CA1041011A - Anhydrous candicidin foam compositions - Google Patents
Anhydrous candicidin foam compositionsInfo
- Publication number
- CA1041011A CA1041011A CA217,528A CA217528A CA1041011A CA 1041011 A CA1041011 A CA 1041011A CA 217528 A CA217528 A CA 217528A CA 1041011 A CA1041011 A CA 1041011A
- Authority
- CA
- Canada
- Prior art keywords
- candicidin
- foam
- weight
- anhydrous
- polyoxyethylated
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
- A61K9/122—Foams; Dry foams
Abstract
ANHYDROUS CANDICIDIN FOAM COMPOSITIONS
ABSTRACT OF THE DISCLOSURE
Stable, anhydrous, foam compositions containing candicidin useful in the treatment of vaginitis.
ABSTRACT OF THE DISCLOSURE
Stable, anhydrous, foam compositions containing candicidin useful in the treatment of vaginitis.
Description
- 10410~1 FIELD OF THE INVENTION
This invention relates to novel anhydrous therapeutic compositions of candicidin which can be dispensed as pressurized foams.
BACKGROUND OF THE INVENT ION
Candicidin is a conjugated heptaene antibiotic complex ; produced by a soil actinomycetes similar to Streptomyces qriseus. This antibiotic has long been found useful for the treatment of vaginitis due to infections caused by Candida albicans and other Candida species. Prior to the present invention such infections were treated topically by means of vaginal ~ablets and vaginal ointments. Alterna- !
tively, such infections have been treated systemically.
Vaginal tablets are unpleasant to administer. Addi-tionally, the antibiotic is not always released in a repro-; ducible and predictable manner inasmuch as its release is I directly dependent upon the disintegration of the tablet in the vagina. Vaginal ointments produce a sensation of warmth when applied due to the inhibition of normal moisture evaporation. In addition, they feel greasy and tacky andhave a tendency to stain the underclothing.
The present invention overcomes these disadvantages and provides a convenient means of vaginal administration ,", -1- .~
WJS:rng ', . . . ' - '' , M-783 104101~
in the form of a stable, non-aqueous, aerosol foam which readily breaks at body temperatures and spreads as a uni-form film along the walls of the vagina. These composi-tions are cosmetically superior to those presently avail-able and provide a readily available controlled dosage directl~ at the situs of inflammation. The need for such formulations has long been recognized but remained unsolved primarily due to the difficulties experienced in formulating candicidin compositions.
Candicidin, encompassing a complex or a mixture of related antibiotics, is relatively unstable and undergoes degradation with a concomitant loss in activity. Thus, when exposed to the action of such physical and chemical agents as heat, light, oxygen and moisture, there is a con-comitant loss in activity. Another object of this inven-tion, therefore, is to provide anhydrous dosage forms wherein the candicidin retains its stability over long periods of time.
SUMMARY OF THE INVENTION
:
This invention relates to novel therapeutic composi-tions of candicidin. More particularly, this invention ; relates to anhydrous, aerosol foam compositions comprising: -(a) from 0.2 to 0.5~ by weight of candicidin;
(b) from 2 to 5~0 by weight of a polyoxyethylated high `
rnolecular weight fatty alcohol;
(c) from 0.5 to 2.0~o by weight of a nonionic sur-factant; -(d) from 0.05 to l.O~o by weight of an antioxidant;
(e) from 5.0 to 20.0~J by weight of an aerosol pro-
This invention relates to novel anhydrous therapeutic compositions of candicidin which can be dispensed as pressurized foams.
BACKGROUND OF THE INVENT ION
Candicidin is a conjugated heptaene antibiotic complex ; produced by a soil actinomycetes similar to Streptomyces qriseus. This antibiotic has long been found useful for the treatment of vaginitis due to infections caused by Candida albicans and other Candida species. Prior to the present invention such infections were treated topically by means of vaginal ~ablets and vaginal ointments. Alterna- !
tively, such infections have been treated systemically.
Vaginal tablets are unpleasant to administer. Addi-tionally, the antibiotic is not always released in a repro-; ducible and predictable manner inasmuch as its release is I directly dependent upon the disintegration of the tablet in the vagina. Vaginal ointments produce a sensation of warmth when applied due to the inhibition of normal moisture evaporation. In addition, they feel greasy and tacky andhave a tendency to stain the underclothing.
The present invention overcomes these disadvantages and provides a convenient means of vaginal administration ,", -1- .~
WJS:rng ', . . . ' - '' , M-783 104101~
in the form of a stable, non-aqueous, aerosol foam which readily breaks at body temperatures and spreads as a uni-form film along the walls of the vagina. These composi-tions are cosmetically superior to those presently avail-able and provide a readily available controlled dosage directl~ at the situs of inflammation. The need for such formulations has long been recognized but remained unsolved primarily due to the difficulties experienced in formulating candicidin compositions.
Candicidin, encompassing a complex or a mixture of related antibiotics, is relatively unstable and undergoes degradation with a concomitant loss in activity. Thus, when exposed to the action of such physical and chemical agents as heat, light, oxygen and moisture, there is a con-comitant loss in activity. Another object of this inven-tion, therefore, is to provide anhydrous dosage forms wherein the candicidin retains its stability over long periods of time.
SUMMARY OF THE INVENTION
:
This invention relates to novel therapeutic composi-tions of candicidin. More particularly, this invention ; relates to anhydrous, aerosol foam compositions comprising: -(a) from 0.2 to 0.5~ by weight of candicidin;
(b) from 2 to 5~0 by weight of a polyoxyethylated high `
rnolecular weight fatty alcohol;
(c) from 0.5 to 2.0~o by weight of a nonionic sur-factant; -(d) from 0.05 to l.O~o by weight of an antioxidant;
(e) from 5.0 to 20.0~J by weight of an aerosol pro-
-2-1~11 pellant selected from the group of chlorofluoro-hydrocarbons having a boiling point between -30CC.
and 30C. in a propylene glycol solvent.
