U.S. patent application number 16/386710 was filed with the patent office on 2020-03-12 for dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof.
This patent application is currently assigned to Foamix Pharmaceuticals Ltd.. The applicant listed for this patent is Foamix Pharmaceuticals Ltd.. Invention is credited to Tal Berman, Doron Friedman, David Schuz, Dov Tamarkin, Enbal Ziv.
Application Number | 20200078298 16/386710 |
Document ID | / |
Family ID | 39101639 |
Filed Date | 2020-03-12 |
United States Patent
Application |
20200078298 |
Kind Code |
A1 |
Tamarkin; Dov ; et
al. |
March 12, 2020 |
Dicarboxylic Acid Foamable Vehicle and Pharmaceutical Compositions
Thereof
Abstract
The present invention teaches a foamable pharmaceutical carrier
comprising a benefit agent, selected from the group consisting of a
dicarboxylic acid and a dicarboxylic acid ester; a stabilizer
selected from the group consisting of at least one surface-active
agent; at least one polymeric agent and mixtures thereof; a solvent
selected from the group consisting of water, a hydrophilic solvent,
a hydrophobic solvent, a potent solvent, a polar solvent, a
silicone, an emollient, and mixtures thereof, wherein the benefit
agent, stabilizer and solvent are selected to provide a composition
that is substantially resistant to aging and to phase separation
and or can substantially stabilize other active ingredients. The
invention further relates to a foamable composition further
containing a liquefied hydrocarbon gas propellant.
Inventors: |
Tamarkin; Dov; (Maccabim,
IL) ; Friedman; Doron; (Karmei Yosef, IL) ;
Berman; Tal; (Rishon Le Ziyyon, IL) ; Ziv; Enbal;
(Gedera, IL) ; Schuz; David; (Gimzu, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Foamix Pharmaceuticals Ltd. |
Rehovot |
|
IL |
|
|
Assignee: |
Foamix Pharmaceuticals Ltd.
|
Family ID: |
39101639 |
Appl. No.: |
16/386710 |
Filed: |
April 17, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16189767 |
Nov 13, 2018 |
10322085 |
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16386710 |
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15903275 |
Feb 23, 2018 |
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16189767 |
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13796860 |
Mar 12, 2013 |
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15903275 |
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11825406 |
Jul 5, 2007 |
9265725 |
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13796860 |
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10532618 |
Dec 22, 2005 |
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PCT/IB2003/005527 |
Oct 24, 2003 |
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11825406 |
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10911367 |
Aug 4, 2004 |
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11825406 |
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11653205 |
Jan 12, 2007 |
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11825406 |
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10835505 |
Apr 28, 2004 |
7820145 |
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11653205 |
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10911367 |
Aug 4, 2004 |
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11653205 |
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11717897 |
Mar 13, 2007 |
8119109 |
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11825406 |
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11078902 |
Mar 11, 2005 |
9668972 |
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11717897 |
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60818634 |
Jul 5, 2006 |
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60429546 |
Nov 29, 2002 |
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60492385 |
Aug 4, 2003 |
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60530015 |
Dec 16, 2003 |
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60492385 |
Aug 4, 2003 |
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60492385 |
Aug 4, 2003 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 31/00 20180101;
A61K 9/122 20130101; A61P 9/00 20180101; A61P 29/00 20180101; A61K
8/4993 20130101; A61K 8/046 20130101; A61P 37/08 20180101; A61K
9/0014 20130101; A61K 8/86 20130101; A61Q 19/00 20130101; A01N
25/16 20130101; A61P 23/00 20180101; A61K 8/37 20130101; A61K 8/362
20130101 |
International
Class: |
A61K 9/12 20060101
A61K009/12; A61Q 19/00 20060101 A61Q019/00; A61K 9/00 20060101
A61K009/00; A61K 8/86 20060101 A61K008/86; A61K 8/49 20060101
A61K008/49; A61K 8/37 20060101 A61K008/37; A61K 8/362 20060101
A61K008/362; A61K 8/04 20060101 A61K008/04; A01N 25/16 20060101
A01N025/16 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 25, 2002 |
IL |
152486 |
Claims
1. A foamable composition comprising a carrier and a liquefied or a
compressed gas propellant, the carrier comprising: i. a
dicarboxylic acid ester; ii. about 0.2% to about 8% by weight of
the carrier of a surface-active agent; iii. about 2% to about 75%
by weight of the carrier of a hydrophobic solvent; and iv. water,
wherein upon release from a foam dispenser, a foam is produced.
2. The foamable composition of claim 1, wherein the liquefied or
compressed gas propellant is present at about 3% to about 25% by
weight of the carrier.
3. The foamable composition of claim 1, wherein the carrier further
comprises an active agent.
4. The foamable composition of claim 3, wherein the active agent is
selected from the group consisting of an active herbal extract, an
acaricide, an age spot and keratose removing agent, an allergen, an
analgesic, a local anesthetic, an antiacne agent, an antiallergic
agent, an antiaging agent, an antibacterial, an antibiotic, an
antibum agent, an anticancer agent, an antidandruff agent, an
antidepressant, an antidermatitis agent, an antiedemic, an
antihistamine, an antihelminth, an antihyperkeratolyte agent, an
antiinflammatory agent, an antiirritant, an antilipemic, an
antimicrobial, an antimycotic, an antiproliferative agent, an
antioxidant, an anti-wrinkle agent, an antipruritic, an
antipsoriatic agent, an antirosacea agent an antiseborrheic agent,
an antiseptic, an antiswelling agent, an antiviral agent, an
antiyeast agent, an astringent, a topical cardiovascular agent, a
chemotherapeutic agent, a corticosteroid, a dicarboxylic acid, a
disinfectant, a fungicide, a hair growth regulator, a hormone, a
hydroxy acid, an immunosuppressant, an immunoregulating agent, an
insecticide, an insect repellent, a keratolytic agent, a lactam, a
metal, a metal oxide, a mitocide, a neuropeptide, a non-steroidal
anti-inflammatory agent, an oxidizing agent, a pediculicide, a
photodynamic therapy agent, a retinoid, a sanative, a scabicide, a
self tanning agent, a skin whitening agent, a vasoconstrictor, a
vasodilator, a vitamin, a vitamin D derivative, a wound healing
agent, a wart remover and mixtures of any two or more thereof.
5. The foamable composition of claim 4, wherein the active agent
comprises tazarotene.
6. The foamable composition of claim 1, wherein the carrier
comprises one or more of an emulsion, a micro-emulsion, a
nano-emulsion and mixtures of any two or more thereof.
7. The foamable composition of claim 6, wherein the carrier
comprises a nano-emulsion.
8. The foamable composition of claim 1, wherein the dicarboxylic
acid ester is selected from the group consisting of diisobutyl
adipate, diisopropyl adipate, diisopropyl sebacate, diisostearyl
dimer dilinoleate, diisostearyl fumerate, diisopropyl dimerate,
diethyl adipate, diethyl sebacate, diethylhexyl adipate,
diethylhexyl malate, dioctyl malate, diethyl succinate, dioctyl
sebacate and mixtures of any two or more thereof.
9. The foamable composition of claim 8, comprising about 2% to
about 50% by weight of the carrier of diisopropyl adipate.
10. The foamable composition of claim 4, wherein the active agent
comprises a dicarboxylic acid selected from the group consisting of
oxalic acid, malonic acid, succinic acid, glutaric acid, adipic
acid, pimelic acid, suberic acid, azelaic acid, sebacic acid,
dodecanedioic acid, maleic acid, fumaric acid and mixtures of any
two or more thereof.
11. The foamable composition of claim 1, wherein the hydrophobic
solvent is selected from the group consisting of a mineral oil,
triglycerides, a medium chain triglyceride oil, capric/caprylic
triglyceride, alkyl esters of fatty acids, isopropyl palmitate,
isopropyl myristate, isopropyl isostearate, polypropylene glycol 15
stearyl ether, octyl palmitate, cetyl lactate, cetyl ricinoleate,
tocopheryl acetate, acetylated lanolin alcohol, cetyl acetate,
phenyl trimethicone, glyceryl oleate, tocopheryl linoleate, wheat
germ glycerides, arachidyl propionate, myristyl lactate, decyl
oleate, ricinoleate, isopropyl lanolate, pentaerythrityl
tetrastearate, neopentylglycol dicaprylate/dicaprate, isononyl
isononanoate, isotridecyl isononanoate, myristyl myristate,
triisocetyl citrate, octyl dodecanol, maleated soybean oil,
unsaturated or polyunsaturated oils, an olive oil, a corn oil, a
soybean oil, a canola oil, a cottonseed oil, a coconut oil, a
sesame oil, a sunflower oil, a borage seed oil, a syzigium
aromaticum oil, a hempseed oil, a herring oil, a cod-liver oil, a
salmon oil, a flaxseed oil, a wheat germ oil, evening primrose oil,
essential oils, silicone oils, a dimethicone, a cyclomethicone, a
polyalkyl siloxane, a polyaryl siloxane, a polyalkylaryl siloxane,
a polyether siloxane copolymer, a
poly(dimethylsiloxane)-(diphenyl-siloxane) copolymer, and mixtures
of any two or more thereof.
12. The foamable composition of claim 11, comprising a mineral
oil.
13. The foamable composition of claim 1, wherein the surface-active
agent is selected from the group consisting of a non ionic
surface-active agent, a cationic surface-active agent, an
amphoteric surface-active agent, an ionic surface-active agent and
mixtures of any two or more thereof.
14. The foamable composition of claim 13, wherein the
surface-active agent is selected from the group consisting of a
polysorbate, polyoxyethylene (20) sorbitan monostearate,
polyoxyethylene (20) sorbitan monooleate, a polyoxyethylene fatty
acid ester, polyoxyethylene (8) stearate, polyoxyethylene (20)
stearate, polyoxyethylene (40) stearate, a polyoxyethylene alkyl
ether, polyoxyethylene cetyl ether, polyoxyethylene (23) cetyl
ether, polyoxyethylene (2) cetyl ether, polyoxyethylene (20) cetyl
ether, a sucrose ester, a partial ester of sorbitol, sorbitan
monooleate, sorbitan monolaurate, sorbitan monostearate, a
monoglyceride, a diglyceride, glyceryl monostearate, isoceteth-20,
steareth 2, steareth 20, steareth 21, ceteareth 20, peg (40)
stearate, polyoxyethylene (100) stearate, polysorbate 20,
polysorbate 60, polysorbate 80, laureth 4, macrogol cetostearyl
ether, peg (30) dipolyhydroxystearate, cetearyl glucoside, methyl
glucose sequistearate, sucrose stearic acid esters, sucrose
distearate, and mixtures of any two or more thereof.
15. The foamable composition of claim 14, wherein the
surface-active agent comprises a macrogol cetostearyl ether.
16. The foamable composition of claim 1, wherein the foamable
composition further comprises about 0.1% to about 5% by weight of
the carrier of a foam adjuvant selected from the group consisting
of a fatty alcohol, a fatty acid and mixtures thereof.
17. The foamable composition of claim 1, wherein the foamable
composition further comprises about 0.01% to about 5% by weight of
the carrier of a polymeric agent selected from the group consisting
of a bioadhesive agent, a gelling agent, a film forming agent, a
phase change agent and mixtures of any two or more thereof.
18. The foamable composition of claim 1, wherein the carrier
further comprises an additional component selected from the group
consisting of a modulating agent, a polar solvent, an anti
perspirant, an anti-static agent, a buffering agent, a bulking
agent, a chelating agent, a colorant, a conditioner, a deodorant, a
diluent, a dye, an emollient, fragrance, a humectant, an occlusive
agent, a penetration enhancer, a perfuming agent, a permeation
enhancer, a pH-adjusting agent, a preservative, a skin penetration
enhancer, a sunscreen, a sun blocking agent, a sunless tanning
agent, a vitamin and mixtures of any two or more thereof.
19. A method of treating a disorder of a mammalian subject,
comprising administering the foamable composition of claim 1 to a
target site having a disorder, wherein the target site is selected
from the group consisting of the skin, a body cavity, a mucosal
surface, the nose, the mouth, the eye, the ear canal, the
respiratory system, the vagina and the rectum.
20. The method of claim 19, wherein the target site is the skin and
the disorder is selected from the group consisting of acne, acne
vulgaris, inflammatory acne, non-inflammatory acne, acne fulminans,
nodular papulopustular acne, acne conglobata and mixtures of any
two or more thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 11/825,406, filed on Jul. 5, 2007, which (1)
claims the benefit under 35 U.S.C. .sctn. 119(e) of U.S.
Provisional Patent Application No. 60/818,634, filed on Jul. 5,
2006, entitled "Dicarboxylic Acid Foamable Vehicle and
Pharmaceutical Compositions Thereof;" (2) is a continuation-in-part
of U.S. patent application Ser. No. 10/532,618, filed Dec. 22,
2005, which is a 371 of International Patent Application No.
1603/005527, designating the United States and filed on Oct. 24,
2003, which claims the benefit of priority under 35 U.S.C. .sctn.
119(e) to U.S. Patent Application No. 60/429,546, filed on Nov. 29,
2002, both entitled "Cosmetic and Pharmaceutical Foam," and which
claims the benefit of priority under 35 USC .sctn. 119(a) to
Israeli Patent Application No. 152486, filed Oct. 25, 2002; (3) is
a continuation-in-part of co-pending U.S. patent application Ser.
No. 10/911,367, filed on Aug. 4, 2004, which claims the benefit of
priority under 35 U.S.C. .sctn. 119(e) to U.S. Patent Application
No. 60/492,385, filed on Aug. 4, 2003, both entitled "Foam Carrier
Containing Amphiphilic Copolymer Gelling Agent;" (4) is a
continuation-in-part of co-pending application U.S. patent
application Ser. No. 11/653,205, filed on Jan. 12, 2007, entitled
"Oleaginous Pharmaceutical And Cosmetic Foam," which is a) a
continuation-in-part application of co-pending U.S. patent
application Ser. No. 10/835,505, filed on Apr. 28, 2004, which
claims the benefit of priority under 35 U.S.C. .sctn. 119(e) to
U.S. Patent Application No. 60/530,015, filed on Dec. 16, 2003, and
U.S. Patent Application No. 60/492,385, filed on Aug. 4, 2003, and
b) a continuation-in-part of U.S. patent application Ser. No.
10/911,367, filed on Aug. 4, 2004, which claims the benefit of
priority under 119(e) to U.S. Patent Application No. 60/492,385,
filed on Aug. 4, 2003; (5) is a continuation-in-part of co-pending
U.S. patent application Ser. No. 11/717,897, filed on Mar. 13,
2007, entitled "Foamable Compositions, Kits and Methods for
Hyperhidrosis;" and (6) is a continuation-in-part of co-pending
U.S. patent application Ser. No. 11/078,902, filed on Mar. 11,
2005, entitled "Nonsteroidal Immunomodulating Kit and Composition
and Uses Thereof;" all of which are incorporated herein by
reference in their entirety.
BACKGROUND OF THE INVENTION
[0002] This invention relates to foamable pharmaceutical and
cosmetic compositions.
[0003] External topical administration is an important route for
the administration of drugs in disease treatment. Many groups of
drugs, including, for example, antibiotic, anti-fungal,
anti-inflammatory, anesthetic, analgesic, anti-allergic,
corticosteroid, retinoid and anti-proliferative medications are
preferably administered in hydrophobic media, namely ointment.
However, ointments often form an impermeable barrier, so that
metabolic products and excreta from the wounds to which they are
applied are not easily removed or drained away. Furthermore, it is
difficult for the active drug dissolved in the carrier to pass
through the white petrolatum barrier layer into the wound tissue,
so the efficacy of the drug is reduced. In addition, ointments and
creams often do not create an environment for promoting respiration
of the wound tissue and it is not favorable to the normal
respiration of the skin. An additional disadvantage of petroleum
jelly-based products relates to the greasy feeling left following
their topical application onto the skin, mucosal membranes and
wounds.
[0004] Foams are considered a more convenient vehicle for topical
delivery of active agents. There are several types of topical
foams, including aqueous foams, such as commonly available shaving
foams; hydroalcoholic foams, emulsion-based foams, comprising oil
and water components, and oleaginous foams, which consist of high
oil content. In skin therapy, oil containing foams are preferred,
since oil contributes to skin protection and moisturization, which
improve the therapeutic effect of the formulation.
[0005] Dicarboxylic acids are known to possess therapeutic
properties. Dicarboxylic acids, and their mercapto, ester and salt
derivatives have been used in the treatment of a variety of skin
disorders and/or conditions.
[0006] Azelaic acid (AZA) is a naturally occurring nine carbon
straight chain molecule with two terminal carboxyl groups. AZA is
an anti-keratinizing agent, displaying antiproliferative effects on
keratinocytes and modulating the early and terminal phases of
epidermal differentiation. AZA is a competitive inhibitor of the
reduction of testosterone to dihydrotestosterone, and as such is
supposed to reduce the production of sebum in the sebaceous gland.
Furthermore, recent investigations have demonstrated that AZA and
sebacic acid also have anti-bacterial and anti-fungal properties.
Structure-activity relationship studies have revealed that these
effects are retained when the dicarboxylic acid has a backbone of
about 6 to about 14 carbons.
[0007] Dicarboxylic acid esters are also known to contribute to the
skin penetration of an active agent. Enhancing effects on skin
penetration of methyl nicotinate have been observed with dibutyl
adipate and dioctyl adipate. Diisopropyl sebacate also markedly
enhances the skin penetration of the erythromycin. The skin
penetration enhancing properties of mono- or di-esters of
dicarboxylic acid, including dibutyl adipate, diethyl sebacate,
diisopropyl dimerate, diisopropyl adipate, diisopropyl sebacate and
dioctyl succinate have been recognized.
[0008] There remains an unmet need for improved, easy to use,
stable oil-containing foam formulations, containing oils, which
effectively deliver and/or deposit various benefit agents into and
onto the skin and/or other target sites and are relatively
non-irritating and thus suitable for use by people having sensitive
skin and eyes.
SUMMARY
[0009] The present invention relates to aqueous and non aqueous
stable compositions comprising a dicarboxylic acid or ester
derivative thereof in which the dicarboxylic acid or ester
derivative is a stabilizing emollient and or has a therapeutic
effect.
[0010] There is provided a pharmaceutical or cosmetic composition
comprising: [0011] a. a beneficially or therapeutically effective
concentration of at least one benefit agent, selected from the
group consisting of [0012] i. a dicarboxylic acid; and [0013] ii. a
dicarboxylic acid ester; [0014] b. a stabilizer selected from the
group consisting of at least one surface-active agent; at least one
polymeric agent and mixtures thereof; and [0015] c. a solvent
selected from the group consisting of water; a hydrophilic solvent;
a hydrophobic solvent; a potent solvent; a polar solvent, a
silicone, an emollient, and mixtures thereof; [0016] wherein the
benefit agent is an emollient solvent and or a pharmaceutical or
cosmetic agent; [0017] wherein the polymeric agent is about 0.01%
to about 5% by weight and is selected from the group consisting of
a bioadhesive agent, a gelling agent, a film forming agent and a
phase change agent; [0018] wherein the benefit agent, stabilizer
and solvent are selected to provide a composition that is
substantially resistant to aging and to phase separation and or can
substantially stabilize other active ingredients; and [0019]
wherein if the composition is contained in a pressurized container
and further comprises a liquefied hydrocarbon gas propellant at a
concentration of about 3% to about 25% by weight of the total
composition it is substantially flowable and provides a foam upon
release.
[0020] There is also provided a foamable composition as described
above wherein the composition is contained in a pressurized
container and further comprises a liquefied hydrocarbon gas
propellant at a concentration of about 3% to about 25% by weight of
the total composition, is substantially flowable and provides a
foam upon release and wherein the benefit agent, stabilizer and
solvent are selected to generate a breakable foam of good to
excellent quality.
[0021] There is also provided a therapeutic composition comprising:
[0022] a. a therapeutically effective amount of an active agent;
[0023] b. a beneficially or therapeutically effective concentration
of at least one benefit agent, selected from the group consisting
of [0024] i. a dicarboxylic acid; and [0025] ii. a dicarboxylic
acid ester; [0026] c. a stabilizer selected from the group
consisting of at least one surface-active agent; at least one
polymeric agent and mixtures thereof; and [0027] d. a solvent
selected from the group consisting of water; a hydrophilic solvent;
a hydrophobic solvent; a potent solvent; a polar solvent, a
silicone, an emollient, and mixtures thereof; [0028] wherein the
benefit agent is an emollient solvent and or a pharmaceutical or
cosmetic agent; [0029] wherein the polymeric agent is about 0.01%
to about 5% by weight and is selected from the group consisting of
a bioadhesive agent, a gelling agent, a film forming agent and a
phase change agent; [0030] wherein the benefit agent, stabilizer
and solvent are selected to provide a composition that is
substantially resistant to aging and to phase separation and or can
substantially stabilize other active ingredients; and [0031]
wherein if the composition is contained in a pressurized container
and further comprises a liquefied hydrocarbon gas propellant at a
concentration of about 3% to about 25% by weight of the total
composition it is substantially flowable and provides a foam upon
release.
