CA1045974A - Oil-free pharmaceutical cream - Google Patents
Oil-free pharmaceutical creamInfo
- Publication number
- CA1045974A CA1045974A CA196,544A CA196544A CA1045974A CA 1045974 A CA1045974 A CA 1045974A CA 196544 A CA196544 A CA 196544A CA 1045974 A CA1045974 A CA 1045974A
- Authority
- CA
- Canada
- Prior art keywords
- composition
- alpha
- beta
- water
- total weight
- 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
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
Abstract
ABSTRACT OF THE DISCLOSURE
The Specification describes a pharmaceutical cream composition comprising a dispersion of a wax in an aqueous phase comprising water and a water-miscible hydroxylic solvent, the total quantity of wax being 5.0 to 30%, the quantity of water being 7.0 to 75% and the total quantity of hydroxylic solvent being 10 to 80%, these amounts being based on the total weight of the composition.
The cream compositions are substantially oil-free and this represents an important practical advantage over prior cream compositions containing oils. The cream compositions may contain a drug intended for topical application, e.g.
an anti-inflammatory steroid.
The Specification describes a pharmaceutical cream composition comprising a dispersion of a wax in an aqueous phase comprising water and a water-miscible hydroxylic solvent, the total quantity of wax being 5.0 to 30%, the quantity of water being 7.0 to 75% and the total quantity of hydroxylic solvent being 10 to 80%, these amounts being based on the total weight of the composition.
The cream compositions are substantially oil-free and this represents an important practical advantage over prior cream compositions containing oils. The cream compositions may contain a drug intended for topical application, e.g.
an anti-inflammatory steroid.
Description
3l~45~74 `
The present invention is concerned with improvements in or relating to the formulation of new -~
pharmaceutical cream composltions ,:
Pharmaceu~ical creams have been widely u~ed for ;
S very many years in the medical arts for the topical application of drugs. It is now believed that the ;
composition of the vehicle may pla~ an important role `~
in determining the rate of reLease of the drug from the cream and its absorption through the skin on which it is topically applied, In recent years, there have been a number of proposals for the formulation of new pharmaceutical creams which are essentlally anhydrous in nature and contain non-aqueous solvents s~ch as glycols.
15We have now discovered that valuable advantages can be achieved by the use of certain new aqueous cream compositions (as more particularly described hereinafter) in the ~ormNlation of topically active drugs.
Thus~ our new cream compositions differ from the ~bove-mentioned anhydrous compositions in that they contain significant ~ounts of water.
The present invention is concerned with improvements in or relating to the formulation of new -~
pharmaceutical cream composltions ,:
Pharmaceu~ical creams have been widely u~ed for ;
S very many years in the medical arts for the topical application of drugs. It is now believed that the ;
composition of the vehicle may pla~ an important role `~
in determining the rate of reLease of the drug from the cream and its absorption through the skin on which it is topically applied, In recent years, there have been a number of proposals for the formulation of new pharmaceutical creams which are essentlally anhydrous in nature and contain non-aqueous solvents s~ch as glycols.
15We have now discovered that valuable advantages can be achieved by the use of certain new aqueous cream compositions (as more particularly described hereinafter) in the ~ormNlation of topically active drugs.
Thus~ our new cream compositions differ from the ~bove-mentioned anhydrous compositions in that they contain significant ~ounts of water.
- 2 -'~
... .. . . .
:lV~5~74 :
In very general ~erms, the new cream composl~ions comprise a dis-persion of one or more waxe9 or wax-like components in an aqueous phase also comprising a water miscible solvent compatible with the skin, preferably a hydroxylic solvent, conveniently at least one glycol and/or glycerol. The new compositions may advantageously be employed as vehicles for drugs which it is desired to apply topically to the skin. Indeed, we have found that the new compositions have certain very valuable advantages, from the point of view of both formulation and application.
We have further found that particularly advantageous results may be achieved by the use of wax, water and hydroxylic solvent in the compositions in the amounts hereinafter specified, the presence of relatively low amounts of wax in the compositions providing especially favourable results~ -According to the present invention we provide a substantially oil-free pharmaceutical cream composition comprising from 0.0001 to 5~ by weight of a topically-active anti-inflammatory steroid in a vehicle comprising a dis-hY~o~o~c C persion of~w~x iTI an aqueous phase comprising water and at least one water~
miscible hydroxylic solvent, the said dispersion further containing a surface active agent, and the wax, water, the water-miscible hydroxylic solvent and surface sctive agent being present in amounts of 5.0 to 30%, 7.0 to 75%, 10 to 80% and 0.1 to 10% respectively, based on the total weight of the composi-tions.
