CA2064325C - External preparation for application to the skin containing lidocaine - Google Patents
External preparation for application to the skin containing lidocaine Download PDFInfo
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- CA2064325C CA2064325C CA002064325A CA2064325A CA2064325C CA 2064325 C CA2064325 C CA 2064325C CA 002064325 A CA002064325 A CA 002064325A CA 2064325 A CA2064325 A CA 2064325A CA 2064325 C CA2064325 C CA 2064325C
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- Prior art keywords
- lidocaine
- water
- external preparation
- drug
- parts
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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
- 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
-
- 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
- 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
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- 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
- 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
- A61K9/7076—Transdermal 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
-
- 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
The present invention is directed to an external preparation for application to the skin containing lidocaine.
The preparation comprises a drug-retaining layer placed on a support, wherein said drug-retaining layer comprises an adhesive gel base and 1 to 10% by weight of lidocaine, said base comprising a water-soluble high molecular weight substance, water and a water-retaining agent, which can release the active lidocaine gradually and constantly so that lidocaine is transdermally absorbed over a long period of time.
The preparation comprises a drug-retaining layer placed on a support, wherein said drug-retaining layer comprises an adhesive gel base and 1 to 10% by weight of lidocaine, said base comprising a water-soluble high molecular weight substance, water and a water-retaining agent, which can release the active lidocaine gradually and constantly so that lidocaine is transdermally absorbed over a long period of time.
Description
External Preparation for Application to the Skin Containincr Lidocaine The present invention relates to an external preparation for application to the skin containing lidocaine. More particularly, it relates t.o an external preparation for application to the skin wherein lidocaine or a salt thereof as an active ingredient is dispersed or dissolved in a water-soluble high molecular weight substance in an adhesive gel base which is spread onto a support, and said active ingredient can be gradually and constantly released from the preparation stably so that. it can be transdermally absorbed over a long period of time..
In recent years, a variety of therapies including nerve block therapy, acupuncture, iontophoresis therapy, or administration of central analgesics or antidepressants, have been used in an attempt to cure herpes zoster neuralgia and posthepetic neuralgia which occur in the aged at a relatively high frequency.
A typical drug used i.n nerve block therapy is lidocaine.
Lidocaine, which has been developed as a local anesthetic, has surface, infiltration and conduction anesthetic actions and has been mainly used as surface anesthetic in the field of dentistry. Lidocaine is widely used as a primary drug for treatment of extrasystole, acute myocardial infarction, and ventricular arrhythmia occurring in cardiac surgery operations.
In order to use lidocaine for the treatment of herpes zoster neuralgia and posthepetic neuralgia, it is administered into the epidural cavity via a block needle as in the case of nerve block therapy. However, this method has the following disadvantages.
(i) Although the drug is quickly conveyed to the tissue to be treated, the treatment should be conducted while monitoring blood pressure, heart rate and systemic conditions.
(ii) There is a high possibility of inducing systemic side effects in the aged or patients with heart disease or ~06~~2~
In recent years, a variety of therapies including nerve block therapy, acupuncture, iontophoresis therapy, or administration of central analgesics or antidepressants, have been used in an attempt to cure herpes zoster neuralgia and posthepetic neuralgia which occur in the aged at a relatively high frequency.
A typical drug used i.n nerve block therapy is lidocaine.
Lidocaine, which has been developed as a local anesthetic, has surface, infiltration and conduction anesthetic actions and has been mainly used as surface anesthetic in the field of dentistry. Lidocaine is widely used as a primary drug for treatment of extrasystole, acute myocardial infarction, and ventricular arrhythmia occurring in cardiac surgery operations.
In order to use lidocaine for the treatment of herpes zoster neuralgia and posthepetic neuralgia, it is administered into the epidural cavity via a block needle as in the case of nerve block therapy. However, this method has the following disadvantages.
(i) Although the drug is quickly conveyed to the tissue to be treated, the treatment should be conducted while monitoring blood pressure, heart rate and systemic conditions.
(ii) There is a high possibility of inducing systemic side effects in the aged or patients with heart disease or ~06~~2~
liver disease.
(iii) Since th~~ treatment cannot be conducted at home, patients must go to 'the hospital for every treatment or they must be hospitalized.
(iv) Each treatment requires a long period of time.
Another means o:E treatment for transdermal absorption is the use of ointments. Although the ointment can advanta-geously be applied to portions of the body, e.g. head, face, etc., areas which normally do not or cannot receive external preparations, it sti:Ll has some disadvantages as follows:
(i) It is difficult 'to quantitatively administer the drug, and quite often hands, fingers, clothes, etc. are stained. In order to prevent this, the applied portions can be covered with gauze, etc. but this too is troublesome.
(ii) As a resu:Lt of 'volatilization of the solvent in the preparation, the dru<~ crystallizes out, and hence, transdermal absorption of the drug is lowered. In order to prevent this, the applied portions can b~e covered with a film, etc. but the water content increases excessively and hence, the occurrence of dermatological al:Lergies, e.g. eczema, hives, etc.
increases.
(iii) In the treatment of herpes zoster neuralgia and posthepetic neuralgi<~, the portion to be treated is preferably continuously provided with the drug. Since lidocaine is quickly metabolized, the ointment must be applied several times a day.
As to iontophoreasis therapy which has recently drawn public attention, this method still has the following disadvantages in spite of many advantages as a local therapy without pain.
(i) Since special eqi.zipment is necessary for the treatment, the patient must go to the hospital for every treatment. In addition, the treatment is time-consuming and troublesome.
(ii) The range of each treatment is limited and the conditions for applying electric current should be changed for each individual.
_ ~os~~~~
(iii) Since th~~ treatment cannot be conducted at home, patients must go to 'the hospital for every treatment or they must be hospitalized.
(iv) Each treatment requires a long period of time.
Another means o:E treatment for transdermal absorption is the use of ointments. Although the ointment can advanta-geously be applied to portions of the body, e.g. head, face, etc., areas which normally do not or cannot receive external preparations, it sti:Ll has some disadvantages as follows:
(i) It is difficult 'to quantitatively administer the drug, and quite often hands, fingers, clothes, etc. are stained. In order to prevent this, the applied portions can be covered with gauze, etc. but this too is troublesome.
(ii) As a resu:Lt of 'volatilization of the solvent in the preparation, the dru<~ crystallizes out, and hence, transdermal absorption of the drug is lowered. In order to prevent this, the applied portions can b~e covered with a film, etc. but the water content increases excessively and hence, the occurrence of dermatological al:Lergies, e.g. eczema, hives, etc.
increases.
(iii) In the treatment of herpes zoster neuralgia and posthepetic neuralgi<~, the portion to be treated is preferably continuously provided with the drug. Since lidocaine is quickly metabolized, the ointment must be applied several times a day.
As to iontophoreasis therapy which has recently drawn public attention, this method still has the following disadvantages in spite of many advantages as a local therapy without pain.
(i) Since special eqi.zipment is necessary for the treatment, the patient must go to the hospital for every treatment. In addition, the treatment is time-consuming and troublesome.
(ii) The range of each treatment is limited and the conditions for applying electric current should be changed for each individual.
_ ~os~~~~
(iii) Since electric current is directly applied to the skin, there is the possibility of secondary side effects, e.g.
burns, though this is rare.
Under the circumstances, the present inventors have studied intensively in order to develop external preparations for application to tlZe skin containing lidocaine suitable for transdermal administration, and as a result, have found that, by dispersing or disosolving lidocaine in a water-soluble high molecular weight substance, there can be obtained an external preparation for application to the skin for transdermal absorption of the drug, which shows an excellent adhesion, has excellent controlled released properties and allows for transdermal absorption of 'the drug over long periods of time.
An object of thc~ present invention is to provide an external preparation for application to the skin containing lidocaine which comprises .a drug-retaining layer placed on a support, wherein said drug-retaining layer comprises an adhesive gel base an<i 1 to 10% (% by weight, hereinafter the same) of lidocaine, raid base comprising a water-soluble high molecular weight substance, water and a water-retaining agent.
These and other objects and advantages of the present invention will be apparent to those skilled in the art from the following description.
In the drawings which illustrate preferred embodiments of the present invention:
Fig. 1 is a graph showing the permeability of the drug with the passage of time in the case of the preparations of Examples 1 to 5 in comparison with the ointment of Comparative Example 1 and the plasters of Comparative Examples 2 and 3.
Fig. 2 is a graph showing mean blood level with the passage of time in the casca of the preparations of Examples 1 to 5 in comparison with thc~ ointment of Comparative Example 1 and the plasters of Comparative Examples 2 and 3.
