CA2056653C - Preparation for transdermal drug administration - Google Patents
Preparation for transdermal drug administration Download PDFInfo
- Publication number
- CA2056653C CA2056653C CA002056653A CA2056653A CA2056653C CA 2056653 C CA2056653 C CA 2056653C CA 002056653 A CA002056653 A CA 002056653A CA 2056653 A CA2056653 A CA 2056653A CA 2056653 C CA2056653 C CA 2056653C
- Authority
- CA
- Canada
- Prior art keywords
- sensitive adhesive
- pressure
- local anesthetic
- preparation
- adhesive layer
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired - Lifetime
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- 238000001647 drug administration Methods 0.000 title claims abstract description 16
- 239000004820 Pressure-sensitive adhesive Substances 0.000 claims abstract description 54
- 239000003589 local anesthetic agent Substances 0.000 claims abstract description 53
- 239000010410 layer Substances 0.000 claims abstract description 44
- 239000000853 adhesive Substances 0.000 claims abstract description 9
- 230000001070 adhesive effect Effects 0.000 claims abstract description 7
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 claims description 20
- 229960004194 lidocaine Drugs 0.000 claims description 20
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 15
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 6
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 claims description 6
- 229940035674 anesthetics Drugs 0.000 claims description 4
- 239000003193 general anesthetic agent Substances 0.000 claims description 4
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 claims description 3
- 239000003522 acrylic cement Substances 0.000 claims description 3
- 125000005907 alkyl ester group Chemical group 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 229960003150 bupivacaine Drugs 0.000 claims description 3
- 229960002023 chloroprocaine Drugs 0.000 claims description 3
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 claims description 3
- 229960001747 cinchocaine Drugs 0.000 claims description 3
- PUFQVTATUTYEAL-UHFFFAOYSA-N cinchocaine Chemical compound C1=CC=CC2=NC(OCCCC)=CC(C(=O)NCCN(CC)CC)=C21 PUFQVTATUTYEAL-UHFFFAOYSA-N 0.000 claims description 3
- 229960003920 cocaine Drugs 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 229960002409 mepivacaine Drugs 0.000 claims description 3
- INWLQCZOYSRPNW-UHFFFAOYSA-N mepivacaine Chemical compound CN1CCCCC1C(=O)NC1=C(C)C=CC=C1C INWLQCZOYSRPNW-UHFFFAOYSA-N 0.000 claims description 3
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 3
- 238000006116 polymerization reaction Methods 0.000 claims description 3
- 229960001807 prilocaine Drugs 0.000 claims description 3
- MVFGUOIZUNYYSO-UHFFFAOYSA-N prilocaine Chemical compound CCCNC(C)C(=O)NC1=CC=CC=C1C MVFGUOIZUNYYSO-UHFFFAOYSA-N 0.000 claims description 3
- 229960004919 procaine Drugs 0.000 claims description 3
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 claims description 3
- 229960002372 tetracaine Drugs 0.000 claims description 3
- GKCBAIGFKIBETG-UHFFFAOYSA-N tetracaine Chemical compound CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 GKCBAIGFKIBETG-UHFFFAOYSA-N 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims 2
- 229940079593 drug Drugs 0.000 abstract description 18
- 239000003814 drug Substances 0.000 abstract description 18
- 230000003444 anaesthetic effect Effects 0.000 abstract description 12
- 239000000463 material Substances 0.000 abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000007787 solid Substances 0.000 description 11
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 10
- -1 poly(vinylidene chloride) Polymers 0.000 description 7
- 230000000694 effects Effects 0.000 description 4
- 229920002521 macromolecule Polymers 0.000 description 4
- 239000002674 ointment Substances 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000013508 migration Methods 0.000 description 3
- 230000005012 migration Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229920000728 polyester Polymers 0.000 description 3
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229920002367 Polyisobutene Polymers 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229920001400 block copolymer Polymers 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 230000002500 effect on skin Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 210000000245 forearm Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- GOXQRTZXKQZDDN-UHFFFAOYSA-N 2-Ethylhexyl acrylate Chemical compound CCCCC(CC)COC(=O)C=C GOXQRTZXKQZDDN-UHFFFAOYSA-N 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 241001269524 Dura Species 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 229920001328 Polyvinylidene chloride Polymers 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 239000012790 adhesive layer Substances 0.000 description 1
- 239000002998 adhesive polymer Substances 0.000 description 1
- 239000002390 adhesive tape Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000007334 copolymerization reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 238000009593 lumbar puncture Methods 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 239000003505 polymerization initiator Substances 0.000 description 1
- 229920000098 polyolefin Polymers 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
- A61P23/02—Local anaesthetics
-
- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
Abstract
Disclosed is a preparation for transdermal drug administration comprising a flexible backing layer and a pressure-sensitive adhesive layer containing a local anesthetic in an amount of 40-65 % by weight based on the total weight of the pressure-sensitive adhesive layer. Since the ratio of the amount of undissolved local anesthetic (Ac) to that of dissolved local anesthetic (As), Ac/As, in the pressure-sensitive adhesive layer is determined to be in the range of 0.1-1.8, the preparation for transdermal drug administration is superior in self-adhesiveness and leaves no adhesive material upon removal from the skin. In addition, burst-like release of the undissolved drug from the pressure-sensitive adhesive layer immediately after application to the skin permits rapid appearance of the anesthetic effect, which enables wide clinical application of the preparations of the present invention.
Description
20~fi~~3 SPECIFICATION
PREPARATION FOR TRANSDERMAL DRUG ADMINISTRATION
BACKGROUND OF THE INVENTION
The present invention relates to a preparation for transdermal drug administration which contains a local anesthetic as a medicinal ingredient.
There have been so far investigated various preparations aiming at transdermal administration of a local anesthetic, and some of them have been marketed as liquid- or ointment-form external preparations. However, application of such preparations to common integument poses problems such as difficulty in controlling the dose, possibility of staining clothes, and so on.
