EP0417245A1 - Topical analgesic composition - Google Patents

Topical analgesic composition

Info

Publication number
EP0417245A1
EP0417245A1 EP90905333A EP90905333A EP0417245A1 EP 0417245 A1 EP0417245 A1 EP 0417245A1 EP 90905333 A EP90905333 A EP 90905333A EP 90905333 A EP90905333 A EP 90905333A EP 0417245 A1 EP0417245 A1 EP 0417245A1
Authority
EP
European Patent Office
Prior art keywords
solution
trolamine
mixture
acid
parahydroxybenzoic acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP90905333A
Other languages
German (de)
French (fr)
Other versions
EP0417245A4 (en
Inventor
Jeffrey Wenig
Vincent Romeo
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Marina Biotech Inc
Original Assignee
MDRNA Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by MDRNA Inc filed Critical MDRNA Inc
Publication of EP0417245A1 publication Critical patent/EP0417245A1/en
Publication of EP0417245A4 publication Critical patent/EP0417245A4/en
Withdrawn legal-status Critical Current

Links

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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
    • A61K31/621—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate having the hydroxy group in position 2 esterified, e.g. benorylate
    • 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
    • A61K31/60—Salicylic acid; Derivatives 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • Trolamine salicylate has long been known as a topical analgesic for temporary relief of musculoskeletal aches and pains especially those associated with strains, sprains, bruises or overexertion. It has also been recommended for temporary alleviation of arthritic and rheumatic pain especially in the hands and feet. It is especially favored by athletes.
  • Trolamine salicylate is a 1:1 complex formed by reaction of equimolar quantities of salicylic acid and trolamine (triethanol amine).
  • the analgesic agent is the salicylic acid which forms in situ when the salt crosses the skin barrier.
  • topical analgesics The principal desideratum of topical analgesics is rapid penetration of the skin barrier to the region of the pain.
  • topical creams, lotions, foams and other viscous compositions containing a large number of emolients, suspending agents, chelating agents, stiffening agents, emulsifiers, oils, buffering agents and other components including, so called oleagenous vehicles have been provided, apparently in the belief that such ingredients are necessary for rapid penetration of the skin barrier.
  • the cream may leave unsightly residues on the skin or they may stain the clothing. Often, especially if used by an athlete during competition they may absorb air-borne dust and particles and become even more unsightly. Moreover, one or more of the components may be allergenic. The art has long searched for compositions which can be usefully employed while avoiding the above mentioned difficulties.
  • aqueous solutions containing trolamine salicylate need not contain the large number of ingredients previously employed, but that the analgesic may be promptly and efficiently delivered to the site where it is needed from a carrier base that contains only water, a preservative, a lower alkanol, and a low molecular weight glycol.
  • the active ingredient will rapidly penetrate the skin barrier to provide a prompt soothing analgesic action despite the absence of the oils, emulsifiers and other excipients normally employed with trolamine salicylate.
  • compositions of the invention are flowable compositions with a viscosity at ambient temperature which is about that of water, i.e. about 0.98 to 1.2 times the viscosity of water. Because they are readily flowable, i.e., "like water", they may be easily and conveniently applied by a very brief rubbing. They are readily applied from easily designed containers such as aerosol, brush or sponge applicators. The volume of solution passing through the applicator can be controlled by any of a number of valve means well known to those skilled in the art. Some applicators may even eliminate the need for touching the compositions of the invention during application.
  • compositions will contain substantially equimolar quantities of the analgesic acid and the base. It is preferred to employ a slight molar excess, say 1% to 10%, of the base to insure that all of the acid will react and solubilize.
  • the amount of trolamine will vary from about 5 to 12%, and of salicylic acid from about 3 to 10% by weight based on the total volume of the composition.
  • the alkanol employed in the compositions will contain two or three carbon atoms and be miscible with water. Such alcohols have low boiling points and high vapor pressure. They promote rapid evaporation of the carrier vehicle of the composition.
  • the amount of alcohol employed is typically from about 3 to 6%.
  • the preferred alkanol is isopropyl alcohol. Mixtures of alcohols which may contain ethanol may be employed.
  • compositions of the invention will also contain a preservative.
  • the presently preferred preservatives are lower alkyl esters of parahydroxybenzoic acid, typically containing up to three carbon atoms.
  • the amount of preservative normally employed will be from about 0.1 to 0.5%, although wide variations are possible without adverse results.
  • the esters may be employed singly, but it is preferred to use a mixture of methyl and propyl esters of parahydroxybenzoic acid since the mixture appears to be more active than either ester taken alone.
  • Propylene glycols or mixtures thereof are utilized in the compositions of the invention as a solubilizer for the preservative system in an amount of from about 2.5 to 6%.
  • the compositions of this invention are solutions. It is important that all of the solid components dissolve. A sufficient amount of glycol is employed to insure such solubility, but too much glycol may increase the viscosity of the composition and will decrease the rate of evaporation from the skin.
  • the preferred glycol is 1,2-propane diol.
  • the components of the mixture must form a solution. It has been discovered that the method of mixing is very important to prevent precipitation of the solid components.
  • the trolamine and salicylic acid are added at ambient temperature to the selected quantity of water, which may be all of the water employed in the composition, and the mixture is allowed to stand until complete solution is effected.
  • a second mixture containing the selected quantities of glycol and alkyl ester(s) of parahydroxybenzoic acid, e.g., a mixture of the methyl and propyl ester is separately prepared and slowly added to the first solution. If it is added too rapidly, it will cause precipitation of the salicylic acid and/or the alkyl ester of parahydroxybenzoic acid.
  • the glycol/preservative mixture may contain some of the water of the final composition. The selected quantity of alkanol is then added to the mixture.
  • the pH of the compositions of this invention are preferably as close to neutral as possible, but a range of 6 to 8, or even slightly wider can be tolerated.
  • compositions of the invention are representative of the analgesic compositions of the invention. % w/v
  • composition A the trolamine, 50% of the volume of water and the salicylic acid were stirred at room temperature until the salicylic acid dissolved.
  • the preservatives were dissolved in propylene glycol and the solution added slowly to the first mixture with stirring. When the addition was complete, the alcohol was added followed by the balance of the water while continually stirring.
  • Composition B was similarly prepared.

