WO1999055287A1 - Topical anesthetic formulation - Google Patents
Topical anesthetic formulation Download PDFInfo
- Publication number
- WO1999055287A1 WO1999055287A1 PCT/US1999/009069 US9909069W WO9955287A1 WO 1999055287 A1 WO1999055287 A1 WO 1999055287A1 US 9909069 W US9909069 W US 9909069W WO 9955287 A1 WO9955287 A1 WO 9955287A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formulation
- prilocaine
- lidocaine
- anesthetic
- weight
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- 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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
Definitions
- This invention relates to a new formulation of a topical anesthetic and, more particularly, to a fast acting transdermal, topical anesthetic formulation having improved stability.
- Surgical techniques such as cosmetic resurfacing involving surgical ablation with an Erbium:YAG laser, and other laser procedures involving vaporization, excision, incision, and coagulation of soft tissue in medical specialties including dermatology, plastic surgery, podiatry, neurosurgery, gynecology, otorhinolaryngology (ENT) , arthroscopy (knee surgery) , and invasive and endoscopic general surgery, can only be performed after the highly sensitive nerve endings in the skin are anesthetized.
- the preferred method of administration of anesthetic is transdermally.
- the skin is a daunting barrier to the absorption of analgesics. Because the skin must serve as a barrier to the ingress of pathogens and toxic materials, and the egress of physiologic fluids, the skin is highly impermeable. Impermeability allows the skin to preserve its own integrity while simultaneously maintaining the delicate dynamic electrolyte balance of the body. Therefore, the skin functions both as a containment mechanism and as a microbial, chemical, radiation and thermal barrier.
- This impermeability may be attributed to the nature of one very thin layer created by normal development and physiological changes in the skin. After cells are formed in the basal layer, they begin to migrate toward the skin surface, until they are eventually sloughed off. As they undergo this migration, they become progressively more dehydrated and keratinized. When they reach the surface, just prior to being discarded, they form a thin layer of dense, metabolically inactive cells approximately ten microns (10-15 cells) thick, the stratum corneum or "cornified layer" . As a result of the high degree of keratinization of the cells which comprise the stratum corneum, a daunting barrier is created. Absorption through a mucosal surface is generally efficient because the stratum corneum is absent. Therefore, any formulation to be utilized as an efficient topical, transdermal anesthetic must be capable of being readily absorbed through the skin.
- percutaneous or transdermal absorption can significantly alter drug kinetics and depends on a variety of factors including site of application, size of active drug molecule, permeability of the membrane of the transdermal drug delivery system, state of skin hydration, pH of the drug, drug metabolism by skin flora, lipid solubility, and alteration of blood flow in the skin by additives and body temperature.
- topical, transdermal anesthetics in dental applications such as in applying an anesthetic to the gum prior to injecting anesthetic.
- mucous membranes such as the lining of the mouth
- topical anesthetics are readily absorbed and work well.
- the mechanics and physiology of absorption are much different.
- Transdermal anesthetics are also useful for numbing an area prior to venipuncture , such as blood drawing. Pain relief is especially important in the area of pediatrics, where even minimal pain may result in an anxious and uncooperative patient .
- transdermal delivery In addition to its advantages over intravenous delivery, other advantages of transdermal delivery include avoidance of risks associated with parenteral treatment, elimination of the inconveniences of parenteral treatment; and elimination of gastrointestinal irritation resulting from exposing the gastrointestinal tract to pharmaceutical actives, preservatives, tableting agents, and the like.
- ethyl chloride chloroethane
- ethyl chloride has many disadvantages. It is difficult to numb large areas with these methods and the effect is short-lived, rarely lasting more than a few seconds to a minute. Further, ethyl chloride is flammable and, when used to produce local freezing, adjacent skin areas must be protected by application of petrolatum. Finally, the thawing process may be painful, and freezing may lower local resistance to infection and delay healing.
- Cocaine solutions are also known, and act by blocking the initiation or conduction of the nerve pulse.
- TAC a mixture of tetracaine, adrenaline and cocaine
- system levels of cocaine have been documented after simple application of TAC soaked-pledgets to an open wound, thus, emphasizing the need for calculating and the limiting the dose of cocaine administered.
- Strict limitation of the total dose of each component according to the patient ' s lean body weight is crucial. As with any narcotic, the potential exists for respiratory depression and oxygen desaturation with the moderately rapid absorption through any mucosa.