The adhesive gel. base used in the preparation of the present invention comprises a water-soluble high molecular weight substance, wager and a water-retaining agent as essential components. The water-soluble high molecular weight h 2~~4~~5 substance includes gelatin, starch, agar, mannan, alginic acid, polyacrylic acid, a salt of polyacrylic acid, dextrin, methylcellulose, methylcellulose sodium, carboxymethylcellu-lose, carboxymethylcellulose sodium, polyvinyl alcohol, polyvinyl pyrrolidone, a copolymer of methyl vinyl ether and malefic anhydride, gum arabic, tragacanth, karaya gum, locust bean gum, etc. There can also be used a metallic salt of the above substances and cross-linked products of the above substances with an organic or inorganic cross-linking agent.
One or more of the water-soluble high molecular weight substances are used in the adhesive gel base. The amount of the water-soluble high molecular weight substance is in a range of 0.5 to 50% (% by weight, hereinafter the same), preferably 5 to 25%.
Water contained in the adhesive gel base increases the swelling of the skin layer and the permeability of the drug.
The water content is preferably in the range of 10 to 70%, more preferably 20 to 50%.
The water-retaining agent used in the preparation of the invention prevents t:he volatilization of water contained in the adhesive gel base so that the water content in the adhesive gel base is maintained at a constant level during storage and use of tl:~e preparation because the volatilization of water affects the release rate of the drug to the skin.
The water-retaining ;gent includes, for example, glycols or saccharides, e.g. ethylene glycol, diethylene glycol, poly-ethylene glycol, gly~~erin, sorbitol, martitol, propylene glycol, 1,3-butylene glycol, etc. One or more water-retaining agents are used. The amount of the water-retaining agent in the adhesive gel bass is preferably in the range of 1 to 70%, more preferably 10 to 60%.
In order to more=_ efficiently retain the water content in the adhesive gel base, an extremely high water-absorbable high molecular weight substance may also be used. Such an extremely high water-absorbable high molecular weight substance includes, ;Eor example, a graft copolymer of starch and acrylonitrile, a graft copolymer of starch and acrylic 20~~3~~
acid, a graft copolymer of starch and styrenesulfonic acid, a graft copolymer of ~,tarch and vinylsulfonic acid, a cross-linked product of polyvinyl alcohol, a saponification product of acrylic acid/vinyl acetate copolymer, a cross-linked 5 product of polyethylene g7.yco1 diacrylate, etc. The amount of the extremely highly watez--absorbable high molecular weight substance in the adhesive gel base is preferably in the range of 0 to 20% more preferable 0.01 to 10%.
If necessary, there c:an also be used a conventional absorbing agent, e.g. sali.cylic acid, hyaluronic acid, oleic acid, N,N-diethyl-m-toluamide, n-butyl stearate, benzyl alcohol, isopropyl myrista~te, isopropyl palmitate, polyprop-ylene glycol, crotamiton, diethyl sebacate, N-methylpyrroli-done, N-ethylpyrrolidone, lauryl alcohol, etc., and a surfactant for emulsifying the absorbing agent in the gel base, including, for example, polyoxyethylene sorbitan monooleate, polyoxyethylerae sorbitan monostearate, sorbitan monooleate, sorbitan monopalmitate, etc. In addition, a preserving agent, an antioxidant, etc. may also be used in a suitable amount. Any type: and amount of antioxidant or preserving agent may be used unless they adversely affect the control release of the drug or the stimuli to the skin.
The adhesive gel base. comprising the above components preferably has a pH value of 5 to 9 in view of the stimuli to the skin and the stability of the drug. The pH may be adjusted to the above range by adding an alkaline substance, e.g. sodium hydroxide or an amine, e.g. triethanolamine, diisopropanolamine, etc. or an acid substance, e.g. tartaric acid, citric acid, malic acid, lactic acid, acetic acid, phthalic acid, etc.
The external preparation for application to the skin containing lidocaine of the invention can be prepared by adding the drug, that is lidocaine or a salt thereof, e.g.
lidocaine hydrochloride, in an effective amount to the above-mentioned adhesive gel base to prepare a drug-retaining layer, the content of the drug being in the range of 0.5 to 15.0%, preferably 2.5 to 10.0%, and spreading the drug-retaining 2064~2~
burns, though this is rare.
Under the circumstances, the present inventors have studied intensively in order to develop external preparations for application to tlZe skin containing lidocaine suitable for transdermal administration, and as a result, have found that, by dispersing or disosolving lidocaine in a water-soluble high molecular weight substance, there can be obtained an external preparation for application to the skin for transdermal absorption of the drug, which shows an excellent adhesion, has excellent controlled released properties and allows for transdermal absorption of 'the drug over long periods of time.
An object of thc~ present invention is to provide an external preparation for application to the skin containing lidocaine which comprises .a drug-retaining layer placed on a support, wherein said drug-retaining layer comprises an adhesive gel base an<i 1 to 10% (% by weight, hereinafter the same) of lidocaine, raid base comprising a water-soluble high molecular weight substance, water and a water-retaining agent.
These and other objects and advantages of the present invention will be apparent to those skilled in the art from the following description.
In the drawings which illustrate preferred embodiments of the present invention:
Fig. 1 is a graph showing the permeability of the drug with the passage of time in the case of the preparations of Examples 1 to 5 in comparison with the ointment of Comparative Example 1 and the plasters of Comparative Examples 2 and 3.
Fig. 2 is a graph showing mean blood level with the passage of time in the casca of the preparations of Examples 1 to 5 in comparison with thc~ ointment of Comparative Example 1 and the plasters of Comparative Examples 2 and 3.
The adhesive gel. base used in the preparation of the present invention comprises a water-soluble high molecular weight substance, wager and a water-retaining agent as essential components. The water-soluble high molecular weight h 2~~4~~5 substance includes gelatin, starch, agar, mannan, alginic acid, polyacrylic acid, a salt of polyacrylic acid, dextrin, methylcellulose, methylcellulose sodium, carboxymethylcellu-lose, carboxymethylcellulose sodium, polyvinyl alcohol, polyvinyl pyrrolidone, a copolymer of methyl vinyl ether and malefic anhydride, gum arabic, tragacanth, karaya gum, locust bean gum, etc. There can also be used a metallic salt of the above substances and cross-linked products of the above substances with an organic or inorganic cross-linking agent.
One or more of the water-soluble high molecular weight substances are used in the adhesive gel base. The amount of the water-soluble high molecular weight substance is in a range of 0.5 to 50% (% by weight, hereinafter the same), preferably 5 to 25%.
Water contained in the adhesive gel base increases the swelling of the skin layer and the permeability of the drug.
The water content is preferably in the range of 10 to 70%, more preferably 20 to 50%.
The water-retaining agent used in the preparation of the invention prevents t:he volatilization of water contained in the adhesive gel base so that the water content in the adhesive gel base is maintained at a constant level during storage and use of tl:~e preparation because the volatilization of water affects the release rate of the drug to the skin.
The water-retaining ;gent includes, for example, glycols or saccharides, e.g. ethylene glycol, diethylene glycol, poly-ethylene glycol, gly~~erin, sorbitol, martitol, propylene glycol, 1,3-butylene glycol, etc. One or more water-retaining agents are used. The amount of the water-retaining agent in the adhesive gel bass is preferably in the range of 1 to 70%, more preferably 10 to 60%.
In order to more=_ efficiently retain the water content in the adhesive gel base, an extremely high water-absorbable high molecular weight substance may also be used. Such an extremely high water-absorbable high molecular weight substance includes, ;Eor example, a graft copolymer of starch and acrylonitrile, a graft copolymer of starch and acrylic 20~~3~~
acid, a graft copolymer of starch and styrenesulfonic acid, a graft copolymer of ~,tarch and vinylsulfonic acid, a cross-linked product of polyvinyl alcohol, a saponification product of acrylic acid/vinyl acetate copolymer, a cross-linked 5 product of polyethylene g7.yco1 diacrylate, etc. The amount of the extremely highly watez--absorbable high molecular weight substance in the adhesive gel base is preferably in the range of 0 to 20% more preferable 0.01 to 10%.
If necessary, there c:an also be used a conventional absorbing agent, e.g. sali.cylic acid, hyaluronic acid, oleic acid, N,N-diethyl-m-toluamide, n-butyl stearate, benzyl alcohol, isopropyl myrista~te, isopropyl palmitate, polyprop-ylene glycol, crotamiton, diethyl sebacate, N-methylpyrroli-done, N-ethylpyrrolidone, lauryl alcohol, etc., and a surfactant for emulsifying the absorbing agent in the gel base, including, for example, polyoxyethylene sorbitan monooleate, polyoxyethylerae sorbitan monostearate, sorbitan monooleate, sorbitan monopalmitate, etc. In addition, a preserving agent, an antioxidant, etc. may also be used in a suitable amount. Any type: and amount of antioxidant or preserving agent may be used unless they adversely affect the control release of the drug or the stimuli to the skin.