Abstract

On décrit des solutions analgésiques aqueuses et fluides contenant des quantités sensiblement équimolaires de trolamine et d'acide salicylique avec un alcanol inférieur, un glycol d'alkylène inférieur et un ester d'alkyle inférieur d'acide paralhydroxybenzoïque et d'eau, ainsi que leur procédé de préparation.Aqueous and fluid analgesic solutions containing substantially equimolar amounts of trolamine and salicylic acid with a lower alkanol, a lower alkylene glycol and a lower alkyl ester of paralhydroxybenzoic acid and water are described. preparation process.

Description

TOPICAL ANALGESIC COMPOSITION
BACKGROUND OF INVENTION
Trolamine salicylate has long been known as a topical analgesic for temporary relief of musculoskeletal aches and pains especially those associated with strains, sprains, bruises or overexertion. It has also been recommended for temporary alleviation of arthritic and rheumatic pain especially in the hands and feet. It is especially favored by athletes.
Trolamine salicylate is a 1:1 complex formed by reaction of equimolar quantities of salicylic acid and trolamine (triethanol amine). The analgesic agent is the salicylic acid which forms in situ when the salt crosses the skin barrier.
The principal desideratum of topical analgesics is rapid penetration of the skin barrier to the region of the pain. To this end, a variety of topical creams, lotions, foams and other viscous compositions have been provided containing a large number of emolients, suspending agents, chelating agents, stiffening agents, emulsifiers, oils, buffering agents and other components including, so called oleagenous vehicles have been provided, apparently in the belief that such ingredients are necessary for rapid penetration of the skin barrier.
These viscous compositions are often difficult to apply and require extensive "rubbing in". This may be burdensome, especially if both hands are affected, or if the affected area is hard to reach such as the rear of the shoulder area.
Additionally, the cream may leave unsightly residues on the skin or they may stain the clothing. Often, especially if used by an athlete during competition they may absorb air-borne dust and particles and become even more unsightly. Moreover, one or more of the components may be allergenic. The art has long searched for compositions which can be usefully employed while avoiding the above mentioned difficulties.
THE INVENTION
It has now been discovered that, despite the indications from the art, aqueous solutions containing trolamine salicylate need not contain the large number of ingredients previously employed, but that the analgesic may be promptly and efficiently delivered to the site where it is needed from a carrier base that contains only water, a preservative, a lower alkanol, and a low molecular weight glycol. The active ingredient will rapidly penetrate the skin barrier to provide a prompt soothing analgesic action despite the absence of the oils, emulsifiers and other excipients normally employed with trolamine salicylate.
The compositions of the invention are flowable compositions with a viscosity at ambient temperature which is about that of water, i.e. about 0.98 to 1.2 times the viscosity of water. Because they are readily flowable, i.e., "like water", they may be easily and conveniently applied by a very brief rubbing. They are readily applied from easily designed containers such as aerosol, brush or sponge applicators. The volume of solution passing through the applicator can be controlled by any of a number of valve means well known to those skilled in the art. Some applicators may even eliminate the need for touching the compositions of the invention during application.
The formation of the trolamine salicylate complex is an equimolar reaction. Accordingly the compositions will contain substantially equimolar quantities of the analgesic acid and the base. It is preferred to employ a slight molar excess, say 1% to 10%, of the base to insure that all of the acid will react and solubilize. The amount of trolamine will vary from about 5 to 12%, and of salicylic acid from about 3 to 10% by weight based on the total volume of the composition.
