U.S. patent application number 16/672590 was filed with the patent office on 2020-02-27 for topical compositions.
The applicant listed for this patent is Novan, Inc.. Invention is credited to Ryan Doxey, Nathan Stasko.
Application Number | 20200061089 16/672590 |
Document ID | / |
Family ID | 47437407 |
Filed Date | 2020-02-27 |
United States Patent
Application |
20200061089 |
Kind Code |
A1 |
Doxey; Ryan ; et
al. |
February 27, 2020 |
TOPICAL COMPOSITIONS
Abstract
Provided herein are anhydrous compositions that include at least
one viscosity increasing agent, at least one organic solvent and at
least one humectant. Such compositions may also include at least
one active pharmaceutical ingredient (API) and/or at least one
water repellant. Related compositions, methods and kits are also
provided.
Inventors: |
Doxey; Ryan; (Raleigh,
NC) ; Stasko; Nathan; (Chapel Hill, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Novan, Inc. |
Morrisville |
NC |
US |
|
|
Family ID: |
47437407 |
Appl. No.: |
16/672590 |
Filed: |
November 4, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16209542 |
Dec 4, 2018 |
10500220 |
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16672590 |
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14887648 |
Oct 20, 2015 |
10265334 |
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16209542 |
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14134737 |
Dec 19, 2013 |
9289442 |
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14887648 |
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PCT/US2012/045384 |
Jul 3, 2012 |
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14134737 |
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61610137 |
Mar 13, 2012 |
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61504628 |
Jul 5, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/695 20130101;
A61P 17/00 20180101; A61K 8/368 20130101; A61K 2800/22 20130101;
A61K 2800/31 20130101; A61P 17/02 20180101; A61K 2800/56 20130101;
A61K 8/34 20130101; A61K 8/585 20130101; A61K 47/38 20130101; A61P
17/10 20180101; A61K 8/345 20130101; A61K 8/731 20130101; A61K
47/34 20130101; A61K 8/40 20130101; A61Q 19/00 20130101; A61K 8/891
20130101; A61K 47/10 20130101; A61K 9/0014 20130101; A61K 9/143
20130101; A61K 47/20 20130101; A61K 2800/592 20130101 |
International
Class: |
A61K 31/695 20060101
A61K031/695; A61K 9/00 20060101 A61K009/00; A61K 47/10 20060101
A61K047/10; A61K 47/20 20060101 A61K047/20; A61K 47/34 20060101
A61K047/34; A61K 47/38 20060101 A61K047/38; A61K 8/34 20060101
A61K008/34; A61K 8/368 20060101 A61K008/368; A61K 8/40 20060101
A61K008/40; A61K 8/58 20060101 A61K008/58; A61K 8/73 20060101
A61K008/73; A61Q 19/00 20060101 A61Q019/00; A61K 8/891 20060101
A61K008/891 |
Claims
1. An anhydrous topical composition comprising at least one
viscosity increasing agent, at least one organic solvent and at
least one humectant.
2. The anhydrous topical composition of claim 1, wherein the at
least one viscosity increasing agent is present in the composition
at a concentration in a range of 0.5 to 30 weight percent; the at
least one organic solvent is present in the composition at a
concentration in a range of 50 to 90 weight percent; and the at
least one humectant is present in the composition at a
concentration in a range of 2 to 20 weight percent.
3. The anhydrous topical composition of claim 2, wherein the at
least one viscosity increasing agent comprises
hydroxypropylcellulose; the at least one organic solvent comprises
ethanol and the at least one humectant comprises hexylene
glycol.
4. The anhydrous topical composition of claim 1, further comprising
at least one water repellant.
5. The anhydrous topical composition of claim 4, wherein the at
least one viscosity increasing agent is present in the composition
at a concentration in a range of 0.5 to 30 weight percent; the at
least one organic solvent is present in the composition at a
concentration in a range of 50 to 90 weight percent; the at least
one humectant is present in the composition at a concentration in a
range of 2 to 20 weight percent; and the at least one water
repellent is present in the composition at a concentration in a
range of 0.5 to 15 weight percent.
6. The anhydrous topical composition of claim 5, wherein the at
least one viscosity increasing agent comprises
hydroxypropylcellulose; the at least one organic solvent comprises
ethanol and the at least one humectant comprises hexylene glycol;
and the at least one water repellent comprises cyclomethicone.
7. The anhydrous topical composition of claim 1, further comprising
a water reactive active pharmaceutical ingredient (API).
8. The anhydrous topical composition of claim 7, wherein the water
reactive API releases nitric oxide (NO) upon contact with
water.