The adhesive gel base. comprising the above components preferably has a pH value of 5 to 9 in view of the stimuli to the skin and the stability of the drug. The pH may be adjusted to the above range by adding an alkaline substance, e.g. sodium hydroxide or an amine, e.g. triethanolamine, diisopropanolamine, etc. or an acid substance, e.g. tartaric acid, citric acid, malic acid, lactic acid, acetic acid, phthalic acid, etc.
The external preparation for application to the skin containing lidocaine of the invention can be prepared by adding the drug, that is lidocaine or a salt thereof, e.g.
lidocaine hydrochloride, in an effective amount to the above-mentioned adhesive gel base to prepare a drug-retaining layer, the content of the drug being in the range of 0.5 to 15.0%, preferably 2.5 to 10.0%, and spreading the drug-retaining 2064~2~
layer onto a suitable support. The thus prepared drug-retaining layer is spread onto the support in an amount of 500 to 2000 g/mz.
In order to protect the drug-retaining layer from the volatilization of water therein, a liner made of a suitable material may also be adhered to the surface of said layer.
The support is preferably made of a flexible material which is capable of cooperating with the movement of the human body and includes, for example, various non-woven fabrics, woven fabrics, spandex, flannel, or a laminate of these materials with polyethylene fi:Lm, polyethylene glycol terephthalate film, polyvinyl chloride film, ethylene-vinyl acetate copolymer film, polyurethane film, and the like.
The external prEaparation for application to the skin of the invention is cap<~ble of releasing the drug quantitatively, is easily handled, and is .capable of being applied for a long period of time. In <~ddition, the external preparation of the invention has the following advantages:
(i) Since the ~~repar~ation of the invention is externally applied to the skin, the first-pass effect through the liver (that is, decomposition of lidocaine occurring when administered orally) can be avoided, and hence, the bioavailability can be increased.
(ii) Since the preparation of the invention is externally applied to the ;skin, the drug is continuously released over a long period of time, and hence, it is expected that the activity of the drug is stably exhibited. In addition, the preparation of the invention can be administered less frequently, and hence, the compliance of patients can be improved.
(iii) The patients suffering from posthepetic neuralgia sometimes feel pain even by the touch of wind or the rubbing of cloth. In such a case, the pain can be reduced by covering the surface of the sl~:in with the external preparation of the invention.
(iv) The preparation of the invention can be administered regardless of the patient's age, health condition, condition of the digestive organs, e.g. stomach or intestines or liver function.
The present imrention is explained in more detail by the following Examples, Comparative Examples and Experiments but should not be construed t~o be limited thereto. In the following Examples <~nd Comparative Examples, "part" or "parts"
means "part by weight" or "parts by weight" unless otherwise mentioned.
Example 1 Lidocaine 5 parts D-Sorbitol 15 parts Glycerin 20 parts Propylene glycol 10 parts Sodium polyacrylate 4 parts Carboxymethylcellulose sodium 5 parts Polyacrylic acid 2 parts Methyl paraoxybenzoate 0.1 part Propyl paraoxybenzoate 0.05 part Aluminum hydroxide 0.3 part Purified water q,s, Total amount 100 parts D-Sorbitol and polyacrylic acid were added to purified water and the mixture was stirred. To the mixture was further added a solution of lidocaine in propylene glycol and the mixture was stirred. Then, to the mixture was added a dispersion of sodium polyacrylate, carboxymethylcellulose sodium, aluminum hyclroxidea, methyl paraoxybenzoate and propyl paraoxybenzoate in g~lycer:en and the mixture was sufficiently stirred until a uniform mixture was obtained. The obtained base was applied onto and spread over a non-woven fabric at 1000 g/m2and a lines- made of polyethylene terephthalate processed with silicone was attached to the base. The obtained preparation. was c:ut to a desired size to give an external preparation. for application to the skin which has a pH value of 7 and contain: 5 mg/cmZOf lidocaine.
A
Examgle 2 Lidocaine 10 parts D-Sorbitol l0 parts Glycerin 2o parts Propylene glycol 10 parts Sodium polyacrylate 4 parts Carboxymethylcellulose sodium 5 parts Polyacrylic acid 3 parts Methyl paraoxybenozate 0.1 part Propyl paraoxybenzoate 0.05 part Aluminum hyroxide 0.3 part Purified water q.s.
Total amount 100 parts The above components were mi xed together in the same manner as in Example 1 to give a base. The obtained base was applied onto and spread over a no n-woven fabric at 1000 g/m2 and a liner made of polyethylene terephthalate processed with silicone was attached to the base . The obtained preparation was cut to a desired size to give an external preparation for application to the shin which has a pH value of 7 and contains 10 mg/cm2of lidocaine.
Example 3 Lidocaine 5 parts Gelatin 1 part Kaolin 1 part D-Sorbitol 15 parts Glycerin 20 parts Propylene glycol 10 parts Sodium polyacrylate 5 parts Carboxymethylcellulo:ae sodium 5 parts Polyacrylic acid 2 parts Urea 1 part Methyl paraoxybenzoai~e 0.1 part Propyl paraoxybenzoai~e 0.05 part Aluminum hydroxide 0.3 part Purified water q.s.
Total amount 100 parts ~~6~~2 To a solution of gela tin and polyacrylic acid in purified water were added kaolin, D-sorbitol and urea and the mixture was well stirred. To the mixture was further added a solution of lidocaine in ropylene glycol and the mixture p was stirred. A dispersion of sodium polyacrylate, carboxymethyl-cellulose sodium, aluminum hydroxide, methyl paraoxybenzoate and propyl paraoxybe~nzoate~in glycerin was added to the mixture and the mixture was stirred until a uniform mixture was obtained. The obtains:d base was applied onto and spread over a non-woven fat~ric 1000 g/m2 and a liner made of at:
polyethylene terephthalate: processed with silicone was attached to the base. The obtained preparation was cut to a desired size to give an e~aernal preparation for application to the skin which has a pea value of 6 and contains 5 mg/cmZOf lidocaine.
Example 4 Lidocaine 5 parts Gelatin 1 part Kaolin 1 part D-Sorbitol 15 parts Glycerin 20 parts Propylene glycol 5 parts Sodium polyacrylate 5 parts Carboxymethylcellulose sodium 5 parts Polyacrylic acid 2 parts Urea 1 part Tartaric acid 1.5 parts Methyl paraoxybenzoate 0.1 part Propyl paraoxybenzoate 0.05 part Dihydroxy aluminum aminoacetate 0.3 part Purified water q.s.
Total amount 100 parts The above components were mixed in the same manner as in Example 3 to give a base. The obtained base was applied onto and spread over a non-woven fabric at 1000 g/m2 and a liner made of polyethylene terephthalate processed with silicone was attached to the base. The obtained preparation was cut to a 20643~~
l0 desired size to give an exaernal preparation for application to the skin which has a pH value of 6 and contains 5 mg/cmZOf lidocaine.
Example 5 Lidocaine 5 parts D-Sorbitol 15 parts Glycerin 20 parts Propylene glycol 10 parts Sodium polyacrylate 4 parts Carboxymethylcellulose sodium 5 parts Polyacrylic acid 2 parts Tartaric acid 0.3 part Methyl paraoxybenzoate 0.1 part Propyl paraoxybenzoate 0.05 part Dihydroxy aluminum aminoacetate 0.3 part Purified water q.s.
Total amount 100 parts The above components were mixed in the same manner as in Example 1 to give a base. The obtained base was applied onto and spread over a non-woven fabric at 1000 g/mz and a liner made of polyethylene terephthalate processed with silicone was attached to the base. The obtained preparation was cut to a desired size to give an external preparation for application to the skin which has a pH value of 7 and contains 5 mg/cm2of lidocaine.
Comparative Example 1 Lidocaine 5 parts White Vaseline* 25 parts Stearyl alcohol 25 parts Propylene glycol 10 parts Polyacrylic acid 2 parts Polyoxyethylated hardened ~~astor oil 4 parts Methyl paraoxybenzoai~e 0.1 part Propyl paraoxybenzoai:e 0.05 part Purified water q.s.
Total amount 100 parts *Trade mark ~0643~~
White Vaseline .and stearyl alcohol were melted on a water bath, mixed well together and kept at about 75°C. A solution of lidocaine in purified water, polyacrylic acid, polyoxy-ethylated hardened castor oil and propylene glycol, and methyl paraoxybenzoate and ~~ropyl paraoxybenzoate were added thereto and the mixture was atirred at room temperature until the mixture solidified to give an ointment which has a pH value of 7 and contains 50 mg,~g of lidocaine.
