WO2008044336A1 - Crystal-containing adhesive preparation - Google Patents

Crystal-containing adhesive preparation Download PDF

Info

Publication number
WO2008044336A1
WO2008044336A1 PCT/JP2007/001104 JP2007001104W WO2008044336A1 WO 2008044336 A1 WO2008044336 A1 WO 2008044336A1 JP 2007001104 W JP2007001104 W JP 2007001104W WO 2008044336 A1 WO2008044336 A1 WO 2008044336A1
Authority
WO
Grant status
Application
Patent type
Prior art keywords
adhesive layer
drug
patch
pressure
adhesive
Prior art date
Application number
PCT/JP2007/001104
Other languages
French (fr)
Japanese (ja)
Inventor
Takaaki Terahara
Kazunosuke Aida
Yasunari Michinaka
Akio Takeuchi
Naoyuki Uchida
Original Assignee
Hisamitsu Pharmaceutical Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703Transdermal 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
    • A61K9/7038Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053Transdermal 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703Transdermal 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
    • A61K9/7038Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053Transdermal 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
    • A61K9/7061Polyacrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703Transdermal 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
    • A61K9/7038Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7076Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising ingredients of undetermined constitution or reaction products thereof, e.g. rosin or other plant resins

Abstract

It is intended to provide an adhesive preparation which makes it possible to transdermally supply a drug sustainedly over at least 24 hours. Namely, an adhesive preparation having a pressure-sensitive adhesive layer on one face of a support, wherein the pressure-sensitive adhesive layer contains more than 5% by mass, preferably more than 5% by mass but less than 15% by mass, of a drug in a molten state and in a crystalline state and the drug in a crystalline state contained in the pressure-sensitive adhesive layer is distributed in a smaller amount on the surface of the pressure-sensitive adhesive layer to be adhered to the skin than in the support side of the pressure-sensitive adhesive layer.

Description

Specification

Crystal-containing patch

Technical field

[0001] The present invention relates to a patch containing a drug in solution and crystalline state in the pressure-sensitive adhesive layer. Furthermore, the present invention can have you to state crystals were precipitated drug in the adhesive layer is excellent in adhesion to the skin, persistently relates patch in which the drug from the skin can be absorbed at a high absorption rate.

BACKGROUND

[0002] The technology of transdermal preparation for a drug contained in the adhesive layer is absorbed through the skin, as one of useful drug delivery system for administering a drug for the treatment of diseases, many pharmaceutically efforts have been made. In a typical transdermal formulation at a pasting agent, depending the concentration of drug drugs supplied into the body from the formulation is dissolved in the adhesive layer, the concentration gradient of the drug concentration in the skin surface to move the skin tissue, if not soluble only a small amount of the drug in the adhesive layer is to absorb speed it is difficult to obtain a sufficient therapeutic effect decreases, also the drug is absorbed patch in If the drug is no longer maintained when the concentration gradient is consumed, the absorption rate is not sustained therapeutic effect decreases. For this, a long time to maintain the transdermal absorption of good drug, the order to sustain the therapeutic effect of absorbed drugs, present in the adhesive layer with more drug dissolved state and, it is necessary that a sufficient concentration can be maintained.

However, the low saturation solubility in the pressure-sensitive adhesive layer drug, the amount of drug can the dissolution child is limited, to increase the absorption rate, the drug concentration required to sustain a long time to Wataru connexion absorption and this to maintain the adhesive layer is difficult.

[0003] Against this background, as one of persistently supply means the drug from the skin, techniques for inclusion to the drug becomes more saturated solubility of the adhesive layer have been developed . For example, the drug in the drug-containing base layer made of fibrous assembly disposed between the pressure-sensitive adhesive layer support film is unevenly dispersed in solid form, the adhesive layer is contained in the drug dissolved state are percutaneously absorbable preparations (see Patent Document 1), chronic bronchitis, crystalline necked butene port on the dissolution type necked butene port Lumpur in plaster layer containing Rrobuteroru a therapeutic agent for bronchial asthma including the amount ratio of Ichiru is from 0.1 to 1 0, which is percutaneously absorptive preparation (see Patent Document 2), isosorbide Nai trait is coronary vasodilator (melting point 7 0 ° C) of the saturation solubility of the pressure-sensitive adhesive 1.5 times by weight or more was recrystallized, mp 5 0-6 0 recrystallized grains of ° C comprising a containing a percutaneous absorption patch (see Patent Document 3), adhesive such as an acrylic copolymer 1. dissolved twice or more drugs recrystallized by saturation solubility agent, URN (see Patent Document 4) percutaneous absorption preparation formed by incorporating a recrystallized grains of uniform size, in order to precipitate recrystallized particles in the adhesive uniformly and stably low and high temperatures in the long such ripening (aging) operation was performed crystalline mixed transdermal therapeutic (see Patent Document 5) have been reported.

However, these techniques crystals are uniformly dispersed in the adhesive layer, the crystal to a portion in close contact with the pressure-sensitive adhesive layer sheet surface or the skin and mucous membranes are precipitated, the drug is completely dissolved in the adhesive layer If the adhesive strength is reduced compared to tend to sticking state becomes insufficient preparation against the skin surface, that adhesion is lowered resulting in the absorption of the drug over a long period of time with the skin or mucous membrane will not last there is an inconvenience. Further, as a method for localizing crystals in an adhesive layer, between the adhesive layer supported fill-time (see Patent Document 1) a method of providing a drug-containing base layer, at a low temperature in order to controls the precipitation of crystals prolonged aging (aging) is a method of performing an operation (see Patent documents 4 and 5) have been proposed, or provided a special layer for holding a drug in these methods, also prolonged aging process there has been a problem that becomes complicated, such as to require the (aging) process.

- How, Donepe Jill like acetylcholinesterase inhibitors have been used as a therapeutic agent for Aruhha timer first die dementia, such as tandospirone a serotonin 5 _ HT 1 A receptor agonist as an antidepressant when a force dementia or psychosis which has been used is progressed, there particularly that the difficult to taken orally, parenteral administration, such as transdermal administration as a dosage form in such a case it has been attention. For example, Patent Document 6, has been proposed formulation for parenteral administration hydrochloride Donepe Jill as ointments or suppositories, in Patent Document 7, transdermal contained in the adhesive composition in a dispersed state absorption type preparation has also been proposed. These preparations, though efficacy in a formulation substantially similar plasma concentration oral administration obtained is expected, because the continued treatment long-term is a necessary re stuck, further enhance the absorption of the drug it had rare Nozomu to provide a formulation of smaller area.

[0005] Patent Document 1: Japanese Patent No. 2 6 9 7 1 9 1 JP

Patent Document 2: Japanese Patent No. 2 7 5 3 8 0 0 No.

Patent Document 3: JP 63- 3 0 7 8 1 8 No.

Patent Document 4: JP-6 0 1 8 5 7 1 3 JP

Patent Document 5: JP 2 0 0 5 _ 3 5 0 3 7 3 JP

Patent Document 6: JP-A 1 1-3 1 5 0 1 6 JP

Patent Document 7: WO 2 0 0 3/0 3 2 9 6 0 No.

Disclosure of the Invention

Problems that the Invention is to you'll solve

[0006] The present invention provides a drug and pasted agent coexist drug in a crystalline state in solution in an adhesive layer, depression won minimize degradation of skin adhesion force resulting from the crystallization of the drug, at least the sustained drug over 2 4 hours or more and to provide a patch capable and this is supplied from the skin.

Means for Solving the Problems

[0007] The present inventors have, Te intensive study the results of adhesive patch odor drug in the adhesive layer is contained in a dissolved state and a crystalline state in the pressure-sensitive adhesive layer in order to solve the above problems, the skin together exhibit good adhesion, even drugs formulated beyond drug saturated dissolved Kaido in the pressure-sensitive adhesive composition is present as crystals, found that the adhesive patch of skin absorption rate of the drug is further improved can be produced It was.

