U.S. patent application number 11/552457 was filed with the patent office on 2007-07-05 for topical pharmaceutical foam composition.
This patent application is currently assigned to Collegium Pharmaceutical, Inc.. Invention is credited to Ronald M. Gurge, Jane C. Hirsh, Mark W. Trumbore.
Application Number | 20070154402 11/552457 |
Document ID | / |
Family ID | 37726926 |
Filed Date | 2007-07-05 |
United States Patent
Application |
20070154402 |
Kind Code |
A1 |
Trumbore; Mark W. ; et
al. |
July 5, 2007 |
Topical Pharmaceutical Foam Composition
Abstract
A stable topical alcohol-free aerosol foam containing one or
more keratolytic agents is provided. The foam-forming formulation
is an emulsion which contains an HFA propellant and one or more
keratolytic agents. The emulsion has an oil phase and an aqueous,
i.e. water-containing, phase. The active agent(s) may be present in
either phase of the emulsion or dispersed in the emulsion. The oil
phase may consist at least in part of the HFA propellant. Either or
both of the oil phase and the aqueous phase may contain one or more
surfactants, emulsifiers, emulsion stabilizers, buffers, and/or
other excipients. The foam is stable on the skin, for example, for
at least 5 minutes at body temperature, preferably at least 20
minutes at body temperature, and disappears into the skin upon
rubbing or after prolonged standing. In one embodiment, the
formulation contains an HFA propellant which does not contain
additional co-solvents or co-propellants. The formulations
demonstrate reduced intensity of the odor and/or color associated
with the keratolytic agent(s) as compared to conventional
formulations containing keratolytic agents.
Inventors: |
Trumbore; Mark W.;
(Westford, MA) ; Gurge; Ronald M.; (Franklin,
MA) ; Hirsh; Jane C.; (Wellesley, MA) |
Correspondence
Address: |
PATREA L. PABST;PABST PATENT GROUP LLP
400 COLONY SQUARE, SUITE 1200
1201 PEACHTREE STREET
ATLANTA
GA
30361
US
|
Assignee: |
Collegium Pharmaceutical,
Inc.
|
Family ID: |
37726926 |
Appl. No.: |
11/552457 |
Filed: |
October 24, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60729788 |
Oct 24, 2005 |
|
|
|
Current U.S.
Class: |
424/45 ; 424/705;
424/725.1; 424/94.65; 514/557; 514/559; 514/562; 514/588 |
Current CPC
Class: |
A61K 31/203 20130101;
A61P 31/00 20180101; A61P 33/02 20180101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 31/17 20130101;
A61K 31/203 20130101; A61K 31/17 20130101; A61K 9/12 20130101; A61P
39/06 20180101; A61K 47/18 20130101; A61P 29/00 20180101; A61K
31/19 20130101; A61P 17/10 20180101; A61K 9/0014 20130101; A61P
31/04 20180101; A61K 45/06 20130101; A61K 9/122 20130101; A61K
31/19 20130101; A61K 9/06 20130101; A61P 31/10 20180101; A61K 9/124
20130101; A61K 38/4873 20130101; A61P 31/12 20180101; C12Y
304/22002 20130101 |
Class at
Publication: |
424/045 ;
424/725.1; 424/094.65; 514/557; 514/559; 514/562; 514/588;
424/705 |
International
Class: |
A61K 38/46 20060101
A61K038/46; A61K 9/12 20060101 A61K009/12; A61K 31/19 20060101
A61K031/19; A61K 31/203 20060101 A61K031/203; A61K 36/18 20060101
A61K036/18; A61K 31/17 20060101 A61K031/17 |
Claims
1. A topical aerosol foam formulation comprising: (a) one or more
keratolytic agents dissolved or dispersed in an oil-in-water
emulsion; and (b) a propellant consisting essentially of one or
more hydrofluoroalkanes contacting the emulsion to produce an
immediate foaming action on expulsion from a pressurized
container.
2. The formulation of claim 1, wherein the keratolytic agent is
selected from the group consisting of urea, salicylic acid, papain,
sulfur, glycolic acid, pyruvic acid, alpha hydroxy acids, beta
hydroxy acids, resorcinol, N-acetylcysteine, retinoids, retinoic
acid, coal tar, derivatives thereof, and combinations thereof.
3. The formulation of claim 1, wherein the concentration of the
keratolytic agent is from about 1% to 60%.
4. The formulation of claim 1, further comprising one or more
active agents selected from the group comprising of antibiotic
agents, antimicrobial agents, anti-acne agents, antibacterial
agents, antifungal agents, antiviral agents, steroidal
anti-inflammatory agents, non-steroidal anti-inflammatory agents,
anesthetics, antipruriginous agents, antiprotozoal agents,
anti-oxidants, antihistamines, hormones, vitamins, skin-soothing
agents, suncreens, and combinations thereof.
5. The formulation of claim 1, wherein the foam is stable for at
least 5 minutes at body temperature.
6. The formulation of claim 1, wherein the foam is stable for at
least 20 minutes at body temperature.
7. The formulation of claim 2, wherein the keratolytic agent is
urea.
8. The formulation of claim 7, wherein the amount of urea is from
about 5% to about 50% (w/w).
9. The formulation of claim 8, wherein the amount of urea is from
about 10% to about 50% (w/w).
10. The formulation of claim 8, wherein the amount of urea is from
about 20% to about 40% (w/w).
11. The formulation of claim 7, further comprising ammonium
lactate.
12. The formulation of claim 11, wherein the amount of ammonium
lactate is from about 1% to about 30% (w/w).
13. The formulation of claim 12, wherein the amount of ammonium
lactate is from about 5% to about 20% (w/w).
14. The formulation of claim 12, wherein amount of ammonium lactate
is from about 10% to about 15% (w/w).
15. The formulation of claim 2, wherein the keratolytic agent is
papain.
16. The formulation of 15, wherein the papain is present in an
amount from about 0.5% to about 40%.
17. The formulation of 16, wherein the papain is present in an
amount from about 1% to about 20%.
18. The formulation of 16, wherein the papain is present in an
amount from about 1% to about 10%.
19. The formulation of claim 15, further comprising urea.
20. The formulation of claim 19, wherein the amount of urea is from
about 1% to about 60% (w/w).
21. The formulation of claim 20, wherein the amount of urea is from
about 2.5% to about 20% (w/w).
22. The formulation of claim 21, wherein the amount of urea is from
about 5% to about 15% (w/w).
23. The formulation of claim 19, further comprising chlorophyllin
copper complex sodium.
24. The formulation of claim 23, wherein the amount of
chlorophyllin copper complex sodium is from about 0.5% to about 40%
(w/w).
25. The formulation of claim 24, wherein the amount of
chlorophyllin copper complex sodium is from about 1% to about 20%
(w/w).
26. The formulation of claim 24, wherein the amount of
chlorophyllin copper complex sodium is from about 1% to about 10%
(w/w).
27. The formulation of claim 2, wherein the one or more keratolytic
agents are sulfur and sodium sulfacetamide.