9. The anhydrous topical composition of claim 8, wherein the water
reactive API comprises a diazeniumdiolate functional group.
10. The anhydrous topical composition of claim 9, wherein the water
reactive API comprises a NO-releasing co-condensed silica.
11. The anhydrous topical composition of claim 10, wherein the
co-condensed silica has a mean particle size of less than 10
.mu.m.
12. A packaged nitric oxide-releasing topical gel having a shelf
life of at least four weeks.
13. The packaged nitric oxide-releasing topical gel of claim 12,
wherein the shelf life is under refrigerated conditions.
14. The packaged nitric oxide-releasing topical gel according to
claim 12, wherein the shelf life is at least 52 weeks.
15. The packaged nitric oxide releasing topical gel according to
claim 12, wherein the shelf life is a predicted shelf life.
16. A packaged nitric oxide-releasing topical gel having a useful
life of at least 30 days.
17. The packaged nitric oxide-releasing topical gel according to
claim 16, wherein the useful shelf life is a predicted useful shelf
life.
18. An anhydrous topical composition comprising: hydroxypropyl
cellulose present in the composition at a concentration in a range
of 0.1 to 15 weight percent; ethyl alcohol or isopropyl alcohol
present in the composition at a concentration in a range of 45 to
95 weight percent; hexylene glycol present in the composition at a
concentration in a range of 1 to 20 weight percent; cyclomethicone
present in the composition at a concentration in a range of 0.5 to
15 weight percent; and a diazeniumdiolated co-condensed silica
particle at a concentration in a range of 0.1 to 40 weight
percent.
19. The anhydrous topical composition of any of claim 1 or 18,
wherein the anhydrous topical composition is non-drying and/or
non-irritating.
20. A method of treating a dermatological condition comprising
applying the anhydrous topical composition of any of claim 1-11 or
18-19 to the skin of a patient to treat the dermatological
condition.
21. The method of claim 20, wherein the dermatological condition
comprises acne.
Description
RELATED APPLICATION DATA
[0001] This application claims the benefit of U.S. Provisional
Patent Application Ser. No. 61/504,628, filed Jul. 5, 2011, and
U.S. Provisional Patent Application Ser. No. 61/610,137, filed Mar.
13, 2012, the disclosure of each of which are incorporated herein
by reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention is directed to pharmaceutical
compositions. In particular, the present invention is directed to
anhydrous topical pharmaceutical compositions.
BACKGROUND OF THE INVENTION
[0003] Acne vulgaris is the most common skin disease in the United
States. It is estimated that 40 to 50 million Americans have acne,
including 80% of people between the ages of 11 and 30. The annual
direct costs associated with the treatment of acne exceeded $2.8
billion in 2007, with the majority of those costs attributable to
prescription drugs. In addition, acne causes both physical and
psychological effects, including permanent scarring, anxiety,
depression, and poor self-esteem. Even in cases of mild acne, the
social stigma associated with the disease frequently results in
significant emotional distress and other psychological issues. Due
to its social impact, frequency of recurrence of relapse, and
necessary maintenance over a prolonged course of therapy, the
American Academy of Dermatologists have recommend that acne
vulgaris be re-classified and investigated as a chronic
disease.
[0004] Acne vulgaris results from the complex interplay of four
major pathogenic factors: 1) overproduction of sebum by the
sebaceous gland; 2) abnormal keratinization in the follicle; 3)
colonization of the hair follicles by the anaerobic, lipophilic
bacterium Propionibacterium acnes, or P. acnes; and 4) release of
inflammatory mediators into the skin. All acne lesions begin when
the combination of excess sebum and abnormal epithelial
desquamation clog up a follicle, forming a microscopic lesion known
as a microcomedo. The anaerobic, lipid-rich environment of the
microcomedo provides an ideal location for P. acnes proliferation.
Each microcomedo may progress to form a non-inflammatory open or
closed comedone (commonly referred to as a "blackhead" or
"whitehead," respectively), or an inflammatory lesion that may be
further categorized as a papule, pustule, nodule, or cyst.
[0005] The complexity of the disease may require multiple
treatments that may span oral and topical antimicrobials, oral and
topical retinoids, oral contraceptives and other prescription skin
cleansers. The most effective therapies for acne are those that may
safely address more than one of the major causes of acne
pathogenesis.
