U.S. patent number 3,924,004 [Application Number 05/201,997] was granted by the patent office on 1975-12-02 for fatty alcohol-propylene carbonate-glycol solvent cream vehicle.
This patent grant is currently assigned to Syntex Corporation. Invention is credited to Kuang Y. Chang, Bonnie Ferrell.
United States Patent |
3,924,004 |
Chang , et al. |
December 2, 1975 |
Fatty alcohol-propylene carbonate-glycol solvent cream vehicle
Abstract
A medicament base containing from 5 to 40 percent saturated
fatty alcohol having from 16 to 24 carbons, from 1 to 40 percent
propylene carbonate, from 25 to 85 percent of glycol cosolvent, a
stabilizing amount of a surfactant and optional amounts of
compatible plasticizer, and/or other pharmaceutical adjuvants. The
base is a suitable vehicle for all types of therapeutic agents for
topical application and has shown particular advantages with
anti-inflammatory topical corticoids.
Inventors: |
Chang; Kuang Y. (Palo Alto,
CA), Ferrell; Bonnie (Clinton, NY) |
Assignee: |
Syntex Corporation (Palo Alto,
CA)
|
Family
ID: |
22748155 |
Appl.
No.: |
05/201,997 |
Filed: |
November 24, 1971 |
Current U.S.
Class: |
514/772;
514/179 |
Current CPC
Class: |
A61K
9/0014 (20130101) |
Current International
Class: |
A61K
47/00 (20060101); A61K 009/06 () |
Field of
Search: |
;424/73,240-243,358 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
1,096,753 |
|
Dec 1967 |
|
UK |
|
1,448,042 |
|
Jun 1966 |
|
FR |
|
Primary Examiner: Rose; Shep K.
Attorney, Agent or Firm: Hirsch; Joesph I. Moran; Thomas M.
Walker; William B.
Claims
We claim:
1. A substantially anhydrous vehicle composition consisting
essentially of
a. from 5 to 40 weight percent of saturated fatty alcohol having
from 16 to 24 carbons;
b. from 1 to 40 weight percent of propylene carbonate;
c. from 25 to 85 weight percent of glycol cosolvent, weight ratio
of the glycol solvent to propylene carbonate being at least
1:2;
d. a stabilizing amount of surfactant;
e. from 0 to 15 weight percent of compatible plasticizer; and
f. from 0 to 3 weight percent water; said vehicle composition being
particularly suitable for providing an occlusive film, for
releasing topically active cortico-steroids which are soluble in
propylene carbonate, and for distributing medication over the skin
surface and maintaining it there until beneficial action
occurs.
2. The composition of claim 1 comprising
a. from 10 to 30 weight percent of saturated fatty alcohol having
from 16 to 24 carbons;
b. from 5 to 30 weight percent of propylene carbonate;
c. from 30 to 80 weight percent of glycol cosolvent, the weight
ratio of glycol solvent to propylene carbonate being at least
1:1;
d. from 0.1 to 10 weight percent surfactant;
e. from 0 to 15 weight percent of compatible plasticizer, and
f. from 0 to 3 weight percent water.
3. The composition of claim 2 wherein the compatible plasticizer
concentration is from 0.1 to 5 weight percent.
4. The composition of claim 1 wherein the weight ratio of the
glycol cosolvent to propylene carbonate is at least 1:1.
5. The composition of claim 1 wherein the weight ratio of the
glycol cosolvent to propylene carbonate is at least 3:1.
Description
BACKGROUND OF THE INVENTION
This invention relates to vehicles for topical application of
medicaments and to mixtures of the vehicle and medicaments. In
particular, this invention relates to new, improved medicament
vehicles having advantages over previously known vehicles.
One of the oldest types of medicament vehicles is the ointment, a
preparation containing active medications that can be readily
applied and rubbed into the skin. It serves as a means for
distributing the medication uniformly over the skin surface and
maintaining it there until beneficial action can occur. The
earliest ointment preparations were based on fats, waxes, greases
and petrolatum. These are, by nature, greasy, or not water-washable
and having a limited ability to release medication to the skin. A
non-aqueous ointment of more recent origin is a mixture of
polyethylene glycols having molecular weights of 1,000 to 20,000.