While there has been proposed an analgesic composition aiming at longer retention of the drug at a local site (Japanese Patent Publication No. 130540/1988), such a composition is within the category of liquid or ointment preparations intended for administration to mucous membrane, which is not entirely suitable for application to common integument.
Japanese Patent Publication No. 272521/1989 proposes a patch preparation for application to gum. This preparation has ,overcome the disadvantages of the conventional liquid or ointment preparations and has improved handling facility.
Still, this preparation is unsuitable for application to common integument since it is originally designed for application to gum and the application site is required to have much moisture in order to secure the preparation tightly on the site.
Also, there has been proposed an adhesive tape preparation as a device for transdermal administration of a local anesthetic (Japanese Patent Publication No. 299215/1989), which offers easy application and easy control of the dose. The self-adhesive matrix used therein comprises an adhesive material selected from among the group of polystyrene-butadiene) block copolymer, polystyrene-isoprene-stylene) block copolymer, high molecular weight polyisobutylene polymer, Iow molecular weight polyisobutylene polymer and ethylene-vinyl acetate copolymer, yet the use of such polymers or copolymers renders the rapid appearance of the anesthetic effect which is one of the expected properties of a local anesthetic unattainable.
Moreover, the self-adhesive matrix used therein comprises an adhesion-imparting agent, a fluidity-imparting agent and an antioxidant besides a local anesthetic as a medicinal ingredient, and such inclusion is not only uneconomical but also may present problems in pharmaceutical stability due to potential reaction between those agents and the medicinal ingredient.
Japanese Patent Publication No. 185713/1985 proposes a preparation for transdermal drug administration in which a transdermally absorbable drug is dispersed as recrystallized fine powder in a pressure-sensitive adhesive macromolecule copolymer and said percutaneously absorbable drug is contained in an amount corresponding to 1.2 times the saturation 205b6~3 solubility of the pressure-sensitive adhesive macromolecule copolymer, or more. This preparation permits easy handling, and easy control of the dose. Yet, according to the description, the amount of the transdermally absorbable drug relative to the pressure-sensitive adhesive macromolecule copolymer is 40 weight% or less, which hardly enables the local anesthetic effect to appear in a short time. For the effect to appear in a short time, it is necessary to let the drug release burst at the initial stage upon application, and the balance between this drug release and the adhesiveness to the skin depends on the proportion of the amount of the dissolved drug to that of the undissolved drug in the pressure-sensitive adhesive macromolecule copolymer. However, this patent gives no description in this regard.
SUMMARY OF THE INVENTION
The present inventors have conducted intensive studies for the purpose of resolving the problems mentioned above, and as a result, newly found that in a preparation for transdermal drug administration comprising a flexible backing layer and a pressure-sensitive adhesive layer formed thereon containing a local anesthetic, the drug release and absorbability via the skin are greatly influenced by the concentration of the local anesthetic in the pressure-sensitive adhesive layer, the ratio of the amount of the dissolved local anesthetic (As) to that of the undissolved local anesthetic (Ac) contained therein~
PREPARATION FOR TRANSDERMAL DRUG ADMINISTRATION
BACKGROUND OF THE INVENTION
The present invention relates to a preparation for transdermal drug administration which contains a local anesthetic as a medicinal ingredient.
There have been so far investigated various preparations aiming at transdermal administration of a local anesthetic, and some of them have been marketed as liquid- or ointment-form external preparations. However, application of such preparations to common integument poses problems such as difficulty in controlling the dose, possibility of staining clothes, and so on.
While there has been proposed an analgesic composition aiming at longer retention of the drug at a local site (Japanese Patent Publication No. 130540/1988), such a composition is within the category of liquid or ointment preparations intended for administration to mucous membrane, which is not entirely suitable for application to common integument.
Japanese Patent Publication No. 272521/1989 proposes a patch preparation for application to gum. This preparation has ,overcome the disadvantages of the conventional liquid or ointment preparations and has improved handling facility.
Still, this preparation is unsuitable for application to common integument since it is originally designed for application to gum and the application site is required to have much moisture in order to secure the preparation tightly on the site.
Also, there has been proposed an adhesive tape preparation as a device for transdermal administration of a local anesthetic (Japanese Patent Publication No. 299215/1989), which offers easy application and easy control of the dose. The self-adhesive matrix used therein comprises an adhesive material selected from among the group of polystyrene-butadiene) block copolymer, polystyrene-isoprene-stylene) block copolymer, high molecular weight polyisobutylene polymer, Iow molecular weight polyisobutylene polymer and ethylene-vinyl acetate copolymer, yet the use of such polymers or copolymers renders the rapid appearance of the anesthetic effect which is one of the expected properties of a local anesthetic unattainable.
Moreover, the self-adhesive matrix used therein comprises an adhesion-imparting agent, a fluidity-imparting agent and an antioxidant besides a local anesthetic as a medicinal ingredient, and such inclusion is not only uneconomical but also may present problems in pharmaceutical stability due to potential reaction between those agents and the medicinal ingredient.
Japanese Patent Publication No. 185713/1985 proposes a preparation for transdermal drug administration in which a transdermally absorbable drug is dispersed as recrystallized fine powder in a pressure-sensitive adhesive macromolecule copolymer and said percutaneously absorbable drug is contained in an amount corresponding to 1.2 times the saturation 205b6~3 solubility of the pressure-sensitive adhesive macromolecule copolymer, or more. This preparation permits easy handling, and easy control of the dose. Yet, according to the description, the amount of the transdermally absorbable drug relative to the pressure-sensitive adhesive macromolecule copolymer is 40 weight% or less, which hardly enables the local anesthetic effect to appear in a short time. For the effect to appear in a short time, it is necessary to let the drug release burst at the initial stage upon application, and the balance between this drug release and the adhesiveness to the skin depends on the proportion of the amount of the dissolved drug to that of the undissolved drug in the pressure-sensitive adhesive macromolecule copolymer. However, this patent gives no description in this regard.