BJ ~3~ ~ ~
~O ~ S g 7 In our new cream compositions, drugs of low water solubility can be in solution, at least in part and preferably to a major extent in the aqueous phase, thus aiding the release of the drug from the vehicle. Another factor which has been found to govern the rate of -release of the drug from the cream is the presence or absence of oils in the cream. Creams have been formulated in the past as oily emulsions containing up to 50% oil. The presence of substantial quantities of oil in a cream, particularly if the drug has a fair solubility in the oil, will generally (to a greater or lesser extent) inhibit release of drug. Even if the drug is deliberately dissolved in the aqueous phase of the cream the presence of an oily phase can only have an adverse effect on the release of the drug, a proportion of which will partition into it. In .
contrast, our new cream compositions avoid the use of substantial quantities of an oil component.
Moreover, the inclusion of substantial quantities o~ water in our new cream compositions reduces the potential irritancy to the skin of the vehicle as compared with the use of prior co~positions based substantially on such non-aqueous solvents as glycols, e.g. propylene glycol.
In addition, the inclusion of water in the new ccmpositions has been found to facilitate their manufacture.
In the manufacture of the above-mentioned prior ,, , ~ O 4 5~97 ~
anhydrous compositlons it has been conventional practice to employ some kind of surface active agent to effect admixture of the ingredients. ~owever, even when a --suitable surface active agent is employed, it is still necessary to employ special manufacturing techniques since the surface active agent cannot properly exert i`
its normal "wetting effect" in the absence of water.
In contrast, our new compositions contain water and surface active agents can be readily employed therein, if so desired. Moreover, our new compositions can be easily manufactured using conventional techniques such as mixing, stirring, cooling etc., and do not require the use of special operating conditions or techniques.
As indicated above, the new compositions contain one or more waxes. The term "wax" is used herein in its broadest sense to include not only conventional waxes but other materials having wax-like physical and/or chemical characteristics. Examples oE waxes which may be employed in the new compositions include long chain (e,g. Cl6-C24) fatty acid monoesters of glycerol, preferab1y saturated fatty acid esters such as glycerol monostearate; wa~y triglycerides including acetoglycerides (i.e. acetylated mono- and di-glycerides);
fatty alcohols, e.g. saturated fatty alcohols preferably 25/ containing 16 to 24 carbon atoms especially cetyl alcohol, stearyl alcohol, cetostearyl alcohol, behenyl ~045~74 ; ~
alcohol etc; saturated fatty acids o a waxy nature preferably containing 14 to 26 carbon atoms, especially stearic acid; and naturaL and sythetic waxes such as beeswax.
The above waxes are all of a hydrophobic nature and with an appropriate surfactant produce a dispersion : ~ - .
in water. Hydrophilic waxes may~if desired be additLonally ~ -~
present; these dissolve in the water component. Examples of such hydrophilic waxes include polyethylene glycols ~ ~
of a waxy nature, e.g. of molecular weight 1500-6000.
The wax components are preferably employed in a total amount of 10 to 20% o the composi~ion.
With regard to the hydroxylic solvent, this may for example consist of or include one or more glycols,preferably ones in which the intended drug is soluble at least to some extent, whereby the drug can be mobilised in the vehicle to reach the surface being treated. Thus, the identity and quantity of glycol solvent may be conveniently selected to ensure partial or complete dissolution of the drug therein. Examples of particularly preferred glycol so~lvents for use in our new compositions include propanediols such as 1,2-propanediol, 1,3-propanediol; liquid polyethylene glycols particularly those having a molecular weight ::
; of from 100 to 800; dipropylene glycols; and mixtures ~ thereof.
, ~ - 6 - ~
~, .
~LV45974 The hydroxylic solvents may consist of or include trihydric alcohols such as glycerol, the latter material being particularly useful for those dermatological purposes where a bland composition is desirable, e.g. in compositions for pediatric usage.
In general the hydroxylic solvent preferably constitutes 25 - 70% of the compositions, particularly when the solvent is a glycol. However, in theparticular case of such trihydric alcohols as glycerols, these preferably constitute up to only 40% (more preferably 25%) of the composition.
The new compositions preferably contain 20 to 60% of wa~er.
As mentioned above, the new compositions may, if desired, contain a surface active agent serving as a dispersing agent for the wax and also as a stabiliser for the resulting dispersion. The surface active agent, which may be a single substance or a mixture, may be non-ionic and preferably has an HLB value of at least 8.
Examples of surface active agents include polyoxyekhylene ethers or esters such as Cetomacrogol 1000 (i.e. polyethylene glycol 1000 monocetyl ether), ~ ~r~ lPm ~r 97~ :
polyoxyethylene s~earat~ ~or a mlxture of s~earatfls) ospeclally polyoxyethy-lene 40 stearate, or polyoxyetllylene lanolin derivAtives especially polyoxy-ethylene 25 lanolin. Alternati~ely, one may employ an anionic surace active agent such as sodium lauryl sulphate, sodium dioctyl ~ulphosuccinate etc. The new compositions advantageously contain 0~1 to 10~ ~preferably 1 to 5%~ of surface active agent, ~he propo~tion and nature o the sur~ace active agent being chosen by preliminar~ experiment to give satis~actor~ release of the drug The cream compositions described abo~e may be advantageously em- ~-ployed in the formulation of drugs or mixtures o~ drugs which are in~ended for topical application, for example, to a~flicted areas of the skin. Such drugs ~-include in particular d~ugs for the topical alleviation of inflammatory con-ditions, for example anti-inflammatory steroids, particul~rly o~ the corticoid type~ Particular classes o~ anti-inflammatory steroid compounds which may be adYantageously ~ormulated with the new composltions include those described in British Patents Nos, 1,047,518; 1,047,519; 1,070,751; 1,139,S06; 1,253,831;
1,281,689; 1,261,650; and Canadian Applications Nos. 132~814J 176~804 and 178,557, -8- ::
~- ~` ......