- Lidocaine is highly effective and is the most commonly used local anesthetic in the United States, especially in the form of aqueous solutions of lidocaine hydrochloride
- Lidocaine® (Xylocaine®) , which are administered intravenously through either direct injection or continuous infusion. Lidocaine stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses thereby effecting local anesthetic action. Lidocaine is also formulated as a jelly (Xylocaine® 2%), ointment, and spray for use as an anesthetic. Unfortunately, these formulations are only effectively absorbed through mucosal surfaces, not the skin.
- EMLA® cream Eutectic Mixture of Local Anesthetics
- EMLA® is an oil-in-water emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 1:1 by weight (2.5% and 2.5%, respectively), and comprising 92% purified water.
- a eutectic mixture is a mixture that has a melting point lower than that of its ingredients; therefore these two anesthetics after being heated and mixed exist as a liquid oil at room temperature, rather than as crystals.
- EMLA® cream is described in U.S. Pat. Nos. 4,529,601 (Broberg, et al . ) and 4,562,060 (Broberg, et al . ) , which teach the mixing of specific proportions of certain local anesthetic agents in the form of their base in order to form a homogenous oil having a melting point below 40° C, preferably below 25° C.
- prilocaine is an amide-type local anesthetic agent.
- Amides are favorable as anesthetic agents, as opposed to esters, which are more sensitizing and can produce redness, swelling, irritation, itching, and other reactions.
- methemoglobinaemia and cyanosis appear to occur more frequently with prilocaine than with other local anesthetics.
- Methemoglobinaemia describes the formation of oxidized iron compound in the heme protein of the red blood cell. It is a disease state of the erythrocyte . Cellular oxidant stress causes a structural change in the hemogloblin. If the oxidant stress is too great, methemoglobin levels rise and erythrocyte function is compromised.
- a major inconvenience with EMLA® is that local anesthesia of intact skin is not achieved until at least 60 minutes following application. For more invasive procedures, such as split skin graft harvesting, at least two hours may be required. This delay in onset is a significant disadvantage, as it is a great inconvenience for both patients and medical staff. Such delay is particularly a problem in the area of pediatrics, where any additional time spent awaiting treatment only contributes to the anxiety of the patient.
- EMLA® cream Another disadvantage with EMLA® cream is that , for deep penetrative effect, it is necessary that the cream be applied under an occlusive dressing. Specifically, a bilayer of laminate and absorbent cellulose is taped to the area of the skin to be anesthetized. Such a dressing is inconvenient and
- Another object of the present invention is to provide a topical, transdermal anesthetic which exhibits comparably rapid onset .
- Yet another object of the present invention is to provide a topical, transdermal anesthetic which is not dependent upon occlusive dressing for rapid absorption through the skin.
- transdermal anesthetic formulation is produced which has significantly more rapid onset than comparable transdermal anesthetics, such as EMLA® cream.
- EMLA® cream a transdermal anesthetic formulation
- the anesthetic of the present invention works in as little as 10 to 40 minutes without occlusion.
- the present formulation is particularly useful prior to laser procedures requiring vaporation, excision, incision, and coagulation of soft tissue in medical specialties including dermatology, plastic surgery, podiatry, neurosurgery,
- the present invention is directed to a topical, transdermal anesthetic preparation comprising (with all percentages being by weight) : about 10-20%, preferably about 15% lidocaine; about 1-5%, preferably about 5% prilocaine; about 0.0-1.0%, preferably about 0.75% dibucaine; about 0.0-2.0%, preferably 0.5-1.0%, as effective for local vasoconstriction, of a sympathomimetic amine, preferably phenylephrine; and the balance being a lipophilic base; wherein the lidocaine and prilocaine are in the form of a eutectic mixture in a ratio of from a weight ratio of from about 15:1 to about 2:1.
- the ratio of lidocaine to prilocaine is from 8:1 to 2:1, most preferably about 3:1. While the recited analgesics are preferred, certain substitutions may be permissible.
- phenylephrine preferably serves as a vasoconstrictor to facilitate localization of the effect.
- Other sympathomimetic amines that may be utilized will be described hereinafter.
- the lipophilic based formulation of the present invention is one which contains no, or substantially no, aqueous component or aqueous functional-equivalent .
- the definition of lipophilic base is not particularly limited, and
- any of those known in the pharmaceutical and cosmetic industries may be employed, and includes lipophilic materials modified with thickeners, thinners, stabilizers, surfactants, etc .