Comparative Example 2 Lidocaine 5 parts Adhesive plaster base 90 parts Propylene glycol 5 parts Total amount 100 parts A solution of l:idocaine in propylene glycol was added to an adhesive plaster base a:nd the base was applied onto and spread over a non-woven fabric at 1000 g/mZin accordance with a conventional method for ;preparing an adhesive plaster to give a plaster containing .5 mg/cmZOf lidocaine.
Comparative Example 3 Lidocaine 10 parts Propylene glycol 10 parts Styrene-isoprene-styrene (SIS) block copolymer 30 parts Alicyclic saturated hydrocarbon petroleum resin 45 parts Liquid paraffin 4 parts Dibutylhydroxytoluensa 1 part Total amount 100 parts The above components other than lidocaine and propylene glycol were dissolved with heating and thereto was added a solution of lidocainea in propylene glycol and the mixture was stirred. Then, the mixture was applied onto and spread over a suitable non-woven fabric at 500 g/mZand cooled. This base was laminated with polyethylene terephthalate film and the obtained laminate cut: to a desired size to give an external preparation for application to the skin which contains 5 mg/cmz of lidocaine.
206~~2~
Experiment 1 Using a Franz diffusion cell, there was measured the amount of lidocaine which permeated through the skin taken from a rat abdomen by HPLC. The external preparations of Examples 1 to 5 and Comparative Examples 2 and 3 were punched into a circle of 1.7 cm diameter (containing 11.35 mg or 22.7 mg of lidocaine:) and the obtained circular preparations were attached to the: rat skin in the diffusion cell. Using a phosphate buffer (pFt 6.8) in a receptor, the samples were removed from the cell at a constant interval and the amount of the drug which permeated through the skin was measured. As to the ointment of Comparative Example 1, it was applied to the rat skin within a circle of 1.7 cm diameter and the same experiment was conducted.
The results are: shown in Figure 1. As is clear from Figure 1, the drugs permeated through the rat skin over the passage of time in t:he case of the preparations of Examples 1 to 5 and Comparative: Example 1, and hence, the permeability of the preparations of Examples 1 to 5 and Comparative Example 1 were higher than that of the preparations of Comparative Examples 2 and 3.
Experiment 2 After removing hair from the backs of rats, the preparations of Examples 1 to 5 and Comparative Examples 2 and 3 which were cut into a size of 4 cm x 4 cm (containing 80.0 mg or 160.0 mg of lidocaine) were attached to the backs.
While attaching the preparations, 0.5 ml of blood was taken from each of the rats at a constant interval and the amount of lidocaine in the serum wa:~ measured by fluorescent polarization immunoassay. As to the ointment of Comparative Example 1, 1.6 g of the ointment (containing 80.0 mg of lidocaine) was applied to a piece of gauze 4 cm x 4 cm and the same experiment was conducaed.
The results are shown in Figure 2 (n = 4). As is clear from Fig. 2, in the case of the preparations of Examples 1 to 5, blood level of lidocaine reached a constant level six to eight hours after the administration of the drug and was maintained at that level for 24 hours measured from the administration, showing higher blood levels than that of the preparations of Comparative Examples 1 to 3. After removing the drug, blood level was drastically lowered in the case of the preparations of Examples 1 to 5. As to the ointment of Comparative Example 1, blood level was quickly increased after the administration of the drug but did not last, i.e. blood level reached a peak four to five hours after the administration and thereafter decreased. The preparations of Comparative Examples 2 and 3 had a poor transdermal absorbability, and hence, blood level was low.
Experiment 3 After removing :hair from the back of a guinea pig, stimulus was given to the back with a mandolin string to confirm a normal contraction reaction of the epidermis. Then, the preparations of :Examples 1 to 5 and Comparative Examples 2 and 3 which were cut to a size of 4 cm x 4 cm (containing 80.0 mg or 160.0 mg ~~f lidocaine) were attached to the back.
The preparations were removed from the back at a constant interval and stimuli were given to the treated portion six times with the mandolin string. When the contraction reaction of the skin was not ~~bserved more than three times, the local anesthetic action of the preparation was regarded as positive.
As to the ointment of Comparative Example 1, 1.6 g of the ointment (containing 80.0 mg of lidocaine) was applied to a piece of gauze 4 cm :K 4 cm and the same experiment was conducted.
The results are shown in Table 1 (n = 5). As is clear from Table 1, in cash of the preparations of Examples 1 to 5, the effect was observed four hours after the administration and lasted until the preparation was removed from the back, showing a high effect rate. After removing the preparation from the back, the effect quickly disappeared. As to the ointment of Comparative Example 1, a high effect was observed four to eight hours ~~fter the administration but did not last.
The preparation of Comparative Example 2 showed but a low effect four hours after the administration and the preparation 2~643j~
of Comparative Example 3 did not show any effect.
Table I
Effect rate of local anesthesis (%) Time after adherence Time after removal or application (hr) of preparation (hr) Ex. 1 60 100 100 80 80 60 20 Ex. 2 80 100 100 80 100 80 20 Ex. 3 60 80 80 80 20 20 0 Ex. 4 60 80 80 60 20 20 0 Ex. 5 60 100 100 80 60 60 20 Comp. Ex. 1 80 80 60 20 0 0 0 Comp. Ex. 2 0 20 40 20 20 0 0 Comp. Ex. 3 0 0 0 0 0 0 0
In order to protect the drug-retaining layer from the volatilization of water therein, a liner made of a suitable material may also be adhered to the surface of said layer.
The support is preferably made of a flexible material which is capable of cooperating with the movement of the human body and includes, for example, various non-woven fabrics, woven fabrics, spandex, flannel, or a laminate of these materials with polyethylene fi:Lm, polyethylene glycol terephthalate film, polyvinyl chloride film, ethylene-vinyl acetate copolymer film, polyurethane film, and the like.
The external prEaparation for application to the skin of the invention is cap<~ble of releasing the drug quantitatively, is easily handled, and is .capable of being applied for a long period of time. In <~ddition, the external preparation of the invention has the following advantages:
(i) Since the ~~repar~ation of the invention is externally applied to the skin, the first-pass effect through the liver (that is, decomposition of lidocaine occurring when administered orally) can be avoided, and hence, the bioavailability can be increased.
(ii) Since the preparation of the invention is externally applied to the ;skin, the drug is continuously released over a long period of time, and hence, it is expected that the activity of the drug is stably exhibited. In addition, the preparation of the invention can be administered less frequently, and hence, the compliance of patients can be improved.
(iii) The patients suffering from posthepetic neuralgia sometimes feel pain even by the touch of wind or the rubbing of cloth. In such a case, the pain can be reduced by covering the surface of the sl~:in with the external preparation of the invention.
(iv) The preparation of the invention can be administered regardless of the patient's age, health condition, condition of the digestive organs, e.g. stomach or intestines or liver function.
The present imrention is explained in more detail by the following Examples, Comparative Examples and Experiments but should not be construed t~o be limited thereto. In the following Examples <~nd Comparative Examples, "part" or "parts"
means "part by weight" or "parts by weight" unless otherwise mentioned.
Example 1 Lidocaine 5 parts D-Sorbitol 15 parts Glycerin 20 parts Propylene glycol 10 parts Sodium polyacrylate 4 parts Carboxymethylcellulose sodium 5 parts Polyacrylic acid 2 parts Methyl paraoxybenzoate 0.1 part Propyl paraoxybenzoate 0.05 part Aluminum hydroxide 0.3 part Purified water q,s, Total amount 100 parts D-Sorbitol and polyacrylic acid were added to purified water and the mixture was stirred. To the mixture was further added a solution of lidocaine in propylene glycol and the mixture was stirred. Then, to the mixture was added a dispersion of sodium polyacrylate, carboxymethylcellulose sodium, aluminum hyclroxidea, methyl paraoxybenzoate and propyl paraoxybenzoate in g~lycer:en and the mixture was sufficiently stirred until a uniform mixture was obtained. The obtained base was applied onto and spread over a non-woven fabric at 1000 g/m2and a lines- made of polyethylene terephthalate processed with silicone was attached to the base. The obtained preparation. was c:ut to a desired size to give an external preparation. for application to the skin which has a pH value of 7 and contain: 5 mg/cmZOf lidocaine.
A
Examgle 2 Lidocaine 10 parts D-Sorbitol l0 parts Glycerin 2o parts Propylene glycol 10 parts Sodium polyacrylate 4 parts Carboxymethylcellulose sodium 5 parts Polyacrylic acid 3 parts Methyl paraoxybenozate 0.1 part Propyl paraoxybenzoate 0.05 part Aluminum hyroxide 0.3 part Purified water q.s.