[0006] Antibiotics were the first successful acne treatment due to
their antimicrobial and anti-inflammatory properties. Both topical
and systemic antibiotics have been very successful, but the
protracted treatment periods required have led to the development
of resistance of P. acnes and in other non-targeted (and
potentially pathogenic) commensal organisms. Combining antibiotics
with topical retinoids targets three of the four major pathogenic
factors associated with acne (all but sebum production). The oral
retinoid isotretinoin (e.g., Accutane.RTM.) is the only
drug-implicated to affect all four pathogenic factors associated
with acne. However, the severity of its potential side effects
(known teratogen and linked to depression, psychosis and suicide)
has limited its use and led to numerous lawsuits.
[0007] While the problems associated with isotretinoin are the most
severe, all of the current acne medications have some adverse
effects. The majority of topical treatments lead to dryness,
irritation and peeling of the skin, and oral antibiotics may cause
gastrointestinal tract irritation, photosensitivity of skin,
headache, dizziness, anemia, bone and joint pain, nausea and/or
depression.
[0008] The most commonly prescribed drugs from acne are
antibiotics, including benzoyl peroxide, clindamycin and
erythromycin, either alone or in combination, and retinoids,
including adapalene, tretinoin and tazarotene, either alone or in
combination with an antibiotic. Treatments may include combination
drugs or combination therapies. For example, a retinoid may be
prescribed for application in the morning and an antibiotic for
application in the evening. Each of these commonly prescribed
drugs, however, has disadvantages that often reduce the
effectiveness of the therapy.
[0009] For example, benzoyl peroxide may be the most effective
topical medicine for acne and may result in a rapid reduction in P.
acnes. It also does not induce drug resistance in the P. acnes and,
when combined with other antibiotics, may reduce the rate at which
drug resistance develops. However, benzoyl peroxide commonly
results in irritation and dryness of the skin and bleaches fabric.
Additionally, about 2% of patients have an allergic reaction to
benzoyl peroxide.
[0010] Clindamycin and erythromycin as monotherapies may be limited
in effectiveness because of the development of drug resistant
strains of P. acnes. In fact, it is estimated that up to 75% of P.
acnes is already resistant to these antibiotics. However, these
products are available in a number of different bases and are
typically non-irritating and non-staining.
[0011] Retinoids mainly target comedonal acne but may also reduce
inflammatory lesions. Retinoids, however, are slow to produce
visible results and may produce irritation, redness and peeling. In
light of these limitations of retinoids, they are typically not
used alone.
[0012] Combinations of these various drugs are also available. For
example, clindamycin and benzoyl peroxide combination drugs are
available as well as combinations of erythromycin and benzoyl
peroxide, combinations of adapalene and benzoyl peroxide and
combinations of clindamycin and tretinoin. These drugs may have
improved efficacy over the individual drugs but also carry with
them the limitations of their constituents. Furthermore, none of
these combinations address all four of the causes of acne.
[0013] In addition to the limitations of the available drugs
themselves, a number of additional factors may affect compliance
with a treatment regime and, therefore, may reduce the regime's
overall efficacy. These factors include the degree of irritation of
the product, the time to noticeable results, the aesthetics of the
product, the repeatability required, the effect on clothing and
other items the product comes in contact with and the convenience
of the packaging and storage of the product. If the product
irritates the skin, the patient may discontinue use. If the product
takes too long to provide visible results, the patient may get
frustrated and stop treatment. If the product feels greasy, leaves
a visible residue or is powdery and grating, the patient may be
less likely to maintain the regime. If the product stains or
bleaches clothes, bedding or other fabrics, the patient may
discontinue its use. Finally, if the product is too difficult to
use or store, the patient may be unlikely to use it or to follow
the use and/or storage directions.
[0014] It may be difficult to obtain compositions that address some
or all of these factors. It may be even more difficult to obtain
anhydrous compositions that address some or all of these factors.
As such, new compositions and methods for making such compositions
may be desirable.
SUMMARY OF THE INVENTION
[0015] Provided according to some embodiments of the invention are
anhydrous topical compositions that include at least one viscosity
increasing agent, at least one organic solvent and at least one
humectant. In some embodiments, the at least one viscosity
increasing agent is present in the composition at a concentration
in a range of 0.5 to 30 weight percent; the at least one organic
solvent is present in the composition at a concentration in a range
of 50 to 90 weight percent; and the at least one humectant is
present in the composition at a concentration in a range of 2 to 20
weight percent.
[0016] In some embodiments of the invention, the topical anhydrous
compositions further include at least one water repellant. In some
embodiments, the at least one viscosity increasing agent is present
in the composition at a concentration in a range of 0.5 to 30
weight percent; the at least one organic solvent is present in the
composition at a concentration in a range of 50 to 90 weight
percent; the at least one humectant is present in the composition
at a concentration in a range of 2 to 20 weight percent; and the at
least one water repellent is present in the composition at a
concentration in a range of 0.5 to 15 weight percent.
