U.S. patent application number 14/294764 was filed with the patent office on 2015-07-30 for corticosteroid compositions.
The applicant listed for this patent is TOLMAR, Inc.. Invention is credited to Robert Lathrop, David Wade Osborne.
Application Number | 20150209429 14/294764 |
Document ID | / |
Family ID | 51985810 |
Filed Date | 2015-07-30 |
United States Patent
Application |
20150209429 |
Kind Code |
A9 |
Lathrop; Robert ; et
al. |
July 30, 2015 |
CORTICOSTEROID COMPOSITIONS
Abstract
The present disclosure generally relates to pharmaceutical
corticosteroid compositions, and methods of making the same.
Inventors: |
Lathrop; Robert; (Fort
Collins, CO) ; Osborne; David Wade; (Fort Collins,
CO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
TOLMAR, Inc. |
Fort Collins |
CO |
US |
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Prior
Publication: |
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Document Identifier |
Publication Date |
|
US 20140357607 A1 |
December 4, 2014 |
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Family ID: |
51985810 |
Appl. No.: |
14/294764 |
Filed: |
June 3, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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PCT/US14/40560 |
Jun 2, 2014 |
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14294764 |
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61830531 |
Jun 3, 2013 |
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Current U.S.
Class: |
514/172 ;
514/174; 514/179 |
Current CPC
Class: |
A61K 47/10 20130101;
A61K 9/06 20130101; A61K 31/567 20130101; A61K 47/14 20130101; A61K
9/107 20130101; A61K 31/573 20130101; A61K 31/56 20130101; A61K
31/58 20130101; A61K 9/0014 20130101 |
International
Class: |
A61K 47/14 20060101
A61K047/14; A61K 31/573 20060101 A61K031/573; A61K 31/58 20060101
A61K031/58; A61K 31/567 20060101 A61K031/567 |
Claims
1. A pharmaceutical composition comprising: at least one fatty acid
ester and at least one corticosteroid.
2. The pharmaceutical composition of claim 1, wherein the fatty
acid ester is selected from a propylene glycol ester and a glyceryl
ester.
3. The pharmaceutical composition of claim 1, wherein the fatty
acid ester is a propylene glycol monoester.
4. The pharmaceutical composition of claim 1, wherein the fatty
acid ester is selected from propylene glycol monoenthantate,
propylene glycol dienthantate, propylene glycol monocaprylate,
propylene glycol dicaprylate, propylene glycol monopelargonate,
propylene glycol dipelargonate, propylene glycol monocaprate,
propylene glycol dicaprate, propylene glycol monoundecylate,
propylene glycol diundecylate, propylene glycol monolaurate,
propylene glycol dilaurate, propylene glycol monotridecylate,
propylene glycol ditridecylate, propylene glycol monomyristate,
propylene glycol dimyristate, propylene glycol monopalmitolate,
propylene glycol dipalmitolate, propylene glycol monoolate,
propylene glycol dioolate, propylene glycol monolinolate, propylene
glocyol dilinoate, propylene glycol monolinolenate, and propylene
glycol dilinolenate.
5. The pharmaceutical composition of claim 1, wherein the fatty
acid ester is selected from propylene glycol monocaprylate,
propylene glycol monocaprate, and propylene glycol monolaurate.
6. The pharmaceutical composition of claim 1, wherein the fatty
acid ester is propylene glycol monocaprylate.
7. The pharmaceutical composition of claim 1, wherein the fatty
acid ester is propylene glycol monolaurate.
8. The pharmaceutical composition of claim 1, wherein the fatty
acid ester is selected from glyceryl monoenthantate, glyceryl
dienthantate, glyceryl monocaprylate, glyceryl dicaprylate,
glyceryl monopelargonate, glyceryl dipelargonate, glyceryl
monocaprate, glyceryl dicaprate, glyceryl monoundecylate, glyceryl
diundecylate, glyceryl monolaurate, glyceryl dilaurate, glyceryl
monotridecylate, glyceryl ditridecylate, glyceryl monomyristate,
glyceryl dimyristate, glyceryl monopalmitolate, glyceryl
dipalmitolate, glyceryl monoolate, glyceryl dioolate, glyceryl
monolinolate, glyceryl dilinolate, glyceryl monolinolenate, and
glyceryl dilinolenate.
9. The pharmaceutical composition of claim 1, further comprising at
least one solvent selected from alcohol, castor oil,
3-[(3-cholamidopropyl)dimethylammonio]-1-propane-sulfonate,
cholesterol NF, cholic acid, citric acid, 3-cyclohexene-1-methanol,
dehydrated alcohol, deoxycholic acid, diethylene glycol monoethyl
ether, diisopropanolamine (1:9), diisopropyl adipate,
.alpha.4-dimethyl-a-(4-methyl-3-pentenyl), ethoxydiglycol,
ethoxylated alcohol, ethyl alcohol, ethylene glycol, fatty alcohol
citrate, glycerin, 1-hexadecanol, 1,2,6-hexanetriol, hexylene
glycol, hydroxypropyl betacyclodextrin, isopropyl alcohol,
isopropyl myristate, isopropyl palmitate, lecithin, mineral oil,
2-methyl-1,3-propanediol, oleyl alcohol, phosphoric acid,
polyethylene glycols, polyethylene glycol 300, polyethylene glycol
400, polyethylene glycol 1450, polyethylene glycol 7000,
polyethylene glycol 8000, polyethylene glycol 1000 monocetyl ether,
polyethylene glycol monostearate, polyoxyl 20 cetostearyl ether,
polyoxypropylene 15-stearyl ether, polysorbates, polysorbate 20,
polysorbate 40, polysorbate 60, polysorbate 80, potassium
hydroxide, propylene carbonate, propylene glycol, propylethylene
glycol 4, neopentyl alcohol, SD alcohol 40, sodium lauryl sulfate,
sorbitan monostearate, sorbitan stearate, taurodeoxycholic acid,
triacetin, triethylene glycol, trimethylene glycol, vitamin E,
vitamin E acetate, and water.
10. The pharmaceutical composition of claim 1, further comprising
at least one solvent selected from ethoxydiglycol, diethylene
glycol monoethyl ether, hexylene glycol, propylene glycol, and
water.
11. The pharmaceutical composition of claim 1, wherein the
corticosteroid is selected from aclovate, alclometasone
dipropionate, amcinafel, amcinafide, amcinonide, aristocort A,
augmented betamethasone dipropionate, beclamethasone,
beclopmethasone dipropionate, betamethasone, betamethasone
benzoate, betamethasone-17-benzoate, betamethasone dipropionate,
betamethasone sodium phosphate and acetate, betamethasone valerate,
betamethasone-17-valerate, chloroprednisone, clobetasol propionate,
clobetasone propionate, clocortelone, cordran, corticosterone,
cortisol, cortisol acetate, cortisol cypionate, cortisol sodium
phosphate, cortisol sodium succinate, cortisone, cortisone acetate,
cortodoxone, cyclocort, deflazacort, defluprednate, descinolone,
desonide, desowen, desoximetasone, desoxycorticosterone acetate,
desoxycorticosterone pivalate, 11-desoxycortisol, dexamethasone,
dexamethasone acetate, dexamethasone sodium phosphate,
dichlorisone, diflorasone diacetate, dihydroxycortisone, diprolen,
diprolene, diprosone, esters of betamethasone, florone,
flucetonide, flucloronide, flucortolone, fludrocortisone,
fludrocortisone acetate, flumethalone, flumethasone, flumethasone
pivalate, flunisolide, fluocinolone acetonide, fluocinolone
acetonide acetate, fluocinonide, fluorametholone, fluorocortisone,
fluperolone, fluprednisolone, flurandrenolide, fluroandrenolone
acetonide, fluticasone propionate, fuprednisolone, halcinonide,
halobetasol propionate, halog, hydrocortamate, hydrocortisone,
hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone
valerate, hydrocortisone-17-valerate, kenalog, lidex, locold,
locorten, maxiflor, medrysone, meprednisone, methylprednisolone,
6.alpha.-methylprednisolone, methylprednisolone acetate,
methylprednisolone sodium succinate, methylprednisone, mometasone
furoate, paramethasone, paramethasone acetate, prednidone,
prednisone, prednisolone, prednisolone acetate, prednisolone sodium
phosphate, prednisolone sodium succinate, prednisolone tebutate,
prednisone, psorcon, synalar, temovate, tetrahydrocortisol,
topicort, topicort LP, triamcinolone, triamcinolone acetonide,
triamcinolone diacetate, triamcinolone hexacotonide, tridesilone,
valisone, and westcort.
12. The pharmaceutical composition of claim 1, wherein the
corticosteroid is selected from betamethasone dipropionate,
clobetasol propionate, hydrocortisone, hydrocortisone acetate, and
triamcinolone acetonide.
13. The pharmaceutical composition of claim 1, wherein the
corticosteroid is hydrocortisone or hydrocortisone acetate.
14. The pharmaceutical composition of claim 1, wherein the
corticosteroid is dissolved at 0.25-4.5% w/w.
15. The pharmaceutical composition of claim 1, wherein the
composition is a topical formulation.
16. The pharmaceutical composition of claim 15, wherein the topical
formulation is selected from a cream, gel, liquid, and
ointment.
17. The pharmaceutical composition of claim 15, further comprising
at least one humectant selected from ethylene glycol, fructose,
glycerol, lactic acid, polyethylene glycol, propylene glycol,
sorbitan, sorbitol, tetraethylene glycol, triethylene glycol, and
vitamin B.
18. The pharmaceutical composition of claim 17, wherein the
humectant is lactic acid.
19. A method of making a pharmaceutical composition comprising:
dissolving at least one corticosteroid in a fatty acid ester.
20-33. (canceled)
34. The pharmaceutical composition of claim 1, further comprising
at least one solvent selected from ethoxydiglycol, propylene
glycol, and combinations thereof.
35. The method of claim 19, further comprising at least one solvent
selected from ethoxydiglycol, propylene glycol, and combinations
thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] The present application claims priority to U.S. Provisional
Patent Application No. 61/830,531, which was filed on Jun. 3, 2013,
and is entitled Corticosteroid Compositions. The contents of the
above-mentioned patent application is hereby incorporated by
reference in its entirety.
TECHNICAL FIELD
[0002] The present disclosure relates to pharmaceutical
corticosteroid compositions, and methods of making the same.
BACKGROUND
[0003] Corticosteroids have limited solubility in many
pharmaceutically acceptable solvents and are often prepared as
suspensions at concentrations above their solubility limits.
Suspending a steroid in a topical product can reduce
bioavailability and, upon storage, lead to changes in suspended
drug particle size, which in turn can cause highly variable
bioavailability. Thus, pharmaceutically suitable solvents and
systems having improved dissolution of topical steroids and/or that
can completely dissolve steroids at typical commercial product
concentration levels are needed.
[0004] The information included in this Background section of the
specification is included for technical reference purposes only and
is not to be regarded as subject matter by which the scope of the
invention as defined in the claims is to be bound.
SUMMARY
[0005] The present disclosure is directed to pharmaceutical
compositions comprising at least one fatty acid ester and at least
one corticosteroid. The fatty acid ester is a propylene glycol
monoester or diester such as propylene glycol monocaprylate or
propylene glycol monolaurate, or a glyceryl monoester or a diester.
The pharmaceutical composition can also include a solvent such as
diethylene glycol monoethyl ether, hexylene glycol, propylene
glycol, or water.