[0008] Namely, the present invention comprises an adhesive layer on one surface of a support, pressure-sensitive adhesive layer is more than 5 mass%, preferably dissolved form of the drug is less than 1 5% by weight to more than 5 wt% contained in state and crystalline state, and the drug in a crystalline state in the adhesive layer than supporting lifting side of the pressure-sensitive adhesive layer, the pressure-sensitive adhesive layer surface on the side that adheres to the skin, to patch that less distribution .

The present invention also provides a surface on which to adhere to the skin of the adhesive layer, to an adhesive patch drug in the crystalline state is not present.

Furthermore, the present invention provides a pressure-sensitive adhesive layer, to adhesive preparation, wherein the drug present in the crystalline state is larger than the drug present in the dissolved state.

Furthermore, the present invention, the drug contained in the adhesive layer is selected Donebe Gilles, Tan Dosupiron, Anpurokiso Ichiru, and Risuperi Don, and from the group consisting of pharmaceutically acceptable salts the present invention relates to one or more in a patch including the pressure-sensitive adhesive layer, a styrene - isoprene - styrene block copolymer, and at least one tackifying resin selected from alicyclic saturated hydrocarbon or a terpene resin patch to be on.

Further, the present invention is a styrene contained in the adhesive layer - isoprene - proportion of Suchirenbu locking copolymer tackifying resin is 1: about 1 0 plaster: 1 to 1.

To describe the present invention more specifically, the following.

(1) In the adhesive patch comprising an adhesive layer on one surface of a support, it has contains from 5 to 1 5% by weight of the drug relative to the total weight of the adhesive layer viscosity Chakuzaiso in solution and crystalline states and adhesive patch drug in a crystalline state in the adhesive layer is in the pressure-sensitive adhesive layer surface on the side that adheres to the skin than the support side of the adhesive layer, characterized in that fewer distribution.

(2) patch according to the amount of drug contained in the adhesive layer is a 2-2 five times the saturated solubility in the adhesive layer (1).

(3) the amount of drug present in a crystalline state in the adhesive layer is adhesive patch according to (1) or (2) 5-1 0% by weight relative to the total weight of the adhesive layer. (4) at the surface on the side that adheres to the skin of the adhesive layer, the adhesive patch according to any of the drug in the crystalline state is not present (1) to (3).

(5) the drug present in a crystalline state in the pressure-sensitive adhesive layer, adhesive patch according to any one of the greater than the drug present in solution in the pressure-sensitive adhesive layer (1) to (4)

(6) drug contained in the adhesive layer is, Donebe Jill, tandospirone, amplifier Rokisoru, and Risuperi Don, as well as at least one selected from these pharmaceutically acceptable salts or Ranaru group wherein (1) patch of the mounting serial to any one of the - (5).

(7) a drug contained in the pressure-sensitive adhesive layer, adhesive patch according to (6) Donebe Jill, tandospirone or Risuperi Don, or their pharmaceutically acceptable salts.

(8) the adhesive layer, a styrene - isoprene - patch according to any one of the those containing styrene block copolymer (1) to (7).

(9) pressure-sensitive adhesive layer, a styrene - isoprene - agent with bonded according to any one of the those containing styrene block copolymer and pressure-sensitive adhesive imparting resin (1) to (8).

(1 0) tackifying resins, adhesive patch according to (9) is at least one selected from alicyclic saturated hydrocarbon resin or a terpene resin.

Isoprene - - (1 1) styrene contained in the adhesive layer blending ratio of styrene block copolymer polymer and tackifying resin, 1: 1 to 1: 1 0 the (9) or

Patch according to (1 0).

(1 2) patch according to any one of the pressure-sensitive adhesive layer contains at least one selected from the further polyisobutylene or an acrylic adhesive ing a polymer (8) to (1 1).

(1 3) adhesive layer further liquid rubber, any petroleum-based oil, and the containing at least one plasticizer selected from the group consisting of liquid fatty S. ethers (8) - (1 2) patch of crab described. (1 4) liquid rubber, adhesive patch according to (1 3) is a liquid polybutene.

(1 5) patch according to the petroleum oil is a liquid paraffin (1 3).

(1 6) a liquid fatty esters, patch according to (1 3) is isopropyl myristate.

(1 7) adhesive layer further fatty acids with carbon number 6-20, ester le such the fatty acids, amino earth of the fatty acids, Pirochiodekan, and at least one selected from the group consisting of propylene glycol fatty acid esters patch according to any one of (8) to (1 6) containing absorption enhancers.

(1 8) patch according to any one of the adhesive force measured by peel measuring instrument of the patch is at 300 g / cm or more (1) - (1 7).

(1 9) Adhesive strength measured by peel measuring machine, 300 g / cm~700 g / cm outcome〗 words himself

Patch according to (1 8).

(20) Adhesive strength measured by the probe tack tester one patch is patch according to any one of 200 gf (gram weight) or more above (1) to (1-9). (2 1) Adhesive force measured by the probe tack tester one can, patch according to (20) is 200 gf to 500 gf.

(22) patch according to any one of the area to be attached to the adhesive patch is 5~40 cm 2 (1) ~ ( 2 1).

(23) was dissolved drug, and an adhesive base agent in a solvent, the obtained solution was coated on a release liner and foremost, the solvent was removed by drying, and then consists of bonding a support to (1) to

Method for producing a patch according to any one of (22).

Effect of the invention

In a conventional adhesive patch drug was excessively blended, because of the very large amount of the drug as compared to the drug saturated solubility in the adhesive layer, crystal is concentrated on the front surface of the release liner side of the adhesive layer precipitated Te, can not be provided as a product. In contrast, 5-1 5% by weight relative to the total weight of the adhesive layer of the present invention, adhesive patch preferably has a pressure-sensitive adhesive layer containing from 5 to 1 0% by weight of the drug in a dissolved state and a crystalline state in was found that the phenomenon that crystals hardly precipitate at the interface between the adhesive layer and the release liner one is seen. Although the detailed reason for such a phenomenon occurs is not always clear, the pressure-sensitive adhesive layer of the adhesive patch of the present invention, the drug in a crystalline state in the pressure-sensitive adhesive layer is adhered to the skin than the support side of the adhesive layer On the side of the pressure-sensitive adhesive layer surface that is because of the less distributed. In other words, this is the density of the drug in the crystalline state in the pressure-sensitive adhesive layer is, toward the side of the pressure-sensitive adhesive layer surface to adhere to the skin surface adhering to the support (opposite side of the pressure-sensitive adhesive layer surface) stepwise, continuous or density discontinuous or irregularly in a crystalline state drug is changed, as a result, the drug in a crystalline state in the pressure-sensitive adhesive layer is adhered to the skin than the support side of the adhesive layer Te on the side of the adhesive layer surface to include a state which will less distributed. Further, when the crystal in the adhesive layer surface on the side which adheres to the skin is not present, may be any in distribution existed drugs crystalline state within the adhesive layer. Also, after the conventional patch was excessively blended drug, that long-term storage (about 2 weeks 3 days) at room temperature even when the deposition of crystals is not observed immediately after preparation (2 5 ° C), Although intensive crystal precipitation is observed in the release liner side of the surface of the adhesive layer, the adhesive patch of the present invention also does not occur such a phenomenon. In particular, these phenomena becomes significant when using a pharmaceutically acceptable salt Donepe Gilles or tandospirone or these as drugs. Furthermore, when using salts Donepe Gilles or tandospirone, or their pharmaceutically acceptable drug, since the solubility against the Akuriru copolymer of these drugs is large, excessively these agents to formulate must be blended with the drug in excess of 1 5% by weight, based on the total weight of the viscosity Chakuzaiso, phenomena, such as patch of the invention would not occur. Accordingly, the present invention is in view of the solubility of the drug to the adhesive, a suitable adhesive to the drug and WASH, the formulation of the drug on the total weight of the adhesive layer 5-1 5% by weight, preferably 5-1 0 which is characterized in that the mass%, according to the present invention, despite the saturation solubility or more drugs in the adhesive layer is included as the crystalline state, for 24 hours adheres against skin is has sufficient adhesive strength to cause, along with excellent skin absorption properties of a drug can be a patch to impart durability to the efficacy. The further, showed stable therapeutic effect in the treatment of such diseases, it is possible to provide a patch that can be used safely as a pharmaceutical.