[0017] In some embodiments, the topical anhydrous compositions
further include a water reactive active pharmaceutical ingredient
(API). In some embodiments, the water reactive API releases nitric
oxide (NO) upon contact with water. In some embodiments, the water
reactive API includes a diazeniumdiolate functional group. In some
embodiments, the water reactive API includes a NO-releasing
co-condensed silica.
[0018] Provided also in some embodiments are packaged nitric
oxide-releasing topical gels having a shelf life of at least four
weeks. Further provided are packaged nitric oxide-releasing topical
gels having useful life of at least 30 days and in some embodiments
at least 60 days.
[0019] A further aspect of the present invention comprises a method
of treating a dermatological condition comprising applying an
anhydrous topical composition of the present invention to the skin
of a patient to treat the dermatological condition. In some
embodiments, an anhydrous topical composition comprises at least
one API. In other embodiments, an anhydrous topical composition
comprises a vehicle and thus does not include at least one API. In
certain embodiments, an anhydrous topical composition of the
present invention is applied to the skin of a patient to treat
acne.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] The following drawings are provided to illustrate various
aspects of the present inventive concept and are not intended to
limit the scope of the present invention unless specified
herein.
[0021] FIG. 1 is a process flow diagram illustrating manufacture
and packaging of a topical therapeutic according to some
embodiments of the present inventive concept.
[0022] FIG. 2 is a flowchart illustrating operations/steps in a
process for manufacturing a topical therapeutic according to some
embodiments of the present inventive concept.
[0023] FIG. 3 is a flowchart illustrating further operations/steps
in a process for manufacturing a topical therapeutic according to
some embodiments of the present inventive concept
[0024] FIGS. 4A through 4C are drawings of a rotor-stator
homogenizer according to some embodiments of the present inventive
concept.
[0025] FIG. 5 shows the reduction in P. acnes for a control blank,
a gel vehicle and a composition according to an embodiment of the
invention.
[0026] FIG. 6 shows the nitric oxide release detected via
chemiluminescence in real time from a 2% API loaded anhydrous gel,
wherein the API is a nitric oxide releasing macromolecule, when
placed in phosphate buffered saline at a representative skin pH of
6.0. Additionally, the total nitric oxide release from the
anhydrous gel in nmol NO/mg gel is shown, demonstrating complete
release in under 30 minutes.
[0027] FIG. 7 shows the stability of a 2% API loaded anhydrous gel,
wherein the API is a nitric oxide releasing macromolecule, packaged
in various sized aluminum tubes and maintained in the following
conditions: refrigerated (4.degree. C.), room temperature with 75%
relative humidity, and 40.degree. C. with 75% relative humidity.
Percent NO recovery values were measured by the total NO release
detected via chemiluminescence at each time point and presented as
a percentage of the nitric oxide loading at time=0.
[0028] FIG. 8 shows a graph of nitric oxide recovery versus time
for a 2% anhydrous gel in 2 gram tubes.
DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION
[0029] The foregoing and other aspects of the present invention
will now be described in more detail with respect to the
description and methodologies provided herein. It should be
appreciated that the invention may be embodied in different forms
and should not be construed as limited to the embodiments set forth
herein. Rather, these embodiments are provided so that this
disclosure will be thorough and complete, and will fully convey the
scope of the invention to those skilled in the art.
[0030] The terminology used in the description of the invention
herein is for the purpose of describing particular embodiments only
and is not intended to be limiting of the invention. As used in the
description of the embodiments of the invention and the appended
claims, the singular forms "a," "an" and "the" are intended to
include the plural forms as well, unless the context clearly
indicates otherwise. Also, as used herein, "and/or" refers to and
encompasses any and all possible combinations of one or more of the
associated listed items. Furthermore, the term "about," as used
herein when referring to a measurable value such as an amount of a
compound, dose, time, temperature, and the like, is meant to
encompass variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the
specified amount. When a range is employed (e.g., a range from x to
y) it is it meant that the measurable value is a range from about x
to about y, or any range therein, such as about x.sub.1 to about
y.sub.1, etc. It will be further understood that the terms
"comprises" and/or "comprising," when used in this specification,
specify the presence of stated features, integers, steps,
operations, elements, and/or components, but do not preclude the
presence or addition of one or more other features, integers,
steps, operations, elements, components, and/or groups thereof.
Unless otherwise defined, all terms, including technical and
scientific terms used in the description, have the same meaning as
commonly understood by one of ordinary skill in the art to which
this invention belongs.