[0032] There is also provided a method of treating a disorder of a
mammalian subject, comprising: [0033] administering a foamable
therapeutic composition to a target site, the composition
comprising: [0034] e. a therapeutically effective amount of an
active agent; [0035] f. a beneficially or therapeutically effective
concentration of at least one benefit agent, selected from the
group consisting of [0036] i. a dicarboxylic acid; and [0037] ii. a
dicarboxylic acid ester; [0038] g. a stabilizer selected from the
group consisting of at least one surface-active agent; at least one
polymeric agent and mixtures thereof. [0039] h. a solvent selected
from the group consisting of water; a hydrophilic solvent; a
hydrophobic solvent; a potent solvent; a polar solvent, a silicone,
an emollient, and mixtures thereof; [0040] wherein the benefit
agent is an emollient solvent and or a pharmaceutical or cosmetic
agent; [0041] wherein the polymeric agent is about 0.01% to about
5% by weight and is selected from the group consisting of a
bioadhesive agent, a gelling agent, a film forming agent and a
phase change agent; [0042] wherein the benefit agent, stabilizer
and solvent are selected to provide a composition that is
substantially resistant to aging and to phase separation and or can
substantially stabilize other active ingredients; and [0043]
wherein if the composition is contained in a pressurized container
and further comprises a liquefied hydrocarbon gas propellant at a
concentration of about 3% to about 25% by weight of the total
composition it is substantially flowable and provides a foam upon
release.
[0044] There is also provided a pharmaceutical or cosmetic non
aqueous composition comprising: [0045] a. a beneficially or
therapeutically effective concentration of at least one benefit
agent, selected from the group consisting of [0046] i. a
dicarboxylic acid; and [0047] ii. a dicarboxylic acid ester; [0048]
b. a stabilizer selected from the group consisting of at least one
surface-active agent; at least one polymeric agent and mixtures
thereof; and [0049] c. a solvent selected from the group consisting
of a hydrophilic solvent; a hydrophobic solvent; a potent solvent;
a polar solvent, a silicone, an emollient, and mixtures thereof;
[0050] wherein the benefit agent is an emollient solvent and or a
pharmaceutical or cosmetic agent; [0051] wherein the polymeric
agent is about 0.01% to about 5% by weight and is selected from the
group consisting of a bioadhesive agent, a gelling agent, a film
forming agent and a phase change agent; [0052] wherein the benefit
agent, stabilizer and solvent are selected to provide a composition
that is substantially resistant to aging and to phase separation
and or can substantially stabilize other active ingredients; and
[0053] wherein if the composition is contained in a pressurized
container and further comprises a liquefied hydrocarbon gas
propellant at a concentration of about 3% to about 25% by weight of
the total composition it is substantially flowable and provides a
foam upon release.
[0054] There is also provided a therapeutic composition comprising:
[0055] a. a therapeutically effective amount of an active agent
wherein the active agent is substantially insoluble in water;
[0056] b. a beneficially or therapeutically effective concentration
of at least one benefit agent, comprising a dicarboxylic acid ester
in which the active agent is substantially soluble; [0057] c. a
stabilizer selected from the group consisting of at least one
surface-active agent; at least one polymeric agent and mixtures
thereof; and [0058] d. a solvent selected from the group consisting
of water; a hydrophilic solvent; a hydrophobic solvent; a potent
solvent; a polar solvent, a silicone, an emollient, and mixtures
thereof; [0059] wherein the benefit agent is an emollient solvent
and or a pharmaceutical or cosmetic agent; [0060] wherein the
polymeric agent is about 0.01% to about 5% by weight and is
selected from the group consisting of a bioadhesive agent, a
gelling agent, a film forming agent and a phase change agent;
[0061] wherein the benefit agent, stabilizer and solvent are
selected to provide a composition that is substantially resistant
to aging and to phase separation and or can substantially stabilize
other active ingredients; and [0062] wherein if the composition is
contained in a pressurized container and further comprises a
liquefied hydrocarbon gas propellant at a concentration of about 3%
to about 25% by weight of the total composition it is substantially
flowable and provides a foam upon release.
[0063] There is also provided a foamable composition comprising:
[0064] a. a liquid dicarboxylic acid ester, said ester having
emollient properties; [0065] b. a stabilizer selected from the
group consisting of at least one surface-active agent; at least one
polymeric agent and mixtures thereof. [0066] c. an active agent,
said active agent soluble in or having enhanced penetration due to
the dicarboxylic acid; [0067] wherein the composition is contained
in a pressurized container and further comprises a liquefied
hydrocarbon gas propellant at a concentration of about 3% to about
25% by weight of the total composition it is substantially flowable
and provides a foam upon release.
[0068] There is also provided a foamable composition comprising:
[0069] a. a beneficially or therapeutically effective concentration
of at least one benefit agent, selected from the group consisting
of [0070] i. a dicarboxylic acid; and [0071] ii. a dicarboxylic
acid ester; [0072] b. an ester-based or ether-based surfactant;
[0073] c. a solvent selected from the group consisting of a
hydrophilic solvent; a hydrophobic solvent; a potent solvent; a
polar solvent, a silicone, an emollient, and mixtures thereof;
[0074] wherein the composition is substantially free of polymeric
material, and [0075] wherein the composition is contained in a
pressurized container and further comprises a liquefied hydrocarbon
gas propellant at a concentration of about 3% to about 25% by
weight of the total composition it is substantially flowable and
provides a foam upon release.
[0076] There is also provided a pharmaceutical or cosmetic
composition comprising: [0077] a. a beneficially or therapeutically
effective concentration of at least one benefit agent, selected
from the group consisting of [0078] i. a dicarboxylic acid; and
[0079] ii. a dicarboxylic acid ester; [0080] b. a stabilizer
selected from the group consisting of at least one surface-active
agent; at least one polymeric agent and mixtures thereof; and
[0081] c. a solvent selected from the group consisting of a
hydrophilic solvent; a hydrophobic solvent; a potent solvent; a
polar solvent, a silicone, an emollient, and mixtures thereof;
[0082] wherein the composition is substantially free of water; and
[0083] wherein the composition is contained in a pressurized
container and further comprises a liquefied hydrocarbon gas
propellant at a concentration of about 3% to about 25% by weight of
the total composition it is substantially flowable and provides a
foam upon release.
[0084] There is also provided a formulation of any of the
compositions described above wherein the composition is in a non
foam state.
[0085] There is also provided a formulation of any of the
compositions described above for use in the manufacture of a
medicament.
DETAILED DESCRIPTION
[0086] The present invention relates to a composition comprising a
benefit agent, selected from the group consisting of (i) a
dicarboxylic acid; and (ii) a dicarboxylic acid ester for use as
vehicle composition.
[0087] According to one or more embodiments of the present
invention, the composition includes: [0088] a. a benefit agent,
selected from the group consisting of [0089] i. a dicarboxylic
acid; and [0090] ii. a dicarboxylic acid ester; [0091] b. a
surface-active agent; [0092] c. about 0.01% to about 5% by weight
of at least one polymeric agent selected from the group consisting
of a bioadhesive agent, a gelling agent, a film forming agent and a
phase change agent; and [0093] d. water.
[0094] The present invention further relates to a foamable
composition including: [0095] a. a benefit agent, selected from the
group consisting of [0096] i. a dicarboxylic acid; and [0097] ii. a
dicarboxylic acid ester; [0098] b. a surface-active agent; [0099]
c. about 0.01% to about 5% by weight of at least one polymeric
agent selected from the group consisting of a bioadhesive agent, a
gelling agent, a film forming agent and a phase change agent;
[0100] d. water; and [0101] e. liquefied hydrocarbon gas propellant
at a concentration of about 3% to about 25% by weight of the total
composition.
[0102] In one or more embodiments there is provided a
pharmaceutical or cosmetic composition comprising: [0103] a. a
beneficially or therapeutically effective concentration of at least
one benefit agent, selected from the group consisting of [0104] i.
a dicarboxylic acid; and [0105] ii. a dicarboxylic acid ester;
[0106] b. a stabilizer selected from the group consisting of at
least one surface-active agent; at least one polymeric agent and
mixtures thereof. [0107] c. a solvent selected from the group
consisting of water; a hydrophilic solvent; a hydrophobic solvent;
a potent solvent; a polar solvent, a silicone, an emollient, and
mixtures thereof; [0108] wherein the benefit agent is an emollient
solvent and or a pharmaceutical or cosmetic agent [0109] wherein
the polymeric agent is about 0.01% to about 5% by weight and is
selected from the group consisting of a bioadhesive agent, a
gelling agent, a film forming agent and a phase change agent;
[0110] wherein the benefit agent, stabilizer and solvent are
selected to provide a composition that is substantially resistant
to aging and to phase separation and or can substantially stabilize
other active ingredients; [0111] wherein if the composition is
contained in a pressurized container and further comprises a
liquefied hydrocarbon gas propellant at a concentration of about 3%
to about 25% by weight of the total composition it is substantially
flowable and provides a foam upon release.
[0112] In one or more embodiments there is provided a foamable
composition which produces a foam upon release and wherein the
benefit agent, stabilizer and solvent are selected to generate a
breakable foam of good to excellent quality.
[0113] In one or more embodiments there is provided a composition
wherein the benefit agent, stabilizer and solvent are selected to
generate an emulsion that is substantially resistant to phase
reversal.
[0114] In one or more embodiments there is provided a composition
wherein, the benefit agent, stabilizer and solvent are selected to
generate a single phase.
[0115] In one or more embodiments there is provided a composition
wherein, the benefit agent, stabilizer and solvent are selected to
generate a substantially uniform suspension of benefit agent
crystals.
[0116] In one or more embodiments there is provided a composition,
wherein the breakable foam comprises micro or nano particles,
crystals or bodies.
[0117] In one or more embodiments there is provided a composition,
which is substantially resistant to one or more Freeze-Thaw cycles
(FTC).
[0118] In one or more embodiments there is provided a composition
wherein the surface-active agent is a solid, a liquid or a mixture
thereof.
[0119] In one or more embodiments there is provided a composition
wherein the surface active agent is selected from the group
consisting of a polysorbate, polyoxyethylene (20) sorbitan
monostearate, polyoxyethylene (20) sorbitan monooleate, a
polyoxyethylene fatty acid ester, Myrj 45, Myrj 49, Myrj 52 and
Myrj 59; a polyoxyethylene alkylyl ether, polyoxyethylene cetyl
ether, polyoxyethylene palmityl ether, polyethylene oxide hexadecyl
ether, polyethylene glycol cetyl ether, brij 38, brij 52, brij 56
and brij W1, a sucrose ester, a partial ester of sorbitol, sorbitan
monolaurate, sorbitan monolaurate a monoglyceride, a diglyceride,
isoceteth-20, a sucrose ester, or selected from the group
consisting of steareth 2, glyceryl monostearate/PEG 100 stearate,
Glyceryl Stearate, Steareth-21, peg 40 stearate, polysorbate 60,
polysorbate 80, sorbitan stearate, laureth 4, Sorbitan monooleate,
ceteareth 20, steareth 20, ceteth 20, Macrogol Cetostearyl Ether,
ceteth 2, PEG-30 Dipolyhydroxystearate, sucrose distearate,
polyoxyethylene (100) stearate, PEG 100 stearate, laureth 4,
cetomacrogol ether, Cetearyl alcohol, Cetearyl glucoside, Oleyl
alcohol, Steareth-2, Diisopropyl adipate, Capric/caprilic
triglicerides, Polysorbate 20; Montanov 68 (CETEARYL ALCOHOL (and)
CETEARYL GLUCOSIDE), Sharonmix 824 (a liquid blend of methyl
paraben, ethyl paraben and propyl paraben--in phenoxyethanol),
Simusol 165 (Glyceryl stearate and PEG-100 stearate). Methyl
glucose sequistearate, Peg 30 dipolyhydroxystearate, sucrose
stearic acid esters, sorbitan laureth, sorbitan stearate and
mixtures thereof.
[0120] In one or more embodiments there is provided a composition
wherein the surface active agent comprises at least one ester based
surfactant or at least one ether based surfactant.
[0121] In one or more embodiments there is provided a composition
wherein the surface active agent is reduced about in proportion to
the increase in dicarboxylic ester.
[0122] In one or more embodiments there is provided a composition
wherein the stabilizer is not a polymeric agent.
[0123] In one or more embodiments there is provided a composition
wherein the surface active agent comprises a non-ionic surfactant
that does not contain a polyoxyethylene (POE) moiety.
[0124] In one or more embodiments there is provided a composition
wherein the surface active agent is selected from the group
consisting of a non-ethoxylated sorbitan ester, a glycerol fatty
acid ester, a sucrose ester and an alkyl polyglycoside or is
selected from the group consisting of sorbitan monopalmitate,
sorbitan monostearate, sorbitan tristearate, sorbitan monooleate,
sorbitan trioleate, sorbitan monolaurate, sorbitan sesquioleate,
glycerol monostearate, glycerol monooleate, sucrose stearate,
sucrose distearate, sucrose palmitate sucrose laurate and lauryl
diglucoside.
[0125] In one or more embodiments there is provided a composition
wherein the polymeric agent is selected from the group consisting
of carbopol 934, pemulen TR2, klucel EF, xanthan gum, methocel A4M,
and carboxy methyl cellulose or selected from the group consisting
of locust bean gum, sodium alginate, sodium caseinate, egg albumin,
gelatin agar, carrageenin gum, sodium alginate, xanthan gum, quince
seed extract, tragacanth gum, guar gum, cationic guars,
hydroxypropyl guar gum, starch, an amine-bearing polymer, chitosan,
alginic acid, hyaluronic acid, a chemically modified starch, a
carboxyvinyl polymer, polyvinylpyrrolidone, polyvinyl alcohol, a
polyacrylic acid polymer, a polymethacrylic acid polymer, polyvinyl
acetate, a polyvinyl chloride polymer, a polyvinylidene chloride
polymer, methylcellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, hydroxyethyl cellulose, hydroxy propylmethyl
cellulose, methylhydroxyethylcellulose,
methylhydroxypropylcellulose, hydroxyethylcarboxymethylcellulose,
carboxymethyl cellulose, carboxymethylcellulose
carboxymethylhydroxyethylcellulose, a cationic cellulose aluminum
starch octenylsuccinate (ASOS), PEG 1000, PEG 4000, PEG 6000 and
PEG 8000.
[0126] In one or more embodiments there is provided a composition
wherein the polymeric agent is a derivatized polymer.
[0127] In one or more embodiments there is provided a composition
wherein the derivatized polymer is a polymeric emulsifier.
[0128] In one or more embodiments there is provided a composition
wherein the benefit agent is selected from the group consisting of
diisopropyl adipate, dimethyl sebacate, dioctyl malate, diethyl
sebacate, azelaic acid and TU-2100.
[0129] In one or more embodiments there is provided a composition
wherein, further comprising an additional active agent.
[0130] In one or more embodiments there is provided a composition
wherein the dicarboxylic acid has the molecular formula
HOOC--(CH.sub.2).sub.n--COON; and wherein n is in the range between
0 and 32.
[0131] In one or more embodiments there is provided a composition
wherein n is in the range between 4 and 10.
[0132] In one or more embodiments there is provided a composition
wherein the dicarboxylic acid is selected from the group consisting
of oxalic acid, malonic acid, succinic acid, glutaric acid, adipic
acid, pimelic acid, suberic acid, azelaic acid, sebacic acid and
dodecanedioic acid, maleic acid and fumaric acid.
[0133] In one or more embodiments there is provided a composition
wherein the dicarboxylic acid is selected from the group consisting
of adipic acid, azelaic acid and sebacic acid.
[0134] In one or more embodiments there is provided a composition
wherein further containing a foam adjuvant selected from the group
consisting of a fatty alcohol having 15 or more carbons in their
carbon chain; a fatty acid having 16 or more carbons in their
carbon chain; fatty alcohols, derived from beeswax and including a
mixture of alcohols, a majority of which has at least 20 carbon
atoms in their carbon chain; a fatty alcohol having at least one
double bond; a fatty acid having at least one double bond; a
branched fatty alcohol; a branched fatty acid and a fatty acid
substituted with a hydroxyl group.
[0135] In one or more embodiments there is provided a composition
wherein further containing at least one organic carrier selected
from the group consisting of a hydrophobic organic carrier, an
emollient and mixtures thereof, at a concentration of about 2% to
about 50% by weight.
[0136] In one or more embodiments there is provided a composition
wherein the dicarboxylic acid or dicarboxylic acid ester is in a
concentration between about 0.1% and about 60%.
[0137] In one or more embodiments there is provided a composition
wherein the dicarboxylic acid is azelaic acid, and wherein the
concentration of azelaic acid is between 5% and 25%.
[0138] In one or more embodiments there is provided a composition
wherein the pH of the composition is below the first pKa of the
dicarboxylic acid.
[0139] In one or more embodiments there is provided a composition
wherein the pH of the composition is between the first and second
pKa of the dicarboxylic acid.
[0140] In one or more embodiments there is provided a composition
wherein the pH of the composition is above the second pKa of the
dicarboxylic acid.
[0141] In one or more embodiments there is provided a composition
wherein the dicarboxylic acid is azelaic acid the pH of the
composition is below 5.3.
[0142] In one or more embodiments there is provided a composition
wherein the dicarboxylic acid is azelaic acid the pH of the
composition is between about 4.5 and about 5.3.
[0143] In one or more embodiments there is provided a composition
wherein the dicarboxylic acid ester is selected from the group
consisting of a mono ester of said dicarboxylic acid, and a diester
of the dicarboxylic acid.
[0144] In one or more embodiments there is provided a composition
wherein the alcohol moiety of the dicarboxylic acid ester is
selected from the group consisting of an alkyl alcohol, an aryl
alcohol, methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl
alcohol, butyl alcohol, isobutyl alcohol, t-butyl alcohol, pentyl
alcohol, hexyl alcohol, octyl alcohol, decyl alcohol, capryl
alcohol, phenol and benzyl alcohol.
[0145] In one or more embodiments there is provided a composition
wherein the alcohol moiety of the dicarboxylic acid ester is a
biologically active alcohol.
[0146] In one or more embodiments there is provided a composition
wherein the biologically active alcohol is selected from the group
consisting of a hydroxyalkylbenzoate, salicylic acid, a
dihydroxybenzene, hydroxytoluene, an alpha-hydroxy acid, retinol, a
vitamin A derivative, a steroid, vitamin E, a vitamin E derivative,
vitamin D and a vitamin D derivative.
[0147] In one or more embodiments there is provided a composition
wherein the dicarboxylic acid ester is selected from the group
consisting of diisobutyl adipate, diisopropyl adipate, diisopropyl
sebacate, diisosteary dimer dilinoleate, diisostearyl fumerate,
diisopropyl dimerate, diethyl adipate, diethyl sebacate,
diethylhexyl adipate, diethylhexyl malate, dioctyl malate, diethyl
succinate, and dioctyl sebacate.
[0148] In one or more embodiments there is provided a composition
wherein the dicarboxylic acid ester is diisopropyl adipate, in an
amount from about 0.1% to about 60%
[0149] In one or more embodiments there is provided a composition
wherein the organic carrier is selected from the group consisting
of mineral oil, triglycerides, medium chain triglyceride (MCT) oil,
capric/caprylic triglyceride, alkyl esters of fatty acids such as
isopropyl palmitate, isopropyl myristate, isopropyl isostearate,
poly propylene glycol 15-stearly ether, octyl palmitate, cetyl
lactate, cetyl ricinoleate, tocopheryl acetate, acetylated lanolin
alcohol, cetyl acetate, phenyl trimethicone, glyceryl oleate,
tocopheryl linoleate, wheat germ glycerides, arachidyl propionate,
myristyl lactate, decyl oleate, ricinoleate, isopropyl lanolate,
pentaerythrityl tetrastearate, neopentylglycol
dicaprylate/dicaprate, isononyl isononanoate, isotridecyl
isononanoate, myristyl myristate, triisocetyl citrate, octyl
dodecanol, maleated soybean oil, unsaturated or polyunsaturated
oils, such as olive oil, corn oil, soybean oil, canola oil,
cottonseed oil, coconut oil, sesame oil, sunflower oil, borage seed
oil, syzigium aromaticum oil, hempseed oil, herring oil, cod-liver
oil, salmon oil, flaxseed oil, wheat germ oil, evening primrose
oils; essential oils; and silicone oils, such as dimethicone,
cyclomethicone, polyalkyl siloxane, polyaryl siloxane,
polyalkylaryl siloxane, a polyether siloxane copolymer and a
poly(dimethylsiloxane)-(diphenyl-siloxane) copolymer.
[0150] In one or more embodiments there is provided a composition
wherein the organic carrier comprises a polypropylene glycol alkyl
ether.
[0151] In one or more embodiments there is provided a composition
further containing at least one polar solvent.
[0152] In one or more embodiments there is provided a composition
wherein the polar solvent is selected from the group consisting of
dimethyl isosorbide, glycerol, propylene glycol, hexylene glycol,
diethylene glycol, propylene glycol n-alkanols, terpenes,
di-terpenes, tri-terpenes, limonene, terpene-ol, 1-menthol,
dioxolane, ethylene glycol, other glycols, oleyl alcohol,
alpha-hydroxy acids, such as lactic acid and glycolic acid,
sulfoxides, such as dimethylsulfoxide (DMSO), dimethylformanide,
methyl dodecyl sulfoxide, dimethylacetamide, azone
(1-dodecylazacycloheptan-2-one), 2-(n-nonyI)-1,3-dioxolane,
alkanols, such as dialkylamino acetates, and admixtures
thereof.
[0153] In one or more embodiments there is provided a composition
wherein the organic carrier is capric/caprylic triglyceride and
wherein the dicarboxylic acid is azelaic acid.