BEST MODE FOR CARRYING OUT THE INVENTION

[001 1] will be described in detail preferred embodiments of the present invention.

But are not limited to the configuration of the patch of the present invention, preferred embodiments include a viscosity Chakuzaiso single layer shown in FIG. 1, for example. That is, provided with a drug-containing adhesive layer on the support surface, is covered constituting the pressure-sensitive adhesive layer surface with a release liner layer is peeled ■ removed during formulation use.

[0012] drug contained in the adhesive layer of the patch of the invention, to be formulated at concentrations above the saturation solubility in the base, that exists in the form of a drug dissolved and crystalline states coexist. That is, the adhesive layer of the patch of the invention, a drug that can not be dissolved in order to exceed the saturation solubility is present as a crystalline state. Furthermore, in this onset Ming patch, Oite a concentration range that exceeds the saturation solubility of the drug in the adhesive layer can also be dependent on the amount of the drug to improve the drug absorption rate. Drug in a crystalline state such as this will not dissolve in the production process of the patch crystal may be any of those recrystallized after dissolving in contact and the manufacturing process does not change the effect of Both present invention. Drug saturation solubility in the pressure-sensitive adhesive layer in the present invention is 0. Preferably 1 to 5% by mass, from 0.5 to 4. More preferably to be 5 mass%. 0.1 The weight percent less than fried small drug in a dissolved state, the drug is not sufficiently absorbed through the skin, or drugs in solution tends liable to impair the durability of the absorbent is consumed. On the other hand, if the saturation solubility is 5 mass% or more, it is necessary to blend a large amount of the drug in the adhesive layer in order to present the drug as a crystalline state, not only inefficient, drug absorption easy persistence becomes insufficient.

[0013] That is, the drugs included in the patch of the present invention is not particularly limited Jowa which is effective for the treatment, it can be formulated in 5-1 5 wt% with respect to the total weight of the adhesive, preferably the amount of less than 5 wt% more than the amount to 1 5 mass%, more preferably from 5.1 to 1 4.9 mass 0 / o, 5. 5~ 1 4. 5 mass 0 / o, or 6-1 4 mass 0 / o, more preferably from 6 1 0% by weight or 8-1 0% by weight. Amount of the drug can not be drug absorption is less than 5 wt% can be sustained sufficient therapeutic effect insufficient. On the other hand, undesirable to URN 及 affect the physical properties of exceeds 1 5 wt% formulations. Also, the drug concentration in the adhesive layer in the can also be formulated in 1-1 5 0 times the saturated solubility in the adhesive layer, more preferable properly is from 2 to 2 5 times.

[0014] Crystals of drugs, present in the adhesive layer in the present invention, despite a state of being uniformly dispersed in the adhesive base of the hydrophobic polymer as a main Ingredient, that apply to the skin adhesive hardly precipitated in the adhesive layer on the surface. The crystal of the drug that exists in the adhesive layer of the present invention, when dispersed in the pressure-sensitive adhesive layer is recrystallized after becoming once dissolved or melted supersaturated also concentrated on the adhesive layer surface precipitation is suppression. Therefore, the patch of the invention, like the dissolution type preparations in the pressure-sensitive adhesive layer no crystal has adhesion to sufficient skin, that the formulation from falling off by peeling the skin or found during application without, it becomes a drug product can be continuously administered through the skin at least 2 4 hours longer.

[0015] Next, the adhesive preparation of the present invention, not less than the drug crystals Drug crystals distributed in the surface of the pressure-sensitive adhesive layer on the side which adheres to the skin is distributed within the adhesive layer (support side of the pressure-sensitive adhesive layer) it is characterized in. The pressure-sensitive adhesive layer surface here, patch a generally refer to a pressure-sensitive adhesive layer side of the solid / solid interface adhesive when you applied to the skin is present at the boundary in contact with the skin, the crystal on the surface of the pressure-sensitive adhesive layer There patch forces present invention the adhesive strength between the pressure-sensitive adhesive come to precipitation you drop may be smaller the crystals to the extent that the adhesive strength is not decreased, more preferably, the pressure-sensitive adhesive layer surface on the side that adheres to the skin it is that the crystal does not exist. If the crystal surface of the pressure-sensitive adhesive layer on the side which adheres to the skin is not present, the pressure-sensitive adhesive layer surface on the side that adheres to the skin is observed as irregularities without smooth plane light microscope level.

Distribution of drug crystals in the adhesive layer surface, the state of the drug crystals precipitated in a predetermined area of ​​the adhesive base surface was observed by the naked eye or an optical microscope, it is assessed on the basis of the index representing the precipitation state of crystals it can. Further, when the crystal is precipitated in the pressure-sensitive adhesive layer surface, since the adhesive strength of the patch decreases, can be evaluated by measurement of the adhesive force with the Purobutatsu Kutesuta one or peel measuring machine. The adhesive strength measured by a probe tack tester patch of the present invention, 2 00 gf (gram weight) or more, preferably 200 gf to 500 gf, Pi - the adhesive force measured in Le measuring machine, 300 gf / cm or more, preferably 30 0 gf / cm~ 1 000 gf / cm, more preferably 300 gf / cm~7 00 gf / cm. It is also possible to relatively evaluate these adhesion. For example, the adhesive strength of the pressure-sensitive adhesive layer containing a drug at a concentration which does not crystals precipitated in the adhesive layer, preferably an adhesive force of the adhesive layer when not containing a drug is taken as 1 100%, 40% of the adhesive strength, preferably 45% or more of adhesion, good Ri preferably adhesion of 50% or more, further 60% or more of the adhesion, more than 70% adhesion, more than 80% adhesion , 85% or more of the adhesion, more than 90% of the viscosity force application, preferably those having an adhesive strength of 95% or more.

The inside of the pressure-sensitive adhesive layer, crystals of the drug is distributed more than a surface on the side that adheres to the skin, is represented by the concentration obtained by subtracting the saturation concentration of the drug concentrations contained in the adhesive layer, the whole adhesive layer 2. 5-1 4.9% is contained as a crystal, and more preferably from 4.8 to 1 0%. 1 4. exceeds 9%, the cohesive force of the adhesive base agent itself beat low, it is feared to cause cohesive failure after application to the skin. Meanwhile, 2. The crystal of the drug when applied to the skin, the adhesive preparation is less than 5% dissolution, is absorbed in a state in which the drug is insufficient in the formulation of the present invention because the absorption of the drug is no longer sustained drugs can be incorporated into patch it is not particularly limited in its kind as long as drug crystallization in the adhesive exceeds the saturation concentration, specifically, for example, hypnotic 'sedatives (Fururazebamu, rilmazafone, etc.) , antipyretic anti-inflammatory agents (Butoru Fano Ichiru, perisoxal, etc.), excitement ■ stimulants (Metanfuwetamin, methylate Rufue two dating, etc.), psychoneurotic agent (Sita opening plums, Furupokisamin, squirrel piperidone, etc.), local anesthetics (Li lidocaine, professional force-in, etc.), urinary officer for the agent (Okishipuchinin, etc.), skeletal muscle relaxants (Chi The two gin, eperisone, Purijino one Lumpur, etc.), autonomic agents Karupuroniumu, neostigmine, etc.), anti-Parkinson's agents (Bae Rugori de, bromocriptine, Kishifue two Jill birds, Amanta Jin, Purami Bae Kiso Ichiru, Robiniroru, rotigotine, etc.), antihistamines

