CA1182396A - Topical antimicrobial anti-inflammatory compositions - Google Patents
Topical antimicrobial anti-inflammatory compositionsInfo
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- CA1182396A CA1182396A CA000405544A CA405544A CA1182396A CA 1182396 A CA1182396 A CA 1182396A CA 000405544 A CA000405544 A CA 000405544A CA 405544 A CA405544 A CA 405544A CA 1182396 A CA1182396 A CA 1182396A
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- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
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- Oncology (AREA)
- Communicable Diseases (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
TOPICAL ANTIMICROBIAL
ANTI-INFLAMMATORY COMPOSITIONS
Mahdi B. Fawzi ABSTRACT OF THE DISCLOSURE
Topical antimicrobial anti-inflammatory compositions, having a pH no greater than about 5, containing C5-C12 fatty acids together with a corticosteroid component, are disclosed. The method of topically treating inflammatory skin conditions using these compositions is also disclosed.
ANTI-INFLAMMATORY COMPOSITIONS
Mahdi B. Fawzi ABSTRACT OF THE DISCLOSURE
Topical antimicrobial anti-inflammatory compositions, having a pH no greater than about 5, containing C5-C12 fatty acids together with a corticosteroid component, are disclosed. The method of topically treating inflammatory skin conditions using these compositions is also disclosed.
Description
39~
TOPICAL ANTIMICROBIAL ANTI-INFLAM~ATORY COMPOSITIONS
TECHNICAL FIELD
The pre.sent invention relates to topical pharmaceu-tical compositions which provide both antimicrobial and anti-inflammatory benefits.
BACKGROUND OF THE INVENTION
The administration of corticosteroids to treat inflamed tissue is an important and widely-used treatment modality, especially in dermatology. Since topical corti-costeroids can act to depress local antimicrobial defenses it would be very helpful to be able to use such compounds together with antimicrobial agents in the topical treatment of skin disorders~ 5ee, Raab, Dermatologica, 152 (Suppl.
1), 67-79 tl976) and Raab, Br. J. Derm., 84r 582 (1971).
C5-C12 carboxylic acids, especially caprylic (octanoic) acid, are lipophilic materials known in the art to be effective, broad spectrum antimicrobial agents which may be used topically. See, Keeney, Bull. Johns Hopkins Hosp., 78, 333 (1946); U.S. Patent 2,466,663, Russ, et al., issued April 5, 1949; and Canadian Patent 1,098,~39, ~0 Stone, issued March 24, 1981.
It is well-known in the pharmaceutical arts that negative interactions can occur when certain types o antimicrobial agents, especially lipophilic antimicrobials are used together with corticosteroids in combination ~5 therapy. Thus, for example, ~obozy, et al., Hautar2t, 1976 (Suppl. 1), 11-13, teach that percutaneous absorption of topical salves containing the lipophilic compounds oxytetracycline, clorte~racycline and doxycycline is inhibited by the addition of glucocortocoids, such as prednisolone, hydrocortisone-17-butyrate, betamethasone 3~
valerate and dexamethasone pivalate. Raab, et al., Chemotherapy, 15 (1), 26-3~ (1970~, indicate that the corticosteroids cortisol, methyl prednisolone hemisuccinate and fluocinolone acetonide significantly reduce the anti-S bacterial activity of dodecyldi(beta-hydroxyethyl) benzyl-ammonium chloride and dodecyl triphenylphosphonium bro-mide (both of which are lipophilic compounds). Raab, Acta.
i Derm. - Venereol., Suppl. 52 (67), 32-39 (1972), teaches that fluocinolone acetonide acetate causes a decrease in the fungicidal activity of 1-p-chlorobenzyl-2-methylben-~, zimidazole and the bactericidal activity of dodecyldi(beta-hydroxyethyl)benzylammonium chloride; yet, there is no :~ impairment of microbiological activity noted when non-lipophilic antimicrobials, such as nystatin, natamycin, or neomycin, are combined with fluocinolone acetonide.
Finally, Zygmunt, et al., Appl. Microbiol., 1~(6), 865 (1966) disclose a wide range of steroid interference with the antifungal activity of a group of lipophilic polyene antibiotics.
Thus, based on the art, one would have expected negative interactions when corti.costeroids were u~sed to-gether with lipophilic C5-C12 fatty acid antimicrob.ial ~' a~ents in combination therapy. Yet, surprisingly, it has now been found that such combinations can be made, ex-hibiting outstanding anti-inflammatory and antimicrobial efficacy, without any negative interactions.
` Accordingly, it is an object of the present in-vention to provide effective topical antimicrobial and anti-inflammatory compositions containing C5-C12 fatty acids and corticosteroid components.
It is a further object of the present invention to provide a method for the ef~ective topical treatment of in-flammatory skin disorders.
~.;
:,~
3~
-- 3 ~
SUMMARY OF TH~ INVENTION
The present invention provides topical pharma-ceutical compositions, having a pH of no greater than about 5, comprising a safe and effective amount of an anti-microbial agent selected from C5-Cl2 fatty acids (espe-cially octanoic or decanoic acid) and mixtures thereof, together with a safe and effective amount of a cortico-steroid component, preferably triamcinolone acetonide, hydrocortisone acetate, betamethasone valerate, or ~ ocinolone acetonide.
In another aspect, the present invention provides a method for treating inflammatory skin conditions in humans i;'~ or animals wherein a safe and effective amount of the composition described above is topically applied to the afflicted situs.
D~`~AILED DESC~IPTION OF THE INVENTION
~` The phrase "safe and effective amount", as used herein, means a sufficient amount of fatty acid, cortico-steroid, or topical composition, to provide the desired antimicrobial and/or anti-inflammatory performance, at a reasonable benefit/risk ratio attendant with any medical ~:~ treatment. Within the scope of sound medical judyment, the required dosage of fatty acid or corticosteroid will vary with the nature and severity of the condition being treated, the duration of the treatment, the nature of adjunct treat-ment, the aye and physical condition of the patient, the specific fatty acid and corticosteroid compounds employed, and like considerations discussed more fully hereinafter.
"Pharmaceutically-acceptable", as used herein, means that the fatty acid and corticosteroid compounds, as well as other ingredients used in the compositions of the present invention, are suitable for use in contact with ~-~ the tissues of humans and lower animals without undue ,~
~ toxicity, irritation, allergic response, and the like, ;~ 35 commensurate with a reasonable benefit/risk ratio.
..~
3~
The term "co~prising", as used herein, means that various other compatible drugs and medicame~ts, as well as inert ingredients, can be conjointly employed in the therapeutic compositions of this invention, as long as the 5 critical fatty acid and corticosteroid components are used in the manner disclosed. The term "comprising" thus encompasses and includes the more restrictive terms "con-sisting of" and "consisting essentially of".
By "compatible" herein is meant that the components 10 of the compositions oE this invention are capable of being commingled without interacting in a manner which would substantially decrease the efficacy of the fatty acid or corticosteroid co~pounds under ordinary usage conditions.
A11 percentages and ratios used herein are by 15 weight, unless otherwise specified.
The fatty acids useful in the present invention contain ~rom 5 to 12 carbon atoms; compounds outside of - this range exhibit significantly less antimicrobial efficacy.
These materials, themselves, are well-known in the art.
20 For example, octanoic acid is an oily liquid havlng a boiling point of 239.7C and a melting point of 16.7C;
it is very slightly soluble in water (0.068 g/100 g at 20C) and freely soluble in alcohol, chloroform,carbon disulfide, petroleum ether and glacial acetic acid.
5 Octanoic acid may be prepared from l-heptene, Dupont, et al., Compt. Rend. ~40, 628 (1955), or by the oxidation of octanol, Langenbeck, et al., Ber. 89, 202 (1956). The manufacture of octanoic acid is described in V.S Patent
TOPICAL ANTIMICROBIAL ANTI-INFLAM~ATORY COMPOSITIONS
TECHNICAL FIELD
The pre.sent invention relates to topical pharmaceu-tical compositions which provide both antimicrobial and anti-inflammatory benefits.
BACKGROUND OF THE INVENTION
The administration of corticosteroids to treat inflamed tissue is an important and widely-used treatment modality, especially in dermatology. Since topical corti-costeroids can act to depress local antimicrobial defenses it would be very helpful to be able to use such compounds together with antimicrobial agents in the topical treatment of skin disorders~ 5ee, Raab, Dermatologica, 152 (Suppl.