SUMMARY OF THE INVENTION
The present inventors have conducted intensive studies for the purpose of resolving the problems mentioned above, and as a result, newly found that in a preparation for transdermal drug administration comprising a flexible backing layer and a pressure-sensitive adhesive layer formed thereon containing a local anesthetic, the drug release and absorbability via the skin are greatly influenced by the concentration of the local anesthetic in the pressure-sensitive adhesive layer, the ratio of the amount of the dissolved local anesthetic (As) to that of the undissolved local anesthetic (Ac) contained therein~
~U56653 Then, the inventors have eventually found that the preparation for transdermal drug administration of the present invention wherein the local anesthetic is contained in an amount within a certain range in a specific pressure-sensitive adhesive shows an excellent local anesthetic effect and adhesiveness to the skin, and also is easy to handle. This finding resulted in the completion of the invention.
That is, the present invention provides a preparation comprising a flexible backing layer and a pressure-sensitive adhesive layer formed on the backing layer, wherein a local anesthetic is contained in the pressure-sensitive adhesive layer in an amount of 40-65 ~ by weight based on the total Weight of the pressure-sensitive adhesive layer and the ratio of the amount of the undissolved local anesthetic (Ac) to that of the dissolved local anesthetic (As), Ac/As, is in the range of from 0.1 to 1.8.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is detailedly described in the following.
The backing layer used in the present invention is subject to no particular limitation as long as it is flexible and imperious to drugs. Examples thereof include films and sheets made of polyolefin, polyester, polyvinyl alcohol), polyvinyl chloride), poly(vinylidene chloride), polyamide, polytetrafluoroethylene, etc.; deposited metal films and sheets thereof; and laminated sheets using two kinds or more thereof, which are about 500 N,m or less, preferably 5-150 ~.m in thickness.
That is, the present invention provides a preparation comprising a flexible backing layer and a pressure-sensitive adhesive layer formed on the backing layer, wherein a local anesthetic is contained in the pressure-sensitive adhesive layer in an amount of 40-65 ~ by weight based on the total Weight of the pressure-sensitive adhesive layer and the ratio of the amount of the undissolved local anesthetic (Ac) to that of the dissolved local anesthetic (As), Ac/As, is in the range of from 0.1 to 1.8.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is detailedly described in the following.
The backing layer used in the present invention is subject to no particular limitation as long as it is flexible and imperious to drugs. Examples thereof include films and sheets made of polyolefin, polyester, polyvinyl alcohol), polyvinyl chloride), poly(vinylidene chloride), polyamide, polytetrafluoroethylene, etc.; deposited metal films and sheets thereof; and laminated sheets using two kinds or more thereof, which are about 500 N,m or less, preferably 5-150 ~.m in thickness.
The pressure-sensitive adhesive layer of the present invention contains and sustains the local anesthetic in an amount of 40-65 ~ by weight based on the total amount of the pressure-sensitive adhesive layer, and releases the drug in a short time to promote adsorption via the skin while securing the preparation of the present invention tightly on the skin.
In the present invention, the pressure-sensitive adhesive is preferably an acrylic pressure-sensitive adhesive of a copolymer of (meth)acrylic acid alkyl ester and (meth)acrylic acid in view of the adhesiveness to the skin, stability of a local anesthetic to be used, and migration and adsorption of the local anesthetic from the adhesive layer to the skin in a short time.
Examples of the (meth)acrylic acid alkyl esters which can be used for forming the copolymers for the acrylic pressure-sensitive adhesive with (meth)acrylic acid include those having an alkyl group of 4 to 13 carbon atoms, such as butyl (meth)acrylate, pentyl (meth)acrylate, hexyl (meth)acrylate, heptyl (meth)acrylate, octyl (meth)acrylate, nonyl (meth)acrylate, decyl (meth)acrylate, undecyl (meth)acrylate, dodecyl (meth)acrylate and tridecyl (meth)acrylate.
The (meth)acrylic acid alkyl ester of the present invention encompasses various isomers whose alkyl moiety is straight or branched, various isomers having different substitution sites and their derivatives.
Such acrylic pressure-sensitive adhesive has a high degree of polymerization, improved cohesiveness and ~U56653 adhesiveness, and permits stable retention of a local anesthetic in a large amount and migration of the local anesthetic to the skin in a short time after application.
It is desirable that the weight ratio of (meth)acrylic acid alkyl ester to (meth)acrylic acid contained in the acrylic pressure-sensitive adhesive be 65/35-99/1 in view of the balance between the adhesiveness to the skin cohesiveness.
In preparing the acrylic pressure-sensitive adhesive, another monomer may optionally replace a part of the above-mentioned monomers for the copolymerization to the degree that the efficacy of the drug and the adhesiveness to the skin are not impaired. Examples thereof include vinyl acetate, (meth)acrylic acid hydroxyalkyl ester, (meth)acrylic acid alkoxyalkyl ester, (meth)acrylic acid alkylaminoalkyl ester, (meth)acrylamide, derivatives thereof, N-vinylpyrrolidone and (meth)acrylonitrile.
The amount of the local anesthetic to be contained in the above-mentioned pressure-sensitive adhesive layer should be 40-65 ~ by weight based on the total weight of the pressure-sensitive adhesive layer, and the ratio of the amount of the undissolved local anesthetic (Ac) to that of the dissolved local anesthetic (As), Ac/As, in the pressure-sensitive adhesive layer should be in the range of 0.1-1.8.