(Clemastine, diphenhydramine, etc.), bronchodilators (professional force Terol, etc.), inotropic agents (isoprenaline, dopamine, etc.), coronary vasodilators (Jiruchiaze-time, verapamil, etc.), peripheral vasodilators (two Kametato, tolazoline, etc.), 循ring organ agents (flunarizine, two Karujipin, benidipine, efonidipine, etc.), antiarrhythmic agents (propranolol, alprenolol, etc.), antiallergic agents

(Ketotifen, Azerasuchin etc.), vertiginous agent (betahistine, Jifuenido one Le etc.), serotonin receptor antagonistic antiemetics (ondansetron, palonosetron, etc.), narcotic analgesics (morphine, fentanyl or the like), non-steroid resistant anti-inflammatory agents (ketoprofen, diclofenac sodium, etc.), antibiotics (Eli Suromaishin, Kuroramufueniko Ichiru etc.), sex hormones (progesterone, estradiol, etc.), coronary vasodilators (isosorbide dinitrate, etc.), anti-dementia agents

(Donebe Jill, rivastigmine, etc.), expectorants (Anpurokiso Ichiru etc.), anti-anxiety drugs (tandospirone, buspirone, etc.). Among these, preferred Donebe Jill, tandospirone, Anpurokiso Ichiru, Risuperi Don, in particular, Risuperi pyrrolidone, a remarkable effect was observed in Donepe Jill. These drugs may be used pharmaceutically acceptable salts, the saturation concentration is different molecule types and salt form of the drug may be mixed in the adhesive. These molecular forms and salt forms of the drug can also be used in different crystal forms are mixed.

Pharmaceutically acceptable salts of the drug in the patch of the present invention, particularly limited Sarezu, the case of a basic drug may be also an organic salt or an inorganic salt, if no machine salt , hydrochloric acid, hydrobromic acid, etc. Kei acid. hydrochloride among them is used good Mashiku. Further, as long as it is an organic salt, acetic, Kuen acid, fumaric acid, Ma maleic acid and the like, acetates among this is preferably used. For acidic drugs, it includes alkali metal salts, sodium salt among them is preferably used.

In the present invention, in the case of acid addition salts forms of the drug is a pharmaceutically acceptable, preferably be contained a basic compound in a viscous Chakuzaiso, as basifying compound used, the basic low molecular compounds containing nitrogen (e.g., Torietano Ruamin, Jiisopuropano one Ruamin, diethanolamine and the like), a low molecular compound containing a basic nitrogen (e.g., aminoalkyl methacrylate copolymer poly Ma _ E, Poribiniruaseta one Rujechiruamino acetate, Poribinirupiri gin etc.), basic alkali metal salt (sodium acetate, potassium acetate, sodium borate, sodium carbonate, Kuen trisodium, sodium Kei acid), sodium hydroxide, and the like of potassium hydroxide can, among which, triethanolamine § Min, diisopropyl Pano one Ruamin, diethanolamine down, aminoalkyl methacrylate one Tokoporima _ E, Poribiniruaseta one distearate E chill § amino acetate, sodium acetate, sodium Kei acid, are preferred, such as sodium hydroxide, in particular, triethanolamine § Min, amino alkyl methacrylate rates copolymers _ E, sodium acetate, sodium hydroxide is preferred. These compounds are the plasticizer in the solution or the adhesive layer in the manufacturing process of the formulation, acts on chemically acceptable acid addition salts of the drug, by generating a molecule-and / or ion pair compound drugs, drug it is also possible to improve the skin permeability.

The solvent used at that time, a lower alcohol, toluene, acetic Echiru, hexane, the solvent used in the production of preparations such as cyclohexane, and the like plasticizer contained in the adhesive layer of the formulation. As the solvent or plasticizer, e.g., methanol, ethanol, isopropanol, toluene, acetic Echiru, hexanes cyclo, liquid paraffin, liquid polybutene, such as myristic acid isopropyl. Of these, methanol, ethanol, iso myristate propyl, liquid paraffin is preferred.

Or The pressure-sensitive adhesive layer of the present invention, drug crystals in the adhesive layer table surface on the side that adheres to the skin as described above if less distribution than drug crystals in the inside of the pressure-sensitive adhesive layer, to what formulations is not limited, as the adhesive base, if example embodiment, such as a polymer of high molecular or Akuriru ester of rubber and can and Mochiiruko.

As the polymer of the rubber-based, styrene one isoprene one styrene block copolymer polymer (hereinafter abbreviated as SIS), isoprene rubber, Poriisopuchiren (hereinafter, abbreviated as PIB), styrene-one butadiene one styrene block copolymer

(Hereinafter. Referred to as the S BS), styrene-one-butadiene rubber (hereinafter, abbreviated to S BR), polysiloxane and the like. Among these hydrophobic polymers, SIS, PIB are preferred, particularly SIS is preferred.

The polymer of Akuriru ester, Kishiruakurire one preparative to 2 _ Echiru, methyl § chestnut rate, butyl § chestnut rate, hydroxy E chill § chestnut Le - typified by preparative, cyclohexyl meth § chestnut rate, etc. to 2 _ Echiru that although the limitation is not a monomer of (meth) Akuri Le acid derivatives in Japanese long as copolymerized with at least one containing, shall be contained cyclohexyl § chestnut rate to 2 _ Echiru 50% or more is preferable. Specific examples of the adhesive, excipient Jiten 200 0 acrylic acid which is listed as a pressure-sensitive adhesive (Japan Pharmaceutical Excipients Council edit)

■ Akuriru acid Okuchiruesuteru copolymer, hexyl Akuriru acid 2 _ Echiru ■ Binirupirori pyrrolidone copolymer solution, an acrylic acid ester ■ vinyl acetate copolymers -, hexyl Akuriru acid 2 _ Echiru ■ cyclohexyl methacrylate 2 _ Echiru ■ main methacrylic acid dodecyl copolymer, Akuriru methyl ■ Akuriru acid 2 _ Echiru hexyl copolymer resin Emarujiyon, adhesives such Akuriru polymer contained in Akuriru resin alkanol § Min solution, DURO- TAK Akuriru adhesive Siri _ 's (National starch and Chemical Co., Ltd., for example 87 - 4098, 87 - 21 94, 87 - 9301, 87 - 2979, 87 - 2074, etc.), it is possible to use the Eudragit series (Higuchi Shokai), and the like. Such hydrophobic polymers may be used by mixing two or more kinds, the amount based on the weight of the total composition of these high molecules, taking into consideration the formation and sufficient permeability of the pressure-sensitive adhesive layer, preferably 5-9 0% by weight, still more preferably 1 0-7 0% by weight, and particularly preferably in particular 1 0-5 0% by weight of the amount.

[0020] The pressure-sensitive adhesive layer of the adhesive patch of the present invention may contain a tackifying resin in order to compensate for the adhesion to the skin. The tackifying resin may be used, rosin derived material (e.g., rosin, glycerin esters of rosin, hydrogenated rosin, glycerol ester of hydrogenated Logistics down, Pentaerisu rosin! Glycol ester and the like), alicyclic saturated hydrocarbon resin ( For example, Alcon P 1 0 0, Arakawa chemical Industries), aliphatic hydrocarbon resins (e.g., Quinton B 1 7 0, Nippon Zeon), terpene resin (e.g., Clearon P- 1 2 5 Yasuhara chemical), maleic acid resins and the like and the like. Of these glycerin esters of hydrogenated rosin, alicyclic saturated hydrocarbons resins, aliphatic hydrocarbon resins, terpene resins are preferred, especially using the alicyclic saturated hydrocarbon resin and terpene resin, constituting the adhesive base compatible to the amorphous portion of the amorphous polymers and semicrystalline polymers increase the glass transition temperature, to induce pressure-sensitive adhesive layer inside the drug crystallization, tends to obtain an adhesive patch having such structure . Amount based on the total composition of the adhesive layer of such a tackifier resin, in consideration of the sufficient adhesive strength and skin irritation upon peeling as patches, 5-7 0% by weight, preferably from 5 1-6 0% by weight, more preferably in an amount between 1 0-5 0 mass%.

