CA1199273A - Anti-inflammatory composition - Google Patents
Anti-inflammatory compositionInfo
- Publication number
- CA1199273A CA1199273A CA000413306A CA413306A CA1199273A CA 1199273 A CA1199273 A CA 1199273A CA 000413306 A CA000413306 A CA 000413306A CA 413306 A CA413306 A CA 413306A CA 1199273 A CA1199273 A CA 1199273A
- Authority
- CA
- Canada
- Prior art keywords
- triclosan
- halometasone
- patients
- cream
- alpha
- 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
- A61K31/56—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
Abstract
New pharmaceutical preparations Abstract The invention concerns new pharmaceutical preparations for topical administration, such as creams, ointments, foams, pastes or gels , which contain the anti-inflammatorily active glucocorticoid 2-chloro-6.alpha.,9.alpha.-difluoro-16.alpha.-methyl-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione (2-chloroflumethasone, halometasone) and the antimicrobial agent 2,4,4'-trichloro-2'-hydroxy-diphenyl ether (triclosan). The new dermatics may contain, besides these two components, pharmaceutical carriers as usually present in formulations for topical administration. The new dermatics are especially suitable for the treatment of infected forms of acute eczematous dermatoses of different origin, for the initial treatment of strongly inflamed dermatomycoses or strongly inflamed forms of pyodermias.
Description
Case 4-14009 New pharmaceutical preparat;ons The present invention concerns new pharmaceutical preparations for topical administration, and in particular, dermatics ;n the form of creams 9 ointments, foams, pastes or gels 9 especially for the treat-ment of infectious dermatvses~ which contain an anti-inflammatorily active glucocorticoid together with a broad-spectrum antimicrobial additive. The corticoidal component of such preparations is halo-metasone, viz the known 2-chloro-6~,9~~difluoro-16a~methyl~ ,17a, 21-trihydroxy-pregna-1,4-diene-3J20-dione ~2-chloroflumethasone), a potent synthetic dermatocorticoid possessing pronounced anti-inflam-matory, antl-exudative, anti-epidermoplastic, anti-allergic and anti-pruritic properties. The antimicrobial additive is triclosan, viz
2,4,4'-trichloro-2'-hydroxy-diphenyl ether, also a known compound9 it displays a broad-spectrum antibacterial, antifungal and anti-monilial action, while being extremely well tolerated. The new dermatics according to the invention may contain, besides these two components, pharmaceutical carriers, as usually present in formula-~ions for topical administration.
Halometasone has been described for instance in US patent 1 245 292 and can be prepared according to the methods therein described. The anti-inflammatory effects of halometasone can be demonstrated in test animals~ which show that it is comparable in potency to fluo-cinolone acetonide (Synalar ~ ), while i~s unwanted effects appear to be less marked. I~hen halometasone and de~amethasone are given in equipotent anti~inflammatory doses~ halometasone displays signi~
ficantly less marked inhibitory effects on the hypothalamo-pituitary--adrenal axis. Epidermo-hyperplasia-inhibition-test shows that ~he 7~
anti-epidermoplas~ic ~ffect of halometasone is only slightly weaker than that of fluocinolone acetonide, indicating that it is likely to exert therapeutically beneficial effects on dermatological dis-orders characterized by epidermal hyperplasia, e.g. psoriasis and chronic ecæema. Vasoconstriction assay, which is an indicator of the anti-inflammatory activity~ carried out on halometasone has shown the substance to be particularly suitable for the topical treatment of the skin in cases of dermatic disorders and diseases, as has been demonstrated in extensive experimental and clinical investigations 3 and in part;cular for an intensive therapy, owing to the rapid onset and efficacy of action in the initial stages of the treatment, characteristic of halometasone.
Triclosan (cf. ~K patent 1 038 185) is an antimicrobial agent with bactericidal properties which is effective against all important bacteria, dermatophytes~ fungi and yeasts, with the exception of the Pseudomonas group. For this reason triclosan represents an ideal antimicrobial agent in all those cases~ in which it is difficult or impossible to deter~ine the microbiological pathogen or where there i5 no time to carry out such an investigation.
~ccording to the finding of the present invention the antimicrobial action of triclosan is enhanced by the presence of the corticoid halometasone when the mixture of these two components in appropriate ratios is administered to patients suffering from various skin infections accompanied by inflammatory processes. The synergistic effect can be shown by the comparison of the action elicited by the said mixture and that elici~ed by the antimicrobic agent triclosan alone in clinical experiments, in certain cases e.g. of acute in-fected eczematous dermatoses, as will be reported below:
the corticoid component appears to significantly accelerate and complete the antibacter;al action of triclosan, while contributing its full arlti-inf]ammatory action at the same time. The use of the pharmaceut;cal preparation according to the invention is therefore a great advance in the art for the therapy of all those conditions and diseases where a rapid and efficient anti-inflammatory and anti bacterial effect is desired.
In German patent 21 25 ~93, which is for an invention ConSiSLing of antimicrobial preparations containing a halogenated o-phenoxyphenol ~halogenated diphenyl ether) of the type of tr;closan (including this latter) and of a derivative of phenyl- or phenoxy-ethylalcohol, rnention is made, in passing, that those combinations of antimicrobials can contain further supplementary active substances, in particular corticosteroids9 as anti-inflammatory agents: flumethasone pivalate and hydrocortisone are specifically mentioned. Nothing9 however, i said in that patent about a synergism of the antibacterial activity caused by the presence of a corticoid. On the contrary, the addition of such further components is contemplated in view of their intrinsic and specific known action, e.g. the anti-inflammatory action. It is also suggested adding those antimicrobics to antiinflammatory agents for the treatment of dermatoses, such as eczemas, psoriasis, acne etc., in order to prevent secondary infec~ions. An antiinflammatory antimicrobial combination medicament has indeed been put on the market containing flumethasone pivalate and triclosan (Logamel Ciba-Geigy AG, Basel, Switzerland) to be used chiefly for long lasting therapies of various infectious dermatoses, especially those caused by fungal pathogeus. The good success of this dermatic is probably due to the rela~ive long duration of the treatment, while it is difficult ~o decide whether there is an interac~ion of the corticoid and the antimicrobial agent resulting in an improved anti-bacterial effect. Experimental pharmacological tests show that a dire~t synergism is not presen~.