[0154] In one or more embodiments there is provided a composition
wherein the polar solvent is selected from the group consisting of
dimethyl isosorbide, glycerol, propylene glycol, hexylene glycol,
terpene-ol, oleyl alcohol, lactic acid and glycolic acid wherein
the dicarboxylic acid is azelaic acid.
[0155] In one or more embodiments there is provided a composition
wherein the organic carrier is capric/caprylic triglyceride.
[0156] In one or more embodiments there is provided a composition
wherein the organic solvent comprises at least one organic carrier,
selected from the group capric/caprylic triglyceride, a
polypropylene glycol alkyl ether an ester of a fatty acid and
mineral oil and wherein the dicarboxylic acid ester is diisopropyl
adipate.
[0157] In one or more embodiments there is provided a composition
further comprising a polar solvent, selected from the group
consisting of dimethyl isosorbide, glycerol, propylene glycol,
hexylene glycol, terpene-ol, oleyl alcohol, lactic acid and
glycolic acid.
[0158] In one or more embodiments there is provided a composition
wherein the benefit agent, stabilizer and solvent are selected to
generate an emulsion that can produce a substantially strong and
closed packed barrier between the oil and the water phases whilst
maintaining a fluid constitution
[0159] In one or more embodiments there is provided a composition
further comprising an additional component selected from the group
consisting of a modulating agent, a polar solvent, an anti
perspirant, an anti-static agent, a buffering agent, a bulking
agent, a chelating agent, a colorant, a conditioner, a deodorant, a
diluent, a dye, an emollient, fragrance, a humectant, an occlusive
agent, a penetration enhancer, a perfuming agent, a permeation
enhancer, a pH-adjusting agent, a preservative, a skin penetration
enhancer, a sunscreen, a sun blocking agent, a sunless tanning
agent, and a vitamin.
[0160] In one or more embodiments there is provided a composition
wherein the organic carrier is selected from the group consisting
of PPG 15-stearyl ether, isopropyl myristate and medium chain
triglyceride oil and capric/caprylic triglyceride and the benefit
agent is a solid at ambient temperature.
[0161] In one or more embodiments there is provided a therapeutic
composition comprising therapeutically effective amount of an
active agent; and a beneficially or therapeutically effective
concentration of at least one benefit agent, selected from the
group consisting of: [0162] i. a dicarboxylic acid; and [0163] ii.
a dicarboxylic acid ester [0164] wherein the active agent is
selected from the group consisting of active herbal extracts,
acaricides, age spot and keratose removing agents, allergen,
analgesics, local anesthetics, antiacne agents, antiallergic
agents, antiaging agents, antibacterials, antibiotics, antiburn
agents, anticancer agents, antidandruff agents, antidepressants,
antidermatitis agents, antiedemics, antihistamines, antihelminths,
antihyperkeratolyte agents, antiinflammatory agents, antiirritants,
antilipemics, antimicrobials, antimycotics, antiproliferative
agents, antioxidants, anti-wrinkle agents, antipruritics,
antipsoriatic agents, antirosacea agents antiseborrheic agents,
antiseptic, antiswelling agents, antiviral agents, antiyeast
agents, astringents, topical cardiovascular agents,
chemotherapeutic agents, corticosteroids, dicarboxylic acids,
disinfectants, fungicides, hair growth regulators, hormones,
hydroxy acids, immunosuppressants, immunoregulating agents,
insecticides, insect repellents, keratolytic agents, lactams,
metals, metal oxides, mitocides, neuropeptides, non-steroidal
anti-inflammatory agents, oxidizing agents, pediculicides,
photodynamic therapy agents, retinoids, sanatives, scabicides, self
tanning agents, skin whitening agents, vasoconstrictors,
vasodilators, vitamins, vitamin D derivatives, wound healing agents
and wart removers.
[0165] In one or more embodiments there is provided a foamable
therapeutic composition wherein the dicarboxylic acid ester is
present in the composition in an amount sufficient to solubilize
the active agent.
[0166] In one or more embodiments there is provided a foamable
therapeutic composition wherein the active agent is a steroid.
[0167] In one or more embodiments there is provided a foamable
therapeutic composition wherein the steroid is selected from the
group consisting of bydrocortisone, hydroxyltriamcinolone,
alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethsone
dipropionate, clobetasol valemate, desonide, desoxymethasone,
desoxycorticosterone acetate, dexamethasone, dichlorisone,
diflorasone diacetate, diflucortolone valerate, fluadrenolone,
fluclorolone acetonide, fludrocortisone, flumethasone pivalate,
fluosinolone acetonide, fluocinonide, flucortine butylester,
fluocortolone, fluprednidene (fluprednylidene) acetate,
flurandrenolone, halcinonide, hydrocortisone acetate,
hydrocortisone butyrate, methylprednisolone, triamcinolone
acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone,
difluorosone diacetate, fluradrenolone acetonide, medrysone,
amcinafel, amcinafide, betamethasone and the balance of its esters,
chloroprednisone, chlorprednisone acetate, clocortelone,
clescinolone, dichlorisone, difluprednate, flucloronide,
flunisolide, fluoromethalone, fluperolone, fluprednisolone,
hydrocortisone valerate, hydrocortisone cyclopentylpropionate,
hydrocortmate, mepreddisone, paramethasone, prednisolone,
prednisone, beclomethasone dipropionate, triamcinolone.
[0168] In one or more embodiments there is provided a foamable
therapeutic composition wherein the active agent is an
immunomodulator.
[0169] In one or more embodiments there is provided a foamable
therapeutic composition, wherein the immunomodulator is selected
from the group consisting of a cyclic peptides, cyclosporine,
tacrolimus, tresperimus, pimecrolimus, sirolimus, verolimus,
laflunimus, laquinimod and imiquimod.
[0170] In one or more embodiments there is provided a foamable
therapeutic composition, wherein the dicarboxylic acid ester is
present in the composition in an amount sufficient to solubilize
the immunomodulator.
[0171] In one or more embodiments there is provided a foamable
therapeutic composition, wherein the dicarboxylic acid ester is
diisopropyl adipate.
[0172] In one or more embodiments there is provided a composition
wherein the surface active agent comprises a non-ionic surfactant
that does not contain a polyoxyethylene (POE) moiety.
[0173] In one or more embodiments there is provided a composition
wherein the surface active agent is selected from the group
consisting of a non-ethoxylated sorbitan ester, a glycerol fatty
acid ester, a sucrose ester and an alkyl polyglycoside or is
selected from the group consisting of sorbitan monopalmitate,
sorbitan monostearate, sorbitan tristearate, sorbitan monooleate,
sorbitan trioleate, sorbitan monolaurate, sorbitan sesquioleate,
glycerol monostearate, glycerol monooleate, sucrose stearate,
sucrose distearate, sucrose palmitate sucrose laurate and lauryl
diglucoside.
[0174] In one or more embodiments there is provided a composition
wherein the dicarboxylic acid is azelaic acid.
[0175] In one or more embodiments there is provided a composition
wherein the dicarboxylic acid is azelaic acid and further
comprising an organic solvent comprising capric/caprylic
triglyceride.
[0176] In one or more embodiments there is provided a composition
wherein the dicarboxylic acid is azelaic acid and further
comprising an organic solvent comprising capric/caprylic
triglyceride and further comprising at least one polar carrier,
selected from the group consisting of dimethyl isosorbide,
glycerol, propylene glycol, hexylene glycol, terpene-ol, oleyl
alcohol, lactic acid and glycolic acid.
[0177] In one or more embodiments there is provided a method of
treating a disorder of a mammalian subject, comprising: [0178]
administering a foamable therapeutic composition to a target site,
the composition comprising a therapeutically effective amount of an
active agent; and a beneficially or therapeutically effective
concentration of at least one benefit agent, selected from the
group consisting of [0179] i. a dicarboxylic acid; and [0180] ii. a
dicarboxylic acid ester; wherein the target site is selected from
the group consisting of the skin, a body cavity, a mucosal surface,
the nose, the mouth, the eye, the ear canal, the respiratory
system, the vagina and the rectum.
[0181] In one or more embodiments there is provided a method of
treating a disorder of a mammalian subject, wherein the disorder is
selected from the group consisting of dermatological pain,
dermatological inflammation, acne, acne vulgaris, inflammatory
acne, non-inflammatory acne, acne fulminans, nodular papulopustular
acne, acne conglobata, dermatitis, bacterial skin infections,
fungal skin infections, viral skin infections, parasitic skin
infections, skin neoplasia, skin neoplasms, pruritis, cellulitis,
acute lymphangitis, lymphadenitis, erysipelas, cutaneous abscesses,
necrotizing subcutaneous infections, scalded skin syndrome,
folliculitis, furuncles, hidradenitis suppurativa, carbuncles,
paronychial infections, rashes, erythrasma, impetigo, ecthyma,
yeast skin infections, warts, molluscum contagiosum, trauma or
injury to the skin, post-operative or post-surgical skin
conditions, scabies, pediculosis, creeping eruption, eczemas,
psoriasis, pityriasis rosea, lichen planus, pityriasis rubra
pilaris, edematous, erythema multiforme, erythema nodosum,
granuloma annulare, epidermal necrolysis, sunburn,
photosensitivity, pemphigus, bullous pemphigoid, dermatitis
herpetiformis, keratosis pilaris, callouses, corns, ichthyosis,
skin ulcers, ischemic necrosis, miliaria, hyperhidrosis, moles,
Kaposi's sarcoma, melanoma, malignant melanoma, basal cell
carcinoma, squamous cell carcinoma, poison ivy, poison oak, contact
dermatitis, atopic dermatitis, rosacea, purpura, moniliasis,
candidiasis, baldness, alopecia, Behcet's syndrome, cholesteatoma,
Dercum disease, ectodermal dysplasia, gustatory sweating, nail
patella syndrome, lupus, hives, hair loss, Hailey-Hailey disease,
chemical or thermal skin burns, scleroderma, aging skin, wrinkles,
sun spots, necrotizing fasciitis, necrotizing myositis, gangrene,
scarring, and vitiligo; and wherein the active agent is suitable
for treating said disorderm or is selected from the group
consisting of chlamydia infection, gonorrhea infection, hepatitis
B, herpes, HIV/AIDS, human papillomavirus (HPV), genital warts,
bacterial vaginosis, candidiasis, chancroid, granuloma Inguinale,
lymphogranuloma venereum, mucopurulent cervicitis (MPC), molluscum
contagiosum, nongonococcal urethritis (NGU), trichomoniasis, vulvar
disorders, vulvodynia, vulvar pain, yeast infection, vulvar
dystrophy, vulvar intraepithelial neoplasia (VIN), contact
dermatitis, pelvic inflammation, endometritis, salpingitis,
oophoritis, genital cancer, cancer of the cervix, cancer of the
vulva, cancer of the vagina, vaginal dryness, dyspareunia, anal and
rectal disease, anal abscess/fistula, anal cancer, anal fissure,
anal warts, Crohn's disease, hemorrhoids, anal itch, pruritus ani,
fecal incontinence, constipation, polyps of the colon and rectum;
and wherein the active agent is suitable for treating said
disorder.
[0182] In one or more embodiments there is provided a method of
treating a disorder of a mammalian subject, wherein the disorder is
a dermatological disorder, which can be treated by a dicarboxylic
acid or dicarboxylic acid ester.
[0183] In one or more embodiments there is provided a method of
treating a disorder of a mammalian subject, wherein the disorder is
a dermatological disorder, which can be treated by a topical
steroid, an immunomodulator or an anti-infective agent.
[0184] In one or more embodiments there is provided a method of
treating a disorder of a mammalian subject, wherein the disorder is
selected from atopic dermatitis and psoriasis; and the active agent
is selected from (i) steroid; and (ii) a combination of steroid and
an additional non-steroidal active agent.
[0185] In one or more embodiments there is provided a method of
treating a disorder of a mammalian subject, wherein the disorder is
selected from psoriasis and atopic dermatitis and the active agent
comprises an immunomodulator.
[0186] In one or more embodiments there is provided a therapeutic
composition comprising: a therapeutically effective amount of an
active agent wherein the active agent is substantially insoluble in
water; and a beneficially or therapeutically effective
concentration of at least one benefit agent, comprising a
dicarboxylic acid ester in which the active agent is substantially
soluble; wherein the benefit agent, stabilizer and solvent are
selected to generate an emulsion that can produce a substantially
strong and closed packed barrier between the oil and the water
phases whilst maintaining a fluid constitution.
[0187] In one or more embodiments there is provided a foamable
composition comprising: a liquid dicarboxylic acid ester, said
ester having emollient properties; a stabilizer selected from the
group consisting of at least one surface-active agent; at least one
polymeric agent and mixtures thereof, an active agent, said active
agent soluble in or having enhanced penetration due to the
dicarboxylic acid; wherein the composition is contained in a
pressurized container and further comprises a liquefied hydrocarbon
gas propellant at a concentration of about 3% to about 25% by
weight of the total composition it is substantially flowable and
provides a foam upon release
[0188] In one or more embodiments the stabilizer comprises a
ether-based or ester-based surfactant.
[0189] In one or more embodiments the stabilizer comprises an
alkyl-derivatized polymer having polymeric emulsifying
properties.
[0190] In one or more embodiments the composition is an oil in
water emulsion.
[0191] In one or more embodiments the dicarboxylic acid ester
comprises about or more than 50 wt % of the composition.
[0192] In one or more embodiments the active agent is otherwise
insoluble or unstable, but is solubilized or stabilized by DCA.
[0193] In one or more embodiments the composition is substantially
free of water In one or more embodiments the composition is in a
non foam state.
[0194] In one or more embodiments there is provided a
pharmaceutical or cosmetic composition comprising: [0195] a. a
benefit agent, selected from the group consisting of [0196] i. a
dicarboxylic acid; and [0197] ii. a dicarboxylic acid ester; [0198]
b. a surface-active agent; [0199] c. about 0.01% to about 5% by
weight of at least one polymeric agent selected from the group
consisting of a bioadhesive agent, a gelling agent, a film forming
agent and a phase change agent; and [0200] d. water.
[0201] All % values are provided on a weight (w/w) basis.
Dicarboxylic Acid and Esters Thereof
[0202] In an embodiment of the present invention, the organic
carrier comprises an ester of a dicarboxylic acid. In the context
of the present invention, a dicarboxylic acid is an organic
material, having two carboxylic acid moieties on its carbon atom
skeleton. They have the general molecular formula
HOOC--(CH.sub.2).sub.n--COON.
[0203] Non limiting examples of some elementary dicarboxylic acids
(DCA's) are succinic acid, glutaric acid, adipic acid, pimelic
acid, suberic acid, azelaic acid, sebacic acid, phthalic acid,
isophthalic acid, terephthalic acid.
[0204] In an embodiment of the present invention, the dicarboxylic
acid is a short-chain dicarboxylic acid. The simplest Short-chain
dicarboxylic acid are oxalic acid (n=0), malonic acid (n=1),
succinic acid (n=2) and glutaric acid (n=3).
[0205] Additional members of dicarboxylic acid group are derived
from natural products or from synthesis, having "n" value from 4 up
to 21. In one or more embodiments of the present invention, the
dicarboxylic acid is selected from the group consisting of adipic
acid (hexanedioic acid; n=4), pimelic acid (heptanedioic acid;
n=5), suberic acid (octanedioic acid; n=6), azelaic acid
(nonanedioic acid; n=7), sebacic acid (decanedioic acid; n=8) and
dodecanedioic acid (n=10).
[0206] In an additional embodiment, the dicarboxylic acid contains
10 to 32 carbon atoms in their carbon atom skeleton, such as
brassylic acid (n=11), thapsic acid (n=14),
14-methylnonacosanedioic acid (C29) and
14,15-dimethyltriacontanedioic acid (C30).
[0207] The carbon atom skeleton of the dicarboxylic acid can be
saturated or unsaturated, such as in the case of maleic acid and
fumaric acid.
[0208] In general terms non-esterified dicarboxylic acids are
usually solid at ambient temperature. Non limiting examples of
solid DCA's are oxalic, malonic glutaric, sebacic, phthalic and
azaleic acid. Similarly, in general terms DCA's with short carbon
chain skeleton are water soluble, such as oxalic, malonic, and
succinic acid. Longer chain DCA's like adipic acid and having up to
10 carbon atoms in the carbon chain are slightly soluble in water.
Also non "simple" DCA's are generally solid at ambient temperature,
insoluble in water, and are usually more oil soluble than their
parent DCA's
[0209] An ester of a dicarboxylic acid is a chemical compound
produced by the reaction between a dicarboxylic acid and at least
one alcohol, with the elimination of a molecule of water. The
reaction of a dicarboxylic acid with one alcohol molecule results
in a mono ester of a dicarboxylic acid. The reaction of a
dicarboxylic acid with two alcohol molecules results in a diester
of the dicarboxylic acid.
[0210] DCA esters are typically hydrophobic and generally insoluble
in water. Most simple esters of DCA are liquid. By simple it is
meant that the alcohol moiety linked to the DCA is a straight or
branched alkyl chain. Examples of liquid simple diesters are
dimethyl phthalate, diethyl phthalate, dibutyl phthalate, diethyl
sebacate, dibutyl sebacate, and diisopropyl adipate. Aromatic
diesters of pthalic, isopthalic and therephalic acids are in the
range of slightly soluble to insoluble.
[0211] The alcohol molecule, to be linked to the dicarboxylic acid,
can be selected from the group of an alkyl an aryl alcohol.
Exemplary alcohol, suitable according to the present invention
include methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl
alcohol, butyl alcohol, isobutyl alcohol, t-butyl alcohol, pentyl
alcohol, hexyl alcohol, octyl alcohol, decyl alcohol, capryl
alcohol, phenol, benzyl alcohol and the like.
[0212] In one or more embodiments, the alcohol is a biologically
active alcohol. In an embodiment, biologically active alcohol
possesses keratolytic activities. Examples of keratolytically
active alcohol suitable according to the present invention include
ortho-, meta- and para-hydroxyalkylbenzoate, salicylic acid,
ortho-, meta-, and para-dihydroxybenzene, ortho-, meta-, and
para-hydroxytoluene, alpha-hydroxy acid, retinol, and derivatives
thereof such as provided in U.S. Pat. No. 6,180,669, which is
incorporated herein by reference. In another embodiment, the
biologically active alcohol is selected from the group consisting
of steroidal hormones, steroidal anti-inflammatory agents, vitamin
E and vitamin D, such as provided in U.S. Pat. Appl. 20040191196,
which is incorporated herein by reference.
[0213] In an embodiment of the present invention, the dicarboxylic
acid is incorporated in the foamable composition in a safe and
effective amount. The term "safe and effective" means an amount of
an active agent that exerts a therapeutic effect on a specific
disorder, without causing adverse effects that may prohibit the use
of said active agent in the treatment of said disorder. The
dicarboxylic acid can be incorporated in the foamable composition
of the present invention in a concentration between about 0.1% and
about 25%, more preferably between about 1% and about 20%.
[0214] In an embodiment of the present invention, the dicarboxylic
acid is azelaic acid, and its concentration in the composition is
between 5% and 25%, or between 10% and 20%.
[0215] In one or more embodiment, the dicarboxylic acid is present
in the composition in an ionized state. The first and second pKa
values for a dicarboxylic acid are different from one another.
Depending on the pH of the composition and the specific first and
second pKa of the dicarboxylic acid, said dicarboxylic acid can be
non-ionized (both carboxy groups are in their acid state);
semi-ionized (one carboxy group is in an acid state and the second
is in an anionic state); or doubly-ionized, wherein both carboxy
groups are anionic. For example, in maleic acid the first pKa is
1.9 and the second pKa is 4.4. Therefore, if the pH of the
composition is between about 2 and about 4.3, the maleic acid is
mostly semi-ionized and at pH above 4.5 the maleic acid is mostly
doubly-ionized. Likewise, in the case of azelaic acid the first pKa
is about 4.5 and the second pKa is about 5.3. Therefore, if the pH
of the composition is below 4.5, the azelaic acid is non-ionized;
between about 4.5 and about 5.3, it is mostly semi-ionized and at a
pH above 5.3, the azelaic acid is mostly doubly-ionized.
[0216] The ionization state of the dicarboxylic acid has influence
on its therapeutic potential. On one hand, if the dicarboxylic acid
is doubly anionic, its penetration into the skin will be very low,
due to the lipophilic nature of the skin. On the other hand, the
non-ionic state is available at very low (acidic) pH values, which
can cause skin irritation.
[0217] Hence, in one or more embodiments, the pH of the composition
is adjusted to a value between the first and second pKa values of
the dicarboxylic acid. For example, in the case of azelaic acid,
the pH is adjusted in the range from about 2.0 to about 4.5,
preferably in the range from about 3.0 to about 4.5. Thus, in an
embodiment of the present invention, the dicarboxylic acid is
azelaic acid, and the pH of the composition is adjusted in the
range from about 4.0 to about 6.0, preferably in the range from
about 4.5.0 to about 5.3.
[0218] Dicarboxylic acid esters are considered excellent emollients
and their inclusion in a composition which is intended for topical
application contributes to the overall improvement of skin
condition. Emollient dicarboxylic esters typically include an alkyl
alcohol moiety, wherein said alkyl alcohol has a carbon chain of at
least one or two or more carbon atoms. In certain embodiments, the
alkyl alcohol is a branched alkyl, such as isopropyl alcohol; and
in other embodiments the alkyl alcohol has a long carbon backbone,
e.g., a carbon chain length of 6-18.