This vehicle, although water-washable, has a greasy texture and
does not provide an occlusive dressing on a treated surface. Prior
to this invention, these anhydrous ointment bases were the only
vehicles available for medicaments which deteriorated in the
presence of moisture.
Emulsified creams, such as cold creams, were developed to reduce
greasiness, while still maintaining the unctuousness and
spreadability of the older greasy-type ointments. The emulsified
creams have an aqueous base, however, and are not suitable for many
drugs because their water content destroy the medicament. The
medicament, in turn may destroy the emulsions, that is, break the
emulsions and permit separation of the vehicle components.
Furthermore, water is frequently not desirable in a medicament
formulation because of its adverse effects on a condition being
treated.
One system which is not subject to the above disadvantages is the
non-aqueous fatty alcohol - propylene glycol vehicles described in
U.S. Pat. No. 3,592,930 granted to Katz et al. The subject of this
invention is an improved non-aqueous vehicle with a propylene
carbonate solvent system.
It is accordingly the purpose of this invention to provide an
essentially anhydrous, water-washable base which is more effective
than standard anhydrous ointment bases of the grease type because
it can preserve the activity of medicaments which deteriorate in
the presence of moisture; provide an occlusive film for longer and
better therapeutic activity; release the medicaments more quickly
and effectively; bring dissolved therapeutic agents in known
dilution in contact with the skin; spread evenly and adhere well
even if the skin is moist; be readily removed from the skin or
fabrics with water; provide media to readily absorb discharges from
wounds; serve as an excellent levigating material for many
prescribed ingredients that usually require separate treatment
before being incorporated into one of the bases; provide a base for
medicament formulations in which water is not desired; and because
it does not hydrolyze, deteriorate, become rancid, support mold
growth or require preservatives.
It is a further object of this invention to provide a vehicle using
a unique solvent, new for topical preparations. Propylene carbonate
has exceptional solubilizing properties, particularly for
corticosteroids. By combining a glycol cosolvent and surfactant
with the fatty alcohol and propylene carbonate, a stable cream can
be prepared. Further, by varying the ratio of propylene carbonate
and glycol cosolvent one can obtain a wide range of saturation
concentrations for a medicament. Thus the ratio can be chosen to
optimize drug delivery for any particular medicament.
SUMMARY
The composition of this invention is a substantially anhydrous
vehicle composition consisting essentially of
a. from 5 to 40 weight percent of saturated fatty alcohol having
from 16 to 24 carbons;
b. from 1 to 40 weight percent of propylene carbonate;
c. from 25 to 85 weight percent of glycol cosolvent, the weight
ratio of the glycol solvent to propylene carbonate being at least
1:2;
d. a stabilizing amount of surfactant; and
e. from 0 to 15 weight percent of compatible plasticizer. The base
is an improved vehicle for all types of therapeutic agents for
topical application and offers particular advantages with
anti-inflammatory topical steroids.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
All concentrations are herein given as weight percents unless
otherwise specified. It is also intended that the chemical
compounds in each class of ingredients discussed hereinafter be
limited to pharmaceutically acceptable, non-toxic compounds in the
concentrations indicated.
The composition of this invention contains from 5 to 40 and
preferably from 10 to 30 percent fatty alcohol. The fatty alcohol
can be any fatty alcohol having from 16 to 24 carbons or mixtures
thereof, and is preferably a saturated monohydric primary alcohol.
Suitable fatty alcohols include cetyl alcohol, stearyl alcohol,
behenyl alcohol, and the like.
The fatty alcohol component should be substantially free from any
significant amount of unsaturated alcohols or fatty alcohols having
fewer than 16 carbons, the term "substantially free from" as used
herein, is defined as indicating the compositions of this invention
containing less than irritating or otherwise medically undesirable
amounts of the indicated substances. Since the commercially
available fatty alcohols having from 16 to 24 carbons contain
impurities including some proportion of fatty alcohols having fewer
than 16 carbons, total avoidance of alcohols having fewer than 16
carbons from the mixture is not practicable. Careful selection of
raw materials is preferable, however, to maintain the percentage of
irritating alcohols to less than 10 percent of the total fatty
alcohol concentration.