1~ 4 5 ~
Particular steroid compounds which may be ~o formulated include betamethasone 17-valerate; 21-chloro- :
21-desoxybetamethasone 17-propionate (21-chloro-9a-fluoro~ hydroxy-16~-methyl 17~-propionyloxy-pregna-1,4-diene-3,20-dione);betamethasone 17-benzoate; fluocinolone acetonide (6a,9a-difluoro~ ,21-dihydroxy-16a,17a ~ -isopropylidenedioxy pregna-1,4-diene-3,20-dione) and the corresponding 21-acetate; 9a-fluoro-16-methylene prednisolone-21-acetate; 6a,9a-difluoro-prednisolone-21-acetate-17-butyrate; 9a,11~-dichloro-6a,21-difluoro- ~:
16a,17a-isopropylidenedioxy pregna-1,4-diene-3,20-dione; 11~, 21-dihydroxy-16a,17a-isopropylidenedioxy ;`~
pregna-1,4-diene-3,20-dione, 9a,11~-dichloro-6a-fluoro-21-hydroxy-16~,17a-isopropylidenedioxy pregna-1,4-diene-3, :.
20-dione, beclomethasone 17J21-dipropionate (9a-chloro- `~
:~ 16~-me~hyl-prednisolone 17,21-dipropionate); 21-chloro-21 soxy~
ll~dehydro-betamethasone 17-butyrate; 21-desoxy- ;
betamethasone 17-propionate; betamethasone 17-isobutyrate 21~acetate; ~8(9)-16~-methyl-prednisolone 17,21-dipropionate;
and methyl ll~-hydrox~-3-oxo-17~-propionyloxy-androst-4-ene 17~-carboxylate.
Other drugs which can conveniently be included in the compositions according to the invention include ~ :
antibiotics, local anaesthetics, antibacterials, antifungals and otherdermatological drugs. ~ ~
The new compositions may also contain, if desired, ~ .
:
further conven~ional ingredients and/or additives as desired, e.g. preservatives such as chlorocresol, parabens, such as methyl and propyl parabens, and mercury compounds, humectants such as sorbitol, or suitable stabilisers where required such as sodium metabisulphite or ethylene diamine tetracetic acid.
Although the compositions of the invention are substantially oil-free, they may contain relatively small amounts of oily lubricants i.e. up to about 5% (preferably 1-2%) of the composition; such lubricants include silicone oil, liquid paraffin, castor oil, isopropyl myristate etc. The compositions may also contain one or more buffer compounds.
;;; ; The base compositions of the invention may for example contain 0~0001 to 5%, conveniently 0.005 to 0.50% and preferably 0.01 to 0.10% o~ an anti-Lnflammatory steroid, the precise percentage to be used being readily chosen by reference to the potency of the steroid. In the case of 21~chloro- 21-desoxybetamethasone 17-propionate a convenient proportion is 0.05%.
Our new cream compositions may be readily manufactured for example by suitable admixture of the components, e.g. in conventional manner, as illustrated by the following Examples. It should be noted that the topically active drug component may be added to the preformed cream or, more preferably, may be incorporated into one ~ - 10 , , ~ L~)4S9~4 of the components of the cream prior to emulsification.
The following Examples illustrate the present invention;
Example 1 Composition Cetostearyl alcohol 10~/o Acetoglyceride 10%
Cetomacrogol 1000 1,5% ~;~
1,2 Propanediol 35%
Methyl paraben 0.08%
Propyl paraben 0.02%
Sodium dihydrogen phosphate0.10%
Water to 100.00%
Method of Preparation Melt the three waxes together and heat to 75C.
` Mix most of the 1,2 propanediol and water and dissolve the other ingredients, heating to effect solution of the parabens. Heat this solution to 75C and mix with the molten waxes. Stir and cool to 40C.
21-chloro-21-desoxy-betamethasone 17-propionate is either dissolved in a small portion of the 1,2-propanediol which is added after the waxes and a~ueous phase have been mixed. Alternatively the steroid is ball milled in an aqueous solution of the surfactant and the resul~ant microfine suspension added to the other components as above `~
- 1 1 - .
., :~0~5~317g~
The same method of preparation is employed for the composition of Example 2 below.