[0006] A method of making a pharmaceutical composition includes
dissolving at least one corticosteroid in at least one fatty acid
ester.
[0007] This Summary is provided to introduce a selection of
concepts in a simplified form that are further described below in
the Detailed Description. This Summary is not intended to identify
key features or essential features of the claimed subject matter,
nor is it intended to be used to limit the scope of the claimed
subject matter.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1 depicts the solubility of hydrocortisone in mixtures
of propylene glycol and propylene glycol monocaprylate, or of
propylene glycol, propylene glycol monocaprylate, and
ethoxydiglycol.
[0009] FIG. 2 depicts the solubility of hydrocortisone in mixtures
of propylene glycol and propylene glycol monolaurate.
[0010] FIG. 3 depicts the solubility of hydrocortisone in mixtures
of ethoxydiglycol and propylene glycol monocaprylate.
[0011] FIG. 4 depicts the solubility of triamcinolone acetonide in
mixtures of propylene glycol and propylene glycol monocaprylate, or
of propylene glycol, propylene glycol monocaprylate, and
ethoxydiglycol.
DETAILED DESCRIPTION
[0012] The present disclosure provides pharmaceutical
corticosteroid compositions and methods of making the same. The
pharmaceutical compositions comprise corticosteroids and fatty acid
esters. In certain aspects, the fatty acid esters, optionally in
combination with other components, dissolve corticosteroids at
surprisingly high concentrations compared to previously known
solvents, compositions, and combinations. In various aspects, the
solubility of corticosteroids unexpectedly increases when they are
combined with fatty acid esters and optionally other
components.
[0013] The compositions and methods allow for improved
bioavailability, both in terms of increased bioavailability and
more consistent delivered drug levels, more reliable processing,
and reduction or elimination of drug particle ripening (i.e.
growing particle size) upon storage, all as compared to known
compositions and methods.
[0014] Corticosteroids
[0015] The presently disclosed pharmaceutical compositions comprise
one or more corticosteroids.
[0016] Examples of corticosteroids include, but are not limited to,
aclovate, alclometasone dipropionate, amcinafel, amcinafide,
amcinonide, aristocort A, augmented betamethasone dipropionate,
beclamethasone, beclopmethasone dipropionate, betamethasone,
betamethasone benzoate, betamethasone-17-benzoate, betamethasone
dipropionate, betamethasone sodium phosphate and acetate,
betamethasone valerate, betamethasone-17-valerate,
chloroprednisone, clobetasol propionate, clobetasone propionate,
clocortelone, cordran, corticosterone, cortisol, cortisol acetate,
cortisol cypionate, cortisol sodium phosphate, cortisol sodium
succinate, cortisone, cortisone acetate, cortodoxone, cyclocort,
deflazacort, defluprednate, descinolone, desonide, desowen,
desoximetasone, desoxycorticosterone acetate, desoxycorticosterone
pivalate, 11-desoxycortisol, dexamethasone, dexamethasone acetate,
dexamethasone sodium phosphate, dichlorisone, diflorasone
diacetate, dihydroxycortisone, diprolen, diprolene, diprosone,
esters of betamethasone, florone, flucetonide, flucloronide,
flucortolone, fludrocortisone, fludrocortisone acetate,
flumethalone, flumethasone, flumethasone pivalate, flunisolide,
fluocinolone acetonide, fluocinolone acetonide acetate,
fluocinonide, fluorametholone, fluorocortisone, fluperolone,
fluprednisolone, flurandrenolide, fluoroandrenolone acetonide,
fluticasone propionate, fuprednisolone, halcinonide, halobetasol
propionate, halog, hydrocortamate, hydrocortisone, hydrocortisone
acetate, hydrocortisone butyrate, hydrocortisone valerate,
hydrocortisone-17-valerate, kenalog, lidex, locold, locorten,
maxiflor, medrysone, meprednisone, methylprednisolone,
6.alpha.-methylprednisolone, methylprednisolone acetate,
methylprednisolone sodium succinate, methylprednisone, mometasone
furoate, paramethasone, paramethasone acetate, prednidone,
prednisone, prednisolone, prednisolone acetate, prednisolone sodium
phosphate, prednisolone sodium succinate, prednisolone tebutate,
prednisone, psorcon, synalar, temovate, tetrahydrocortisol,
topicort, topicort LP, triamcinolone, triamcinolone acetonide,
triamcinolone diacetate, triamcinolone hexacotonide, tridesilone,
valisone, and westcort. It will be understood that any single
corticosteroid can be used separately, or in combination with any
other corticosteroid or corticosteroids.
[0017] In one aspect, the corticosteroid is betamethasone
dipropionate. In another aspect, the corticosteroid is clobetasol
propionate. In another aspect, the corticosteroid is fluticasone
propionate. In still another aspect, the corticosteroid is
hydrocortisone. In still another aspect, the corticosteroid is
hydrocortisone butyrate. In yet another aspect, the corticosteroid
is triamcinolone acetonide.
[0018] Fatty Acid Esters
[0019] The presently disclosed pharmaceutical compositions can
comprise one or more fatty acid esters.
[0020] Fatty acid esters are produced from combinations of an
alcohol and one or more fatty acids according to the following
general formula (I):
##STR00001##
[0021] A hydroxyl oxygen of the alcohol forms a bond with a
carboxyl carbon of the fatty acid in a reaction that releases water
and creates an ester bond between the alcohol and fatty acid.
[0022] The fatty acid of a fatty acid ester can be saturated or
unsaturated. A saturated fatty acid of a fatty acid ester can
include, but is not limited to, ethantic acid (7 carbon atoms),
caprylic acid (8 carbon atoms), pelargonic acid (9 carbon atoms),
capric acid (10 carbon atoms), undecylic acid (11 carbon atoms),
lauric acid (12 carbon atoms), tridecylic acid (13 carbon atoms),
and myristic acid (14 carbon atoms). An unsaturated fatty acid of a
fatty acid ester can include, but is not limited to, palmitoleic
acid (16:1(.DELTA..sup.9)), oleic acid (18:1(.DELTA..sup.9)),
linoleic acid (18:2(.DELTA..sup.9,12)), and linolenic acid
(18:3(.DELTA..sup.9,12,15)).
[0023] Fatty acid esters can be liquid or solid at room
temperature. Their melting temperature is based at least in part on
the carbon chain length and level of saturation of the component
fatty acid or acids. The melting points of long-chain fatty acids
and the corresponding fatty acid esters tend to decrease with the
introduction of double bonds into the chain.
[0024] Propylene Glycol Esters
[0025] In one embodiment, a fatty acid ester is a propylene glycol
ester.
[0026] Propylene glycol esters are esters produced from
combinations of propylene glycol and one fatty acid (a propylene
glycol monoester) or two fatty acids (a propylene glycol diester).
The fatty acid moieties in a propylene glycol diester can be the
same or different. In a propylene glycol monoester, a fatty acid
substituted at one hydroxyl group of propylene glycol creates one
ester linkage, as shown in the following formula (III). In a
propylene glycol diester, two fatty acids substituted at both
hydroxyl groups of propylene glycol create two ester linkages, as
shown in the following formula (IV):
##STR00002##
[0027] The fatty acid moieties in a propylene glycol ester include,
but are not limited to, enthantic acid, caprylic acid, pelargonic
acid, capric acid, undecylic acid, lauric acid, tridecylic acid,
myristic acid, palmitoleic acid, oleic acid, linoleic acid, and
linolenic acid.
[0028] Examples of propylene glycol monoesteres include, but are
not limited to, propylene glycol monoenthantate, propylene glycol
monocaprylate, propylene glycol monopelargonate, propylene glycol
monocaprate, propylene glycol monoundecylate, propylene glycol
monolaurate, propylene glycol monotridecylate, propylene glycol
monomyristate, propylene glycol monopalmitolate, propylene glycol
monolate, propylene glycol monolinolate, and propylene glycol
monolinolenate.
[0029] Examples of propylene glycol diesters include, but are not
limited to, propylene glycol dienthantate, propylene glycol
dicaprylate, propylene glycol dipelargonate, propylene glycol
dicaprate, propylene glycol diundecylate, propylene glycol
dilaurate, propylene glycol ditridecylate, propylene glycol
dimyristate, propylene glycol dipalmitolate, propylene glycol
dioolate, propylene glycol dilinolate, and propylene glycol
dilinolenate. Other examples of propylene glycol diesters include a
diester of any two different fatty acids such as propylene glycol
diester of caprylic acid and capric acid, a propylene glycol
diester of caprylic acid and lauric acid, and a propylene glycol
diester of capric acid and lauric acids.
[0030] In one embodiment, a propylene glycol ester is propylene
glycol monocaprylate. In another embodiment, a propylene glycol
ester is propylene glycol monolaurate.
[0031] Commercially available propylene glycol fatty acid esters
include, but are not limited to, propylene glycol monocaprylate
(Capmul 908P, Capmul PG-8 NF, Abitec), propylene glycol dicaprylate
(Nikkol Sefsol 228, Nikko), propylene glycol dipelargonate,
propylene glycol caprylate caprate (LABRAFAC PG, Gattefosse),
propylene glycol dicaprate (Captex 100, Abitec), propylene glycol
dicaprylate dicaprate (Captex 200, Abitec), propylene glycol
monolaurate (Capmul PG-12 EP/NF, Abitec), propylene glycol
dilaurate (Capmul PG-2L EP/NF, Abitec), and propylene glycol
myristate.
[0032] Glyceryl Esters
[0033] In one embodiment, a fatty acid ester is a glyceryl
ester.
[0034] Glyceryl esters are esters produced from combinations of
glycerol and one fatty acid (a glyceryl monoester, or
monoacylglycerol), two fatty acids (a glyceryl diester, or
diacylglycerol), or three fatty acids (a glyceryl triester, or
triacylglycerol). The fatty acids moieties in a glyceryl diester or
triester can be the same or different. A fatty acid substituted at
one hydroxyl group of glycerol creates one ester linkage, as shown
in formula (VI) below. Fatty acids substituted at two hydroxyl
groups of glycerol create two ester linkages, as shown in the
following formula (VII), and fatty acids substituted at the three
hydroxyl groups of glycerol create three ester linkages, as shown
in the following formula (VIII):
##STR00003##
[0035] The fatty acid moieties in a glyceryl ester include, but are
not limited to, ethantic acid, caprylic acid, pelargonic acid,
capric acid, undecylic acid, lauric acid, tridecylic acid, myristic
acid, palmitoleic acid, oleic acid, linoleic acid, and linolenic
acid.
[0036] Examples of glyceryl monoesters include, but are not limited
to, glyceryl monoethantate, glyceryl monocaprylate, glyceryl
monopelargonate, glyceryl monocaprate, glyceryl monoundecylate,
glyceryl monolaurate, glyceryl monotridecylate, glyceryl
monomyristate, glyceryl monopalmitolate, glyceryl monoolate,
glyceryl monolinolate, and glyceryl monolinolenate.
[0037] Examples of glyceryl diesters include, but are not limited
to, glyceryl dienthantate, glyceryl dicaprylate, glyceryl
dipelargonate, glyceryl dicaprate, glyceryl diundecylate, glyceryl
dilaurate, glyceryl ditridecylate, glyceryl dimyristate, glyceryl
dipalmitolate, glyceryl dioolate, glyceryl dilinolate, and glyceryl
dilinolenate. Other examples of glyceryl diesters include a diester
of any two different fatty acids such as a glyceryl diester of
caprylic acid and capric acid, a glyceryl diester of caprylic acid
and lauric acid, and a glyceryl diester of capric acid and lauric
acids.