Total amount 100 parts The above components were mi xed together in the same manner as in Example 1 to give a base. The obtained base was applied onto and spread over a no n-woven fabric at 1000 g/m2 and a liner made of polyethylene terephthalate processed with silicone was attached to the base . The obtained preparation was cut to a desired size to give an external preparation for application to the shin which has a pH value of 7 and contains 10 mg/cm2of lidocaine.
Example 3 Lidocaine 5 parts Gelatin 1 part Kaolin 1 part D-Sorbitol 15 parts Glycerin 20 parts Propylene glycol 10 parts Sodium polyacrylate 5 parts Carboxymethylcellulo:ae sodium 5 parts Polyacrylic acid 2 parts Urea 1 part Methyl paraoxybenzoai~e 0.1 part Propyl paraoxybenzoai~e 0.05 part Aluminum hydroxide 0.3 part Purified water q.s.
Total amount 100 parts ~~6~~2 To a solution of gela tin and polyacrylic acid in purified water were added kaolin, D-sorbitol and urea and the mixture was well stirred. To the mixture was further added a solution of lidocaine in ropylene glycol and the mixture p was stirred. A dispersion of sodium polyacrylate, carboxymethyl-cellulose sodium, aluminum hydroxide, methyl paraoxybenzoate and propyl paraoxybe~nzoate~in glycerin was added to the mixture and the mixture was stirred until a uniform mixture was obtained. The obtains:d base was applied onto and spread over a non-woven fat~ric 1000 g/m2 and a liner made of at:
polyethylene terephthalate: processed with silicone was attached to the base. The obtained preparation was cut to a desired size to give an e~aernal preparation for application to the skin which has a pea value of 6 and contains 5 mg/cmZOf lidocaine.
Example 4 Lidocaine 5 parts Gelatin 1 part Kaolin 1 part D-Sorbitol 15 parts Glycerin 20 parts Propylene glycol 5 parts Sodium polyacrylate 5 parts Carboxymethylcellulose sodium 5 parts Polyacrylic acid 2 parts Urea 1 part Tartaric acid 1.5 parts Methyl paraoxybenzoate 0.1 part Propyl paraoxybenzoate 0.05 part Dihydroxy aluminum aminoacetate 0.3 part Purified water q.s.
Total amount 100 parts The above components were mixed in the same manner as in Example 3 to give a base. The obtained base was applied onto and spread over a non-woven fabric at 1000 g/m2 and a liner made of polyethylene terephthalate processed with silicone was attached to the base. The obtained preparation was cut to a 20643~~
l0 desired size to give an exaernal preparation for application to the skin which has a pH value of 6 and contains 5 mg/cmZOf lidocaine.
Example 5 Lidocaine 5 parts D-Sorbitol 15 parts Glycerin 20 parts Propylene glycol 10 parts Sodium polyacrylate 4 parts Carboxymethylcellulose sodium 5 parts Polyacrylic acid 2 parts Tartaric acid 0.3 part Methyl paraoxybenzoate 0.1 part Propyl paraoxybenzoate 0.05 part Dihydroxy aluminum aminoacetate 0.3 part Purified water q.s.
Total amount 100 parts The above components were mixed in the same manner as in Example 1 to give a base. The obtained base was applied onto and spread over a non-woven fabric at 1000 g/mz and a liner made of polyethylene terephthalate processed with silicone was attached to the base. The obtained preparation was cut to a desired size to give an external preparation for application to the skin which has a pH value of 7 and contains 5 mg/cm2of lidocaine.
Comparative Example 1 Lidocaine 5 parts White Vaseline* 25 parts Stearyl alcohol 25 parts Propylene glycol 10 parts Polyacrylic acid 2 parts Polyoxyethylated hardened ~~astor oil 4 parts Methyl paraoxybenzoai~e 0.1 part Propyl paraoxybenzoai:e 0.05 part Purified water q.s.
Total amount 100 parts *Trade mark ~0643~~
White Vaseline .and stearyl alcohol were melted on a water bath, mixed well together and kept at about 75°C. A solution of lidocaine in purified water, polyacrylic acid, polyoxy-ethylated hardened castor oil and propylene glycol, and methyl paraoxybenzoate and ~~ropyl paraoxybenzoate were added thereto and the mixture was atirred at room temperature until the mixture solidified to give an ointment which has a pH value of 7 and contains 50 mg,~g of lidocaine.
Comparative Example 2 Lidocaine 5 parts Adhesive plaster base 90 parts Propylene glycol 5 parts Total amount 100 parts A solution of l:idocaine in propylene glycol was added to an adhesive plaster base a:nd the base was applied onto and spread over a non-woven fabric at 1000 g/mZin accordance with a conventional method for ;preparing an adhesive plaster to give a plaster containing .5 mg/cmZOf lidocaine.
Comparative Example 3 Lidocaine 10 parts Propylene glycol 10 parts Styrene-isoprene-styrene (SIS) block copolymer 30 parts Alicyclic saturated hydrocarbon petroleum resin 45 parts Liquid paraffin 4 parts Dibutylhydroxytoluensa 1 part Total amount 100 parts The above components other than lidocaine and propylene glycol were dissolved with heating and thereto was added a solution of lidocainea in propylene glycol and the mixture was stirred. Then, the mixture was applied onto and spread over a suitable non-woven fabric at 500 g/mZand cooled. This base was laminated with polyethylene terephthalate film and the obtained laminate cut: to a desired size to give an external preparation for application to the skin which contains 5 mg/cmz of lidocaine.
206~~2~
Experiment 1 Using a Franz diffusion cell, there was measured the amount of lidocaine which permeated through the skin taken from a rat abdomen by HPLC. The external preparations of Examples 1 to 5 and Comparative Examples 2 and 3 were punched into a circle of 1.7 cm diameter (containing 11.35 mg or 22.7 mg of lidocaine:) and the obtained circular preparations were attached to the: rat skin in the diffusion cell. Using a phosphate buffer (pFt 6.8) in a receptor, the samples were removed from the cell at a constant interval and the amount of the drug which permeated through the skin was measured. As to the ointment of Comparative Example 1, it was applied to the rat skin within a circle of 1.7 cm diameter and the same experiment was conducted.
The results are: shown in Figure 1. As is clear from Figure 1, the drugs permeated through the rat skin over the passage of time in t:he case of the preparations of Examples 1 to 5 and Comparative: Example 1, and hence, the permeability of the preparations of Examples 1 to 5 and Comparative Example 1 were higher than that of the preparations of Comparative Examples 2 and 3.
Experiment 2 After removing hair from the backs of rats, the preparations of Examples 1 to 5 and Comparative Examples 2 and 3 which were cut into a size of 4 cm x 4 cm (containing 80.0 mg or 160.0 mg of lidocaine) were attached to the backs.
While attaching the preparations, 0.5 ml of blood was taken from each of the rats at a constant interval and the amount of lidocaine in the serum wa:~ measured by fluorescent polarization immunoassay. As to the ointment of Comparative Example 1, 1.6 g of the ointment (containing 80.0 mg of lidocaine) was applied to a piece of gauze 4 cm x 4 cm and the same experiment was conducaed.
The results are shown in Figure 2 (n = 4). As is clear from Fig. 2, in the case of the preparations of Examples 1 to 5, blood level of lidocaine reached a constant level six to eight hours after the administration of the drug and was maintained at that level for 24 hours measured from the administration, showing higher blood levels than that of the preparations of Comparative Examples 1 to 3. After removing the drug, blood level was drastically lowered in the case of the preparations of Examples 1 to 5. As to the ointment of Comparative Example 1, blood level was quickly increased after the administration of the drug but did not last, i.e. blood level reached a peak four to five hours after the administration and thereafter decreased. The preparations of Comparative Examples 2 and 3 had a poor transdermal absorbability, and hence, blood level was low.
Experiment 3 After removing :hair from the back of a guinea pig, stimulus was given to the back with a mandolin string to confirm a normal contraction reaction of the epidermis. Then, the preparations of :Examples 1 to 5 and Comparative Examples 2 and 3 which were cut to a size of 4 cm x 4 cm (containing 80.0 mg or 160.0 mg ~~f lidocaine) were attached to the back.
The preparations were removed from the back at a constant interval and stimuli were given to the treated portion six times with the mandolin string. When the contraction reaction of the skin was not ~~bserved more than three times, the local anesthetic action of the preparation was regarded as positive.
As to the ointment of Comparative Example 1, 1.6 g of the ointment (containing 80.0 mg of lidocaine) was applied to a piece of gauze 4 cm :K 4 cm and the same experiment was conducted.
The results are shown in Table 1 (n = 5). As is clear from Table 1, in cash of the preparations of Examples 1 to 5, the effect was observed four hours after the administration and lasted until the preparation was removed from the back, showing a high effect rate. After removing the preparation from the back, the effect quickly disappeared. As to the ointment of Comparative Example 1, a high effect was observed four to eight hours ~~fter the administration but did not last.