The composition of this invention also contains from 1 to 40 and
preferably from 5 to 30 percent propylene carbonate.
The composition of this invention also contains from 25 to 85
preferably from 30 to 80 percent of glycol cosolvent. Suitable
glycol cosolvents include 1,2-propanediol, 1,3-propanediol,
polyethylene glycol having a molecular weight of from 100 to 800,
dipropylene glycol, and the like or mixtures thereof. The weight
ratio of glycol cosolvent to propylene carbonate must be at least
1:2 to provide a stable composition. It is preferably at least 1:1,
and the optimum ratio is at least 3:1. In the absence of the glycol
cosolvent, the propylene carbonate and fatty alcohol do not form a
physically stable mixture. Thus, the glycol cosolvent functions
primarily as a coupling ingredient for the fatty alcohol and
propylene carbonate. It also functions as an auxiliary solvent in
the system.
The composition of this invention also contains a stabilizing
amount of a surfactant, that is, an amount sufficient to maintain
homogeneity of the other ingredients. The particular concentration
will vary depending upon the choice of surfactant and the selection
of the other ingredients. In general, stabilizing amounts can be as
low as 0.1 percent or lower. In some instances as high as 10
percent or higher of surfactant may be desired. Generally from 2 to
5 percent is suitable. The amount of surfactant should be the
minimum required for stability. The surfactant functions as a
coupling agent, linking diverse phases and maintaining a dispersion
of immisicible components. Suitable surfactants include
pharmaceutically acceptable, non-toxic non-ionic, anionic and
cationic surfactants. Examples of suitable non-ionic surfactants
include glycerol fatty acid esters such as glycerol monostearate,
glycol fatty acid esters such as propylene glycol monostearate,
polyhydric alcohol fatty acid esters such as sorbitan monostearate,
polyethylene glycol fatty acid esters such as polyethylene glycol
(400) monooleate, polyoxyethylene fatty acid esters such as
polyoxyethylene (40) stearate, polyoxyethylene fatty alcohol ethers
such as polyoxyethylene (20) stearyl ether, polyoxyethylene
sorbitan fatty acid esters such as polyoxyethylene sorbitan
monostearate, fatty acid ethanolamides and their derivatives such
as the diethanolamide of stearic acid, and the like. Examples of
suitable anionic surfactants are soaps including alkali soaps, such
as sodium, potassium and ammonium salts of aliphatic carboxylic
acids, usually fatty acids, such as sodium stearate. Organic amine
soaps, also included, include organic amine salts of aliphatic
carboxylic acids, usually fatty acids, such as triethanolamine
stearate. Another class of suitable soaps is the metallic soaps,
salts of polyvalent metals and aliphatic carboxylic acids, usually
fatty acids, such as aluminum stearate. Other classes of suitable
anionic surfactants include sulfated fatty alcohols such as sodium
lauryl sulfate, sulfated oils such as the sulfuric ester of
ricinoleic acid disodium salt, and sulfonated compounds such as
alkyl sulfonates including sodium cetane sulfonate, amide
sulfonates such as sodium N-methyl-N-oleyl taurate, sulfonated
dibasic acid esters such as sodium dioctyl sulfosuccinate, alkyl
aryl sulfonates such as sodium dodecylbenzene sulfonate, alkyl
naphthalene sulfonates such as sodium isopropyl naphthalene
sulfonate, petroleum sulfonates such as arylnaphthene with alkyl
substituents. Examples of suitable cationic surfactants include
amine salts such as octadecyl ammonium chloride, quaternary
ammonium compounds such as benzalkonium chloride. Other examples of
these and other suitable surfactants can be found in
"Pharmaceutical Emulsions and Emulsifying Agents" by Lawrence M.
Spatton, second edition, The Chemist and Druggist, London;
"Emulsions; Theory and Practice" by Paul Becher, Reinhold
Publishing Corporation, New York; and "Detergents and Emulsificers,
1969 Annual" by John M. McCutcheon, Morriston, N.J., the
disclosures thereof being incorporated herein by reference.