[0038] Examples of glyceryl triesters include, but are not limited
to, glyceryl trienthantate, glyceryl tricaprylate, glyceryl
tripelargonate, glyceryl tricaprate, glyceryl triundecylate,
glyceryl trilaurate, glyceryl tritridecylate, glyceryl
trimyristate, glyceryl tripalmitolate, glyceryl trioolate, glyceryl
trilinolate, glyceryl trilinolenate. Other examples of glyceryl
triesters include a trimester of any combination of fatty acids
such as a glyceryl triester of caprylic acid, capric acid and
lauric acid.
[0039] Commercially available glyceryl fatty acid esters include,
but are not limited to, glyceryl monocaprylate (Capmul 708G, Capmul
MCM C8, Capmul MCM C8 EP, Abitec), glyceryl monocaprate (Capmul MCM
C10, Abitec), and glyceryl caprylate/caprate (Capmul MCM NF, Campul
MCM EP, Abitec).
[0040] Composition Solvent Components
[0041] A pharmaceutical composition can comprise one or more
components that can serve as corticosteroid solvents. In one
embodiment, a fatty acid ester, optionally in combination with one
or more additional fatty acid esters, serves as a corticosteroid
solvent. In another embodiment, a fatty acid ester, optionally in
combination with one or more pharmaceutically acceptable solvents,
serves as corticosteroid solvent. In another embodiment, a fatty
acid ester, optionally in combination with one or more additional
fatty acid esters and one or more pharmaceutically acceptable
solvents, serves as corticosteroid solvent.
[0042] A fatty acid ester in combination with one or more
additional fatty acid esters includes, but is not limited to, two
or more propylene glycol esters; two or more propylene glycol
monoesters; two or more propylene glycol diesters; and one or more
propylene glycol monoesters with one or more propylene glycol
diesters.
[0043] Other fatty acid ester combinations include, but are not
limited to, two or more glyceryl esters; two or more glyceryl
monoesters; two or more glyceryl diesters; two or more glyceryl
triesters; one or more glyceryl monoesters with one or more
glyceryl diesters; one or more glyceryl diesters with one or more
glyceryl triesters; one or more glyceryl monoesters with one or
more glyceryl triesters; and one or more glyceryl monoesters with
one or more glyceryl diesters and with one or more glyceryl
triesters.
[0044] Further fatty acid ester combinations include, but are not
limited to, propylene glycol monocaprylate and propylene glycol
dicaprylate; propylene glycol monocaprylate and propylene glycol
monocaprate; propylene glycol monocaprylate and propylene glycol
dicaprate; propylene glycol monocaprylate and glyeryl
monocaprylate; propylene glycol monocaprylate and glyeryl
dicaprylate; propylene glycol monocaprylate and glyceryl
monocaprate; propylene glycol monocaprylate and glyceryl dicaprate;
propylene glycol monocaprylate and propylene glycol monolaurate;
propylene glycol monocaprylate and propylene glycol dilaurate;
propylene glycol monocaprylate and glyceryl monolaurate; propylene
glycol monocaprylate and glyceryl dilaurate; propylene glycol
dicaprylate and propylene glycol monocaprate; propylene glycol
dicaprylate and propylene glycol dicaprate; propylene glycol
dicaprylate and glyeryl monocaprylate; propylene glycol dicaprylate
and glyeryl dicaprylate; propylene glycol dicaprylate and glyceryl
monocaprate; propylene glycol dicaprylate and glyceryl dicaprate;
propylene glycol dicaprylate and propylene glycol monolaurate;
propylene glycol dicaprylate and propylene glycol dilaurate;
propylene glycol dicaprylate and glyceryl monolaurate; and
propylene glycol dicaprylate and glyceryl dilaurate.
[0045] Still further fatty acid ester combinations include, but are
not limited to, propylene glycol monocaprate and propylene glycol
dicaprylate; propylene glycol monocaprate and propylene glycol
dicaprate; propylene glycol monocaprate and glyeryl monocaprylate;
propylene glycol monocaprate and glyeryl dicaprylate; propylene
glycol monocaprate and glyceryl monocaprate; propylene glycol
monocaprate and glyceryl dicaprate; propylene glycol monocaprate
and propylene glycol monolaurate; propylene glycol monocaprate and
propylene glycol dilaurate; propylene glycol monocaprate and
glyceryl monolaurate; propylene glycol monocaprate and glyceryl
dilaurate; propylene glycol dicaprate and propylene glycol
monocaprate; propylene glycol dicaprate and glyeryl monocaprylate;
propylene glycol dicaprate and glyeryl dicaprylate; propylene
glycol dicaprate and glyceryl monocaprate; propylene glycol
dicaprate and glyceryl dicaprate; propylene glycol dicaprate and
propylene glycol monolaurate; propylene glycol dicaprate and
propylene glycol dilaurate; propylene glycol dicaprate and glyceryl
monolaurate; and propylene glycol dicaprate and glyceryl
dilaurate.
[0046] When a fatty acid ester is optionally combined with one or
more pharmaceutically acceptable solvents, the one or more
pharmaceutically acceptable solvents can be present in any
combination. Examples of pharmaceutically acceptable solvents
include, but are not limited to, alcohol, castor oil,
3-[(3-cholamidopropyl)dimethylammonio]-1-propane-sulfonate,
cholesterol NF, cholic acid, citric acid, 3-cyclohexene-1-methanol,
dehydrated alcohol, deoxycholic acid, diethylene glycol monoethyl
ether, diisopropanolamine (1:9), diisopropyl adipate,
.alpha.4-dimethyl-a-(4-methyl-3-pentenyl), ethoxydiglycol,
ethoxylated alcohol, ethyl alcohol, ethylene glycol, fatty alcohol
citrate, glycerin, 1-hexadecanol, 1,2,6-hexanetriol, hexylene
glycol, hydroxypropyl betacyclodextrin, isopropyl alcohol,
isopropyl myristate, isopropyl palmitate, lecithin, mineral oil,
2-methyl-1,3-propanediol, oleyl alcohol, phosphoric acid,
polyethylene glycols, polyethylene glycol 300, polyethylene glycol
400, polyethylene glycol 1450, polyethylene glycol 7000,
polyethylene glycol 8000, polyethylene glycol 1000 monocetyl ether,
polyethylene glycol monostearate, polyoxyl 20 cetostearyl ether,
polyoxypropylene 15-stearyl ether, polysorbates, polysorbate 20,
polysorbate 40, polysorbate 60, polysorbate 80, potassium
hydroxide, propylene carbonate, propylene glycol, propylethylene
glycol 4, neopentyl alcohol, SD alcohol 40, sodium lauryl sulfate,
sorbitan monostearate, sorbitan stearate, taurodeoxycholic acid,
triacetin, triethylene glycol, trimethylene glycol, vitamin E,
vitamin E acetate, and water.
[0047] In one embodiment, the one or more pharmaceutically
acceptable solvents are selected from diethylene glycol monoethyl
ether, hexylene glycol, propylene glycol, and water. In one
embodiment, the pharmaceutically acceptable solvent is diethylene
glycol monoethyl ether. In another embodiment, the pharmaceutically
acceptable solvent is hexylene glycol. In another embodiment, the
pharmaceutically acceptable solvent is propylene glycol. In another
embodiment, the pharmaceutically acceptable solvent is water. In
another embodiment, the one or more pharmaceutically acceptable
solvents may be selected from benzyl alcohol, glycerin, dimethyl
isosorbide, and propylene carbonate. In certain embodiments, the
pharmaceutically acceptable solvent is benzyl alcohol. In certain
embodiments, the pharmaceutically acceptable solvent is glycerin.
In certain embodiments, the pharmaceutically acceptable solvent is
isosorbide. In certain embodiments, the pharmaceutically acceptable
solvent is propylene carbonate.
[0048] The one or more components that can serve as corticosteroid
solvents can be used with any corticosteroid. The fatty acid esters
that can serve as corticosteroid solvents can be used in any
application for which a pharmaceutically acceptable solvent is
used.
[0049] Solubility of Corticosteroids
[0050] A. Solubility in Fatty Acid Esters
[0051] Corticosteroids can partially or completely dissolve in the
presently disclosed fatty acid esters. Corticosteroids can be
soluble in a fatty acid ester at any percent (w/w). In one
embodiment, a corticosteroid is soluble in a fatty acid ester at
0.25% w/w to 4.5% w/w. In one embodiment, a corticosteroid is
soluble in a fatty acid ester at more than 0.25% w/w. In another
embodiment, a corticosteroid can be soluble at more than 0.50% w/w.
In another embodiment, a corticosteroid can be soluble at more than
0.75% w/w. In still another embodiment, a corticosteroid can be
soluble at more than 1.0% w/w. In yet another embodiment, a
corticosteroid can be soluble at more than 2.0% w/w. In a further
embodiment, a corticosteroid can be soluble at more than 3.0% w/w.
In a still further embodiment, a corticosteroid can be soluble at
more than 4.0% w/w.
[0052] In one embodiment, a corticosteroid can be soluble in a
fatty acid ester at less than 5.0% w/w. In another embodiment, a
corticosteroid can be soluble at less than 4.0% w/w. In another
embodiment, a corticosteroid can be soluble at less than 3.0% w/w.
In still another embodiment, a corticosteroid can be soluble at
less than 2.0% w/w. In yet another embodiment, a corticosteroid can
be soluble at less than 1.0% w/w. In a further embodiment, a
corticosteroid can be soluble at less than 0.75% w/w. In a still
further embodiment, a corticosteroid can be soluble at less than
0.5% w/w.
[0053] It is unexpected that corticosteroids can be more soluble in
a fatty acid ester than in a pharmaceutically acceptable solvent
such as isopropyl myrsitate. As depicted in Table 1 and described
in Example 1, examples of corticosteroids that are more soluble in
a fatty acid ester, such as propylene glycol monocaprylate, than in
a pharmaceutically acceptable solvent, such as isopropyl myrsitate,
include, but are not limited to, betamethasone dipropionate,
clobetasol propionate, fluticasone propionate, hydrocortisone,
hydrocortisone butyrate, and triamcinolone acetonide.
[0054] A corticosteroid can be any number of times more soluble in
a fatty acid ester than in a pharmaceutically acceptable solvent
such as isopropyl myristate. In one embodiment, a corticosteroid is
5 or more times more soluble in a fatty acid ester than in
isopropyl myristate. In another embodiment, a corticosteroid is 10
or more times more soluble in a fatty acid ester than in isopropyl
myristate. In another embodiment, a corticosteroid is 15 or more
times more soluble in a fatty acid ester than in isopropyl
myristate. In yet another embodiment, a corticosteroid is 20 or
more times more soluble in a fatty acid ester than in isopropyl
myristate. In still another embodiment, a corticosteroid is 25 or
more times more soluble in a fatty acid ester than in isopropyl
myristate. In a further embodiment, a corticosteroid is 30 or more
times more soluble in a fatty acid ester than in isopropyl
myristate.
[0055] In one embodiment, a corticosteroid is 30 or fewer times
more soluble in a fatty acid ester than in isopropyl myristate. In
another embodiment, a corticosteroid is 25 or fewer times more
soluble in a fatty acid ester than in isopropyl myristate. In
another embodiment, a corticosteroid is 20 or fewer times more
soluble in a fatty acid ester than in isopropyl myristate. In still
another embodiment, a corticosteroid is 15 or fewer times more
soluble in a fatty acid ester than in isopropyl myristate. In yet
another embodiment, a corticosteroid is 10 or fewer times more
soluble in a fatty acid ester than in isopropyl myristate.