Note that the undissolved local anesthetic means the crystalline precipitate or dispersed drug resulting from addition beyond the saturation solubility in the adhesive polymer, and the dissolved local anesthetic means the drug 2U5b653 existing in molecule dispersion or noncrystalline state in the polymer, which can be confirmed by a microscope examination or an X-ray diffractometry. where the Ac/As is below 0.1, the local anesthetic acts like a plasticizer to the acrylic adhesive in the pressure-sensitive adhesive layer of the present invention, resulting in gooey threads from the pressure-sensitive adhesive layer itself upon removal from the skin after application, which in turn results in remainder from the pressure-sensitive adhesive layer partially or in the entirety of the applied site on the skin, staining the common integument, and delayed appearance of the local anesthetic effect. On the other hand, where the Ac/As exceeds 1.8, self-adhesiveness of the pressure-sensitive adhesive layer decreases so that the layer cannot be adhered to the skin.
Where the Ac/As is in the range of 0.1-1.8, most favorably 0.6 or above, the local anesthetic is in part undissolved in the pressure-sensitive adhesive layer, which contributes to the improved cohesiveness of the pressure-sensitive adhesive. In addition, the presence of the undissolved local anesthetic in a rather large amount leads to burst of the drug release soon after the application, causing prompt migration of the drug in an amount necessary for the exertion of the effect upon application of the preparation, which will eventually assure rapid appearance of the anesthetic effect which is expected of a local anesthetic.
While the amount of the local anesthetic to be contained in the pressure-sensitive adhesive layer is determined to be in the range of from 40 to 65 ~ by weight 20~06~3 based on the total weight of the pressure-sensitive adhesive layer, it is preferably not less than 45 weight ~ to ensure the rapid appearance of the effect.
The local anesthetic to be used in the present invention is selected from among amide type anesthetics and ester type anesthetics, and preferably selected from among cocaine, procaine, chloroprocaine, tetracaine, lidocaine, mepivacaine, prilocaine, bupivacaine and dibucaine.
The preparation of the present invention contains one or more of the above-mentioned local anesthetics in the pressure-sensitive adhesive layer.
The thickness of the pressure-sensitive adhesive layer containing local anesthetic is preferably in the range of from 5 to 30 ~,cm in view of the short application time and economic feasibility.
The preparation of the present invention has the components as descried above and contains a local anesthetic in a proportion of 40-65 weight ~ in the pressure-sensitive adhesive layer. Since the ratio of the amount of the undissolved local anesthetic (Ac) to that of the dissolved local anesthetic (As), Ac/As, in the pressure-sensitive adhesive layer is determined to be in the range of 0.1-1.8, the preparation of the present invention is superior in self-adhesiveness and leaves no adhesive material upon removal from the skin. In addition, burst-like release of the undissolved drug from the pressure-sensitive adhesive layer immediately after application to the skin permits rapid appearance of the local anesthetic effect, which makes it possible to be A
utilized for the pre-operational treatment of needle indwelling in a vein or an artery, dura or lumbar puncture, arthrocentesis and minor dermic operation. As a result, pain of patients can be vastly reduced and many clinical applications become possible.
The present invention is hereinbelow described in detail by illustrating working examples. The present invention is not strictly limited to those examples but can be modified in various manners.
In the following description, parts) and ~ refer to parts) by weight and weight ~, respectively.
Example 1 2-Ethylhexyl acrylate (95 parts) and acrylic acid (5 parts) were charged in a flask under an inert gas atmosphere and azobisisobutyronitrile (0.3 part) was added thereto as a polymerization initiator. The polymerization was conducted in ethyl acetate while maintaining the temperature at 60°C to give the acrylic pressure-sensitive adhesive solution A
(solids: 41.2 $).
Thereto was added lidocaine, wherein the ratio (w/w) of lidocaine to the solids was 60/40, after which ethyl acetate was added to give a solution containing 35 ~ solids.
The thus-obtained solution was coated on a polyester release paper to make the thickness after drying become 20 ~C.m, which was then dried at 100°C for 5 minutes to form a pressure-sensitive adhesive layer containing 60 ~ lidocaine. After the obtained pressure-sensitive adhesive layer containing 60 lidocaine was adhered onto a 12 ~m-thick polyester backing layer, it was allowed to stand at room temperature for 24 hours to crystallize the lidocaine in the pressure-sensitive adhesive layer, by which a preparation of the present invention was obtained (Ac/As was about 1.6).
Example 2 To the acrylic pressure-sensitive adhesive solution A as used in Example 1 was added lidocaine, wherein the ratio (w/w) of lidocaine to the solids was 50/50, to give a solution containing 30 ~ solid.
The obtained solution was treated in the same manner as in Example 1 to give a preparation of the present invention (Ac/As was about 0.7).
Example 3 To the acrylic pressure-sensitive adhesive solution A as used in Example 1 was added lidocaine, wherein the ratio (w/w) of lidocaine to the solids was 50/50, and ethyl acetate was further added to give a solution containing 33 $ solids.
The obtained solution was treated in the same manner as in Example 1 to give a preparation of the present invention (Ac/As was about 1.2).
Comparative Example 1 To the acrylic pressure-sensitive adhesive solution A as used in Example 1 was added lidocaine, wherein the ratio (w/w) of lidocaine to the solids was 70/30, and ethyl acetate was further added to give a solution containing 30 $ solids.
The obtained solution was treated in the same manner as in Example 1 to give a preparation containing a local anesthetic (Ac/As was about 2.0).
Comparative Example 2 To the acrylic pressure-sensitive adhesive solution A as used in Example 1 Was added lidocaine, wherein the ratio (w/w) of lidocaine to the solids was 20/80 and ethyl acetate was further added to give a solution containing 25 $ solids.
The obtained solution was treated in the same manner as in Example 1 to give a preparation containing a local anesthetic (Ac/As was 0).
Reference Example 1 Carboxyvinyl polymer (Wako Junyaku Kogyo, Hibis Waco*105, 2.6 weight ~), ethanol (40 weight ~) and purified water (47.4 weight ~) were mixed thoroughly to dissolve the carboxyvinyl polymer. Thereto was added lidocaine (10 weight and the mixture was mixed to dissolve lidocaine, by which there was obtained a gel ointment containing lidocaine.