1), 67-79 tl976) and Raab, Br. J. Derm., 84r 582 (1971).
C5-C12 carboxylic acids, especially caprylic (octanoic) acid, are lipophilic materials known in the art to be effective, broad spectrum antimicrobial agents which may be used topically. See, Keeney, Bull. Johns Hopkins Hosp., 78, 333 (1946); U.S. Patent 2,466,663, Russ, et al., issued April 5, 1949; and Canadian Patent 1,098,~39, ~0 Stone, issued March 24, 1981.
It is well-known in the pharmaceutical arts that negative interactions can occur when certain types o antimicrobial agents, especially lipophilic antimicrobials are used together with corticosteroids in combination ~5 therapy. Thus, for example, ~obozy, et al., Hautar2t, 1976 (Suppl. 1), 11-13, teach that percutaneous absorption of topical salves containing the lipophilic compounds oxytetracycline, clorte~racycline and doxycycline is inhibited by the addition of glucocortocoids, such as prednisolone, hydrocortisone-17-butyrate, betamethasone 3~
valerate and dexamethasone pivalate. Raab, et al., Chemotherapy, 15 (1), 26-3~ (1970~, indicate that the corticosteroids cortisol, methyl prednisolone hemisuccinate and fluocinolone acetonide significantly reduce the anti-S bacterial activity of dodecyldi(beta-hydroxyethyl) benzyl-ammonium chloride and dodecyl triphenylphosphonium bro-mide (both of which are lipophilic compounds). Raab, Acta.
i Derm. - Venereol., Suppl. 52 (67), 32-39 (1972), teaches that fluocinolone acetonide acetate causes a decrease in the fungicidal activity of 1-p-chlorobenzyl-2-methylben-~, zimidazole and the bactericidal activity of dodecyldi(beta-hydroxyethyl)benzylammonium chloride; yet, there is no :~ impairment of microbiological activity noted when non-lipophilic antimicrobials, such as nystatin, natamycin, or neomycin, are combined with fluocinolone acetonide.
Finally, Zygmunt, et al., Appl. Microbiol., 1~(6), 865 (1966) disclose a wide range of steroid interference with the antifungal activity of a group of lipophilic polyene antibiotics.
Thus, based on the art, one would have expected negative interactions when corti.costeroids were u~sed to-gether with lipophilic C5-C12 fatty acid antimicrob.ial ~' a~ents in combination therapy. Yet, surprisingly, it has now been found that such combinations can be made, ex-hibiting outstanding anti-inflammatory and antimicrobial efficacy, without any negative interactions.
` Accordingly, it is an object of the present in-vention to provide effective topical antimicrobial and anti-inflammatory compositions containing C5-C12 fatty acids and corticosteroid components.
It is a further object of the present invention to provide a method for the ef~ective topical treatment of in-flammatory skin disorders.
~.;
:,~
3~
-- 3 ~
SUMMARY OF TH~ INVENTION
The present invention provides topical pharma-ceutical compositions, having a pH of no greater than about 5, comprising a safe and effective amount of an anti-microbial agent selected from C5-Cl2 fatty acids (espe-cially octanoic or decanoic acid) and mixtures thereof, together with a safe and effective amount of a cortico-steroid component, preferably triamcinolone acetonide, hydrocortisone acetate, betamethasone valerate, or ~ ocinolone acetonide.
In another aspect, the present invention provides a method for treating inflammatory skin conditions in humans i;'~ or animals wherein a safe and effective amount of the composition described above is topically applied to the afflicted situs.
D~`~AILED DESC~IPTION OF THE INVENTION
~` The phrase "safe and effective amount", as used herein, means a sufficient amount of fatty acid, cortico-steroid, or topical composition, to provide the desired antimicrobial and/or anti-inflammatory performance, at a reasonable benefit/risk ratio attendant with any medical ~:~ treatment. Within the scope of sound medical judyment, the required dosage of fatty acid or corticosteroid will vary with the nature and severity of the condition being treated, the duration of the treatment, the nature of adjunct treat-ment, the aye and physical condition of the patient, the specific fatty acid and corticosteroid compounds employed, and like considerations discussed more fully hereinafter.
"Pharmaceutically-acceptable", as used herein, means that the fatty acid and corticosteroid compounds, as well as other ingredients used in the compositions of the present invention, are suitable for use in contact with ~-~ the tissues of humans and lower animals without undue ,~
~ toxicity, irritation, allergic response, and the like, ;~ 35 commensurate with a reasonable benefit/risk ratio.
..~
3~
The term "co~prising", as used herein, means that various other compatible drugs and medicame~ts, as well as inert ingredients, can be conjointly employed in the therapeutic compositions of this invention, as long as the 5 critical fatty acid and corticosteroid components are used in the manner disclosed. The term "comprising" thus encompasses and includes the more restrictive terms "con-sisting of" and "consisting essentially of".
By "compatible" herein is meant that the components 10 of the compositions oE this invention are capable of being commingled without interacting in a manner which would substantially decrease the efficacy of the fatty acid or corticosteroid co~pounds under ordinary usage conditions.
A11 percentages and ratios used herein are by 15 weight, unless otherwise specified.
The fatty acids useful in the present invention contain ~rom 5 to 12 carbon atoms; compounds outside of - this range exhibit significantly less antimicrobial efficacy.
These materials, themselves, are well-known in the art.
20 For example, octanoic acid is an oily liquid havlng a boiling point of 239.7C and a melting point of 16.7C;
it is very slightly soluble in water (0.068 g/100 g at 20C) and freely soluble in alcohol, chloroform,carbon disulfide, petroleum ether and glacial acetic acid.
5 Octanoic acid may be prepared from l-heptene, Dupont, et al., Compt. Rend. ~40, 628 (1955), or by the oxidation of octanol, Langenbeck, et al., Ber. 89, 202 (1956). The manufacture of octanoic acid is described in V.S Patent
2,821,534, issued in 1958 and assigned to GAF, and U.S.
30 Patent 3,053,869, issued in 1960 and assigned to Standard Oil of Indiana. See also Fatty Acids, Part 1, K.S.
Markley, ed. (Interscience, New York, 2d edition, 1960) pages 3~, 38. Decanoic acid is a crystalline solld ~ having a melting point of 31.~C; it is practically :;; 35 lnsoluble ln water. See Fatty Acids, Part 1, supra,
30 Patent 3,053,869, issued in 1960 and assigned to Standard Oil of Indiana. See also Fatty Acids, Part 1, K.S.
Markley, ed. (Interscience, New York, 2d edition, 1960) pages 3~, 38. Decanoic acid is a crystalline solld ~ having a melting point of 31.~C; it is practically :;; 35 lnsoluble ln water. See Fatty Acids, Part 1, supra,
3~
pages 3~, 39. Decanoic acid may be prepared from octyl bromide, Shishido, et al., J. Am. Chem Soc. 81, 5817 (1959), and U.S. Patent 2,918,494, lssued in 1959 and assigned to ~thyl Corporation.
S It is preferred that the fatty acid component be a C5-C12 non-aromatic carboxylic acid, such as n-pentanoic acid, n-hexanoic acid, n-heptanoic acid, n-octanoic acid, n-nonanoic acid, n-decanoic acid, n-undecanoic acid, or n-dodecanoic acid. Preferred fatty acids contain from 6 to 10 carbon atoms, with octanoic acid and decanoic acid being especially preferred. Mixtures of these acids may also he used, as well as the acid salts, provided that the pH cri~eria for the entire compositions are met. The Ea-tty acid components are included in the compositions of the present invention in a safe and effective amount, pre~erably comprising from about 0. 596 to about 20P6, more preferably from about 1~ to about 10%, of the completed compositions.
The compositions of the present invention are ~0 formulated such that they have a pH no greater than about 5, preferably no greater than about 4, most preferably between about 3 and ". At pH's greater than 5, antimi-crobial performance of the composition falls off signi-ficantly; obviously, a pH which is -too low (acidic) would not be suitable for topical use. Compatible acidic or basic ingredients may be used in order to adjust the com-position pH to the deslred range.