The composition of this invention can also contain from 0 to 15 and
preferably from 0.1 to 5 percent of a compatible plasticizer.
Suitable compatible plasticizers include carboxylic vinyl polymers
(Carbopols), polyethylene glycol having a molecular weight of from
above 800 to 20,000; natural gums including acacia gum, guar gum,
karaya, tragacanth, and the like; seaweed products such as agar,
irish moss and alginates; cellulose derivatives including cellulose
ethers such as methyl cellulose, ethyl cellulose, sodium
carboxymethyl cellulose and the like; starch, starch derivatives
and dextrins; pectin and pectates; saponins; and water soluble or
water dispersible vinyl polymers such as polyvinylpyrrolidone,
polyvinyl alcohol, vinyl pyrrolidonevinyl alcohol copolymers, and
the like. The plasticizer maintains homogeneity in the mixture at
ambient temperatures, that is, temperatures at which the fatty
alcohol is a solid. This component also improves the plasticity,
and uniformity of the medicament mixtures with the vehicle and
provides to the vehicle smoothness and a more pleasing "feel;"
hence the vehicle containing the plasticizer is more cosmetically
acceptable. In general, the particular plasticizer concentration
necessary to provide a desired consistency, degree of smoothness
and plasticity will vary with the choice of the fatty alcohol
component and cosolvent, and the ratio of these components in the
vehicle. Preferably, the plasticizer concentration should be
balanced so the vehicle has freeze-thaw stability, i.e., does not
separate after repeated cycles of solidification (by cooling) and
liquefaction (by heating). The term "compatible" is defined herein
to indicate a component which will not cause separation (loss of
homogeneity) of the other components at temperatures up to
45.degree.C.
It should be understood that the medicament vehicles of this
invention can also contain other non-essential ingredients. The
vehicle can contain up to 10 weight percent of conventional
pharmaceutical adjuvants. These adjuvants or additives are used to
improve consistency, emolliency, homogeneity, spreadability,
texture and appearance of the vehicle or its residual film or the
stability of the medicament. They can be used to give a residual
film, varying degrees of continuity, flexibility, adhesion,
occlusion, water repellancy, washability, and the like. Suitable
auxiliary adjuvants include hydrocarbons ranging from liquid
petrolatum to solid paraffins and waxes, beeswax, saturated fatty
acids having from 16 to 24 carbons such as stearic acid, palmitic
acid, behenic acid; fatty acid amides such as oleamide,
palmitamide, stearamide, behenamide; and esters of fatty acids
having from 14 to 24 carbons such as isopropyl myristate sorbitan
monostearate, polyethylene glycol monostearate, propylene glycol
monostearate and the corresponding mono- and diesters of other
fatty acids such as oleic and acid and palmitic acid. It is
preferable that the fatty acids be saturated and the fatty acids
and amides be substantially free from irritating amounts of acids
or amides having fewer than 14 carbons. Other optional adjuvants
include miscellaneous natural products such as wool fat, wool
alcohol, cholesterol and its derivatives, lecithin and proteins
such as gelatin, casein, soyabean protein, egg albumen. Finely
dispersed mineral solids useful as thickeners include colloidal
clays such as bentonite and polyvalent metal hydroxides such as
magnesium hydroxide. Suitable chemical stabilizers include citric
acid and other agents to adjust pH, ethylenediamine tetraacetic
acid and its salts and other chelating or sequestering agents,
propyl gallate, butylated hydroxy anisole or toluene, and other
antioxidants.
The medicament vehicle of this invention is essentially a
non-aqueous base, that is, it is not an aqueous emulsion and
consequently is not a "cream" in the usual sense. It is preferably
totally anhydrous, but can contain minor amounts of water such as
up to 3 percent water. The water concentration should not be
sufficient to cause separation of the other vehicle components or
precipitate medicaments dissolved in the vehicle.
The vehicle of this invention can be made thoroughly mixing the
components at ambient or elevated temperatures. Preferably the
components are thoroughly mixed while each is in a liquid state,
and the mixture is cooled with good agitation to room temperature.