Experiment Example 1 A 3.17 x 3.17 (10 cm2) specimen cut out from each of the preparations as obtained in Examples 1-3 and Comparative Examples 1 and 2 was adhered onto the human inner forearm and maintained for 30 minutes. The adhesiveness, remaining *Trade-mark 2056~~3 adhesive material upon removal from the skin, and anesthetic effect were examined. The effect was examined by the pin pricking method. That is, after 30 minutes of adhesion, the specimen was removed and an intracutaneous pin was pricked on the applied area to see the degree of pain, based on which numerical evaluation of the anesthetic effect was made according to the evaluation criteria.
As regards the Reference Example, 0.1 g of the lidocaine-containing gel ointment obtained therein was applied onto the area of 3.15 x 3.15 cm of the human inner forearm, and the similar experiment conducted.
was Anesthetic effect evaluation criteria 0 . no ain was sensedon 5 points.
p 1 . painwas sensed 1 of 5 points.
on 2 . painwas sensed 2 of 5 points.
on 3 . painwas sensed 3 of 5 points.
on 4 . painwas sensed 4 of 5 points.
on . painwas sensed 5 points.
on The results are summarized in Table 1.
~~~6~~3 Table 1 Adhesiveness Adhesive material Anesthetic to the skin remaining on the skin effect Examp 1 a 1 Q none 0.
Example 2 Q partial remainder around 1.6 the adhesion site Examp 1 a 3 Q none 1.
Comp. Ex. 1 x adhesion unattainable due to -the residual adhesive material on the release paper Comp. Ex. 2 Q remainder on the entire site 3.1 Ref. Ex. - - 4.1 Q . good adhesion x . adhesion unattainable Note that the anesthetic effect of the Reference Example was 1.9 after 3 hours' application.
In the present invention, the pressure-sensitive adhesive is preferably an acrylic pressure-sensitive adhesive of a copolymer of (meth)acrylic acid alkyl ester and (meth)acrylic acid in view of the adhesiveness to the skin, stability of a local anesthetic to be used, and migration and adsorption of the local anesthetic from the adhesive layer to the skin in a short time.
Examples of the (meth)acrylic acid alkyl esters which can be used for forming the copolymers for the acrylic pressure-sensitive adhesive with (meth)acrylic acid include those having an alkyl group of 4 to 13 carbon atoms, such as butyl (meth)acrylate, pentyl (meth)acrylate, hexyl (meth)acrylate, heptyl (meth)acrylate, octyl (meth)acrylate, nonyl (meth)acrylate, decyl (meth)acrylate, undecyl (meth)acrylate, dodecyl (meth)acrylate and tridecyl (meth)acrylate.
The (meth)acrylic acid alkyl ester of the present invention encompasses various isomers whose alkyl moiety is straight or branched, various isomers having different substitution sites and their derivatives.
Such acrylic pressure-sensitive adhesive has a high degree of polymerization, improved cohesiveness and ~U56653 adhesiveness, and permits stable retention of a local anesthetic in a large amount and migration of the local anesthetic to the skin in a short time after application.
It is desirable that the weight ratio of (meth)acrylic acid alkyl ester to (meth)acrylic acid contained in the acrylic pressure-sensitive adhesive be 65/35-99/1 in view of the balance between the adhesiveness to the skin cohesiveness.
In preparing the acrylic pressure-sensitive adhesive, another monomer may optionally replace a part of the above-mentioned monomers for the copolymerization to the degree that the efficacy of the drug and the adhesiveness to the skin are not impaired. Examples thereof include vinyl acetate, (meth)acrylic acid hydroxyalkyl ester, (meth)acrylic acid alkoxyalkyl ester, (meth)acrylic acid alkylaminoalkyl ester, (meth)acrylamide, derivatives thereof, N-vinylpyrrolidone and (meth)acrylonitrile.
The amount of the local anesthetic to be contained in the above-mentioned pressure-sensitive adhesive layer should be 40-65 ~ by weight based on the total weight of the pressure-sensitive adhesive layer, and the ratio of the amount of the undissolved local anesthetic (Ac) to that of the dissolved local anesthetic (As), Ac/As, in the pressure-sensitive adhesive layer should be in the range of 0.1-1.8.
Note that the undissolved local anesthetic means the crystalline precipitate or dispersed drug resulting from addition beyond the saturation solubility in the adhesive polymer, and the dissolved local anesthetic means the drug 2U5b653 existing in molecule dispersion or noncrystalline state in the polymer, which can be confirmed by a microscope examination or an X-ray diffractometry. where the Ac/As is below 0.1, the local anesthetic acts like a plasticizer to the acrylic adhesive in the pressure-sensitive adhesive layer of the present invention, resulting in gooey threads from the pressure-sensitive adhesive layer itself upon removal from the skin after application, which in turn results in remainder from the pressure-sensitive adhesive layer partially or in the entirety of the applied site on the skin, staining the common integument, and delayed appearance of the local anesthetic effect. On the other hand, where the Ac/As exceeds 1.8, self-adhesiveness of the pressure-sensitive adhesive layer decreases so that the layer cannot be adhered to the skin.
Where the Ac/As is in the range of 0.1-1.8, most favorably 0.6 or above, the local anesthetic is in part undissolved in the pressure-sensitive adhesive layer, which contributes to the improved cohesiveness of the pressure-sensitive adhesive. In addition, the presence of the undissolved local anesthetic in a rather large amount leads to burst of the drug release soon after the application, causing prompt migration of the drug in an amount necessary for the exertion of the effect upon application of the preparation, which will eventually assure rapid appearance of the anesthetic effect which is expected of a local anesthetic.
While the amount of the local anesthetic to be contained in the pressure-sensitive adhesive layer is determined to be in the range of from 40 to 65 ~ by weight 20~06~3 based on the total weight of the pressure-sensitive adhesive layer, it is preferably not less than 45 weight ~ to ensure the rapid appearance of the effect.