DETAILED DESCRIPTION OF THE INVENTION
In general the novel pressurized compositions of this invention contain the antibiotic candicidin, a foaming agent, a nonionic surfactant and a propellant contained in a vehicle of propylene glycol. These mixtures have certain critical features both with respect to the nature and amount of the various components employed. When prepared in the manner described, these compositions retain their activity over long periods of time and produce homogenous, creamy foams that are particularly useful in the treatment of vaginitis.
Candicidin is an antifungal polyene antibiotic complex, fully described in U.S. Patent 2,992,162. As recovered from culture filtrates the complex consists of three frac-tions, designated Candicidin A, B and C. The A fraction is a reddish brown powder soluble in water and is simply the sodium salt of B, a greenish powder which is water insoluble.
Fraction C appears to be a degradation product which, relatively speaking, is biologically inactive. Candicidin is particularly useful for topical treatment of vaginal candidiasis (moniliasis). Candicidin, however, is not very stable and formulations thereof are generally kept in dark, refrigerated, air-tight containers to prevent loss of activity. The present invention provides formulations which retain as much as 95% of their original antibiotic activity when kept at 4~C. over a one-year period.
and 30C. in a propylene glycol solvent.
DETAILED DESCRIPTION OF THE INVENTION
In general the novel pressurized compositions of this invention contain the antibiotic candicidin, a foaming agent, a nonionic surfactant and a propellant contained in a vehicle of propylene glycol. These mixtures have certain critical features both with respect to the nature and amount of the various components employed. When prepared in the manner described, these compositions retain their activity over long periods of time and produce homogenous, creamy foams that are particularly useful in the treatment of vaginitis.
Candicidin is an antifungal polyene antibiotic complex, fully described in U.S. Patent 2,992,162. As recovered from culture filtrates the complex consists of three frac-tions, designated Candicidin A, B and C. The A fraction is a reddish brown powder soluble in water and is simply the sodium salt of B, a greenish powder which is water insoluble.
Fraction C appears to be a degradation product which, relatively speaking, is biologically inactive. Candicidin is particularly useful for topical treatment of vaginal candidiasis (moniliasis). Candicidin, however, is not very stable and formulations thereof are generally kept in dark, refrigerated, air-tight containers to prevent loss of activity. The present invention provides formulations which retain as much as 95% of their original antibiotic activity when kept at 4~C. over a one-year period.
-3-Both the nature and the amount of foaming agent employed are critical with respect to the solvent vehicle utilized. Various nonionic and emulsifying agents, including the condensation products of ethylene oxide and organic acids were tried unsatisfactorily, forming either foams that were unstable or failing to produce any foams whatsoever.
I have discovered that the reaction products of ethyl-ene oxide and the higher fatty alcohols, marketed as "Polawax,"* produce thick, uniform, creamy foams with candicidin which are quite stable at room temperature.
Furthermore, when warmed to 37C. (body temperature) these foams have the surprising property of flattening out to form a fluid cream with the antibiotic. This characteristic f the foams described herein is highly desirable and can be utilized in the preparation of other vaginal foam products.
The soft, cushiony foams which are produced can be safely introduced into the vagina and, after warming to body tem-perature, will flatten leaving a thin film of the medicament 20 evenly distributed along the vaginal walls. The ethylene -oxide and higher fatty alcohol reaction products are creamy, wax-like, nonionic, emulsifying waxes having a melting range of 48-52~C., a maximum iodine value of 3.5 and a maximum saponification value of 14. The foaming agent of choice is the reaction product of ethylene oxide with stearyl alcohol.
Various amounts of the foaming agent are added to the pre-sent compositions, preferably ranging from 2 to 5% by weight of the total composition. Amounts beyond 5~0 provide stiff ; foams which are too stable and which do not break upon warm-ing. On the other hand, amounts below 2% provide loose, * trademark
I have discovered that the reaction products of ethyl-ene oxide and the higher fatty alcohols, marketed as "Polawax,"* produce thick, uniform, creamy foams with candicidin which are quite stable at room temperature.
Furthermore, when warmed to 37C. (body temperature) these foams have the surprising property of flattening out to form a fluid cream with the antibiotic. This characteristic f the foams described herein is highly desirable and can be utilized in the preparation of other vaginal foam products.
The soft, cushiony foams which are produced can be safely introduced into the vagina and, after warming to body tem-perature, will flatten leaving a thin film of the medicament 20 evenly distributed along the vaginal walls. The ethylene -oxide and higher fatty alcohol reaction products are creamy, wax-like, nonionic, emulsifying waxes having a melting range of 48-52~C., a maximum iodine value of 3.5 and a maximum saponification value of 14. The foaming agent of choice is the reaction product of ethylene oxide with stearyl alcohol.
Various amounts of the foaming agent are added to the pre-sent compositions, preferably ranging from 2 to 5% by weight of the total composition. Amounts beyond 5~0 provide stiff ; foams which are too stable and which do not break upon warm-ing. On the other hand, amounts below 2% provide loose, * trademark
-4-' ~,1 , ' ' ' , ~04~
wet foams, which break too rapidly and which have a tendency to run.
Candicidin is insoluble in water and ethanol but is soluble in various organic solvents such as butanol, ethylene glycol, various lower molecular weight polyethylene glycols and glycerine. Butanol and ethylene glycol are unsuitable for pharmaceutical use due to their toxicity Glycerine is non-toxic but very hygroscopic. Solutions of glycerine above 10~ cause a burning sensation with the sen-sitive vaginal mucous membranes due to their dehydratingnature. In addition, candicidin lacks the requisite sta-bility in various mixtures of polyethylene glycols tested.
Surprisingly, anhydrous propylene glycol was found to be effective. Propylene glycol is non-hygroscopic, non-toxic, - pharmaceutically acceptable and dissolves sufficient candicidin to be therapeutically useful. Most importantly, the stability of candicidin is preserved in anhydrous propyl- ;
ene glycol solutions.
Candicidin is an amorphous, non-wettable,electrostatic powder. A surfactant is necessary to stabilize these com-positions by preventing agglomeration and evenly dispersing the candicidin in the solvent vehicle so that solution can occur. Nonionic surfactants are utilized because of their pharmacological compatibility and their lack of irritation and toxicity. The preferred nonionic surfactants are the fatty acid partial esters of sorbitol anhydride, marketed as Spans~, which are prepared by the esterification of sorbitan with a fatty acid such as oleic or stearic acid. Addi-tionally, the polyoxyethylene derivatives of fatty acid partial esters of sorbitol anhydrides, marketed as Tweens~, 104~
are useful. The nonionic surfactant of choice is the oleate ester of sorbitol and its anhydride, which has been copolymerized with approximately 20 moles of ethylene oxide for each mole of sorbitol and sorbitol anhydride.