The corticosteroid components useEul in the present invention are well-known in the pharmaceutical arts and are described in detail in Mi.ller and Munro, Drugs, 19, 119-13~l (1~80). The essential steroid structure consists oE 17 carbon atoms, arranged in four rings, 3 six-membered rings and 1 five-membered ring (see E'ormulas I-III, below). Since this is a rigid structure, small changes in the position of substitutents can lead to significant changes in bio-logical activity, presumably as a consequence of interactions with specific receptors.
3~
~ 1`~ ' ~ 6 ~ K
I. Basic steroid sc.ucture II. Hydrocortisone C=O
0/~,~
~ III. Betamethasone ":
The anti-inflmmatory steroids were developed by various modifications of this basic nucleus, for example:
(1) The introduction of a 1:2 double bond into hy-drocortisone both increased glucocorticoid S activity (by approximately 4 times) and reduced mineralocorticoid effects. Prednisone and ', prednisolone resulted.
(2) The synthesis of the 9 alpha-halogenated deri-vatives had a large effect on glucocorticoid ~, 10 activity, but also enhanced mineralocorticoid properties. This latter problem was counter-acted by further substitution at the 16 position with an alpha-hydroxyl (triamcinolone), alpha-methyl(dexamethasone) or beta-methyl(betametha-sone) group.
Other modifications .in the molecular structure could possibly have the effect of removing some of the re-maining undesirable side effects or enhancing the positive effects of the corticosteroids. Changes in 20 these systemically active anti-lnflammatory steroids to improve lipophilicity (i.e., increased fat solubility relative to that in water) greatly improved their topical effectiveness. This generally involves masking or removing hydroxyl groups or the introduction of long ~5 carbon side chains.
Examples of specific corticosteroids and their customary dosage levels useful in the present invention !' can be broken down into four classes:
(1) Very potent Beclomethasone dipropionate 0.5%
Clobetasol propionate 0.05%
Diflucortolone valerate 0.3%
Fluocinolone acetonide 0.2%
(2) Potent Beclomethasone dipropionate 0.025%
` Betamethasone benzoate 0.025%
3~6 Betamethasone dlpropionate 0.05%
: Betamethasone valerate 0.1%
Desonide 0.05%
' Desox~lethasone 0.25~
Diflorasone dlacetate 0.05%
Diflucortolone valerate 0.1%
Fluclorolone acetonicle 0.025 Fluocinolone acetonide 0.025%
Fluocinonide 0.05%
Fluocortolone 0.5%
Fluprednidene (fluprednylidene) acetate 0.1%
Flurandrenolone 0.05%
.~, Halcinonide 0.1%
.~. .
Hydrocortisone butyrate 0.1%
Triamcinolone acetonide 0.1%
(3) Moderately Potent Clobetasone butyrate 0.05%
Flumethasone pivalate 0.02%
Fluocinolone acetonide 0.01%
Flucortin butylester 0.75%
; 20 Flucortolone 0.2%
' Flurandrenalone 0.0125%-0.025%
Hydrocortisone with urea 1%
pages 3~, 39. Decanoic acid may be prepared from octyl bromide, Shishido, et al., J. Am. Chem Soc. 81, 5817 (1959), and U.S. Patent 2,918,494, lssued in 1959 and assigned to ~thyl Corporation.
S It is preferred that the fatty acid component be a C5-C12 non-aromatic carboxylic acid, such as n-pentanoic acid, n-hexanoic acid, n-heptanoic acid, n-octanoic acid, n-nonanoic acid, n-decanoic acid, n-undecanoic acid, or n-dodecanoic acid. Preferred fatty acids contain from 6 to 10 carbon atoms, with octanoic acid and decanoic acid being especially preferred. Mixtures of these acids may also he used, as well as the acid salts, provided that the pH cri~eria for the entire compositions are met. The Ea-tty acid components are included in the compositions of the present invention in a safe and effective amount, pre~erably comprising from about 0. 596 to about 20P6, more preferably from about 1~ to about 10%, of the completed compositions.
The compositions of the present invention are ~0 formulated such that they have a pH no greater than about 5, preferably no greater than about 4, most preferably between about 3 and ". At pH's greater than 5, antimi-crobial performance of the composition falls off signi-ficantly; obviously, a pH which is -too low (acidic) would not be suitable for topical use. Compatible acidic or basic ingredients may be used in order to adjust the com-position pH to the deslred range.
The corticosteroid components useEul in the present invention are well-known in the pharmaceutical arts and are described in detail in Mi.ller and Munro, Drugs, 19, 119-13~l (1~80). The essential steroid structure consists oE 17 carbon atoms, arranged in four rings, 3 six-membered rings and 1 five-membered ring (see E'ormulas I-III, below). Since this is a rigid structure, small changes in the position of substitutents can lead to significant changes in bio-logical activity, presumably as a consequence of interactions with specific receptors.
3~
~ 1`~ ' ~ 6 ~ K
I. Basic steroid sc.ucture II. Hydrocortisone C=O
0/~,~
~ III. Betamethasone ":
The anti-inflmmatory steroids were developed by various modifications of this basic nucleus, for example:
(1) The introduction of a 1:2 double bond into hy-drocortisone both increased glucocorticoid S activity (by approximately 4 times) and reduced mineralocorticoid effects. Prednisone and ', prednisolone resulted.
(2) The synthesis of the 9 alpha-halogenated deri-vatives had a large effect on glucocorticoid ~, 10 activity, but also enhanced mineralocorticoid properties. This latter problem was counter-acted by further substitution at the 16 position with an alpha-hydroxyl (triamcinolone), alpha-methyl(dexamethasone) or beta-methyl(betametha-sone) group.
Other modifications .in the molecular structure could possibly have the effect of removing some of the re-maining undesirable side effects or enhancing the positive effects of the corticosteroids. Changes in 20 these systemically active anti-lnflammatory steroids to improve lipophilicity (i.e., increased fat solubility relative to that in water) greatly improved their topical effectiveness. This generally involves masking or removing hydroxyl groups or the introduction of long ~5 carbon side chains.
Examples of specific corticosteroids and their customary dosage levels useful in the present invention !' can be broken down into four classes:
(1) Very potent Beclomethasone dipropionate 0.5%
Clobetasol propionate 0.05%
Diflucortolone valerate 0.3%
Fluocinolone acetonide 0.2%
(2) Potent Beclomethasone dipropionate 0.025%
` Betamethasone benzoate 0.025%
3~6 Betamethasone dlpropionate 0.05%
: Betamethasone valerate 0.1%
Desonide 0.05%
' Desox~lethasone 0.25~
Diflorasone dlacetate 0.05%
Diflucortolone valerate 0.1%
Fluclorolone acetonicle 0.025 Fluocinolone acetonide 0.025%
Fluocinonide 0.05%
Fluocortolone 0.5%
Fluprednidene (fluprednylidene) acetate 0.1%
Flurandrenolone 0.05%
.~, Halcinonide 0.1%
.~. .
Hydrocortisone butyrate 0.1%
Triamcinolone acetonide 0.1%
(3) Moderately Potent Clobetasone butyrate 0.05%
Flumethasone pivalate 0.02%
Fluocinolone acetonide 0.01%
Flucortin butylester 0.75%
; 20 Flucortolone 0.2%
' Flurandrenalone 0.0125%-0.025%
Hydrocortisone with urea 1%
(4) Mild Vexamethasone 0.01%
Hydrocortisone,,(alcohol or acetate) 0.1~-1%
Methylprednisolone 0.25%
-:~
3~6 Mixtures of corticosteroids are also useful in the present invention. Particularly preferred cortico-steroids for use in the present invention include triamcinolone acetonide, hydrocortisone acetate, beta-
Hydrocortisone,,(alcohol or acetate) 0.1~-1%
Methylprednisolone 0.25%
-:~
3~6 Mixtures of corticosteroids are also useful in the present invention. Particularly preferred cortico-steroids for use in the present invention include triamcinolone acetonide, hydrocortisone acetate, beta-
5 methasone valerate, fluocinolone acetonide, and mixturesthereof. Compositions of the present invention contain a safe and effective amount of the corticosteroid component; preferably the compositions contain from about 0.01% to about 10%, more preferably from about 10 O.n2% to about 5~, of corticosteroid.