~ ~3 ~ ~ J ~
In the case of the clermatics ofthe present i.nvention, however, a synergism appears to be present, as a drastic improvement of the therapeutic effect with regard to both inflan~ati.on and infection is immediately detectable. This result~ which could not be foreseen from the art, represents a great advance in the art making a medi-cament available which is excellently suitable for the intensive therapy of infected dermatoses. The superiority of the halometasone -triclosan preparations over corresponding prepaxations containing only triclosan or over the best known dermatics on the market in-cluding a corticoid and antimicrobial agent and envisaged for in-tensive therapies of infectious dermatoses is revealed by the following clinical data.
The dermatic of the present invention was used in the form of a cream as described in Example 1. The tests with triclosan alone were also carried out with a cream of the same composition but without halometasone.
CLINICAL TRI~LS IN INFECTED ACUTE ECZEMATOUS DE~ATOSES
Trial population Three clinical tr;als were carried out in 537 patients with infected acute eczematous dermatoses of various etiologic&l origin. Excluding 28 drop-outs, who were withdrawn from the trial for reasons not related to the treatment, 509 patients, 254 females and 255 males, (255 patients treated with halometasone-triclosan and 254 treated with the comparative preparations~ were evaluated for the assessment of efficacy; a total of 529 patients were evaluated for the assess-ment of tolerability (only 8 patients who were receiving the trial ~reatment for less than 7 days and did no~ develop any adverse reaction were e~cluded). The age of the pat;ents ranged from 18 to 82 years; in most of the patients the extent of the lesions treated ~3 was less than 20% of the bocly s~lrrace. The duration of the presen~
disease varied between 1 alld 98 days. Only a small proportion (12%) of the patients reported contact allergies in their case history.
Premature discontinuation The most frequent reason for premature discontinuation of the treat-ment was an early cure, i.e. in less than 20 days. The average per-centage of patients achievi~g an "early cure" was higher with halometasone-triclosan cream (41.2%) than in the group receiving treatment with the comparative preparations (27.9%~
Therapeutic effect According to the global assessment of the therape~ltic effect made at the end of trial, halometasone-triclosan cream yielded very satis-factory results. Halometasone-triclosan cream proved significantly superior to Diprogenta ~ and triclosan creams wi-th regard to both "very good" ~= cured) and "very good and good" results, an~ almost reached the level of statistically significant superiority to Betnesol ~ VN cream with respect to "very good and good" results.
The overall success rate obtained by pooling "good" and "very good"
(= cured) results shows that 92% of the patients markedly benefited from the treatment with halometasone-triclosan.
Onset of therapeutic effect within the first 3 days was reported in 55.2% of the patients treated with halometasone-triclosan cream.
-- 6 ~
Table 1: T~IERAPEUTIC EFFECT IN PATIENTS WITH INFECTED ACUTE
ECZEMATOUS DERMATOSES.
Preparations No. of Patients Therapeutic Effect (Creams) ~ery good and good ~ery good n % n %
halometasone- 134 129 96.3 99 80.4 -triclosan (P = O.0001) (P = O.00~) Diprogenta ~ 133 107 80.4 78 58.6 halometasone- 9O 79 87.8 57 63.3 -triclosan (p = 0.055) Betnesol~ VN 91 70 76.9 49 53.8 halome~asone- 31 28 90.3 21 o7.7 -triclosan (P~ 0.003) (Pc 0.001) ~riclosan 30 14 46.7 7 23.3 . 7 _ TRIALS IN ACUTE SUPERFICIAL B~CTERIAL SKIN INFECTIONS
Trial population A total of 2~2 patients with acute superficial pyoden~ias were ad-mitted to these trials carried out by 9 dermatologists in Germany, Spain and Yugoslavia. Thirteen patients considered as drop-outs ~due to reasons not related to the trial treatments3 were e~cluded from the assessment of efficacy, the rennaining trial population consisted of 279 patients, 141 females and 138 males (139 patients treated with halometasone-triclosan and 140 treated with the comparative prepara-t;ons). A total of 289 patients were evaluated for the assessment of tolerability (only 3 patients, who received the trial treatment for less than 7 days and did not develop any adverse reaction, were excluded). The age of the patients ranged from 2 to 78 years. The most frequent type of pyodermia was "impetigo contagiosa"; repor~ed in 40.8% of the patients. The duration of the target disease varied between 1 and 90 days. Only 3% of the patients reported contact al]ergy in their case history.
Premature discontinuation In a total of 80 patients the trial treatment was discontinued prematurely; the Most frequent reason was "early cure", which was reported in 66 patients (75%). The average percentage of patients achieving "early cure" ~i.e. in less than 15 days) was higher in the group treated with halometasone triclosan cream (27.3%) than in the group receiving treatment with the compara~ive preparations (20%).
Therapeutic effect Halometasone-triclosan cream showed satisfactory efficacy according to the global assessment made at the end of the trial. Halometasone--triclosan cream proved significantly superior to Synalar Neomycin cream with respect to the number of both "good & very good" and "very ~ood" (= cured) evaluations (Table 2). In comparison with Deco-derm~ Irivalent and triclosan cream, halometasone-triclosan cream did not display significan-tly different therapeutic efEicacy. The overall success rate obtained by pooling "very good" (- cured) and "good"
results shows that 83.4% of the patients treated with halometasone--triclosan cream markedly benefited from the treatment. In the group trea~ed with halometasone-triclosan 85% of the patients had negative bacteriological fiilding~ in direct microscopy and 78% had negative findings in bacteriological culture after the treatment.
Table 2: TUERAPEUTIC EFFECT IN PATIENTS WITH ACUTE SUPERFICIAL
BACTERIAL SKIN INFECTIONS.
Preparation~ No. of Patients ~herapeutic Effect (Creams) Very good & good Very good n % n %
halometasone~ 62 56 90.3 52 8309 -triclosan (P = 0.0002) (P0.003) Synalar;~ 63 39 61.9 3758.7 Neomycln halometasone- 48 3675.0 27 56.2 -triclosan Decoderm 47 27 57.4 2144.7 Trivalent halometasone- 29 2482.8 12 41.4 -triclosan Triclosan cr. 30 2273.3 18 60.0 ~ a~ O~
_ 9 _ The onset of therapeutic effect ~ithin the first 3 days was reported in 38% of the patients treated with halo~etasolle-tr;closan cream.
In the~se clinical trials the preparation of the present invention9 halometasone/triclosan9was used in the form of a cream having a content of 0.05% halometasone and 1% triclosan in a specially formu-lated absorption base free from perfumes, parabens and allergenic lipids, as is more particularly described in the illustrative Example.