Preferably, additional mechanical agitation and/or shock cooling
steps are used as intermediate or final steps in the manufacturing
process to impart more homogeneity or improved texture. Process
equipment for these techniques includes heat exchangers, propeller
mixers, colloid mills, homogenizers, roller mills and the like.
The base of this invention can be used as a vehicle for all types
of medicaments or therapeutic agents for topical application
including antibiotics such as oxytetracycline, chlortetracycline,
streptomycin, bacitracin, chloramphenicol, tyrothricin and the
like; steroids having anti-inflammatory or other beneficial
activity; antihistamines such as prophenpyridamine maleate and
diphenhydramine hydrochloride; anesthetics such as benzocaine and
lidocaine; antibacterials including iodine; iodochlorohydroxyquin,
nitrofurazone, sulfanilamide and derivatives, and benzalkonium
chloride; fungicides such as undecylenic acid vitamins such as
Vitamin A derivatives; and other therapeutic agents including coal
tar, balsam Peru, ammoniated mercury, anthralin, chrysarobin,
ichthammol, sulfur and the like.
The medicaments can be incorporated into this base by conventional
techniques. A bulky, insoluble powder should be mixed beforehand
with a small proportion of the base mixture, propylene carbonate,
or propylene glycol, and then blended with the remainder of the
base. The products are usually improved by passing them through an
ointment or roller mill. Coal tar, ichthammol, balsam Peru and
others that require special processing in greasy bases can be
readily incorporated in the base of this invention. The medicaments
can be incorporated into the final base or introduced into the base
mixture with one of its components. Heat sensitive medicaments (in
particular some antibiotics) can be dissolved or suspended in a
small amount of propylene carbonate, glycol cosolvent or other
liquid, and then mixed with the vehicle during or after its
preparation.
The amount of medicament to be incorporated into the base will, of
course, depend upon the type of medicament and its intended use;
the determination of suitable medicament concentrations is a
routine matter fully within the conventional skill of the art. In
general, therapeutically effective amounts of the medicament are
incorporated into the vehicle.
The vehicle of this invention is particularly suitable for use with
anti-inflammatory topical steroids represented by Formulas I, II
and III. ##SPC1##
In the above formulas
R.sub.1 is hydrogen, methyl, fluoro, or chloro and when Z.sub.2 is
a single bond, R.sub.1 can be either .alpha. or .beta.
oriented;
R.sub.2 is hydrogen, chloro, or fluoro;
R.sub.3 is keto or ##EQU1## wherein R.sub.3 ' is hydrogen, hydroxy,
chloro, or fluoro;
R.sub.4 is hydrogen, methyl, hydroxy, or a conventional
hydrolyzable ester thereof;
R.sub.5 is hydrogen, hydroxy, a conventional hydrolyzable ester
thereof, or when taken together with R.sub.4 ; ##EQU2## wherein
R.sub.6 is hydrogen or alkyl of up to eight carbons, and
R.sub.7 is hydrogen, or alkyl or an aryl group of up to eight
carbons;
R.sub.8 is hydroxy, conventional hydrolyzable esters thereof,
tetrahydropyranyloxy, tetrahydrofuranyloxy,
4'-(lower)alkoxytetrahydropyran-4'-yloxy, lower alkoxy, lower
cycloalkoxy, lower cycloalkenyloxy, chloro, or fluoro;
R.sub.9 and R.sub.10 are hydrogen, methyl, phenyl, chlorophenyl,
fluorophenyl, methylphenyl, or methoxyphenyl (the substituted
phenyls preferably being substituted in the para position);
R.sub.11 and R.sub.12 each is hydrogen, chloro or fluoro;
Z.sub.1 and Z.sub.2 each is a single bond, double bond, or
##EQU3##
The terms "(lower)alkyl" and derivations thereof appearing in the
above definitions and elsewhere in the instant specification denote
alkyl groups having from one to six carbon atoms, inclusive, such
as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,
pentyl, amyl, hexyl, and the like.