28. The formulation of claim 27, wherein the amounts of sulfur and
sodium sulfacetamide are each from about 0.01% to about 20%
(w/w).
29. The formulation of claim 28, wherein the amounts of sulfur and
sodium sulfacetamide are each from about 1% to about 15% (w/w).
30. The formulation of claim 28, wherein the amounts of sulfur and
sodium sulfacetamide are each from about 6% to about 12% (w/w).
31. The formulation of claim 27, further comprising one or more
agents selected from the group consisting of vitamins,
skin-soothing agents, and suncreens.
32. The formulation of claim 2, wherein the keratolytic agent is
salicylic acid.
33. The formulation of claim 32, wherein the amount of salicylic
acid is from about 1% to about 30% (w/w).
34. The formulation of claim 33, wherein the amount of salicylic
acid is from about 4% to about 10% (wlw).
35. The formulation of claim 32, further comprising one or more
agents selected from the group consisting of vitamins,
skin-soothing agents, and suncreens.
36. The formulation of claim 4, wherein the antibiotic is selected
from the group consisting of sodium sulfacetamide, clindamycin,
erthyromycin, and metronidazole.
37. The formulation of claim 36, wherein the antibiotic is present
in an amount from about 0.01% to about 20% by weight of the
composition.
38. The formulation of claim 37, wherein the antibiotic is present
in an amount from about 1% to about 15% by weight of the
composition.
39. The formulation of claim 37, wherein the antibiotic is present
in an amount from about 6% to about 12% by weight of the
composition.
40. The formulation of claim 1, further comprising one or more
excipients selected from the group consisting of surfactants,
emollients, emulsifiers, stabilizing agents, chelating agents,
antioxidants, buffers, stabilizers, preservatives and combinations
thereof.
41. The formulation of claim 1, wherein the hydrofluorocarbon
propellant is present in an amount from about 5% to about 30% by
weight of the composition.
42. The formulation of claim 1, wherein the hydrofluorocarbon is
selected from the group consisting of 1,1,1,2-tetrafluoroethane
(134a); 1,1,1,2,3,3,3-heptafluoropropane (227); and combinations
thereof.
43. The formulation of claim 1, wherein the yield stress of the
dispensed foam is between 250 and 60,000 dynes/cm.sup.2.
44. The formulation of claim 1, where the zero shear viscosity of
the dispensed foam is between 15,000 and 700,000 cP.
45. The formulation of claim 1, wherein the expansion factor of the
dispensed foam is between 1.5 and 15 cm.sup.3/g.
46. The formulation of claim 1, wherein the foam density is from
about 0.1 g/mL to about 0.6 g/mL.
47. The formulation of claim 1, further comprising a fragrance or
odor masking agent.
48. A method of making a topical foam aerosol formulation, the
method comprising: (a) making an oil in water emulsion with a
predominantly, more than 50%, aqueous phase, (b) dissolving or
dispersing one or more keratolytic agents in the aqueous phase or
oil phase prior to emulsification, and (c) adding a propellant
consisting essentially of a hydrofluoroalkane or a mixture of
hydrofluoroalkanes, without additional co-solvents or
co-propellants, to the emulsion, wherein the emulsion produces an
immediate foaming action on expulsion from a pressurized
container.
49. A HFA containing topical foam formulation free of volatile
lower alcohols produced by the method of claim 48.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This invention claims the benefit of the priority of U.S.
Ser. No. 60/729,788, filed Oct. 24, 2005.
FIELD OF THE INVENTION
[0002] This invention is generally in the field of pharmaceutical
compositions, specifically pharmaceutical foam compositions
containing keratolytic agents intended for topical
administration.
BACKGROUND OF THE INVENTION
[0003] Pharmaceutical foams are pressurized dosage forms containing
one or more active ingredients that, upon valve actuation, emit a
fine dispersion of liquid and/or solid materials in a gaseous
medium. Foam formulations are generally easier to apply, are less
dense, and spread more easily than other topical dosage forms.
Foams may be formulated in various ways to provide emollient or
drying functions to the skin, depending on the formulation
constituents. Accordingly, this delivery technology is a useful
addition to the spectrum of formulations available for topical use.
However, as yet, only a few pharmaceutical foams are commercially
available. Most commercially available foam dosage forms contain
corticosteroids, although some products have also been used to
deliver antiseptics, antifungal agents, anti-inflammatory agents,
local anesthetic agents, skin emollients, and protectants (American
Journal of Drug Delivery, 2003, vol. 1(1), pp. 71-75).
[0004] There is growing interest in converting non-foam topical
treatments to aerosol foam or mousse formulations, which better
penetrate the skin, provide faster treatment and do not leave any
greasy residue on skin or clothing compared with conventional
ointments. Until now, the most common gas propellant used in
aerosol products is chlorofluorocarbon (CFC), an ozone-depleting
agent. The Montreal Protocol International Treaty, signed by180
nations, banned the use of chlorofluorocarbons (CFCs) as aerosol
propellants and mandated the phasing out of CFC agents. No new or
revised aerosol formulations may contain CFC propellants and
alternative propellants must be used that are more environmentally
friendly. Therefore, manufacturers must reformulate or modify
existing products to use non-CFC propellants, while maintaining
important aspects of the previous formulation, such as accuracy of
delivery, stability, etc. The primary CFC substitute are
hydrofluoroalkanes (HFA), also known as hydrofluorocarbons
(HFC).
[0005] Although hydrocarbon propellants, such as propane and
butane, can be used in the manufacturing of pharmaceutical foams,
these propellants are not suited for human use since they are
flammable. Just as is the case with CFC propellants,
hydrofluoroalkanes (HFAs) that possess high chemical stability can
be used as a primary substitute for hydrocarbons. Examples of HFAs
are 1,1,1,2,3,3,3-heptafluoropropane (HFA-134a) and
1,1,1,2-tetrafluoroethane (HFA-227). Hydrofluoroalkanes (HFAs) are
also referred to as hydrofluorocarbons (HFCs) and these terms are
used interchangeably.
[0006] Since replacing a component of any formulation means
introducing new properties, and HFAs differ in their solvating
power from CFCs and hydrocarbons, providing reproducible
performance of reformulated aerosols for pharmaceutical uses
represents a challenging task. Co-solvents (such as ethanol) are
often incorporated into the formulation in order to arrive at a
stable product (Pharmaceutical Aerosols, June 2003, p. 21). Such
formulations, however, have a number of undesirable aspects.
Alcohol co-solvents can dry and irritate the skin. U.S. Pat. No.
6,126,920 suggests that the use of alcohol co-solvents can lead to
burning, itching, and irritation observed in the use of topical
foam for delivering betamethasone. Further, volatile alcohols are
highly irritating to mucous membranes.
[0007] Formulations that contain volatile alcohols and/or alkanes
are potential safety hazards due to the high flammability of the
product. Moreover, the flammability characteristics of the product
require expensive precautions during manufacturing, and may require
controlled environments for storage and for disposal of containers
after use. For example, WO 85/01876 describes the fire hazards
associated with alcohol- and alkane-containing aerosol foam
formulations.