The preparation of Comparative Example 2 showed but a low effect four hours after the administration and the preparation 2~643j~
of Comparative Example 3 did not show any effect.
Table I
Effect rate of local anesthesis (%) Time after adherence Time after removal or application (hr) of preparation (hr) Ex. 1 60 100 100 80 80 60 20 Ex. 2 80 100 100 80 100 80 20 Ex. 3 60 80 80 80 20 20 0 Ex. 4 60 80 80 60 20 20 0 Ex. 5 60 100 100 80 60 60 20 Comp. Ex. 1 80 80 60 20 0 0 0 Comp. Ex. 2 0 20 40 20 20 0 0 Comp. Ex. 3 0 0 0 0 0 0 0
Claims (7)
1 Claims 1. An external preparation for application to the skin containing lidocaine which comprises a drug-retaining layer placed on a support, wherein said drug-retaining layer comprises an adhesive gel base and 1 to 10% by weight of lidocaine, said base comprising a water-soluble high molecular weight substance, water and a water-retaining agent.
2. The external preparation of claim 1 wherein said adhesive gel base is capable of controlling the release of drugs and has a pH value of 5 to 9.
3. The external preparation of claim 1 wherein the water content of said adhesive gel base is 20 to 70% by weight.
4. The external preparation of claim 1, 2 or 3 wherein said water-soluble high molecular weight substance is selected from the group consisting of gelatin, starch, agar, mannan, alginic acid, polyacrylic acid, a salt of polyacrylic acid, dextrin, methylcellulose, methylcellulose sodium, carboxymethylcellulose, carboxymethylcellulose sodium, polyvinyl alcohol, polyvinyl pyrrolidone, copolymer of methyl vinyl ether and maleic anhydride, gum arabic, tragacanth, karaya gum and locust bean gum.
5. The external preparation of claim 1, 2, or 3 wherein said water-retaining agent is selected from the group consisting of ethylene glycol, diethylene glycol, polyethylene glycol, glycerin, sorbitol, martitol, propylene glycol and 1,3-butylene glycol.
6. The external preparation of claim 1, 2 or 3 wherein said drug-retaining layer further comprises an absorbing agent and a surfactant.
7. The external preparation of claim 1, 2 or 3 wherein said drug-retaining layer further comprises an absorbing agent and a surfactant and said absorbing agent is selected from the group consisting of salicylic acid, hyaluronic said, oleic acid, N,N-diethyl-m-toluamide, n-butyl stearate, benzyl alcohol, isopropyl myristate, isopropyl palmitate, polypropylene glycol, crotamiton, diethyl sebacate, N-methylpyrrolidone, N-ethylpyrrolidone and lauryl alcohol, and said surfactant is selected from the group consisting of polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, sorbitan monooleate and sorbitan monopalmitate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP067353/1991 | 1991-03-30 | ||
| JP03067353A JP3115625B2 (en) | 1991-03-30 | 1991-03-30 | Topical patch containing lidocaine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2064325A1 CA2064325A1 (en) | 1992-10-01 |
| CA2064325C true CA2064325C (en) | 2002-05-28 |
Family
ID=13342573
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002064325A Expired - Lifetime CA2064325C (en) | 1991-03-30 | 1992-03-27 | External preparation for application to the skin containing lidocaine |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US5827529A (en) |
| EP (1) | EP0507160B1 (en) |
| JP (1) | JP3115625B2 (en) |
| AT (1) | ATE149351T1 (en) |
| CA (1) | CA2064325C (en) |
| DE (1) | DE69217685T2 (en) |
| ES (1) | ES2100970T3 (en) |
| SG (1) | SG50517A1 (en) |
Families Citing this family (121)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0594233U (en) * | 1992-05-22 | 1993-12-24 | 啓恵 小泉 | Anti-perspirant sun visor and anti-perspirant |
| JPH07157424A (en) * | 1993-12-03 | 1995-06-20 | Lintec Corp | Gel formulation for local anesthesia |
| DE4416927C1 (en) * | 1994-05-13 | 1995-08-31 | Lohmann Therapie Syst Lts | Device for release of active agents from melt-type adhesive |
| SK284332B6 (en) | 1996-10-14 | 2005-01-03 | Kowa Company, Ltd. | Local anaesthetic for external use |
| US5977143A (en) | 1997-02-15 | 1999-11-02 | Edelstam; Greta | Medicament against infertility which reduces phagocytosis of spermatozoa in women |
| NZ504108A (en) | 1997-09-26 | 2002-06-28 | Noven Pharma | Bioadhesive compositions comprising a polyvinylpyrrolidone polymer and methods for topical administration of active agents |
| WO2000019986A1 (en) * | 1998-10-05 | 2000-04-13 | Yutoku Pharmaceutical Ind. Co. Ltd. | Tape material for transcutaneous absorption |
| US6093417A (en) * | 1999-01-11 | 2000-07-25 | Advanced Medical Instruments | Composition to treat ear disorders |
| US6413699B1 (en) | 1999-10-11 | 2002-07-02 | Macdermid Graphic Arts, Inc. | UV-absorbing support layers and flexographic printing elements comprising same |
| US6383511B1 (en) | 1999-10-25 | 2002-05-07 | Epicept Corporation | Local prevention or amelioration of pain from surgically closed wounds |
| JP4774179B2 (en) * | 1999-12-27 | 2011-09-14 | 帝國製薬株式会社 | External patch |
| KR100362924B1 (en) * | 2000-01-11 | 2002-11-30 | 주식회사 동구약품 | Epidermal preparations |
| US6455066B1 (en) | 2000-03-10 | 2002-09-24 | Epicept Corporation | Intradermal-penetration agents for topical local anesthetic administration |
| US6698162B2 (en) | 2000-03-23 | 2004-03-02 | Teikoku Pharma Usa, Inc. | Methods of producing a terminally sterilized topical patch preparation |
| KR20020026402A (en) * | 2000-10-02 | 2002-04-10 | 한상철 | Compositions containing local anesthesia for topical application which have an improved skin permeation rate |
| JP4820024B2 (en) | 2001-01-10 | 2011-11-24 | 昭和薬品化工株式会社 | Local anesthetic composition |
| JP4317693B2 (en) * | 2001-05-31 | 2009-08-19 | ニプロパッチ株式会社 | Pharmaceutical composition for percutaneous absorption |
| US6846846B2 (en) * | 2001-10-23 | 2005-01-25 | The Trustees Of Columbia University In The City Of New York | Gentle-acting skin disinfectants |
| DE60213457T2 (en) | 2001-12-03 | 2007-10-18 | Ekos Corp., Bothell | ULTRASONIC CATHETER FOR SMALL VESSELS |
| AU2002359576A1 (en) | 2001-12-03 | 2003-06-17 | Ekos Corporation | Catheter with multiple ultrasound radiating members |
| US7879365B2 (en) * | 2002-02-07 | 2011-02-01 | The Trustees Of Columbia University In The City Of New York | Zinc salt compositions for the prevention of dermal and mucosal irritation |
| WO2003072165A2 (en) | 2002-02-28 | 2003-09-04 | Ekos Corporation | Ultrasound assembly for use with a catheter |
| US20030198616A1 (en) * | 2002-04-23 | 2003-10-23 | Combe Incorporated | Moisturizing skin gel and method |
| US7338433B2 (en) | 2002-08-13 | 2008-03-04 | Allergan, Inc. | Remotely adjustable gastric banding method |
| ES2339009T3 (en) | 2002-08-28 | 2010-05-14 | Allergan, Inc. | FATIGUE RESISTANT GASTRIC BAND DEVICE. |
| US6800295B2 (en) * | 2002-10-09 | 2004-10-05 | The Dial Corporation | Water soluble sheet composition |
| US20040076671A1 (en) * | 2002-10-21 | 2004-04-22 | Aletha Tippett | Methods and compositions for topical wound treatment |
| DE10260872B4 (en) * | 2002-12-23 | 2013-09-26 | Beiersdorf Ag | Use of gelling polymer, water, alcohol and seaweed extract for adjusting the elasticity and adhesion of self-adhesive cosmetic polymer matrices |