The term "conventional hydrolyzable ester" as used herein denotes
those hydrolyzable ester groups conventional employed in the
steriod art, preferably those derived from hydrocarbon carboxylic
acids or phosphoric acids and their salts. The term "hydrocarbon
carboxylic acid" defines both substituted and unsubstituted
hydrocarbon carboxylic acids. These acids can be completely
saturated or possess varying degrees of unsaturation (including
aromatic), can be of straight chain, branched chain, or cyclic
structure, and preferably contain from one to 12 carbon atoms. In
addition, they can be substituted by functional groups, for
example, hydroxy, alkoxy containing up to six carbon atoms, acyloxy
containing up to 12 carbon atoms, nitro, amino, halogeno, and the
like, attached to the hydrocarbon backbone chain. Typical
conventional hydrolyzable esters thus included within the scope of
the term and the instant invention are acetate, propionate,
butyrate, valerate, caproate, enanthate, caprylate, pelargonate,
acrylate, undecenoate, phenoxyacetate, benzoate, phenylacetate,
diphenylacetate, diethylacetate, trimethylacetate, t-butylacetate,
trimethylhexanoate, methylneopentylacetate, cyclohexylacetate,
cyclopentylpropionate, adamantoate, glycolate, methoxyacetate,
hemisuccinate, hemiadipate, hemi-.beta.,.beta.-dimethylglutarate,
acetoxyacetate, 2-chloro-4-nitrobenzoate, aminoacetate,
diethylaminoacetate, piperidinoacetate, .beta.-chloropropionate,
trichloroacetate, .beta.-chlorobutyrate, dihydrogen phosphate,
dibenzyl phosphate, benzyl hydrogen phosphate, sodium benzyl
phosphate, cyclohexylammonium benzyl phosphate, sodium phenyl
phosphate, sodium ethyl phosphate, di-p-nitrobenzyl phosphate,
sodium o-methoxyphenyl phosphate, cyclohexylammonium p-cyanobenzyl
phosphate, sodium phenacyl phosphate, benzyl o-carbomethoxyphenyl
phosphate, and the like.
By the term "aryl" are included aryl, aralkyl, and alkaryl groups,
such as phenyl, p-chlorophenyl, p-methoxyphenyl, benzyl, phenethyl,
tolyl, ethylphenyl, and the like. The wavy line ( ) designates and
includes both the alpha and beta configurations.
The above anti-inflammatory steroids have been previously disclosed
in U.S. Pat. Nos. 3,365,446, 3,067,194, 3,364,203, 3,053,838 and
3,513,162, for example.
The above anti-inflammatory topical medicaments are thoroughly
mixed with the base in therapeutically effective amounts. The
particular concentration of the medicament in the base will vary
depending upon the particular activity of the steroid used
considered in conjunction with the condition and subject to be
treated. In general, therapeutically effective amounts of these
compounds can be as low as 0.00001 weight percent or lower, for
example. For some uses, as high as 5 weight percent steroid or
higher may be desired.
The medicament base of this invention has been found to be
particularly suitable for use with topical corticoids, for example,
6.alpha.-fluoro-11
.beta.-hydroxy-16.alpha.,17.alpha.-isopropylidenedioxy-21-acetoxypregna-1,
4-diene-3,20-dione, fluocinolone acetonide
(6.alpha.,9.alpha.-difluoro-11.beta.,21-dihydroxy-15.alpha.,17.alpha.-isop
ropylidenedioxypregna-1,4-diene-3,20-dione), fluocinolide
(16.alpha.-acetoxy-6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.,1
7.alpha.-isopropylidenedioxypregna-1,4-diene-3,20-dione),
9.alpha.,11.beta.-dichloro-6.alpha.-fluoro-21-hydroxy-16.alpha.,17.alpha.-
isopropylidenedioxypregna-1,4-diene-3,20-dione,
9.alpha.,11.beta.-dichloro-6.alpha.,21-difluoro-16.alpha.,17.alpha.-isopro
pylidenedioxypregna-1,4-diene-3,20-dione and
9.alpha.,11.beta.,21-trichloro-6.alpha.-fluoro-16.alpha.,17.alpha.-isoprop
ylidenedioxypregna-1,4-diene-3,20-dione.
This invention is further illustrated by the following specific but
non-limiting examples.
EXAMPLE 1
The following ingredients are mixed at 80.degree.C and cooled to
room temperature with good agitation.