Example 2 Stearic acid 8.0%
Cetostearyl alcohol 8.0%
1,2-Propanediol 45.0%
Cetomacrogol 1000 0.5%
Polyoxyethylene 40 stearate . 2.00 Chlorocresol 0~05 Sodium citrate 0.15 Citric acid 0.15 Water to 100.00 _ 12 , . :
S~
_X~
Glyceryl rnonostearat;e (G.t~ .) 10.0%
Cetostearyl alcohol (C.S.A.) 8.0%
Polyoxyethylene 25 lanolin deri.va~ve 3.0%
1, 2 Propanediol 67.0%
Thiomersal - 0,01%
Sodium dihydroge~ phosphate 0.05i~
Disodium hydrogen phosphate 0.05% ; ;~
.
Water to100.0%
Method of Preparation_ Melt the G.M.S., C.S.A. and ]anolin derivative together and heat to 75C. Mix most of the propanediol and water, add the other ingredients and heat to efEect solution. Mix both solutions at 75C, stir and cool to 40C. . ;
Dissolve the steroid in the remaining propanediol and add to the above after the phases have been mixed.
xam~ 4 Glyceryl monostearate (G.M.S.) 10.0% ;
Cetostearyl alcohol (C.S.A,) S.0%
Beeswax ~r 2~ 0%
Acid stable self-emulsifying mono-stearin ) 2.0%
. ~.
, :~.04~
Glycerol 10.0%
Sodium citlate 0.05/O
Citric acid 0.05%
Chlorocresol 0.10%
Water to 100.0% :
_ethod O~ e~
Melt the G.M~S., C.S.A., Beeswax and monostearin togethQr and heat to 75C. Mix most of the glycerol and water, add the other ingredients and heat to aid solution. Mix the two phases at 75C, stir and cool to 40C.
Ball mill the steroid in the remaining glycerol ànd add to the above atter tbe two phases have been mixed, Example 5 As Example 4 with addition of 1% dimethylpolysilvxane o-L:L.
~ .
~ ' ' ' ' ' ; ` ' ' ' ~ '
... .. . . .
:lV~5~74 :
In very general ~erms, the new cream composl~ions comprise a dis-persion of one or more waxe9 or wax-like components in an aqueous phase also comprising a water miscible solvent compatible with the skin, preferably a hydroxylic solvent, conveniently at least one glycol and/or glycerol. The new compositions may advantageously be employed as vehicles for drugs which it is desired to apply topically to the skin. Indeed, we have found that the new compositions have certain very valuable advantages, from the point of view of both formulation and application.
We have further found that particularly advantageous results may be achieved by the use of wax, water and hydroxylic solvent in the compositions in the amounts hereinafter specified, the presence of relatively low amounts of wax in the compositions providing especially favourable results~ -According to the present invention we provide a substantially oil-free pharmaceutical cream composition comprising from 0.0001 to 5~ by weight of a topically-active anti-inflammatory steroid in a vehicle comprising a dis-hY~o~o~c C persion of~w~x iTI an aqueous phase comprising water and at least one water~
miscible hydroxylic solvent, the said dispersion further containing a surface active agent, and the wax, water, the water-miscible hydroxylic solvent and surface sctive agent being present in amounts of 5.0 to 30%, 7.0 to 75%, 10 to 80% and 0.1 to 10% respectively, based on the total weight of the composi-tions.
BJ ~3~ ~ ~
~O ~ S g 7 In our new cream compositions, drugs of low water solubility can be in solution, at least in part and preferably to a major extent in the aqueous phase, thus aiding the release of the drug from the vehicle. Another factor which has been found to govern the rate of -release of the drug from the cream is the presence or absence of oils in the cream. Creams have been formulated in the past as oily emulsions containing up to 50% oil. The presence of substantial quantities of oil in a cream, particularly if the drug has a fair solubility in the oil, will generally (to a greater or lesser extent) inhibit release of drug. Even if the drug is deliberately dissolved in the aqueous phase of the cream the presence of an oily phase can only have an adverse effect on the release of the drug, a proportion of which will partition into it. In .
contrast, our new cream compositions avoid the use of substantial quantities of an oil component.
Moreover, the inclusion of substantial quantities o~ water in our new cream compositions reduces the potential irritancy to the skin of the vehicle as compared with the use of prior co~positions based substantially on such non-aqueous solvents as glycols, e.g. propylene glycol.
In addition, the inclusion of water in the new ccmpositions has been found to facilitate their manufacture.
In the manufacture of the above-mentioned prior ,, , ~ O 4 5~97 ~
anhydrous compositlons it has been conventional practice to employ some kind of surface active agent to effect admixture of the ingredients. ~owever, even when a --suitable surface active agent is employed, it is still necessary to employ special manufacturing techniques since the surface active agent cannot properly exert i`
its normal "wetting effect" in the absence of water.
In contrast, our new compositions contain water and surface active agents can be readily employed therein, if so desired. Moreover, our new compositions can be easily manufactured using conventional techniques such as mixing, stirring, cooling etc., and do not require the use of special operating conditions or techniques.