[0056] Without being limited to any mechanism or mode of action,
fatty acid esters can act as solvents for corticosteroids due to
their water miscible and polar nature. Propylene glycol monoesters
can act as solvents for corticosteroids due to the polar
contribution of the free hydroxyl group on propylene glycol. The
close proximity of the free hydroxyl group to the ester bond
between the alcohol and the fatty acid can also contribute to the
solvent properties of propylene glycol monoesters. Further, the
ester bond alone can contribute to the solvent properties of any
propylene glycol ester. Glyceryl diesters and glyceryl monoesters
can act as solvents for corticosteroids due to the polar
contribution of the one or two, respectively, free hydroxyl groups
on glycerol. The close proximity of the free hydroxyl group or
groups to the ester bond or bonds between the alcohol and the fatty
acid can also contribute to the solvent properties of glyceryl
monoesters and diesters. Further, the ester bonds alone can
contribute to the solubilizing properties of any glyceryl
ester.
[0057] B. Solubility in Solvent Components
[0058] Corticosteroids can partially or completely dissolve in
composition components that can serve as corticosteroid
solvents.
[0059] Each corticosteroid has a given solubility in a given
solvent. When two or more solvents are combined, it is common and
expected that the two solvents will act independently of each
other. For example, it is common and expected that the solubility
of a corticosteroid in a combination solvent consisting of two
solvents in equal proportion will be approximately the average of
the solubility in each solvent alone. When two or more solvents are
combined, it is also common and expected that the poorer solvent
will have a diluting or interfering effect on the solvent
properties of the better solvent when the two solvents are
combined. For example, it is common and expected that a
corticosteroid will be less soluble in a combination solvent
consisting of two solvents in equal proportion than the average of
the solubility in each solvent alone.
[0060] It is unexpected that a corticosteroid is more soluble in a
mixture of solvent components than in each component alone. As
depicted in FIG. 1 and described in Example 2, the solubility of
hydrocortisone in each of a 50:50, 75:25, and 90:10 propylene
glycol:propylene glycol monocaprylate solvent mixture is greater
than in propylene glycol alone. The solubility of hydrocortisone in
each of a 12:4:8, 12:6:6, 12:8:4, 12:9:3, and 12:12:0
ethoxydiglycol:propylene glycol:propylene glycol monocaprylate
solvent mixture is greater than in propylene glycol alone. These
results demonstrate the higher solubility of hydrocortisone in a
combination of propylene glycol and propylene glycol monocaprylate;
and in a combination of ethoxydiglycol, propylene glycol, and
propylene glycol monocaprylate than expected.
[0061] Further examples of the unexpected solubility of a
corticosteroid in a mixture of solvent components are provided in
FIG. 2 and Example 3. The solubility of hydrocortisone in both a
50:50 and a 75:25 propylene glycol:propylene glycol monolaurate
solvent mixture were higher than in propylene glycol alone. These
results demonstrate the higher solubility of hydrocortisone in a
combination of propylene glycol and propylene glycol monolaurate
than expected
[0062] Still further examples of the unexpected solubility of a
corticosteroid in a mixture of solvent components are provided in
FIG. 4 and Example 5. The solubility of triamcinolone acetonide in
each of a 25:75, 50:50, 75:25, and 90:10 propylene glycol:propylene
glycol monocaprylate solvent mixture is greater than in propylene
glycol alone. As additional examples, the solubility of
hydrocortisone in each of a 12:3:9, 12:6:6, 12:9:3, and 12:12:0
ethoxydiglycol:propylene glycol:propylene glycol monocaprylate
solvent mixture is greater than in propylene glycol alone. These
results demonstrate the higher solubility of triamcinolone
acetonide in a combination of propylene glycol and propylene glycol
monocaprylate; and in a combination of ethoxydiglycol, propylene
glycol, and propylene glycol monocaprylate than expected.
[0063] It is also unexpected that the solubility of a
corticosteroid in a given solvent improves upon the addition of
water to the solvent because water is known to be a poor
corticosteroid solvent. As described in Example 6 and Table 8, the
solubility of hydrocortisone in ethoxydiglycol with purified water
is greater than in ethoxydiglycol alone. Hydrocortisone is also
more soluble in propylene glycol monocaprylate with purified water
than in propylene glycol monocaprylate alone. Hydrocortisone is
also more soluble in an ethoxydiglycol:propylene glycol
monocaprylate:propylene glycol solvent mixture with purified water
than in the mixture alone.
[0064] A fatty acid ester can retain its solvent properties when
combined with one or more pharmaceutically acceptable solvents in a
mixture of solvent components. Combining a fatty acid ester with a
pharmaceutically acceptable solvent can improve the corticosteroid
solvent properties of the mixture compared to the pharmaceutically
acceptable solvent alone. Combining a mixture of a fatty acid ester
and a pharmaceutically acceptable solvent with another solvent,
such as another pharmaceutically acceptable solvent, can further
increase the solvent properties of the mixture compared to either
or both of the pharmaceutically acceptable solvents alone. The
pharmaceutically acceptable solvent can be diethylene glycol
monoethyl ether, hexylene glycol, propylene glycol, or water.
[0065] A fatty acid ester can be compatible with any excipient in a
formulation.
[0066] Formulations
[0067] The presently disclosed pharmaceutical compositions can be
provided in a formulation. The formulation can be an injectable
formulation. An injectable formulation can be a liquid that can be
injected into the skin, underlying tissue, or any other area of the
body. An injectable can be aqueous-based or solvent-based. An
injectable can comprise dissolved polymers/copolymers or liquid
polymers/copolymers such as polyglycolides, polylactides, and
polycaprolactones, as described in U.S. Pat. No. 8,187,640, which
is hereby expressly incorporated by reference in its entirety.
[0068] The formulation can be a topical formulation. For example,
the topical formulation can be in the form of a liquid, an
emulsion, a semisolid, or a colloidal dispersion, which are
described in Osborne, Pharmaceutical Technology 32(10), 66-74
(2008), and Buhse et. al., Int. J. Pharma. 295, 101-112 (2005),
which are hereby expressly incorporated by reference in their
entirety. Examples of topical formulations include, but are not
limited to, a cream, emulsion, foam, gel, liquid, lotion, mist,
ointment, paste, shampoo, shampoo suspension, solution, spray, and
suspension, which are described in Osborne, supra, and Buhse et.
al., supra.
[0069] A topical formulation can be selected based on numerous
factors including, but not limited to, the location to which the
formulation will be applied, the condition to be treated, the
desired corticosteroid potency, the desired corticosteroid
penetration, and the desired hydration provided by the
formulation.
[0070] In various aspects, the formulation is a cream. A cream can
be a viscous liquid or semisolid emulsion, and can comprise greater
than 20% water and volatiles and/or less than 50% hydrocarbons,
waxes, or polyethylene glycol. A cream is either an oil-in-water
cream with water as the continuous phase, or a water-in-oil cream
with oil as the continuous phase. A cream can contain an emulsifier
in addition to the oil phase and the water phase. The oil phase can
be comprised of petrolatum and a fatty alcohol such as cetyl or
stearyl alcohol. The aqueous phase can exceed the oil phase in
volume and can comprise a humectant. The emulsifier can be a
nonionic, anionic, cationic, or amphoteric surfactant. Various
specific embodiments of creams comprising one or more fatty acid
esters are described in Examples 7-10.
[0071] In various aspects, the formulation is a foam. A foam can be
a dispersion of gas within a liquid or solid. A foam for topical
application can be formed by packaging a pressurized gas with an
emulsion; upon expulsion from the container the gas is trapped
within the emulsion.
[0072] In various aspects, the formulation is a gel. A gel can be a
semisolid solution or colloidal dispersion that can contain
suspended particles. A gel can be solid at room temperature but
melt on the skin. A gel can comprise an aqueous or alcoholic
vehicle. A gel can also comprise a gelling agent, such as starch,
cellulose derivatives, carbomers, magnesium-aluminum silicates,
xanthan gum, colloidal silica, and aluminum or zinc soaps. The
gelling agent can cross-link to form a gel-like structure, which
can provide stiffness. Cross-linking can be pH-dependent. A gel can
also comprise a dispersing agent such as alcohol or glycerin to
help disperse components such as the gel-forming agent.
Alternatively, or additionally, components can be dispersed by
mechanical mixing or titration. Various specific embodiments of
gels comprising one or more fatty acid esters are described in
Examples 11 and 12.
[0073] In various aspects, the formulation is a lotion. A lotion
can be a liquid emulsion comprising an aqueous vehicle and more
than 50% water and volatiles. A lotion can exhibit Newtonian or
pseudoplastic flow behavior. When rubbed onto the skin, a lotion
can evaporate rapidly with a cooling sensation. A lotion can
comprise an agent to help an active pharmaceutical agent remain in
contact with the skin. Various specific embodiments of lotions
comprising one or more fatty acid esters are described in Examples
11 and 12.
[0074] In various aspects, the formulation is an ointment. An
ointment can be a semisolid suspension or emulsion, and can have a
medium to high viscosity. An ointment can comprise less than 20%
water and volatiles, and can comprise greater than 50%
hydrocarbons, waxes, or polyethylene glycol. An ointment can be
hydrating and an ointment can be occlusive. An ointment can not
evaporate or be absorbed when rubbed onto the skin. An ointment can
enhance the penetration of a corticosteroid into the skin. Various
specific embodiments of ointments comprising one or more fatty acid
esters are described in Examples 13 and 14.
[0075] In various aspects, the formulation is a paste. A paste can
be a semisold that contains a large proportion (i.e., 20-50%) of
solids finely dispersed in a fatty vehicle. A paste can adhere well
to the skin and form a protective layer.
[0076] In various aspects, the formulation is a shampoo. A shampoo
can be a liquid soap or detergent. A shampoo can be used to clean
the hair and scalp, and can be used as a vehicle for a
corticosteroid.
[0077] In various aspects, the formulation is a shampoo suspension.
A shampoo suspension can be a liquid soap or detergent comprising
one or more solid, insoluble substances dispersed in a liquid
vehicle. A shampoo suspension can be used to clean the hair and
scalp, and can be used as a vehicle for a corticosteroid.
[0078] In various aspects, the formulation is a solution. A
solution can be a clear, homogeneous liquid molecular dispersion of
at least one solute (solid, liquid, or gas) dissolved in a suitable
vehicle. The vehicle can comprise one or more miscible liquids. A
solution can comprise an aqueous component, an alcoholic component,
and/or a gelling agent.
[0079] In various aspects, the formulation is a suspension. A
suspension can be a two-phase liquid system comprising a solid
suspended in an aqueous or alcoholic liquid vehicle.
[0080] Components of Formulations
[0081] A. Fatty Acid Esters
[0082] A formulation can comprise a fatty acid ester, as described
above. In one embodiment, a formulation comprises a fatty acid
ester at 1% w/w to 40% w/w. In another embodiment, a formulation
comprises a fatty acid ester at 1% w/w to 30% w/w. In another
embodiment, a formulation comprises a fatty acid ester at 2% w/w to
20% w/w. In yet another embodiment, a formulation comprises a fatty
acid ester at 2% w/w to 12% w/w. In still another embodiment, a
formulation comprises a fatty acid ester at 3% w/w to 12% w/w. In a
further embodiment, a formulation comprises a fatty acid ester at
2% w/w to 10% w/w.