[0031] All patents, patent applications and publications referred
to herein are incorporated by reference in their entirety. In the
event of conflicting terminology, the present specification is
controlling.
[0032] The embodiments described in one aspect of the present
invention are not limited to the aspect described. The embodiments
may also be applied to a different aspect of the invention as long
as the embodiments do not prevent these aspects of the invention
from operating for its intended purpose.
Chemical Definitions
[0033] As used herein the term "alkyl" refers to C1-20 inclusive,
linear (i.e., "straight-chain"), branched, or cyclic, saturated or
at least partially and in some cases fully unsaturated (i.e.,
alkenyl and alkynyl) hydrocarbon chains, including for example,
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,
pentyl, hexyl, octyl, ethenyl, propenyl, butenyl, pentenyl,
hexenyl, octenyl, butadienyl, propynyl, butynyl, pentynyl, hexynyl,
heptynyl, and allenyl groups. "Branched" refers to an alkyl group
in which a lower alkyl group, such as methyl, ethyl or propyl, is
attached to a linear alkyl chain. Exemplary branched alkyl groups
include, but are not limited to, isopropyl, isobutyl, tert-butyl.
"Lower alkyl" refers to an alkyl group having 1 to 8 carbon atoms
(i.e., a C1-8 alkyl), e.g., 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms.
"Higher alkyl" refers to an alkyl group having 8 to 20 or more
carbon atoms, e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,
20, or more carbon atoms. In certain embodiments, "alkyl" refers,
in particular, to C1-5 straight-chain alkyls. In other embodiments,
"alkyl" refers, in particular, to C1-5 branched-chain alkyls.
[0034] Alkyl groups may optionally be substituted (a "substituted
alkyl") with one or more alkyl group substituents, which may be the
same or different. The term "alkyl group substituent" includes but
is not limited to alkyl, substituted alkyl, halo, arylamino, acyl,
hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl,
aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl. There
may be optionally inserted along the alkyl chain one or more
oxygen, sulfur or substituted or unsubstituted nitrogen atoms,
wherein the nitrogen substituent is hydrogen, lower alkyl (also
referred to herein as "alkylaminoalkyl"), or aryl.
[0035] Thus, as used herein, the term "substituted alkyl" includes
alkyl groups, as defined herein, in which one or more atoms or
functional groups of the alkyl group are replaced with another atom
or functional group, including for example, alkyl, substituted
alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro,
amino, alkylamino, dialkylamino, sulfate, and mercapto.
[0036] The term "aryl" is used herein to refer to an aromatic
substituent that may be a single aromatic ring, or multiple
aromatic rings that are fused together, linked covalently, or
linked to a common group, such as, but not limited to, a methylene
or ethylene moiety. The common linking group also may be a
carbonyl, as in benzophenone, or oxygen, as in diphenylether, or
nitrogen, as in diphenylamine. The term "aryl" specifically
encompasses heterocyclic aromatic compounds. The aromatic ring(s)
may comprise phenyl, naphthyl, biphenyl, diphenylether,
diphenylamine and benzophenone, among others. In particular
embodiments, the term "aryl" means a cyclic aromatic comprising 5
to 10 carbon atoms, e.g., 5, 6, 7, 8, 9, or 10 carbon atoms, and
including 5- and 6-membered hydrocarbon and heterocyclic aromatic
rings.
[0037] The aryl group may be optionally substituted (a "substituted
aryl") with one or more aryl group substituents, which may be the
same or different, wherein "aryl group substituent" includes alkyl,
substituted alkyl, aryl, substituted aryl, aralkyl, hydroxyl,
alkoxyl, aryloxyl, aralkyloxyl, carboxyl, acyl, halo, nitro,
alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acyloxyl,
acylamino, aroylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
arylthio, alkylthio, alkylene, and --NR1R'', wherein R1 and R'' may
each be independently hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, and aralkyl.
[0038] Thus, as used herein, the term "substituted aryl" includes
aryl groups, as defined herein, in which one or more atoms or
functional groups of the aryl group are replaced with another atom
or functional group, including for example, alkyl, substituted
alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro,
amino, alkylamino, dialkylamino, sulfate, and mercapto. Specific
examples of aryl groups include, but are not limited to,
cyclopentadienyl, phenyl, furan, thiophene, pyrrole, pyran,
pyridine, imidazole, benzimidazole, isothiazole, isoxazole,
pyrazole, pyrazine, triazine, pyrimidine, quinoline, isoquinoline,
indole, carbazole, and the like.