As indicated above, the new compositions contain one or more waxes. The term "wax" is used herein in its broadest sense to include not only conventional waxes but other materials having wax-like physical and/or chemical characteristics. Examples oE waxes which may be employed in the new compositions include long chain (e,g. Cl6-C24) fatty acid monoesters of glycerol, preferab1y saturated fatty acid esters such as glycerol monostearate; wa~y triglycerides including acetoglycerides (i.e. acetylated mono- and di-glycerides);
fatty alcohols, e.g. saturated fatty alcohols preferably 25/ containing 16 to 24 carbon atoms especially cetyl alcohol, stearyl alcohol, cetostearyl alcohol, behenyl ~045~74 ; ~
alcohol etc; saturated fatty acids o a waxy nature preferably containing 14 to 26 carbon atoms, especially stearic acid; and naturaL and sythetic waxes such as beeswax.
The above waxes are all of a hydrophobic nature and with an appropriate surfactant produce a dispersion : ~ - .
in water. Hydrophilic waxes may~if desired be additLonally ~ -~
present; these dissolve in the water component. Examples of such hydrophilic waxes include polyethylene glycols ~ ~
of a waxy nature, e.g. of molecular weight 1500-6000.
The wax components are preferably employed in a total amount of 10 to 20% o the composi~ion.
With regard to the hydroxylic solvent, this may for example consist of or include one or more glycols,preferably ones in which the intended drug is soluble at least to some extent, whereby the drug can be mobilised in the vehicle to reach the surface being treated. Thus, the identity and quantity of glycol solvent may be conveniently selected to ensure partial or complete dissolution of the drug therein. Examples of particularly preferred glycol so~lvents for use in our new compositions include propanediols such as 1,2-propanediol, 1,3-propanediol; liquid polyethylene glycols particularly those having a molecular weight ::
; of from 100 to 800; dipropylene glycols; and mixtures ~ thereof.
, ~ - 6 - ~
~, .
~LV45974 The hydroxylic solvents may consist of or include trihydric alcohols such as glycerol, the latter material being particularly useful for those dermatological purposes where a bland composition is desirable, e.g. in compositions for pediatric usage.
In general the hydroxylic solvent preferably constitutes 25 - 70% of the compositions, particularly when the solvent is a glycol. However, in theparticular case of such trihydric alcohols as glycerols, these preferably constitute up to only 40% (more preferably 25%) of the composition.
The new compositions preferably contain 20 to 60% of wa~er.
As mentioned above, the new compositions may, if desired, contain a surface active agent serving as a dispersing agent for the wax and also as a stabiliser for the resulting dispersion. The surface active agent, which may be a single substance or a mixture, may be non-ionic and preferably has an HLB value of at least 8.
Examples of surface active agents include polyoxyekhylene ethers or esters such as Cetomacrogol 1000 (i.e. polyethylene glycol 1000 monocetyl ether), ~ ~r~ lPm ~r 97~ :
polyoxyethylene s~earat~ ~or a mlxture of s~earatfls) ospeclally polyoxyethy-lene 40 stearate, or polyoxyetllylene lanolin derivAtives especially polyoxy-ethylene 25 lanolin. Alternati~ely, one may employ an anionic surace active agent such as sodium lauryl sulphate, sodium dioctyl ~ulphosuccinate etc. The new compositions advantageously contain 0~1 to 10~ ~preferably 1 to 5%~ of surface active agent, ~he propo~tion and nature o the sur~ace active agent being chosen by preliminar~ experiment to give satis~actor~ release of the drug The cream compositions described abo~e may be advantageously em- ~-ployed in the formulation of drugs or mixtures o~ drugs which are in~ended for topical application, for example, to a~flicted areas of the skin. Such drugs ~-include in particular d~ugs for the topical alleviation of inflammatory con-ditions, for example anti-inflammatory steroids, particul~rly o~ the corticoid type~ Particular classes o~ anti-inflammatory steroid compounds which may be adYantageously ~ormulated with the new composltions include those described in British Patents Nos, 1,047,518; 1,047,519; 1,070,751; 1,139,S06; 1,253,831;
1,281,689; 1,261,650; and Canadian Applications Nos. 132~814J 176~804 and 178,557, -8- ::
~- ~` ......
1~ 4 5 ~
Particular steroid compounds which may be ~o formulated include betamethasone 17-valerate; 21-chloro- :
21-desoxybetamethasone 17-propionate (21-chloro-9a-fluoro~ hydroxy-16~-methyl 17~-propionyloxy-pregna-1,4-diene-3,20-dione);betamethasone 17-benzoate; fluocinolone acetonide (6a,9a-difluoro~ ,21-dihydroxy-16a,17a ~ -isopropylidenedioxy pregna-1,4-diene-3,20-dione) and the corresponding 21-acetate; 9a-fluoro-16-methylene prednisolone-21-acetate; 6a,9a-difluoro-prednisolone-21-acetate-17-butyrate; 9a,11~-dichloro-6a,21-difluoro- ~:
16a,17a-isopropylidenedioxy pregna-1,4-diene-3,20-dione; 11~, 21-dihydroxy-16a,17a-isopropylidenedioxy ;`~
pregna-1,4-diene-3,20-dione, 9a,11~-dichloro-6a-fluoro-21-hydroxy-16~,17a-isopropylidenedioxy pregna-1,4-diene-3, :.