[0008] Pharmaceutical foam formulations containing keratolytic
agents have not been described in the literature. Keratolytic
agents are agents that soften, separate, and cause desquamation
(i.e. shedding or peeling) of the cornified epithelium, or horny
layer, of the skin. These agents are used to expose mycelia of
infecting fungi or to treat corns, warts, and certain other skin
diseases. Commonly used keratolytic agents include urea, urea in
combination with ammonium lactate, salicylic acid, papain, papain
in combination with urea, and sulfur. Sulfur is also used in
combination with sodium sulfacetamide to treat acne, rosacea,
seborrheic dermatitis, eczema, xerosis, scabies, pediculosis and
psoriasis.
[0009] Keratolyic agents can be administered in the form of a
liquid, cream, lotion or cleanser. Topical formulations containing
keratolytic agents typically have an intense color and/or strong
odor. For example, sulfur containing products typically have an
intense yellow color and/or a strong odor characteristic of sulfur.
Urea-containing products frequently exhibit a strong ammonia odor,
while papain-containing products exhibit a distinctive papain odor.
Current products on the market typically contain substantial
amounts of odor masking agents, such as fragrances, in order to
mask or shield the odor associated with the pharmaceutical agent.
However, the use of high concentrations of fragrances can be
problematic. The use of fragrances in topical formulations can
result in skin sensitizing reactions in which the patient develops
sensitivity to the odor masking agent. Furthermore, the presence of
fragrances, which are often complex mixtures of different
compounds, may result in undesirable side reactions between the
fragrance and the active agent(s).
[0010] There exists a need for topical keratolytic foam
formulations which, once applied to the skin, have little or no
odor or color and are non-staining and which contain little or no
odor masking agents such as fragrances.
[0011] It is therefore an object of the invention to provide
alcohol-free keratolytic topical foam aerosol formulations that use
hydrofluoroalkanes (HFAs) as the propellant.
[0012] It is a further object of the invention to provide
keratolytic topical foam formulations which exhibit reduced
intensity of the odor and/or color associated with the keratolytic
agent.
BRIEF SUMMARY OF THE INVENTION
[0013] A stable topical alcohol-free aerosol foam containing one or
more keratolytic agents is described herein. The foam-forming
formulation is an emulsion which contains an HFA propellant and one
or more keratolytic agents. The formulation optionally contains one
or more additional pharmaceutically active agents including, but
not limited to, antibiotic agents, antimicrobial agents, anti-acne
agents, antibacterial agents, antifungal agents, antiviral agents,
steroidal anti-inflammatory agents, non-steroidal anti-inflammatory
agents, anesthetic agents, antipruriginous agents, antiprotozoal
agents, anti-oxidants, chemotherapeutic agents, antidepressants,
antihistamines, vitamins, suncreens, skin-soothing agents,
hormones, and anti-dandruff agents.
[0014] The emulsion contains an oil phase and an aqueous, i.e.
water-containing, phase. The active agent(s) may be dissolved in
either phase or dispersed in the emulsion. The oil phase may
contain, at least in part, the HFA propellant. The foam is stable
on the skin, preferably for at least five minutes, more preferably
at least twenty minutes, at body temperature, and disappears into
the skin upon rubbing or after prolonged standing. The formulations
demonstrate reduced intensity of the odor and/or color associated
with the keratolytic agent(s) as compared to conventional
formulations containing keratolytic agents.
[0015] The composition can further contain one or more
pharmaceutically acceptable excipients such as surfactants,
emollients, emulsifiers, pH stabilizing agents, chelating agents,
humectants, stabilizers, preservatives, and combinations thereof,
which may be present in the oil phase and/or the aqueous phase. The
formulations contain little or no fragrances and/or odor masking
agents, thus minimize the skin sensitizing reactions that can occur
due to the presence of such agents.
[0016] The inert non-flammable HFA propellant does not require the
use of additional co-solvents or co-propellants. Besides their high
volatility and vapor pressure, the HFA propellants have been found
to provide an additional benefit in terms of reduction of apparent
odor of active ingredients, such as sulfur and urea. They also mask
color by the formation of stable foams; and leave depots of
materials on the skin, which in practice, are less staining to
linen and clothing than prior art preparations with the same active
ingredients.
[0017] In one embodiment the active agent is a keratolytic agent or
agents such as urea or urea in combination with ammonium lactate,
salicylic acid, papain, and/or sulfur. The keratolytic agent is
present in an amount from about 1% to about 60% by weight of the
final composition. In another embodiment, the formulation contains
a keratolytic agent in combination with an antibiotic. The
concentration of the antibiotic is from about 0.01% to about 20%,
preferably from about 1% to about 15%, more preferably from about
6% to about 12% by weight of the final composition. In a preferred
embodiment, the formulation contains a combination of sulfur and
sulfacetamide.
[0018] In yet another embodiment, the composition includes a
proteolytic enzymes such as papain in combination with urea. The
concentration of papain is from about 0.5% to about 40%, preferably
from about 1% to about 20%, more preferably from about 1% to about
1.0% by weight of the final composition. The concentration of urea
is from about 1% to about 60%, preferably from about 2.5% to about
40%, more preferably from about 5% to about 15% by weight of the
final composition. In still another embodiment, the composition
includes the enzyme papain in combination with urea and
chlorophyllin copper complex sodium. The concentration of papain is
from about 0.5% to about 40%, preferably from about 1% to about
20%, more preferably from about 1% to about 10% by weight of the
final composition. The concentration of urea is from about 1% to
about 60%, preferably from about 2.5% to about 40%, more preferably
from about 5% to about 15% by weight of the final composition. The
concentration of chlorophyllin copper complex sodium is from about
0.05% to about 5%, preferably from about 0.1% to about 3%, more
preferably from about 0.3% to about 1% by weight of the final
composition.
[0019] The composition can be administered as a continuous or
metered dose that can be applied to the skin or mucous
membranes.
DETAILED DESCRIPTION OF THE INVENTION
1. Concentrate
[0020] A. Propellants
[0021] In one embodiment, the propellant is a HFA or a mixture of
one or more hydrofluorocarbons. Suitable hydrofluorocarbons include
1,1,1,2-tetrafluoroethane (HFA 134a);
1,1,1,2,3,3,3-heptafluoropropane (HFA 227); and mixtures and
admixtures of these and other HFAs that are currently approved or
may become approved for medical use are suitable. The concentration
of the HFA propellant is from about 5% lo about 30% by weight of
the concentrate, which corresponds to about 4% to about 23% by
weight of the final composition.
[0022] Hydrocarbon propellants such as butane/isobutane/propane
have inherent, unpleasant odors which may impart negative olfactory
sensory attributes to pharmaceutical foam products. When these foam
products are dispensed, the propellant expands and evaporates,
creating a bubble structure within the foam. It is the evaporative
release of the propellant which is detected by the olfactory senses
of the user. Therefore, it is advantageous to have a propellant
which is odor free and essentially provides no additional base
odors to the foamed composition. HFAs, particularly
1,1,1,2-Tetrafluoroethane (Freon-134a, HFC-134a), have no
unpleasant odors associated with them and are preferred in the
compositions described herein.