[0021] Moreover, styrene one isoprene one styrene block copolymer as the adhesive base, a tackifier resin, alicyclic saturated hydrocarbon (e.g., Alcon P 1 0 0), or a combination of terpene resins are preferred, the SIS in the pressure-sensitive adhesive layer when: the ratio of tackifier resin, 1: 1 to 1: 1 0, preferably 1: 3 to 1: be formulated to be 9 ratio, the pressure-sensitive adhesive layer the formulation showing a crystal distribution can be suitably configuring the like in, and has a sufficient adhesion to the skin can be a patch preparation the skin permeability of the drug and excellent durability.

[0022] the pressure-sensitive adhesive layer of the present invention may contain a plasticizer if necessary. Plasticizers which may be used include petroleum oils (e.g., paraffinic process for oil, liquid paraffin, naphthenic process oils, aromatic process oils and the like), Sukuwaran, squalene, vegetable oils (e.g., cage part oil, collar key oil, castor oil, tall oil, Rakkasi oil), silicone oil, dibasic Sane ester (e.g., dibutyl phthalate, di-O-lipped Le phthalate), liquid rubber (e.g., liquid polybutene, liquid isoprene rubber), liquid fatty acid esters (e.g., isopropyl myristate, hexyl laurate, Jechiru sebacate, diisopropyl sebacate), diethylene glycol, Poryechi glycol, glycol salicylate, propylene glycol, dipropylene glycol Toriasechin, Kuen acid triethyl, Kurotami tons, etc. can be mentioned up. Among them, liquid paraffin, liquid polybutene, myristic Sani an isopropyl, Jechiru sebacate, hexyl laurate are preferred, in particular, liquid polybutene, Isopuropiru myristate, or flow Barafin is not preferable.

These components may be used in combinations of two or more, the amount based on the total composition tacky adhesive layer of such a plasticizer, the maintenance of sufficient cohesive force as a sufficient permeability and adhesive preparation in total in consideration, 1 0-7 0% by weight, preferably 1 0-6 0% by weight, more preferably in an amount between 1 0-5 0 wt%

[0023] the adhesive layer of the present invention, in addition to the above, may further contain an absorption enhancer, the absorption enhancer may be used, any compound absorption promoting effect has been observed in conventional skin But often, for example, fatty acids, saturated or unsaturated carbon number 6-2 0, fatty alcohols, saturated or unsaturated 2-1 0 carbon atoms, esters of fatty acids, saturated or unsaturated carbon atoms 6-2 0 kind, of saturated or unsaturated fatty acid 6-2 0 carbon atoms Ami de, ethers, aromatic organic acids, aromatic alcohols, aromatic organic acid esters or ethers (these may be saturated, unsaturated either good, also annular, may be linear branched), furthermore, lactic acid ester le acids, acetic acid esters, monoterpene compounds, sesquiterpene compounds, Azone (a zone), Azone (a zone) induction , Pirochiodekan, glycerol fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters (S pan system) polysorbate one preparative system (Twe en-based), polyethylene glycol fatty acid esters, polyoxyethylene hardened castor oils (HCO type ), polyoxyethylene alkyl ethers, sucrose fatty acid esters, vegetable oils and the like. Specifically, the force prills acid, turnip phosphoric acid, Kaburon acid, lauric acid, myristic acid, palmitic acid, stearic phosphate, isostearic acid, Orein acid, linoleic acid, linolenic acid, lauryl alcohol, myristyl alcohol, O Rail alcohol , isostearyl alcohol, cetyl alcohol, methyl laurate, hexyl laurate, lauric acid diethanolamine de, isopropyl myristate, myristyl myristate, Okuchirudodeshiru myristate, cetyl palmitate, Salici Le acid, methyl salicylate, salicylate ethylene glycol, Kei cinnamate, Kei cinnamate methyl, cresol, cetyl lactate, lauryl lactate, acetate Echiru acetate flop port pills, geraniol, thymol, eugenol, Terubineo Ichiru, I -men! Le, Poruneororu, d-limonene, isoeugenol, Isoporune ol, nerol, d I - camphor, glycerin monocaprylate, glycerin Rinmono force plate, glycerol monolaurate, glycerol mono O milled by wet one preparative, sorbitan monolaurate, sucrose monolaurate, polysorbate one DOO 2 0, propylene glycol, propylene glycol monolaurate, polyethylene Chirenguriko one Rumonoraure Ichito, polyethylene glycol one Rumonosuteare one preparative, polyoxyethylene lauryl ether, HCO_60, Pirochiodekan, Ori some oil and the recited particularly Orein acid, O rail alcohol, Lau Lil alcohol, isostearyl alcohol, lauric acid diethanolamine de, glycerol mono force Purireto, glycerol mono force , Glycerin Monooree Ichito, sorbitan monolaurate, propylene glycol one Rumonora urethane Ichito, polyoxyethylene lauryl ether, etc. is good preferable Pirochiodekan.

Such absorption enhancers may also be used in combinations of two or more, sticking sufficient permeability and redness of the formulation and to, in consideration of irritation or the like to the skin edema, etc., the overall composition of the adhesive layer based on the weight, 0. is preferably 0 to 2 0% by weight, more preferably 0. 0 5-1 0% by weight, particularly preferably in an amount of 0.1 to 5 mass% be able to.

[0024] The support layer of the present invention is adhesive patch is not particularly limited as long as it is suitable for supporting the adhesive layer, Ru can be used those stretchable or non-stretchable. For example fabric, it can be used nonwoven fabric, polyurethane, polyester, polyvinyl acetate, polychlorinated vinylidene, polyethylene, polyethylene terephthalate Ichito, secondary aluminum Umushito like, or their composite materials or the like. Upon the viscosity Chakuzaiso laminated to the support, have a water vapor permeability, also may either be hardly have. Even plaster of closed system (has little water vapor permeability) In the present invention, not reduce the skin permeability of the drug.

The thickness of the support of the patch of the present invention is preferably 2 0 m~ 8 0 m.

In 2 cases is less than O m patch to be difficult to apply to the skin may, 8 0 exceeds m flexibility is impaired, liable Do Ri a factor of reduction and primary skin irritation adhesion is there.

Furthermore, preparation area of the patch of the present invention, it is favorable preferable is 5 to 4 0 cm 2. 5 cm 2 under a is the absorption of the drug is insufficient sufficient therapeutic effect is not obtained, et al., 4 0 cm 2 by weight, the easier or summer peeling edge of the adhesive patch when affixing a long time, the support This is because in the easy tends to occur death Wa to.

[0025] adhesive patch of the present invention can be produced, for example, by the following method.

For example, an adhesive base containing a drug is heat-melted, after coating E a release liner or a support, to give the present preparations by affixing to the backing or the removable paper to. Further, hexane the adhesive base component comprising a drug toluene, to, acetate Echiru, a lower alcohol, is dissolved in an organic solvent of key Sun like cyclohexane, extension to drying the solvent at a predetermined temperature to release liner or support on after removal, it is possible to obtain this drug laminated to the support or release liner. More specifically, the pressure-sensitive adhesive component drug saturation solubility Ru 1 to 5 mass% der 0.1, lower alcohols drug so that the concentration with respect to the whole mass of the drug in the pressure-sensitive adhesive becomes 5-1 5 mass%, toluene , acetic Echiru, hexane, dissolved in an organic preparations such as hexane consequent opening, uniformly dispersed in the adhesive base mainly composed of a hydrophobic polymer, which is then extended to a release liner or support on after almost complete removal of the organic solvent agent is dried at a predetermined temperature, it is possible to produce the plaster of the present invention by causing Hariawa a support or a release liner. The thickness of the adhesive layer containing a drug was collected using this good Unishi is preferably 20 but more preferably m ~ 1 50 U m is about 50 m to 1 20 m, unless not extremely thick <limit no.