__________________________________________________________________________
Concentration, Wt. Percent
__________________________________________________________________________
Ingredients A B C D E Stearyl alcohol 16.0 20.0 25.0 20.0 16.0
Sorbitan monostearate 2.2 0.4 2.2 0.5 2.2 Polyoxyethylene sorbitan
monostearate (Tween 60) 1.8 1.8 1.8 0.3 1.8 Propylene glycol 64.0
61.4 46.0 62.5 40.0 Propylene carbonate 16.0 16.0 25.0 16.0 40.0
Carboxy vinyl polymer -- 0.4 -- 0.7 -- (Carbopol)
__________________________________________________________________________
EXAMPLE 2
A vehicle having the composition "B" of Example 1 and containing
0.025 g. of
6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropylidenediox
y-21-acetoxypregna-1,4-diene-3,20-dione is prepared as follows.
The propylene glycol and propylene carbonate are mixed and heated
to 80.degree.-85.degree.C, and the steroid is dissolved in the
mixture. The carboxy vinyl polymer (Carbopol) and stearyl alcohol
are blended, and together with the sorbitan monostearate and
polyoxyethylene sorbitan monostearate, are mixed with the steroid
solution. The mixture is then cooled to room temperature while
maintaining dispersion with suitable mixing equipment.
EXAMPLE 3
The following ingredients are mixed at 80.degree.C and cooled to
room temperature with good agitation.
______________________________________ Ingredients Concentration,
Wt. Percent ______________________________________ F G Propylene
carbonate 15.0 15.0 Dipropylene glycol 53.0 -- Propylene glycol --
50.0 Stearyl alcohol 30.0 -- Cetyl alcohol -- 32.0 Carboxy vinyl
polymer 1.0 -- (Carbopol) Sorbitan monostearate 1.0 3.0
______________________________________
EXAMPLE 4
Each of 0.25, 0.5 and 1.0 gm. quantities of the following
anti-inflammatory steroids, when incorporated into 1,000 gm. the
mixtures described in Example 1, are effective for topical
treatment of inflammation:
9.alpha.-11.beta.-dichloro-6.alpha.-fluoro-21-hydroxy-16.alpha.,17.alpha.-i
sopropylidenedioxypregna-1,4-diene-3,20-dione,
9.alpha.-fluoro-11.beta.,17.alpha.,21-trihydroxy-16.beta.-methylpregna-1,4-
diene-3,20-dione,
9.alpha.-fluoro-11.beta.,21-dihydroxy-16.beta.-methyl-17.alpha.-valeroxypre
gna-1,4-diene-3,20-dione,
17.alpha.,21-dihydroxypregn-4-ene-3,11,20-trione,
17.alpha.-hydroxy-21-acetoxypregn-4-ene-3,11,20-trione,
21-hydroxypregn-4-ene-3,20-dione,
21-acetoxypregn-4-ene-3,20-dione,
21-pivaloxypregn-4-3,20-dione,
9.alpha.-fluoro-11.beta.,17.alpha.,21-trihydroxy-16.alpha.-methylpregna-1,4
-diene-3,20 -dione,
9.alpha.-fluoro-11.beta.,17.alpha.,21-trihydroxy-16.alpha.-methylpregna-1,4
-diene-3,20-dione-21-sodium phosphate,
6.alpha.,9.alpha.-difluoro-11.beta.,21-dihydroxy-16.alpha.,17.alpha.-isopro
pylidenedioxypregna-1,4-diene-3,20-dione,
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropylid
enedioxy-21-acetoxypregna-1,4-diene-3,20-dione,
6.alpha.-methyl-9.alpha.-fluoro-11.beta.,17.alpha.-dihydroxypregna-1,4-dien
e-3,20-dione,
6.alpha.-fluoro-11.beta.,17.alpha.,21-trihydroxypregna-1,4-diene-3,20-dione
,
6.alpha.-fluoro-11.beta.,21-dihydroxy-16.alpha.,17.alpha.-isopropylidened