20-dione, beclomethasone 17J21-dipropionate (9a-chloro- `~
:~ 16~-me~hyl-prednisolone 17,21-dipropionate); 21-chloro-21 soxy~
ll~dehydro-betamethasone 17-butyrate; 21-desoxy- ;
betamethasone 17-propionate; betamethasone 17-isobutyrate 21~acetate; ~8(9)-16~-methyl-prednisolone 17,21-dipropionate;
and methyl ll~-hydrox~-3-oxo-17~-propionyloxy-androst-4-ene 17~-carboxylate.
Other drugs which can conveniently be included in the compositions according to the invention include ~ :
antibiotics, local anaesthetics, antibacterials, antifungals and otherdermatological drugs. ~ ~
The new compositions may also contain, if desired, ~ .
:
further conven~ional ingredients and/or additives as desired, e.g. preservatives such as chlorocresol, parabens, such as methyl and propyl parabens, and mercury compounds, humectants such as sorbitol, or suitable stabilisers where required such as sodium metabisulphite or ethylene diamine tetracetic acid.
Although the compositions of the invention are substantially oil-free, they may contain relatively small amounts of oily lubricants i.e. up to about 5% (preferably 1-2%) of the composition; such lubricants include silicone oil, liquid paraffin, castor oil, isopropyl myristate etc. The compositions may also contain one or more buffer compounds.
;;; ; The base compositions of the invention may for example contain 0~0001 to 5%, conveniently 0.005 to 0.50% and preferably 0.01 to 0.10% o~ an anti-Lnflammatory steroid, the precise percentage to be used being readily chosen by reference to the potency of the steroid. In the case of 21~chloro- 21-desoxybetamethasone 17-propionate a convenient proportion is 0.05%.
Our new cream compositions may be readily manufactured for example by suitable admixture of the components, e.g. in conventional manner, as illustrated by the following Examples. It should be noted that the topically active drug component may be added to the preformed cream or, more preferably, may be incorporated into one ~ - 10 , , ~ L~)4S9~4 of the components of the cream prior to emulsification.
The following Examples illustrate the present invention;
Example 1 Composition Cetostearyl alcohol 10~/o Acetoglyceride 10%
Cetomacrogol 1000 1,5% ~;~
1,2 Propanediol 35%
Methyl paraben 0.08%
Propyl paraben 0.02%
Sodium dihydrogen phosphate0.10%
Water to 100.00%
Method of Preparation Melt the three waxes together and heat to 75C.
` Mix most of the 1,2 propanediol and water and dissolve the other ingredients, heating to effect solution of the parabens. Heat this solution to 75C and mix with the molten waxes. Stir and cool to 40C.
21-chloro-21-desoxy-betamethasone 17-propionate is either dissolved in a small portion of the 1,2-propanediol which is added after the waxes and a~ueous phase have been mixed. Alternatively the steroid is ball milled in an aqueous solution of the surfactant and the resul~ant microfine suspension added to the other components as above `~
- 1 1 - .
., :~0~5~317g~
The same method of preparation is employed for the composition of Example 2 below.
Example 2 Stearic acid 8.0%
Cetostearyl alcohol 8.0%
1,2-Propanediol 45.0%
Cetomacrogol 1000 0.5%
Polyoxyethylene 40 stearate . 2.00 Chlorocresol 0~05 Sodium citrate 0.15 Citric acid 0.15 Water to 100.00 _ 12 , . :
S~
_X~
Glyceryl rnonostearat;e (G.t~ .) 10.0%
Cetostearyl alcohol (C.S.A.) 8.0%
Polyoxyethylene 25 lanolin deri.va~ve 3.0%
1, 2 Propanediol 67.0%
Thiomersal - 0,01%
Sodium dihydroge~ phosphate 0.05i~
Disodium hydrogen phosphate 0.05% ; ;~
.
Water to100.0%
Method of Preparation_ Melt the G.M.S., C.S.A. and ]anolin derivative together and heat to 75C. Mix most of the propanediol and water, add the other ingredients and heat to efEect solution. Mix both solutions at 75C, stir and cool to 40C. . ;
Dissolve the steroid in the remaining propanediol and add to the above after the phases have been mixed.
xam~ 4 Glyceryl monostearate (G.M.S.) 10.0% ;
Cetostearyl alcohol (C.S.A,) S.0%
Beeswax ~r 2~ 0%
Acid stable self-emulsifying mono-stearin ) 2.0%
. ~.