- at least one of said anesthetics is selected from the group consisting of prilocaine and lidocaine.
- the formulation of the present invention is free of the pronounced dosage limitations of other prilocaine-containing transdermal anesthetics. Further, the formulation is, advantageously, not dependent upon occlusive dressing for optimal transdermal absorption.
- the present formulation may be used in lieu of infiltration anesthetics for minor procedures, or in conjunction with such anesthetics for more invasive procedures.
- Cosmetic applications include, but are not limited to laser resurfacing, electrolysis, permanent makeup application, body piercing, and tattooing.
- the formulation may also be utilized in post-operatory pain relief therapy, especially in pediatrics and overly emotional patients.
- An advantage, as well as a major distinguishing feature, of the formulation of the present invention is attributable first to the eutectic mixture of the two preferred anesthetic agents, lidocaine and prilocaine, in the respective proportionate ratio of approximately 15:1 to 2:1 by weight; second, in the amount of the eutectic mixture in the lipophilic vehicle; and thirdly, in the utilization of a lipophilic base rather than an aqueous vehicle or an oil-in-water emulsion (the term "water”, when referring to oil-in-water emulsions, includes hydrophilic liquids which serve as water substitutes) .
- the formulation of the present invention preferably contains from 10% to 20% by weight lidocaine and 1% to 5% by weight prilocaine based upon the total weight of formulation.
- the formulation contains about 20% by weight lidocaine and about 5% by weight prilocaine.
- the present lipophilic based formulation exhibits superior properties, including accelerated rate of onset, lack of pronounced dosage-limitations normally characteristic of other prilocaine transdermal anesthetics, and no dependency upon occlusive dressing for optimum transdermal absorption.
- the present invention is not particularly limited, and any of those known in the pharmaceutical and cosmetic industries may be employed, and includes lipophilic materials modified with thickeners, thinners, stabilizers, surfactants, etc.
- lipophilic materials an oleaginous material such as petrolatum, mineral oil thickened or gelled with polyethylene, high molecular weight paraffin waxes, mono and diglycerides of fatty acids gelled with high molecular weight fatty acids or polyamide complex of hydroxystearate, propylene glycol isostearate or isostearyl alcohol gelled with high molecular weight fatty acids and mixtures thereof may be used.
- the lipophilic base should satisfy the following characteristics : the base must allow the oils, and particularly the eutectic mixture, to be completely miscible therein; the base must be compatible with the skin with the least possible number of adverse reactions; the base must be smooth and pliable with no adverse odor; the base should have a color appealing to the consumer; the base must be stable and must provide a stable vehicle
- the base should be hydrophobic, i.e., have a low water absorbing capacity; and the base should be able to readily release the medication incorporated therein into the skin.
- the lipophilic component is a higher aliphatic alcohol, preferably of 8-18 carbon atoms, or an ester thereof.
- oleagenous (lipophilic) ointment bases include White Ointment USP, Yellow Ointment NF, Oleic Acid USP, Olive Oil USP, Paraffin USP, Petrolatum NF, White Petrolatum USP, Spermaceti Wax USP, Syntheticspermaceti NF, Starch Glycerite NF, White Wax USP, and Yellow Wax USP.
- Lidocaine is chemically designated as an acetamide, 2- (diethylamino) -N (2 , 6-dimethylphenyl) and has an octanol : water partition ratio of 43 at pH 7.4.
- Prilocaine is chemically designated as a propanamide, N- (2 -methyl-phenyl) -2- (propylamino) and has an octanol :water partition ratio of 25 at pH 7.4.
- lidocaine and prilocaine exist in the formulation as an eutectic mixture in the ratio of about 3:1.
- the formulation of the present invention provides dermal analgesia by the release of lidocaine and prilocaine from the formulation into the epidermal and dermal layers of the skin and the accumulation of lidocaine and prilocaine in the vicinity of dermal pain receptors and nerve endings.
- Lidocaine and prilocaine are amide-type local anesthetic agents. Both lidocaine and prilocaine stabilize neuronal membranes by inhibiting the ionic fluxes required for the initiation of and conduction of impulses, thereby effecting local anesthetic action.
- the dose of the present formulation which provides effective analgesia depends in part on the duration of the application over the treated area.
- At least one sympathomimetic amine is preferably added to the formulation for its ability to mimic stimulation of the sympathetic nervous system. Specifically, when used with topical anesthetics, such amines act as vasoconstrictors to limit the locality of the anesthetic effect.