This particular nonionic surFactant accelerates the disper-sion of the otherwise particulate agglomerate of candicidin and aids in the desegregation and stabilization of candicidin in the aerosol container with relative ease.
The amount of surfactant necessary to prevent agglomeration is not critical. Generally the surfactant is present in an amount ranging from 0.5 to 2.0% by weight of the total com-position. Preferably, a concentration of about 1.0~ by weight is employed.
Due to the relative ease with which candicidin under- !
goes oxidative degradation, it is necessary to add an anti-oxidant to the present compositions. The complexity of free radical oxidative processes and their sensitivity to trace amounts of impurities present critically affects both the nature and the amount of antioxidant to be used. The use of propyl gallate as an antioxidant in the propylene glycol system of the present invention has been found to be superior to all other antioxidants tried. Surprisingly, candicidin activity rapidly diminishes with propyl gallate concentrations in excess of 1%, representing the outer limits of usefulness for this antioxidant. On the other hand, a minimum or threshold amount of 0.05~ of propyl gallate is found to be necessary. Maximum candicidin sta-bility is obtained with propyl gallate at a concentration of about 0.1% by weight.
The propellant is responsible for developing the ,. ' . .
necessary pressure within the container and expelling the product once the aerosol valve is opened. The propellants used in this invention are selected from a group of fluorinated hydrocarbons known as "Freons"~ due to their excellent solubilization characteristics, their compati-bility with candicidin and their widespread use in pharma-ceutical aerosols. More particularly, those chlorofluoro-hydrocarbons having a boiling point of from -30C. to 30~C.
are employed. Specifically enumerated within this group of compounds are dichlorodifluoromethane, dichlorotetrafluoro-ethane, monochlorodifluoroethane, difluoroethane and octa-fluorocyclobutane. The propellants are used individually or as mixtures. A preferred propellant mixture consists of a mixture of nine parts by weight of dichlorotetrafluoro-ethane to one part by weight of dichlorodifluoromethane.
The amount of propellant employed varies with the actual propellants being used. In general, an amount less than 5.0% of propellant by weight will not produce useful results. On the other hand, an amount as high as 20% by weight of propellant can be used with propellants of low vapor pressure. As a preferred embodiment an amount of 10%
by weight of a 9:1 mixture of dichlorotetrafluoroethane to dichlorodifluoromethane is employed to gassify the instant foam composition. The propellant can be added to the foam producing composition prior to its addition to the aerosol container which is then capped with a foam valve. Prefer-ably, the foam producing composition is added to an aerosol container, capped with a foam valve and charged through the valve with the propellant on a weight basis.
The compositions of this invention are prepared by * trademark M-78~
lQ41011 dissolving the antioxidant in a solution of the nonionic surfactant to form a nonionic surfactant solution. The candicidin is then added to the nonionic surfactant solu-tion to form a candicidin dispersion. The polyoxyethylated high molecular weight fatty alcohol is dissolved in the propylene glycol to form a propylene glycol solution and the candicidin dispersion prepared is added to the propylene glycol solution to form an anhydrous, foam-producing com-position. This composition is placed in a suitable aerosol container, capped with a foam valve and charged with the chlorofluorohydrocarbon propellant mixture.
Additional minor ingredients, such as emollients, perfumes and dyes, may be added to the compositions herein described in order to increase their versatility and attractiveness without fundamentally departing from the nature of this invention. The non-aqueous candicidin ~ -pressurized aerosol foam compositions described herein are -more particularly illustrated in conjunction with the fol-lowing specific examples.
This example illustrates the use of a variety of foaming agents and the effect they have in a polyethylene glycol solvent, having an average molecular weight of 400.
In each of the lettered compositions below candicidin is dispersed with the foaming agent and added to the solvent with the aid of gentle heat, if necessary, to effect - dispersion. The resulting dispersion was gassed using a mixture of 4 parts of dichlorotetrafluoroethane to 1 part of dichlorodifluoromethane. All numerical values are - ~ M-783 104~0~1 expressed in grams.
Components Compositions A B C D E
:
Polyethylene gly-col (avg ~ w 400) 860 86 97 97 97 Polyoxyethylated vegetable oil 40 4 -- -- --Polyoxyethylated high molecular wt fatty alcohol -- 3 3 -- --Polyoxyethylene glycol (avg m w 400) monostearate -- -- -- 3 --Polyoxyethyleneglycol (avg m w 400) distearate -- -- -- -- 3 Candicidin 0.73 0.073 0.04 0.04 0.04 Type of foam no stable dry no no foam foam stable foam foam foam Following essentially the same procedure without the candicidin, the following example illustrates the use of - various foaming agents in different solvent vehicles.
Components Compositions A B C D
Mineral oil, heavy 97 95 40 --_g_ 10~1011 Polyethylene glycol (avg m w 400) 40 97 Polyoxyethylated high molecular weight fatty alcohol 3 3 3 Polyoxyethylated vegetable oil -- 2 7 --Type of foam no no no good foam when foam foam foam cool-breaks upon warming Following essentially the same procedure as in Example Il, the following Example illustrates the effect of a foaming agent, polyoxyethylated high molecular weight fatty alcohol, and a nonionic surfactant, the oleate ester of sorbitol and its anhydride copolymerized with ethylene oxide, with various non-aqueous solvent vehicles.
Components Compositions - A B C D
Polyoxyethylated high molecular weight fatty alcohol 1.5 1.5 1.5 1.5 Nonionic surfactant 0.5 0.5 0.5 0.5 Oleyl alcohol q.s. ad. 50 _ _ -Polyoxyethylene ether of oleyl alcohol q.s. ad. -- 50 -- --, . .