[0083] In one embodiment, a formulation comprises a fatty acid
ester at more than 1% w/w. In another embodiment, a formulation
comprises a fatty acid ester at more than 5% w/w. In another
embodiment, a formulation comprises a fatty acid ester at more than
10% w/w. In yet another embodiment, a formulation comprises a fatty
acid ester at more than 15% w/w. In still another embodiment, a
formulation comprises a fatty acid ester at more than 20% w/w. In a
further embodiment, a formulation comprises a fatty acid ester at
more than 30% w/w.
[0084] In one embodiment, a formulation comprises a fatty acid
ester at less than 40% w/w. In another embodiment, a formulation
comprises a fatty acid ester at less than 30% w/w. In another
embodiment, a formulation comprises a fatty acid ester at less than
20% w/w. In yet another embodiment, a formulation comprises a fatty
acid ester at less than 15% w/w. In still another embodiment, a
formulation comprises a fatty acid ester at less than 10% w/w. In a
further embodiment, a formulation comprises a fatty acid ester at
less than 5% w/w.
[0085] B. Pharmaceutically Acceptable Solvents
[0086] A formulation can comprise a pharmaceutically acceptable
solvent, as described above. In one embodiment, a formulation
comprises a pharmaceutically acceptable solvent at 1% w/w to 40%
w/w. In another embodiment, a formulation comprises a
pharmaceutically acceptable solvent at 1% w/w to 30% w/w. In
another embodiment, a formulation comprises a pharmaceutically
acceptable solvent at 2% w/w to 25% w/w. In yet another embodiment,
a formulation comprises a pharmaceutically acceptable solvent at 3%
w/w to 20% w/w. In still another embodiment, a formulation
comprises a pharmaceutically acceptable solvent at 5% w/w to 12%
w/w.
[0087] In one embodiment, a formulation comprises a
pharmaceutically acceptable solvent at more than 1% w/w. In another
embodiment, a formulation comprises a pharmaceutically acceptable
solvent at more than 5% w/w. In another embodiment, a formulation
comprises a pharmaceutically acceptable solvent at more than 10%
w/w. In yet another embodiment, a formulation comprises a
pharmaceutically acceptable solvent at more than 15% w/w. In still
another embodiment, a formulation comprises a pharmaceutically
acceptable solvent at more than 20% w/w. In a further embodiment, a
formulation comprises a pharmaceutically acceptable solvent at more
than 30% w/w.
[0088] In one embodiment, a formulation comprises a
pharmaceutically acceptable solvent at less than 40% w/w. In
another embodiment, a formulation comprises a pharmaceutically
acceptable solvent at less than 30% w/w. In another embodiment, a
formulation comprises a pharmaceutically acceptable solvent at less
than 20% w/w. In yet another embodiment, a formulation comprises a
pharmaceutically acceptable solvent at less than 15% w/w. In still
another embodiment, a formulation comprises a pharmaceutically
acceptable solvent at less than 10% w/w. In a further embodiment, a
formulation comprises a pharmaceutically acceptable solvent at less
than 5% w/w.
[0089] C. Mixtures of Solvent Components
[0090] A formulation can comprise more than one component that can
serve as corticosteroid solvents, as described above. The solvent
components can be combined prior to being added to a formulation,
or the components can be combined in the process of making the
formulation.
[0091] Each component that can serve as a corticosteroid solvent
can be present in any amount relative to another component. In one
embodiment, the ratio (w:w) of one solvent component to another
solvent component is 1:0. In another embodiment, the ratio (w:w) of
one solvent component to another solvent component is from 1:0.1 to
1:5. In another embodiment, the ratio (w:w) of one solvent
component to another solvent component is from 1:0.3 to 1:4. In
still another embodiment, the ratio (w:w) of one solvent component
to another solvent component is from 1:0.375 to 1:3.75.
[0092] In one embodiment, the ratio (w:w) of one solvent component
to a combination of two other solvent components is from 1:0.5 to
1:7.5. In another embodiment, the ratio (w:w) of one solvent
component to a combination of two other solvent components is from
1:1 to 1:6. In another embodiment, the ratio (w:w) of one solvent
component to a combination of two other solvent components is from
1:1.5 to 1:5.5.
[0093] In one embodiment, a formulation comprises more than one
component that can serve as corticosteroid solvents
("corticosteroid solvent mixture") at 2% w/w to 50% w/w. In another
embodiment, a formulation comprises a corticosteroid solvent
mixture at 3% w/w to 30% w/w. In another embodiment, a formulation
comprises a corticosteroid solvent mixture at 3% w/w to 25% w/w. In
yet another embodiment, a formulation comprises a corticosteroid
solvent mixture at 3% w/w to 60% w/w. In still another embodiment,
a formulation comprises a corticosteroid solvent mixture at 4% w/w
to 40% w/w. In a further embodiment, a formulation comprises a
corticosteroid solvent mixture at 5% w/w to 30% w/w.
[0094] In one embodiment, a formulation comprises a corticosteroid
solvent mixture at more than 2% w/w. In another embodiment, a
formulation comprises a corticosteroid solvent mixture at more than
5% w/w. In another embodiment, a formulation comprises a
corticosteroid solvent mixture at more than 10% w/w. In yet another
embodiment, a formulation comprises a corticosteroid solvent
mixture at more than 20% w/w. In still another embodiment, a
formulation comprises a corticosteroid solvent mixture at more than
30% w/w. In a further embodiment, a formulation comprises a
corticosteroid solvent mixture at more than 40% w/w.
[0095] In one embodiment, a formulation comprises a corticosteroid
solvent mixture at less than 60% w/w. In another embodiment, a
formulation comprises a corticosteroid solvent mixture at less than
50% w/w. In another embodiment, a formulation comprises a
corticosteroid solvent mixture at less than 40% w/w. In yet another
embodiment, a formulation comprises a corticosteroid solvent
mixture at less than 30% w/w. In still another embodiment, a
formulation comprises a corticosteroid solvent mixture at less than
20% w/w. In a further embodiment, a formulation comprises a
corticosteroid solvent mixture at less than 10% w/w.
[0096] Each component that can serve as a corticosteroid solvent
can be present in any amount relative to another component. In one
embodiment, the ratio (w:w) of one solvent component to another
solvent component is 1:0. In another embodiment, the ratio (w:w) of
one solvent component to another solvent component is from 1:0.1 to
1:5. In another embodiment, the ratio (w:w) of one solvent
component to another solvent component is from 1:0.3 to 1:4. In
still another embodiment, the ratio (w:w) of one solvent component
to another solvent component is from 1:0.375 to 1:3.75.
[0097] In one embodiment, the ratio (w:w) of one solvent component
to a combination of two other solvent components is from 1:0.5 to
1:7.5. In another embodiment, the ratio (w:w) of one solvent
component to a combination of two other solvent components is from
1:1 to 1:6. In another embodiment, the ratio (w:w) of one solvent
component to a combination of two other solvent components is from
1:1.5 to 1:5.5.
[0098] D. Corticosteroids
[0099] A formulation can also comprise one or more corticosteroids,
as described above. In one embodiment, a formulation comprises one
or more corticosteroids at 0.001% w/w to 5% w/w. In another
embodiment, a formulation comprises one or more corticosteroids at
0.005% w/w to 3% w/w. In another embodiment, a formulation
comprises one or more corticosteroids at 0.01% w/w to 2.5% w/w.
[0100] In one embodiment, a formulation comprises one or more
corticosteroids at more than 0.001% w/w. In another embodiment, a
formulation comprises one or more corticosteroids at more than
0.01% w/w. In another embodiment, a formulation comprises one or
more corticosteroids at more than 0.05% w/w. In yet another
embodiment, a formulation comprises one or more corticosteroids at
more than 0.1% w/w. In still another embodiment, a formulation
comprises one or more corticosteroids at more than 0.5% w/w. In a
further embodiment, a formulation comprises one or more
corticosteroids at more than 1% w/w.
[0101] In one embodiment, a formulation comprises one or more
corticosteroids at less than 5% w/w. In another embodiment, a
formulation comprises one or more corticosteroids at less than 3%
w/w. In another embodiment, a formulation comprises one or more
corticosteroids at less than 1% w/w. In yet another embodiment, a
formulation comprises one or more corticosteroids at less than 0.5%
w/w. In still another embodiment, a formulation comprises one or
more corticosteroids at less than 0.1% w/w.
[0102] E. Penetration Enhancers
[0103] A topical formulation can comprise one or more penetration
enhancers. In one embodiment, the one or more penetration enhancers
enhance penetration of one or more corticosteroids through the
skin. In another embodiment, the one or more penetration enhancers
enhance penetration by reversibly decreasing the barrier resistance
of the skin. In another embodiment, the one or more penetration
enhancers enhance penetration by increasing the permeability of the
stratum corneum.
[0104] Examples of suitable penetration enhancers include, but are
not limited to, alcohols, alkanols, alkanones such as benzyl
alcohol, decanol, ethanol, octanol, and propanol; amides and other
nitrogenous compounds such as diethanolamine, dimethylacetamide,
dimethylformamide, ethanolamine, 1-methyl-2-pyrrolidone,
2-pyrrolidone, triethanolamine, and urea; diisopropyl adipate;
dimethyl isosorbide; ethers such as diethylene glycol monoethyl
ether and diethylene glycol monomethyl ether; fatty acids such as
lauric acid, oleic acid, and valeric acid; fatty acid esters such
as ethyl oleate, isopropyl myristate, isopropyl palmitate, and
methylpropionate; organic acids such as citric acid, salicylic
acid, salicylates, and succinic acid; polyols and esters thereof
such as butanediol, ethylene glycol, glycerol, 1,2,6 hexanetriol,
polyethylene glycol, polyethylene glycol monolaurate, and propylene
glycol; pyrrolidones such as 2-pyrrolidone; 1-substituted
azacycloheptan-2-ones, such as 1-n-dodecylcyclazacycloheptan-2-one
(laurocapram); sulphoxides such as decylmethylsulfoxide and
dimethylsulphoxide; surfactants such as benzalkonium chloride,
cetyltrimethylammonium bromide, lecithin, Poloxamer (231, 182,
184), sodium laurate, sodium lauryl sulfate, and Tween (20, 40, 60,
80); and terpenes.
[0105] F. Humectants
[0106] A topical formulation can comprise one or more humectants.
In one embodiment, the one or more humectants are moistening agents
that promote water retention due to their hygroscopic properties.
In one embodiment, a humectant holds water against the skin so that
the formulation does not dry out or dry down. Without being limited
to any mechanism of mode of action, a humectant can improve
solubility of a corticosteroid by promoting water retention because
water can increase corticosteroid solubility. (Example 6.)
[0107] Examples of suitable humectants include, but are not limited
to, ethylene glycol, fructose, glycerol, lactic acid, polyethylene
glycol, propylene glycol, sorbitan, sorbitol, tetraethylene glycol,
triethylene glycol, vitamin B, and any combination thereof.
[0108] One or more humectants can be present in a topical
formulation at any acceptable amount. In one embodiment, a
formulation comprises one or more humectants at 2% w/w to 25% w/w.
In another embodiment, a formulation comprises one or more
humectants at 8% w/w to 22% w/w. In another embodiment, a
formulation comprises one or more humectants at 10% w/w to 14%
w/w.