in this disclosure and claims, all defined amounts are in percent by weight based on the total volume.
The alkanol employed in the compositions will contain two or three carbon atoms and be miscible with water. Such alcohols have low boiling points and high vapor pressure. They promote rapid evaporation of the carrier vehicle of the composition. The amount of alcohol employed is typically from about 3 to 6%.
The preferred alkanol is isopropyl alcohol. Mixtures of alcohols which may contain ethanol may be employed.
The compositions of the invention will also contain a preservative. The presently preferred preservatives are lower alkyl esters of parahydroxybenzoic acid, typically containing up to three carbon atoms. The amount of preservative normally employed will be from about 0.1 to 0.5%, although wide variations are possible without adverse results. The esters may be employed singly, but it is preferred to use a mixture of methyl and propyl esters of parahydroxybenzoic acid since the mixture appears to be more active than either ester taken alone.
Propylene glycols or mixtures thereof are utilized in the compositions of the invention as a solubilizer for the preservative system in an amount of from about 2.5 to 6%. The compositions of this invention are solutions. It is important that all of the solid components dissolve. A sufficient amount of glycol is employed to insure such solubility, but too much glycol may increase the viscosity of the composition and will decrease the rate of evaporation from the skin. The preferred glycol is 1,2-propane diol.
As indicated above, the components of the mixture must form a solution. It has been discovered that the method of mixing is very important to prevent precipitation of the solid components. In the preferred procedure, the trolamine and salicylic acid are added at ambient temperature to the selected quantity of water, which may be all of the water employed in the composition, and the mixture is allowed to stand until complete solution is effected. A second mixture containing the selected quantities of glycol and alkyl ester(s) of parahydroxybenzoic acid, e.g., a mixture of the methyl and propyl ester is separately prepared and slowly added to the first solution. If it is added too rapidly, it will cause precipitation of the salicylic acid and/or the alkyl ester of parahydroxybenzoic acid. The glycol/preservative mixture may contain some of the water of the final composition. The selected quantity of alkanol is then added to the mixture.
The pH of the compositions of this invention are preferably as close to neutral as possible, but a range of 6 to 8, or even slightly wider can be tolerated.
It is surprising to observe how quickly the active ingredient penetrates the skin barrier from the solutions of this invention. Athletes have been particularly satisfied. They have observed relief from muscular pain of the arms and legs within a few minutes after topical application.
The following formulations A and B are representative of the analgesic compositions of the invention. % w/v
trolamine 99% N.F. 5.76 salicylic acid U.S.P. 4.81 methyl parahydroxybenzoic acid, N.F. 0.2 propyl parahydroxybenzoic acid, N.F. 0.1 propylene glycol U.S.P. 3.0 isopropyl alcohol U.S.P. 3.0 water U.S.P. 83.13
B
grams
trolamine 99% N.F. 28.80 salicylic acid U.S.P. 24.05 methyl parahydroxybenzoic acid, N.F. 1.00 propyl parahydroxybenzoic acid, N.F. 0.50 propylene glycol U.S.P. 15.00 isopropyl alcohol U.S.P. 15.00 water U.S.P. 415.65
For composition A, the trolamine, 50% of the volume of water and the salicylic acid were stirred at room temperature until the salicylic acid dissolved. In a separate vessel, the preservatives were dissolved in propylene glycol and the solution added slowly to the first mixture with stirring. When the addition was complete, the alcohol was added followed by the balance of the water while continually stirring. Composition B was similarly prepared.