[0023] Furthermore, the compositions preferably contain no volatile
alcohols or hydrocarbon propellant gases, which can produce
flammable or explosive vapors during use. However, small amounts of
such propellants may be used as adjunct propellants if required for
particular formulations.
[0024] B. Keratolytic Agents
[0025] Suitable keratolytic agents include, but are not limited to,
urea, salicylic acid, papain, sulfur, glycolic acid, pyruvic acid,
resorcinol, N-acetylcysteine, retinoids such as retinoic acid and
its derivatives (e.g., cis and trans, esters), alpha hydroxy acids,
beta hydroxy acids, coal tar, and combinations thereof. The
concentration of the keratolytic agent is from about 1% to about
60% by weight of the final composition.
[0026] In one embodiment, the keratolytic agent is urea. Urea is
present in an amount from about 5 to about 50%, preferably from
about 10% to about 50%, more preferably from about 20% to about 40%
by weight of the final composition. In another embodiment, ammonium
lactate is added to a urea-containing formulation. Ammonium lactate
is present in an amount from about 1 to about 30%, preferably from
about 5% to about 20%, more preferably from about 10% to about 15%
by weight of the final composition.
[0027] In another embodiment, the keratolytic agent is salicylic
acid. Salicylic acid is present in an amount from about 1 to about
30%, preferably from about 4% to about 10%.
[0028] In another embodiment, the formulation comprises the enzyme
papain and, optionally, urea. Papain is a protein-cleaving enzyme
derived from papaya and certain other plants. The concentration of
papain is from about 0.5% to about 40%, preferably from about 1% to
about 20%, more preferably from about 1% to about 10% by weight of
the final composition. The concentration of urea is from about 1%
to about 60%, preferably from about 2.5% to about 40%, more
preferably from about 5% to about 15% by weight of the final
composition.
[0029] In yet another embodiment, the composition comprises the
enzyme papain in combination with urea and chlorophyllin copper
complex sodium. The concentration of papain is from about 0.5% to
about 40%, preferably from about 1% to about 20%, more preferably
from about 1% to about 10% by weight of the final composition. The
concentration of urea is from about 1% to about 60%, preferably
from about 2.5% to about 40%, more preferably from about 5% to
about 15% by weight of the final composition. The concentration of
chlorophyllin copper complex sodium is from about 0.05% to about
5%, preferably from about 0.1% to about 3%, more preferably from
about 0.3% to about 1% by weight of the final composition.
[0030] C. Other Active Agents
[0031] The compositions optionally contain one or more additional
pharmaceutically active agents. Suitable classes of active agents
include, but are not limited to, antibiotic agents, antimicrobial
agents, anti-acne agents, antibacterial agents, antifungal agents,
antiviral agents, steroidal anti-inflammatory agents, non-steroidal
anti-inflammatory agents, anesthetic agents, antipruriginous
agents, antiprotozoal agents, anti-oxidants, antihistamines,
vitamins, and hormones.
[0032] i. Antibiotics
[0033] Representative antibiotics include, without liimitation,
benzoyl peroxide, octopirox, erythromycin, zinc, tetracyclin,
triclosan, azelaic acid and its derivatives, phenoxy ethanol and
phenoxy proponol, ethylacetate, clindamycin and meclocycline;
sebostats such as flavinoids; alpha and beta hydroxy acids; and
bile salts such as scymnol sulfate and its derivatives,
deoxycholate and cholate. The antibiotic can be an antifungal
agent. Suitable antifungal agents include, but are not limited to,
clotrimazole, econazole, ketoconazole, itraconazole, miconazole,
oxiconazole, sulconazole, butenafine, naftifine, terbinafine,
undecylinic acid, tolnaftate, and nystatin.
[0034] In one embodiment, the formulation contains one or more
keratolytic agents in combination with an antibiotic agent. The
concentration of the antibiotic is from about 0.01% to about 20%,
preferably from about 1% to about 15%, more preferably from about
6% to about 12% by weight of the final composition.
[0035] ii. Non-Steroidal Anti-Inflammatory Agents
[0036] Representative examples of non-steroidal anti-inflammatory
agents include, without limitation, oxicams, such as piroxicam,
isoxicam, tenoxicam, sudoxicam; salicylates, such as aspirin,
disalcid, benorylate, trilisate, safapryn, solprin, diflunisal, and
fendosal; acetic acid derivatives, such as diclofenac, fenclofenac,
indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac,
zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac,
felbinac, and ketorolac, fenamates, such as mefenamic,
meclofenamic, flufenamic, niflumic, and tolfenamic acids; propionic
acid derivatives, such as ibuprofen, naproxen, benoxaprofen,
flurbiprofen, ketoprofen, fenoprofen, fenbufen, indopropfen,
pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen,
tioxaprofen, suprofen, alminoprofen, and tiaprofenic; pyrazoles,
such as phenylbutazone, oxyphenbutazone, feprazone, azapropazone,
and trimethazone. Mixtures of these non-steroidal anti-inflammatory
agents may also be employed, as well as the dermatologically
acceptable salts and esters of these agents. For example,
etofenamiate, a flufenamic acid derivative, is particularly useful
for topical application.
[0037] iii. Steroidal Anti-Inflammatory Agents
[0038] Representative examples of steroidal anti-inflammatory drugs
include, without limitation, corticosteroids such as
hydrocortisone, hydroxyl-triamcinolone, alpha-methyl dexamethasone,
dexamethasone-phosphate, beclomethasone dipropionates, clobetasol
valerate, desonide, desoxymethasone, desoxycorticosterone acetate,
dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone
valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone,
flumethasone pivalate, fluosinolone acetonide, fluocinonide,
flucortine butylesters, fluocortolone, fluprednidene
(fluprednylidene) acetate, flurandrenolone, halcinonide,
hydrocortisone acetate, hydrocortisone butyrate,
methylprednisolone, triamcinolone acetonide, cortisone,
cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate,
fluradrenolone, fludrocortisone, diflurosone diacetate,
fluradrenolone acetonide, medrysone, amcinafel, amcinafide,
betamethasone and the balance of its esters, chloroprednisone,
chlorprednisone acetate, clocortelone, clescinolone, dichlorisone,
diflurprednate, flucloronide, flunisolide, fluoromethalone,
fluperolone, fluprednisolone, hydrocortisone valerate,
hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone,
paramethasone, prednisolone, prednisone, beclomethasone
dipropionate, triamcinolone, and mixtures thereof.
[0039] iv. Anesthetics
[0040] Representative anesthetics include, but are not limited to,
lidocaine, bupivacaine, chlorprocaine, dibucaine, etidocaine,
mepivacaine, tetracaine, dyclonine, hexylcaine, procaine, cocaine,
ketamine, pramoxine and phenol.