[0109] In one embodiment, a formulation comprises one or more
humectants at more than 2% w/w. In another embodiment, a
formulation comprises one or more humectants at more than 5% w/w.
In another embodiment, a formulation comprises one or more
humectants at more than 10% w/w. In yet another embodiment, a
formulation comprises one or more humectants at more than 15% w/w.
In still another embodiment, a formulation comprises one or more
humectants at more than 20% w/w.
[0110] In one embodiment, a formulation comprises one or more
humectants at less than 25% w/w. In another embodiment, a
formulation comprises one or more humectants at less than 20% w/w.
In another embodiment, a formulation comprises one or more
humectants at less than 15% w/w. In yet another embodiment, a
formulation comprises one or more humectants at less than 10% w/w.
In still another embodiment, a formulation comprises one or more
humectants at less than 5% w/w.
[0111] G. Emulsifiers
[0112] A formulation can comprise one or more emulsifiers. In one
embodiment, the one or more emulsifiers are substances that promote
the formation of an emulsion. In another embodiment, the one or
more emulsifiers are substances that stabilize an emulsion.
[0113] Examples of suitable emulsifiers include, but are not
limited to, carbomer copolymers, glyceryl mono and di-fatty acid
esters, polyglycerin fatty acid esters, polyoxyethylene fatty acid
esters, fatty alcohol ethoxylated ethers, sorbitan esters of fatty
acids, sucrose esters of fatty acids, ethoxylated alkyl phenols,
polyoxyethylene polyoxypropylene block polymers, polyoxypropylene
polyoxyethylene ethers of fatty alcohols.
[0114] Methods of Use
[0115] Pharmaceutical compositions and/or corticosteroid
formulation as disclosed herein can be used to treat any medical
condition known in the art to be treated by corticosteroids. In
some embodiments, pharmaceutical compositions and/or corticosteroid
formulations disclosed herein can be used to decrease inflammation
and/or to reduce the activity of the immune system in a variety of
medical conditions. Medical conditions include, for example, atopic
dermatitis, psoriasis, eczematous dermatitis, nummular dermatitis,
irritant contact dermatitis, allergic contact dermatitis (such as
poison ivy exposure, poison oak exposure, and poison sumac
exposure), seborrheic dermatitis, stasis dermatitis, and other
steroid responsive dermatoses. Corticosteroid formulation can also
be used to treat, for example, acne vulgaris, alopecia, alopecia
greata, vitiligo, eczema, xerotic eczema, keratosis pilaris, lichen
planus, lichen sclerosus, lichen striatus, lichen simplex
chronicus, prurigo nodularis, discoid lupus erythematosus,
lymphocytic infiltrate of Jessner/Kanof, lymphacytoma cutis,
pyoderma gangrenosum, pruritis ani, sarcoidosis, chondrodermatitis
nodularis helices and other inflammatory dermatological disorders.
Medical conditions can also include, for example, keloids,
hypertrophic scars, pretibial myxedema and other infiltrative
dermatological disorders. Additional medical conditions include,
for example, granuloma annulare, necrobiosis lipoidica
diabeticorum, sarcoidosis, and other noninfectious granulomas.
Pharmaceutical compositions and/or corticosteroid formulations can
also be used for their anti-pruritic and vasoconstriction
properties.
EXAMPLES
[0116] The following examples illustrate various aspects of the
disclosure, and should not be considered limiting.
Example 1
Solubility of Corticosteroids in Neat Solvents
[0117] The solubilities of various corticosteroids in propylene
glycol (PG) monocaprylate, PG monolaurate, or isopropyl myristate
were measured gravimetrically. Corticosteroid, PG monocaprylate, PG
monolaurate, and/or isopropyl myristate were placed in glass vials
and weighed on an analytical balance to four decimals places. Test
solutions were stirred and shaken at room temperature for up to 30
minutes. Test solutions were examined at about 24 hours for clarity
or non-dissolved material.
[0118] Solubility (% w/w) results are presented in Table 1. The
results demonstrate that the highest percent solubility obtained
with isopropyl myristate (0.25% w/w for clobetasol propionate) was
lower than the lowest percent solubility obtained with either PG
monocaprylate (0.3% w/w for fluticasone propionate) or PG
monolaurate (0.3% w/w for each of hydrocortisone and triamcinolone
acetonide).
TABLE-US-00001 TABLE 1 PG PG Isopropyl Monocaprylate Monolaurate
Myristate Corticosteroid (% w/w) (% w/w) (% w/w) Fluticasone 0.3 --
<0.03 Propionate Hydrocortisone 0.55 0.30 <0.02 Triamcinolone
0.65 0.30 <0.04 Acetonide Mometasone 0.7 -- -- Fuorate Desonide
1.15 0.40 -- Hydrocortisone 2.0 1.35 0.10 Butyrate Betamethasone
4.0 2.30 0.15 Dipropionate Clobetasol 4.0 1.80 0.25 Propionate
[0119] The results also demonstrate that each tested corticosteroid
was more soluble in PG monocaprylate than in isopropyl myristate.
Fluticasone propionate was 10 times more soluble in PG
monocaprylate than in isopropyl myristate. Hydrocortisone was at
least 27 times more soluble in PG monocaprylate than in isopropyl
myristate. Triamcinolone acetonide was at least 16 times more
soluble in PG monocaprylate than in isopropyl myristate.
Hydrocortisone butyrate was 20 times more soluble in PG
monocaprylate than in isopropyl myristate. Betamethasone
dipropionate was 27 times more soluble in PG monocaprylate than in
isopropyl myristate. Clobetasol propionate was 16 times more
soluble in PG monocaprylate than in isopropyl myristate.
[0120] Additionally, the results demonstrate that each tested
corticosteroid was more soluble in PG monolaurate than in isopropyl
myristate. Hydrocortisone was at least 15 times more soluble in PG
monolaurate than in isopropyl myristate. Triamcinolone acetonide
was at least 7.5 times more soluble in PG monolaurate than in
isopropyl myristate. Hydrocortisone butyrate was 13.5 times more
soluble in PG monolaurate than in isopropyl myristate.
Betamethasone dipropionate was 15.3 times more soluble in PG
monolaurate than in isopropyl myristate. Clobetasol propionate was
7.2 times more soluble in PG monolaurate than in isopropyl
myristate.
[0121] Further, the results demonstrate that each tested
corticosteroid was more soluble in PG monocapyrlate than in PG
monolaurate. On average, a given corticosteroid was twice as
soluble in PG monocapyrlate than in PG monolaurate.
Example 2
Solubility of Hydrocortisone in Mixtures of Components
[0122] A) Mixtures of PG and PG monocaprylate
[0123] The solubility of hydrocortisone in mixtures of PG and PG
monocaprylate was measured according to the procedure in Example
1.
[0124] Solubility (% w/w) results are presented in Table 2 and FIG.
1.
TABLE-US-00002 TABLE 2 PG:PG Monocaprylate Solubility (% w/w) 100:0
1.30 90:10 1.50 75:25 1.70 50:50 1.65 25:75 1.25 0:100 0.55
[0125] In FIG. 1, the vertical axes indicate solubility (% w/w).
The horizontal axis indicates the PG:PG monocaprylate ratio (w:w)
in a given solvent mixture. The dashed solubility line indicates
the expected solubility if each solvent (PG and PG monocaprylate)
acted independently in a solvent mixture. The middle line
(.diamond-solid.) depicts actual results of hydrocortisone
solubility in a PG:PG monocaprylate solvent mixture. The upper line
(.tangle-solidup.) depicts actual results of hydrocortisone
solubility in an ethoxydigycol:PG:PG monocaprylate solvent
mixture.
[0126] FIG. 1 demonstrates that for each tested solvent mixture
that contained both PG and PG monocaprylate (.diamond-solid.),
hydrocortisone was more soluble in the mixture than expected
(dashed line).
[0127] Solubility of hydrocortisone in a 50:50 PG:PG monocaprylate
solvent mixture (1.65% w/w), a 75:25 PG:PG monocaprylate solvent
mixture (1.70% w/w), and a 90:10 PG:PG monocaprylate solvent
mixture (1.50% w/w) were all higher than in PG alone (i.e. 100:0
solvent mixture; 1.30% w/w). These results suggest a synergistic
effect between PG and PG monocaprylate.
[0128] B) Effect of Addition of Ethoxydiglycol on Hydrocortisone
Solubility in Mixtures of PG and PG Monocaprylate
[0129] The solubility of hydrocortisone in mixtures of PG, PG
monocaprylate, and ethoxydiglycol was measured according to the
procedure in Example 1.
[0130] Solubility (% w/w) results are presented in Table 3 and FIG.
1.
TABLE-US-00003 TABLE 3 Ethoxydiglycol:PG:PG Monocaprylate
Solubility (% w/w) 12:12:0 2.20 12:9:3 2.43 12:8:4 2.33 12:6:6 2.17
12:4:8 1.90 12:0:12 1.25
[0131] FIG. 1 demonstrates that hydrocortisone was more soluble in
a ethoxydiglycol:PG:PG monocaprylate solvent mixture
(.tangle-solidup.) than in a PG:PG monocaprylate solvent mixture
(.diamond-solid.).
[0132] Solubility of hydrocortisone in a 12:4:8
ethoxydiglycol:PG:PG monocaprylate solvent mixture (1.90% w/w), a
12:6:6 ethoxydiglycol:PG:PG monocaprylate solvent mixture (2.17%
w/w), a 12:8:4 ethoxydiglycol:PG:PG monocaprylate solvent mixture
(2.33% w/w), a 12:9:3 ethoxydiglycol:PG:PG monocaprylate solvent
mixture (2.43% w/w), and a 12:12:0 ethoxydiglycol:PG:PG
monocaprylate solvent mixture (2.20% w/w) were all higher than in
PG alone (i.e. 1.30% w/w) (see Table 2).
[0133] Addition of ethoxydiglycol to PG alone (i.e. a 12:12:0
ethoxydiglycol:PG:PG monocaprylate solvent mixture) increased the
solubility of hydrocortisone 1.7-fold over its solubility in PG
alone (2.20% w/w compared to 1.30% w/w). Addition of ethoxydiglycol
to PG monocaprylate alone (i.e. a 12:0:12 ethoxydiglycol:PG:PG
monocaprylate solvent mixture) also increased the solubility of
hydrocortisone 2.3-fold over its solubility in PG monocaprylate
alone (1.25% w/w compared to 0.55% w/w).
[0134] The results suggest a synergistic effect between
ethoxydiglycol and each of PG, PG monocaprylate, and a PG:PG
monocaprylate mixture. Specifically, the results demonstrate the
increased solubility of hydrocortisone in a combination of
ethoxydiglycol and PG; ethoxydiglycol and PG monocaprylate; and
ethoxydiglycol and a PG:PG monocaprylate mixture over the
solubility of hydrocortisone in each of PG, PG monocaprylate, and a
PG:PG monocaprylate mixture alone, respectively.
Example 3
Solubility of Hydrocortisone in Mixtures of Components
[0135] The solubility of hydrocortisone in mixtures of PG and PG
monolaurate was measured according to the procedure in Example
1.
[0136] Solubility (% w/w) results are presented in Table 4 and FIG.
2.
TABLE-US-00004 TABLE 4 PG:PG Monolaurate Solubility (% w/w) 100:0
1.30 75:25 1.75 50:50 1.40 25:75 0.80 0:100 0.30
[0137] In FIG. 2, the vertical axes indicate solubility (% w/w).