BRIEF DESCRIPTION OF THE DRAWINGS

[0026] FIG. 1 is an illustration of a cross-section of the patch of the present invention.

FIG. 2 is the patches of Examples 2 and 3 of the present invention, and after attaching a patch of Comparative Example 7, a graph illustrating results of measuring the skin permeation rate at 24 hours

[0027] In addition the features of the present invention will be described in more detail in Example. These various modifications are possible in the scope not departing from the technical idea of ​​the present invention. Note that in real 施例, "%" is intended to mean all mass%.

Example 1

[0028] was produced patch of the composition 9. below containing 0% Donepe Jill as a drug.

■ SIS: tackifying resin = 1: 1

Donepe Jill 9.0%

SIS 2 1. 0% Poriisopuchiren 1 4.9% alicyclic saturated hydrocarbon resin (Arcon P _ 1 00) 2 1. 0% Liquid paraffin 27.1% Orein acid 7.0%

1 100% Donebe Jill, after well pulverized and mixed to Orein acid and flow / Ruffin, this SI s, Poriisopuchiren to give 撹 拌 dissolved solution by adding tackifying resins, and toluene. After coating the thus-obtained solution onto a release liner, the solvent was removed by drying, to form a pressure-sensitive adhesive layer having a thickness of 1 OO m. It was Awa bond the polyester film to a support (S cotchpak 9732) and cut into a predetermined size to obtain a patch. Patches, was put into a moisture-proof packaging bag, and subjected to the test described below after storage 2 weeks at room temperature.

Example 2

It was produced plaster of the following composition to 9. containing 0% hydrochloride Donepe Jill as a drug.

SIS: tackifying resin = 1 3

Hydrochloric acid Donepe Jill 9.0%

SIS 1 1. 8% Poriisopuchiren 1 2.6% alicyclic saturated hydrocarbon resin (Arcon P- 1 00) 35. 4% Liquid paraffin 1 8.9% Sodium acetate 5.3% Orein acid 7.0%

To obtain a patch 1 100% Example 1 and same manufacturing method.

Example 3

The plaster of the following composition to 9. containing 0% Donepe Jill as a drug was prepared

SIS: tackifier resin = 1: 5

Donepe Jill 9. 0% SIS 8. 7% Poriisopuchiren 1 0.3% alicyclic saturated hydrocarbon resin (Arcon P- 1 00) 43. 3% Liquid paraffin 21.7% Orein acid 7.0%

To obtain a patch 1 100% Example 1 and same manufacturing method.

Example 4

[0031] and manufacture the plaster of the following composition containing tandospirone 1 0.0% as a drug.

■ SIS: tackifying resin = 1: 3.4

Tandospirone 1 0. 0% SIS 1 4. 4%

DURO-TAK 87-4098 1 0. 0% alicyclic saturated hydrocarbon resin (Arcon P _ 1 00) 48. 6% liquid paraffin 1 2.0% Propylene glycol monolaurate 5.0%

To obtain a patch 1 100% Example 1 and same manufacturing method.

Example 5

[0032] was produced plaster of the following composition containing Donepe Jill 1 0.0% as a drug.

■ SIS: tackifier resin = 1: 6.3

Donepe Jill 1 0.0%

SIS 7. 7%

DURO-TAK 87-4098 1 2. 0% terpene resin (Clearon P- 1 25) 48. 6% Liquid paraffin 1 6.7% glycerol monolaurate 5.0% 1 100% Example 1 and same manufacturing method in was carried out to obtain an adhesive patch.

Example 6

The pasting agent of the following composition containing 1 0.0% a Kuen acid tandospirone as a drug was prepared.

■ SIS: tackifier resin = 1: 9

Kuen acid tandospirone 1 0. 0% SIS 5. 4%

DURO-TAK 87-4098 1 0. 0% terpene resin (Clearon P- 1 25) 48. 6% liquid paraffin 1 2.0% acetic acid 4.7% Sodium acetate 4.3% Pirochiodekan 5.0%

To obtain a patch 1 100% Example 1 and same manufacturing method.

[Comparative Example 1]

It was prepared analogously to patch the composition shown below in Example 1

Donepe Jill 1 5.0%

D uro - TAK 87-251 6 69. 0% Poriisopuchiren 1 0.0% palmitic acid 3.0% cetyl palmitate 3.0%

1 100%

[Comparative Example 2]

The patch of the composition shown below was prepared in the same manner as in Example 1.

Donepe Jill 25.0%

D uro - T ak 87-251 6 70. 5% palmitic acid 3.0% lauric acid diethanolamine de 1.5%

1 100%

[0036] [Comparative Example 3]

It was prepared analogously to patch the composition shown below in Example 1

Donepe Jill 1 5.0%

D uro - T ak 87-251 6 79. 5% cetyl palmitate 3.0% benzyl alcohol 2.0% lauric acid diethanolamine de 0.5%

1 100%

[0037] [Comparative Example 4]

The patch of the composition shown below was prepared in the same manner as in Example 1 (

Tandospirone 20.0%

D uro - T ak 87- 21 94 65. 0% Isopropyl myristate 1 5.0%

1 100%

[0038] [Comparative Example 5]

It was prepared analogously to patch the composition shown below in Example 1

SIS: tackifier resin = 1: 2.4

(Donepe No Jill 0. 0%) SIS 1 8. 5% Poriisopuchiren 3% alicyclic saturated hydrocarbon resin (Arcon P _ 1 00) 44. 2% Liquid paraffin 27.0% Orein acid 3.0%

100%

[0039] The adhesive patch of the composition shown in Comparative Example 6 below was prepared in the same manner as in Example 1

SIS: tackifier resin = 1: 2.4

Donepe Jill 0. 3% SIS 1 8. 4% Poriisopuchiren 3% alicyclic saturated hydrocarbon resin (Arcon P _ 1 00) 44. 0% Liquid paraffin 27.0% Orein acid 3.0%

1 100%

[Comparative Example 7]

It was prepared analogously to patch the composition shown below in Example 1

SIS: tackifier resin = 1: 2.4

Hydrochloride Donepe Jill 5. 0% SIS 1 6. 0% Poriisopuchiren 6.8% alicyclic saturated hydrocarbon resin (Arcon P _ 1 00) 38. 8% Liquid paraffin 27.4% Sodium acetate 3.0% sorbitan monolaurate Ichito 3.0%

1 100%

[Test Example 1]

Hairless mouse skin permeation test

Stripping the hairless mouse dorsal skin, the dermis side was the receptor layer side, it was attached to the 37 ° C flow-through cell in which warm water is circulated through the outer peripheral portion (5 cm 2). Example stratum corneum side 1-6, and the resulting adhesive patch adhered to in Comparative Example 1 to 7 with saline to the receptor layer, every two hours at a speed of 5 m l / Time (hr) sampling was carried out up to 24 hours. Receptor solution obtained for each time measure the flow rate accurately, the drug concentration was measured by high performance liquid chromatography to calculate the permeation rate per hour, over-permeable skin per unit area at steady state to determine the speed. The results are shown in the following Table 1.

[Test Example 2]

Adhesion test

The adhesive strength of the plasters obtained in Examples 1-6 and Comparative Examples 1-4, were measured by Purobuta Kkutesuta and peel measuring machine. The results are shown in the following Table 1.

[Test Example 3]

Saturated solubility measurement test

After the formulation was varied amount of drug was prepared in each of Examples and Comparative Examples were stored for 2 weeks at room temperature, was confirmed drug crystals in the formulation by visual observation. From the result, the concentration of drug formulations crystal of the drug was confirmed was the drug saturated solubility definitive to the embodiments base and Comparative Examples base. The results are shown in the following Table 1.

[Test Example 4]

Observation of the crystal inside of the pressure-sensitive adhesive layer

The state of the drug crystals precipitated in the adhesive base was observed by the naked eye or an optical microscope to confirm the presence or absence of the precipitation of crystals. The results are shown in the following Table 1.