[0041] v. Antimicrobial Agents
[0042] Suitable antimicrobial agents include, but are not limited
to, antibacterial, antifungal, antiprotozoal and antiviral agents,
such as beta-lactam drugs, quinolone drugs, ciprofloxacin,
norfloxacin, tetracycline, erythromycin, amikacin, triclosan,
doxycycline, capreomycin, chlorhexidine, chlortetracycline,
oxytetracycline, clindamycin, ethambutol, metronidazole,
pentamidine, gentamicin, kanamycin, lineomycin, methacycline,
methenamine, minocycline, neomycin, netilmicin, streptomycin,
tobramycin, and miconazole. Also included are tetracycline
hydrochloride, famesol, erythromycin estolate, erythromycin
stearate (salt), amikacin sulfate, doxycycline hydrochloride,
chlorhexidine gluconate, chlorhexidine hydrochloride,
chlortetracycline hydrochloride, oxytetracycline hydrochloride,
clindamycin hydrochloride, ethambutol hydrochloride, metronidazole
hydrochloride, pentamidine hydrochloride, gentamicin sulfate,
kanamycin sulfate, lineomycin hydrochloride, methacycline
hydrochloride, methenamine hippurate, methenamine mandelate,
minocycline hydrochloride, neomycin sulfate, netilmicin sulfate,
paromomycin sulfate, streptomycin sulfate, tobramycin sulfate,
miconazole hydrochloride, amanfadine hydrochloride, amanfadine
sulfate, triclosan, octopirox, nystatin, tolnaftate, clotrimazole,
anidulafungin, micafungin, voriconazole, lanoconazole, ciclopirox
and mixtures thereof.
[0043] vi. Other Agents
[0044] Suitable other agents include, but are not limited to,
deodorant agents, antiperspirants, sun screening agents, sunless
tanning agents, vitamins, hair conditioning agents, anti-irritants,
and combinations thereof.
[0045] Examples of skin soothing agents include, but are not
limited to, aloe, avocado oil, green tea extract, hops extract,
chamomile extract, colloidal oatmeal, calamine, cucumber extract,
and combinations thereof.
[0046] Examples of vitamins include, but are not limited to,
vitamins A, D, E, K, and combinations thereof.
[0047] Examples of sunscreens include, but are not limited to,
p-Aminobenzoic acid, Avobenzone, Cinoxate, Dioxybenzone,
Homosalate, Menthyl anthranilate, Octocrylene, Octyl
methoxycinnamate, Octyl salicylate, Oxybenzone, Padimate O,
Phenylbenzimidazole sulfonic acid, Sulisobenzone, Titanium dioxide,
Trolaminie salicylate, Zinc oxide, 4-methylbenzylidene camphor,
Methylene Bis-Benzotriazolyl Tetramethylbutylphenol,
Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine, Terephthalylidene
Dicamphor Sulfonic Acid, Drometrizole Trisiloxane, Disodium Phenyl
Dibenzimidazole Tetrasulfonate, Diethylamino Hydroxybenzoyl Hexyl
Benzoate, Octyl Triazone, Diethylhexyl Butamido Triazone,
Polysilicone-15, and combinations thereof.
[0048] D. Excipients
[0049] The concentrate can be in the form of an emulsion. An
emulsion is a preparation of one liquid distributed in small
globules throughout the body of a second liquid. The dispersed
liquid is the discontinuous phase, and the dispersion medium is the
continuous phase. When oil is the dispersed liquid and an aqueous
solution is the continuous phase, it is known as an oil-in-water
emulsion, whereas when water or aqueous solution is the dispersed
phase and oil or oleaginous substance is the continuous phase, it
is known as a water-in-oil emulsion. The oil phase may consist at
least in part of the propellant. Either or both of the oil phase
and the aqueous phase may contain one or more excipients such as
surfactants, emulsifiers, emulsion stabilizers, anti-oxidants,
emollients, humectants, chelating agents, suspending agents,
thickening agents, occlusive agents, preservatives, stabilizing
agents, pH modifying agents, solubilizing agents, penetration
enhancers, and other excipients.
[0050] Suitable emulsifiers include, but are not limited to,
straight chain or branched fatty acids, polyoxyethylene sorbitan
fatty acid esters sorbitan fatty acid esters, propylene glycol
stearate, glyceryl stearate, polyethylene glycol, fatty alcohols,
polymeric ethylene oxide-propylene oxide block copolymers, and
combinations thereof.
[0051] Suitable surfactants include, but are not limited to,
anionic surfactants, non-ionic surfactants, cationic surfactants,
and amphoteric surfactants. Examples of anionic surfactants
include, but are not limited to, ammonium lauryl sulfate, sodium
lauryl sulfate, ammonium laureth sulfate, sodium laureth sulfate,
alkyl glyceryl ether sulfonate, triethylamine lauryl sulfate,
triethylamine laureth sulfate, triethanolamine lauryl sulfate,
triethanolamine laureth sulfate, monoethanolamine lauryl sulfate,
monoethanolamine laureth sulfate, diethanolamine lauryl sulfate,
diethanolamine laureth sulfate, lauric monoglyceride sodium
sulfate, potassium lauryl sulfate, potassium laureth sulfate,
sodium lauryl sarcosinate, sodium lauroyl sarcosinate, lauryl
sarcosine, cocoyl sarcosine, ammonium cocoyl sulfate, ammonium
lauroyl sulfate, sodium cocoyl sulfate, sodium lauroyl sulfate,
potassium cocoyl sulfate, potassium lauryl sulfate, triethanol
amine lauryl sulfate, triethanol amine lauryl sulfate,
monoethanolamine cocoyl sulfate, monoethanolamine lauryl sulfate,
sodium tridecyl benzene sulfonate, sodium dodecyl benzene
sulfonate, sodium and ammonium salts of coconut alkyl triethylene
glycol ether sulfate; tallow alkyl triethylene glycol ether
sulfate, tallow alkyl hexaoxyethylene sulfate, disodium
N-octadecylsulfosuccinnate, disodium lauryl sulfosuccinate,
diammonium lauryl sulfosuccinate, tetrasodium
N-(1,2-dicarboxyethyl)-N-octadecylsulfosuccinnate, diamyl ester of
sodium sulfosuccinic acid, dihexyl ester of sodium sulfosuccinic
acid, dioctyl esters of sodium sulfosuccinic acid, docusate sodium,
and combinations thereof.