The comparative medicaments set forth in the above Tables are regis-tered trademarks of the following origin and composi~ions "Diprogenta~ " cream - Plough Schering Corpora~ion, Kenilworth9 New Jersey 0.05% betamethasone 0.1% gentamycin "Betnesol VN ~ " cream - Glaxo Laboratorie5 Ltd.9 Greenford, Middlesex9 England 0.1% betamethasone 21-valerate 0.5% neomycinsulfate "Synalar~ / -N " cream - Syntex Laboratories, Inc.9 Palo Alto9 California fluocinolone acetonide neomycin "Decoderm trivalent~ " - Merck AG, Darmstadt, BRD
ream fluprednyliden acetate gentamycin chlorohydroxyquinoline P'~3 - lO -Tolerabil;ty The overa]l tolerability of halometasone-triclosan cream was good.
Adverse reactions were reported in a ]imited number of cases (ca. 5 of patients treated and in about 10% of patients treated with the comparative preparations. The tolerability of halometasone/triclosan cream was sign;ficantly better than that of Synalar ~ neomycin cream3 otherwise it was similar to that of the comparative preparations. The adverse effects reported were usually signs and &ymptoms of local irritation, sometimes even possibly related to deterioration of the underlying symptomatology. No syste~ic effects were observed in any of the patients treated with halomeeasone/triclosan.
The antimicrobial component of the new preparations according to the present invention viz triclosan, encompasses a broad-spectrum of pathogens, of bot~ gran~-positive and gram-negative microorganisms as well as dermatophytes (epidermophytes, erichophytes 9 microsporum and yeasts~ The allergenicity of triclosan is extremely low.
The new preparations of the invention are especially suitable for the treatment of infected (or in danger to be infected) forms of acute eczematous dermatoses of different origin, such as acute contact dermatitis, acute endogenous eczema (acute constitutional eczema, acute atopic dermatitis, acute neurodermatitis), acute nummular eczema (acute nummular dermatitis), acute seborrheic eczema (acute seborrheic dermatitis), for the initial treatment of serongly in-flamed dermatomycoses, the initial treatment of strongly inflamed fonns of pyodermias, e.g. impetigo contagiosa, ostiofolliculitis (impetigo Eollicularis Bockhart), folliculitis barbae, ecthyma, intertrigo and erythrasma. Insome cases a supplementary systemic treatment may be necessary~ in cases of severe skin infeceions.
The pharmaceutical preparations of the present inventioll contain the two active in~redients in combination Witll at least one pharmaceutical excipient suitable for the topical administration, such as creams9 ointments, pastes or foams or gels 9 which contain preferably from approximately 0.01% to about 2.5% of halome~asone and from approxi-mately 0.1% to about 5% of triclosan. The preferred range of halo-metasone is, however, between 0.02% to about 0.8% and that for tri-closan from about 0.5% to about 3%.
Creams are oil-in-water emulsions which contain more than 50% of water. Fatty alcohols are chiefly used as oleaginous base, for example lauryl, cetyl or stearyl alcohol9 fatty acids, for example palmitic or stearic acid, liquid to solid waxes9 for example isopropyl myristate9 wool-wax or bees-wax, and/or hydrocarbons9 for cxample petroleum jelly ~petrolatum) or paraffin oil. Suitable emulsiiers are surface-active substances with primarily hydrophilic properties, such as corresponding non-ionic emulsifiers, for example fatty acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tweens~; polyoxyethylene fatty alcohol ethers or esters, or corresponding ionic emulsifiers, such as alkali metal salts of fa~y alcohol sulphates, for example sodium lauryl sulphate, sodium cetyl sulphate or sodium stearyl sulphate, which are customarily used in the presence of fatty alcohol, for example cetyl alcohol or stearyl alcohol. Additîves to the water phase include agents which reduce water loss through evaporation, for example polyalcohols, such as glycerol, sorbitol9 propylene glycol and/or polyethylene glycols, as well as preserva~ives 7 perfumes etc.
Ointments are water-in~oil emulsions which contain up to 70~, prefer-ably however, approxO 20% to aboll~ 50%9 of wa~er or aqueous phase.
The oleaginous phase comprises chiefly hydrocarbons9 for example *Tr~de Mark petroLeum jellyl paraffin oil and/or hard paraffins, which cont.~in pre~erably hydroxy compounds suitable for improving the water-absorp-tion7 such as fatty alcohols or esters thereof, for e~ample cetyl alcohol or wool wax alcohols, or wool wax. Emulsifiers are corre-sponding lipophilic substances, such as sorbitan fatty acid esters (Spans~, for example sorbitan oleate and/or sorbitan isostearate.
Additives to the water phase include humectants, such as polyalcohols, for example glycerol, propylene glycol, sorbitol and/or polyethylene glycol, and preservatives, perfumes etc.
Greasy ointments are anhydrous and contain as base in particular hydrocarbons~ for example paraffin, petroleum jelly and/or l;quid paraffins, furthermore, natural or partially synthetic fat, for example coconut fatty acid triglycerides, or preferably hardened oils, for example hydrated ground nut or cas~or oil, and also fatty acid partial esters of glycerol~ for example glycerol mono- and distearate, and, for example, the fatty alcohols, emulsifiers and/or additives for increasing the water-absorption mentioned in connection with the ointments.
Pastes are creams and ointments containing powdered ingredients which absorb secretions, such as metal oxides 3 for example titanium oxide or zinc oxide, and ~alc and~or aluminium silicates whose purpose it is to bind moisture or secretion present.
Foams are adminis~ered from pressurised dispensers and are liquid oil-in~water emulsions in aerosol form, with halogenated hydrocarbons 9 such as chlorofluoro~lower alkanes, for example dichlorodifluoro-methane and dichlorotetrafluoroethane being used as propellants. For the oleaginous phase there are used, inter alia, hydrocarbons, for example paraffin oil, fatty alcohols, for ex~mple cetyl alcohol, fatty acid es~ers~ for example isopropyl myristate 3 and/or other *Trade Mark waxes~ As emuls;fiers there are used, inter ~lia, mixtures oE those emulsifiers with primarily hydrophilic properties~ such as polyoxy-ethylene sorbitan fatty acid esters (Tweens~, and those with primarily lipophilic properties, such as sorbitan fatty acid esters (Spans)*
In addition, the conventional additives are used, such as preserva-tives etc.
Gels are in particular aqueous solutions or suspensions of the active substances in which gel formers, preferably those of the group of cellulose ethers, for e~ample me~hyl cellulose, hydroxyethyl cellulose or carboxymethyl cellulose, or of the vegetable hydrocolloids, such as sodium alginate, tragacanth or gum arabic, are dispersed and swelled. The gels preferably also contain in addition humectants from the group o the polyalcohols, such as propylene glycol, glycerin and/or lower polyethylene glycols, as ~ell as wetting agents, for example polyoxyethylene sorbitan fatty acid esters, such as polyoxy-ethylene sorbitan monostearate, monolaurate or monooleate, in concen-trations of about 0.02% to 5%. As further adjuvants, the gels contain conventional preservatives, for e~ample benzyl alcohol, phenethyl alcohol 7 phenoxyethanol, lower alkyl esters of p-hydroxybenzoic acid such as the methyl and/or propyl esters, sorbic acid or organic mercury compounds such as merthiolate.
