Kk | Preparation for percutaneous application |
WO2010146872A1 (en) * | 2009-06-19 | 2010-12-23 | 株式会社メドレックス | Composition for external application comprising aripiprazole and organic acid as active ingredients |
-
2012
- 2012-02-01 WO PCT/JP2012/052794 patent/WO2012105715A1/en active Application Filing
- 2012-02-01 JP JP2013534873A patent/JP5913335B2/en active Active
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KR20080024118A (en) * | 2005-06-13 | 2008-03-17 | 다이닛본 스미토모 세이야꾸 가부시끼가이샤 | Solubilization preparation |
US20090286805A1 (en) * | 2005-06-13 | 2009-11-19 | Kazuya Otoda | Solubiliazation preparation |
WO2006134864A1 (en) * | 2005-06-13 | 2006-12-21 | Dainippon Sumitomo Pharma Co., Ltd. | Solubilization preparation |
CN101198331A (en) * | 2005-06-13 | 2008-06-11 | 大日本住友制药株式会社 | Solubilization preparation |
EP1891956A1 (en) * | 2005-06-13 | 2008-02-27 | Dainippon Sumitomo Pharma Co., Ltd. | Solubilization preparation |
MX2008015794A (en) * | 2006-06-09 | 2009-01-12 | Dainippon Sumitomo Pharma Co | Novel tape preparation. |
WO2007142295A1 (en) * | 2006-06-09 | 2007-12-13 | Dainippon Sumitomo Pharma Co., Ltd. | Novel tape preparation |
AU2007255724A1 (en) * | 2006-06-09 | 2007-12-13 | Dainippon Sumitomo Pharma Co., Ltd. | Novel tape preparation |
EP2036559A1 (en) * | 2006-06-09 | 2009-03-18 | Dainippon Sumitomo Pharma Co., Ltd. | Novel tape preparation |
KR20090031407A (en) * | 2006-06-09 | 2009-03-25 | 다이닛본 스미토모 세이야꾸 가부시끼가이샤 | Novel tape preparation |
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JP2014504585A (en) | 2014-02-24 |
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