, :~.04~
Glycerol 10.0%
Sodium citlate 0.05/O
Citric acid 0.05%
Chlorocresol 0.10%
Water to 100.0% :
_ethod O~ e~
Melt the G.M~S., C.S.A., Beeswax and monostearin togethQr and heat to 75C. Mix most of the glycerol and water, add the other ingredients and heat to aid solution. Mix the two phases at 75C, stir and cool to 40C.
Ball mill the steroid in the remaining glycerol ànd add to the above atter tbe two phases have been mixed, Example 5 As Example 4 with addition of 1% dimethylpolysilvxane o-L:L.
~ .
~ ' ' ' ' ' ; ` ' ' ' ~ '
Claims (21)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A substantially oil-free pharmaceutical cream composition comprising from 0.0001 to 5% by weight of a topically-active anti-inflammatory steroid in a vehicle comprising a dispersion of hydrophobic wax in an aqueous phase comprising water and at least one water-miscible hydroxylic solvent, the said dispersion further containing a surface active agent, and the wax, water, water-miscible hydroxy-lic solvent and surface active agent being present in amounts of 5.0 to 30%, 7.0 to 75%, 10 to 80% and 0.1 to 10%, respectively, based on the total weight of the compositions.
2. A composition as defined in claim 1, containing not more than 1%
oil.
oil.
3. A composition as defined in claim 1, which is oil free.
4. A composition as defined in claim 1 wherein the steroid is 21-chloro-9.alpha.-fluoro-11 .beta.-hydroxy-16 .beta.-methyl-17.alpha.-propionyloxy-pregna-1,4-diene-3,20-dione.
5. A composition as defined in claim 1 wherein the steroid is beta-methasone 17-valerate; betamethasone 17-benzoate; 6.alpha.,9.alpha.-difluoro-11 .beta.,21-di-hydroxy-16.alpha.,17.alpha.-isopropylidenedioxy-pregna-1,4-diene-3,20-dione and the cor-responding 21-acetate; 9.alpha.-fluoro-16-methylene-prednisolone-21-acetate; 6.alpha.,9.alpha.-difluoro-prednisolone-21-acetate-17-butyrate; 9.alpha.,11 .beta.-dichloro-6.alpha.,21-difluoro-16.alpha.,l7.alpha.-isopropylidenedioxy-pregna-1,4-diene-3,20-dione; 11.beta.,21-dihydroxy-16.alpha.,17.alpha.-isopropylidenedioxy-pregna-1,4-diene-3,20-dione; 9.alpha.,11 .beta.-dichloro-6.alpha.-fluoro-21-hydroxy-16.alpha.,17.alpha.-isopropylidenedioxy-pregna-1,4-diene-3,20-dione.
6. A composition as defined in claim 1, 2 or 3 wherein the hydroxylic solvent comprises at least one glycol.
7. A composition as defined in claim 1, 2 or 3 wherein the hydroxylic solvent comprises a propanediol, a dipropylene glycol and/or a liquid poly-ethylene glycol.
8. A composition as defined in claim 1, 2 or 3 wherein the hydroxylic solvent is present in an amount of 25 to 70% based on the total weight of the composition.
9. A composition as defined in claim 1, 2 or 3 wherein the hydroxylic solvent comprises at least one trihydric alcohol, said alcohol being present in the composition in an amount of up to 40% based on the total weight of the composition.
10. A composition as defined in claim 1, 2 or 3 wherein the hydroxylic solvent comprises at least one trihydric alcohol, the said trihydric alcohol being present in an amount of 10 to 25% based on the total weight of the com-position.
11. A composition as defined in claim 1, 2 or 3 wherein the water is present in an amount of 20 to 60% based on the total weight of the composition.
12. A composition as defined in claim 1, 2 or 3 wherein the wax comprises a waxy triglyceride; a waxy fatty alcohol; a waxy saturated fatty acid; or a long chain fatty acid monoester of glycerol.
13. A composition as defined in claim 1, 2 or 3 which additionally con-tains a waxy polyethylene glycol.
14. A composition as defined in claim 1, 2 or 3 wherein the wax is pre-sent in an amount of 10 to 20% based on the total weight of the composition.
15. A composition as defined in claim 1, 2 or 3 wherein the surface ac-tive agent comprises a non-ionic surface active agent.
16. A composition as defined in claim 1, 2 or 3 wherein the surface ac-tive agent comprises an anionic surface active agent.
17. A composition as defined in claim 1, 2 or 3, wherein the surface ac-tive agent is present in an amount of 1 to 5% based on the total weight of the composition.
18. A composition as defined in claim 1 wherein the steroid is beclo-methasone 17,21-dipropionate (9a-chloro-16 .beta.-methyl-prednisolone-17,21-dipro-pionate); 21-desoxy-betamethasone-17-propionate; betamethasone 17-isobutyrate 21-acetate; .DELTA.8(9)-16 .beta.-methyl-prednisolone 17,21-dipropionate; or methyl 11 .beta.-hydroxy-3-oxo-17.alpha.-propionyloxy-androst-4-ene 17 .beta.-carboxylate.