| US7993654B2 (en) | 2002-12-23 | 2011-08-09 | Beiersdorf Ag | Self-adhesive polymer matrix containing sea algae extract |
| DE10260873A1 (en) * | 2002-12-23 | 2004-07-15 | Beiersdorf Ag | Self-adhesive polymer matrix containing marine algae extract and glycerin |
| WO2004060448A2 (en) | 2003-01-03 | 2004-07-22 | Ekos Corporation | Ultrasonic catheter with axial energy field |
| FR2861734B1 (en) | 2003-04-10 | 2006-04-14 | Corneal Ind | CROSSLINKING OF LOW AND HIGH MOLECULAR MASS POLYSACCHARIDES; PREPARATION OF INJECTABLE SINGLE PHASE HYDROGELS; POLYSACCHARIDES AND HYDROGELS OBTAINED |
| EP1619995A2 (en) | 2003-04-22 | 2006-02-01 | Ekos Corporation | Ultrasound enhanced central venous catheter |
| BRPI0412675A (en) | 2003-07-17 | 2006-10-03 | Univ Columbia | antimicrobial compositions containing synergistic combinations of quaternary ammonium compounds and essential oils and / or constituents |
| ES2399951T3 (en) | 2004-01-23 | 2013-04-04 | Allergan, Inc. | Adjustable gastric band of a piece that can be fixed releasably |
| CA2551831A1 (en) * | 2004-01-29 | 2005-08-11 | Ekos Corporation | Small vessel ultrasound catheter |
| DE602005016901D1 (en) | 2004-03-08 | 2009-11-12 | Allergan Medical S A | CLOSING SYSTEM FOR TUBULAR ORGANS |
| EP1732635B1 (en) | 2004-03-18 | 2011-07-27 | Allergan, Inc. | Apparatus for volume adjustment of intragastric balloons |
| PL1863469T3 (en) * | 2005-03-15 | 2012-05-31 | Animal Ethics Pty Ltd | A topical analgesic composition |
| WO2006099541A2 (en) * | 2005-03-15 | 2006-09-21 | Richard Daniel Carliss | Therapeutic wound care product |
| US8251888B2 (en) | 2005-04-13 | 2012-08-28 | Mitchell Steven Roslin | Artificial gastric valve |
| US20060240084A1 (en) * | 2005-04-20 | 2006-10-26 | Xylos Corporation | Microbial cellulose materials for use in transdermal drug delivery systems, method of manufacture and use |
| US20060263415A1 (en) | 2005-05-05 | 2006-11-23 | Sensient Flavors Inc. | Production of beta-glucans and mannans |
| DE102005053909A1 (en) | 2005-05-13 | 2006-11-16 | Beiersdorf Ag | Self-adhesive skin layer and combination set for cosmetic skin care |
| US20070093555A1 (en) | 2005-10-24 | 2007-04-26 | Jutaro Shudo | Topical pain relief compositions of N,2,3-trimethyl-2-isopropylbutamide and methods for using the same |
| DE102005059058A1 (en) | 2005-12-08 | 2007-06-14 | Beiersdorf Ag | Acrylic adhesive with waterproof adhesive properties |
| US8043206B2 (en) | 2006-01-04 | 2011-10-25 | Allergan, Inc. | Self-regulating gastric band with pressure data processing |
| US7798954B2 (en) | 2006-01-04 | 2010-09-21 | Allergan, Inc. | Hydraulic gastric band with collapsible reservoir |
| US8337883B2 (en) | 2006-11-03 | 2012-12-25 | Durect Corporation | Transdermal delivery systems |
| US10182833B2 (en) | 2007-01-08 | 2019-01-22 | Ekos Corporation | Power parameters for ultrasonic catheter |
| US20080293637A1 (en) | 2007-05-23 | 2008-11-27 | Allergan, Inc. | Cross-linked collagen and uses thereof |
| US9044568B2 (en) | 2007-06-22 | 2015-06-02 | Ekos Corporation | Method and apparatus for treatment of intracranial hemorrhages |
| US8318695B2 (en) * | 2007-07-30 | 2012-11-27 | Allergan, Inc. | Tunably crosslinked polysaccharide compositions |
| EP2187969A2 (en) * | 2007-08-17 | 2010-05-26 | Arcion Therapeutics, Inc. | High concentration local anesthetic formulations |
| US8697044B2 (en) | 2007-10-09 | 2014-04-15 | Allergan, Inc. | Crossed-linked hyaluronic acid and collagen and uses thereof |
| WO2009065116A1 (en) | 2007-11-16 | 2009-05-22 | Aspect Pharmaceuticals Llc | Compositions and methods for treating purpura |
| US8394784B2 (en) | 2007-11-30 | 2013-03-12 | Allergan, Inc. | Polysaccharide gel formulation having multi-stage bioactive agent delivery |
| US8394782B2 (en) | 2007-11-30 | 2013-03-12 | Allergan, Inc. | Polysaccharide gel formulation having increased longevity |
| JP2010024223A (en) | 2008-06-16 | 2010-02-04 | Teikoku Seiyaku Co Ltd | Oxybuprocaine-containing analgesic/antipruritic preparation for external use |
| US8357795B2 (en) | 2008-08-04 | 2013-01-22 | Allergan, Inc. | Hyaluronic acid-based gels including lidocaine |
| US8119694B2 (en) | 2008-08-15 | 2012-02-21 | Arcion Therapeutics, Inc. | High concentration local anesthetic formulations |
| EP2324064B1 (en) | 2008-09-02 | 2017-11-08 | Tautona Group LP | Threads of hyaluronic acid and/or derivatives thereof, methods of making thereof and uses thereof |
| PL2344329T3 (en) | 2008-10-02 | 2013-05-31 | Mylan Inc | Method of making a multilayer adhesive laminate |
| US8317677B2 (en) | 2008-10-06 | 2012-11-27 | Allergan, Inc. | Mechanical gastric band with cushions |
| US20100305397A1 (en) * | 2008-10-06 | 2010-12-02 | Allergan Medical Sarl | Hydraulic-mechanical gastric band |
| US20100185049A1 (en) | 2008-10-22 | 2010-07-22 | Allergan, Inc. | Dome and screw valves for remotely adjustable gastric banding systems |
| EP2349337A1 (en) * | 2008-11-06 | 2011-08-03 | Nuvo Research Inc. | Formulations for the treatment of acute herpes zoster pain |
| WO2010114121A1 (en) * | 2009-04-02 | 2010-10-07 | ダイヤ製薬株式会社 | Aqueous gel base and aqueous gel plaster |
| JP5758290B2 (en) | 2009-05-01 | 2015-08-05 | 久光製薬株式会社 | Transdermal preparation |
| US8390326B2 (en) * | 2009-05-05 | 2013-03-05 | William Marsh Rice University | Method for fabrication of a semiconductor element and structure thereof |
| US20110092881A1 (en) * | 2009-05-08 | 2011-04-21 | Isis Biopolymer Inc. | Iontophoretic device with contact sensor |
| JP2012525943A (en) * | 2009-05-08 | 2012-10-25 | アイシス バイオポリマー，インク． | Iontophoresis device with improved counter electrode |
| WO2011074015A2 (en) | 2009-12-17 | 2011-06-23 | Themis Medicare Limited | Novel composition of pharmaceutical product to treat sexual dysfunction |
| US20110172180A1 (en) | 2010-01-13 | 2011-07-14 | Allergan Industrie. Sas | Heat stable hyaluronic acid compositions for dermatological use |
| US9114188B2 (en) | 2010-01-13 | 2015-08-25 | Allergan, Industrie, S.A.S. | Stable hydrogel compositions including additives |
| US8758221B2 (en) | 2010-02-24 | 2014-06-24 | Apollo Endosurgery, Inc. | Source reservoir with potential energy for remotely adjustable gastric banding system |
| US8840541B2 (en) * | 2010-02-25 | 2014-09-23 | Apollo Endosurgery, Inc. | Pressure sensing gastric banding system |
| AU2010348090B2 (en) * | 2010-03-12 | 2015-09-03 | Allergan Industrie Sas | A fluid composition comprising a hyaluronan polymer and mannitol for improving skin condition |
| ES2729994T3 (en) | 2010-03-22 | 2019-11-07 | Allergan Inc | Crosslinked polysaccharide and protein polysaccharide hydrogels for soft tissue augmentation |
| TWI506117B (en) * | 2010-03-23 | 2015-11-01 | Nipro Patch Co Ltd | Water - based adhesive |
| CA2796575C (en) | 2010-04-13 | 2018-05-15 | Relmada Therapeutics, Inc. | Dermal pharmaceutical compositions of 1-methyl-2',6'-pipecoloxylidide and method of use |
| US9044298B2 (en) | 2010-04-29 | 2015-06-02 | Apollo Endosurgery, Inc. | Self-adjusting gastric band |
| US9028394B2 (en) | 2010-04-29 | 2015-05-12 | Apollo Endosurgery, Inc. | Self-adjusting mechanical gastric band |