[0052] Examples of nonionic surfactants include, but are not
limited to, polyoxyethylene fatty acid esters, sorbitan esters,
cetyl octanoate, cocamide DEA, cocamide MEA, cocamido propyl
dimethyl amine oxide, coconut fatty acid diethanol amide, coconut
fatty acid monoethanol amide, diglyceryl diisostearate, diglyceryl.
monoisostearate, diglyceryl monolaurate, diglyceryl monooleate,
ethylene glycol distearate, ethylene glycol monostearate,
ethoxylated castor oil, glyceryl monoisostearate, glyceryl
monolaurate, glyceryl monomyristate, glyceryl monooleate, glyceryl
monostearate, glyceryl tricaprylate/caprate, glyceryl
triisostearate, glyceryl trioleate, glycol distearate, glycol
monostearate, isooctyl stearate, lauramide DEA, lauric acid
diethanol amide, lauric acid monoethanol amide, lauric/myristic
acid diethanol amide, lauryl dimethyl amine oxide, lauryl/myristyl
amide DEA, lauryl/myristyl dimethyl amine oxide, methyl gluceth,
methyl glucose sesquistearate, oleamide DEA, PEG-dislearate,
polyoxyethylene butyl ether, polyoxyethylene cetyl ether,
polyoxyethylene lauryl amine, polyoxyethylene lauryl ester,
polyoxyethylene lauryl ether, polyoxyethylene nonylphenyl ether,
polyoxyethylene octyl ether, polyoxyethylene octylphenyl ether,
polyoxyethylene oleyl amine, polyoxyethyelen oleyl cetyl ether,
polyoxyethylene oleyl ester, polyoxyethylene oleyl ether,
polyoxyethylene stearyl amine, polyoxyethylene stearyl ester,
polyoxyethylene stearyl ether, polyoxyethylene tallow amine,
polyoxyethylene tridecyl ether, propylene glycol monostearate,
sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate,
sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate,
stearamide DEA, stearic acid diethanol amide, stearic acid
monoethanol amide, laureth-4, and combinations thereof.
[0053] Examples of amphoteric surfactants include, but are not
limited to, sodium N-dodecyl-.beta.-alanine, sodium
N-lauryl-.beta.-iminodipropionate, myristoamphoacetate, lauryl
betaine, lauryl sulfobetaine, sodium 3-dodecyl-aminopropionate,
sodium 3-dodecylaminopropane sulfonate, sodium lauroamphoacetate,
cocodimethyl carboxymethyl betaine, cocoamidopropyl betaine,
cocobetaine, lauryl amidopropyl betaine, oleyl betaine, lauryl
dimethyl carboxymethyl betaine, lauryl dimethyl alphacarboxyethyl
betaine, cetyl dimethyl carboxymethyl betaine, lauryl
bis-(2heptafluoropropane -hydroxyethyl)carboxymethyl betaine,
stearyl bis-(2-hydroxypropyl)carboxymethyl betaine, oleyl dimethyl
gamma-carboxypropyl betaine, lauryl
bis-(2-hydroxypropyl)alpha-carboxyethyl betaine, oleamidopropyl
betaine, coco dimethyl sulfopropyl betaine, stearyl dimethyl
sulfopropyl betaine, lauryl dimethyl sulfoethyl betaine, lauryl
bis-(2-hydroxyethyl)sulfopropyl betaine, and combinations
thereof.
[0054] Examples of cationic surfactants include, but are not
limited to, behenyl trimethyl ammonium chloride,
bis(acyloxyethyl)hydroxyethyl methyl ammonium methosulfate,
cetrimonium bromide, cetrimonium chloride, cetyl trimethyl ammonium
chloride, cocamido propylamine oxide, distearyl dimethyl ammonium
chloride, ditallowdimonium chloride, guar hydroxypropyltrimonium
chloride, lauralkonium chloride, lauryl dimethylamine oxide, lauryl
dimethylbenzyl ammonium chloride, lauryl polyoxyethylene
dimethylamine oxide, lauryl trimethyl ammonium chloride,
lautrimonium chloride, methyl-1-oleyl amide ethyl-2-oleyl
imidazolinium methyl sulfate, picolin benzyl ammonium chloride,
polyquaternium, stearalkonium chloride, sterayl dimethylbenzyl
ammonium chloride, stearyl trimethyl ammonium chloride,
trimethylglycine, and combinations thereof.
[0055] Suitable suspending agents include, but are not limited to,
alginic acid, bentonite, carbomer, carboxymethylcellulose and salts
thereof, colloidal oatmeal, hydroxyethylcellulose,
hydroxypropylcellulose, microcrystalline cellulose, colloidal
silicon dioxide, dextrin, gelatin, guar gum, xanthan gum, kaolin,
magnesium aluminum silicate, maltitol, triglycerides,
methylcellulose, polyoxyethylene fatty acid esters,
polyvinylpyrrolidone, propylene glycol alginate, sodium alginate,
sorbitan fatty acid esters, tragacanth, and combinations
thereof.
[0056] Suitable antioxidants include, but are not limited to,
butylated hydroxytoluene, alpha tocopherol, ascorbic acid, fumaric
acid, malic acid, butylated hydroxyanisole, propyl gallate, sodium
ascorbate, sodium metabisulfite, ascorbyl palmitate, ascorbyl
acetate, ascorbyl phosphate, Vitamin A, folic acid, flavons or
flavonoids, histidine, glycine, tyrosine, tryptophan, carotenoids,
carotenes, alpha-Carotene, beta-Carotene, uric acid,
pharmaceutically acceptable salts thereof, derivatives thereof, and
combinations thereof.
[0057] Suitable chelating agents include, but are not limited to,
EDTA, disodium edetate,
trans-1,2-diaminocyclohexane-N,N,N',N'-tetraaceticacid monohydrate,
N,N-bis(2-hydroxyethyl)glycine,
1,3-diamino-2-hydroxypropane-N,N,N',N'-te-traacetic acid,
1,3-diaminopropane-N,N,N',N'-tetraacetic acid,
ethylenediamine-N,N'-diacetic acid,
ethylenediamine-N,N'-dipropionic acid,
ethylenediamine-N,N'-bis(methylenephosphonic acid),
N-(2-hydroxyethyl)ethylenediamine-N,N',N'-triacetic acid,
ethylenediamine-N,N,N',N'-tetrakis(methlenephosponic acid),
O,O'-bis(2-aminoethyl)ethyleneglycol-N,N,N',N'-tetraacetic acid,
N,N-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid,
1,6-hexamethylenediamine-N,N,N',N'-tetraacetic acid,
N-(2-hydroxyethyl)iminodiacetic acid, iminodiacetic acid,
1,2-diaminopropane-N,N,N',N'-tetraacetic acid, nitrilotriacetic
acid, nitrilotripropionic acid, nitrilotris(methylenephosphoric
acid),
7,19,30-trioxa-1,4,10,13,16,22,27,33-octaazabicyclo[11,11,11]pentatriacon-
tane hexahydrobromide,
triethylenetetramine-N,N,N',N'',N''',N'''-hexaacetic acid, and
combinations thereof.
[0058] Suitable emollients include, but are not limited to,
myristyl lactate, isopropyl palmitate, light liquid paraffin,
cetearyl alcohol, lanolin, lanolin derivatives, mineral oil,
petrolatum, cetyl esters wax, cholesterol, glycerol, glycerol
monostearate, isopropyl myristate, lecithin, and combinations
thereof thereof.
[0059] Suitable humectants include, but are not limited to,
glycerin, butylene glycol, propylene glycol, sorbitol, triacetin,
and combinations thereof.