[0219] Dicarboxylic acid esters can be complex substances. One
example is TU 2100 (Nonanedioic acid,
bis[(2-(ethoxycarbonyl)phenyl] ester). It is also known as Azelaoyl
di(ethyl salicylate) and has a CAS Registry Number: [207972-39-2]
and is a solid. TU-2100 is a "non-simple" diester; with a high
molecular weight, and a melting point of 34-36, which is relatively
low with reference to its molecular weight.
[0220] Non-limiting examples of emollient dicarboxylic acid esters
include diisobutyl adipate, diisopropyl adipate, diisopropyl
sebacate, diisosteary dimer dilinoleate, diisostearyl fumerate,
diisopropyl dimerate, diethyl adipate, diethyl sebacate,
diethylhexyl adipate, diethylhexyl malate, dioctyl malate, diethyl
succinate, and dioctyl sebacate. Other diccarboxylic acid esters
are dimethyl phthalate, diethyl phthalate, diethyl sebacate,
diisopropyl dimerate, dibutyl sebacate, dibutyl phthalate and
dioctyl phthalate. Additionally dicarboxylic acid esters are
capable of solubilizing active components which are difficult to
dissolve by other oils. Furthermore, certain dicarboxylic acid
esters, such as diisopropyl adipate and dimethyl sebacate are known
to enhance the skin penetration of active agents. Hence in an
embodiment of the present invention, the dicarboxylic acid ester is
incorporated in the foamable composition in an amount, suitable to
exert its emollient effect, solubilizing effect or skin penetration
enhancing effect. In one or more embodiments, the dicarboxylic acid
ester is incorporated in the foamable composition of the present
invention in a concentration between about 0.1% and about 30%, more
preferably between about 1% and about 25%.
[0221] In one embodiment, the dicarboxylic acid ester is
diisopropyl adipate (DISPA), in an amount between about 0.1% and
about 30%, or about 1% and about 25%.
[0222] As can be appreciated by the discussion above, there is a
varied range of dicarboxylic acids and esters; some are solid, some
are liquid, some are water soluble, some are slightly soluble and
others are insoluble in water. There is also a varied range of
functions and physical properties. Some are active agents and
others are solvents and some are penetration enhancers. The
challenges of making a uniform solution of solid DCA's without
crystal formation or precipitation or a uniform suspension of
insoluble agent, or using a DCA to solubilise a substance which is
otherwise insoluble or as an emollient or as a penetration enhancer
or more than one of them are as varied as their different natures
and properties as may be appreciated by a man of the art. In other
words each agent has its own properties and challenges which are
interrelated to the objectives and other ingredients of the
formulation
[0223] The sensory properties of foams containing a dicarboxylic
acid or a dicarboxylic acid ester are favorable, as revealed by
consumer panel tests.
Foam Adjuvant
[0224] Optionally, the foamable vehicle further includes a foam
adjuvant selected from the group consisting of a fatty alcohol
having 15 or more carbons in their carbon chain; a fatty acid
having 16 or more carbons in their carbon chain; fatty alcohols,
derived from beeswax and including a mixture of alcohols, a
majority of which has at least 20 carbon atoms in their carbon
chain; a fatty alcohol having at least one double bond; a fatty
acid having at least one double bond; a branched fatty alcohol; a
branched fatty acid and a fatty acid substituted with a hydroxyl
group.
Additional Organic Carrier
[0225] Optionally, the foamable vehicle further includes at least
one additional organic carrier selected from the group consisting
of a hydrophobic organic carrier, an emollient and mixtures
thereof, at a concentration of about 2% to about 50% by weight. The
hydrophobic solvent and/or the emollient can be selected from the
group consisting of mineral oil, triglycerides, capric/caprylic
triglyceride, alkyl esters of fatty acids such as isopropyl
palmitate, isopropyl isostearate, octyl palmitate, cetyl lactate,
cetyl ricinoleate, tocopheryl acetate, acetylated lanolin alcohol,
cetyl acetate, phenyl trimethicone, glyceryl oleate, tocopheryl
linoleate, wheat germ glycerides, arachidyl propionate, myristyl
lactate, decyl oleate, ricinoleate, isopropyl lanolate,
pentaerythrityl tetrastearate, neopentylglycol
dicaprylate/dicaprate, isononyl isononanoate, isotridecyl
isononanoate, myristyl myristate, triisocetyl citrate, octyl
dodecanol, maleated soybean oil, unsaturated or polyunsaturated
oils, such as olive oil, corn oil, soybean oil, canola oil,
cottonseed oil, coconut oil, sesame oil, sunflower oil, borage seed
oil, syzigium aromaticum oil, hempseed oil, herring oil, cod-liver
oil, salmon oil, flaxseed oil, wheat germ oil, evening primrose
oils; essential oils; and silicone oils, such as dimethicone,
cyclomethicone, polyalkyl siloxane, polyaryl siloxane,
polyalkylaryl siloxane, a polyether siloxane copolymer and a
poly(dimethylsiloxane)-(diphenyl-siloxane) copolymer.
[0226] In an embodiment of the present invention, the organic
carrier is a polypropylene glycol alkyl ether (PPG alkyl ether).
PPG alkyl ethers are liquid, water-insoluble propoxylated fatty
alcohols, having the molecular formula of
RO(CH.sub.2CHOCH.sub.3).sub.n; wherein "R" is a straight-chained or
branched C.sub.4 to C.sub.22 alkyl group; and "n" is in the range
between 4 and about 50. They are organic liquids that function as
skin-conditioning agent in pharmaceutical and cosmetic
formulations. Non-limiting exemplary PPG alkyl ethers include PPG
stearyl ethers and PPG Butyl Ether. Preferred PPG alkyl ethers
according to the present invention include PPG-15 Stearyl Ether,
PPG-2 Butyl Ether, PPG-9-13 Butyl Ether and PPG-40 Butyl Ether.
[0227] According to a preferred embodiment, the organic carrier
does not contain petrolatum, which is also termed "white
petrolatum" and "Vaseline". Petrolatum often forms an impermeable
occlusive barrier, so that metabolic products and excreta from
damaged tissue are not easily removed or drained away. Furthermore,
it is difficult for the active drug dissolved in the carrier to
pass through the white petrolatum barrier layer into the treated
tissue, so the efficacy of the drug is reduced. An additional
disadvantage of petroleum jelly-based products relates to the
greasy feeling left following their topical application onto the
skin, mucosal membranes and wounds causing inconvenience to the
user, thereby decreasing treatment compliance.
Polymeric Agent
[0228] The composition of the present invention contains a
polymeric agent selected from the group consisting of a bioadhesive
agent, a gelling agent, a film forming agent and a phase change
agent. A polymeric agent enhances the creation of foam having fine
bubble structure, which does not readily collapse upon release from
the pressurized aerosol can. The polymeric agent serves to
stabilize the foam composition and to control drug residence in the
target organ.
[0229] Exemplary polymeric agents include, in a non-limiting
manner, naturally-occurring polymeric materials, such as locust
bean gum, sodium alginate, sodium caseinate, egg albumin, gelatin
agar, carrageenin gum, sodium alginate, xanthan gum, quince seed
extract, tragacanth gum, guar gum, cationic guars, hydroxypropyl
guar gum, starch, amine-bearing polymers such as chitosan; acidic
polymers obtainable from natural sources, such as alginic acid and
hyaluronic acid; chemically modified starches and the like,
carboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcohol,
polyacrylic acid polymers, polymethacrylic acid polymers, polyvinyl
acetate polymers, polyvinyl chloride polymers, polyvinylidene
chloride polymers and the like.
[0230] Additional exemplary polymeric agents include semi-synthetic
polymeric materials such as cellulose ethers, such as
methylcellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, hydroxyethyl cellulose, hydroxy propylmethyl
cellulose, methylhydroxyethylcellulose,
methylhydroxypropylcellulose, hydroxyethylcarboxymethylcellulose,
carboxymethyl cellulose, carboxymethylcellulose
carboxymethylhydroxyethylcellulose, and cationic celluloses,
carbomer (homopolymer of acrylic acid is crosslinked with an allyl
ether pentaerythritol, an allyl ether of sucrose, or an allyl ether
of propylene, such as Carbopol.RTM. 934, Carbopol.RTM. 940,
Carbopo.RTM. 941, Carbopol.RTM. 980 and Carbopol.RTM. 981, pemulen
and aluminum starch octenylsuccinate (ASOS). Polyethylene glycol,
having molecular weight of 1000 or more (e.g., PEG 1,000, PEG
4,000, PEG 6,000 and PEG 10,000) also have gelling capacity and
while they are considered herein as "secondary polar solvents", as
detailed herein, they are also considered polymeric agents.
[0231] In one or more embodiments the polymeric agents have
emulsifying properties. In certain preferred embodiments the
polymeric agent is a derivatized hydrophilic polymer with
hydrophobic alkyl moieties Other types that may also a similar
stabilizing effect are silicone copolymers and derivatized starch
ASOS.
[0232] Mixtures of the above polymeric agents are contemplated.
[0233] The concentration of the polymeric agent should be selected
so that the composition, after filling into aerosol canisters, is
flowable, and can be shaken in the canister. In one or more
embodiments, the concentration of the polymeric agent is selected
such that the viscosity of the composition, prior to filling of the
composition into aerosol canisters, is less than 12,000 CPs, and
more preferably, less than 10,000 CPs.
Surface Active Agent
[0234] The composition of the present invention further contains a
surface-active agent. Surface-active agents (also termed
"surfactants") include any agent linking oil and water in the
composition, in the form of emulsion. A surfactant's
hydrophilic/lipophilic balance (HLB) describes the emulsifier's
affinity toward water or oil. HLB is defined for non-ionic
surfactants. The HLB scale ranges from 1 (totally lipophilic) to 20
(totally hydrophilic), with 10 representing an equal balance of
both characteristics. Lipophilic emulsifiers form water-in-oil
(w/o) emulsions; hydrophilic surfactants form oil-in-water (o/w)
emulsions. The HLB of a blend of two emulsifiers equals the weight
fraction of emulsifier A times its HLB value plus the weight
fraction of emulsifier B times its HLB value (weighted average). In
many cases a single surfactant may suffice. In other cases a
combination of two or more surfactants is desired. Reference to a
surfactant in the specification can also apply to a combination of
surfactants or a surfactant system. As will be appreciated by a
person skilled in the art which surfactant or surfactant system is
more appropriate is related to the vehicle and intended purpose. In
general terms a combination of surfactants is usually preferable
where the vehicle is an emulsion. In an emulsion environment a
combination of surfactants can be significant in producing
breakable forms of good quality. It has been further discovered
that the generally thought considerations for HLB values for
selecting a surfactant or sufactant combination are not always
binding for emulsions and that good quality foams can be produced
with a surfactant or surfactant combination both where the HLB
values are in or towards the lipophilic side of the scale and where
the HLB values are in or towards the hydrophilic side of the scale.
Surfactants also play a role in foam formation where the foamable
formulation is a single phase composition.
[0235] According to one or more embodiments the composition
contains a single surface active agent having an HLB value between
about 2 and 9, or more than one surface active agent and the
weighted average of their HLB values is between about 2 and about
9. Lower HLB values may in certain embodiments be more applicable
to water in oil emulsions.
[0236] According to one or more embodiments the composition
contains a single surface active agent having an HLB value between
about 7 and 14, or more than one surface active agent and the
weighted average of their HLB values is between about 7 and about
14. Mid range HLB values may in certain embodiments be more
suitable for oil in water emulsions.
[0237] According to one or more other embodiments the composition
contains a single surface active agent having an HLB value between
about 9 and about 19, or more than one surface active agent and the
weighted average of their HLB values is between about 9 and about
19. In a waterless or substantially waterless environment a wide
range of HLB values may be suitable.
[0238] Preferably, the composition of the present invention
contains a non-ionic surfactant. Nonlimiting examples of possible
non-ionic surfactants include a polysorbate, polyoxyethylene (20)
sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate, a
polyoxyethylene fatty acid ester, Myrj 45, Myrj 49, Myrj 52 and
Myrj 59; a polyoxyethylene alkyl ether, polyoxyethylene cetyl
ether, polyoxyethylene palmityl ether, polyethylene oxide hexadecyl
ether, polyethylene glycol cetyl ether, steareths such as steareth
2, brij 21, brij 721, brij 38, brij 52, brij 56 and brij W1, a
sucrose ester, a partial ester of sorbitol and its anhydrides,
sorbitan monolaurate, sorbitan monolaurate, a monoglyceride, a
diglyceride, isoceteth-20 and mono-, di- and tri-esters of sucrose
with fatty acids. In certain embodiments, suitable sucrose esters
include those having high monoester content, which have higher HLB
values.
[0239] In certain embodiments with DCA esters as emollient,
surfactants are selected which can provide a close packed sufacant
layer separating the oil and water phases. To achieve such
objectives combinations of at least two surfactants are selected.
Preferrably, they should be complex emulgators and more preferably
they should both be of a similar molecular type. For example, a
pair of ethers like steareth 2 and steareth 21, or a pair of esters
for example, PEG-40 stearate and polysorbate 80. In Certain
circumstances POE esters cannot be used and a combination of
sorbitan laurate and sorbitan stearate or a combination of sucrose
stearic acid ester mixtures and sodium laurate may be used. All
these combinations due to heir versatility and strength may also be
used satisfactorily and effectively with solutions of DCA's and
with solid/crystalline suspensions, although the amounts and
proportion may be varied according to the formulation and its
objectives as will be appreciated by a man of the art.
[0240] It has been discovered also that by using a derivatized
hydrophilic polymer with hydrophobic alkyl moieties as a polymeric
emulsifier such as pemulen it is possible to stabilize the emulsion
better about or at the region of phase reversal tension. Other
types of derivatized polymers like silicone copolymers, derivatized
starch [Aluminum Starch Octenylsuccinate (ASOS)]/[DRY-FLO AF
Starch], and derivatized dexrin may also a similar stabilizing
effect.
[0241] A series of dextrin derivative surfactants prepared by the
reaction of the propylene glycol polyglucosides with a hydrophobic
oxirane-containing material of the glycidyl ether are highly
biodegradable. [Hong-Rong Wang and Keng-Ming Chen, Colloids and
Surfaces A: Physicochemical and Engineering Aspects Volume 281,
Issues 1-3, 15 Jun. 2006, Pages 190-193].
[0242] Non-limiting examples of non-ionic surfactants that have HLB
of about 7 to about 12 include steareth 2 (HLB.about.4.9); glyceryl
monostearate/PEG 100 stearate (Av HLB.about.11.2); stearate Laureth
4 (HLB.about.9.7) and cetomacrogol ether (e.g., polyethylene glycol
1000 monoacetyl ether).
[0243] Non-limiting examples of preferred surfactants, which have a
HLB of 4-19 are set out in the Table below:
TABLE-US-00001 Surfactant HLB steareth 2 ~4.9 glyceryl
monostearate/PEG 100 stearate Av ~11.2 Glyceryl Stearate ~4
Steareth-21 ~15.5 peg 40 stearate ~16.9 polysorbate 80 ~15 sorbitan
stearate ~4.7 laureth 4 ~9.7 Sorbitan monooleate (span 80) ~4.3
ceteareth 20 ~15.7 steareth 20 ~15.3 ceteth 20 ~15.7 Macrogol
Cetostearyl Ether ~15.7 ceteth 2 (Lipocol C-2) ~5.3 PEG-30
Dipolyhydroxystearate ~5.5 sucrose distearate (Sisterna SP30) ~6
polyoxyethylene (100) stearate ~18.8
[0244] More exemplary stabilizing surfactants which may be suitable
for use in the present invention are found below.
PEG-Fatty Acid Monoester Surfactants
TABLE-US-00002 [0245] Chemical name Product example name HLB PEG-30
stearate Myrj 51 >10 PEG-40 laurate Crodet L40 (Croda) 17.9
PEG-40 oleate Crodet O40 (Croda) 17.4 PEG-45 stearate Nikkol MYS-45
(Nikko) 18 PEG-50 stearate Myrj 53 >10 PEG-100 stearate Myrj 59,
Arlacel 165 (ICI) 19
PEG-Fatty Acid Diester Surfactants:
TABLE-US-00003 [0246] Chemical name Product example name HLB PEG-4
dilaurate Mapeg .RTM. 200 DL (PPG), 7 Kessco .RTM.PEG 200 DL
(Stepan), LIPOPEG 2-DL (Lipo Chem.) PEG-4 distearate Kessco .RTM.
200 DS 5 (Stepan.sub) PEG-32 dioleate Kessco .RTM. PEG 1540 DO
(Stepan) 15 PEG-400 dioleate Cithrol 4DO series (Croda) >10
PEG-400 disterate Cithrol 4DS series (Croda) >10 PEG-20 glyceryl
oleate Tagat .RTM. O (Goldschmidt) >10
Transesterification Products of Oils and Alcohols
TABLE-US-00004 [0247] Chemical name Product example name HLB PEG-30
castor oil Emalex C-30 (Nihon Emulsion) 11 PEG-40 hydrogenated
Cremophor RH 40 (BASF), 13 castor oil Croduret (Croda), Emulgin HRE
40 (Henkel)
Polyglycerized Fatty Acids, such as:
TABLE-US-00005 Chemical name Product example name LB Polyglyceryl-6
Caprol .RTM. 6G20 (ABITEC); 8.5 dioleate PGO-62 (Calgene), PLUROL
OLEIQUE CC 497 (Gattefosse)Hodag
PEG-Sorbitan Fatty Acid Esters
TABLE-US-00006 [0248] Chemical name Product example name HLB PEG-20
sorbitan Tween-20 (Atlas/ICI), Crillet 1 17 monolaurate (Croda),
DACOL MLS 20 (Condea) PEG-20 sorbitan Tween 40 (Atlas/ICI), Crillet
2 16 Monopalmitate (Croda) PEG-20 sorbitan Tween-60 (Atlas/ICI),
Crillet 3 15 monostearate (Croda) PEG-20 sorbitan Tween-80
(Atlas/ICI), Crillet 4 15 monooleate (Croda)
Polyethylene Glycol Alkyl Ethers
TABLE-US-00007 [0249] Chemical name Product example name HLB PEG-2
oleyl ether oleth-2 Brij 92/93 (Atlas/ICI) 4.9 PEG-3 oleyl ether
oleth-3 Volpo 3 (Croda) <10 PEG-5 oleyl ether oleth-5 Volpo 5
(Croda) <10 PEG-10 oleyl ether oleth-10 Volpo 10 (Croda), Brij
12 96/97 (Atlas/ICI) PEG-20 oleyl ether oleth-20 Volpo 20 (Croda),
Brij 15 98/99 (Atlas/ICI) PEG-4 lauryl ether laureth-4Brij 30
(Atlas/ICI) 9.7 PEG-23 lauryl ether laureth-23Brij 35 (Atlas/ICI)
17 PEG-10 stearyl ether Brij 76 (ICI) 12 PEG-2 cetyl ether Brij 52
(ICI) 5.3
Sugar Ester Surfactants
TABLE-US-00008 [0250] Chemical name Product example name HLB
Sucrose distearate Sisterna SP50, Surfope 1811 11
Sorbitan Fatty Acid Ester Surfactants
TABLE-US-00009 [0251] Chemical name Product example name HLB
Sorbitan monolaurate Span-20 (Atlas/ICI), Crill 1 8.6 (Croda),
Arlacel 20 (ICI) Sorbitan monopalmitate Span-40 (Atlas/ICI), Crill
2 6.7 (Croda), Nikkol SP-10 (Nikko) Sorbitan monooleate Span-80
(Atlas/ICI), Crill 4 4.3 (Croda), Crill 50 (Croda) Sorbitan
monostearate Span-60 (Atlas/ICI), Crill 3 4.7 (Croda), Nikkol SS-10
(Nikko)
[0252] In one or more embodiments the surface active agent is a
complex emulgator in which the combination of two or more surface
active agents can be more effective than a single surfactant and
provides a more stable emulsion or improved foam quality than a
single surfactant. For example and by way of non-limiting
explanation it has been found that by choosing say two surfactants,
one hydrophobic and the other hydrophilic the combination can
produce a more stable emulsion than a single surfactant.
Preferably, the complex emulgator comprises a combination of
surfactants wherein there is a difference of about 4 or more units
between the HLB values of the two surfactants or there is a
significant difference in the chemical nature or structure of the
two or more surfactants.
[0253] Specific non limiting examples of surfactant systems are,
combinations of polyoxyethylene alkyl ethers, such as Brij
59/Brij10; Brij 52/Brij 10; Steareth 2/Steareth 20; Steareth
2/Steareth 21 (Brij 72/Brij 721); combinations of polyoxyethylene
stearates such as Myrj 52/Myrj 59; combinations of sucrose esters,
such as Surphope 1816/Surphope 1807; combinations of sorbitan
esters, such as Span 20/Span 80; Span 20/Span 60; combinations of
sucrose esters and sorbitan esters, such as Surphope 1811 and Span
60; combinations of liquid polysorbate detergents and PEG
compounds, such as Tween 80/PEG-40 stearate; methyl glucaso
sequistearate; polymeric emulsifiers, such as Permulen (TRI or
TR2); liquid crystal systems, such as Arlatone (2121), Stepan (Mild
RM1), Nikomulese (41) and Montanov (68) and the like.