The pharmaceutical preparations for topical application are obtained in kno~n manner, for e~ample by dissolving or suspending the active substance in the base or in a part thereof, if necessary. When pro~
eessing the active substance in the form of a solution, it is usually dissolved in one of the two phases before the emulsification, and when Frocessing the active substance in the form of a suspension, it is mixed with a part of the base before the emulsification and then added to the remainder of the formulation.
*Trade Mark - 14 ~ qD ~
The preferred forms of the nei~ pharmaceutical preparations according to the present invention are creams having e.g. the a~ove mentioned range oE active substances, especially a cream containing from 0.03% -0.1% of halometasone and 0.7% - 2~ triclosan, preferab]y a cream with a content of about 0.05% halometasone and 1% triclosan7 e.g. one as exemplified in Example l.
The following Example describes the invention in more details.
Example : A cream for the topical trea~ment of infectious dermatoses of the following composit;on:
Each 100 g co~tains halometasone 0~05 g triclosan 1.00 g ascorbyl palmitate 0.05 g cetyl alcohol9 PH 4.50 g cetyl palmitate 4.00 g Duponol C*(sodium lauryl sulpha~e) 1.00 g EDTA*, dis~dium salt of 0.10 g glycerin, pure, PH 6.00 g propylene glycol, dist. (1.2 propanediol) 5.50 g stearic acid7 ;n flakes, PH 4.00 g stearyl alcohol, PH 4.50 g water, deionised 64.30 g white petrolatunl 5.00 g 100.00 g * ethylenediaminetetraacetic acid *Trade Mark 7~3 Meti~od of m~nufacture Duponol C*and sodium salt of EDTA are dissolved in hot deionised water. Propylene glycol is added.
Cetyl alcohol~ stearyl alcohol, stearic acid, cetyl palmitate, ascorby] palmita~e, trîclosan and white petrolatum are ~ixed and melted together.
The t~70 phases are emulsified and cooled.
Halometasone, viz 2-chloro-6~,9~-difluoro~16~-methyl~ ,17~921-tri-hydroxy-pregna-1,4-diene-3,20-dione is suspended in glycerin and the suspension is homogeneously dispersed in a portion of the cream base.
This concentrate is incorporated in the remainder o the cream base.
Batch size: 400 kg ~or a multiple thereof) Each portion weighed in corresponds ~o the stated composition.
*Trade Mark
Halometasone has been described for instance in US patent 1 245 292 and can be prepared according to the methods therein described. The anti-inflammatory effects of halometasone can be demonstrated in test animals~ which show that it is comparable in potency to fluo-cinolone acetonide (Synalar ~ ), while i~s unwanted effects appear to be less marked. I~hen halometasone and de~amethasone are given in equipotent anti~inflammatory doses~ halometasone displays signi~
ficantly less marked inhibitory effects on the hypothalamo-pituitary--adrenal axis. Epidermo-hyperplasia-inhibition-test shows that ~he 7~
anti-epidermoplas~ic ~ffect of halometasone is only slightly weaker than that of fluocinolone acetonide, indicating that it is likely to exert therapeutically beneficial effects on dermatological dis-orders characterized by epidermal hyperplasia, e.g. psoriasis and chronic ecæema. Vasoconstriction assay, which is an indicator of the anti-inflammatory activity~ carried out on halometasone has shown the substance to be particularly suitable for the topical treatment of the skin in cases of dermatic disorders and diseases, as has been demonstrated in extensive experimental and clinical investigations 3 and in part;cular for an intensive therapy, owing to the rapid onset and efficacy of action in the initial stages of the treatment, characteristic of halometasone.
Triclosan (cf. ~K patent 1 038 185) is an antimicrobial agent with bactericidal properties which is effective against all important bacteria, dermatophytes~ fungi and yeasts, with the exception of the Pseudomonas group. For this reason triclosan represents an ideal antimicrobial agent in all those cases~ in which it is difficult or impossible to deter~ine the microbiological pathogen or where there i5 no time to carry out such an investigation.
~ccording to the finding of the present invention the antimicrobial action of triclosan is enhanced by the presence of the corticoid halometasone when the mixture of these two components in appropriate ratios is administered to patients suffering from various skin infections accompanied by inflammatory processes. The synergistic effect can be shown by the comparison of the action elicited by the said mixture and that elici~ed by the antimicrobic agent triclosan alone in clinical experiments, in certain cases e.g. of acute in-fected eczematous dermatoses, as will be reported below:
the corticoid component appears to significantly accelerate and complete the antibacter;al action of triclosan, while contributing its full arlti-inf]ammatory action at the same time. The use of the pharmaceut;cal preparation according to the invention is therefore a great advance in the art for the therapy of all those conditions and diseases where a rapid and efficient anti-inflammatory and anti bacterial effect is desired.
In German patent 21 25 ~93, which is for an invention ConSiSLing of antimicrobial preparations containing a halogenated o-phenoxyphenol ~halogenated diphenyl ether) of the type of tr;closan (including this latter) and of a derivative of phenyl- or phenoxy-ethylalcohol, rnention is made, in passing, that those combinations of antimicrobials can contain further supplementary active substances, in particular corticosteroids9 as anti-inflammatory agents: flumethasone pivalate and hydrocortisone are specifically mentioned. Nothing9 however, i said in that patent about a synergism of the antibacterial activity caused by the presence of a corticoid. On the contrary, the addition of such further components is contemplated in view of their intrinsic and specific known action, e.g. the anti-inflammatory action. It is also suggested adding those antimicrobics to antiinflammatory agents for the treatment of dermatoses, such as eczemas, psoriasis, acne etc., in order to prevent secondary infec~ions. An antiinflammatory antimicrobial combination medicament has indeed been put on the market containing flumethasone pivalate and triclosan (Logamel Ciba-Geigy AG, Basel, Switzerland) to be used chiefly for long lasting therapies of various infectious dermatoses, especially those caused by fungal pathogeus. The good success of this dermatic is probably due to the rela~ive long duration of the treatment, while it is difficult ~o decide whether there is an interac~ion of the corticoid and the antimicrobial agent resulting in an improved anti-bacterial effect. Experimental pharmacological tests show that a dire~t synergism is not presen~.