Claims

IN THE CLAIMS :
1. A flowable, analgesic, aqueous solution having a p of from about 6 to 8, a viscosity of from about 0.98 to 1.2 time that of water and containing, from, about 5 to 12% trolamine, about r to 10% salicylic acid, about 0.1 to 0.5% of a lower alky ester c parahydroxybenzoic acid, about 2.5 to 6% of a propylene glycol or mixtures thereof, and about 3 to 5% of an alkanol containing two or three carbon atoms, the salicyclic acid and trolamine being present in substantially equimolar quantities.
2. A solution of claim 1 containing from 1% to 10% molar excess of trolamine.
3. A solution of claim 1 or 2 wherein the alkyl group of the lower alkyl ester of parahydroxybenzoic acid contains up to three carbon atoms.
4. A solution of claim 1 or 2 wherein the propylene glycol is 1,2-propane diol.
5. A solution of claim 1 or 2 containing a mixture of methyl and propyl esters of parahydroxybenzoic acid.
6. A solution of claim 1 or 2 containing a mixture of ethyl and isopropyl alcohol.
7. A solution of claim 1 or 2 containing a mixture of methyl and propyl parahydroxybenzoic acid together with, isopropyl alcohol, and 1,2-propane diol.
8. A method for the preparation of an aqueous solutio of claim 1 dissolving the trolamine and salicylic acid in a portion of the total water of the solution which will dissolve all of the trolamine and salicylic acid to form a first mixture. s -
separately forming a second mixture containing the lower alkyl ester of parahydroxybenzoic acid and the alkylene glycol; combining the first and second mixtures at a rate which is insufficient to cause precipitation of any solid and thereafter adding the alkanol and any additional water necessary to form the said aqueous solution.
9. A method of claim 8 employing from 1% to 10% molar excess of trolamine.
EP19900905333 1989-03-17 1990-03-15 Topical analgesic composition Withdrawn EP0417245A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US32491289A 1989-03-17 1989-03-17
US324912 1989-03-17

Publications (2)

Publication Number Publication Date
EP0417245A1 true EP0417245A1 (en) 1991-03-20
EP0417245A4 EP0417245A4 (en) 1991-09-18

Family

ID=23265643

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19900905333 Withdrawn EP0417245A4 (en) 1989-03-17 1990-03-15 Topical analgesic composition

Country Status (5)

Country Link
EP (1) EP0417245A4 (en)
JP (1) JPH03504610A (en)
AU (1) AU5341390A (en)
CA (1) CA2012395A1 (en)
WO (1) WO1990011014A1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8697043B1 (en) * 2013-01-08 2014-04-15 Chattem, Inc. Odor suppression of volatile organic analgesic compounds and method of use

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4353896A (en) * 1981-06-08 1982-10-12 Levy Michael A Penetrating topical medicament
US4511563A (en) * 1983-07-15 1985-04-16 Basf Wyandotte Corporation Clear analgesic gels with reduced tackiness

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA613768A (en) * 1961-01-31 P. Modderno John Topical analgesic compositions

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4353896A (en) * 1981-06-08 1982-10-12 Levy Michael A Penetrating topical medicament
US4511563A (en) * 1983-07-15 1985-04-16 Basf Wyandotte Corporation Clear analgesic gels with reduced tackiness

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO9011014A1 *

Also Published As

Publication number Publication date
AU5341390A (en) 1990-10-22
WO1990011014A1 (en) 1990-10-04
EP0417245A4 (en) 1991-09-18
JPH03504610A (en) 1991-10-09
CA2012395A1 (en) 1990-09-17

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