.:
Polyethylene glycol dilaurate (avg m w 200) q.s. ad. -- -- 50 --Propylene glycol q.s. ad. -- -- 50 Type of foam no slight no good foam foam foam white rapidly foam breaks The following Example indicates the lack of candicidin stability in a polyethylene glycol solvent foam formulation.
Polyoxyethylated high molecular weight fatty alcohol foaming agent, 3 gms, is melted and dispersed in approxi-mately 97 ml of polyethylene glycol solvent vehicle having an average molecular weight of 400. Candicidin, o.o84 gm, is dispersed in 10 gms of the oleate ester of sorbitol and its anhydride copolymerized with ethylene oxide. The poly-ethylene glycol solution is added to the candicidin sus-pension and 75 gm portions filled while still warm in aerosol containers equipped with a foam head. A mixture of 4 parts of dichlorotetrafluoroethane to 1 part of dichloro-difluoromethane is added via the foaming head. Initial recovery of candicidin including control values was only 50.2% and 53.2~ of theory.
; EXAMPLE 5 The following aerosol foam formulations illustrate the stability of candicidin using various antioxidants with a polyoxyethylated high molecular weight fatty alcohol foaming agent and a nonionic surfactant, such as the oleate -~ M-78~
1~)4~0~
ester of sorbitol and its anhydride copolymerized with ethylene oxide. Each composition was gassed with a mixture of 4 parts of dichlorotetrafluoroethane and 1 part of dichlorodifluoromethane.
Components Compositions A B C D
Polyoxyethylated high molecular weight : fatty alcohol 2 2 2 2 Butylated hydroxy anisole 0.01 -- 0.01 --Disodium ethylene-diaminetetra-acetic acid -- 0.01 0.01 --Propyl gallate -- -- -- 0.01 Oleate ester of sorbitol Candicidin 0.21 0,210.210.21 Polyethylene glycol (avg m w 400~
q.s. ad. 100 100100 100 Initial candicidin activity (% Theory) 71.069.076.0 80.0 1 Month at room tem-perature (~ Theory) -- 38.8 41.7 41.7 .
Following essentially the same procedure the following results were obtained.
,.
_ M-7~
la4~0ll Components Compositions A B C D
Polyoxyethylated high molecular weight fatty alcohol 3 3 3 3 Butylated hydroxy anisole 0.10 Disodium ethylene-diaminetetraacetic acid -- -- 0.10 0.10 Propyl gallate -- -- 0.10 0.50 Oleate ester of sorbitol Candicidin 0.21 0.21 0.21 0.21 Polyethylene glycol (avg m w 400) q.s. ad. 100 100 100 100 Initial candicidin activity (% Theory)87.8 87.4 78.3 86.o 1 Month at room tem-perature (~ Theory)45.0 41.4 45.4 44.6 1 Month at 4C. - non-pressurized (~ Theory) -- 69.o 90.8 --The following Example illustrates the increased sta-bility of candicidin in a propylene glycol vehicle. All of the samples were gassed with a mixture of 9 parts dichlorotetrafluoroethane and 1 part of dichlorodifluoro-methane.
1 ~4 ~0 1~
Components Compositions .
A B C D E
Polyoxyethyl-ated high molecular weight fatty alcohol 3 3 3 3 3 Polyoxyethyl-ene sorbitan monooleate Propyl gallate 0.1 -- 0.1 -- --Disodium ethyl-ene diamine-; tetraacetic acid -- 0.1 -- 0.1 --Candicidin0.210.21 0.21 0.21 --Polyethylene glycol (avg mw 400) q.s. ad. 100 100 -- -- -Propylene : .
glycol q.s. ad. -- -- 100 100 100 Initial Candicidin :
activity (~ Theory)82.878.o 95.2 98.1 __ ~ .
The following Example illustrates aerosol foam formu- ~ -lations of candicidin in a propylene glycol solvent vehicle ~:
using various antioxidants. All formulations were gassed with a mixture of 9 parts of dichlorotetrafluoroethane and 1 part of dichlorodifluoromethane.
1~41011 Components Compositions A B C
Polyoxyethylated high molecular weight fatty alcohol 3 3 3 Polyoxyethylene sorbitan monooleate Ethyl vanillin 0.1 -- --Ascorbyl palmitate -- 0.1 --Potassium sorbate -- -- 0.1 Candicidin 0.21 0.21 0.21 Propylene glycol q.s. ad. 100 100 100 Initial Candicidin assay (mg/gm) 3.68 3.21 3.69 - 1 Month at room tem-perature (mg/gm) 3.16 2.05 3.o6 1 Month at 4C. (mg/gm) 3.75 3.76 4.00 2 Months at room tem-perature (mg/gm) 2.79~~ 2 .11 . 20 2 Months at 4C. (mg/gm)2.762.61 4.49 ,~, . ' The following Example illustrates aerosol foam formu-lations of candicidin in a propylene glycol vehicle using various amounts of propyl gallate as an antioxidant. All of the compositions were gassed using a mixture of 9 parts of dichlorotetrafluoroethane and 1 part of dichloro-difluoromethane.
~ M-783 10410~1 .
Components Compositions A B C D E
Polyoxyethylated high molecular weight fatty alcohol 6 6 9 6 6 Polyoxyethylene sorbitan mono-oleate 2 2 3 2 2 1C Propyl gallateo .12 .oO .3 - - - -Potassium sorbate -- -- -- -- 0.2 Candicidin 0.42 0.42 0.63 0.42 --Propylene gly-col q.s. ad.200 200 300 200 200 Initial Candi-cidin assay ~-(mg/gm) 4.24 3.92 3.67 3.36 o 3 Months at room temperature -( mg/gm) 2 .81 - -2 .31 3 Months at 4C.
(mg/gm) 4.52 4.o6 4.27 3.23 --6 Months at 4C.
(mg/gm) 4 .12 4 .123 .89 - - - - ~-o 1/2 Months at 4c. (mg/gm)3.38 2.93 3.65 ~2.7 --.
- The following Example illustrates variations in the propellants, nonionic surfactants and amount of candicidin 30 used.