[Test Example 5]

Observation of the crystal of the adhesive surface

The state of the drug crystals precipitated in a predetermined area of ​​the adhesive surface was observed by the naked eye or an optical microscope, and evaluated on the basis of the index representing the precipitation state of the next crystal. The results are shown in the following Table 1.

© ■■ 'No precipitation of crystals in the pressure-sensitive adhesive surface

Is observed precipitation of sparsely crystal to 〇 ... the pressure-sensitive adhesive surface

X · ■ 'There precipitation of crystals in the pressure-sensitive adhesive surface ho 1]

¾ «

Qin ^ t X ...

The plaster of Comparative Examples 1-4, formulated for using Akuriru based adhesive only, increased solubility of the drug, the amount of more than 1 5% by mass to excessive formulated drug as an adhesive must, crystals are deposited on the release liner side of the surface of the adhesive layer, the effect of the present invention was not obtained. On the other hand, can have contact to Example 4-6 is an acrylic adhesive is used, are used in conjunction with SIS-based adhesives, the solubility of the drug for this purpose is lowered, the amount of drug 1 be sufficient at about 0 mass%, led to the effect of the present invention can be obtained.

Comparative Example 5, in which the drug showed adhesive force when not blended, the adhesive strength of the pressure-sensitive adhesive of the present invention shown in Examples 1 6, adhesive strength by incorporation of the drug is somewhat reduced , Note that retains sufficient adhesive strength was shown. In Comparative Example 6 is an example in the amount of the drug is too small, the maximum skin permeation rate, it can be seen that it is impossible to produce satisfactory results. Comparative Example 7 likewise adhesion by blending the drug slightly degraded, but the crystals precipitated in the inside of the pressure-sensitive layer was observed, in the maximum skin permeation rate when the amount of the drug is 5% by mass, sufficient such values ​​were obtained. Also when stored for 2 weeks at room temperature (2 5 ° C), the analysis and out of the crystals was observed immediately after preparation to the release liner side of the surface of the adhesive layer was observed.

[Test Example 5]

Hairless mouse skin permeation test

In the same manner as in Test Example 1, using the patch, and the ratio Comparative Examples 7 of the patch described in Examples 2 and 3, after 1 hour, 3 hours, 5 hours, 7 hours, 9:00 after while, 1 hour later, after 1 3 hours, after 1 5 hours, after 1 7 hours, 1 9 hours, 2 1 hour after, and were measured respective skin permeation rate after 2 3 hours.

The result is shown in figure 2. 2, the horizontal axis represents time (hour) and the vertical axis indicates skin permeation speed of (g / cm 2 / hr) . Black circle in FIG. 2 (writing) shows a case of the adhesive patch of Example 2, filled squares (land) shows the case of the adhesive patch of Example 3, open circle (〇) is affixed in Comparative Example 7 It shows the case of the agent, respectively.

As a result, after starting the patches of Examples 2 and 3 of the test the invention, about 1 to 2 hours after skin permeation rate until after 2 3 hours but been made can be kept substantially constant, Comparative Example 7 after start of the patch test, after reaching a maximum at about 9_ 1 hour, reduced skin permeation rate, it was shown that there is no persistence.

The cumulative permeation amount up these 24 hours, respectively,

Patch 302 of Example 2; U g / C m2,

Patch 289 of Example 3; U g / C m2,

Patch 203 of Comparative Example 7; U g / cm 2,

Met.

Industrial Applicability

The present invention has sufficient adhesive strength to adhere for 24 hours to the skin, excellent skin absorbability of drug product, there is provided a patch to have sustained the efficacy, the drug exhibits a stable therapeutic effect, safe as a medicament are those useful and has industrial applicability.

Claims

The scope of the claims
[1] In the adhesive patch comprising an adhesive layer on one surface of a support, pressure-sensitive adhesive layer contains a drug in excess of 5 wt% in a dissolved state and a crystalline state, and the drug in a crystalline state in the adhesive layer is pressure-sensitive patch skin Te side of the pressure-sensitive adhesive layer surface odor adhering to, characterized by less distribution than the support side of the adhesive layer.
[2] In the surface on the side that adheres to the skin of the adhesive layer, the adhesive patch according to claim 1, characterized that no drug in the crystalline state is not exist.
[3] In the pressure-sensitive adhesive layer, adhesive patch according to paragraph 1 or claim 2, wherein the drug present in the crystalline state is larger than the drug that is present in a dissolved state.
[4] drug contained in the adhesive layer is, Donepe Jill, tandospirone, Anburoki sole, and Risuperi Don, as well as at least one selected from the group ing these pharmaceutically acceptable salts patch according to any one of claims 1 through Section third term.
[5] the adhesive layer, a styrene - isoprene - styrene block copolymer, and claims, characterized in that it contains at least one tackifying resin selected from the group consisting of alicyclic saturated hydrocarbon and terpene resins patch according to any one of the ranges the first to fourth terms.
Isoprene - - [6] styrene contained in the adhesive layer blending ratio of styrene block copolymer tackifying resin is 1: 1 to 1: any of claims paragraph 1 - paragraph 5 1 0 patch of crab described.
PCT/JP2007/001104 2006-10-11 2007-10-11 Crystal-containing adhesive preparation WO2008044336A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2006-277367 2006-10-11
JP2006277367 2006-10-11

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP2008538566A JP5243254B2 (en) 2006-10-11 2007-10-11 Crystal-containing patch

Publications (1)

Publication Number Publication Date
WO2008044336A1 true true WO2008044336A1 (en) 2008-04-17

Family

ID=39282548

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2007/001104 WO2008044336A1 (en) 2006-10-11 2007-10-11 Crystal-containing adhesive preparation

Country Status (2)

Country Link
JP (1) JP5243254B2 (en)
WO (1) WO2008044336A1 (en)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009145177A1 (en) * 2008-05-30 2009-12-03 日東電工株式会社 Donepezil-containing patch preparation and packaging thereof
WO2009145269A1 (en) * 2008-05-30 2009-12-03 エーザイ・アール・アンド・ディー・マネジメント株式会社 Transdermal preparation
JP2011522019A (en) * 2008-06-02 2011-07-28 イギリス国The Secretary Of State For Defence In Her Britannic Majesty’S Government Of The Uneted Kingdom Of Great Britain And Northern Ireland Transdermal drug delivery device
WO2011136283A1 (en) * 2010-04-28 2011-11-03 久光製薬株式会社 Skin irritation suppressant and transdermal preparation
WO2012016569A1 (en) 2010-08-05 2012-02-09 Conrig Pharma Aps Deuterated tandospirone derivatives as 5-ht1a receptor agonists
WO2012043801A1 (en) * 2010-09-30 2012-04-05 積水メディカル株式会社 Patch
EP2491931A1 (en) * 2009-10-21 2012-08-29 Teikoku Seiyaku Co., Ltd. Transdermally absorbable donepezil-containing preparation
JP2014502639A (en) * 2011-01-12 2014-02-03 タイワン バイオテック カンパニー リミテッドTaiwan Biotech Co.,Ltd A method of treatment of donepezil transdermal patch and Alzheimer's disease
JP5415645B1 (en) * 2013-06-28 2014-02-12 久光製薬株式会社 A method of manufacturing a patch, patch and package
JP2014508728A (en) * 2010-12-24 2014-04-10 サムヤン バイオファーマシューティカルズ コーポレイション Transdermal preparation containing rivastigmine
WO2014181840A1 (en) * 2013-05-08 2014-11-13 株式会社 ケイ・エム トランスダーム Adhesive patch
JP2015522012A (en) * 2012-07-05 2015-08-03 エスケー ケミカルス カンパニー リミテッド Percutaneous absorption preparation containing rotigotine (Transdermalcompositioncomprisingrotigotine)
WO2016103999A1 (en) * 2014-12-26 2016-06-30 ニチバン株式会社 Package for patch and packaging method
US9987361B1 (en) 2014-12-29 2018-06-05 Noven Pharmaceuticals, Inc. Compositions and method for sustained drug delivery by active transdermal technology