[0060] The compositions described herein may further contain
sufficient amounts of at least one pH modifier to ensure that the
composition has a final pH of about 3 to about 11. Suitable pH
modifying agents include, but are not limited to, sodium hydroxide,
citric acid, hydrochloric acid, acetic acid, phosphoric acid,
succinic acid, sodium hydroxide, potassium hydroxide, ammonium
hydroxide, magnesium oxide, calcium carbonate, magnesium carbonate,
magnesium aluminum silicates, malic acid, potassium citrate, sodium
citrate, sodium phosphate, lactic acid, gluconic acid, tartaric
acid, 1,2,3,4-butane tetracarboxylic acid, fumaric acid,
diethanolamine, monoethanolamine, sodium carbonate, sodium
bicarbonate, triethanolamine, and combinations thereof.
[0061] Preservatives can be used to prevent the growth of bacteria,
fungi and other microorganisms. Suitable preservatives include, but
are not limited to, benzoic acid, butylparaben, ethyl paraben,
methyl paraben, propylparaben, sodium benzoate, sodium propioniate,
benzalkonium chloride, benzethonium chloride, benzyl alcohol,
cetypyridinium chloride, chlorobutanol, phenol, phenylethyl
alcohol, thimerosal, and combinations thereof.
II. Method of Making the Formulation
[0062] A. Method of Preparing an Emulsion Concentrate
[0063] The oil phase is prepared by mixing together the
surfactant(s) and emulsifier(s), and heating if necessary. The
aqueous phase is prepared separately by dissolving the propylene
glycol and preservatives in water with heating. The oil phase is
added to the aqueous phase with continuous high shear mixing to
produce a milky emulsion. The emulsion is cooled and if necessary,
the pH is adjusted by the addition of a pH modifying agent.
[0064] If desired, the active agent(s) can be separately suspended
or dissolved in water and/or propylene glycol and treated to
eliminate any large aggregates. In a small scale operation, the
mixture can be milled. The final active agent particle size is
small enough to allow aerosolization, for example, less than about
20 microns in diameter, preferably less than about 10 microns, more
preferably, less than about 5 microns. The liquid containing the
active agent is added to the emulsion with mixing. Alternatively,
the active agent can be added directly to the water phase prior to
emulsification. The formulation is brought to the final weight by
the addition of water.
[0065] The concentration of the surfactant(s) in the concentrate is
from about 0.5 to about 15% by weight of the final composition. The
concentration of the emulsifier(s) is from about 0.5% to about 5%
by weight of the final composition. The concentration of the pH
modifying agent(s) is from about 0.1% to about 5% by weight of the
final composition. The concentration of the preservative(s) is from
about 0.01% to about 1% by weight of the final composition.
[0066] B. Method of Preparing the Formulation
[0067] The emulsion concentrate is placed in pressure cans,
preferably coated aluminum cans to prevent corrosion, such as
epoxy-coated cans. The lid and dispensing apparatus are crimped in
place. The can is charged with propellant to the stated level, for
example, by adding 10 grams of propellant per 90 grams of emulsion.
At the time of application, the mixture of the emulsion with the
propellant may be insured by shaking, optionally with the aid of a
mixing bead. The dispenser may be metered or unmetered
(continuous). The can may be arranged for either "upside down"
spraying with the valve at the bottom, or the can have a dip tube
so that the foam can be sprayed while the can is upright with the
valve at the top. In one embodiment, the concentration of the HFC
propellant(s) is from about 5% to about 40% by weight of the final
composition, more preferably about 5% to about 20% by weight of the
final composition. In another embodiment, the emulsion concentrate
is mixed with an HFC propellant so that the final formulation in an
aerosol can comprises about 90% to about 95% of concentrate and
about 5% to about 10% of propellant.
[0068] C. Foam Viscosity
[0069] In one embodiment, the foam has a sufficiently high
viscosity to prevent the formulation from "running off" the site of
application. The formulation also preferably has a sufficiently low
viscosity that the formulation efficiently releases the actives to
the treatment site. These contrasting attributes can be realized in
a shear-thinning foam. "Shear-thinning" describes the rheological
condition where the viscosity of a material subjected to constant
shear stress decreases. The amount of decrease in viscosity is a
function of the degree of shear stress applied. Upon removal of the
shear stress, the viscosity again increases to the original value
over time. Two values are of particular importance in developing
shear-thinning formulations for hyperkeratotic conditions. These
are the zero shear viscosity and the yield stress. The zero shear
viscosity dictates the resistance of the formulation to flow after
application and ability of the formulation to release actives. The
yield stress defines the stress level at which the material
transitions from a "solid-like" poorly flowing high viscosity foam
to a "liquid-like" well flowing low viscosity foam. The lower the
yield stress, the easier it is to uniformly spread and rub-in the
formulation over the treatment site.
[0070] Foam rheology is a function of the composition of the foam
base and the expansion factor of the foam. Expansion factor is the
volume a given mass of foam occupies and is the reciprocal of the
foam density. Foam expansion factor is determined by the foam base
composition and the composition and concentration of propellant.
For a given foam base and propellant composition, changes in the
expansion factor of the foam can be achieved by varying the
concentration of propellant.
[0071] For topical foam products, the zero shear viscosities are
preferably greater than about 30,000 cP, more preferably greater
than about 45,000 cP, and most preferably greater than about 60,000
cP; and also less than about 700,000 cP, more preferably less than
about 500,000 cP and still more preferably less than about 300,000
cP. The preferred yield stress values are preferably greater than
about 250 dynes/cm.sup.2, more preferably greater than about 750
dynes/cm.sup.2, and most preferably greater than about 1000
dynes/cm.sup.2, and also preferably lower than about 60,000
dynes/cm.sup.2, more preferably lower than about 30,000
dynes/cm.sup.2 and still more preferably lower than about 10,000
dynes/cm.sup.2. The preferred foam expansion factor is from 1.5 to
15 cm.sup.3/g, more preferably from 1.8 to 10 cm.sup.3/g, most
preferably from 2.0 and 7.0 cm.sup.3/g.
III. Mode of Administration
[0072] a. Method of Administration to a Patient
[0073] The formulation is administered to the skin or wound of a
human or animal. A selected amount of product is dispensed from the
spray can, preferably onto the site to be treated. The foam can be
administered into the palm of the hand. Alternatively, the foam can
be applied to a wound dressing. The amount to be delivered can be
determined by the prescribing physician or as directed in the
instructions for non-prescription products. Alternatively, a fixed
dose using the metering dispenser can be administered. The foam is
rubbed into the skin at the site to be treated. Because the foam is
stable at body temperature, this step does not need to be hurried.
Moreover, the exact site of application can be more easily
controlled. If contact with the hand is to be avoided, a glove may
be worn; or, the foam can be first be applied to a wound dressing
or may be left in place, wherein it will eventually collapse and
deliver the active ingredient to the surface of the skin.