19. A composition as defined in claim 1, wherein the steroid is 21-chloro-21-desoxy-11-dehydro-betamethasone 17-butyrate.
20. A composition as defined in claim 1, 4 or 19, containing 0.005 to 0.50% by weight of the anti-inflammatory steroid.
21. A composition as defined in claim 1, 4 or 19, containing 0.01 to 0.10% by weight of the anti-inflammatory steroid.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1575873A GB1478009A (en) | 1973-04-02 | 1973-04-02 | Pharmaceutical compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1045974A true CA1045974A (en) | 1979-01-09 |
Family
ID=10064952
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA196,544A Expired CA1045974A (en) | 1973-04-02 | 1974-04-01 | Oil-free pharmaceutical cream |
Country Status (11)
| Country | Link |
|---|---|
| JP (1) | JPS589081B2 (en) |
| BE (1) | BE813153A (en) |
| CA (1) | CA1045974A (en) |
| DE (1) | DE2347243A1 (en) |
| DK (1) | DK144358C (en) |
| FR (1) | FR2222998B1 (en) |
| GB (1) | GB1478009A (en) |
| IE (1) | IE39113B1 (en) |
| LU (1) | LU69751A1 (en) |
| NL (1) | NL7404378A (en) |
| ZA (1) | ZA742064B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE8004580L (en) * | 1980-06-19 | 1981-12-20 | Draco Ab | PHARMACEUTICAL PREPARATION |
| GB2080106B (en) * | 1980-07-18 | 1984-03-07 | Weelcome Foundation Ltd | Acyclovin preparations |
| KR830005852A (en) * | 1980-07-18 | 1983-09-14 | 미첼 페터 잭슨 | Preparation of topical treatments suitable for the treatment of viral infections on skin and mucous membranes |
| DE3225848A1 (en) * | 1982-07-07 | 1984-01-19 | Schering AG, 1000 Berlin und 4709 Bergkamen | PREPARATION OF CORTICOIDS FOR TOPICAL APPLICATION |
| US4868169A (en) * | 1987-11-13 | 1989-09-19 | E. R. Squibb & Sons, Inc. | Steroid cream formulation |
| LU87457A1 (en) * | 1989-02-24 | 1990-09-19 | Oreal | USE, AS A COSMETIC COMPOSITION FOR HAIR, OF A WAX MICRODISPERSION, AND METHOD FOR TREATING HAIR WITH SUCH A COMPOSITION |
| US8491875B2 (en) * | 2010-08-18 | 2013-07-23 | Kao Corporation | Hair volumizing compositions |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB765600A (en) * | 1954-01-15 | 1957-01-09 | Drug Houses Of Australia Ltd | Salves for veterinary use |
| GB903407A (en) * | 1958-07-25 | 1962-08-15 | Upjohn Co | Improvements in or relating to antibacterial antiperspirant compositions |
| DE1198011B (en) * | 1962-08-04 | 1965-08-05 | Iwao Kawakami | Skin care products |
| BR6789910D0 (en) * | 1966-10-17 | 1973-05-17 | Fmc Corp | PROCESS TO PREPARE EDIBLE CONTAINING MICRO CRYSTALLINE COLLAGEN |
-
1973
- 1973-04-02 GB GB1575873A patent/GB1478009A/en not_active Expired
- 1973-09-19 DE DE19732347243 patent/DE2347243A1/en active Pending
-
1974
- 1974-04-01 LU LU69751A patent/LU69751A1/xx unknown
- 1974-04-01 CA CA196,544A patent/CA1045974A/en not_active Expired
- 1974-04-01 FR FR7411572A patent/FR2222998B1/fr not_active Expired
- 1974-04-01 DK DK179474A patent/DK144358C/en not_active IP Right Cessation
- 1974-04-01 NL NL7404378A patent/NL7404378A/xx unknown
- 1974-04-01 ZA ZA00742064A patent/ZA742064B/en unknown
- 1974-04-01 BE BE142726A patent/BE813153A/en not_active IP Right Cessation
- 1974-04-01 JP JP49035716A patent/JPS589081B2/en not_active Expired
- 1974-04-01 IE IE00703/74A patent/IE39113B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK144358B (en) | 1982-03-01 |
| IE39113L (en) | 1974-10-02 |
| FR2222998B1 (en) | 1977-11-04 |
| LU69751A1 (en) | 1974-07-17 |
| GB1478009A (en) | 1977-06-29 |
| DK144358C (en) | 1984-04-09 |
| BE813153A (en) | 1974-10-01 |
| FR2222998A1 (en) | 1974-10-25 |
| IE39113B1 (en) | 1978-08-02 |
| JPS5058218A (en) | 1975-05-21 |
| JPS589081B2 (en) | 1983-02-18 |
| DE2347243A1 (en) | 1974-10-10 |
| ZA742064B (en) | 1975-03-26 |
| NL7404378A (en) | 1974-10-04 |
| AU6724674A (en) | 1975-10-02 |
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