The local anesthetic to be used in the present invention is selected from among amide type anesthetics and ester type anesthetics, and preferably selected from among cocaine, procaine, chloroprocaine, tetracaine, lidocaine, mepivacaine, prilocaine, bupivacaine and dibucaine.
The preparation of the present invention contains one or more of the above-mentioned local anesthetics in the pressure-sensitive adhesive layer.
The thickness of the pressure-sensitive adhesive layer containing local anesthetic is preferably in the range of from 5 to 30 ~,cm in view of the short application time and economic feasibility.
The preparation of the present invention has the components as descried above and contains a local anesthetic in a proportion of 40-65 weight ~ in the pressure-sensitive adhesive layer. Since the ratio of the amount of the undissolved local anesthetic (Ac) to that of the dissolved local anesthetic (As), Ac/As, in the pressure-sensitive adhesive layer is determined to be in the range of 0.1-1.8, the preparation of the present invention is superior in self-adhesiveness and leaves no adhesive material upon removal from the skin. In addition, burst-like release of the undissolved drug from the pressure-sensitive adhesive layer immediately after application to the skin permits rapid appearance of the local anesthetic effect, which makes it possible to be A
utilized for the pre-operational treatment of needle indwelling in a vein or an artery, dura or lumbar puncture, arthrocentesis and minor dermic operation. As a result, pain of patients can be vastly reduced and many clinical applications become possible.
The present invention is hereinbelow described in detail by illustrating working examples. The present invention is not strictly limited to those examples but can be modified in various manners.
In the following description, parts) and ~ refer to parts) by weight and weight ~, respectively.
Example 1 2-Ethylhexyl acrylate (95 parts) and acrylic acid (5 parts) were charged in a flask under an inert gas atmosphere and azobisisobutyronitrile (0.3 part) was added thereto as a polymerization initiator. The polymerization was conducted in ethyl acetate while maintaining the temperature at 60°C to give the acrylic pressure-sensitive adhesive solution A
(solids: 41.2 $).
Thereto was added lidocaine, wherein the ratio (w/w) of lidocaine to the solids was 60/40, after which ethyl acetate was added to give a solution containing 35 ~ solids.
The thus-obtained solution was coated on a polyester release paper to make the thickness after drying become 20 ~C.m, which was then dried at 100°C for 5 minutes to form a pressure-sensitive adhesive layer containing 60 ~ lidocaine. After the obtained pressure-sensitive adhesive layer containing 60 lidocaine was adhered onto a 12 ~m-thick polyester backing layer, it was allowed to stand at room temperature for 24 hours to crystallize the lidocaine in the pressure-sensitive adhesive layer, by which a preparation of the present invention was obtained (Ac/As was about 1.6).
Example 2 To the acrylic pressure-sensitive adhesive solution A as used in Example 1 was added lidocaine, wherein the ratio (w/w) of lidocaine to the solids was 50/50, to give a solution containing 30 ~ solid.
The obtained solution was treated in the same manner as in Example 1 to give a preparation of the present invention (Ac/As was about 0.7).
Example 3 To the acrylic pressure-sensitive adhesive solution A as used in Example 1 was added lidocaine, wherein the ratio (w/w) of lidocaine to the solids was 50/50, and ethyl acetate was further added to give a solution containing 33 $ solids.
The obtained solution was treated in the same manner as in Example 1 to give a preparation of the present invention (Ac/As was about 1.2).
Comparative Example 1 To the acrylic pressure-sensitive adhesive solution A as used in Example 1 was added lidocaine, wherein the ratio (w/w) of lidocaine to the solids was 70/30, and ethyl acetate was further added to give a solution containing 30 $ solids.
The obtained solution was treated in the same manner as in Example 1 to give a preparation containing a local anesthetic (Ac/As was about 2.0).
Comparative Example 2 To the acrylic pressure-sensitive adhesive solution A as used in Example 1 Was added lidocaine, wherein the ratio (w/w) of lidocaine to the solids was 20/80 and ethyl acetate was further added to give a solution containing 25 $ solids.
The obtained solution was treated in the same manner as in Example 1 to give a preparation containing a local anesthetic (Ac/As was 0).
Reference Example 1 Carboxyvinyl polymer (Wako Junyaku Kogyo, Hibis Waco*105, 2.6 weight ~), ethanol (40 weight ~) and purified water (47.4 weight ~) were mixed thoroughly to dissolve the carboxyvinyl polymer. Thereto was added lidocaine (10 weight and the mixture was mixed to dissolve lidocaine, by which there was obtained a gel ointment containing lidocaine.
Experiment Example 1 A 3.17 x 3.17 (10 cm2) specimen cut out from each of the preparations as obtained in Examples 1-3 and Comparative Examples 1 and 2 was adhered onto the human inner forearm and maintained for 30 minutes. The adhesiveness, remaining *Trade-mark 2056~~3 adhesive material upon removal from the skin, and anesthetic effect were examined. The effect was examined by the pin pricking method. That is, after 30 minutes of adhesion, the specimen was removed and an intracutaneous pin was pricked on the applied area to see the degree of pain, based on which numerical evaluation of the anesthetic effect was made according to the evaluation criteria.
As regards the Reference Example, 0.1 g of the lidocaine-containing gel ointment obtained therein was applied onto the area of 3.15 x 3.15 cm of the human inner forearm, and the similar experiment conducted.
was Anesthetic effect evaluation criteria 0 . no ain was sensedon 5 points.
p 1 . painwas sensed 1 of 5 points.
on 2 . painwas sensed 2 of 5 points.
on 3 . painwas sensed 3 of 5 points.
on 4 . painwas sensed 4 of 5 points.
on . painwas sensed 5 points.
on The results are summarized in Table 1.
~~~6~~3 Table 1 Adhesiveness Adhesive material Anesthetic to the skin remaining on the skin effect Examp 1 a 1 Q none 0.