The horizontal axis indicates the PG:PG monolaurate ratio in a
given solvent mixture. The dashed solubility line indicates the
expected solubility if each solvent (PG and PG monolaurate) acted
independently in a solvent mixture. The upper line
(.diamond-solid.) depicts actual results of hydrocortisone
solubility in a PG:PG monolaurate solvent mixture.
[0138] FIG. 2 demonstrates that for each tested solvent mixture
that contained both solvents (.diamond-solid.), hydrocortisone was
more soluble in the mixture than expected (dashed line).
[0139] Solubility of hydrocortisone in a 50:50 PG:PG monolaurate
solvent mixture (1.40% w/w) and a 75:25 PG:PG monolaurate solvent
mixture (1.75% w/w) were each higher than in PG alone (i.e. 100:0
solvent mixture; 1.30% w/w). These results suggest a synergistic
effect between PG and PG monolaurate.
Example 4
Solubility of Hydrocortisone in Mixtures of Components
[0140] The solubility of hydrocortisone in mixtures of
ethoxydiglycol and PG monocaprylate was measured according to the
procedure in Example 1.
[0141] Solubility (% w/w) results are presented in Table 5 and FIG.
3.
TABLE-US-00005 TABLE 5 Ethoxydiglycol:PG Monocaprylate Solubility
(% w/w) 100:0 2.25 90:10 2.00 75:25 1.62 50:50 1.25 25:75 0.85
0:100 0.55
[0142] In FIG. 3, the vertical axes indicate solubility (% w/w).
The horizontal axis indicates the ethoxydiglycol:PG monocaprylate
ratio in a given solvent mixture. The dashed solubility line
indicates the expected solubility if each solvent (ethoxydiglycol
and PG monocaprylate) acted independently in a solvent mixture. The
lower line depicts actual results of hydrocortisone solubility in a
ethoxydiglycol:PG monocaprylate solvent mixture.
[0143] FIG. 3 demonstrates that for each tested solvent mixture
that contained both solvents (lower line), hydrocortisone was less
soluble in the mixture than expected (dashed line). These results
suggest a diluting or interfering effect between ethoxydiglycol and
PG monocaprylate.
Example 5
Solubility of Triamcinolone Acetonide in Mixtures of Components
[0144] A) Mixtures of PG and PG monocaprylate
[0145] The solubility of triamcinolone acetonide in mixtures of PG
and PG monocaprylate was measured according to the procedure in
Example 1.
[0146] Solubility (% w/w) results are presented in Table 6 and FIG.
4.
TABLE-US-00006 TABLE 6 PG:PG Monocaprylate Solubility (% w/w) 100:0
0.90 90:10 1.15 75:25 1.50 50:50 1.60 25:75 1.25 0:100 0.60
[0147] In FIG. 4, the vertical axes indicate solubility (% w/w).
The horizontal axis indicates the PG:PG monocaprylate ratio (w:w)
in a given solvent mixture. The dashed solubility line indicates
the expected solubility if each solvent (PG and PG monocaprylate)
acted independently in a solvent mixture. The middle line
(.diamond-solid.) depicts actual results of triamcinolone acetonide
solubility in a PG:PG monocaprylate solvent mixture. The upper line
(.tangle-solidup.) depicts actual results of triamcinolone
acetonide solubility in an ethoxydigycol:PG:PG monocaprylate
solvent mixture.
[0148] FIG. 4 demonstrates that for each tested solvent mixture
that contained both PG and PG monocaprylate (.diamond-solid.),
triamcinolone acetonide was more soluble in the mixture than
expected (dashed line).
[0149] Solubility of triamcinolone acetonide in a 25:75 PG:PG
monocaprylate solvent mixture (1.25% w/w), a 50:50 PG:PG
monocaprylate solvent mixture (1.60% w/w), a 75:25 PG:PG
monocaprylate solvent mixture (1.50% w/w), and a 90:10 PG:PG
monocaprylate solvent mixture (1.15% w/w) were all higher than in
PG alone (i.e. 100:0 solvent mixture; 0.90% w/w). These results
suggest a synergistic effect between PG and PG monocaprylate.
[0150] B) Effect of Addition of Ethoxydiglycol on Triamcinolone
Acetonide Solubility in Mixtures of PG and PG Monocaprylate
[0151] The solubility of triamcinolone acetonide in mixtures of PG,
PG monocaprylate, and ethoxydiglycol was measured according to the
procedure in Example 1.
[0152] Solubility (% w/w) results are presented in Table 7 and FIG.
4.
TABLE-US-00007 TABLE 7 Ethoxydiglycol:PG:PG Monocaprylate
Solubility (% w/w) 12:12:0 2.45 12:9:3 2.45 12:6:6 2.30 12:3:9 2.00
12:0:12 1.53
[0153] FIG. 4 demonstrates that triamcinolone acetonide was more
soluble in a ethoxydiglycol:PG:PG monocaprylate solvent mixture
(.tangle-solidup.) than in a PG:PG monocaprylate solvent mixture
(.diamond-solid.).
[0154] Solubility of triamcinolone acetonide in a a 12:3:9
ethoxydiglycol:PG:PG monocaprylate solvent mixture (2.00% w/w), a
12:6:6 ethoxydiglycol:PG:PG monocaprylate solvent mixture (2.30%
w/w), a 12:9:3 ethoxydiglycol:PG:PG monocaprylate solvent mixture
(2.45% w/w), and a 12:12:0 ethoxydiglycol:PG:PG monocaprylate
solvent mixture (2.45% w/w) were all higher than in PG alone (i.e.
0.90% w/w) (see Table 6).
[0155] Addition of ethoxydiglycol to PG alone (i.e. a 12:12:0
ethoxydiglycol:PG:PG monocaprylate solvent mixture) increased the
solubility of triamcinolone acetonide 1.7-fold over its solubility
in PG alone (2.45% w/w compared to 0.90% w/w). Addition of
ethoxydiglycol to PG monocaprylate alone (i.e. a 12:0:12
ethoxydiglycol:PG:PG monocaprylate solvent mixture) also increased
the solubility of hydrocortisone 2.3-fold over its solubility in PG
monocaprylate alone (1.53% w/w compared to 0.60% w/w).
[0156] The results suggest a synergistic effect between
ethoxydiglycol and each of PG, PG monocaprylate, and a PG:PG
monocaprylate mixture. Specifically, the results demonstrate the
increased solubility of triamcinolone acetonide in a combination of
ethoxydiglycol and PG; ethoxydiglycol and PG monocaprylate; and
ethoxydiglycol and a PG:PG monocaprylate mixture over the
solubility of hydrocortisone in each of PG, PG monocaprylate, and a
PG:PG monocaprylate mixture alone, respectively.
Example 6
Effect of Water on Corticosteroid Solubility
[0157] The solubility of hydrocortisone in various solvents, each
with and without the addition of water, was measured according to
the procedure in Example 1.
[0158] Solubility (% w/w) results are presented in Table 8.
TABLE-US-00008 TABLE 8 Solubility Solvent Mixture (% w/w) (% w/w)
Ethoxydiglycol:Purified Water 100:0 2.25 Ethoxydiglycol:Purified
Water 90:10 3.65 PG Monocaprylate:Purified Water 100:0 0.55 PG
Monocaprylate:Purified Water 95:5 1.32 Ethoxydiglycol:PG
Caprylate:PG 12:8:4 1.90 Ethoxydiglycol:PG Caprylate:PG
(12:8:4):Purified Water 90:10 2.85
[0159] Results demonstrate that hydrocortisone was more soluble in
a given solvent with water than the same solvent without water.
Hydrocortisone was 1.6 times more soluble in ethoxydiglycol with
water than without. Hydrocortisone was 2.4 times more soluble in
propylene glycol monocaprylate with water than without.
Hydrocortisone was 1.5 times more soluble in an ethoxydiglycol,
propylene glycol monocaprylate, and propylene glycol solvent
mixture with water than without.
[0160] The results suggest a synergistic effect between water and
each of ethoxydiglycol, PG monocaprylate, and an ethoxydiglycol:PG
monocaprylate:PG mixture. Specifically, the results demonstrate the
increased solubility of hydrocortisone in a combination of water
and ethoxydiglycol; water and PG monocaprylate; and water and an
ethoxydiglycol:PG monocaprylate:PG mixture over the solubility of
hydrocortisone in each of ethoxydiglycol, PG monocaprylate, and an
ethoxydiglycol:PG monocaprylate:PG mixture alone, respectively.
Example 7
Hydrocortisone Topical Cream Formulations
[0161] A topical formulation is prepared as a cream comprising the
corticosteroid hydrocortisone, the fatty acid ester propylene
glycol monocaprylate, and the pharmaceutically acceptable solvents
propylene glycol and diethylene glycol monoethyl ether. Components
(w/w %) of various formulations of hydrocortisone 1% (Formulations
A and B) and 2.5% (Formulations C and D) creams are presented in
Table 9.
TABLE-US-00009 TABLE 9 Ingredient A B C D Hydrocortisone 1.0 1.0
2.5 2.5 Lactic Acid 12.0 12.0 12.0 12.0 Stearyl Alcohol 8.8 8.8 8.0
6.0 Cetyl Alcohol 2.3 2.3 2.0 2.0 Propylene Glycol Monocaprylate
8.0 6.0 8.0 8.0 Steareth-2 2.0 2.0 2.0 -- Steareth-21 2.0 2.0 2.0
-- Sorbitan Monostearate -- -- -- 2.0 PEG-40 Stearate -- -- -- 2.0
Propylene Glycol 4.0 6.0 3.0 4.0 Diethylene Glycol Monoethyl Ether
10.0 6.0 9.0 10.0 Methylparaben 0.12 0.12 0.12 0.12 Propylparaben
0.03 0.03 0.03 0.03 Sodium Hydroxide 3.1 3.1 3.1 3.1 Purified Water
qs 100 qs 100 qs 100 qs 100
Example 8
Hydrocortisone Acetate Topical Cream Formulations
[0162] A topical formulation is prepared as a cream comprising the
corticosteroid hydrocortisone acetate, the fatty acid ester
propylene glycol monocaprylate, and the pharmaceutically acceptable
solvents propylene glycol, hexylene glycol, and diethylene glycol
monoethyl ether. Components (w/w %) of various formulations of
hydrocortisone acetate 1% (Formulations A) and 2.5% (Formulations
B, C, and D) creams are presented in Table 10.
TABLE-US-00010 TABLE 10 Ingredient A B C D Hydrocortisone Acetate
1.0 2.5 2.5 2.5 Lactic Acid 12.0 12.0 12.0 12.0 Stearyl Alcohol 9.0
9.0 8.0 8.0 Cetyl Alcohol 2.5 2.0 2.0 2.5 Propylene Glycol
Monocaprylate 8.0 8.0 6.0 6.0 Steareth-2 2.0 2.0 1.5 2.0
Steareth-21 2.0 2.0 1.5 2.0 Propylene Glycol 4.0 4.0 2.0 --
Hexylene Glycol -- -- -- 2.0 Diethylene Glycol Monoethyl Ether 8.0
8.0 6.0 6.0 Methylparaben 0.12 0.12 0.12 0.12 Propylparaben 0.03
0.03 0.03 0.03 Sodium Hydroxide 3.1 3.1 3.1 3.1 Purified Water qs
100 qs 100 qs 100 qs 100
Example 9
Hydrocortisone Acetate Topical Oil-in-Water Emulsion
Formulations
[0163] A topical formulation is prepared as an oil-in-water
emulsion comprising the corticosteroid hydrocortisone acetate, the
fatty acid esters propylene glycol monocaprylate or propylene
glycol monolaurate, and the pharmaceutically acceptable solvents
propylene glycol, and diethylene glycol monoethyl ether. Components
(w/w %) of various formulations of hydrocortisone acetate 1%
(Formulations A) and 2.5% (Formulations B, C, and D) emulsions are
presented in Table 11.