-~~ M-783 Components Compositions A B C D
Polyoxyethylated high molecular weight stearyl alcohol2.7 2.7 2.7 2.7 Polyoxyethylene sor-bitan monooleate0.9 0.9 -- 0.9 Propyl gallate 0.09 0.09 0.09 0.05 Sorbitan monooleate -- -- 0.9 --Candicidin o.38 o.38 0.38 0.27 Dichlorotetra-fluoroethane -- 10 -- 10 Dichlorotetrafluoro-ethane to dichloro-difluoromethane ~ (9:1) 10 -- 10 --Propylene glycol q.s. ad.100100 100100
wet foams, which break too rapidly and which have a tendency to run.
Candicidin is insoluble in water and ethanol but is soluble in various organic solvents such as butanol, ethylene glycol, various lower molecular weight polyethylene glycols and glycerine. Butanol and ethylene glycol are unsuitable for pharmaceutical use due to their toxicity Glycerine is non-toxic but very hygroscopic. Solutions of glycerine above 10~ cause a burning sensation with the sen-sitive vaginal mucous membranes due to their dehydratingnature. In addition, candicidin lacks the requisite sta-bility in various mixtures of polyethylene glycols tested.
Surprisingly, anhydrous propylene glycol was found to be effective. Propylene glycol is non-hygroscopic, non-toxic, - pharmaceutically acceptable and dissolves sufficient candicidin to be therapeutically useful. Most importantly, the stability of candicidin is preserved in anhydrous propyl- ;
ene glycol solutions.
Candicidin is an amorphous, non-wettable,electrostatic powder. A surfactant is necessary to stabilize these com-positions by preventing agglomeration and evenly dispersing the candicidin in the solvent vehicle so that solution can occur. Nonionic surfactants are utilized because of their pharmacological compatibility and their lack of irritation and toxicity. The preferred nonionic surfactants are the fatty acid partial esters of sorbitol anhydride, marketed as Spans~, which are prepared by the esterification of sorbitan with a fatty acid such as oleic or stearic acid. Addi-tionally, the polyoxyethylene derivatives of fatty acid partial esters of sorbitol anhydrides, marketed as Tweens~, 104~
are useful. The nonionic surfactant of choice is the oleate ester of sorbitol and its anhydride, which has been copolymerized with approximately 20 moles of ethylene oxide for each mole of sorbitol and sorbitol anhydride.
This particular nonionic surFactant accelerates the disper-sion of the otherwise particulate agglomerate of candicidin and aids in the desegregation and stabilization of candicidin in the aerosol container with relative ease.
The amount of surfactant necessary to prevent agglomeration is not critical. Generally the surfactant is present in an amount ranging from 0.5 to 2.0% by weight of the total com-position. Preferably, a concentration of about 1.0~ by weight is employed.
Due to the relative ease with which candicidin under- !
goes oxidative degradation, it is necessary to add an anti-oxidant to the present compositions. The complexity of free radical oxidative processes and their sensitivity to trace amounts of impurities present critically affects both the nature and the amount of antioxidant to be used. The use of propyl gallate as an antioxidant in the propylene glycol system of the present invention has been found to be superior to all other antioxidants tried. Surprisingly, candicidin activity rapidly diminishes with propyl gallate concentrations in excess of 1%, representing the outer limits of usefulness for this antioxidant. On the other hand, a minimum or threshold amount of 0.05~ of propyl gallate is found to be necessary. Maximum candicidin sta-bility is obtained with propyl gallate at a concentration of about 0.1% by weight.
The propellant is responsible for developing the ,. ' . .
necessary pressure within the container and expelling the product once the aerosol valve is opened. The propellants used in this invention are selected from a group of fluorinated hydrocarbons known as "Freons"~ due to their excellent solubilization characteristics, their compati-bility with candicidin and their widespread use in pharma-ceutical aerosols. More particularly, those chlorofluoro-hydrocarbons having a boiling point of from -30C. to 30~C.
are employed. Specifically enumerated within this group of compounds are dichlorodifluoromethane, dichlorotetrafluoro-ethane, monochlorodifluoroethane, difluoroethane and octa-fluorocyclobutane. The propellants are used individually or as mixtures. A preferred propellant mixture consists of a mixture of nine parts by weight of dichlorotetrafluoro-ethane to one part by weight of dichlorodifluoromethane.
The amount of propellant employed varies with the actual propellants being used. In general, an amount less than 5.0% of propellant by weight will not produce useful results. On the other hand, an amount as high as 20% by weight of propellant can be used with propellants of low vapor pressure. As a preferred embodiment an amount of 10%
by weight of a 9:1 mixture of dichlorotetrafluoroethane to dichlorodifluoromethane is employed to gassify the instant foam composition. The propellant can be added to the foam producing composition prior to its addition to the aerosol container which is then capped with a foam valve. Prefer-ably, the foam producing composition is added to an aerosol container, capped with a foam valve and charged through the valve with the propellant on a weight basis.
The compositions of this invention are prepared by * trademark M-78~
lQ41011 dissolving the antioxidant in a solution of the nonionic surfactant to form a nonionic surfactant solution. The candicidin is then added to the nonionic surfactant solu-tion to form a candicidin dispersion. The polyoxyethylated high molecular weight fatty alcohol is dissolved in the propylene glycol to form a propylene glycol solution and the candicidin dispersion prepared is added to the propylene glycol solution to form an anhydrous, foam-producing com-position. This composition is placed in a suitable aerosol container, capped with a foam valve and charged with the chlorofluorohydrocarbon propellant mixture.
Additional minor ingredients, such as emollients, perfumes and dyes, may be added to the compositions herein described in order to increase their versatility and attractiveness without fundamentally departing from the nature of this invention. The non-aqueous candicidin ~ -pressurized aerosol foam compositions described herein are -more particularly illustrated in conjunction with the fol-lowing specific examples.
This example illustrates the use of a variety of foaming agents and the effect they have in a polyethylene glycol solvent, having an average molecular weight of 400.
In each of the lettered compositions below candicidin is dispersed with the foaming agent and added to the solvent with the aid of gentle heat, if necessary, to effect - dispersion. The resulting dispersion was gassed using a mixture of 4 parts of dichlorotetrafluoroethane to 1 part of dichlorodifluoromethane. All numerical values are - ~ M-783 104~0~1 expressed in grams.