[0254] In certain embodiments the surfactant is preferably one or
more of the following: a combination of steareth-2 and steareth-21
on their own or in combination with glyceryl monostearate (GMS); in
certain other embodiments the surfactant is a combination of
polysorbate 80 and PEG-40 stearate. In certain other embodiments
the surfactant is a combination of glyceryl monostearate/PEG 100
stearate. In certain other embodiments the surfactant is a
combination of two or more of stearate 21, PEG 40 stearate, and
polysorbate 80. In certain other embodiments the surfactant is a
combination of two or more of laureth 4, span80, and polysorbate
80. In certain other embodiments the surfactant is a combination of
two or more of GMS and ceteareth. In certain other embodiments the
surfactant is a combination of two or more of steareth 21,
ceteareth 20, ceteth 2 and laureth 4 In certain other embodiments
the surfactant is a combination of ceteareth 20 and polysorbate 40
stearate. In certain other embodiments the surfactant is a
combination of span 60 and GMS.
[0255] In certain other embodiments the surfactant is one or more
of sucrose stearic acid esters, sorbitan laureth, and sorbitan
stearate.
[0256] In one or more embodiments the stability of the composition
can be improved when a combination of at least one non-ionic
surfactant having HLB of less than 9 and at least one non-ionic
surfactant having HLB of equal or more than 9 is employed. The
ratio between the at least one non-ionic surfactant having HLB of
less than 9 and the at least one non-ionic surfactant having HLB of
equal or more than 9, is between 1:8 and 8:1, or at a ratio of 4:1
to 1:4. The resultant HLB of such a blend of at least two
emulsifiers is preferably between about 9 and about 14.
[0257] Thus, in an exemplary embodiment, a combination of at least
one non-ionic surfactant having HLB of less than 9 and at least one
non-ionic surfactant having HLB of equal or more than 9 is
employed, at a ratio of between 1:8 and 8:1, or at a ratio of 4:1
to 1:4, wherein the HLB of the combination of emulsifiers is
preferably between about 5 and about 18.
[0258] In certain cases, the surface active agent is selected from
the group of cationic, zwitterionic, amphoteric and ampholytic
surfactants, such as sodium methyl cocoyl taurate, sodium methyl
oleoyl taurate, sodium lauryl sulfate, triethanolamine lauryl
sulfate and betaines.
[0259] Many amphiphilic molecules can show lyotropic
liquid-crystalline phase sequences depending on the volume balances
between the hydrophilic part and hydrophobic part. These structures
are formed through the micro-phase segregation of two Many
amphiphilic molecules can show lyotropic liquid-crystalline phase
sequences depending on the volume balances between the hydrophilic
part and hydrophobic part. These structures are formed through the
micro-phase segregation of two incompatible components on a
nanometer scale. Soap is an everyday example of a lyotropic liquid
crystal. Certain types of surfactants tend to form lyotropic liquid
crystals in emulsions interface (oil-in-water) and exert a
stabilizing effect
[0260] In one or more embodiments the surfactant is a surfactant or
surfactant combination is capable of or which tends to form liquid
crystals. Surfactants which tend to form liquid crystals may
improve the quality of foams. Non limiting examples of surfactants
with postulated tendency to form interfacial liquid crystals are:
phospholipids, alkyl glucosides, sucrose esters, sorbitan
esters.
[0261] In one or more embodiments the at least one surface active
agent is liquid.
[0262] In one or more embodiments the at least one surface active
agent is solid, semi solid or waxy.
[0263] It should be noted that HLB values may not be so applicable
to non ionic surfactants, for example, with liquid crystals or with
silicones. Also HLB values may be of lesser significance in a
waterless or substantially non-aqueous environment.
[0264] In one or more embodiments the surfactant can be, a
surfactant system comprising of a surfactant and a co surfactant, a
waxy emulsifier, a liquid crystal emulsifier, an emulsifier which
is solid or semi solid at room temperature and pressure, or
combinations of two or more agents in an appropriate proportion as
will be appreciated a person skilled in the art. Where a solid or
semi solid emulsifier combination is used it can also comprise a
solid or semi solid emulsifier and a liquid emulsifier.
[0265] In one or more embodiments of the present invention, the
surface-active agent includes at least one non-ionic surfactant.
Ionic surfactants are known to be irritants. Therefore, non-ionic
surfactants are preferred in applications including sensitive
tissue such as found in most mucosal tissues, especially when they
are infected or inflamed. Non-ionic surfactants alone can provide
formulations and foams of good or excellent quality in the carriers
and compositions of the present invention.
[0266] Thus, in a preferred embodiment, the surface active agent,
the composition contains a non-ionic surfactant. In another
preferred embodiment the composition includes a mixture of
non-ionic surfactants as the sole surface active agent. Yet, in
additional embodiments, the foamable composition includes a mixture
of at least one non-ionic surfactant and at least one ionic
surfactant in a ratio in the range of about 100:1 to 6:1. In one or
more embodiments, the non-ionic to ionic surfactant ratio is
greater than about 6:1, or greater than about 8:1; or greater than
about 14:1, or greater than about 16:1, or greater than about 20:1.
In further embodiments, surface active agent comprises a
combination of a non-ionic surfactant and an ionic surfactant, at a
ratio of between 1:1 and 20:1
[0267] In one or more embodiments of the present invention, a
combination of a non-ionic surfactant and an ionic surfactant (such
as sodium lauryl sulphate and cocamidopropylbetaine) is employed,
at a ratio of between 1:1 and 20:1, or at a ratio of 4:1 to 10:1;
for example, about 1:1, about 4:1, about 8:1, about 12:1, about
16:1 and about 20:1 or at a ratio of 4:1 to 10:1, for example,
about 4:1, about 6:1, about 8:1 and about 10:1.
[0268] In selecting a suitable surfactant or combination thereof it
should be borne in mind that the upper amount of surfactant that
may be used may be limited by the shakability of the composition.
If the surfactant is non liquid, it can make the formulation to
viscous or solid. This can be particularly significant if the
formulation has high molecular weight, e.g., a high molecular
weight PEG or polymeric agents or petroleum or if the surfactants
are large. Solvents and polymeric agents which have high molecular
weight and are very viscous or solid or waxy (e.g., Peg 1500, 2000,
etc. or petrolatum) can exacerbate the effect of a waxy or solid
surfactant on shakability or flowability. In general terms, as the
amount of non-liquid surfactant is increased the shakability of the
formulation reduces until a limitation point is reached where the
formulation becomes non shakable and unsuitable. Thus in one
embodiment, an effective amount of surfactant may be used provided
the formulation remains shakable. In other certain exceptional
embodiments the upper limit may be determined by flowability such
as in circumstances where the composition is marginally or
apparently non-shakable. The formulation is sufficiently flowable
to be able to flow through an actuator valve and be released and
still expand to form a good quality foam.
[0269] In certain embodiments of the present invention the amount
of surfactant or combination of surfactants is between about 0.05%
to about 20%; between about 0.05% to about 15%, or between about
0.05% to about 10%. In a preferred embodiment the concentration of
surface active agent is between about 0.2% and about 8%. In a more
preferred embodiment the concentration of surface active agent is
between about 1% and about 6%.
[0270] In some embodiments, it is desirable that the surface active
agent does not contain a polyoxyethylene (POE) moiety, such as
polysorbate surfactants, POE fatty acid esters, and POE alkyl
ethers, because the active agent is incompatible with such surface
active agents. For example, the active agent pimecrolimus is not
stable the presence of POE moieties, yet benefits greatly from the
use of dicarboxylic esters as penetration enhancers. In such cases,
alternative surface active agents are employed. In an exemplary
manner, POE-free surfactants include non-ethoxylated sorbitan
esters, such as sorbitan monopalmitate, sorbitan monostearate,
sorbitan tristearate, sorbitan monooleate, sorbitan trioleate,
sorbitan monolaurate and sorbitan sesquioleate; glycerol fatty acid
esters, such as glycerol monostearate and glycerol monooleate;
mono-, di- and tri-esters of sucrose with fatty acids (sucrose
esters), sucrose stearate, sucrose distearate sucrose palmitate and
sucrose laurate; and alkyl polyglycosides, such as lauryl
diglucoside.
[0271] If the composition as formulated is a substantially non
shakable composition it is nevertheless possible as an exception in
the scope of the present invention for the formulation to be
flowable to a sufficient degree to be able to flow through an
actuator valve and be released and still expand to form a good
quality foam. This surprising and unusual exception may be due one
or more of a number of factors such as the high viscosity, the
softness, the lack of crystals, the pseudoplastic or semi pseudo
plastic nature of the composition and the dissolution of the
propellant into the composition.
[0272] In one or more embodiments of the present invention, the
surface-active agent includes mono-, di- and tri-esters of sucrose
with fatty acids (sucrose esters), prepared from sucrose and esters
of fatty acids or by extraction from sucro-glycerides. Suitable
sucrose esters include those having high monoester content, which
have higher
Phase Inversion and Tension
[0273] Phase inversion is a factor in the preparation and
stabilization of emulsions and can be both an aid and a detriment.
Phase inversion involves the change of emulsion type from o/w to
w/o or vice versa. Prior to phase inversion occurring there is a
tension in the emulsion which if destabilized or driven will lead
to phase inversion and if controlled or ameliorated or dissipated
will result in a more stable emulsion. The occurrence of phase
inversion during preparation can be a sign of instability. If
controlled, it can result in a finer product but if due to other
factors after the the emulsion was prepared it can cause problems.
Inversion can occur by for example adding calcium chloride to an
o/w emulsion stabilized with sodium stearate to form calcium
stearate. Inversion can also occur as the product of changes to the
phase-volume ratio. For example if a small amount of water is added
to surfactant mixed with oil and agitated aw/o emulsion is formed.
As the amount of water added is gradually increased a point will be
reached where the water and emulsifier envelop the oil as small
droplets to form an o/w emulsion. The amount of each ingredient
including the surfactants will have their part to play in the
phenomenum.
Substantially Alcohol-Free
[0274] According to one or more embodiments, the foamable
composition is substantially alcohol-free, i.e., free of short
chain alcohols. Short chain alcohols, having up to 5 carbon atoms
in their carbon chain skeleton and one hydroxyl group, such as
ethanol, propanol, isopropanol, butaneol, iso-butaneol, t-butaneol
and pentanol, are considered less desirable solvents or polar
solvents due to their skin-irritating effect. Thus, the composition
is substantially alcohol-free and includes less than about 5% final
concentration of lower alcohols, preferably less than about 2%,
more preferably less than about 1%.
Substantially Non Aqueous
[0275] In certain cases, the active agent degrades in the presence
of water, and therefore, in such cases the present of water in the
composition is not desirable. Thus, in certain preferred
embodiments, the composition is substantially non-aqueous. The term
"substantially non-aqueous" or "substantially waterless" is
intended to indicate that the composition has a water content below
about 5%, preferably below about 2%, such as below about 1.5%. In
certain other preferred embodiments the composition is non aqueous
or waterless.
[0276] By non aqueous or waterless is meant that the composition
contains no or substantially no, free or unassociated or absorbed
water. It will be understood by a person of the art that the
waterless solvents and substances miscible with them of the present
invention can be hydrophilic and can contain water in an associated
or unfree or absorbed form and may absorb water from the atmosphere
and the ability to do so is its hygroscopic water capacity. It is
intended that essentially non-aqueous formulations are included
within its scope such that the formulations may have present a
small amount of water. In some embodiments the composition
ingredients are pretreated to reduce, remove or eliminate any
residual or associated or absorbed water.
Shakability
[0277] `Shakability` means that the composition contains some or
sufficient flow to allow the composition to be mixed or remixed on
shaking. That is, it has fluid or semi fluid properties. In some
very limited cases possibly aided by the presence of silicone it
may exceptionally be possible to have a foamable composition which
is flowable but not apparently shakable.
Breakability
[0278] A breakable foam is one that is thermally stable, yet breaks
under sheer force.
[0279] The breakable foam of the present invention is not "quick
breaking", i.e., it does not readily collapse upon exposure to body
temperature environment. Sheer-force breakability of the foam is
clearly advantageous over thermally induced breakability, since it
allows comfortable application and well directed administration to
the target area.
Modulating Agent
[0280] The term modulating agent is used to describe an agent which
can improve the stability of or stabilize a foamable carrier or
composition and or an active agent by modulating the effect of a
substance or residue present in the carrier or composition.
[0281] In one or more embodiments the modulating agent is used in a
water in oil or oil in water emulsion. In one or more other
embodiments the modulating agent is used in a unique waterless
emulsion.
[0282] In certain embodiments the substance or residue may for
example be acidic or basic and potentially alter pH in an emulsion
environment or it may be one or more metal ions which may act as a
potential catalyst in an emulsion environment.
[0283] In certain other embodiments the substance or residue may
for example be acidic or basic and potentially alter an artificial
pH in a waterless or substantially non aqueous environment or it
may be one or more metal ions which may act as a potential catalyst
in a waterless or substantially non aqueous environment.
[0284] In one or more embodiments the modulating agent is used to
describe an agent which can affect pH in an aqueous solution. The
agent can be any of the known buffering systems used in
pharmaceutical or cosmetic formulations as would be appreciated by
a man of the art. It can also be an organic acid, a carboxylic
acid, a fatty acid an amino acid, an aromatic acid, an alpha or
beta hydroxyl acid an organic base or a nitrogen containing
compound.
[0285] In one or more further embodiments the modulating agent is
used to describe an agent, which is a chelating or sequestering or
complexing agent that is sufficiently soluble or functional in the
solvent to enable it to "mop up" or "lock" metal ions.
[0286] In an embodiment modulating agent is used to describe an
agent which can effect pH in an aqueous solution the term
modulating agent more particularly means an acid or base or buffer
system or combinations thereof, which is introduced into or is
present in and acts to modulate the ionic or polar characteristics
and any acidity or basesity balance of an emulsion carrier,
composition, foamable carrier or foamable composition or resultant
foam of the present invention.
[0287] In other embodiments modulating agent is used to describe an
agent which can effect pH in an aqueous solution the term
modulating agent more particularly means an acid or base or buffer
system or combinations thereof, which is introduced into or is
present in and acts to modulate the ionic or polar characteristics
and any acidity or basesity balance of a waterless or substantially
non aqueous carrier, composition, foamable carrier or foamable
composition or resultant foam of the present invention.
[0288] The substance or residue can be introduced into the
formulation from any one or more of the ingredients, some of which
themselves may have acidic or basic properties. For example the
polymer or solvent may contain basic residues in which case it may
be desirable or beneficial to add an acid. Alternatively the
surfactant may contain some acid residues in which case the
addition of a base may be desirable and beneficial. In some cases
more than one ingredient may contain residues which may ameliorate
or compound their significance. For example if one ingredient
provided weak acid residues and another stronger acid residues the
pH in an emulsion environment (or artificial pH in a waterless
environment) should be lower. In contrast if one residue was acid
and the other basic the net effect in the formulation may be
significantly reduced. In some circumstances the active ingredient
may favor an acidic pH or more significantly may need to be
maintained at a certain acidic pH otherwise it may readily
isomerize, chemically react or breakdown, in which case introducing
acidic components such as an acidic polymer might be of help. In an
embodiment of the present invention sufficient modulating agent is
added to achieve a pH in which the active agent is preferably
stable. In another embodiment of the present invention sufficient
modulating agent is added to achieve an artificial pH in which the
active agent is preferably stable.
[0289] The terms pH, pKa, and pKb, buffers and the like are used in
classical measurements of an aqueous solution. Such measurements
are artificial in a waterless environment. Nevertheless, reference
to and description below of such terms are made for convenience and
clarity, since such terms are well defined and understood with
reference to aqueous solutions and further due to the lack of an
appropriate uniform way of describing and identifying the
artificial or virtual pH, pK etc in a waterless environment in
relation to the present invention. Although predictions of
artificial pH can be made using dilution techniques of measurements
of waterless formulations diluted in water they are formulation
sensitive and specific and have to be carefully calibrated with
complex formulas.
[0290] Waterless medium can be polar and protic yet it does not
conform to classical ionic behavior.
[0291] A buffer, as defined by Van Slyke [Van Slyke, J. Biol. Chem.
52, 525 (1922)], is "a substance which by its presence in solution
increases the amount of acid or alkali that must be added to cause
unit change in pH."
[0292] A buffer solution is a solution of a definite pH made up in
such a way that this pH alters only gradually with the addition of
alkali or acid. Such a solution consists of a solution of a salt of
the week acid in the presence of the three acid itself. The pH of
the solution is determined by the dissociation equilibrium of the
free acid.
[0293] An acid can be a strong acid or a weak acid. A strong acid
is an acid, which is a virtually 100% ionized in solution. In
contrast, a week acid is one which does not ionize fully. When it
is dissolved in water. The lower the value for pKa, the stronger is
the acid and likewise, the higher the value for pKa the weaker is
the acid.
[0294] A base can be a strong base or a weak base. A strong base is
something, which is fully ionic with 100% hydroxide ions. In
contrast, a weak base is one which does not convert fully into
hydroxide ions in solution. The lower the value for pKb, the
stronger is the base and likewise, the higher the value for pKb the
weaker is the base.
[0295] In one or more embodiments of the present invention the
modulating agent comprises an organic compound.
[0296] In one or more preferred embodiments of the present
invention the chelating agent is selected from the group consisting
of ethylenediaminetetraacetic acid (EDTA),
diethylenetriaminepentaacetic acid (DTPA),
hydroxyethylenediaminetriacetic acid (HEDTA), nitrilotriacetic acid
(NTA), O,O'-bis(2-aminoethyl)ethyleneglycol-N,N,N',N'-tetraacetic
acid (EGTA), trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic
acid (CyDTA) or a pharmaceutically acceptable salt thereof
(normally as a sodium salt), more preferably EDTA, HEDTA and their
salts; most preferably EDTA and its salts.
[0297] In one or more embodiments of the present invention a
preferred non limiting example of the chelating agent is EDTA.
Typically, the chelating and sequestering agent is present in the
composition at a level of up to about 5.0%, preferably 1.0 percent,
by weight, of the composition.
[0298] In one or more embodiments of the present invention the
modulating agent may also be a preservative or an antioxidant or an
ionization agent. Any preservative, antioxidant or ionization
agents suitable for pharmaceutical or cosmetic application may be
used. Non limiting examples of antioxidants are tocopherol
succinate, propyl galate, butylated hydroxy toluene and butyl
hydroxy anisol. Ionization agents may be positive or may be
negative depending on the environment and the active agent or
composition that is to be protected. Ionization agents may for
example act to protect or reduce sensitivity of active agents. Non
limiting examples of positive ionization agents are benzyl conium
chloride, and cetyl pyridium chloride. Non limiting examples of
negative ionization agents are sodium lauryl sulphate, sodium
lauryl lactylate and phospholipids.
Humectant
[0299] A humectant is a substance that helps retain moisture and
also prevents rapid evaporation. Non limiting examples are
propylene glycol, propylene glycol derivatives, glycerin,
hydrogenated starch hydrosylate, hydrogenated lanolin, lanolin wax,
D manitol, sorbitol, sodium 2-pyrrolidone-5-carboxylate, sodium
lactate, sodium PCA, soluble collagen, dibutyl phthalate, and
gelatin. Other examples may be found in the Handbook of
Pharmaceutical Additives published by Gower.
Moisturizers
[0300] A moisturizer, is a substance that helps retain moisture or
add back moisture to the skin. Examples are allantoin, petrolatum,
urea, lactic acid, sodium PCV, glycerin, shea butter,
caprylic/capric/stearic triglyceride, candelilla wax, propylene
glycol, lanolin, hydrogenated oils, squalene, sodium hyaluronate
and lysine PCA. Other examples may be found in the Handbook of
Pharmaceutical Additives published by Gower.
[0301] Pharmaceutical compositions of the present invention may in
one or more embodiments usefully comprise in addition a humectant
or a moisturizer or combinations thereof.
Polar Solvent
[0302] Optionally, the foamable vehicle further includes at least
one polar solvent.
[0303] A "polar solvent" is an organic solvent, typically soluble
in both water and oil. Certain polar solvents, for example
propylene glycol and glycerin, possess the beneficial property of a
heumectant.
[0304] In one or more embodiments, the polar solvent is a
heumectant.
[0305] In one or more embodiments, the polar solvent is a polyol.
Polyols are organic substances that contain at least two hydroxy
groups in their molecular structure.
[0306] In one or more embodiments, the polar solvent contains an
diol (a compound that contains two hydroxy groups in its molecular
structure), such as propylene glycol (e.g., 1,2-propylene glycol
and 1,3-propylene glycol), butaneediol (e.g., 1,4-butaneediol),
butaneediol (e.g., 1,3-butaneediol and 1,4-butenediol), butynediol,
pentanediol (e.g., 1,5-pentanediol), hexanediol (e.g.,
1,6-hexanediol), octanediol (e.g., 1,8-octanediol), neopentyl
glycol, 2-methyl-1,3-propanediol, diethylene glycol, triethylene
glycol, tetraethylene glycol, dipropylene glycol and dibutylene
glycol.
[0307] In one or more embodiments, the polar solvent contains a
triol (a compound that contains three hydroxy groups in its
molecular structure), such as glycerin and 1,2,6-Hexanetriol.