| US20110270024A1 (en) | 2010-04-29 | 2011-11-03 | Allergan, Inc. | Self-adjusting gastric band having various compliant components |
| US20110270025A1 (en) | 2010-04-30 | 2011-11-03 | Allergan, Inc. | Remotely powered remotely adjustable gastric band system |
| US8517915B2 (en) | 2010-06-10 | 2013-08-27 | Allergan, Inc. | Remotely adjustable gastric banding system |
| US20120046354A1 (en) * | 2010-08-18 | 2012-02-23 | Ehrenpreis Eli D | Anti-oxidant lozenges for the prevention and treatment of radiation induced mucositis, precancerous lesions, oral cancer and other oral cavity mucosal disorders |
| US8883139B2 (en) | 2010-08-19 | 2014-11-11 | Allergan Inc. | Compositions and soft tissue replacement methods |
| US8697057B2 (en) | 2010-08-19 | 2014-04-15 | Allergan, Inc. | Compositions and soft tissue replacement methods |
| US8889123B2 (en) | 2010-08-19 | 2014-11-18 | Allergan, Inc. | Compositions and soft tissue replacement methods |
| US9005605B2 (en) | 2010-08-19 | 2015-04-14 | Allergan, Inc. | Compositions and soft tissue replacement methods |
| WO2012029097A1 (en) * | 2010-09-03 | 2012-03-08 | 株式会社ケイ・エム トランスダーム | Transdermal preparation |
| US20120059216A1 (en) | 2010-09-07 | 2012-03-08 | Allergan, Inc. | Remotely adjustable gastric banding system |
| US8961393B2 (en) | 2010-11-15 | 2015-02-24 | Apollo Endosurgery, Inc. | Gastric band devices and drive systems |
| JP5875246B2 (en) * | 2010-12-10 | 2016-03-02 | 日東電工株式会社 | Sheet-form preparation and method for producing sheet-form preparation |
| EP2708229B1 (en) | 2011-05-10 | 2019-07-31 | Itochu Chemical Frontier Corporation | Non-aqueous patch |
| US11786455B2 (en) | 2011-05-10 | 2023-10-17 | Itochu Chemical Frontier Corporation | Non-aqueous patch |
| US9925264B2 (en) | 2011-05-10 | 2018-03-27 | Itochu Chemical Frontier Corporation | Non-aqueous patch |
| US20130096081A1 (en) | 2011-06-03 | 2013-04-18 | Allergan, Inc. | Dermal filler compositions |
| US9393263B2 (en) | 2011-06-03 | 2016-07-19 | Allergan, Inc. | Dermal filler compositions including antioxidants |
| US9408797B2 (en) | 2011-06-03 | 2016-08-09 | Allergan, Inc. | Dermal filler compositions for fine line treatment |
| CN103702659B (en) | 2011-06-03 | 2016-12-21 | 阿勒根公司 | Dermal filler composition including antioxidant |
| CN103608009B (en) * | 2011-06-20 | 2015-04-29 | 久光制药株式会社 | Lidocaine-containing cataplasm |
| AU2012297609A1 (en) * | 2011-08-25 | 2014-03-27 | Nipro Patch Co., Ltd. | Hydrous adhesive skin patch |
| US20130244943A1 (en) | 2011-09-06 | 2013-09-19 | Allergan, Inc. | Hyaluronic acid-collagen matrices for dermal filling and volumizing applications |
| US9662422B2 (en) | 2011-09-06 | 2017-05-30 | Allergan, Inc. | Crosslinked hyaluronic acid-collagen gels for improving tissue graft viability and soft tissue augmentation |
| CA2850024C (en) | 2011-09-27 | 2020-07-07 | Itochu Chemical Frontier Corporation | Non-aqueous patch comprising lidocaine |
| US8876694B2 (en) | 2011-12-07 | 2014-11-04 | Apollo Endosurgery, Inc. | Tube connector with a guiding tip |
| US8961394B2 (en) | 2011-12-20 | 2015-02-24 | Apollo Endosurgery, Inc. | Self-sealing fluid joint for use with a gastric band |
| WO2014159815A1 (en) * | 2013-03-13 | 2014-10-02 | RINGVOLD, Fredrik, Ove Haug | Externally heated thermal pack |
| WO2014159798A1 (en) * | 2013-03-13 | 2014-10-02 | Avery Dennison Corporation | Improving adhesive properties |
| JP6608382B2 (en) | 2014-02-26 | 2019-11-20 | ルマ セラピューティクス，インク． | Ultraviolet light treatment apparatus and method |
| US10722444B2 (en) | 2014-09-30 | 2020-07-28 | Allergan Industrie, Sas | Stable hydrogel compositions including additives |
| EP3212162A2 (en) | 2014-10-31 | 2017-09-06 | Avent, Inc. | Method and articles for inhibiting bladder contractions |
| WO2016128783A1 (en) | 2015-02-09 | 2016-08-18 | Allergan Industrie Sas | Compositions and methods for improving skin appearance |
| EP3307388B1 (en) | 2015-06-10 | 2022-06-22 | Ekos Corporation | Ultrasound catheter |
| CN109310527A (en) | 2016-02-09 | 2019-02-05 | 鲁玛治疗公司 | For treating psoriasic method, composition and equipment by light therapy |
| KR102132590B1 (en) * | 2018-08-10 | 2020-07-13 | 대화제약 주식회사 | A composition comprising local anesthetics and sodium polyacrylate |
| CN109172546A (en) * | 2018-09-26 | 2019-01-11 | 北京茗泽中和药物研究有限公司 | Lidocaine gel emplastrum |
| CN109200033A (en) * | 2018-09-26 | 2019-01-15 | 北京茗泽中和药物研究有限公司 | A kind of lidocaine gel emplastrum |
| DE202021003113U1 (en) | 2021-10-04 | 2021-10-21 | Qais Aburok | Active ingredient combination of lidocaine and allcin against irritation of the skin and mucous membranes |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3797494A (en) * | 1969-04-01 | 1974-03-19 | Alza Corp | Bandage for the administration of drug by controlled metering through microporous materials |
| US4914131A (en) * | 1984-03-08 | 1990-04-03 | Dana P. Brigham | Antiviral pharmaceutical preparations and methods for their use |
| US4628063A (en) * | 1984-03-08 | 1986-12-09 | Dana P. Brigham | Antiviral pharmaceutical preparations and methods for their use |
| US4834978A (en) * | 1984-10-01 | 1989-05-30 | Biotek, Inc. | Method of transdermal drug delivery |
| DE3722775A1 (en) * | 1987-07-09 | 1989-01-19 | Lohmann Therapie Syst Lts | TRANSDERMAL THERAPEUTIC SYSTEM |
| US5059189A (en) * | 1987-09-08 | 1991-10-22 | E. R. Squibb & Sons, Inc. | Method of preparing adhesive dressings containing a pharmaceutically active ingredient |
| US5002974A (en) * | 1988-04-04 | 1991-03-26 | Warner-Lambert Co. | Anesthetic/skin moisturizing composition and method of preparing same |
| GB8810951D0 (en) * | 1988-05-09 | 1988-06-15 | Innovata Biomed Ltd | Buccal local anaesthetic |
| CA1338779C (en) * | 1989-03-17 | 1996-12-10 | Harry Hind | Method for treating pain associated with herpes-zoster and post-herpetic neuralgia by topical application of local anesthetics |
| US5120544A (en) * | 1989-06-19 | 1992-06-09 | Henley International, Inc. | Crosslinked hydrogel and method for making same |
-
1991
- 1991-03-30 JP JP03067353A patent/JP3115625B2/en not_active Expired - Lifetime
-
1992
- 1992-03-20 ES ES92104883T patent/ES2100970T3/en not_active Expired - Lifetime
- 1992-03-20 DE DE69217685T patent/DE69217685T2/en not_active Expired - Lifetime
- 1992-03-20 SG SG1996003288A patent/SG50517A1/en unknown
- 1992-03-20 AT AT92104883T patent/ATE149351T1/en not_active IP Right Cessation
- 1992-03-20 EP EP92104883A patent/EP0507160B1/en not_active Expired - Lifetime
- 1992-03-27 CA CA002064325A patent/CA2064325C/en not_active Expired - Lifetime
-
1994
- 1994-06-10 US US08/258,378 patent/US5827529A/en not_active Expired - Lifetime
Also Published As
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|---|---|
| SG50517A1 (en) | 1998-07-20 |
| JP3115625B2 (en) | 2000-12-11 |
| ATE149351T1 (en) | 1997-03-15 |
| DE69217685D1 (en) | 1997-04-10 |
| JPH04305523A (en) | 1992-10-28 |
| ES2100970T3 (en) | 1997-07-01 |
| EP0507160A1 (en) | 1992-10-07 |
| CA2064325A1 (en) | 1992-10-01 |
| DE69217685T2 (en) | 1997-06-12 |
| US5827529A (en) | 1998-10-27 |
| EP0507160B1 (en) | 1997-03-05 |
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