[0039] "Cyclic" and "cycloalkyl" refer to a non-aromatic mono- or
multicyclic ring system of 3 to 10 or more carbon atoms, e.g., 3,
4, 5, 6, 7, 8, 9, 10, or more carbon atoms. The cycloalkyl group
may be optionally partially unsaturated. The cycloalkyl group also
may be optionally substituted with an alkyl group substituent as
defined herein, oxo, and/or alkylene. There may be optionally
inserted along the cyclic alkyl chain one or more oxygen, sulfur or
substituted or unsubstituted nitrogen atoms, wherein the nitrogen
substituent is hydrogen, alkyl, substituted alkyl, aryl, or
substituted aryl, thus providing a heterocyclic group.
Representative monocyclic cycloalkyl rings include cyclopentyl,
cyclohexyl, and cycloheptyl. Multicyclic cycloalkyl rings include
adamantyl, octahydronaphthyl, decalin, camphor, camphane, and
noradamantyl.
[0040] "Alkoxyl" refers to an alkyl-O-- group wherein alkyl is as
previously described. The term "alkoxyl" as used herein may refer
to, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl,
f-butoxyl, and pentoxyl. The term "oxyalkyl" may be used
interchangeably with "alkoxyl". In some embodiments, the alkoxyl
has 1, 2, 3, 4, or 5 carbons.
[0041] "Aralkyl" refers to an aryl-alkyl group wherein aryl and
alkyl are as previously described, and included substituted aryl
and substituted alkyl. Exemplary aralkyl groups include benzyl,
phenylethyl, and naphthylmethyl.
[0042] "Alkylene" refers to a straight or branched bivalent
aliphatic hydrocarbon group having from 1 to 20 or more carbon
atoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19, 20, or more carbon atoms. The alkylene group may be
straight, branched or cyclic. The alkylene group also may be
optionally unsaturated and/or substituted with one or more "alkyl
group substituents." There may be optionally inserted along the
alkylene group one or more oxygen, sulfur or substituted or
unsubstituted nitrogen atoms (also referred to herein as
"alkylaminoalkyl"), wherein the nitrogen substituent is alkyl as
previously described. Exemplary alkylene groups include methylene
(--CH2-); ethylene (--CH2-CH2-); propylene (--(CH2)3-);
cyclohexylene (--C6H10-); --CH.dbd.CH--CH.dbd.CH--;
--CH.dbd.CH--CH2-; wherein each of q and r is independently an
integer from 0 to 20, e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, or 20, or any range therein, and R
is hydrogen or lower alkyl; methylenedioxyl (--O--CH2-O--); and
ethylenedioxyl (--O--(CH2)2-O--). An alkylene group may have 2 to 3
carbon atoms and may further have 6-20 carbons.
[0043] "Arylene" refers to a bivalent aryl group. An exemplary
arylene is phenylene, which may have ring carbon atoms available
for bonding in ortho, meta, or para positions with regard to each
other, i.e., respectively. The arylene group may also be
naphthylene. The arylene group may be optionally substituted (a
"substituted arylene") with one or more "aryl group substituents"
as defined herein, which may be the same or different.
[0044] "Aralkylene" refers to a bivalent group that contains both
alkyl and aryl groups. For example, aralkylene groups may have two
alkyl groups and an aryl group (i.e., -alkyl-aryl-alkyl-), one
alkyl group and one aryl group (i.e., -alkyl-aryl-) or two aryl
groups and one alkyl group (i.e., -aryl-alkyl-aryl-).
[0045] The term "amino" and "amine" refer to nitrogen-containing
groups such as NR3, NH3, NHR2, and NH2R, wherein R may be alkyl,
branched alkyl, cycloalkyl, aryl, alkylene, arylene, aralkylene.
Thus, "amino" as used herein may refer to a primary amine, a
secondary amine, or a tertiary amine. In some embodiments, one R of
an amino group may be a cation stabilized diazeniumdiolate (i.e.,
NONO--X+).
[0046] The terms "cationic amine" and "quaternary amine" refer to
an amino group having an additional (i.e., a fourth) group, for
example a hydrogen or an alkyl group bonded to the nitrogen. Thus,
cationic and quarternary amines carry a positive charge.
[0047] The term "alkylamine" refers to the -alkyl-NH2 group.
[0048] The term "carbonyl" refers to the --(C.dbd.O)-- group.
[0049] The term "carboxyl" refers to the --COOH group and the term
"carboxylate" refers to an anion formed from a carboxyl group,
i.e., --COO--.
[0050] The terms "halo", "halide", or "halogen" as used herein
refer to fluoro, chloro, bromo, and iodo groups.