Components Compositions A B C D E
:
Polyethylene gly-col (avg ~ w 400) 860 86 97 97 97 Polyoxyethylated vegetable oil 40 4 -- -- --Polyoxyethylated high molecular wt fatty alcohol -- 3 3 -- --Polyoxyethylene glycol (avg m w 400) monostearate -- -- -- 3 --Polyoxyethyleneglycol (avg m w 400) distearate -- -- -- -- 3 Candicidin 0.73 0.073 0.04 0.04 0.04 Type of foam no stable dry no no foam foam stable foam foam foam Following essentially the same procedure without the candicidin, the following example illustrates the use of - various foaming agents in different solvent vehicles.
Components Compositions A B C D
Mineral oil, heavy 97 95 40 --_g_ 10~1011 Polyethylene glycol (avg m w 400) 40 97 Polyoxyethylated high molecular weight fatty alcohol 3 3 3 Polyoxyethylated vegetable oil -- 2 7 --Type of foam no no no good foam when foam foam foam cool-breaks upon warming Following essentially the same procedure as in Example Il, the following Example illustrates the effect of a foaming agent, polyoxyethylated high molecular weight fatty alcohol, and a nonionic surfactant, the oleate ester of sorbitol and its anhydride copolymerized with ethylene oxide, with various non-aqueous solvent vehicles.
Components Compositions - A B C D
Polyoxyethylated high molecular weight fatty alcohol 1.5 1.5 1.5 1.5 Nonionic surfactant 0.5 0.5 0.5 0.5 Oleyl alcohol q.s. ad. 50 _ _ -Polyoxyethylene ether of oleyl alcohol q.s. ad. -- 50 -- --, . .
.:
Polyethylene glycol dilaurate (avg m w 200) q.s. ad. -- -- 50 --Propylene glycol q.s. ad. -- -- 50 Type of foam no slight no good foam foam foam white rapidly foam breaks The following Example indicates the lack of candicidin stability in a polyethylene glycol solvent foam formulation.
Polyoxyethylated high molecular weight fatty alcohol foaming agent, 3 gms, is melted and dispersed in approxi-mately 97 ml of polyethylene glycol solvent vehicle having an average molecular weight of 400. Candicidin, o.o84 gm, is dispersed in 10 gms of the oleate ester of sorbitol and its anhydride copolymerized with ethylene oxide. The poly-ethylene glycol solution is added to the candicidin sus-pension and 75 gm portions filled while still warm in aerosol containers equipped with a foam head. A mixture of 4 parts of dichlorotetrafluoroethane to 1 part of dichloro-difluoromethane is added via the foaming head. Initial recovery of candicidin including control values was only 50.2% and 53.2~ of theory.
; EXAMPLE 5 The following aerosol foam formulations illustrate the stability of candicidin using various antioxidants with a polyoxyethylated high molecular weight fatty alcohol foaming agent and a nonionic surfactant, such as the oleate -~ M-78~
1~)4~0~
ester of sorbitol and its anhydride copolymerized with ethylene oxide. Each composition was gassed with a mixture of 4 parts of dichlorotetrafluoroethane and 1 part of dichlorodifluoromethane.
Components Compositions A B C D
Polyoxyethylated high molecular weight : fatty alcohol 2 2 2 2 Butylated hydroxy anisole 0.01 -- 0.01 --Disodium ethylene-diaminetetra-acetic acid -- 0.01 0.01 --Propyl gallate -- -- -- 0.01 Oleate ester of sorbitol Candicidin 0.21 0,210.210.21 Polyethylene glycol (avg m w 400~
q.s. ad. 100 100100 100 Initial candicidin activity (% Theory) 71.069.076.0 80.0 1 Month at room tem-perature (~ Theory) -- 38.8 41.7 41.7 .
Following essentially the same procedure the following results were obtained.
,.
_ M-7~
la4~0ll Components Compositions A B C D
Polyoxyethylated high molecular weight fatty alcohol 3 3 3 3 Butylated hydroxy anisole 0.10 Disodium ethylene-diaminetetraacetic acid -- -- 0.10 0.10 Propyl gallate -- -- 0.10 0.50 Oleate ester of sorbitol Candicidin 0.21 0.21 0.21 0.21 Polyethylene glycol (avg m w 400) q.s. ad. 100 100 100 100 Initial candicidin activity (% Theory)87.8 87.4 78.3 86.o 1 Month at room tem-perature (~ Theory)45.0 41.4 45.4 44.6 1 Month at 4C. - non-pressurized (~ Theory) -- 69.o 90.8 --The following Example illustrates the increased sta-bility of candicidin in a propylene glycol vehicle. All of the samples were gassed with a mixture of 9 parts dichlorotetrafluoroethane and 1 part of dichlorodifluoro-methane.
1 ~4 ~0 1~
Components Compositions .
A B C D E
Polyoxyethyl-ated high molecular weight fatty alcohol 3 3 3 3 3 Polyoxyethyl-ene sorbitan monooleate Propyl gallate 0.1 -- 0.1 -- --Disodium ethyl-ene diamine-; tetraacetic acid -- 0.1 -- 0.1 --Candicidin0.210.21 0.21 0.21 --Polyethylene glycol (avg mw 400) q.s. ad. 100 100 -- -- -Propylene : .
glycol q.s. ad. -- -- 100 100 100 Initial Candicidin :
activity (~ Theory)82.878.o 95.2 98.1 __ ~ .
The following Example illustrates aerosol foam formu- ~ -lations of candicidin in a propylene glycol solvent vehicle ~:
using various antioxidants. All formulations were gassed with a mixture of 9 parts of dichlorotetrafluoroethane and 1 part of dichlorodifluoromethane.