~ he compositions of the present invention may additionally contain adjunct components conventionally ic found in pharmaceutical compositions in their art-estab-lished usage levels. Thus, for example, the compositions 15 may contain additional compatible pharmaceutically-active materials for combination therapy (such as supplernentary antimicrobials, antipruritics, astrin-gents, local anaesthetics, or non-steroidal anti-in-flammatory agents), or may contain materials useful in 20 physically formulating various dosage forms of the present invention, such as excipients, dyes, perfumes, thickening agents, stabilizers, skin penetration en-hancers, preservatives, or antioxidants. The balance of the compositions of the present invention may also ~5 contain, in an amount which can range from about 1% to about 99. 5b of the comp~sitions, compatible pharma--ceutical carrier materials, generally in liquid or semi-: liquid form, especially adapted for topical application.
It is desirable that the carrier selected be capable of 30 codissolving the materials used in the composition.Carrier materials suitable for use in the ins~ant com-position include those well-known for use in the cos-metic and medical arts as a basis for ointments, lotions, ~; creams, salves, aerosols, suppositories, gels and the l 35 like. A particularly preferred composition of the ~;~ present invention is formulated as an aqueous lotion .....
3~6 or an aqueous gel, containin~ at least about 15% water;
the preferred aqueous gels, also contain an acidic carboxy polymer as the gelling agent. Such lotion and gel compositions are described in concurrently-filed Canadian patent application Serial No. ~05,575, Fawzi, entitled "Topical Antimicrobial Compositions". Sui~able carriers include, for example, water, liquid alcohols, liquid glycols, liquid polyalkalene glycols, liquid esters, liquid amides, liquid protein hydrolysates, liquid alkalated protein hydrolysates, liquid lanolin and lanolin derivatives, and like materials. Exemplary carriers include both monohydric and polyhydric alcohols, for example, ethanol, isopropanol, glycerol, sorbitol, 2-methoxy ethanol, diethylene glycol, ethylene glycol, hexalene glycol, mannitolv and propylene glycol; ethers, such as diethyl or dipropyl ether; polyethylene glycols and methoxy polyoxyethylenes (such as carbowaxes havin~
molecular weights ranging from 200 t~ 20,000); polyoxy-ethylene glycerols, polyoxethylene sorbitols, and stearoyl diacetin. Oil-in-water emulsions, such as cold cream bases, can also be used.
Topical treatment regimens according to the practice of this invention comprise applying the compositions herein directly to the skinr i.e., at the situs of an inflammatory skin disorder. The composltions may also be formulated for use in the oral or vaginal cavities. The rate of application and duration of treatment will, of course, depend on the severity and nature of the condition bein~ treated, the response, and physical condition of the particular patient, and related factors within ~he sound medical judgment of the attending ph~sician. In general, for the compositions of the present invention, application rates of from about 5 milligrams/cm2 to abo~t 100, prefer-ably from about 5 to about 50, milli~rams/cm2 per day are used. Application can be made once, or preferably several ~, 3g~i times, daily for periods of a week or more. Conditions usefully treated with the compositions of the present ;invention include, but are not limited to, cutaneous candidiasis; superficial bacterial infections; the 5 following conditions when complicated by candidal and/or bacterial infection: dermatitis (atopic, eczematoid, stasis, nummular, contact, or seborrheic), neuroder-~'matitis, and dermatitis venenate; pruritus ani; pruritus vulvae; infantile eczema; and lichen simplex chronicus.
~i10 In addition, the present inven~.ion may be formulated and used in a veterinary context, for example in the treat-ment of dermatological disorders characterized by in-flammation and dry or exudative dermatitis, eczematous dermatitis, contact dermatitis, seborrheic dermatitis, 15 and as an adjunct in the treatment of dermatitis due to parasitic infestation.
The following examples illustrate the content, preparation and use of topical compositions of this in vention, but are not intended to be limiting thereof.
EXAMPLE I
The antimicrobial efficacy of aqueous ~el formu-lations of the present invention was compared to that of similar compositions formulated as creams, ointments and 25 non aqueous gels, using an ln vitro disk diffusion test procedure. In this procffdure, filter paper disks (11-13 mm diameter) were coated with the compositions to be tested and placed on top of agar media containing the microorganisms of interest. ~he agar was incubated (under 30 conditions dictated by the particular microorganisms being used) overnight to allow the microorganlsms to grow. As the test formulation diffused from the disk out through the agar, the growth of the microorganism was ;~inhibited. Clear zones of inhibition were formed around `~35 the disks and were measured the following day. The size ,~
.
of the zone represents the degree of antimicrobial activity of the particular composition. The antimicrobial efficacy of the compositions was tested against Candida albicans (Candida~, Staphylococcus aureaus (Staph) and Pseudomonas aeruginosa (Pseudo). The compositions were tested both with and without a layer of synthetic sebum spread over the surface of the agar.
The compositions tested are summarized in the following tab~e.
Composition Triamcinolone Octanoic AcidAcetonide . .
1 (aqueous gel) 4% 0.1~
2 (cream) 4% 0.1%
3 (ointment) 4% 0.1%
4 (non-aqueous gel) 4% 0.1%
5 (aqueous gel) 4%
~ he compositions of the present invention may additionally contain adjunct components conventionally ic found in pharmaceutical compositions in their art-estab-lished usage levels. Thus, for example, the compositions 15 may contain additional compatible pharmaceutically-active materials for combination therapy (such as supplernentary antimicrobials, antipruritics, astrin-gents, local anaesthetics, or non-steroidal anti-in-flammatory agents), or may contain materials useful in 20 physically formulating various dosage forms of the present invention, such as excipients, dyes, perfumes, thickening agents, stabilizers, skin penetration en-hancers, preservatives, or antioxidants. The balance of the compositions of the present invention may also ~5 contain, in an amount which can range from about 1% to about 99. 5b of the comp~sitions, compatible pharma--ceutical carrier materials, generally in liquid or semi-: liquid form, especially adapted for topical application.
It is desirable that the carrier selected be capable of 30 codissolving the materials used in the composition.Carrier materials suitable for use in the ins~ant com-position include those well-known for use in the cos-metic and medical arts as a basis for ointments, lotions, ~; creams, salves, aerosols, suppositories, gels and the l 35 like. A particularly preferred composition of the ~;~ present invention is formulated as an aqueous lotion .....
3~6 or an aqueous gel, containin~ at least about 15% water;
the preferred aqueous gels, also contain an acidic carboxy polymer as the gelling agent. Such lotion and gel compositions are described in concurrently-filed Canadian patent application Serial No. ~05,575, Fawzi, entitled "Topical Antimicrobial Compositions". Sui~able carriers include, for example, water, liquid alcohols, liquid glycols, liquid polyalkalene glycols, liquid esters, liquid amides, liquid protein hydrolysates, liquid alkalated protein hydrolysates, liquid lanolin and lanolin derivatives, and like materials. Exemplary carriers include both monohydric and polyhydric alcohols, for example, ethanol, isopropanol, glycerol, sorbitol, 2-methoxy ethanol, diethylene glycol, ethylene glycol, hexalene glycol, mannitolv and propylene glycol; ethers, such as diethyl or dipropyl ether; polyethylene glycols and methoxy polyoxyethylenes (such as carbowaxes havin~
molecular weights ranging from 200 t~ 20,000); polyoxy-ethylene glycerols, polyoxethylene sorbitols, and stearoyl diacetin. Oil-in-water emulsions, such as cold cream bases, can also be used.
Topical treatment regimens according to the practice of this invention comprise applying the compositions herein directly to the skinr i.e., at the situs of an inflammatory skin disorder. The composltions may also be formulated for use in the oral or vaginal cavities. The rate of application and duration of treatment will, of course, depend on the severity and nature of the condition bein~ treated, the response, and physical condition of the particular patient, and related factors within ~he sound medical judgment of the attending ph~sician. In general, for the compositions of the present invention, application rates of from about 5 milligrams/cm2 to abo~t 100, prefer-ably from about 5 to about 50, milli~rams/cm2 per day are used. Application can be made once, or preferably several ~, 3g~i times, daily for periods of a week or more. Conditions usefully treated with the compositions of the present ;invention include, but are not limited to, cutaneous candidiasis; superficial bacterial infections; the 5 following conditions when complicated by candidal and/or bacterial infection: dermatitis (atopic, eczematoid, stasis, nummular, contact, or seborrheic), neuroder-~'matitis, and dermatitis venenate; pruritus ani; pruritus vulvae; infantile eczema; and lichen simplex chronicus.