~ ~3 ~ ~ J ~
In the case of the clermatics ofthe present i.nvention, however, a synergism appears to be present, as a drastic improvement of the therapeutic effect with regard to both inflan~ati.on and infection is immediately detectable. This result~ which could not be foreseen from the art, represents a great advance in the art making a medi-cament available which is excellently suitable for the intensive therapy of infected dermatoses. The superiority of the halometasone -triclosan preparations over corresponding prepaxations containing only triclosan or over the best known dermatics on the market in-cluding a corticoid and antimicrobial agent and envisaged for in-tensive therapies of infectious dermatoses is revealed by the following clinical data.
The dermatic of the present invention was used in the form of a cream as described in Example 1. The tests with triclosan alone were also carried out with a cream of the same composition but without halometasone.
CLINICAL TRI~LS IN INFECTED ACUTE ECZEMATOUS DE~ATOSES
Trial population Three clinical tr;als were carried out in 537 patients with infected acute eczematous dermatoses of various etiologic&l origin. Excluding 28 drop-outs, who were withdrawn from the trial for reasons not related to the treatment, 509 patients, 254 females and 255 males, (255 patients treated with halometasone-triclosan and 254 treated with the comparative preparations~ were evaluated for the assessment of efficacy; a total of 529 patients were evaluated for the assess-ment of tolerability (only 8 patients who were receiving the trial ~reatment for less than 7 days and did no~ develop any adverse reaction were e~cluded). The age of the pat;ents ranged from 18 to 82 years; in most of the patients the extent of the lesions treated ~3 was less than 20% of the bocly s~lrrace. The duration of the presen~
disease varied between 1 alld 98 days. Only a small proportion (12%) of the patients reported contact allergies in their case history.
Premature discontinuation The most frequent reason for premature discontinuation of the treat-ment was an early cure, i.e. in less than 20 days. The average per-centage of patients achievi~g an "early cure" was higher with halometasone-triclosan cream (41.2%) than in the group receiving treatment with the comparative preparations (27.9%~
Therapeutic effect According to the global assessment of the therape~ltic effect made at the end of trial, halometasone-triclosan cream yielded very satis-factory results. Halometasone-triclosan cream proved significantly superior to Diprogenta ~ and triclosan creams wi-th regard to both "very good" ~= cured) and "very good and good" results, an~ almost reached the level of statistically significant superiority to Betnesol ~ VN cream with respect to "very good and good" results.
The overall success rate obtained by pooling "good" and "very good"
(= cured) results shows that 92% of the patients markedly benefited from the treatment with halometasone-triclosan.
Onset of therapeutic effect within the first 3 days was reported in 55.2% of the patients treated with halometasone-triclosan cream.
-- 6 ~
Table 1: T~IERAPEUTIC EFFECT IN PATIENTS WITH INFECTED ACUTE
ECZEMATOUS DERMATOSES.
Preparations No. of Patients Therapeutic Effect (Creams) ~ery good and good ~ery good n % n %
halometasone- 134 129 96.3 99 80.4 -triclosan (P = O.0001) (P = O.00~) Diprogenta ~ 133 107 80.4 78 58.6 halometasone- 9O 79 87.8 57 63.3 -triclosan (p = 0.055) Betnesol~ VN 91 70 76.9 49 53.8 halome~asone- 31 28 90.3 21 o7.7 -triclosan (P~ 0.003) (Pc 0.001) ~riclosan 30 14 46.7 7 23.3 . 7 _ TRIALS IN ACUTE SUPERFICIAL B~CTERIAL SKIN INFECTIONS
Trial population A total of 2~2 patients with acute superficial pyoden~ias were ad-mitted to these trials carried out by 9 dermatologists in Germany, Spain and Yugoslavia. Thirteen patients considered as drop-outs ~due to reasons not related to the trial treatments3 were e~cluded from the assessment of efficacy, the rennaining trial population consisted of 279 patients, 141 females and 138 males (139 patients treated with halometasone-triclosan and 140 treated with the comparative prepara-t;ons). A total of 289 patients were evaluated for the assessment of tolerability (only 3 patients, who received the trial treatment for less than 7 days and did not develop any adverse reaction, were excluded). The age of the patients ranged from 2 to 78 years. The most frequent type of pyodermia was "impetigo contagiosa"; repor~ed in 40.8% of the patients. The duration of the target disease varied between 1 and 90 days. Only 3% of the patients reported contact al]ergy in their case history.
Premature discontinuation In a total of 80 patients the trial treatment was discontinued prematurely; the Most frequent reason was "early cure", which was reported in 66 patients (75%). The average percentage of patients achieving "early cure" ~i.e. in less than 15 days) was higher in the group treated with halometasone triclosan cream (27.3%) than in the group receiving treatment with the compara~ive preparations (20%).
Therapeutic effect Halometasone-triclosan cream showed satisfactory efficacy according to the global assessment made at the end of the trial. Halometasone--triclosan cream proved significantly superior to Synalar Neomycin cream with respect to the number of both "good & very good" and "very ~ood" (= cured) evaluations (Table 2). In comparison with Deco-derm~ Irivalent and triclosan cream, halometasone-triclosan cream did not display significan-tly different therapeutic efEicacy. The overall success rate obtained by pooling "very good" (- cured) and "good"
results shows that 83.4% of the patients treated with halometasone--triclosan cream markedly benefited from the treatment. In the group trea~ed with halometasone-triclosan 85% of the patients had negative bacteriological fiilding~ in direct microscopy and 78% had negative findings in bacteriological culture after the treatment.
Table 2: TUERAPEUTIC EFFECT IN PATIENTS WITH ACUTE SUPERFICIAL
BACTERIAL SKIN INFECTIONS.
Preparation~ No. of Patients ~herapeutic Effect (Creams) Very good & good Very good n % n %
halometasone~ 62 56 90.3 52 8309 -triclosan (P = 0.0002) (P0.003) Synalar;~ 63 39 61.9 3758.7 Neomycln halometasone- 48 3675.0 27 56.2 -triclosan Decoderm 47 27 57.4 2144.7 Trivalent halometasone- 29 2482.8 12 41.4 -triclosan Triclosan cr. 30 2273.3 18 60.0 ~ a~ O~
_ 9 _ The onset of therapeutic effect ~ithin the first 3 days was reported in 38% of the patients treated with halo~etasolle-tr;closan cream.
In the~se clinical trials the preparation of the present invention9 halometasone/triclosan9was used in the form of a cream having a content of 0.05% halometasone and 1% triclosan in a specially formu-lated absorption base free from perfumes, parabens and allergenic lipids, as is more particularly described in the illustrative Example.