1~41011 Components Compositions A B C
Polyoxyethylated high molecular weight fatty alcohol 3 3 3 Polyoxyethylene sorbitan monooleate Ethyl vanillin 0.1 -- --Ascorbyl palmitate -- 0.1 --Potassium sorbate -- -- 0.1 Candicidin 0.21 0.21 0.21 Propylene glycol q.s. ad. 100 100 100 Initial Candicidin assay (mg/gm) 3.68 3.21 3.69 - 1 Month at room tem-perature (mg/gm) 3.16 2.05 3.o6 1 Month at 4C. (mg/gm) 3.75 3.76 4.00 2 Months at room tem-perature (mg/gm) 2.79~~ 2 .11 . 20 2 Months at 4C. (mg/gm)2.762.61 4.49 ,~, . ' The following Example illustrates aerosol foam formu-lations of candicidin in a propylene glycol vehicle using various amounts of propyl gallate as an antioxidant. All of the compositions were gassed using a mixture of 9 parts of dichlorotetrafluoroethane and 1 part of dichloro-difluoromethane.
~ M-783 10410~1 .
Components Compositions A B C D E
Polyoxyethylated high molecular weight fatty alcohol 6 6 9 6 6 Polyoxyethylene sorbitan mono-oleate 2 2 3 2 2 1C Propyl gallateo .12 .oO .3 - - - -Potassium sorbate -- -- -- -- 0.2 Candicidin 0.42 0.42 0.63 0.42 --Propylene gly-col q.s. ad.200 200 300 200 200 Initial Candi-cidin assay ~-(mg/gm) 4.24 3.92 3.67 3.36 o 3 Months at room temperature -( mg/gm) 2 .81 - -2 .31 3 Months at 4C.
(mg/gm) 4.52 4.o6 4.27 3.23 --6 Months at 4C.
(mg/gm) 4 .12 4 .123 .89 - - - - ~-o 1/2 Months at 4c. (mg/gm)3.38 2.93 3.65 ~2.7 --.
- The following Example illustrates variations in the propellants, nonionic surfactants and amount of candicidin 30 used.
-~~ M-783 Components Compositions A B C D
Polyoxyethylated high molecular weight stearyl alcohol2.7 2.7 2.7 2.7 Polyoxyethylene sor-bitan monooleate0.9 0.9 -- 0.9 Propyl gallate 0.09 0.09 0.09 0.05 Sorbitan monooleate -- -- 0.9 --Candicidin o.38 o.38 0.38 0.27 Dichlorotetra-fluoroethane -- 10 -- 10 Dichlorotetrafluoro-ethane to dichloro-difluoromethane ~ (9:1) 10 -- 10 --Propylene glycol q.s. ad.100100 100100
Claims (3)
1. An anhydrous, aerosol foam composition comprising:
(a) from 0.2 to 0.5% by weight of candicidin;
(b) from 2 to 5% by weight of a polyoxyethylated high molecular weight fatty alcohol;
(c) from 0.5 to 2.0% by weight of polyoxyethylene sorbitan monooleate;
(d) from 0.05 to 1.0% by weight of propyl gallate;
and (e) from 5.0 to 20.0% by weight of an aerosol pro-pellant selected from the group of chlorofluoro-hydrocarbons having a boiling point between -30°C. and 30°C.
in a propylene glycol solvent.
(a) from 0.2 to 0.5% by weight of candicidin;
(b) from 2 to 5% by weight of a polyoxyethylated high molecular weight fatty alcohol;
(c) from 0.5 to 2.0% by weight of polyoxyethylene sorbitan monooleate;
(d) from 0.05 to 1.0% by weight of propyl gallate;
and (e) from 5.0 to 20.0% by weight of an aerosol pro-pellant selected from the group of chlorofluoro-hydrocarbons having a boiling point between -30°C. and 30°C.
in a propylene glycol solvent.
2. A composition according to Claim 1 wherein the polyoxyethylated high molecular weight fatty alcohol is polyoxyethylated stearyl alcohol.
3. An anhydrous, aerosol foam composition which comprises:
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US434391A US3929985A (en) | 1974-01-18 | 1974-01-18 | Anhydrous candicidin foam compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1041011A true CA1041011A (en) | 1978-10-24 |
Family
ID=23724043
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA217,528A Expired CA1041011A (en) | 1974-01-18 | 1975-01-07 | Anhydrous candicidin foam compositions |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US3929985A (en) |
| BE (1) | BE824503A (en) |
| CA (1) | CA1041011A (en) |
| DE (1) | DE2500920A1 (en) |
| FR (1) | FR2258169B1 (en) |
| GB (1) | GB1450512A (en) |
| NL (1) | NL7500560A (en) |
| ZA (1) | ZA7542B (en) |
Families Citing this family (37)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4639367A (en) * | 1985-03-18 | 1987-01-27 | Product Resources International, Inc. | Aerosol foam |
| US4889709A (en) * | 1985-03-18 | 1989-12-26 | Product Resources International, Inc. | Aerosol foam with adsorbate and container containing same |
| US4752465A (en) * | 1985-09-20 | 1988-06-21 | Product Resources International, Inc. | Aerosol foam |
| US8512718B2 (en) | 2000-07-03 | 2013-08-20 | Foamix Ltd. | Pharmaceutical composition for topical application |
| IL152486A0 (en) | 2002-10-25 | 2003-05-29 | Meir Eini | Alcohol-free cosmetic and pharmaceutical foam carrier |
| US7820145B2 (en) | 2003-08-04 | 2010-10-26 | Foamix Ltd. | Oleaginous pharmaceutical and cosmetic foam |
| US10117812B2 (en) | 2002-10-25 | 2018-11-06 | Foamix Pharmaceuticals Ltd. | Foamable composition combining a polar solvent and a hydrophobic carrier |
| US8119109B2 (en) | 2002-10-25 | 2012-02-21 | Foamix Ltd. | Foamable compositions, kits and methods for hyperhidrosis |
| US7700076B2 (en) | 2002-10-25 | 2010-04-20 | Foamix, Ltd. | Penetrating pharmaceutical foam |
| US9211259B2 (en) | 2002-11-29 | 2015-12-15 | Foamix Pharmaceuticals Ltd. | Antibiotic kit and composition and uses thereof |
| US8119150B2 (en) * | 2002-10-25 | 2012-02-21 | Foamix Ltd. | Non-flammable insecticide composition and uses thereof |