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108135860A (en) * 2015-06-22 2018-06-08 考里安国际公司 Transdermal adhesive composition comprising a poorly soluble therapeutic agent

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997014411A1 (en) * 1995-10-17 1997-04-24 Nitto Denko Corporation Percutaneous tulobuterol preparation and process for producing the same
WO2003032960A1 (en) * 2001-10-17 2003-04-24 Hisamitsu Pharmaceutical Co., Inc. Percutaneous absorption preparations
WO2005117886A1 (en) * 2004-06-01 2005-12-15 Hisamitsu Pharmaceutical Co., Inc. Adhesive patch
JP2005350373A (en) * 2004-06-08 2005-12-22 Nitto Denko Corp Crystal coexistence-type endermic preparation and method for producing the same
JP2006248996A (en) * 2005-03-10 2006-09-21 Nitto Denko Corp Percutaneous absorption type cataplasm
JP2007302582A (en) * 2006-05-09 2007-11-22 Hisamitsu Pharmaceut Co Inc Percutaneously absorbable donepezil preparation

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4986411B2 (en) * 2004-06-01 2012-07-25 久光製薬株式会社 Patch
JP5075334B2 (en) * 2004-11-22 2012-11-21 久光製薬株式会社 Drug-containing patch

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997014411A1 (en) * 1995-10-17 1997-04-24 Nitto Denko Corporation Percutaneous tulobuterol preparation and process for producing the same
WO2003032960A1 (en) * 2001-10-17 2003-04-24 Hisamitsu Pharmaceutical Co., Inc. Percutaneous absorption preparations
WO2005117886A1 (en) * 2004-06-01 2005-12-15 Hisamitsu Pharmaceutical Co., Inc. Adhesive patch
JP2005350373A (en) * 2004-06-08 2005-12-22 Nitto Denko Corp Crystal coexistence-type endermic preparation and method for producing the same
JP2006248996A (en) * 2005-03-10 2006-09-21 Nitto Denko Corp Percutaneous absorption type cataplasm
JP2007302582A (en) * 2006-05-09 2007-11-22 Hisamitsu Pharmaceut Co Inc Percutaneously absorbable donepezil preparation

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5208209B2 (en) * 2008-05-30 2013-06-12 日東電工株式会社 Adhesive preparation containing donepezil and package
WO2009145269A1 (en) * 2008-05-30 2009-12-03 エーザイ・アール・アンド・ディー・マネジメント株式会社 Transdermal preparation
JP5421252B2 (en) * 2008-05-30 2014-02-19 エーザイ・アール・アンド・ディー・マネジメント株式会社 Percutaneous absorption preparation
CN102046171B (en) 2008-05-30 2013-06-19 日东电工株式会社 Transdermal preparation
WO2009145177A1 (en) * 2008-05-30 2009-12-03 日東電工株式会社 Donepezil-containing patch preparation and packaging thereof
JP2011522019A (en) * 2008-06-02 2011-07-28 イギリス国The Secretary Of State For Defence In Her Britannic Majesty’S Government Of The Uneted Kingdom Of Great Britain And Northern Ireland Transdermal drug delivery device
EP2491931A1 (en) * 2009-10-21 2012-08-29 Teikoku Seiyaku Co., Ltd. Transdermally absorbable donepezil-containing preparation
EP2491931A4 (en) * 2009-10-21 2013-06-12 Teikoku Seiyaku Kk Transdermally absorbable donepezil-containing preparation
CN102858372A (en) * 2010-04-28 2013-01-02 久光制药株式会社 Skin irritation suppressant and transdermal preparation
WO2011136283A1 (en) * 2010-04-28 2011-11-03 久光製薬株式会社 Skin irritation suppressant and transdermal preparation
JP5654006B2 (en) * 2010-04-28 2015-01-14 久光製薬株式会社 Skin irritation inhibitors and transdermal formulations
WO2012016569A1 (en) 2010-08-05 2012-02-09 Conrig Pharma Aps Deuterated tandospirone derivatives as 5-ht1a receptor agonists
JP5850371B2 (en) * 2010-09-30 2016-02-03 積水メディカル株式会社 Patch
WO2012043801A1 (en) * 2010-09-30 2012-04-05 積水メディカル株式会社 Patch
JP2014508728A (en) * 2010-12-24 2014-04-10 サムヤン バイオファーマシューティカルズ コーポレイション Transdermal preparation containing rivastigmine
JP2014502639A (en) * 2011-01-12 2014-02-03 タイワン バイオテック カンパニー リミテッドTaiwan Biotech Co.,Ltd A method of treatment of donepezil transdermal patch and Alzheimer's disease
JP2015522012A (en) * 2012-07-05 2015-08-03 エスケー ケミカルス カンパニー リミテッド Percutaneous absorption preparation containing rotigotine (Transdermalcompositioncomprisingrotigotine)
WO2014181840A1 (en) * 2013-05-08 2014-11-13 株式会社 ケイ・エム トランスダーム Adhesive patch
JP5415645B1 (en) * 2013-06-28 2014-02-12 久光製薬株式会社 A method of manufacturing a patch, patch and package
WO2016103999A1 (en) * 2014-12-26 2016-06-30 ニチバン株式会社 Package for patch and packaging method
US9987361B1 (en) 2014-12-29 2018-06-05 Noven Pharmaceuticals, Inc. Compositions and method for sustained drug delivery by active transdermal technology

Also Published As

Publication number Publication date Type
JPWO2008044336A1 (en) 2010-02-04 application
JP5243254B2 (en) 2013-07-24 grant

Similar Documents

Publication Publication Date Title
US5124157A (en) Method and device for administering dexmedetomidine transdermally
US6448303B1 (en) Hot melt adhesives for dermal application
US20040096491A1 (en) Adhesive patch
US20020119187A1 (en) Composition for the transdermal delivery of fentanyl
US5843472A (en) Transdermal drug delivery sytem for the administration of tamsulosin, and related compositions and methods of use
US6316022B1 (en) Transdermal compositions containing low molecular weight drugs which are liquid at room temperatures
US20050019385A1 (en) Composition and method for controlling drug delivery from silicone adhesive blends
US20050260255A1 (en) Adhesive patch
WO2012065740A1 (en) Transdermal therapeutic system comprising buprenorphine
JPH09315957A (en) Device for percutaneous therapy
JP2003313122A (en) Bisoprolol-containing plaster
EP2016941A1 (en) Transdermally absorbable donepezil preparation
WO2003032960A1 (en) Percutaneous absorption preparations
WO2005011662A1 (en) Adhesive patch
JPH11302161A (en) Transdermal plaster preparation
WO2006093139A1 (en) Transdermally absorbable preparation
JP2006169238A (en) Medicament-containing patch
US20040202710A1 (en) Microreservoir system based on polysiloxanes and ambiphilic solvents
JP2007284378A (en) Preparation containing selective serotonin reuptake inhibition component
WO1996040085A2 (en) Transdermal compositions containing low molecular weight drugs which are liquid at room temperatures
US20070264319A1 (en) Transdermal Antiemesis Delivery System, Method and Composition Therefor
WO2009152777A1 (en) A stable and release-controlled rasagiline transdermal patch and method of preparation thereof
WO2005102393A1 (en) Patch for external use with elevated content of absorption promoter in pressure-sensitive adhesive base
JP2007099759A (en) Adhesive preparation containing bisoprolol
WO2009110351A1 (en) Transdermally absorbable preparation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07827883

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2008538566

Country of ref document: JP

ENP Entry into the national phase in:

Ref document number: 2008538566

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct app. not ent. europ. phase

Ref document number: 07827883

Country of ref document: EP

Kind code of ref document: A1