[0051] The term "hydroxyl" and "hydroxy" refer to the --OH
group.
[0052] The term "hydroxyalkyl" refers to an alkyl group substituted
with an --OH group.
[0053] The term "mercapto" or "thio" refers to the --SH group. The
term "silyl" refers to groups comprising silicon atoms (Si).
[0054] As used herein the term "alkoxysilane" refers to a compound
comprising one, two, three, or four alkoxy groups bonded to a
silicon atom. For example, tetraalkoxysilane refers to Si(OR)4,
wherein R is alkyl. Each alkyl group may be the same or different.
An "alkylsilane" refers to an alkoxysilane wherein one or more of
the alkoxy groups has been replaced with an alkyl group. Thus, an
alkylsilane comprises at least one alkyl-Si bond. The term
"fluorinated silane" refers to an alkylsilane wherein one of the
alkyl groups is substituted with one or more fluorine atoms. The
term "cationic or anionic silane" refers to an alkylsilane wherein
one of the alkyl groups is further substituted with an alkyl
substituent that has a positive (i.e., cationic) or a negative
(i.e. anionic) charge, or may become charged (i.e., is ionizable)
in a particular environment (i.e., in vivo).
[0055] The term "silanol" refers to a Si--OH group.
Pharmaceutical Compositions
[0056] One aspect of the present invention is directed to
pharmaceutical compositions. Provided according to some embodiments
of the invention are pharmaceutical compositions that include at
least one active pharmaceutical ingredient (API). According to
other embodiments of the present invention, provided are
pharmaceutical compositions that do not include at least one API.
Compositions described herein that do not have an API are referred
to herein as "vehicles." Pharmaceutical compositions according to
embodiments of the invention may, therefore, include at least one
API or may be vehicles that do not include at least one API. In
some embodiments, the pharmaceutical compositions are anhydrous,
and in some embodiments, the pharmaceutical compositions are
topical compositions. "Anhydrous," as used herein means that there
is no direct addition of water to a composition of the present
invention. However, those skilled in the art will recognize that
water may be physically and/or chemically absorbed by a composition
and/or by one or more ingredients in a composition at any time
during the preparation, storage, and/or use of a composition of the
present invention (i.e., indirect addition of water to the
composition). In some embodiments, the term "anhydrous" means that
a composition has a water content of less than 5% by weight of the
composition or any range therein. A composition of the present
invention may have a water content of less than 5, 4.5, 4, 3.5, 3,
2.5, 2, 1.5, 1, 0.5%, or any range therein, by weight of the
composition. Water content may be measured by methods known to
those of skill in the art, such as, but not limited to, Karl
Fischer titration.
[0057] In some embodiments of the invention, the pharmaceutical
composition is a topical composition, which may also be referred to
as a "dermatological composition" herein. A topical composition may
be applied to body surfaces, including skin, mucous membranes,
scalp, hair and/or nails.
[0058] Provided according to embodiments of the invention are
anhydrous pharmaceutical compositions that include excipients that
include at least one viscosity agent, at least one solvent and at
least one humectant. The term excipient refers to "inert"
constituents of pharmaceutically acceptable compositions. The term
"inert" indicates that such constituents are not considered active
pharmaceutical ingredients, such as a nitric oxide-releasing
compound or other antimicrobial compounds, anti-inflammatory
agents, pain-relievers, immunosuppressants and vasodilators.
However, as one of ordinary skill in the art will understand, the
excipients may provide beneficial or therapeutic action to the skin
(e.g., moisturize, provide anti-inflammatory effects) that may
directly affect a topical ailment. The excipients may also
indirectly affect the treatment of topical ailments by affecting
the stability of NO-releasing compounds or other active
pharmaceutical ingredients (APIs) within the compositions. It will
be understood that any suitable combination of excipients may be
present in the pharmaceutical compositions described herein.
[0059] Excipients for use in topical formulations are well-known in
the art and examples may be found in the Handbook of Pharmaceutical
Excipients (Rowe, R. C. et al., APhA Publications; 5th ed., 2005).
Classes of excipients may include waxes, emollients, thickening
agents/viscosity increasing agents, humectants, pH modifiers, water
repelling agents, anti-foaming agents, surfactants, solubilizers,
wetting agents, penetration enhancers, antioxidants, and solvents.
The excipients may also be present in the topical composition at
any suitable concentration. In some embodiments, the topical
composition includes excipients at a concentration in a range from
70 to 99.99 weight percent.