~i10 In addition, the present inven~.ion may be formulated and used in a veterinary context, for example in the treat-ment of dermatological disorders characterized by in-flammation and dry or exudative dermatitis, eczematous dermatitis, contact dermatitis, seborrheic dermatitis, 15 and as an adjunct in the treatment of dermatitis due to parasitic infestation.
The following examples illustrate the content, preparation and use of topical compositions of this in vention, but are not intended to be limiting thereof.
EXAMPLE I
The antimicrobial efficacy of aqueous ~el formu-lations of the present invention was compared to that of similar compositions formulated as creams, ointments and 25 non aqueous gels, using an ln vitro disk diffusion test procedure. In this procffdure, filter paper disks (11-13 mm diameter) were coated with the compositions to be tested and placed on top of agar media containing the microorganisms of interest. ~he agar was incubated (under 30 conditions dictated by the particular microorganisms being used) overnight to allow the microorganlsms to grow. As the test formulation diffused from the disk out through the agar, the growth of the microorganism was ;~inhibited. Clear zones of inhibition were formed around `~35 the disks and were measured the following day. The size ,~
.
of the zone represents the degree of antimicrobial activity of the particular composition. The antimicrobial efficacy of the compositions was tested against Candida albicans (Candida~, Staphylococcus aureaus (Staph) and Pseudomonas aeruginosa (Pseudo). The compositions were tested both with and without a layer of synthetic sebum spread over the surface of the agar.
The compositions tested are summarized in the following tab~e.
Composition Triamcinolone Octanoic AcidAcetonide . .
1 (aqueous gel) 4% 0.1~
2 (cream) 4% 0.1%
3 (ointment) 4% 0.1%
4 (non-aqueous gel) 4% 0.1%
5 (aqueous gel) 4%
6 (non-aqueous gel) 4~ -
7 (ointment) 4%
8 (cream) 4%
All compositions had a pH between about 3 and 4.
The aqueous gel compositions included (vehicle) 1 myristyl alcohol; 25% propylene glycol; 5% Pluroni ~
L-64; 1% beta-alanine; 25% o 4% aqueous Carbopo ~ 934;
with the balance being water. Conventional cream, ointment and non-aqueous gel bases were used for the remaining compositions. The antimicrobial performance of these compositions is given in the following table.
zones of Inhibition (mm~
Candida sebum 29 22 19 18 26 19 21 23 no sebum 45 37 30 24 42 26 30 35 Staph sebum 21 19 17 15 21 16 16 19 no sebum 33 32 24 20 34 20 24 30 Pseudo no sebum 42 31 23 20 39 20 25 32 These data indicate that the compositions when formu-lated as aqueous gels of the present invention demonstrate clear antimicrobial performance advantages over similar compositions formulated as creams, ointments or non-aqueous gels.
Substantially similar results are obtained where the aqueous gel formulations, descrihed above, are formulated as aqueous lotions by eliminating the Carbopo ~ gelling agent.
Substantially similar results are also obtained where the octanoic acid in the above compositions is replaced, in whole or in part, with pentanoic, hexanoic, heptanoic, nonanoic, decanoic, undecanoic or dodecanolc acid, or mixtures thereof.
Similar re~ults are also obtained where the tri-amcinolone acetonide in the above compositlons is replaced, in whole or in part, with beclomethasone dipropionate, clobetasol propionate, diflucortolone valerate, fluocino-lone acetonide, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, desonide, desoxy~
methasone, diflorasone diacetate, fluclorolone acetonide, fluocinonide, fluocortolone, fluprednidene (fluprednyl-idene) acetate, flurandrenolone, halcinonide, hydro--cortisone butyrate, clobetasone butyrate, flumetha-sone pivalate, fluocortin bu~ylester, hydrocortisone with urea, dexamethasone, hydrocortisone alcohol or acetate, methylprednisolone, or mixtures thereof.
EXAMPLE II
Using the disk diffusion procedure described in Example I, the antimicrobial efficacy of compositions of the present invention was tested. All of the compositions had pH's in the range of from 3 to 4. The compositions tested are described in the table below; in addition to the listed components all of the compositions were formu-laked as aqueous gels, containing 1% myristyl alcohol, 25 propylene glycol, 5% Pluroni ~ L-64, 25% of 4% Carbopol~
934 gelling agent, with the balance of the compositions being water.
Composition (wei~ht %?
Components l 2 3 4 5 6 Octanoic Acid - - - - 4.0 A.O
Decanoic Acid 4.0 4.0 6.0 6.0 ~ -Triamcinolone Acetonide 0.1 0.1 0.1 0.1 0.1 0.1 Beta-alanine l O - l.O - l.O
l N NaO~I - 7.0 - 7.0 - 7.0 The antimicrobial performance of each of these compositions, expressed as zone of inhibition diameters, over a range of gram positive and gram negative bacteria, both in the presence and absence oE se4um, is summarized in the following table.
Zones of Inhibiiion ~mm~
l 2 3 4 5 6 Staph no sebum 25 24 27 27 30 31 sebum 16 16 16 18 21 22 Candida no sebum 21 21 24 20 38 38 sebum O O O 0 2~ 25 Pseudo no sebum 25 18 25 17 30 23 3~
Similar results are obta.ined were the aqueous gel compositions, described above, are formulated without the Carbopo ~ gelling agent, yielding aqueous lotion compositions.
EXAMPLE III
Using conventional pharmaceutical formulational techniyues, antimicrobial compositions described in the ~ollowing table were formulated as aqueous gels; each composition had a pH below 5.
_mposition (weight %) Components 1 2 3 4 5 6 7 8 9 Octanoic Acid 4.0 Monolauren 1.0 - - ---------~
Pluronic L-641 5.0 5.0 Pluronic F-108 2.4 Pluronic F-127 5.0 2~5 5.0 2.5 Pluronic F-123 5.0 2.5 5.0 2.5 Pluronic F-122 2.6 Propylene glycol 20.0 ?
Glycerin 20.0 20.0 20.0 20.0 1 N NaOH 7.5 Carbopol 9342 1.0 -~
Water 61.5 ~~-~~~~~~
ComRosition ~e~i~ht_%l C ~ 10 11 12 13 14 15 16 17 Octanoic Acid 4.0 ~ >
Monolauren 1.0 -~
Pluronic L-64 S.0 Pluronic F-108 2.4 2.4 2.4 Pluronic F-127 5.0 2.5 5.0 Pluronic F-123 5.0 2.5 Pluronic L-122 2.6 2.6 2.6 Propylene glycol 10.0 3~'~
Components 10 11 12 13 14 15 1617 Glycerin 20.0 10.0 1 N NaOH 7.5 ,.
Carbopol 934 1.0 - - 3 Water 61.5 - ~ 62.5 62.5 Pluronics are trademarks for a series of nonionic block-copolymer condensates of ethylene oxide with hydrophobic bases formed by condensing propylene oxide with propylene glycol, commercially available from Wyandotte Chemicals Corporation. For example, Pluronic L-64 has a molecular weight of about 2900 and an HLB of 15Ø Pluronic F-108 has a molecular weight of about 14,000.
Carbopol 934 is the trademark for a polyacrylic acid polymer available from B.F. Goodrich; it is soluble in water, polar solvents and many non-polar solvent blends.
These compositions, when applied topically to an adult human, in an amount of about 8 milligrams/cm2, are effective antimicrobial agents. Using the disk diffusion procedure, described above each of these compositions has been shown to be effective against Staphyloccus epider-midis, Propionibacterium acnes, Candida albicans, and Pseudomonas aeruginosaO Similar results are also obtained when a corticosteroid selected from the group triamcino-lone acetonide, hydrocortisone acetate, betamethasone valerate, fluocinolone acetonide, and mixtures thereof is added to any of these compositions in an amount constitut ing about 0.025~ to about 0.5% of the final composition.
EXAMPLE IV
Using the disk diffusion method, described in Example I, aqueous gel, cream, ointment and non-aqueous 1~`
, --3~
gel compositions, having the formulae given in the following table~ were screened for their antimicrobial effectiveness. All of the compositions tested had pH's below 5. The aqueous gel compositions contained 1%
myristyl alcohol, 25% propylene glycol, 5% pluronic ~
L-64, 1~ beta-alanine, 25% of 4% carbopol~ 934, with the balance being water. Conventional cream, ointment and non-aqueous gel bases were used in formulating the remaining compositions.