[0308] Other non-limiting examples of polar solvents include
pyrrolidones, (such as N-methyl-2-pyrrolidone and
1-methyl-2-pyrrolidinone), dimethyl isosorbide, 1,2,6-hexapetriol,
dimethyl sulfoxide (DMSO), ethyl proxitol, dimethylacetamide (DMAc)
and alpha hydroxy acids, such as lactic acid and glycolic acid.
[0309] According to still other embodiments, the polar solvent is a
polyethylene glycol (PEG) or PEG derivative that is liquid at
ambient temperature, including PEG200 (MW (molecular weight) about
190-210 kD), PEG300 (MW about 285-315 kD), PEG400 (MW about 380-420
kD), PEG600 (MW about 570-630 kD) and higher MW PEGs such as PEG
4000, PEG 6000 and PEG 10000 and mixtures thereof.
[0310] Polar solvents are known to enhance the penetration of
active agent into the skin and through the skin, and therefore,
their inclusion in the composition of the present invention can be
desirable, despite their undesirable skin drying and irritation
potential. There is at one level a commonality between the
different polar solvents and their penetration enhancement
properties. Lower molecular weight alcohols can sometimes be more
potent as a solvent, for example by extracting lipids from the skin
layers more effectively, which characteristic can adversely affect
the skin structure and cause dryness and irritation. Therefore the
selection of lower molecular weight alcohols is ideally
avoided.
[0311] Polar solvents, such as detailed below possess high
solubilizing capacity and contribute to the skin penetration of an
active agent. Non limiting examples include dimethyl isosorbide
polyols, such as glycerol (glycerin), propylene glycol, hexylene
glycol, diethylene glycol, propylene glycol n-alkanols, terpenes,
di-terpenes, tri-terpenes, limonene, terpene-ol, 1-menthol,
dioxolane, ethylene glycol, other glycols, oleyl alcohol,
alpha-hydroxy acids, such as lactic acid and glycolic acid,
sulfoxides, such as dimethylsulfoxide (DMSO), dimethylformanide,
methyl dodecyl sulfoxide, dimethylacetamide, azone
(1-dodecylazacycloheptan-2-one), 2-(n-nonyl)-1,3-dioxolane,
alkanols, such as dialkylamino acetates, and admixtures thereof. In
certain preferred embodiments, the polar solvent is selected from
the group consisting of dimethyl isosorbide glycerol (glycerin),
propylene glycol, hexylene glycol, terpene-ol, oleyl alcohol,
lactic acid and glycolic acid.
Skin Penetration Enhancer
[0312] A "skin penetration enhancer", also termed herein
"penetration enhancer," is an organic solvent, typically soluble in
both water and oil. Examples of penetration enhancer include
polyols, such as glycerol (glycerin), propylene glycol, hexylene
glycol, diethylene glycol, propylene glycol n-alkanols, terpenes,
di-terpenes, tri-terpenes, terpen-ols, limonene, terpene-ol,
1-menthol, dioxolane, ethylene glycol, hexylene glycol, other
glycols, sulfoxides, such as dimethylsulfoxide (DMSO),
dimethylformanide, methyl dodecyl sulfoxide, dimethylacetamide,
dimethylisosorbide, monooleate of ethoxylated glycerides (with 8 to
10 ethylene oxide units), azone (1-dodecylazacycloheptan-2-one),
2-(n-nonyl)-1,3-dioxolane, esters, such as isopropyl
myristate/palmitate, ethyl acetate, butyl acetate, methyl
proprionate, capric/caprylic triglycerides, octylmyristate,
dodecyl-myristate; myristyl alcohol, lauryl alcohol, lauric acid,
lauryl lactate ketones; amides, such as acetamide oleates such as
triolein; various alkanoic acids such as caprylic acid; lactam
compounds, such as azone; alkanols, such as dialkylamino acetates,
and admixtures thereof.
[0313] According to one or more embodiments, the penetration
enhancer is a polyethylene glycol (PEG) or PEG derivative that is
liquid at ambient temperature
Potent Solvent
[0314] In one or more embodiments of the present invention, the
foamable composition includes a potent solvent, in addition to or
in place of one of the hydrophobic solvents, polar solvents or
emollients of the composition. A potent solvent is a solvent other
than mineral oil that solubilizes a specific active agent
substantially better than a hydrocarbon solvent such as mineral oil
or petrolatum. For example, a potent solvent solubilizes the active
agent 5 fold better than a hydrocarbon solvent; or even solubilizes
the active agent 10-fold better than a hydrocarbon solvent.
[0315] In one or more embodiments of the present invention, the
composition includes at least one active agent in a therapeutically
effective concentration; and at least one potent solvent in a
sufficient amount to substantially solubilize the at least one
active agent in the composition. The term "substantially soluble"
means that at least 95% of the active agent has been solubilized,
i.e., 5% or less of the active agent is present in a solid state.
In one or more embodiments, the concentration of the at least one
potent solvent is more than about 40% of the at least one solvent
of the composition of the present invention; or even more than
about 60%.
[0316] Non-limiting examples of pairs of active agent and potent
solvent include: Betamethasone valerate: Practically insoluble in
mineral oil (<0.01%); soluble more than 1% in glycofurol;
Hydrocortisone butyrate: Practically insoluble in mineral oil
(<0.01%); soluble more than 1% in glycofurol; Metronidazole:
Practically insoluble in mineral oil (<0.01%); soluble more than
1% in dimethyl isosorbide; Ketoconazole: Practically insoluble in
mineral oil (<0.01%); soluble more than 1% in glycofurol,
propylene glycol and dimethyl isosorbide; Mupirocin: Practically
insoluble in mineral oil (<0.01%); soluble more than 1% in
glycofurol, hexylene glycol, dimethyl isosorbide, propylene glycol
and polyethylene glycol 400 (PEG 400); Meloxicam, a nonsteroidal
anti-inflammatory agent: Practically insoluble in mineral oil
(<0.001%); soluble in propylene glycol: 0.3 mg/mL; and in PEG
400: 3.7 mg/mL; and Progesterone: Practically insoluble in mineral
oil (<0.001%); soluble in PEG 400: 15.3 mg/mL.
[0317] A non-limiting exemplary list of solvents that can be
considered as potent solvents includes polyethylene glycol,
propylene glycol, hexylene glycol, butaneediols and isomers
thereof, glycerol, benzyl alcohol, DMSO, ethyl oleate, ethyl
caprylate, diisopropyl adipate, dimethylacetamide,
N-methylpyrrolidone, N-hydroxyethylpyrrolidone,
polyvinylpyrrolidone, isosorbide derivatives, such as dimethyl
isosorbide, glycofurol and ethoxydiglycol (transcutol) and
laurocapram.
[0318] The use of a potent solvent in a foam composition provides
an improved method of delivering poorly soluble therapeutic agents
to a target area. It is known that low drug solubility results in
poor bioavailability, leading to decreased effectiveness of
treatment. Foam compositions of the present invention, for which
the solvent includes a potent solvent, increase the levels of the
active agent in solution and thus, provide high delivery and
improved therapy.
[0319] Potent solvents, as defined herein, are usually liquid.
Formulations comprising potent solvents and active agents are
generally disadvantageous as therapeutics, since their usage
involves unwanted dripping and inconvenient method of application;
resulting in inadequate dosing. Surprisingly, the foams of the
present invention, which are drip-free, provide a superior vehicle
for such active agents, enabling convenient usage and accurate
effective dosing.
[0320] In one or more embodiments of the present invention the
present invention the foamable pharmaceutical composition may
additionally include a mixture of two or more of the solvents
selected from the group of hydrophobic solvents, silicone oils,
emollients, polar solvents and potent solvents in an appropriate
proportion as would be appreciated to a person skilled in the
art.
[0321] In one or more embodiments of the present invention, the PPG
alkyl ether may act as a potent solvent
Additional Components
[0322] In an embodiment of the present invention, a composition of
the present invention includes one or more additional components.
Such additional components include but are not limited to anti
perspirants, anti-static agents, buffering agents, bulking agents,
chelating agents, cleansers, colorants, conditioners, deodorants,
diluents, dyes, emollients, fragrances, hair conditioners,
humectants, pearlescent aids, perfuming agents, permeation
enhancers, pH-adjusting agents, preservatives, protectants, skin
penetration enhancers, softeners, solubilizers, sunscreens, sun
blocking agents, sunless tanning agents, viscosity modifiers and
vitamins. As is known to one skilled in the art, in some instances
a specific additional component may have more than one activity,
function or effect.
Propellants
[0323] Suitable propellants include volatile hydrocarbons such as
butane, propane, isobutane and fluorocarbon gases, or mixtures
thereof.
[0324] The propellant makes up about 5-25 wt % of the foamable
composition. The propellants are used to generate and administer
the foamable composition as a foam. The total composition including
propellant, foamable compositions and optional ingredients is
referred to as the foamable composition.
[0325] Alcohol and organic solvents render foams inflammable. It
has been surprisingly discovered that fluorohydrocarbon
propellants, other than chloro-fluoro carbons (CMOs), which are
non-ozone-depleting propellants, are particularly useful in the
production of a non-flammable foamable composition. A test
according to European Standard prEN 14851, titled "Aerosol
containers--Aerosol foam flammability test" revealed that
compositions containing an organic carrier that contains a
hydrophobic organic carrier and/or a polar solvent, which are
detected as inflammable when a hydrocarbon propellant is used,
become non-flammable, while the propellant is an HFC
propellant.
[0326] Such propellants include, but are not limited to,
hydrofluorocarbon (HFC) propellants, which contain no chlorine
atoms, and as such, fall completely outside concerns about
stratospheric ozone destruction by chlorofluorocarbons or other
chlorinated hydrocarbons. Exemplary non-flammable propellants
according to this aspect of the invention include propellants made
by DuPont under the registered trademark Dymel, such as 1,1,1,2
tetrafluorethane (Dymel 134), and 1,1,1,2,3,3,3 heptafluoropropane
(Dymel 227). HFCs possess Ozone Depletion Potential of 0.00 and
thus, they are allowed for use as propellant in aerosol
products.
[0327] Notably, the stability of foamable emulsions including HFC
as the propellant can be improved in comparison with the same
composition made with a hydrocarbon propellant.
[0328] In one or more embodiments foamable compositions comprise a
combination of a HFC and a hydrocarbon propellant such as n-butanee
or mixtures of hydrocarbom propellants such as propane, ispbutane
and butane.
Microemulsions and Nanoemulsions
[0329] Microemulsions and nanoemulsion are monophasic, transparent
(or slightly translucent) dispersions of oil and water. Unlike
conventional emulsions, microemulsions and nanoemulsion are
thermodynamically stable, making them a favorable vehicle for
pharmaceutical compositions, which have to maintain stability for
long periods of time. They and a method of manufacture are more
particularly described in US2006/0233721 which is incorporated
herein by way of reference. As will be appreciated by a man of the
art the methodology may be adapted according to the type of carrier
composition.
Aging
[0330] In order to project the potential shelf life and stability
of the compositions and their ingredients particularly active or
benefit agents the compositions can subjected to a number of tests,
including centrifugation to look for resistance to creaming, phase
separation; one or more freeze thaw cycles, standing at room and
higher temperatures as an indicator of resistance to aging.
Composition and Foam Physical Characteristics and Advantages
[0331] A pharmaceutical or cosmetic composition manufactured using
the foamable carrier of the present invention is very easy to use.
When applied onto the afflicted body surface of mammals, i.e.,
humans or animals, it is in a foam state, allowing free application
without spillage. Upon further application of a mechanical force,
e.g., by rubbing the composition onto the body surface, it freely
spreads on the surface and is rapidly absorbed.
[0332] The foamable composition of the present invention is stable,
having an acceptable shelf-life of at least one year, or
preferably, at least two years at ambient temperature, as revealed
in accelerated stability tests. The foamable compositions according
to the present invention are stable. Following accelerated
stability studies, they demonstrate desirable texture; they form
fine bubble structures that do not break immediately upon contact
with a surface, spread easily on the treated area and absorb
quickly.
[0333] The composition should also be free flowing, to allow it to
flow through the aperture of the container, e.g., and aerosol
container, and create an acceptable foam.
[0334] Foam quality can be graded as follows:
[0335] Grade E (excellent): very rich and creamy in appearance,
does not show any bubble structure or shows a very fine (small)
bubble structure; does not rapidly become dull; upon spreading on
the skin, the foam retains the creaminess property and does not
appear watery.
[0336] Grade G (good): rich and creamy in appearance, very small
bubble size, "dulls" more rapidly than an excellent foam, retains
creaminess upon spreading on the skin, and does not become
watery.
[0337] Grade FG (fairly good): a moderate amount of creaminess
noticeable, bubble structure is noticeable; upon spreading on the
skin the product dulls rapidly and becomes somewhat lower in
apparent viscosity.
[0338] Grade F (fair): very little creaminess noticeable, larger
bubble structure than a "fairly good" foam, upon spreading on the
skin it becomes thin in appearance and watery.
[0339] Grade P (poor): no creaminess noticeable, large bubble
structure, and when spread on the skin it becomes very thin and
watery in appearance.
[0340] Grade VP (very poor): dry foam, large very dull bubbles,
difficult to spread on the skin.
[0341] Topically administrable foams are typically of quality grade
E or G, when released from the aerosol container. Smaller bubbles
are indicative of more stable foam, which does not collapse
spontaneously immediately upon discharge from the container. The
finer foam structure looks and feels smoother, thus increasing its
usability and appeal.
[0342] As further aspect of the foam is breakability. The breakable
foam is thermally stable, yet breaks under sheer force. Sheer-force
breakability of the foam is clearly advantageous over thermally
induced breakability. Thermally sensitive foams immediately
collapse upon exposure to skin temperature and, therefore, cannot
be applied on the hand and afterwards delivered to the afflicted
area.
[0343] Another property of the foam is specific gravity, as
measured upon release from the aerosol can. Typically, foams have
specific gravity of less than 0.12 g/mL; or less than 0.10 g/mL; or
less than 0.08 g/mL, depending on their composition and on the
propellant concentration.
Pharmaceutical Composition
[0344] The foamable carrier of the present invention is an ideal
vehicle for active pharmaceutical ingredients and active cosmetic
ingredients. In the context of the present invention, active
pharmaceutical ingredients and active cosmetic ingredients are
collectively termed "active agent" or "active agents."
[0345] In one or more embodiments, the dicarboxylic acid or
dicarboxylic ester is the active ingredient. It can be used in the
formulation as a suspended solid or in solution, alone or in
combination with other active agents. As is known to one skilled in
the art, in some instances a specific active agent may have more
than one activity, function or effect.
[0346] In one embodiment, the dicarboxylic acid or dicarboxylic
acid ester is useful as an antibiotic, an antifungal agent, a
keratolytic agent, an inhibitor of the reduction of testosterone to
dihydrotestosterone, an inhibitor of the production of sebum in the
sebaceous gland, an anti-acne agent, by way of example.
Dicarboxylic acids, and azxelaic acid in particular, may be used
for the treatment of diaper rash, hyperpigmentary drmatoses, acne,
presbyderma of aging skin, hyperhydrosis, ischthyosis, and
wrinkling of the skin, anti-tumor agents (for example, in
conjunction with vitamins A, E and D), rosacea, a pigmentation
disorder, a cell proliferation abnormality a skin infection and a
skin inflammation and treatment of corns and callouses due to the
anti-keratolytic effects.
[0347] In one or more embodiments, the dicarboxylic acid or
dicarboxylic ester is used as a solvent for an active agent or as a
penetration enhancer for an active agent.
[0348] Suitable active agents for use in conjunction with a
dicarboxylic acid or a dicarboxylic ester include, but are not
limited to, active herbal extracts, acaricides, age spot and
keratose removing agents, allergen, analgesics, local anesthetics,
antiacne agents, antiallergic agents, antiaging agents,
antibacterials, antibiotics, antiburn agents, anticancer agents,
antidandruff agents, antidepressants, antidermatitis agents,
antiedemics, antihistamines, antihelminths, antihyperkeratolyte
agents, antiinflammatory agents, antiirritants, antilipemics,
antimicrobials, antimycotics, antiproliferative agents,
antioxidants, anti-wrinkle agents, antipruritics, antipsoriatic
agents, antirosacea agents antiseborrheic agents, antiseptic,
antiswelling agents, antiviral agents, antiyeast agents,
astringents, topical cardiovascular agents, chemotherapeutic
agents, corticosteroids, dicarboxylic acids, disinfectants,
fungicides, hair growth regulators, hormones, hydroxy acids,
immunosuppressants, immunoregulating agents, insecticides, insect
repellents, keratolytic agents, lactams, metals, metal oxides,
mitocides, neuropeptides, non-steroidal anti-inflammatory agents,
oxidizing agents, pediculicides, photodynamic therapy agents,
retinoids, sanatives, scabicides, self tanning agents, skin
whitening agents, vasoconstrictors, vasodilators, vitamins, vitamin
D derivatives, wound healing agents and wart removers. As is known
to one skilled in the art, in some instances a specific active
agent may have more than one activity, function or effect.
[0349] In one or more embodiments, the formulation additionally
includes a steroidal anti-inflammatory agent. The dicarboxylic acid
ester is present in the composition in an amount sufficient to
solubilize the steroid. Exemplary steroidal anti-inflammatory
agents include, but are not limited to, corticosteroids such as
bydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone,
dexamethasone-phosphate, beclomethsone dipropionate, clobetasol
valemate, desonide, desoxymethasone, desoxycorticosterone acetate,
dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone
valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone,
flumethasone pivalate, fluosinolone acetonide, fluocinonide,
flucortine butylester, fluocortolone, fluprednidene
(fluprednylidene) acetate, flurandrenolone, halcinonide,
hydrocortisone acetate, hydrocortisone butyrate,
methylprednisolone, triamcinolone acetonide, cortisone,
cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate,
fluradrenolone acetonide, medrysone, amcinafel, amcinafide,
betamethasone and the balance of its esters, chloroprednisone,
chlorprednisone acetate, clocortelone, clescinolone, dichlorisone,
difluprednate, flucloronide, flunisolide, fluoromethalone,
fluperolone, fluprednisolone, hydrocortisone valerate,
hydrocortisone cyclopentylpropionate, hydrocortmate, mepreddisone,
paramethasone, prednisolone, prednisone, beclomethasone
dipropionate, triamcinolone, and mixtures thereof. In an embodiment
of the present invention, the dicarboxylic acid ester is present in
the composition in an amount sufficient to solubilize the
steroid.
[0350] In one embodiment, the formulation additionally includes an
immunomodulator. The dicarboxylic acid ester is present in the
composition in an amount sufficient to solubilize the
immunomodulator. Immunomodulators are chemically or
biologically-derived agents that modify the immune response or the
functioning of the immune system (as by the stimulation of antibody
formation or the inhibition of white blood cell activity).
Immunomodulators include, among other options, cyclic peptides,
such as cyclosporine, tacrolimus, tresperimus, pimecrolimus,
sirolimus (rapamycin), verolimus, laflunimus, laquinimod and
imiquimod. Such compounds, delivered in the foam of the present
invention, are especially advantageous in skin disorders such as
psoriasis, eczema and atopic dermatitis, where the large skin areas
are to be treated.
[0351] In an embodiment of the present invention, the active agent
is selected from a dicarboxylic acid and a dicarboxylic acid
ester.
[0352] Because of the multiple therapeutic properties of
dicarboxylic acids and their respective esters, the combination of
such dicarboxylic acids or their respective esters with another
active agents can result in a synergistic therapeutic benefit. For
example, psoriasis is characterized by a heperkeratinization aspect
and an inflammation, and therefore, its treatment can benefit from
the combination of a dicarboxylic acid, which is keratolytic and a
steroid.
Fields of Applications
[0353] The foamable carrier of the present invention is suitable
for treating any inflicted surface. In one or more embodiments,
foamable carrier is suitable for administration to the skin, a body
surface, a body cavity or mucosal surface, e.g., the cavity and/or
the mucosa of the nose, mouth, eye, ear, respiratory system, vagina
or rectum (severally and interchangeably termed herein "target
site").
[0354] In one embodiment, the disorder is a dermatological
disorder, which can be treated by a dicarboxylic acid.
[0355] In another embodiment, the disorder is a dermatological
disorder that benefits from the use of a dicarboxylic acid or
dicarboxylic ester in conjunction with another active agent. The
dicarboxylic acid or dicarboxylic ester may benefit by improving
the solubility of the active agent or increasing the penetration of
the active agent. The dicarboxylic acid or dicarboxylic ester may
also provide a synergistic therapeutic effect in combination with
the active agent.