The comparative medicaments set forth in the above Tables are regis-tered trademarks of the following origin and composi~ions "Diprogenta~ " cream - Plough Schering Corpora~ion, Kenilworth9 New Jersey 0.05% betamethasone 0.1% gentamycin "Betnesol VN ~ " cream - Glaxo Laboratorie5 Ltd.9 Greenford, Middlesex9 England 0.1% betamethasone 21-valerate 0.5% neomycinsulfate "Synalar~ / -N " cream - Syntex Laboratories, Inc.9 Palo Alto9 California fluocinolone acetonide neomycin "Decoderm trivalent~ " - Merck AG, Darmstadt, BRD
ream fluprednyliden acetate gentamycin chlorohydroxyquinoline P'~3 - lO -Tolerabil;ty The overa]l tolerability of halometasone-triclosan cream was good.
Adverse reactions were reported in a ]imited number of cases (ca. 5 of patients treated and in about 10% of patients treated with the comparative preparations. The tolerability of halometasone/triclosan cream was sign;ficantly better than that of Synalar ~ neomycin cream3 otherwise it was similar to that of the comparative preparations. The adverse effects reported were usually signs and &ymptoms of local irritation, sometimes even possibly related to deterioration of the underlying symptomatology. No syste~ic effects were observed in any of the patients treated with halomeeasone/triclosan.
The antimicrobial component of the new preparations according to the present invention viz triclosan, encompasses a broad-spectrum of pathogens, of bot~ gran~-positive and gram-negative microorganisms as well as dermatophytes (epidermophytes, erichophytes 9 microsporum and yeasts~ The allergenicity of triclosan is extremely low.
The new preparations of the invention are especially suitable for the treatment of infected (or in danger to be infected) forms of acute eczematous dermatoses of different origin, such as acute contact dermatitis, acute endogenous eczema (acute constitutional eczema, acute atopic dermatitis, acute neurodermatitis), acute nummular eczema (acute nummular dermatitis), acute seborrheic eczema (acute seborrheic dermatitis), for the initial treatment of serongly in-flamed dermatomycoses, the initial treatment of strongly inflamed fonns of pyodermias, e.g. impetigo contagiosa, ostiofolliculitis (impetigo Eollicularis Bockhart), folliculitis barbae, ecthyma, intertrigo and erythrasma. Insome cases a supplementary systemic treatment may be necessary~ in cases of severe skin infeceions.
The pharmaceutical preparations of the present inventioll contain the two active in~redients in combination Witll at least one pharmaceutical excipient suitable for the topical administration, such as creams9 ointments, pastes or foams or gels 9 which contain preferably from approximately 0.01% to about 2.5% of halome~asone and from approxi-mately 0.1% to about 5% of triclosan. The preferred range of halo-metasone is, however, between 0.02% to about 0.8% and that for tri-closan from about 0.5% to about 3%.
Creams are oil-in-water emulsions which contain more than 50% of water. Fatty alcohols are chiefly used as oleaginous base, for example lauryl, cetyl or stearyl alcohol9 fatty acids, for example palmitic or stearic acid, liquid to solid waxes9 for example isopropyl myristate9 wool-wax or bees-wax, and/or hydrocarbons9 for cxample petroleum jelly ~petrolatum) or paraffin oil. Suitable emulsiiers are surface-active substances with primarily hydrophilic properties, such as corresponding non-ionic emulsifiers, for example fatty acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tweens~; polyoxyethylene fatty alcohol ethers or esters, or corresponding ionic emulsifiers, such as alkali metal salts of fa~y alcohol sulphates, for example sodium lauryl sulphate, sodium cetyl sulphate or sodium stearyl sulphate, which are customarily used in the presence of fatty alcohol, for example cetyl alcohol or stearyl alcohol. Additîves to the water phase include agents which reduce water loss through evaporation, for example polyalcohols, such as glycerol, sorbitol9 propylene glycol and/or polyethylene glycols, as well as preserva~ives 7 perfumes etc.
Ointments are water-in~oil emulsions which contain up to 70~, prefer-ably however, approxO 20% to aboll~ 50%9 of wa~er or aqueous phase.
The oleaginous phase comprises chiefly hydrocarbons9 for example *Tr~de Mark petroLeum jellyl paraffin oil and/or hard paraffins, which cont.~in pre~erably hydroxy compounds suitable for improving the water-absorp-tion7 such as fatty alcohols or esters thereof, for e~ample cetyl alcohol or wool wax alcohols, or wool wax. Emulsifiers are corre-sponding lipophilic substances, such as sorbitan fatty acid esters (Spans~, for example sorbitan oleate and/or sorbitan isostearate.
Additives to the water phase include humectants, such as polyalcohols, for example glycerol, propylene glycol, sorbitol and/or polyethylene glycol, and preservatives, perfumes etc.
Greasy ointments are anhydrous and contain as base in particular hydrocarbons~ for example paraffin, petroleum jelly and/or l;quid paraffins, furthermore, natural or partially synthetic fat, for example coconut fatty acid triglycerides, or preferably hardened oils, for example hydrated ground nut or cas~or oil, and also fatty acid partial esters of glycerol~ for example glycerol mono- and distearate, and, for example, the fatty alcohols, emulsifiers and/or additives for increasing the water-absorption mentioned in connection with the ointments.
Pastes are creams and ointments containing powdered ingredients which absorb secretions, such as metal oxides 3 for example titanium oxide or zinc oxide, and ~alc and~or aluminium silicates whose purpose it is to bind moisture or secretion present.
Foams are adminis~ered from pressurised dispensers and are liquid oil-in~water emulsions in aerosol form, with halogenated hydrocarbons 9 such as chlorofluoro~lower alkanes, for example dichlorodifluoro-methane and dichlorotetrafluoroethane being used as propellants. For the oleaginous phase there are used, inter alia, hydrocarbons, for example paraffin oil, fatty alcohols, for ex~mple cetyl alcohol, fatty acid es~ers~ for example isopropyl myristate 3 and/or other *Trade Mark waxes~ As emuls;fiers there are used, inter ~lia, mixtures oE those emulsifiers with primarily hydrophilic properties~ such as polyoxy-ethylene sorbitan fatty acid esters (Tweens~, and those with primarily lipophilic properties, such as sorbitan fatty acid esters (Spans)*
In addition, the conventional additives are used, such as preserva-tives etc.