Compositions (weight %) Octanoic Triamcinolone Decanoic Acid Acetonide Acid .. . . ... .. _ 1 (aqueous gel) 4 ~ -2 (aqueous gel) 4 Ool 15 3 (cream) 4 - -4 (cream) 4 0.1 5 (o~ntment) 4 6 (o~Jintment) 4 0.1 7 (aqueous gel) - - 4 20 8 (aqueous gel) - 0~1 4
All compositions had a pH between about 3 and 4.
The aqueous gel compositions included (vehicle) 1 myristyl alcohol; 25% propylene glycol; 5% Pluroni ~
L-64; 1% beta-alanine; 25% o 4% aqueous Carbopo ~ 934;
with the balance being water. Conventional cream, ointment and non-aqueous gel bases were used for the remaining compositions. The antimicrobial performance of these compositions is given in the following table.
zones of Inhibition (mm~
Candida sebum 29 22 19 18 26 19 21 23 no sebum 45 37 30 24 42 26 30 35 Staph sebum 21 19 17 15 21 16 16 19 no sebum 33 32 24 20 34 20 24 30 Pseudo no sebum 42 31 23 20 39 20 25 32 These data indicate that the compositions when formu-lated as aqueous gels of the present invention demonstrate clear antimicrobial performance advantages over similar compositions formulated as creams, ointments or non-aqueous gels.
Substantially similar results are obtained where the aqueous gel formulations, descrihed above, are formulated as aqueous lotions by eliminating the Carbopo ~ gelling agent.
Substantially similar results are also obtained where the octanoic acid in the above compositions is replaced, in whole or in part, with pentanoic, hexanoic, heptanoic, nonanoic, decanoic, undecanoic or dodecanolc acid, or mixtures thereof.
Similar re~ults are also obtained where the tri-amcinolone acetonide in the above compositlons is replaced, in whole or in part, with beclomethasone dipropionate, clobetasol propionate, diflucortolone valerate, fluocino-lone acetonide, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, desonide, desoxy~
methasone, diflorasone diacetate, fluclorolone acetonide, fluocinonide, fluocortolone, fluprednidene (fluprednyl-idene) acetate, flurandrenolone, halcinonide, hydro--cortisone butyrate, clobetasone butyrate, flumetha-sone pivalate, fluocortin bu~ylester, hydrocortisone with urea, dexamethasone, hydrocortisone alcohol or acetate, methylprednisolone, or mixtures thereof.
EXAMPLE II
Using the disk diffusion procedure described in Example I, the antimicrobial efficacy of compositions of the present invention was tested. All of the compositions had pH's in the range of from 3 to 4. The compositions tested are described in the table below; in addition to the listed components all of the compositions were formu-laked as aqueous gels, containing 1% myristyl alcohol, 25 propylene glycol, 5% Pluroni ~ L-64, 25% of 4% Carbopol~
934 gelling agent, with the balance of the compositions being water.
Composition (wei~ht %?
Components l 2 3 4 5 6 Octanoic Acid - - - - 4.0 A.O
Decanoic Acid 4.0 4.0 6.0 6.0 ~ -Triamcinolone Acetonide 0.1 0.1 0.1 0.1 0.1 0.1 Beta-alanine l O - l.O - l.O
l N NaO~I - 7.0 - 7.0 - 7.0 The antimicrobial performance of each of these compositions, expressed as zone of inhibition diameters, over a range of gram positive and gram negative bacteria, both in the presence and absence oE se4um, is summarized in the following table.
Zones of Inhibiiion ~mm~
l 2 3 4 5 6 Staph no sebum 25 24 27 27 30 31 sebum 16 16 16 18 21 22 Candida no sebum 21 21 24 20 38 38 sebum O O O 0 2~ 25 Pseudo no sebum 25 18 25 17 30 23 3~
Similar results are obta.ined were the aqueous gel compositions, described above, are formulated without the Carbopo ~ gelling agent, yielding aqueous lotion compositions.
EXAMPLE III
Using conventional pharmaceutical formulational techniyues, antimicrobial compositions described in the ~ollowing table were formulated as aqueous gels; each composition had a pH below 5.
_mposition (weight %) Components 1 2 3 4 5 6 7 8 9 Octanoic Acid 4.0 Monolauren 1.0 - - ---------~
Pluronic L-641 5.0 5.0 Pluronic F-108 2.4 Pluronic F-127 5.0 2~5 5.0 2.5 Pluronic F-123 5.0 2.5 5.0 2.5 Pluronic F-122 2.6 Propylene glycol 20.0 ?
Glycerin 20.0 20.0 20.0 20.0 1 N NaOH 7.5 Carbopol 9342 1.0 -~
Water 61.5 ~~-~~~~~~
ComRosition ~e~i~ht_%l C ~ 10 11 12 13 14 15 16 17 Octanoic Acid 4.0 ~ >
Monolauren 1.0 -~
Pluronic L-64 S.0 Pluronic F-108 2.4 2.4 2.4 Pluronic F-127 5.0 2.5 5.0 Pluronic F-123 5.0 2.5 Pluronic L-122 2.6 2.6 2.6 Propylene glycol 10.0 3~'~
Components 10 11 12 13 14 15 1617 Glycerin 20.0 10.0 1 N NaOH 7.5 ,.
Carbopol 934 1.0 - - 3 Water 61.5 - ~ 62.5 62.5 Pluronics are trademarks for a series of nonionic block-copolymer condensates of ethylene oxide with hydrophobic bases formed by condensing propylene oxide with propylene glycol, commercially available from Wyandotte Chemicals Corporation. For example, Pluronic L-64 has a molecular weight of about 2900 and an HLB of 15Ø Pluronic F-108 has a molecular weight of about 14,000.
Carbopol 934 is the trademark for a polyacrylic acid polymer available from B.F. Goodrich; it is soluble in water, polar solvents and many non-polar solvent blends.
These compositions, when applied topically to an adult human, in an amount of about 8 milligrams/cm2, are effective antimicrobial agents. Using the disk diffusion procedure, described above each of these compositions has been shown to be effective against Staphyloccus epider-midis, Propionibacterium acnes, Candida albicans, and Pseudomonas aeruginosaO Similar results are also obtained when a corticosteroid selected from the group triamcino-lone acetonide, hydrocortisone acetate, betamethasone valerate, fluocinolone acetonide, and mixtures thereof is added to any of these compositions in an amount constitut ing about 0.025~ to about 0.5% of the final composition.
EXAMPLE IV
Using the disk diffusion method, described in Example I, aqueous gel, cream, ointment and non-aqueous 1~`
, --3~
gel compositions, having the formulae given in the following table~ were screened for their antimicrobial effectiveness. All of the compositions tested had pH's below 5. The aqueous gel compositions contained 1%
myristyl alcohol, 25% propylene glycol, 5% pluronic ~
L-64, 1~ beta-alanine, 25% of 4% carbopol~ 934, with the balance being water. Conventional cream, ointment and non-aqueous gel bases were used in formulating the remaining compositions.
Compositions (weight %) Octanoic Triamcinolone Decanoic Acid Acetonide Acid .. . . ... .. _ 1 (aqueous gel) 4 ~ -2 (aqueous gel) 4 Ool 15 3 (cream) 4 - -4 (cream) 4 0.1 5 (o~ntment) 4 6 (o~Jintment) 4 0.1 7 (aqueous gel) - - 4 20 8 (aqueous gel) - 0~1 4
9 (aqueous gel) - 0.1
10 (aqueous gel) - - 4
11 (non-aqueous gel) - 0.1
12 (non-aqueous gel) - - 4 The results of these tests are summari2ed in the Eollowing table. These data indicate that the addition oE
triamcinolone acetonide to the octanoic acid and decanoic acid aqueous gel, cream, ointment or non~aqueous gel compositions resulted in no antagonistic effects on their antimicrobial activity.