[0356] By selecting a suitable active agent, or a combination of
two or more active agents, the foamable composition of the present
invention is useful in treating an animal or a human patient having
any one of a variety of dermatological disorders, including
dermatological pain, dermatological inflammation, acne, acne
vulgaris, inflammatory acne, non-inflammatory acne, acne fulminans,
nodular papulopustular acne, acne conglobata, dermatitis, bacterial
skin infections, fungal skin infections, viral skin infections,
parasitic skin infections, skin neoplasia, skin neoplasms,
pruritis, cellulitis, acute lymphangitis, lymphadenitis,
erysipelas, cutaneous abscesses, necrotizing subcutaneous
infections, scalded skin syndrome, folliculitis, furuncles,
hidradenitis suppurativa, carbuncles, paronychial infections,
rashes, erythrasma, impetigo, ecthyma, yeast skin infections,
warts, molluscum contagiosum, trauma or injury to the skin,
post-operative or post-surgical skin conditions, scabies,
pediculosis, creeping eruption, eczemas, psoriasis, pityriasis
rosea, lichen planus, pityriasis rubra pilaris, edematous, erythema
multiforme, erythema nodosum, granuloma annulare, epidermal
necrolysis, sunburn, photosensitivity, pemphigus, bullous
pemphigoid, dermatitis herpetiformis, keratosis pilaris, callouses,
corns, ichthyosis, skin ulcers, ischemic necrosis, miliaria,
hyperhidrosis, moles, Kaposi's sarcoma, melanoma, malignant
melanoma, basal cell carcinoma, squamous cell carcinoma, poison
ivy, poison oak, contact dermatitis, atopic dermatitis, rosacea,
purpura, moniliasis, candidiasis, baldness, alopecia, Behcet's
syndrome, cholesteatoma, Dercum disease, ectodermal dysplasia,
gustatory sweating, nail patella syndrome, lupus, hives, hair loss,
Hailey-Hailey disease, chemical or thermal skin burns, scleroderma,
aging skin, wrinkles, sun spots, necrotizing fasciitis, necrotizing
myositis, gangrene, scarring, and vitiligo.
[0357] Likewise, the foamable composition of the present invention
is suitable for treating a disorder of a body cavity or mucosal
surface, e.g., the mucosa of the nose, mouth, eye, ear, respiratory
system, vagina or rectum. Non limiting examples of such conditions
include chlamydia infection, gonorrhea infection, hepatitis B,
herpes, HIV/AIDS, human papillomavirus (HPV), genital warts,
bacterial vaginosis, candidiasis, chancroid, granuloma Inguinale,
lymphogranuloma venereum, mucopurulent cervicitis (MPC), molluscum
contagiosum, nongonococcal urethritis (NGU), trichomoniasis, vulvar
disorders, vulvodynia, vulvar pain, yeast infection, vulvar
dystrophy, vulvar intraepithelial neoplasia (VIN), contact
dermatitis, pelvic inflammation, endometritis, salpingitis,
oophoritis, genital cancer, cancer of the cervix, cancer of the
vulva, cancer of the vagina, vaginal dryness, dyspareunia, anal and
rectal disease, anal abscess/fistula, anal cancer, anal fissure,
anal warts, Crohn's disease, hemorrhoids, anal itch, pruritus ani,
fecal incontinence, constipation, polyps of the colon and
rectum.
[0358] In an embodiment of the present invention, the disorder is a
dermatological disorder, which can be treated by a dicarboxylic
acid.
[0359] In an embodiment of the present invention, the disorder is a
dermatological disorder, which can be treated by a dicarboxylic
acid ester.
[0360] In an embodiment of the present invention, the disorder is a
dermatological disorder, which can be treated by a topical steroid,
and the dicarboxylic acid or dicarboxylic ester provides a
beneficial effect by increasing the solubility or penetration of
the topical steroid.
[0361] In an embodiment of the present invention, the disorder is a
dermatological disorder, which can be treated by an immunomodulator
and the dicarboxylic acid or dicarboxylic ester provides a
beneficial effect by increasing the solubility or penetration of
the topical immunomodulator.
[0362] In an embodiment of the present invention, the disorder is a
dermatological disorder, which can be treated by an anti-infective
agent, such as an antibacterial agent, and antibiotic, an
antifungal agent and an antiviral agent, and the dicarboxylic acid
or dicarboxylic ester provides a beneficial effect as an
anti-infective agent or by increasing the solubility or penetration
of the anti-infective agent.
[0363] In an embodiment of the present invention, the disorder is a
dermatological disorder, which is common in children. Foam is
advantageous in the topical treatment of children, who are
sensitive to treatment with a cream or ointment.
[0364] In an embodiment of the present invention, the disorder is
atopic dermatitis and the active agent is a steroid, further
including a dicarboxylic acid (DCA) or DCA ester to stabilize or
solubilize the topical steroid.
[0365] In an embodiment of the present invention, the disorder is
psoriasis and the active agent is a steroid, further including a
DCA or DCA ester to stabilize or solubilize the topical
steroid.
[0366] In an embodiment of the present invention, the disorder is
selected from psoriasis and atopic dermatitis and the active agent
comprises a steroid and an additional non-steroidal active agent,
such as a vitamin D derivative, further including a DCA or DCA
ester to stabilize or solubilize the topical steroid and/or
non-steroidal active agent.
[0367] In an embodiment of the present invention, the disorder is
selected from psoriasis and atopic dermatitis and the active agent
comprises an immunomodulator, further including a DCA or DCA ester
to stabilize or solubilize the immunomodulator.
[0368] In an embodiment of the present invention, the composition
is useful for the treatment of an infection. In one or more
embodiments, the composition is suitable for the treatment of an
infection, selected from the group of a bacterial infection, a
fungal infection, a yeast infection, a viral infection and a
parasitic infection.
[0369] In an embodiment of the present invention, the composition
is useful for the treatment of wound, ulcer and burn.
[0370] The composition of the present invention is also suitable
for administering a hormone to the skin or to a mucosal membrane or
to a body cavity, in order to deliver the hormone into the tissue
of the target organ, in any disorder that responds to treatment
with a hormone.
[0371] Other foamable compositions are described in: U.S.
Publication No. 05-0232869, published on Oct. 20, 2005, entitled
NONSTEROIDAL IMMUNOMODULATING KIT AND COMPOSITION AND USES THEREOF;
U.S. Publication No. 05-0205086, published on Sep. 22, 2005,
entitled RETINOID IMMUNOMODULATING KIT AND COMPOSITION AND USES
THEREOF; U.S. Publication No. 06-0018937, published on Jan. 26,
2006, entitled STEROID KIT AND FOAMABLE COMPOSITION AND USES
THEREOF; U.S. Publication No. 05-0271596, published on Dec. 8,
2005, entitled VASOACTIVE KIT AND COMPOSITION AND USES THEREOF;
U.S. Publication No. 06-0269485, published on Nov. 30, 2006,
entitled ANTIBIOTIC KIT AND COMPOSITION AND USES THEREOF; U.S.
Publication No. 07-0020304, published on Jan. 25, 2007, entitled
NON-FLAMMABLE INSECTICIDE COMPOSITION AND USES THEREOF; U.S.
Publication No. 06-0193789, published on Aug. 31, 2006, entitled
FILM FORMING FOAMABLE COMPOSITION; U.S. patent application Ser. No.
11/732,547, filed on Apr. 4, 2007, entitled ANTI-INFECTION
AUGMENTATION OF FOAMABLE COMPOSITIONS AND KIT AND USES THEREOF;
U.S. Provisional Patent Application No. 60/789,186, filed on Apr.
4, 2006, KERATOLYTIC ANTIFUNGAL FOAM; U.S. Provisional Patent
Application No. 0/815948, filed on Jun. 23, 2006, entitled FOAMABLE
COMPOSITIONS COMPRISING A CALCIUM CHANNEL BLOCKER, A CHOLINERGIC
AGENT AND A NITRIC OXIDE DONOR; U.S. Provisional Patent Application
No. 60/818,634, filed on Jul. 5, 2006, entitled DICARBOXYLIC ACID
FOAMABLE VEHICLE AND PHARMACEUTICAL COMPOSITIONS THEREOF; U.S.
Provisional Patent Application No. 60/843,140, filed on Sep. 8,
2006, entitled FOAMABLE VEHICLE AND VITAMIN PHARMACEUTICAL
COMPOSITIONS THEREOF, all of which are incorporated herein by
reference in their entirety. More particularly any of the active
ingredients; the solvents; the surfactants; foam adjuvants;
penetration enhancers; humectants; moisturizers; and other
excipients as well as the propellants listed therein can be applied
herein and are incorporated by reference.
[0372] The following examples further exemplify the benefit agent
foamable pharmaceutical carriers, pharmaceutical compositions
thereof, methods for preparing the same, and therapeutic uses of
the compositions. The examples are for the purposes of illustration
only and are not intended to be limiting of the invention. Many
variations may be carried out by one of ordinary skill in the art
and are contemplated within the full scope of the present
invention.
Methodology
[0373] A general procedure for preparing foamable compositions is
set out in WO 2004/037225, which is incorporated herein by
reference.
Emulsion Foam
[0374] 1. Mix oily phase ingredients and heat to 75.degree. C. to
melt all ingredients and obtain homogeneous mixture. [0375] 2. Mix
polymers in water with heating or cooling as appropriate for
specific polymer. [0376] 3. Add all other water soluble ingredients
to water-polymer solution and heat to 75.degree. C. [0377] 4. Add
slowly internal phase to external phase at 75.degree. C. under
vigorous mixing and homogenize to obtain fine emulsion.
Alternatively the external phase is added slowly to the internal
phase. [0378] 5. Cool to below 40.degree. C. and add sensitive
ingredients with mild mixing. [0379] 6. Cool to room
temperature.
Waterless Foam
[0379] [0380] 1. Dissolve the polymers in the main solvent with
heating or cooling as appropriate for specific polymer. Add the all
other ingredients and heat to 75.degree. C. to melt and dissolve
the various ingredients. [0381] 2. Cool to below 40.degree. C. and
add sensitive ingredients with mild mixing. [0382] 3. Cool to room
temperature.
Oily Waterless Foam
[0382] [0383] 1. Mix all ingredients excluding polymers and heat to
75.degree. C. to melt and dissolve and obtain homogeneous mixture.
[0384] 2. Mix well and cool to below 40.degree. C. and add the
polymers and sensitive ingredients with moderate mixing. [0385] 3.
Cool to room temperature. Oily Foam with Phospholipids and/or Water
[0386] 1. Swell the phospholipids in the main oily solvent under
mixing for at least 20 minutes until uniform suspension is
obtained. [0387] 2. Add all other ingredients excluding polymers
and heat to 75.degree. C. to melt and dissolve and obtain
homogeneous mixture. [0388] 3. Mix well and cool to below
40.degree. C. and add the polymers and sensitive ingredients with
moderate mixing. [0389] 4. Cool to room temperature. [0390] 5. In
case of polymers dissolved in water or organic solvent, dissolve
the polymers in the solvent with heating or cooling as appropriate
for specific polymer and add to the oily mixture under vigorous
mixing at .about.40.degree. C.
Canisters Filling and Crimping
[0391] Each aerosol canister is filled with PFF and crimped with
valve using vacuum crimping machine.
Pressurizing
[0392] Propellant Filling
[0393] Pressurizing is carried out using a hydrocarbon gas or gas
mixture
[0394] Canisters are filled and then warmed for 30 sec in a warm
bath at 50.degree. C. and well shaken immediately thereafter.
[0395] Closure Integrity Test.
[0396] Each pressurized canister is subjected to bubble and
crimping integrity testing by immersing the canister in a
60.degree. C. water bath for 2 minutes. Canisters are observed for
leakage as determined by the generation of bubbles. Canisters
releasing bubbles are rejected.
Tests
[0397] By way of non limiting example the objectives of hardness,
collapse time and FTC stability tests are briefly set out below as
would be appreciated by a person of the art.
[0398] Hardness
[0399] LFRA100 instrument is used to characterize hardness. A probe
is inserted into the test material. The resistance of the material
to compression is measured by a calibrated load cell and reported
in units of grams on the texture analyzer instrument display.
Preferably at least three repeat tests are made. The textural
characteristics of a dispensed foam can effect the degree of dermal
penetration, efficacy, spreadability and acceptability to the user.
The results can also be looked at as an indicator of softness.
Note: the foam sample is dispensed into an aluminum sample holder
and filled to the top of the holder.
[0400] Collapse Time
[0401] Collapse time (CT) is examined by dispensing a given
quantity of foam and photographing sequentially its appearance with
time during incubation at 36.degree. C. It is useful for evaluating
foam products, which maintain structural stability at skin
temperature for at least 1 min.
[0402] Viscosity
[0403] Viscosity is measured with Brookfield LVDV-II+PRO with
spindle SC4-25 at ambient temperature and 10, 5 and 1 RPM.
Viscosity is usually measured at 10 RPM. However, at about the
apparent upper limit for the spindle of .about.>50,000 CP, the
viscosity at 1 RPM may be measured, although the figures are of a
higher magnitude.
[0404] FTC (Freeze Thaw Cycles)
[0405] To check the foam appearance under extreme conditions of
repeated cycles of cooling, heating, (first cycle) cooling, heating
(second cycle) etc., commencing with -100.degree. C. (24 hours)
followed by +400.degree. C. (24 hours) measuring the appearance and
again repeating the cycle for up to three times.
[0406] Creaming by Centrifugation:
1. Principle of Test
[0407] The centrifugation used in this procedure serves as a stress
condition simulating the aging of the liquid dispersion under
investigation. Under these conditions, the centrifugal force
applied facilitates the coalescence of dispersed globules or
sedimentation of dispersed solids, resulting in loss of the desired
properties of the formulated dispersion.
2. Procedure
[0408] 2.1. Following preparation of the experimental
formulation/s, allow to stand at room temperature for .gtoreq.24 h.
[0409] 2.2. Handle pentane in the chemical hood. Add to each
experimental formulation in a 20-mL glass vial a quantity of
pentane equivalent to the specified quantity of propellant for that
formulation, mix and allow formulation to stand for at least 1 h
and not more than 24 h. [0410] 2.3. Transfer each mixture to 1.5 mL
microtubes. Tap each microtube on the table surface to remove
entrapped air bubbles. [0411] 2.4. Place visually balanced
microtubes in the centrifuge rotor and operate the centrifuge at
3,000 rpm for 10 min or at 1,000 rpm for 10 min.
[0412] Intra-Canister Uniformity
[0413] 1. Representative product containers are collected, sample
test solutions are prepared and the content of the analyte is
determined according to standard methods in the art. Variability of
content is characterized as percent difference or relative standard
deviation, as appropriate, according to the number of samples
evaluated.
[0414] 2. The results ascertain variability or uniformity within a
given container in content of analytes (primarily active
pharmaceutical ingredients, but also preservatives) taken from
different parts of a pressurized canister drug products
[0415] 3. Two full canisters were shaken according to product
instructions. About 1-3 g of Foam was dispensed from each canister
and discarded. Foam sufficient for two replicate sample solution
preparations was then dispensed into a glass beaker. This
represents the initial sample. A middle portion is then dispensed
from each canister being about half the canister contents. This
middle dispensed portion may be discarded or collected for testing
purposes, as necessary. Foam sufficient for two replicate sample
solution preparations was then dispensed into a glass beaker. This
represents the final sample. A small amount of formulation remains
in the canister. The foam samples were stirred to remove gas/air
bubbles. From both the initial and final foam portions from each
canister 4 separate sample solutions are prepared and analyzed, 2
from the initial portion and 2 from the final portion. The percent
difference is calculated as follows:
Difference between content determined in initial & final
portions Mean of content of initial & final portions .times.
100 ##EQU00001## [0416] and the intra canister uniformity evaluated
from the results.
Stock Compositions
[0417] Non-limiting examples of how stock solutions are made up
with and without API. Other stock solutions may be made using the
same methodology by simply varying adding or omitting ingredients
as would be appreciated by one of the ordinary skills in the
art.
EXAMPLES
[0418] The invention is described with reference to the following
examples. This invention is not limited to these examples and
experiments. Many variations will suggest themselves and are within
the full intended scope of the appended claims.
Section A--Aqueous
A1--Emollient Formulations
A1--Example 1--Vehicle Composition Containing Diisopropyl Adipate
(DISPA)
[0419] The following foamable vehicles were prepared and the
quality of the resultant foam was ascertained.
TABLE-US-00010 GOG GOG GOG GOG 08 09 10 11 PHASE Ingredient % w/w %
w/w % w/w % w/w Oil Capric/caprylic 10.00 10.00 Phase triglyceride
(A) Diisopropyladipate 20.00 20.00 20.00 20.00 (DISPA) Benzyl
alcohol 2.00 2.00 2.00 2.00 Oleyl alcohol 20.00 20.00 10.00 10.00
PPG 15 stearyl ether 2.00 2.00 2.00 2.00 Sorbitan laurate 1.50
Sorbitan stearate 4.00 4.00 2.00 2.00 Stearic acid 4.00 4.00 2.00
Stearyl alcohol 3.00 Pemulen TR2 0.05 0.05 Water Hydroxypropyl
methyl 0.15 Phase cellulose (B) Xanthan gum 0.15 Sucrose ester 2.00
2.00 1.00 2.00 Propylene glycol 8.00 8.00 8.00 8.00 Glycerin 5.00
5.00 5.00 8.00 TEA 0.10 0.10 0.10 Water 37.85 32.90 37.85 31.20
Foam quality E E G E Emulsion stability Stable Stable Stable Stable
(10000 RPM)
[0420] Notes: [0421] Compositions GOG 08 and GOG 09 contain 20%
DISPA and 20% oleyl alcohol to provide (1) high emolliency; (2)
high solubilizing capacity of an oil-soluble active agent; and (3)
enhanced skin delivery of an active agent. [0422] Compositions GOG
10 and GOG 11 contain 20% DISPA, 20% oleyl alcohol and 10%
capric/caprylic triglyceride to provide (1) enhanced emolliency;
(2) high solubilizing capacity of an oil-soluble active agent; and
(3) enhanced skin delivery of an active agent. [0423] The
compositions contain about 30% water. Therefore, they provide high
skin barrier build-up effect. [0424] The compositions are oil in
water emulsions, despite the fact that there is oil more than water
in the formulation. Oil in water emulsion is maintained and
stabiized by selecting a surfactant that favors oil in water
emulsions over water in oil emulsions. Hence, the skin feeling of
the composition is favorable. [0425] The surfactants, sorbitan
laurate, sorbitan stearate and sucrose esters, are POE-free and
hence this formulation may be used with active agents that are not
compatible with POE. [0426] The compositions can be used as lotions
for topical therapy of an inflammatory skin disorder. [0427] In
order to create a foamable composition, the composition is filled
into an aerosol canister and pressurized using a liquefied or gas
propellant can be added at a concentration of about 3% to about
25%.
A1--Example 2--Vehicle Composition Containing Diisopropyl Adipate
(DISPA)
[0428] The following foamable vehicles were prepared and the
quality of the resultant foam was ascertained.
TABLE-US-00011 GOG 13 GOG 14 GOG 15 PHASE Ingredient % w/w % w/w %
w/w Oil Phase Capric/caprylic 10.00 10.00 10.00 (A) triglyceride
Diisopropyladipate 20.00 Dimethyl sebacate 20.00 Dioctyl malate
20.00 Benzyl alcohol 2.00 2.00 2.00 Oleyl alcohol 10.00 10.00 10.00
PPG 15 stearyl ether 2.00 2.00 2.00 Sorbitan laurate 2.00 2.00
Sorbitan stearate 2.00 Stearic acid 1.20 Stearyl alcohol 3.00 1.00
er Phase Hydroxypropyl 0.15 0.15 0.15 methyl cellulose Xanthan gum
0.15 0.15 0.15 Sucrose ester HLB 16 Sucrose ester HLB 11 3.00 2.00
2.00 Propylene glycol 17.70 17.70 17.70 Glycerin TEA 0.06 Water
30.00 33.00 32.74 Foam quality E G E Emulsion stability Stable
Stable Stable (10000 RPM) indicates data missing or illegible when
filed
[0429] Notes: [0430] Composition GOG 13 contains 20% DISPA, 10%
oleyl alcohol and 10% capric/caprylic triglyceride, to provide (1)
enhanced emolliency; (2) high solubilizing capacity of an
oil-soluble active agent; and (3) enhanced skin delivery of an
active agent. [0431] Composition GOG 14 contains 20% dietthyl
sebacate, 10% oleyl alcohol and 10% capric/caprylic triglyceride,
to provide (1) enhanced emolliency; (2) high solubilizing capacity
of an oil-soluble active agent; and (3) enhanced skin delivery of
an active agent. [0432] Composition GOG 15 contains 20% dioctyl
malate, 10% oleyl alcohol and 10% capric/caprylic triglyceride, to
provide (1) enhanced emolliency; (2) high solubilizing capacity of
an oil-soluble active agent; and (3) enhanced skin delivery of an
active agent. [0433] The compositions contain about 30% water.
Therefore, they provide high skin barrier build-up effect [0434]
The compositions are oil in water emulsions, despite the fact that
there is oil more than water in the formulation. Hence, the skin
feeling of the composition is favorable. [0435] The surfactants are
POE-free: sorbitan laurate, sorbitan stearate and sucrose esters.
[0436] The compositions can be used as lotions for topical therapy
of an inflammatory skin disorder. [0437] In order to create a
foamable composition, the composition is filled into an aerosol
canister and pressurized using a liquefied or gas propellant can be
added at a concentration of about 3% to about 25%.
A1--Example 3--Vehicle Compositions Containing 10% to 50%
Diisopropyl Adipate (DISPA) as Solvent
[0438] The following foamable vehicles were prepared and the
quality of the resultant foam was ascertained.
TABLE-US-00012 DCA001 DCA002 DCA003 DCA011 diisopropyl 10.00 20.00
30.00 40.00 adipate (DISPA) Steareth 2 3.06 3.67 4.89 4.89 Steareth
21 1.94 2.33 3.11 3.11 Carboxy methyl 0.50 0.50 0.50 0.50 cellulose
Water purified 84.50 73.50 61.50 51.50 Total 100.00 100.00 100.00
100.00 Propellant 8.00 8.00 8.00 8.00 propane, isobutene and butane
mixture Appearance: foam quality E E E E color White White White
White odor No odor No odor No odor No odor density 0.049 0.045
0.064 collapse time >300 >300 Hardness 18.76 31.77
[0439] Excellent foam formulations were prepared with DISPA,
surfactant, and a nominal amount of polymeric agent.