- Sympathomimetic amines that may be used in the preparation of the present invention include, but are not limited to, adrenaline, amezinium metilsulphate, cinnamedrine, clonazoline, clorprenaline, coumazoline, cyclopentamine, dimepropion, dimetofrine, dipivefrine, ephedra, ephedrine, etilefrine, fenoxazoline, hydroxyamphetamine, hydroxyephedrine , indanazoline, isometheptene, levonordefrin, mephentermine , metaraminol , methoxamine , methylephedrine , midodrine , naphazoline, noradrenaline acid, norfenefrine, octodrine, octopamine, oxedrine, oxilofrine, oxymetazoline, phenylephrine, phenylpropanolamine ,
- the formulation comprise about .75% dibucaine .
- the formulation remains effective with a dibucaine content between 0.0% and 1.0%, however.
- alternative embodiments include all formulations comprising a eutectic mixture of at least one first pharmaceutically active
- anesthetic selected from the group consisting of benzocaine, lidocaine, bupivacaine, dibucaine, mepivacaine, etidocaine, tetracaine, butanilicaine and trimecaine and at least one second pharmaceutically active anesthetic selected from the group consisting of prilocaine, tetracaine, butanilicaine and trimecaine, said first and second pharmaceutically active agents present in a weight ratio of from about 15:1 to about 2:1 in a lipophilic base, and said anesthetic (s) selected from the first group differing from the anesthetic (s) selected from the second group, and at least one of said anesthetics preferably being either prilocaine or lidocaine.
- the formulation of the present invention may be applied to a carrier of paper, patches, or pads, as disclosed in U.S. Pat. Nos. 4,529,601 (Broberg, et al . ) and 4,562,060 (Broberg, et al . ) , so that the cellulose fibers of the pre-formed carrier is soaked with the formulation.
- the present formulation may be prepared as a stick formulation suitable for delivery of pharmacologically-active compounds, as disclosed in U.S. Pat. No. 5,622,993 (McGinity, et al . ) .
- EXAMPLE 1 The formulation according to the invention was made in the following manner (total quantity: 800g) : a) 50g of prilocaine were weighed out and dissolved in 200ml of distilled water. b) Once the prilocaine was dissolved, the solution was added to the separatory funnel . c) In a small beaker, 30g of sodium hydroxide pellets was added to 50ml of water. This solution was then added to the
- step f) was added to the lidocaine/prilocaine mixture.
- step h) Once this solution was clear, the final weight was obtained.
- the weight of the mixture was subtracted from 800 in order to determine the amount of petrolatum needed.
- j The petrolatum and the mixture were placed in a vessel of sufficient size and mixed thoroughly. The mixture had less than 1% water.
- k) The mixture was dispensed into loz tubes . The approximate shelf life was found to be about 12 months.
- EXAMPLE 2 Method of application of the formulation to the skin: a) the skin was thoroughly de-fatted using 70% isopropyl alcohol or acetone . b) a thin layer of the product was applied using a finger
- the duration of desensitization was found to vary with the amount of product applied and the length of the waiting period. The minimum time reported was 90 minutes and the longest reported was six hours. The average desensitization period reported was 180 minutes.