EXAMPLES
Example 1
Reduced Odor Topical Formulation Containing Sulfur and Sodium
Sulfacetamide
[0074] A topical formulation containing sulfur and sodium
sulfacetamide was prepared wherein the formulation exhibited
diminished color. The composition of the formulation and the
physical and mechanical properties of the formulation are shown in
Table 1.
[0075] The formulation was prepared by mixing the water and
propylene glycol together and adding the methylparaben,
propylparaben and sodium sulfacetamide to form a uniform solution.
The solution was heated to 70.degree. C. and the sulfur was
dispersed in the solution with moderate stirring. Separately, cetyl
alcohol, emulsifying wax, and BRIJ 76 were melted together and
heated to 70.degree. C. The water and oil phases were combined and
mixed for 10 minutes at high shear to form the emulsion. The
emulsion was allowed to cool to 45.degree. C. with moderate
stirring at which time trolamine was added to the formulation and
the formulation was adjusted to 100% with water.
[0076] The final formulation consisted of 91% by weight emulsion
concentrate and 9% by weight HFC 134a propellant.
Example 2
Reduced Odor Topical Formulation Containing Urea
[0077] A topical formulation containing urea was prepared, wherein
the formulation exhibited diminished odor. The composition of the
formulation and the physical and mechanical properties of the
formulation are shown in Table 1.
[0078] The formulation was prepared by mixing the water and
propylene glycol together and adding the methylparaben,
propylparaben and urea to form a uniform solution. The solution was
heated to 70.degree. C. with moderate stirring. Separately the
cetyl alcohol, emulsifying wax and BRIJ 76 were melted together and
heated to 70.degree. C. The water and oil phases were combined and
mixed for 10 minutes at high shear to form the emulsion. The
emulsion was allowed to cool to 45.degree. C. with moderate
stirring at which time the trolamine was added and the formulation
was adjusted to 100% with water.
[0079] The final formulation consisted of 91% by weight emulsion
concentrate and 9% by weight HFC 134a propellant. TABLE-US-00001
TABLE 1 Formulation Composition and Physical and Mechanical
Properties of Examples 1 and 2 Ingredient Example 1 (w/w %) Example
2 (w/w %) Propylene Glycol USP 10 10.1 Cetyl Alcohol, NF 0.7 0.75
Trolamine, NF 0.1 0.1 Emulsifying Wax, NF 1.5 1.5 BRIJ 76 0.5 0.5
Water 72.06 76.905 Methylparaben, USP/NF 0.11 0.11 Propylparaben,
USP/NF 0.03 0.035 Na Sulfacetamide, USP 10 0 Sulfur, USP 5 0 Urea,
USP 0 10 Total 100 100 Mechanical Property Example 1 Example 2 Foam
Yield Stress 2074 dynes/cm.sup.2 2143 dynes/cm.sup.2 Foam Flow
Index 0.525 0.582 Foam Zero Shear Viscosity 105600 cP 118200 cP
Conc Yield Stress 7081 dynes/cm.sup.2 3355 dynes/cm.sup.2 Conc
Consistency Index 17286 cP 13511 cP Conc Flow Index 0.2818 0.397
Conc Zero Shear Viscosity 169600 cP 106400 cP Conc Infinite Shear
Viscosity 1884 cP 3017 cP
Example 3
Organoleptic Analysis of Formulation Odor and Color
[0080] The odor and color of the formulations outlined in Table 1
were measured. Samples of the sulfur and urea aerosol foams were
dispensed into weighing boats in a manner similar to that used to
dispense the product for use. The samples of sulfur and urea
emulsion concentrates were observed for color and odor in bulk
packaging under conditions similar to that in which currently
marketed products are used. Panelists were asked to rate on a scale
of 0 to 5 each sample for the attributes of color and odor. In the
scale, 0 corresponded to no detectable odor or color and 5
corresponded to strong odor or color. The results are shown in
Table 2. TABLE-US-00002 TABLE 2 Organoleptic Analysis of
Formulation Odor and Color Sulfacetamide/Sulfur Urea Foam
Concentrate Foam Concentrate Odor Color Odor Color Odor Odor Score
Score Score Score Score Score Average 0.7 1.5 2.0 3.9 0.1 4.3 Std
Dev 0.8 0.8 1.2 1.1 0.3 1.3 p Value 0.0005 0.0001 n/a n/a
.ltoreq.0.0001 n/a n 10 10 10 10 10 10
Example 4
Reduced Odor Topical Formulation Containing Papain and Urea
[0081] A topical formulation containing papain and urea was
prepared, wherein the formulation exhibited diminished color. The
composition of the formulation is shown in Table 3.
[0082] The formulation was prepared by mixing the water and
propylene glycol together and adding methylparaben, propylparaben,
lactose, urea and sodium phosphate monobasic to form a uniform
solution. The solution was then heated to 70.degree. C. with
moderate stirring. Separately the cetyl alcohol, emulsifying wax
and BRIJ 76 were melted together and heated to 70.degree. C. The
water and oil phases were combined and mixed for 10 minutes at high
shear to form the emulsion. The emulsion was then allowed to cool
to 45.degree. C. with moderate stirring at which time the papain
was added and the formulation was adjusted to 100% with water.
[0083] The final formulation consisted of 91% by weight emulsion
concentrate and 9% by weight HFC 134a propellant. TABLE-US-00003
TABLE 3 Papain-Urea Formulation Composition Ingredient Example 4
(w/w %) Propylene Glycol USP 5 Cetyl Alcohol, NF 0.7 Sodium
Phosphate monobasic 0.1 Glycerol, USP 5 Lactose, USP 1 Sodium
Bisulfite 1 Emulsifying Wax, NF 1.5 BRIJ 76 0.5 Water 72.26
Methylparaben, USP/NF 0.11 Propylparaben, USP/NF 0.03 Papain, USP
2.8 Urea, USP 10
Example 5
Salicylic Acid Foam Formulation
[0084] A concentrate was prepared containing the following
ingredients: TABLE-US-00004 Ingredient % W/W Crodafos CS 20A 1
Cetostearyl Alcohol 0.5 Crodafos CES 1 Tocopheryl Acetate USP 0.5
White Petrolatum 0.5 DI Water 66.92 Glycerin USP 5 Disodium EDTA
0.05 Aloe (Aloe Vera Gel) 0.1 5N Sodium Hydroxide solution 0.4
Salicylic Acid USP 6 Ammonium Lactate 5 5N Sodium Hydroxide
solution 10.807 Propylene Glycol USP 3 Methyl Paraben 0.3 Propyl
Paraben 0.03 Total 100
[0085] The concentrate and foam were prepared as described in
Examples 1 and 2.
[0086] Unless defined otherwise, all technical and scientific terms
used herein have the same meanings as commonly understood by one of
skill in the art to which the disclosed invention belongs.
Publications cited herein and the material for which they are cited
are specifically incorporated by reference. Those skilled in the
art will recognize, or be able to ascertain using no more than
routine experimentation, many equivalents to the specific
embodiments of the invention described herein. Such equivalents are
intended to be encompassed by the following claims.
* * * * *