3~
_nes o Inhibition (mm) Candida Staph Pseudo sebum no sebum sebum no sebum no sebum 5 2 29 ~5 22 34 42 ~`~ 11 0 0 0 15 0 Substantially similar results are obtained where the octanoic or decanoic acids of ,he above compositions are replaced, in whole or in part, with equivalent amounts of pentanoic, hexanoic, heptanoic, nonanoic, undecanoic or dodecanoic acid, or mixtures thereof. Similar results are also obtained where the triamcinolone acetonide is re-placed, in whole or in part, with effective amounts of hydrooortisone acetate, betamethasone valerate, fluocino-lone acetonide, beclomethasone dipropionate, clobetasol propionate, diflucortolone valerate, betamethasone ~t~J~ benzoate, betamethasone dipropionate, desonide, desoxy-methasone, diflorasone diacetate, fluclorolone acetonide, ~- fluocinonide, fluocortolone, fluprednidene (fluprednyli-dene) acetate, flurandrenooone, halcinonide, hydrocorti-sone butyrate, clobetasone butyrate, flumethasone pi-~-alate, fluocortin butylester, hydrocortisone with urea, dexamethasone, hydrocortisone alcohol or acetate, methyl-prednisolone, or mixtures thereof.
., ~. ~
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EXA~PLE V
In order to compare the antimicrobial activity of octanoic acid/triamcinolone acetonide combinations against the activity of compositions containing three other corticosteroids at concentrations which are common in current:ly marketed products, the following compositions were screened using the disk diffusion procedure~ All of the compositions were in the form of aqueous gels; these gel compositions contained (vehicle) 1~ myristyl alcohol, 25~ propylene glycol, 5% Pluroni ~ L-~4, l~ beta-alanine, 25% of 4% aqueous Carbopo ~ 934, with the balance being water. A11 of the gel compositions had pH's between about 3 and 4.
1 Compositions ~wei~t l - 0.05% triamcinolone acetonide 2 - 0.05~ triamcinolone acetonide ~ 4% octanoic acid 3 - O.S% hydrocortisone-21-acetate 4 - 0.5% hydrocortisone-21-acetate ~ 4~ octanoic acid 5 - 0.1% betamethasone valerate ~ - 0.1% betamethasone valerate ~ ~% octanoic acid 7 - 0.0~5% fluocinolone acetonide 8 - 0~02S% fluocinolone acetonide ~ 4~ octanoic acid 9 - vehicle (no active) The results oE these experiments are summarized in ~5 the table, below. In all instances~ ~he corticosteroid alone showed no antimicrobial activity. All of the compositions containing 4~ octanoic acid showed good activity. Zones of inhibition were approximately the same size for all of these compositions regardless ~f the steroid or its concentration.
) 3~6 Zones of Inhibition (mm) Staph Candida Pseudo sebum no sebum sebum No sebum no sebum l 0 0 0 0 32 EXAMPLE VI
_ The croton oil mouse ear assay was used to assess the topical anti-inflammatory activity of the compositions set forth in the table, below. The croton oil assay procedure is described in Tonelli, et al., Endocrinology, 77, 625-634 ~1965); this procedure was utilized herein except that the compositions being tested were applied 24 hours before the croton oil. In this assay, the corticosteroid-containing formulation was applied to one ear prior to inducing inflammation in both ears with a 2 croton oil application. The relative suppression of the croton oil-induced inflammation in the cortico~teroid treated ear is a measure of an~i-inflammatory activity.
The triamcinolone acetonide ~ octanoic acid composition was in the form of an aqueous gel (pH-3-4) containing l~
myristyl alcohol, 25% propylene glycol, 5~ Pluroni ~
L-64, l~ beta-alanine, 25% of 4% aqueous Carbopol~ 934, with the balance being water. The vehicle alone, without any active components, was also tested. The following table shows the key data generated using this model systern~
3~
Avg. Left Ear Formulation ~t. (mg) % Inhibition ; 1. Croton oil (control) 22.03 0 2. O.l~ Triamcinolone Acetonide + 4~
Octaonic Acid (aqueous gel) 11.32 97 3. Vehicle (aqueous gel) 23.83 10 ~. 0.1% Triamcinolone Ancetonide (aqueous gel) 98 Formulations 2 and 4 were significantly better in their anti-inflammatory performance than the croton oil control group (P <0.05). Comparison of formulations 2 and 4 shows that there were no negative interactions regarding anti-inflammatory activity when octanoic acid was combined with Triamcinolone ~cetonide. However, the aqueous gel vehicle was not significantly different from the croton oil group.
Substantially similar results are obtained where the triamcinolone acetonide contained in formulation 2 is replaced, in whole or in part, with an equivalent amount of beclomethasone dipropionate, clobetasol propionate, ~i flllcortolone valerate, fluocinolone acetonide, beta-methasone benzoate, betamethasone dipropionate, beta-methasone valerate, desonide, desoxymethasone, diflorasone diacetate, fluclorolone acetonide, fluocinonide, fluo-cortolone, fluprednidene (fluprednylidene) acetate, flu-randrenolone, halcinonide, hydrocortisone butyrate, triamcinolone acetonide, clobetasone butyrate, flumetha-sone pivalate, fluocortin butylester, hydrocortisone with urea, dexamethasone, hydrocortisone alcohol or acetate, methylprednisolone, or mixtures thereof.
Similar results are also obtained where the octanoic acid in formulation 2 is replaced, in whole or in part, ~, with equivalent amounts of pentanoic, hexanonic, heptanoic, nonanoic, decanoic, undecanoic or dodecanoic acid, or , mixtures thereof.
3~
.. Substantially similar anti-inflammatory results : are also obtained when formulation 2 is prepared as a "
liquid, non-aqueous gel, ointment, cream or lotion, rather than as an aqueous gel.
:., ' WHAT IS CLAIMED IS:
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triamcinolone acetonide to the octanoic acid and decanoic acid aqueous gel, cream, ointment or non~aqueous gel compositions resulted in no antagonistic effects on their antimicrobial activity.
3~
_nes o Inhibition (mm) Candida Staph Pseudo sebum no sebum sebum no sebum no sebum 5 2 29 ~5 22 34 42 ~`~ 11 0 0 0 15 0 Substantially similar results are obtained where the octanoic or decanoic acids of ,he above compositions are replaced, in whole or in part, with equivalent amounts of pentanoic, hexanoic, heptanoic, nonanoic, undecanoic or dodecanoic acid, or mixtures thereof. Similar results are also obtained where the triamcinolone acetonide is re-placed, in whole or in part, with effective amounts of hydrooortisone acetate, betamethasone valerate, fluocino-lone acetonide, beclomethasone dipropionate, clobetasol propionate, diflucortolone valerate, betamethasone ~t~J~ benzoate, betamethasone dipropionate, desonide, desoxy-methasone, diflorasone diacetate, fluclorolone acetonide, ~- fluocinonide, fluocortolone, fluprednidene (fluprednyli-dene) acetate, flurandrenooone, halcinonide, hydrocorti-sone butyrate, clobetasone butyrate, flumethasone pi-~-alate, fluocortin butylester, hydrocortisone with urea, dexamethasone, hydrocortisone alcohol or acetate, methyl-prednisolone, or mixtures thereof.
., ~. ~
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EXA~PLE V
In order to compare the antimicrobial activity of octanoic acid/triamcinolone acetonide combinations against the activity of compositions containing three other corticosteroids at concentrations which are common in current:ly marketed products, the following compositions were screened using the disk diffusion procedure~ All of the compositions were in the form of aqueous gels; these gel compositions contained (vehicle) 1~ myristyl alcohol, 25~ propylene glycol, 5% Pluroni ~ L-~4, l~ beta-alanine, 25% of 4% aqueous Carbopo ~ 934, with the balance being water. A11 of the gel compositions had pH's between about 3 and 4.
1 Compositions ~wei~t l - 0.05% triamcinolone acetonide 2 - 0.05~ triamcinolone acetonide ~ 4% octanoic acid 3 - O.S% hydrocortisone-21-acetate 4 - 0.5% hydrocortisone-21-acetate ~ 4~ octanoic acid 5 - 0.1% betamethasone valerate ~ - 0.1% betamethasone valerate ~ ~% octanoic acid 7 - 0.0~5% fluocinolone acetonide 8 - 0~02S% fluocinolone acetonide ~ 4~ octanoic acid 9 - vehicle (no active) The results oE these experiments are summarized in ~5 the table, below. In all instances~ ~he corticosteroid alone showed no antimicrobial activity. All of the compositions containing 4~ octanoic acid showed good activity. Zones of inhibition were approximately the same size for all of these compositions regardless ~f the steroid or its concentration.