Gels are in particular aqueous solutions or suspensions of the active substances in which gel formers, preferably those of the group of cellulose ethers, for e~ample me~hyl cellulose, hydroxyethyl cellulose or carboxymethyl cellulose, or of the vegetable hydrocolloids, such as sodium alginate, tragacanth or gum arabic, are dispersed and swelled. The gels preferably also contain in addition humectants from the group o the polyalcohols, such as propylene glycol, glycerin and/or lower polyethylene glycols, as ~ell as wetting agents, for example polyoxyethylene sorbitan fatty acid esters, such as polyoxy-ethylene sorbitan monostearate, monolaurate or monooleate, in concen-trations of about 0.02% to 5%. As further adjuvants, the gels contain conventional preservatives, for e~ample benzyl alcohol, phenethyl alcohol 7 phenoxyethanol, lower alkyl esters of p-hydroxybenzoic acid such as the methyl and/or propyl esters, sorbic acid or organic mercury compounds such as merthiolate.
The pharmaceutical preparations for topical application are obtained in kno~n manner, for e~ample by dissolving or suspending the active substance in the base or in a part thereof, if necessary. When pro~
eessing the active substance in the form of a solution, it is usually dissolved in one of the two phases before the emulsification, and when Frocessing the active substance in the form of a suspension, it is mixed with a part of the base before the emulsification and then added to the remainder of the formulation.
*Trade Mark - 14 ~ qD ~
The preferred forms of the nei~ pharmaceutical preparations according to the present invention are creams having e.g. the a~ove mentioned range oE active substances, especially a cream containing from 0.03% -0.1% of halometasone and 0.7% - 2~ triclosan, preferab]y a cream with a content of about 0.05% halometasone and 1% triclosan7 e.g. one as exemplified in Example l.
The following Example describes the invention in more details.
Example : A cream for the topical trea~ment of infectious dermatoses of the following composit;on:
Each 100 g co~tains halometasone 0~05 g triclosan 1.00 g ascorbyl palmitate 0.05 g cetyl alcohol9 PH 4.50 g cetyl palmitate 4.00 g Duponol C*(sodium lauryl sulpha~e) 1.00 g EDTA*, dis~dium salt of 0.10 g glycerin, pure, PH 6.00 g propylene glycol, dist. (1.2 propanediol) 5.50 g stearic acid7 ;n flakes, PH 4.00 g stearyl alcohol, PH 4.50 g water, deionised 64.30 g white petrolatunl 5.00 g 100.00 g * ethylenediaminetetraacetic acid *Trade Mark 7~3 Meti~od of m~nufacture Duponol C*and sodium salt of EDTA are dissolved in hot deionised water. Propylene glycol is added.
Cetyl alcohol~ stearyl alcohol, stearic acid, cetyl palmitate, ascorby] palmita~e, trîclosan and white petrolatum are ~ixed and melted together.
The t~70 phases are emulsified and cooled.
Halometasone, viz 2-chloro-6~,9~-difluoro~16~-methyl~ ,17~921-tri-hydroxy-pregna-1,4-diene-3,20-dione is suspended in glycerin and the suspension is homogeneously dispersed in a portion of the cream base.
This concentrate is incorporated in the remainder o the cream base.
Batch size: 400 kg ~or a multiple thereof) Each portion weighed in corresponds ~o the stated composition.
*Trade Mark
Claims (7)
1. Pharmaceutical preparation containing an amount of halometasone in the range of from about 0.01 % to about 2.5 % of halometasone and from about 0.1 % to about 5 % of triclosan in the presence of at least one pharmaceutical excipient suitable for topical application.
2. Pharmaceutical preparation as claimed in claim 1 containing an amount of halometasone in the range from about 0.02 % to about 0.8 %
and from about 0.5 % to about 3 % of triclosan.
and from about 0.5 % to about 3 % of triclosan.
3. Pharmaceutical preparation as claimed in claim 1 having a content of halometasone in the range from about 0.03 % to about 0.1 % and of triclosan in the range from about 0.7 % - 2 %.
4. Pharmaceutical preparation as claimed in claim 1 having a content of about 0.05 % halometasone and about 1 % triclosan.
5. Pharmaceutical preparation as claimed in anyone of claims 1 - 3 in the form of a cream, ointment, paste, foam or gel.
6. Pharmaceutical preparation as claimed in anyone of claims 2 - 4 in the form of a cream.
7. Pharmaceutical dermatic preparation containing an effective amount of halometasone and an effective amount of triclosan in the presence of at least one pharmaceutical excipient suitable for topical admini-stration.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8220561 | 1982-07-15 | ||
| GB8220561 | 1982-07-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1199273A true CA1199273A (en) | 1986-01-14 |
Family
ID=10531699
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000413306A Expired CA1199273A (en) | 1982-07-15 | 1982-10-13 | Anti-inflammatory composition |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US4512987A (en) |
| JP (1) | JPS5913715A (en) |
| CA (1) | CA1199273A (en) |
| JO (1) | JO1250B1 (en) |
| ZW (1) | ZW15983A1 (en) |
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|---|---|---|---|---|
| EP0177654B1 (en) * | 1984-10-10 | 1989-05-31 | Societe D'etudes Scientifiques Et Industrielles De L'ile-De-France | Synergistic contraceptive mixture |
| AU573158B2 (en) * | 1984-10-10 | 1988-05-26 | Societe D'etudes Scientifiques Et Industrielles De L'ile-De-France | Synergistic contraceptive |
| JPS61260575A (en) * | 1985-05-15 | 1986-11-18 | 藤好 克聡 | Manufacture of interconnector |
| IT1203814B (en) * | 1986-06-30 | 1989-02-23 | Fidia Farmaceutici | ESTERS OF ALGINIC ACID |
| US5264422A (en) * | 1986-06-30 | 1993-11-23 | Fidia S.P.A. | Esters of alginic acid with steroidal alcohols |
| US5147861A (en) * | 1986-06-30 | 1992-09-15 | Fidia S.P.A. | Esters of alginic acid |
| US4897260A (en) * | 1987-05-22 | 1990-01-30 | The Rockefeller University | Compositions that affect suppression of cutaneous delayed hypersensitivity and products including same |