Example 2 Q partial remainder around 1.6 the adhesion site Examp 1 a 3 Q none 1.
Comp. Ex. 1 x adhesion unattainable due to -the residual adhesive material on the release paper Comp. Ex. 2 Q remainder on the entire site 3.1 Ref. Ex. - - 4.1 Q . good adhesion x . adhesion unattainable Note that the anesthetic effect of the Reference Example was 1.9 after 3 hours' application.
Claims (9)
1. A preparation for transdermal drug administration comprising a flexible backing layer and a pressure-sensitive adhesive layer containing a local anesthetic in an amount of 40-65 % by weight based on the total weight of the pressure-sensitive adhesive layer, wherein the ratio of the amount of the undissolved local anesthetic (Ac) to that of the dissolved local anesthetic (As), Ac/As, is 0.1-1.8
2. A preparation for transdermal drug administration according to claim 1, wherein the local anesthetic is at least one member selected from the group consisting of amide type anesthetics and ester type anesthetics.
3. A preparation for transdermal drug administration according to claim 1, wherein the local anesthetic is at least one member selected from the group consisting of cocaine, procaine, chloroprocaine, tetracaine, lidocaine, mepivacaine, prilocaine, bupivacaine, dibucaine and their pharmaceutically acceptable salts.
4. A preparation for transdermal drug administration according to claim 1, wherein the pressure-sensitive adhesive layer is a layer of acrylic pressure-sensitive adhesive.
5. A preparation for transdermal drug administration according to claim 4, Wherein the acrylic pressure-sensitive adhesive is a copolymer of (meth)acrylic acid alkyl ester and (meth)acrylic acid.
6. A preparation for transdermal drug administration according to claim 4, wherein the acrylic pressure-sensitive adhesive is obtained by polymerization of 65-99 weight % of (meth)acrylic acid alkyl ester and 1-35 weight % of (meth)acrylic acid.
7. A preparation for transdermal administration of an amide type or ester type local anesthetic, comprising (i) a backing layer having a thickness of 5 to 150 µm which is flexible and impervious to the local anesthetic and (ii) a pressure-sensitive acrylic adhesive layer containing the local anesthetic in an amount of 40 to 65 % by weight based on the total weight of the pressure-sensitive adhesive layer, wherein a part of the local anesthetic is dissolved in the acrylic adhesive and the rest of the local adhesive is undissolved at an undissolved/dissolved weight ratio of 0.1 to 1.8.
8. A preparation of transdermal drug administration according to claim 7, wherein the local anesthetic is at least one member selected from the group consisting of cocaine, procaine, chloroprocaine, tetracaine, lidocaine, mepivacaine, prilocaine, bupivacaine, dibucaine and their pharmacologically acceptable salts.
9. A preparation for transdermal drug administration according to claim 8, wherein the acrylic pressure-sensitive adhesive is a copolymer of (meth)acrylic acid alkyl ester and (meth)acrylic acid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP338885/1990 | 1990-11-30 | ||
| JP2338885A JP2849950B2 (en) | 1990-11-30 | 1990-11-30 | Transdermal formulation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2056653A1 CA2056653A1 (en) | 1992-05-31 |
| CA2056653C true CA2056653C (en) | 2000-08-08 |
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ID=18322294
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002056653A Expired - Lifetime CA2056653C (en) | 1990-11-30 | 1991-11-29 | Preparation for transdermal drug administration |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US5368860A (en) |
| EP (1) | EP0488137B1 (en) |
| JP (1) | JP2849950B2 (en) |
| KR (1) | KR0185715B1 (en) |
| AT (1) | ATE120642T1 (en) |
| CA (1) | CA2056653C (en) |
| DE (1) | DE69108683T2 (en) |
| DK (1) | DK0488137T3 (en) |
| ES (1) | ES2070401T3 (en) |
| TW (1) | TW198692B (en) |
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| WO1993020138A2 (en) * | 1992-03-30 | 1993-10-14 | Alza Corporation | Polymer system containing a partially soluble compound |
| PT781122E (en) * | 1994-09-14 | 2000-11-30 | Minnesota Mining & Mfg | MATRIX FOR TRANSDERMIC DISTRIBUTION OF DRUGS |
| US5573778A (en) * | 1995-03-17 | 1996-11-12 | Adhesives Research, Inc. | Drug flux enhancer-tolerant pressure sensitive adhesive composition |
| DE19524691A1 (en) * | 1995-07-06 | 1997-01-09 | Liedtke Pharmed Gmbh | Method and composition of topical therapy for inner ear and labyrinth symptoms |
| US5667799A (en) * | 1995-10-30 | 1997-09-16 | Caldwell; Larry J. | Method for treating headache pain with topical local anesthetic compositions |
| DE19546159A1 (en) * | 1995-12-11 | 1997-06-12 | Liedtke Pharmed Gmbh | Method and composition of a topically effective therapy for post-operative and post-traumatic wound pain |
| US6365178B1 (en) * | 1996-09-06 | 2002-04-02 | Watson Pharmaceuticals, Inc. | Method of making pressure sensitive adhesive matrix patches for transdermal drug delivery using hydrophilic salts of drugs and hydrophobic pressure sensitive adhesive dispersions |