[0440] In foamable compositions using less than 40 wt % DISPA, no
solvent other than water is required to make foamable composition
with resultant excellent foams. The use of a combination of
ether-based or ester-based surfactants was found to be useful in
forming excellent foams with a minimal number of ingredients.
Without being bound by any particular theory or mode of operation,
it is believed that the use of non-ionic surfactants with
significant hydrophobic and hydrophilic components, increase the
emulsifier or foam stabilization characteristics of the
composition. Similarly, without being bound by any particular
theory or mode of operation, using combinations of surfactants with
high and low HLB's to provide a relatively close packed surfactant
layer may strengthen the emulsion.
[0441] Visual test after addition of water indicated that DCA011 is
an oil in water emulsion.
A1--Example 4--Minimal Vehicle Compositions, Containing 40%
Diisopropyl Adipate (DISPA) with and without Polymer
[0442] The following foamable vehicles were prepared and the
quality of the resultant foam was ascertained.
TABLE-US-00013 DCA011 DCA011A diisopropyl 40.00 40.00 adipate
(DISPA) Steareth 2 4.89 4.89 Steareth 21 3.11 3.11 Carboxy methyl
0.50 cellulose Water purified 51.50 52.00 Total 100.00 100.00
Propellant 8.00 8.00 propane, isobutene and butane mixture
Appearance: foam quality E E color White White odor No odor No
odor
[0443] Polymeric agents are introduced to improve foam.
Surprisingly, it was possible to prepare excellent foam
formulations without a polymeric agent from DISPA, surfactant, and
water (and without a foam adjuvant or another solvent). This is
especially surprising as the use of water in the composition is
understood to benefit from the use of a polymeric agent that can
thicken or increase the viscosity of the compositions and improve
the resultant foam strength.
[0444] As in Example 3 and in Example 6, the combination of
ether-based or ester-based surfactants was found to be useful in
forming excellent foams with a minimal number of ingredients.
A1--Example 5--Vehicle Compositions Containing about 50%
Diisopropyl Adipate (DISPA) with Polymer
[0445] The following foamable vehicles were prepared and the
quality of the resultant foam was ascertained.
TABLE-US-00014 DCA012 DCA013 diisopropyl adipate (DISPA) 46.00
50.00 Steareth 2 4.58 Steareth 21 2.92 Isoceteth 20 3.00 Pemulen
TR2 0.22 TEA 0.12 Carboxy methyl cellulose 0.50 Water purified
46.00 46.66 Total 100.00 100.00 Propellant propane, isobutene and
butane mixture 8.00 8.00 Appearance: foam quality E E color White
White odor No odor No odor
[0446] Increasing the amount of DISPA above 46% resulted in a poor
foam and precipitation in formulations containing a polymer.
Changing the surfactant to GMS eliminated the precipitation but the
foam remained poor. Replacing the carboxy methyl cellulose
polymeric agent with carbopol did not result in any improvement.
[0447] Surprisingly, removal of the polymer at 50% DISPA, and
steareth 21 and steareth 2 improved the foam quality but did not
eliminate the precipitation. [0448] However, by changing the
surfactants and polymeric agents it was possible to increase the
level of the DISPA and achieve excellent foams without
precipitation. [0449] A combination of ether-based or ester-based
surfactants was found to be useful in forming excellent foams with
a minimal number of ingredients [0450] It has been discovered also
that by using a derivatized hydrophilic polymer with hydrophobic
alkyl moieties as a polymeric emulsifier it is possible to
stabilize the emulsion better about or at the region of phase
reversal tension. Other types of derivatized polymers like silicone
copolymers, derivatized starch and derivatized dexrin may also a
similar stabilizing effect.
A1--Example 6--Vehicle Compositions Containing 60% Diisopropyl
Adipate (DISPA) without Polymer
[0451] The following foamable vehicles were prepared and the
quality of the resultant foam was ascertained.
TABLE-US-00015 DCA028 DCA029 DCA030 DCA031 diisopropyl adipate
60.00 60.00 diethyl sebacate 60.00 60.00 Steareth 2 3.00 3.00
Steareth 21 2.00 2.00 PEG-40 Stearate 4.00 4.00 Polysorbate 80 2.00
2.00 Water purified 34.00 34.00 35.00 35.00 Total 100.00 100.00
100.00 100.00 Propellant (1681) 8.00 8.00 8.00 8.00 Appearance:
foam quality E E E E color White White White White odor No odor No
odor No odor No odor 1000 rpm for 10 mins stable stable stable
stable 3000 rpm for 10 mins % 80% 80% stable 75% creaming DCA
028-80% Creaming, 029-80% Creaming, 030-Homogenous, 031-75%
Creaming at 3 K.
[0452] More surprisingly, by removal of the polymer and by reducing
the levels of steareth 21 and steareth 2 (ethers) (by about 40 to
50%) it was possible to obtain excellent foams without
precipitation at 60% DISPA and at 60% diethyl sebacate.
[0453] Without being bound to any particular theory the physical
change in the formulation may be due to DISPA reaching a
concentration where phase reversal from o/w to w/o emulsion is
possible. Also at this concentration range of DISPA removal of the
polymeric agent, which itself can absorb water may--without being
bound by any theory--have resulted in additional water being
available and perhaps reducing internal emulsion tensions including
any resulting from the presence of the polymeric agent and thereby
unexpectedly resulting in improved foam quality even though
polymeric agents are normally added to strengthen foam quality.
Also as the concentration of DISPA increased and consequently the
amount of water decreased it appears that the amount of surfactant
required reduction as the external water phase is thinner.
[0454] It has also been discovered by using a different surfactant
(ester based in place of an ether based) system it was possible to
achieve compositions that can generate good quality foam and
without precipitation with 60% DISPA or 60% diethyl sebacate in the
absence of polymer. Addition of small amounts of xantham gum and
methocel with 60% DISPA and the ester based surfactants resulted in
poor foam.
[0455] It further appears to be the case that--without being
limited by any theory--for any given emulsion system as the oil
phase is increased with a corresponding decrease in the water phase
the internal tension or pressure for phase reversal will increase
and the point at which the phase reversal can occur can be retarded
by selective use of non traditional derivatized polymeric agents
with emulsifying properties, such as permulen that can stabilize
the formulation and push back the point at which pressure for phase
reversal might otherwise occur.
[0456] Surprisingly it was observed that more traditional polymeric
agents like carboxy methyl cellulose or carbopol or combinations
like xantham gum and methocel can interfere with foam formulation
at higher levels of dicarboxylic esters.--all these formulations
were examined by conductivity, by water addition test and by
microscopic examination and were found to be oil in water emulsions
despite the fact that the amount of oil phase was approximately
double that of the aqueous phase.
A1--Example 7--Vehicle Compositions Containing 10% to 45% Diethyl
Sebacate
[0457] The following foamable vehicles were prepared and the
quality of the resultant foam was ascertained.
TABLE-US-00016 DCA004 DCA005 DCA006 DCA024 DCA025 diethyl 10.00
20.00 30.00 40.00 45.00 sebacate Steareth 2 4.00 5.00 5.33 6.00
6.00 Steareth 21 2.00 2.50 2.67 3.00 3.00 Carboxy 0.50 0.50 0.50
0.50 0.50 methyl cellulose Water 83.50 72.00 61.50 50.50 45.50
purified Total 100.00 100.00 100.00 100.00 100.00 Propellant 8.00
8.00 8.00 8.00 8.00 (1681) Appearance: foam quality E E E E E color
White White White White White odor No odor No odor No odor No odor
No odor density 0.065 0.063 0.063 collapse time >300 >300
>300 Hardness 17.23 24.67 27.39
[0458] Excellent foam formulations were prepared with diethyl
sebacate, surfactant, a nominal amount of polymeric agent and water
(and without any foam adjuvant or another solvent).
A1--Example 8--DISPA Formulation to Provide Stable Environment for
Pimecrolimus
Part 1--Composition of Placebo or Stock Formulation PIMF-001P
TABLE-US-00017 [0459] Material % w/w Caprylic/capric triglyceride
10.00 Diisopropyl adipate (DISPA) 20.00 Oleyl alcohol 10.00 PPG-15
stearyl ether 2.00 Stearic acid 1.20 Sorbitan laurate 2.00 Benzyl
alcohol 2.00 Methocel A4M (methylcellulose) 0.15 Xanthan gum 0.15
Sucrose stearic acid esters, mixture 2.00 Propylene glycol 17.70
Water purified 32.74 Trolamine (TEA) 0.06 Total 100.00 Propellant
8.00
[0460] Pimecrolimus is sensitive to polyethylene glycol polymers so
it was necessary to develop formulations with emulsifying agents
other than for example Twin, Myrj, or Brij surfactants, which are
mainstream surfactants for pharmaceutical formulations. The
combination of sorbitan laurate with sucrose stearic acid esters
was found to be effective. Pimecrolimus is insoluble in water but
is soluble in DISPA.
Part 2--Pimecrolimus Content Determined by HPLC in PFF and Foam
Formulation Samples at Various Times and Storage Conditions
[0461] The formulations were comprised of 98.8%; 98.6% and 98.4%
stock plus 1.2%, 1.4% and 1.6% pimecrolimus respectively.
TABLE-US-00018 30 14 days, 30 days, days, 50.degree. C., 30 days,
50.degree. C. 50.degree. C. glass vials, 40.degree. C., glass
canisters Sample name Zero time PFF Foam vials, PFF PFF PIM 1.2%:
Result 1 1.12 1.14 1.22 1.05 1.13 batch PIMF001- Result 2 1.12 1.13
1.22 1.05 1.13 060620 Average 1.12 1.14 1.22 1.05 1.13 PIM 1.4%:
Result 1 1.45 1.31 1.41 1.39 1.37 batch PIMF002- Result 2 1.41 1.33
1.41 1.39 1.37 060620 Average 1.41 1.32 1.41 1.39 1.37 PIM 1.6%:
Result 1 1.58 1.5 1.59 1.56 1.55 batch PIMF003- Result 2 1.58 1.5
1.59 1.56 1.56 060620 Average 1.58 1.5 1.59 1.56 1.56
[0462] As can be seen from the above there is no significant
breakdown of the active agent after a month when solubilized in
DISPA.
Part 3--Physical Properties of PFF and Foam Preparations
TABLE-US-00019 [0463] PFF Formula Centrifugation, Centrifugation,
Foam Appearance Name 3000 rpm 10,000 rpm Quality Color Odor PIMF001
stable 80% creaming good white no odor PIMF002 stable stable good
white no odor PIMF003 stable 95% creaming excellent white no
odor
[0464] The basic formulation is a liquid emulsion which is
inherently not stable with a tendency to cream or separate. Two
contradictory forces had to be overcome to produce a good to
excellent stable foam. One is to have a liquid formulation that
stabilizes the active agent and the other is to have a thick almost
solid like constitution which resists or retards creaming and or
separation. Nevertheless, by introducing into the formulation a
mixture of non-poly ethylene glycol polymer surfactants, which can
produce a strong and closed packed barrier between the oil and the
water that stabilizes the emulsion, together with polymeric agents
that retard creaming and or separation whilst maintaining a fluid
constitution, it was possible to stabilize the foam and active
agent.
[0465] Microscopic examination disclosed that there were no
crystals and that Pimecrolimus was solubilized.
A2--Suspensions
A2--Example 9--Dicarboxylic Acid Composition
[0466] The following foamable vehicles were prepared and the
quality of the resultant foam was ascertained.
Part A--Formulation
TABLE-US-00020 [0467] Ingredient % w/w Azelaic Acid 15.00 Water
51.90 Caprylic/Capric triglyceride 10.87 Propylene glycol 10.87
Dimethyl isosorbide 5.44 PEG-40 stearate 2.83 Cetostearyl alcohol
1.09 Polysorbate 80 0.98 Glyceryl stearate 0.54 Xanthan gum 0.27
Methylcellulose A4M 0.11 Benzoic acid 0.10 NaOH (18% Solution) to
pH = 4.5 Total: 100
[0468] Notes [0469] The composition contains azelaic acid as a
benefit agent, which is suitable for treating a skin disorder,
selected from acne, rosacea, a pigmentation disorder, a cell
proliferation abnormality a skin infection and a skin inflammation.
[0470] The composition contains about 10% capric/caprylic
triglyceride to provide emolliency and about 10% propylene glycol
and 10% dimethyl isosorbide, to provide (1) enhanced emolliency;
(2) improved solubilizing capacity of the azelaic acid; and (3)
enhanced skin delivery. [0471] The compositions contain about 50%
water. Therefore, they provide high skin barrier build-up effect.
[0472] The composition can be used as a cream/lotion for topical
therapy of a skin disorder. [0473] In order to create a foamable
composition, the composition is filled into an aerosol canister and
pressurized using a liquefied or gas propellant can be added at a
concentration of about 3% to about 25%.
Part B--12 Month Stability Test
TABLE-US-00021 [0474] T-12 Test parameter T-0 upright inverted API*
assay % amount of label 99.3 100.5 101.7 by HPLC (%) % w/w 14.90
15.07 15.26 Product content uniformity (Intra 1.79 0.10 0.88
canister) of API (%) *API = active pharmaceutical ingredient
[0475] The total amount of active agent at T-0 and at T-12 months
as a percentage of 100% of ingredient that should be present
according to the label and as a percentage in the formulation w/w,
respectively was determined. As can be seen, no reduction in API
content was observed within the limits of detection and that the
content remained uniform. The differences between samples taken
from the top of the canisters and from samples taken from the
bottom of the canisters were not significant and were well within
the acceptable range.
[0476] Furthermore, the formulation comprising active ingredient
azaleic acid--despite being a suspension and subject to
graviational effect--was able to withstand sedimentation and
degredation such that it has remained stable and uniformly
distributed in the formulation as a suspension over a prolonged
period of 12 months, whilst remaining flowable and shakable.
Example 10--Additional Dicarboxylic Acid Compositions
[0477] The following foamable vehicles were prepared and the
quality of the resultant foam was ascertained.
TABLE-US-00022 Formulation: AZL018 AZL034 AZL035 AZL036 AZL037
AZL038 AZL039 % w/w % w/w % w/w % w/w % w/w % w/w % w/w Azelaic
Acid 15.00 15.00 15.00 15.00 15.00 15.00 15.00 Caprylic/capric 5.00
10.00 5.00 5.00 5.00 5.00 10.00 triglyceride Cetostearyl alcohol
0.90 1.00 1.00 1.00 1.00 1.00 1.00 Glyceryl stearate 0.45 0.50 0.50
0.50 0.50 0.50 0.50 Cholesterol 1.00 -- -- -- -- 1.00 -- Benzoic
acid 0.20 -- 0.20 0.20 0.20 -- Benzyl alcohol 1.00 -- 1.00 -- -- --
1.00 PEG-40 stearate 2.60 2.60 2.60 2.60 2.60 2.60 Methylcellulose
0.10 0.10 0.10 0.10 0.10 0.10 Hydroxypropyl 0.10 -- -- -- -- -- --
methylcellulose Xanthan gum 0.25 0.10 0.25 0.10 0.25 0.10 0.10
Polysorbate 80 0.90 0.90 0.90 0.90 0.90 0.90 0.90 EDTA disodium
0.10 -- -- -- -- -- -- dehydrate PEG-400 -- -- -- -- 5.00 -- --
Dimethyl isosorbide 10.00 -- -- 5.00 -- -- 5.00 50%
phosphotidylcholine -- 2.80 2.80 -- 2.80 -- 2.80 in propylene
glycol propylene glycol 6.00 5.00 10.00 10.00 -- -- -- Sodium
hydroxide to to to to to to to pH = 4.5 pH = 4.5 pH = 5.3 pH = 4.5
pH = 4.5 pH = 4.5 pH = 5.3 Propellant (butane + 8.00 8.00 8.00 8.00
8.00 8.00 8.00 isobutane + propane) Purified water to 100 to 100 to
100 to 100 to 100 to 100 to 100
Example 11--Compositions with Azaleic Acid with and without
Different Polymeric Agents
[0478] The following foamable vehicles were prepared and the
quality of the resultant foam was ascertained.
TABLE-US-00023 DCA021 DCA023 DCA023A DCA026 DCA026a Isopropyl 11.00
11.00 myristate MCT oil 35.00 35.00 Azelaic acid 20.00 15.00 15.00
15.00 15.00 Propylene 30.00 glycol Steareth 2 8.00 8.00 Steareth 21
2.00 2.00 PEG-40 4.00 6.00 Stearate Polysorbate 30.00 1.40 2.10 80
Xanthan 0.30 0.27 gum Methocel 0.30 0.11 A4M Carboxy 0.50 methyl
cellulose Water 19.40 39.50 40.00 68.22 65.90 purified Total 100.00
100.00 100.00 100.00 100.00 Propellant 8.00 8.00 8.00 8.00 8.00
(propane, isobutene and butane mixture Appearance: foam quality G-E
G-E G-E E E color White White White White White odor No odor No
odor No odor No odor No odor Microscope Crystals Crystals Crystals
Crystals Crystals
[0479] Good to excellent foam formulations were prepared with
azelaic acid, surfactant, polymeric agent, and either another oil
or propylene glycol water (and without any foam adjuvant). Reducing
the levels of azelaic acid to lower levels eliminated the
appearance of crystals (See below).
[0480] Surprisingly, it was possible to prepare good to excellent
foam after removal of the polymeric agent. Thus, the presence of a
polymeric agent, is surprisingly not essential for foam quality.
Nonetheless, polymeric agents may still contribute to and can be
significant with respect to foam and active agent stability.
A3--in Solution
Example 12--Azalaic Acid Composition
[0481] The following foamable vehicles were prepared and the
quality of the resultant foam was ascertained.
TABLE-US-00024 DCA022 Azelaic acid 6.00 Propylene glycol 50.00
Polysorbate 80 20.00 Xanthan gum 0.30 Methocel A4M 0.30 Water
purified 23.40 Total 100.00 Propellant) propane, isobutene 8.00 and
butane mixture Appearance: foam quality G-E Color White Odor No
odor Microscope No crystals
[0482] Lower azaleic acid levels provide a soluble composition. No
solids or precipitates are observed. No crystals were observed at
the level of microscopic examination. By no crystals means the
ingredients dissolve and it is not a suspension.
Example 13--Compositions with Diethyl Salicylates Azelate
(TU-2100)
TABLE-US-00025 [0483] DCA016 DCA017 DCA016A PPG 15-Stearyl 40.00
40.00 Ether (PPG) Isopropyl 40.00 myristate (IPM) TU-2100 10.00
10.00 10.00 Steareth 2 6.00 4.95 6.00 Steareth 21 1.50 3.00 1.50
Carboxy methyl 0.50 0.50 cellulose Water purified 42.00 41.55 42.50
Total 100.00 100.00 100.00 Propellant 8.00 8.00 8.00 propane,
isobutene and butane mixture Appearance: foam quality G-E G- G-E
color White White White odor No odor No odor No odor Microscope No
crystals No crystals No crystals
[0484] When medium chain triglycerides were used as the emollient
the formulation was poor. However, when they were substituted by
PPG or IPM the foam quality increased substantially. Without being
bound by any particular theory this may be because the formulations
are close to phase reversal and or is due to internal tensions.
[0485] Good to excellent foam formulations were prepared with
TU-2100, PPG or IPM, surfactant, polymeric agent, and water (and
without any foam adjuvant). Surprisingly a good to excellent foam
was produced even after removal of polymer.
Section B--Non Aqueous
B1--Example 14--PEG Based Non Aqueous Formulations with TU 2100
[0486] The following foamable vehicles were prepared and the
quality of the resultant foam was ascertained.
TABLE-US-00026 DCA014 DCA014A DCA014B TU-2100 10.00 10.00 10.00 PEG
400 87.50 85.00 88.00 Steareth 2 2.00 5.00 Klucel EF 0.50 2.00
Total 100.00 100.00 100.00 Propellant propane, 8.00 8.00 8.00
isobutene and butane mixture Appearance: foam quality G-E G-E G-E
Color White White White Odor No odor No odor No odor Microscope No
crystals No crystals No crystals
[0487] Surprisingly it was possible to make non aqueous PEG based
minimal foam compositions of good to excellent quality with a)
active ingredient, PEG, a single surfactant and optionally a
polymeric agent and also with b) active ingredient, PEG, and a
polymeric agent.
B2--Example 15--PG Based Non Aqueous Formulation with TU 2100 and
with Azaleic Acid
[0488] The following foamable vehicles were prepared and the
quality of the resultant foam was ascertained.
TABLE-US-00027 DCA015 DCA020 TU-2100 10.00 Azelaic acid 9.00 PEG
400 Propylene glycol 87.50 88.50 Steareth 2 2.00 2.00 Klucel EF
0.50 0.50 Total 100.00 100.00 Propellant propane, 8.00 8.00
isobutene and butane mixture Appearance: foam quality G-E G-E color
White White odor No odor No odor Microscope crystals No
crystals
[0489] Surprisingly it was possible to make non aqueous PG based
minimal foam compositions of good to excellent quality with active
ingredient, PG, a single surfactant and a polymeric agent. Whilst
TU 2100 was not soluble in the non aqueous PG based composition,
azelaic acid was soluble.
* * * * *