| US5098693A (en) * | 1989-07-21 | 1992-03-24 | Cast Blast | Anti-irritant spray for use with cast and method of application |
| EP0417821A1 (en) * | 1989-09-13 | 1991-03-20 | Duphar International Research B.V | Method of stabilising colostrum for immunochemical examination |
| DE59108814D1 (en) * | 1990-09-05 | 1997-09-11 | Ciba Geigy Ag | Diphenyl compounds inhibiting arachidonic acid metabolism and their use in pharmaceutical compositions |
| US5290541A (en) * | 1992-06-18 | 1994-03-01 | The Procter & Gamble Company | Methods for making oral compositions |
| US5290542A (en) * | 1993-04-08 | 1994-03-01 | The Procter & Gamble Company | Oral compositions for treating plaque and gingivitis |
| US5474761A (en) * | 1993-04-08 | 1995-12-12 | The Procter & Gamble Company | Oral compositions for treating plaque and gingivitis |
| JP2601131B2 (en) * | 1993-04-30 | 1997-04-16 | 株式会社新潟鉄工所 | Method and apparatus for controlling starting operation of spindle unit |
| US6579516B1 (en) * | 1995-06-13 | 2003-06-17 | Zahra Mansouri | Methods of delivering materials into the skin, and compositions used therein |
| GB2302807A (en) * | 1995-07-04 | 1997-02-05 | Surtech Int Ltd | Method and composition for treating atopic eczema |
| EP0928187A4 (en) * | 1996-06-24 | 2002-10-02 | Bio Safe Entpr Inc | Antibacterial composition |
| US6190674B1 (en) | 1997-06-04 | 2001-02-20 | Procter & Gamble Company | Liquid antimicrobial cleansing compositions |
| US6210695B1 (en) | 1997-06-04 | 2001-04-03 | The Procter & Gamble Company | Leave-on antimicrobial compositions |
| US6183757B1 (en) | 1997-06-04 | 2001-02-06 | Procter & Gamble Company | Mild, rinse-off antimicrobial cleansing compositions which provide improved immediate germ reduction during washing |
| US6214363B1 (en) | 1997-11-12 | 2001-04-10 | The Procter & Gamble Company | Liquid antimicrobial cleansing compositions which provide residual benefit versus gram negative bacteria |
| US6197315B1 (en) | 1997-06-04 | 2001-03-06 | Procter & Gamble Company | Antimicrobial wipes which provide improved residual benefit versus gram negative bacteria |
| US6287577B1 (en) | 1997-11-12 | 2001-09-11 | The Procter & Gamble Company | Leave-on antimicrobial compositions which provide improved residual benefit versus gram positive bacteria |
| US6183763B1 (en) | 1997-06-04 | 2001-02-06 | Procter & Gamble Company | Antimicrobial wipes which provide improved immediate germ reduction |
| US6190675B1 (en) | 1997-06-04 | 2001-02-20 | Procter & Gamble Company | Mild, rinse-off antimicrobial liquid cleansing compositions which provide improved residual benefit versus gram positive bacteria |
| US6284259B1 (en) | 1997-11-12 | 2001-09-04 | The Procter & Gamble Company | Antimicrobial wipes which provide improved residual benefit versus Gram positive bacteria |
| US5968539A (en) * | 1997-06-04 | 1999-10-19 | Procter & Gamble Company | Mild, rinse-off antimicrobial liquid cleansing compositions which provide residual benefit versus gram negative bacteria |
| FR2767689B1 (en) * | 1997-08-26 | 1999-10-15 | Oreal | USE OF OXAMATE DERIVATIVES AS DEPIGMENTING AGENTS |
| US6287583B1 (en) | 1997-11-12 | 2001-09-11 | The Procter & Gamble Company | Low-pH, acid-containing personal care compositions which exhibit reduced sting |
| US20030091667A1 (en) * | 2001-06-01 | 2003-05-15 | Gormley John L. | Solutions of alkoxylated alkanol amide surfactants and antimicrobial compounds |
| TR200201343A2 (en) * | 2002-05-17 | 2003-12-22 | Orva İlaç Sanayi̇ Ve Ti̇caret A. Ş. | Pharmaceutical composition containing corticosteroid and antiseptic |
| US20050058673A1 (en) | 2003-09-09 | 2005-03-17 | 3M Innovative Properties Company | Antimicrobial compositions and methods |
| US20060051384A1 (en) * | 2004-09-07 | 2006-03-09 | 3M Innovative Properties Company | Antiseptic compositions and methods of use |
| US8198326B2 (en) * | 2004-09-07 | 2012-06-12 | 3M Innovative Properties Company | Phenolic antiseptic compositions and methods of use |
| US9028852B2 (en) | 2004-09-07 | 2015-05-12 | 3M Innovative Properties Company | Cationic antiseptic compositions and methods of use |
| US8476319B2 (en) * | 2005-03-10 | 2013-07-02 | 3M Innovative Properties Company | Methods of treating ear infections |
| CA2599667C (en) * | 2005-03-10 | 2014-12-16 | 3M Innovative Properties Company | Antimicrobial compositions comprising esters of hydroxy carboxylic acids |
| KR20070113284A (en) * | 2005-03-10 | 2007-11-28 | 쓰리엠 이노베이티브 프로퍼티즈 캄파니 | Methods of reducing microbial contamination |
| EP2091324B1 (en) | 2006-10-27 | 2016-12-28 | 3M Innovative Properties Company | Antimicrobial compositions |
| WO2009063493A2 (en) * | 2007-09-10 | 2009-05-22 | Glenmark Pharmaceuticals Limited | Topical pharmaceutical composition for the combination of fusidic acid and a corticosteroid |
| FR3044898B1 (en) * | 2015-12-15 | 2019-11-01 | L'oreal | COSMETIC COMPOSITION COMPRISING ANIONIC SURFACTANT, AT LEAST 3.5% BY WEIGHT OF A FATTY ACID AND ANTIPELLICULAR AGENT |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH431780A (en) * | 1963-02-22 | 1967-03-15 | Geigy Ag J R | cleaning supplies |
| GB1505701A (en) * | 1975-06-14 | 1978-03-30 | Pierrel Spa | 2-chloro-6beta-fluoropregnanes |
| US4076737A (en) * | 1975-02-20 | 1978-02-28 | Ciba-Geigy Corporation | Aldehydes of the pregnane series and derivatives thereof |
| US4298604B1 (en) * | 1980-10-06 | 1998-12-22 | Schering Corp | Clotrimazole-betamethasone dipropionate combination |
-
1982
- 1982-10-13 US US06/434,094 patent/US4512987A/en not_active Expired - Lifetime
- 1982-10-13 CA CA000413306A patent/CA1199273A/en not_active Expired
- 1982-10-25 JP JP57186213A patent/JPS5913715A/en active Pending
-
1983
- 1983-05-24 JO JO19831250A patent/JO1250B1/en active
- 1983-07-13 ZW ZW159/83A patent/ZW15983A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZW15983A1 (en) | 1984-02-08 |
| JPS5913715A (en) | 1984-01-24 |
| US4512987A (en) | 1985-04-23 |
| JO1250B1 (en) | 1985-04-20 |
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