TABLE-US-00011 TABLE 11 Ingredient A B C D Hydrocortisone Acetate
1.0 2.5 2.5 2.5 Stearyl Alcohol 8.0 9.0 9.0 9.0 Cetyl Alcohol 2.0
2.0 3.0 3.0 Propylene Glycol Monocaprylate 6.0 8.0 6.0 -- Propylene
Glycol Monolaurate -- -- -- 6.0 Steareth-2 1.5 2.0 -- 2.0
Steareth-21 1.5 1.0 -- 2.0 PEG-100 Stearate -- -- 1.5 -- Sorbitan
Monostearate -- -- 1.5 -- Propylene Glycol 3.0 4.0 3.0 3.0
Diethylene Glycol Monoethyl Ether 6.0 8.0 6.0 6.0 Methylparaben
0.12 0.12 0.12 0.12 Propylparaben 0.03 0.03 0.03 0.03 Purified
Water qs 100 qs 100 qs 100 qs 100
Example 10
Hydrocortisone Acetate Topical Oil-in-Water Emulsion
Formulations
[0164] A topical formulation is prepared as a gel or lotion
comprising the corticosteroid hydrocortisone acetate, the fatty
acid esters propylene glycol monocaprylate or propylene glycol
monolaurate, and the pharmaceutically acceptable solvents propylene
glycol, and diethylene glycol monoethyl ether. Components (w/w %)
of various formulations of hydrocortisone acetate 1% (Formulations
A) and 2.5% (Formulations B and C) gels or lotions are presented in
Table 12.
TABLE-US-00012 TABLE 12 Ingredient A B C Hydrocortisone Acetate 1.0
2.5 2.5 Cetostearyl Alcohol -- 3.0 3.0 Propylene Glycol
Monocaprylate 5.0 8.0 -- Propylene Glycol Monolaurate -- -- 6.0
Carbomer Homopolymer Type B 0.5 0.5 0.5 Carbomer Copolymer Type A
0.2 0.2 0.2 PEG-100 Stearate 0.3 0.3 0.3 Propylene Glycol 3.0 4.0
3.0 Diethylene Glycol Monoethyl Ether 5.0 8.0 10.0 Methylparaben
0.12 0.12 0.12 Propylparaben 0.03 0.03 0.03 Sodium Hydroxide 0.1
0.1 0.1 Purified Water qs 100 qs 100 qs 100
Example 11
Clobetasol Propionate Topical Cream Formulations
[0165] A topical formulation is prepared as a cream comprising the
corticosteroid clobetasol propionate, the fatty acid esters
propylene glycol monocaprylate or propylene glycol monolaurate, and
the pharmaceutically acceptable solvent propylene glycol with or
without diethylene glycol monoethyl ether. Components (w/w %) of
various formulations (A and B) of clobetasol propionate creams are
presented in Table 13.
TABLE-US-00013 TABLE 13 Ingredient A B Clobetasol Propionate 0.05
0.05 Lactic Acid 12.0 -- Stearyl Alcohol 6.0 8.0 Cetyl Alcohol 1.5
2.0 Propylene Glycol Monocaprylate 3.0 -- Propylene Glycol
Monolaurate -- 5.0 Steareth-2 2.0 -- Steareth-21 2.0 -- Carbomer
Copolymer Type A -- 0.2 PEG-40 Stearate -- 1.0 Propylene Glycol 4.0
10.0 Diethylene Glycol Monoethyl Ether 12.0 -- Methylparaben 0.12
0.12 Propylparaben 0.03 0.03 Sodium Hydroxide 3.1 0.1 Purified
Water qs 100 qs 100
Example 12
Betamethasone Dipropionate Topical Cream Formulations
[0166] A topical formulation is prepared as a cream comprising the
corticosteroid betamethasone dipropionate, the fatty acid esters
propylene glycol monocaprylate or propylene glycol monolaurate, and
the pharmaceutically acceptable solvent propylene glycol with or
without diethylene glycol monoethyl ether. Components (w/w %) of
various formulations (A and B) of betamethasone dipropionate creams
are presented in Table 14.
TABLE-US-00014 TABLE 14 Ingredient A B Betamethasone Dipropionate
0.05 0.05 Lactic Acid 12.0 -- Stearyl Alcohol 6.0 8.0 Cetyl Alcohol
1.5 2.0 Propylene Glycol Monocaprylate 3.0 -- Propylene Glycol
Monolaurate -- 5.0 Steareth-2 2.0 -- Steareth-21 2.0 -- Carbomer
Copolymer Type A -- 0.2 PEG-40 Stearate -- 1.0 Propylene Glycol 3.0
10.0 Diethylene Glycol Monoethyl Ether 9.0 -- Methylparaben 0.12
0.12 Propylparaben 0.03 0.03 Sodium Hydroxide 3.1 0.1 Purified
Water qs 100 qs 100
Example 13
Triamcinolone Acetonide Topical Cream Formulations
[0167] A topical formulation is prepared as a cream comprising the
corticosteroid triamcinolone acetonide, the fatty acid esters
propylene glycol monocaprylate or propylene glycol monolaurate, and
the pharmaceutically acceptable solvents propylene glycol and
diethylene glycol monoethyl ether. Components (w/w %) of various
formulations (A and B) of triamcinolone acetonide creams are
presented in Table 15.
TABLE-US-00015 TABLE 15 Ingredient A B C Triamcinolone Acetonide
0.1 0.5 0.1 Lactic Acid 12.0 -- -- Stearyl Alcohol 8.0 8.0 8.0
Cetyl Alcohol 2.0 2.0 2.0 Propylene Glycol Monocaprylate 4.0 8.0 --
Propylene Glycol Monolaurate -- -- 6.0 Steareth-2 2.0 -- --
Steareth-21 2.0 -- -- Carbomer Copolymer Type A -- 0.2 0.2 PEG-40
Stearate -- 1.0 1.0 Propylene Glycol 4.0 6.0 6.0 Diethylene Glycol
Monoethyl Ether 8.0 6.0 -- Methylparaben 0.12 0.12 0.12
Propylparaben 0.03 0.03 0.03 Sodium Hydroxide 3.1 0.05 0.05
Purified Water qs 100 qs 100 qs 100
Example 14
Clobetasol Propionate Topical Gel and Lotion Formulations
[0168] A topical formulation is prepared as a gel or lotion
comprising the corticosteroid clobetasol propionate, the fatty acid
ester propylene glycol monocaprylate, and the pharmaceutically
acceptable solvent propylene glycol with or without diethylene
glycol monoethyl ether. Components (w/w %) of various formulations
(A and B) of clobetasol propionate gels or lotions are presented in
Table 16.
TABLE-US-00016 TABLE 16 Ingredient A B Clobetasol Propionate 0.05
0.05 Cetostearyl Alcohol -- 3.0 Propylene Glycol Monocaprylate 5.0
3.0 Carbomer Copolymer Type A 0.2 0.2 Carbomer Homopolymer Type C
0.5 0.5 PEG-40 Stearate 0.5 0.5 Propylene Glycol 5.0 10.0
Diethylene Glycol Monoethyl Ether 5.0 -- Methylparaben 0.12 0.12
Propylparaben 0.03 0.03 Sodium Hydroxide 0.1 0.1 Purified Water qs
100 qs 100
Example 15
Betamethasone Dipropionate Topical Gel and Lotion Formulations
[0169] A topical formulation is prepared as a gel or lotion
comprising the corticosteroid betamethasone dipropionate, the fatty
acid ester propylene glycol monolaurate, and the pharmaceutically
acceptable solvent propylene glycol with or without diethylene
glycol monoethyl ether. Components (w/w %) of various formulations
(A and B) of betamethasone dipropionate gels or lotions are
presented in Table 17.
TABLE-US-00017 TABLE 17 Ingredient A B Betamethasone Dipropionate
0.05 0.05 Cetostearyl Alcohol -- 3.0 Propylene Glycol Monolaurate
5.0 3.0 Carbomer Copolymer Type A 0.2 0.2 Carbomer Homopolymer Type
C 0.5 0.5 PEG-40 Stearate 0.5 0.5 Propylene Glycol 5.0 10.0
Diethylene Glycol Monoethyl Ether 5.0 -- Methylparaben 0.12 0.12
Propylparaben 0.03 0.03 Sodium Hydroxide 0.1 0.1 Purified Water qs
100 qs 100
Example 16
Hydrocortisone Topical Ointment Formulations
[0170] A topical formulation is prepared as an ointment comprising
the corticosteroid hydrocortisone, the fatty acid ester propylene
glycol monocaprylate, and the pharmaceutically acceptable solvents
propylene glycol and diethylene glycol monoethyl ether. Components
(w/w %) of various formulations (A and B) of hydrocortisone
ointments are presented in Table 18.
TABLE-US-00018 TABLE 18 Ingredient A B Hydrocortisone 1.0 2.5
Stearyl Alcohol 10.0 12.0 Polyethylene Glycol 400 51.0 40.5
Methoxy-PEG 350 -- 10.0 Propylene Glycol Monocaprylate 10.0 12.0
Sorbitan Monostearate 3.0 3.0 Propylene Glycol 20.0 10.0 Diethylene
Glycol Monoethyl Ether 5.0 10.0
Example 17
Betamethasone Dipropionate Topical Ointment Formulations
[0171] A topical formulation is prepared as an ointment comprising
the corticosteroid betamethasone dipropionate, the fatty acid ester
propylene glycol monolaurate or propylene glycol monocaprylate, and
the pharmaceutically acceptable solvents propylene glycol and
diethylene glycol monoethyl ether. Components (w/w %) of various
formulations (A and B) of betamethasone dipropionate ointments are
presented in Table 19.
TABLE-US-00019 TABLE 19 Ingredient A B Betamethasone Dipropionate
0.05 0.05 Stearyl Alcohol 10.0 8.0 Polyethylene Glycol 400 62.95
53.95 Methoxy-PEG 350 -- 10.0 Propylene Glycol Monolaurate -- 5.0
Propylene Glycol Monocaprylate 4.0 -- Sorbitan Monostearate 3.0 3.0
Propylene Glycol 15.0 10.0 Diethylene Glycol Monoethyl Ether 5.0
10.0
[0172] The above specification and examples provide a complete
description of fatty acid esters as steroid solvents. Although
various embodiments have been described above with a certain degree
of particularity, or with reference to one or more individual
embodiments, those skilled in the art could make numerous
alterations to the disclosed embodiments without departing from the
spirit or scope of this disclosure. Other embodiments are therefore
contemplated. All matter contained in the above description is
illustrative only of particular embodiments and not limiting.
Changes in detail or structure can be made without departing from
the basic elements described herein. For instance, various
combinations of components, amounts, and ratios, and selection of
individual components, amounts, and ratios from those listed and
embodied are within the scope of the disclosure, including
individual selections, selections of two in combination, selections
of three in combination, etc. from within those listed and
embodied.
* * * * *