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002323211A CA2323211C (en) | 1998-04-28 | 1999-04-27 | Topical anesthetic formulation |
BR9909948-9A BR9909948A (en) | 1998-04-28 | 1999-04-27 | Topical anesthetic formulation |
AU38683/99A AU743516B2 (en) | 1998-04-28 | 1999-04-27 | Topical anesthetic formulation |
EP99921482A EP1073401A4 (en) | 1998-04-28 | 1999-04-27 | Topical anesthetic formulation |
IL13850999A IL138509A0 (en) | 1998-04-28 | 1999-04-27 | Topical transdermal anesthetic formulation |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/067,948 US5993836A (en) | 1998-04-28 | 1998-04-28 | Topical anesthetic formulation |
US09/067,948 | 1998-04-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999055287A1 true WO1999055287A1 (en) | 1999-11-04 |
Family
ID=22079486
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1999/009069 WO1999055287A1 (en) | 1998-04-28 | 1999-04-27 | Topical anesthetic formulation |
Country Status (8)
Country | Link |
---|---|
US (1) | US5993836A (en) |
EP (1) | EP1073401A4 (en) |
AU (1) | AU743516B2 (en) |
BR (1) | BR9909948A (en) |
CA (1) | CA2323211C (en) |
IL (1) | IL138509A0 (en) |
TR (1) | TR200003180T2 (en) |
WO (1) | WO1999055287A1 (en) |
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US8822416B2 (en) | 2005-03-15 | 2014-09-02 | Animal Ethics Pty Ltd. | Topical analgesic composition |
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US11213501B2 (en) | 2011-12-27 | 2022-01-04 | Cmpd Licensing, Llc | Composition and method for compounded therapy |
US10653738B2 (en) * | 2014-07-22 | 2020-05-19 | Meridian Research and Development Inc. | Topical medications for bruises and burns |
US10039830B2 (en) | 2016-03-04 | 2018-08-07 | Cetylite Industries, Inc. | Topical anesthetic composition |
CA3038870A1 (en) | 2016-10-13 | 2018-04-19 | Trilogic Pharma Llc | Lidocaine formulations for use in chronic open wounds |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US5332576A (en) * | 1991-02-27 | 1994-07-26 | Noven Pharmaceuticals, Inc. | Compositions and methods for topical administration of pharmaceutically active agents |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
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SE7713618L (en) * | 1977-12-01 | 1979-06-02 | Astra Laekemedel Ab | LOCAL ANESTHETIC MIXTURE |
EP0103911A1 (en) * | 1982-06-30 | 1984-03-28 | THE PROCTER & GAMBLE COMPANY | Emollient-containing topical pharmaceutical compositions |
US5002974A (en) * | 1988-04-04 | 1991-03-26 | Warner-Lambert Co. | Anesthetic/skin moisturizing composition and method of preparing same |
SE8802040D0 (en) * | 1988-06-01 | 1988-06-01 | Astra Ab | NEW USE |
SE9200762D0 (en) * | 1992-03-12 | 1992-03-12 | Astra Ab | NEW TOPICAL USE |
US5585398A (en) * | 1994-07-15 | 1996-12-17 | Ernst; Amy A. | Topical anesthetic comprising lidocaine, adrenaline, and tetracaine, and its method of use |
AU5578096A (en) * | 1995-04-28 | 1996-11-18 | Pharmetrix, Inc. | Compositions and methods for inducing dermal analgesia |
GB9610359D0 (en) * | 1996-05-17 | 1996-07-24 | Edko Trading Representation | Pharmaceutical compositions |
JPH101441A (en) * | 1996-06-14 | 1998-01-06 | Tendou Seiyaku Kk | Local anesthetic composition |
-
1998
- 1998-04-28 US US09/067,948 patent/US5993836A/en not_active Expired - Lifetime
-
1999
- 1999-04-27 CA CA002323211A patent/CA2323211C/en not_active Expired - Lifetime
- 1999-04-27 WO PCT/US1999/009069 patent/WO1999055287A1/en not_active Application Discontinuation
- 1999-04-27 TR TR2000/03180T patent/TR200003180T2/en unknown
- 1999-04-27 BR BR9909948-9A patent/BR9909948A/en not_active IP Right Cessation
- 1999-04-27 IL IL13850999A patent/IL138509A0/en unknown
- 1999-04-27 EP EP99921482A patent/EP1073401A4/en not_active Withdrawn
- 1999-04-27 AU AU38683/99A patent/AU743516B2/en not_active Ceased
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5332576A (en) * | 1991-02-27 | 1994-07-26 | Noven Pharmaceuticals, Inc. | Compositions and methods for topical administration of pharmaceutically active agents |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8822416B2 (en) | 2005-03-15 | 2014-09-02 | Animal Ethics Pty Ltd. | Topical analgesic composition |
US8960128B2 (en) | 2005-03-15 | 2015-02-24 | Animal Ethics Pty Ltd | Topical anesthetic composition |
US9592318B2 (en) | 2005-03-15 | 2017-03-14 | Animal Ethics Pty Ltd | Topical analgesic composition |
Also Published As
Publication number | Publication date |
---|---|
IL138509A0 (en) | 2001-10-31 |
EP1073401A4 (en) | 2006-09-13 |
EP1073401A1 (en) | 2001-02-07 |
US5993836A (en) | 1999-11-30 |
CA2323211A1 (en) | 1999-11-04 |
CA2323211C (en) | 2003-12-23 |
AU743516B2 (en) | 2002-01-24 |
BR9909948A (en) | 2000-12-26 |
TR200003180T2 (en) | 2001-04-20 |
AU3868399A (en) | 1999-11-16 |
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