ioxypregn-4-ene-3,20-dione,
6.alpha.-fluoro-11.beta.,21-dihydroxy-16.alpha.,17.alpha.-isopropylidenedio
xypregna-1,4-diene-3,20-dione,
11.beta.,17.alpha.-dihydroxy-21-acetoxypregn-4-ene-3,20-dione,
6.alpha.-methyl-11.beta.,17.alpha.,21-trihydroxypregna-1,4-diene-3,20-dione
,
6.alpha.-methyl-11.beta.,17.alpha.-dihydroxy-21-acetoxypregna-1,4-diene-3
,20-dione,
6.alpha.-fluoro-11.beta.,17.alpha.,21-trihydroxy-16.alpha.-methylpregna-1,4
-diene-3,20-dione,
6.alpha.-fluoro-11.beta.,17.alpha.-dihydroxy-16.alpha.-methyl-21-acetoxypre
gna-1,4-diene-3,20-dione,
6.alpha.-fluoro-11.beta.,17.alpha.-dihydroxy-16.alpha.-methyl-21-valeroxypr
egna-1,4-diene-3,20-dione,
6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropylidenedioxy-21
-acetoxypregna-1,4-diene-3,20-dione,
11.beta.,17.alpha.,21-trihydroxypregna-1,4-diene-3,20-dione,
11.beta.,17.alpha.-dihydroxy-21-acetoxypregna-1,4-diene-3,20-dione,
17.alpha.,21-dihydroxypregna-1,4-diene-3,11,20-trione,
17.alpha.-hydroxy-21-acetoxypregna-1,4-diene-3,11,20-trione,
9.alpha.-fluoro-11.beta.,16.alpha.,17.alpha.,21-tetrahydroxypregna-1,4-dien
e-3,20-dione,
9.alpha.-fluoro-11.beta.,16.alpha.,17.alpha.-trihydroxy-21-acetoxypregna-1,
4-diene-3,20-dione,
9.alpha.-fluoro-11.beta.,21-dihydroxy-16.alpha.,17.alpha.-isopropylidenedio
xypregna-1,4-diene-3,20-dione,
6.alpha.-fluoro-9.alpha.,11.beta.-dichloro-16.alpha.,17.alpha.-isopropylide
nedioxy-21-hydroxypregna-1,4-diene-3,20-dione,
6.alpha.,9.alpha.-difluoro-11.beta.,21-dihydroxy-16.alpha.-methyl-17.alpha.
-valeroxypregna-1,4-diene-3,20-dione,
6.alpha.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-16.alpha.-methy
lpregna-1,4-diene-3,20-dione,
6.alpha.,7.alpha.-difluoromethylene-11.beta.,17.alpha.,21-trihydroxypregn-4
-ene-3,20-dione,
6.alpha.-fluoro-11.beta.,21-dihydroxy-16.alpha.-methylpregna-1,4-diene-3,20
-dione,
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropylid
enedioxy-21-chloropregna-1,4-diene-3,20-dione,
9.alpha.,11.beta.-dichloro-6.alpha.,21-difluoro-16.alpha.,17.alpha.-isoprop
ylidenedioxypregna-1,4-diene-3,20-dione, and
9.alpha.,11.beta.,21-trichloro-6.alpha.-fluoro-16.alpha.,17.alpha.-isopropy
lidenedioxypregna-1,4-diene-3,20-dione.
EXAMPLE 5
Repeating the procedure of Example 1 with
a. from 5 to 40 percent of a fatty alcohol having from 16 to 24
carbons, e.g. cetyl alcohol, stearyl alcohol, behenyl alcohol,
etc.;
b. from 1 to 40 percent of propylene carbonate;
c. from 25 to 85 percent glycol cosolvent such as 1,2-propanediol,
1,3-propanediol, polyethylene glycol (M.W. 100 to 800), dipropylene
glycol, etc., the weight ratio of the glycol solvent to propylene
carbonate being at least 1:2;
d. a stabilizing quantity of a surfactant such as sorbitan
monooleate; and
e. from 0 to 15 percent compatible plasticizer, e.g., carboxy vinyl
polymer (Carbopol) yields an improved medicament base according to
this invention.
EXAMPLE 6
Repeating the procedure of Example 4 with the ingredients of
Example 5 yields improved compositions for topical treatment of
inflammation according to this invention.
* * * * *