| US5985317A (en) * | 1996-09-06 | 1999-11-16 | Theratech, Inc. | Pressure sensitive adhesive matrix patches for transdermal delivery of salts of pharmaceutical agents |
| US6103771A (en) * | 1998-03-20 | 2000-08-15 | Caldwell Galer Incorporated | Method of treating neuroma pain |
| JP2003520191A (en) * | 1998-09-08 | 2003-07-02 | ワトソン ファーマシューティカルズ， インコーポレイテッド | Method for producing pressure-sensitive adhesive matrix patches containing hydrophilic salts of drugs |
| EP1280485A4 (en) * | 2000-02-29 | 2006-11-29 | Zars Inc | Improved transdermal drug patch |
| EP1747033A1 (en) | 2004-04-30 | 2007-01-31 | Burrell E. Clawson | Apparatus and methods for isolating human body areas for localized cooling |
| US7666914B2 (en) * | 2004-06-03 | 2010-02-23 | Richlin David M | Topical preparation and method for transdermal delivery and localization of therapeutic agents |
| US7718674B2 (en) * | 2004-09-27 | 2010-05-18 | Bridge Pharma, Inc. | Methods of relieving neuropathic pain with the S-isomer of 2-{2[N-(2-indanyl)-N-phenylamino]ethyl}piperidine |
| WO2006037047A2 (en) * | 2004-09-27 | 2006-04-06 | Bridge Pharma, Inc. | The r-isomer of 2-{2-[n-(2-indanyl)-n-phenylamino]ethyl}piperidine and other dermal anesthetic agents |
| JP2006248996A (en) * | 2005-03-10 | 2006-09-21 | Nitto Denko Corp | Percutaneous absorption type cataplasm |
| CA2655809C (en) * | 2006-07-21 | 2013-10-01 | Bridge Pharma, Inc. | Dermal anesthetic compounds |
| ES2388355T3 (en) | 2006-11-03 | 2012-10-11 | Durect Corporation | Transdemic delivery systems comprising bupivacaine |
| ES2400210T3 (en) | 2008-10-02 | 2013-04-08 | Mylan Inc. | Method for preparing a multilayer adhesive laminate |
| KR101080380B1 (en) | 2009-08-14 | 2011-11-04 | 한국수력원자력 주식회사 | Film for adhesion of hydrogel having enhanced adhesive strength and preparation method thereof |
| AU2016259348B9 (en) * | 2010-04-13 | 2018-11-29 | Relmada Therapeutics, Inc. | Dermal pharmaceutical compositions of 1-Methyl-2',6' pipecoloxylidide and method of use |
| CN107115326B (en) * | 2010-04-13 | 2021-01-22 | 雷尔玛达治疗股份有限公司 | Skin pharmaceutical composition of 1-methyl-N- (2, 6-xylyl) -2-piperidine formamide and using method thereof |
| DE102011100619A1 (en) | 2010-05-05 | 2012-01-05 | Amw Gmbh | Therapeutic system, useful to treat chronic pain, comprises active agent impermeable carrier, active agent reservoir containing e.g. opioid receptor agonist, optionally active agent-permeable membrane and active agent impermeable layer |
| KR20170055487A (en) * | 2014-10-02 | 2017-05-19 | 닛토덴코 가부시키가이샤 | Vaccine pharmaceutical composition for transdermal administration |
| CN109316469B (en) * | 2018-10-09 | 2022-02-22 | 北京德默高科医药技术有限公司 | Stable high-drug-loading lidocaine transdermal patch and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58148815A (en) * | 1982-02-26 | 1983-09-05 | Nitto Electric Ind Co Ltd | Preparation of complex medicinal pharmaceutical |
| ATE42901T1 (en) * | 1984-03-05 | 1989-05-15 | Nitto Denko Corp | ADHESIVE MEDICATION FOR PERCUTANEOUS ABSORPTION. |
| US4655768A (en) * | 1984-07-06 | 1987-04-07 | Avery International Corporation | Bandage for sustained delivery of drugs |
| US4764381A (en) * | 1985-12-06 | 1988-08-16 | Key Pharmaceuticals, Inc. | Percutaneous penetration enhancer of oleic acid and 2-ethyl-1, 3-hexanediol |
| EP0331392A3 (en) * | 1988-03-01 | 1990-02-14 | Alza Corporation | Anesthesia and antisepsis of the skin |
| WO1989011872A1 (en) * | 1988-06-09 | 1989-12-14 | Alza Corporation | Permeation enhancer comprising ethanol and glycerol monooleate |
| US5120325A (en) * | 1991-06-12 | 1992-06-09 | Fleshtones Products Co., Inc. | Color-matched sterile adhesive bandages containing melanin-like pigment composition |
-
1990
- 1990-11-30 JP JP2338885A patent/JP2849950B2/en not_active Expired - Lifetime
-
1991
- 1991-11-19 TW TW080109062A patent/TW198692B/zh not_active IP Right Cessation
- 1991-11-26 DE DE69108683T patent/DE69108683T2/en not_active Expired - Lifetime
- 1991-11-26 ES ES91120100T patent/ES2070401T3/en not_active Expired - Lifetime
- 1991-11-26 AT AT91120100T patent/ATE120642T1/en not_active IP Right Cessation
- 1991-11-26 DK DK91120100.2T patent/DK0488137T3/en active
- 1991-11-26 EP EP91120100A patent/EP0488137B1/en not_active Expired - Lifetime
- 1991-11-26 US US07/798,149 patent/US5368860A/en not_active Expired - Lifetime
- 1991-11-29 CA CA002056653A patent/CA2056653C/en not_active Expired - Lifetime
- 1991-11-29 KR KR1019910021715A patent/KR0185715B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| US5368860A (en) | 1994-11-29 |
| CA2056653A1 (en) | 1992-05-31 |
| KR920009387A (en) | 1992-06-25 |
| JPH04208229A (en) | 1992-07-29 |
| DK0488137T3 (en) | 1995-08-28 |
| JP2849950B2 (en) | 1999-01-27 |
| EP0488137A2 (en) | 1992-06-03 |
| KR0185715B1 (en) | 1999-05-01 |
| ATE120642T1 (en) | 1995-04-15 |
| DE69108683D1 (en) | 1995-05-11 |
| EP0488137A3 (en) | 1993-02-03 |
| DE69108683T2 (en) | 1995-10-05 |
| EP0488137B1 (en) | 1995-04-05 |
| TW198692B (en) | 1993-01-21 |
| ES2070401T3 (en) | 1995-06-01 |
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| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed | ||
| MKEC | Expiry (correction) |
Effective date: 20121202 |