) 3~6 Zones of Inhibition (mm) Staph Candida Pseudo sebum no sebum sebum No sebum no sebum l 0 0 0 0 32 EXAMPLE VI
_ The croton oil mouse ear assay was used to assess the topical anti-inflammatory activity of the compositions set forth in the table, below. The croton oil assay procedure is described in Tonelli, et al., Endocrinology, 77, 625-634 ~1965); this procedure was utilized herein except that the compositions being tested were applied 24 hours before the croton oil. In this assay, the corticosteroid-containing formulation was applied to one ear prior to inducing inflammation in both ears with a 2 croton oil application. The relative suppression of the croton oil-induced inflammation in the cortico~teroid treated ear is a measure of an~i-inflammatory activity.
The triamcinolone acetonide ~ octanoic acid composition was in the form of an aqueous gel (pH-3-4) containing l~
myristyl alcohol, 25% propylene glycol, 5~ Pluroni ~
L-64, l~ beta-alanine, 25% of 4% aqueous Carbopol~ 934, with the balance being water. The vehicle alone, without any active components, was also tested. The following table shows the key data generated using this model systern~
3~
Avg. Left Ear Formulation ~t. (mg) % Inhibition ; 1. Croton oil (control) 22.03 0 2. O.l~ Triamcinolone Acetonide + 4~
Octaonic Acid (aqueous gel) 11.32 97 3. Vehicle (aqueous gel) 23.83 10 ~. 0.1% Triamcinolone Ancetonide (aqueous gel) 98 Formulations 2 and 4 were significantly better in their anti-inflammatory performance than the croton oil control group (P <0.05). Comparison of formulations 2 and 4 shows that there were no negative interactions regarding anti-inflammatory activity when octanoic acid was combined with Triamcinolone ~cetonide. However, the aqueous gel vehicle was not significantly different from the croton oil group.
Substantially similar results are obtained where the triamcinolone acetonide contained in formulation 2 is replaced, in whole or in part, with an equivalent amount of beclomethasone dipropionate, clobetasol propionate, ~i flllcortolone valerate, fluocinolone acetonide, beta-methasone benzoate, betamethasone dipropionate, beta-methasone valerate, desonide, desoxymethasone, diflorasone diacetate, fluclorolone acetonide, fluocinonide, fluo-cortolone, fluprednidene (fluprednylidene) acetate, flu-randrenolone, halcinonide, hydrocortisone butyrate, triamcinolone acetonide, clobetasone butyrate, flumetha-sone pivalate, fluocortin butylester, hydrocortisone with urea, dexamethasone, hydrocortisone alcohol or acetate, methylprednisolone, or mixtures thereof.
Similar results are also obtained where the octanoic acid in formulation 2 is replaced, in whole or in part, ~, with equivalent amounts of pentanoic, hexanonic, heptanoic, nonanoic, decanoic, undecanoic or dodecanoic acid, or , mixtures thereof.
3~
.. Substantially similar anti-inflammatory results : are also obtained when formulation 2 is prepared as a "
liquid, non-aqueous gel, ointment, cream or lotion, rather than as an aqueous gel.
:., ' WHAT IS CLAIMED IS:
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Claims (15)
1. A topical pharmaceutical composition, having a pH no greater than about 5, comprising a safe and effective amount of an antimicrobial agent selected from C5-C12 fatty acids and mixtures thereof, together with a safe and effective amount of a corticosteroid component.
2. A composition according to Claim 1 wherein the corticosteroid component is selected from the group con-sisting of beclomethasone dipropionate, clobetasol pro-pionate, diflucortolone valerate, fluocinolone acetonide, betamethasone benzoate, betamethasone dipropionate, beta-methasone valerate, desonide, desoxymethasone, diflorasone diacetate, fluclorolone acetonide, fluocinonide, fluo-cortolone, fluprednidene (fluprednylidene) acetate, flu-randrenolone, halcinonide, hydrocortisone butyrate, triamcinolone acetonide, clobetasone butyrate, flumethasone pivalate, fluocortin butylester, hydrocortisone with urea, dexamethasone, hydrocortisone alcohol or acetate, methyl-prednisolone, and mixtures thereof.
3. A composition according Claim 2 which contains from about 0.5% to about 20% of the antimicrobial agent.
4. A composition according to Claim 3 which contains from about 0.01% to about 10% of the cortico-steroid component.
5. A composition according to Claim 4 which additionally contains from about 1% to about 99.5% of a pharmaceutically-acceptable topical carrier.
6. A composition according to Claim 5 wherein the antimicrobial agent is selected from C6-C10 fatty acids and mixtures thereof.
7. A composition according to Claim 6 wherein the antimicrobial agent is selected from octanoic acid, decanoic acid, and mixtures thereof.
8. A composition according to Claim 7 wherein the corticosteroid component is selected from the group con-sisting of triamcinolone acetonide, hydrocortisoneacetate, betamethasone valerate, fluocinolone acetonide, and mix-tures thereof.
9. A composition according to Claim 8 which con-tains from about 1% to about 10% of the antimicrobial agent.
10. A composition according to Claim 9 which con-tains from about 0.0 % to about 5% of the corticosteroid component.
11. A composition according to Claim 10 wherein the corticosteroid component is triamcinolone acetonide.
12. A composition according to Claim 2 wherein the corticosteroid component is triamcinolone acetonide.
13. A composition according to Claim 2 wherein the antimicrobial agent is octanoic acid.
14. A composition according to Claim 2 having a pH
no greater than about 4.
no greater than about 4.
15. A composition according to Claim 2 in the form of an aqueous gel or an aqueous lotion.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US276,556 | 1981-06-23 | ||
| US06/276,556 US4343798A (en) | 1981-06-23 | 1981-06-23 | Topical antimicrobial anti-inflammatory compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1182396A true CA1182396A (en) | 1985-02-12 |
Family
ID=23057107
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000405544A Expired CA1182396A (en) | 1981-06-23 | 1982-06-21 | Topical antimicrobial anti-inflammatory compositions |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US4343798A (en) |
| EP (1) | EP0068553B1 (en) |
| JP (1) | JPS5841819A (en) |
| AU (1) | AU549201B2 (en) |
| CA (1) | CA1182396A (en) |
| DE (1) | DE3267559D1 (en) |
| ES (1) | ES513340A0 (en) |
| NZ (1) | NZ201029A (en) |
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| CA553057A (en) * | 1958-02-11 | J. Ferlin Henry | Production of bactericidal compositions | |
| US2466663A (en) * | 1944-10-20 | 1949-04-05 | Ward Baking Co | Fungicide containing caprylic acid and its salt |
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| DE2912438A1 (en) * | 1979-03-29 | 1980-10-16 | Eckert Theodor | Topical treatment of skin diseases - with alcoholic soln. of fatty acid |
| US4246261A (en) * | 1979-08-09 | 1981-01-20 | Scott Eugene J Van | Additives enhancing topical corticosteroid action |
| DE2934090A1 (en) * | 1979-08-23 | 1981-03-12 | Miroslav T Dipl Ing Dr Bomar | Agent for treating hyper:keratotic skin diseases - contains undecylenic acid pref. in combination with ascorbic acid |
-
1981
- 1981-06-23 US US06/276,556 patent/US4343798A/en not_active Expired - Lifetime
-
1982
- 1982-06-14 EP EP82200731A patent/EP0068553B1/en not_active Expired
- 1982-06-14 DE DE8282200731T patent/DE3267559D1/en not_active Expired
- 1982-06-21 AU AU85038/82A patent/AU549201B2/en not_active Ceased
- 1982-06-21 NZ NZ201029A patent/NZ201029A/en unknown
- 1982-06-21 CA CA000405544A patent/CA1182396A/en not_active Expired
- 1982-06-22 ES ES513340A patent/ES513340A0/en active Granted
- 1982-06-23 JP JP57108244A patent/JPS5841819A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| DE3267559D1 (en) | 1986-01-02 |
| AU8503882A (en) | 1983-01-06 |
| EP0068553A1 (en) | 1983-01-05 |
| AU549201B2 (en) | 1986-01-16 |
| JPS5841819A (en) | 1983-03-11 |
| US4343798A (en) | 1982-08-10 |
| EP0068553B1 (en) | 1985-11-21 |
| ES8308213A1 (en) | 1983-08-16 |
| ES513340A0 (en) | 1983-08-16 |
| NZ201029A (en) | 1985-10-11 |
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