| US9668972B2 (en) | 2002-10-25 | 2017-06-06 | Foamix Pharmaceuticals Ltd. | Nonsteroidal immunomodulating kit and composition and uses thereof |
| US8900554B2 (en) | 2002-10-25 | 2014-12-02 | Foamix Pharmaceuticals Ltd. | Foamable composition and uses thereof |
| US9265725B2 (en) | 2002-10-25 | 2016-02-23 | Foamix Pharmaceuticals Ltd. | Dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof |
| KR101108439B1 (en) * | 2002-10-25 | 2012-01-31 | 포믹스 리미티드 | Cosmetic and pharmaceutical foam |
| US20080138296A1 (en) | 2002-10-25 | 2008-06-12 | Foamix Ltd. | Foam prepared from nanoemulsions and uses |
| US8486376B2 (en) | 2002-10-25 | 2013-07-16 | Foamix Ltd. | Moisturizing foam containing lanolin |
| US7704518B2 (en) | 2003-08-04 | 2010-04-27 | Foamix, Ltd. | Foamable vehicle and pharmaceutical compositions thereof |
| US7575739B2 (en) * | 2003-04-28 | 2009-08-18 | Foamix Ltd. | Foamable iodine composition |
| US8795693B2 (en) | 2003-08-04 | 2014-08-05 | Foamix Ltd. | Compositions with modulating agents |
| US8486374B2 (en) | 2003-08-04 | 2013-07-16 | Foamix Ltd. | Hydrophilic, non-aqueous pharmaceutical carriers and compositions and uses |
| US8211449B2 (en) * | 2004-06-24 | 2012-07-03 | Dpt Laboratories, Ltd. | Pharmaceutically elegant, topical anhydrous aerosol foam |
| AU2006298442A1 (en) * | 2005-05-09 | 2007-04-12 | Foamix Ltd. | Saccharide foamable compositions |
| CN100427082C (en) * | 2005-08-02 | 2008-10-22 | 盛华（广州）医药科技有限公司 | Application of hydroxybenzoate acid and its analogue in the preparing process of medicine for preventing and treating virus infection |
| WO2008015583A1 (en) * | 2006-06-13 | 2008-02-07 | Wescast Industries, Inc. | Exhaust manifolds including heat shield assemblies |
| US20080260655A1 (en) | 2006-11-14 | 2008-10-23 | Dov Tamarkin | Substantially non-aqueous foamable petrolatum based pharmaceutical and cosmetic compositions and their uses |
| US8636982B2 (en) | 2007-08-07 | 2014-01-28 | Foamix Ltd. | Wax foamable vehicle and pharmaceutical compositions thereof |
| US9439857B2 (en) | 2007-11-30 | 2016-09-13 | Foamix Pharmaceuticals Ltd. | Foam containing benzoyl peroxide |
| WO2010041141A2 (en) | 2008-10-07 | 2010-04-15 | Foamix Ltd. | Oil-based foamable carriers and formulations |
| WO2009072007A2 (en) | 2007-12-07 | 2009-06-11 | Foamix Ltd. | Carriers, formulations, methods for formulating unstable active agents for external application and uses thereof |
| CA2712120A1 (en) | 2008-01-14 | 2009-07-23 | Foamix Ltd. | Poloxamer foamable pharmaceutical compositions with active agents and/or therapeutic cells and uses |
| WO2010125470A2 (en) | 2009-04-28 | 2010-11-04 | Foamix Ltd. | Foamable vehicle and pharmaceutical compositions comprising aprotic polar solvents and uses thereof |
| WO2011013008A2 (en) | 2009-07-29 | 2011-02-03 | Foamix Ltd. | Non surface active agent non polymeric agent hydro-alcoholic foamable compositions, breakable foams and their uses |
| WO2011013009A2 (en) | 2009-07-29 | 2011-02-03 | Foamix Ltd. | Non surfactant hydro-alcoholic foamable compositions, breakable foams and their uses |
| WO2011064631A1 (en) | 2009-10-02 | 2011-06-03 | Foamix Ltd. | Surfactant-free, water-free, foamable compositions and breakable foams and their uses |
| US9849142B2 (en) | 2009-10-02 | 2017-12-26 | Foamix Pharmaceuticals Ltd. | Methods for accelerated return of skin integrity and for the treatment of impetigo |
| MX2020012139A (en) | 2016-09-08 | 2021-01-29 | Vyne Pharmaceuticals Inc | Compositions and methods for treating rosacea and acne. |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3092555A (en) * | 1958-04-21 | 1963-06-04 | Roy H Horn | Relatively collapsible aerosol foam compositions |
| US3244589A (en) * | 1962-10-26 | 1966-04-05 | Sunnen | Alkyl phenoxy polyethoxy ether spermicidal aerosol |
| GB1026831A (en) * | 1963-05-31 | 1966-04-20 | Mediline Ag | Preparations for use in feminine hygiene |
| US3384541A (en) * | 1964-10-28 | 1968-05-21 | William G. Clark | Spermicidal vaginal pharmaceutical concentrate for producing nonaqueous foam with aerosol propellants |
| US3751562A (en) * | 1972-09-22 | 1973-08-07 | Princeton Biomedix | Medicated gelled oils |
-
1974
- 1974-01-18 US US434391A patent/US3929985A/en not_active Expired - Lifetime
-
1975
- 1975-01-02 ZA ZA00750042A patent/ZA7542B/en unknown
- 1975-01-07 CA CA217,528A patent/CA1041011A/en not_active Expired
- 1975-01-11 DE DE19752500920 patent/DE2500920A1/en active Pending
- 1975-01-15 FR FR7501153A patent/FR2258169B1/fr not_active Expired
- 1975-01-17 NL NL7500560A patent/NL7500560A/en not_active Application Discontinuation
- 1975-01-17 BE BE152475A patent/BE824503A/en unknown
- 1975-01-20 GB GB231875A patent/GB1450512A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| DE2500920A1 (en) | 1975-07-24 |
| US3929985A (en) | 1975-12-30 |
| ZA7542B (en) | 1976-01-28 |
| FR2258169A1 (en) | 1975-08-18 |
| NL7500560A (en) | 1975-07-22 |
| GB1450512A (en) | 1976-09-22 |
| FR2258169B1 (en) | 1978-06-30 |
| AU7701574A (en) | 1976-07-01 |
| BE824503A (en) | 1975-05-15 |
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