[0060] Any suitable viscosity increasing agent may be used, and
combinations of viscosity increasing agents may also be used. In
some embodiments of the invention, the polymeric portion of the
viscosity increasing agent may act as a visco-elastic substance and
may retain the gel at the site of application, along with the APIs
dispersed therein. Examples of viscosity increasing agents include
co-polymers of carboxymethylcellulose and acrylic acid,
N-vinylpyrrolidone, polyalkylene glycols (e.g., poly(ethylene
glycol)), polyalkylene oxides (e.g., polyethylene oxide), polyvinyl
alcohols, polyvinylpyrrolidone, polysiloxanes, poly(vinyl
acetates), cellulose, derivatized celluloses, alginates, copolymers
thereof and blends thereof. A specific example of a viscosity agent
is hydroxypropylcellulose, such as Klucel.RTM.
hydroxypropylcellulose (e.g., Klucel.RTM. MF Pharm grade).
[0061] Any suitable solvent or combinations of solvents may be used
in the topical compositions. Examples of solvents include acetone,
methyl alcohol, ethanol, isopropanol, butyl alcohol, ethyl acetate,
dimethyl isosorbide, propylene glycol, glycerol, ethylene glycol,
polyethylene glycol, diethylene glycol monoethyl ether or mixtures
thereof. In particular examples, the solvent includes ethanol. In
some embodiments, the solvent includes isopropyl alcohol. The
skilled artisan will appreciate that the solvents may also be
considered excipients, particularly at lower concentrations.
[0062] Any suitable humectant or combination of humectants may be
used. Examples include glycols, such as diethylene glycol monoethyl
ether; glycerols; sugar polyols, such as sorbitol, xylitol and
maltitol; polyols such as polydextroses; quillaia, urea, and blends
thereof. In particular examples, the humectant includes an alkylene
glycol, such as hexylene glycol.
[0063] In some embodiments, the anhydrous topical compositions
include at least one water repelling agent, also referred to as a
water repellant. Examples of water repelling agents include
silicones, such as cyclomethicone, dimethicone, simethicone, C26-28
alkyl dimethicone, C26-28 alkyl methicone, polyphenylsisquioxane,
trimethylsiloxysilicate and crosspolymers of cyclopentasiloxane and
dimethicone/vinyltrimethylsiloxysilicate, and blends thereof. The
water repelling agent may be particularly useful in embodiments
where the topical vehicle is used with a water-reactive API, such
as a nitric oxide-releasing API whereby the nitric oxide is
released in the presence of water (e.g., a diazeniumdialate). In
other cases, such as when the API is not water sensitive, a water
repelling agent may not be included.
[0064] In some embodiments of the invention, the anhydrous topical
compositions may have a viscosity increasing agent concentration in
a range from 0.5 to 30% by weight, a solvent concentration in a
range from 50 to 90% by weight, and a humectant concentration in a
range from 2 to 20% by weight. In some embodiments, the anhydrous
topical compositions may also include a water repelling agent at a
concentration in a range from 0.5% to 15% by weight. In some
embodiments, the topical anhydrous compositions further include at
least one API, for example, at a concentration in a range from 0.01
to 30% by weight, or any range therein.
[0065] In particular embodiments, the solvent is ethyl alcohol, 200
proof, anhydrous, the humectant is hexylene glycol available from
Nexio Solutions; the water repelling agent is ST-cyclomethicone-5
NF available from Dow Corning Corp.; and the viscosity increasing
agent is a hydroxypropylcellulose (HPC), such as Klucel.RTM. MF
Pharm available from Ashland Aqualon.
[0066] In specific embodiments, the vehicle has the formulation of
about 83.5% ethyl alcohol as a solvent, about 10% hexylene glycol
as a humectant, about 2.5% ST-cyclomethicon-5 as a water repelling
agent, about 2% HPC as a viscosity increasing agent, leaving about
2% available for inclusion of an API. In other embodiments the API
is a nitric oxide donor. In other embodiments, the API is
Nitricil.TM., a NO-releasing co-condensed silica, from Novan, Inc.
In some embodiments, the total nitric oxide loading in the topical
gel may be in a range from 0.01 to 5.0 wt/wt %. In some
embodiments, the total nitric oxide loading in the topical gel is
in a range from 0.24 to 0.36 wt/wt %.
[0067] In particular embodiments, the solvent is isopropyl alcohol,
USP, the humectant is hexylene glycol available from Nexio
Solutions; the water repelling agent is ST-cyclomethicone-5 NF
available from Dow Corning Corp.; and the viscosity increasing
agent is a hydroxypropylcellulose (HPC), such as Klucel.RTM. MF
Pharm available from Ashland Aqualon.
[0068] In particular embodiments, the vehicle has the formulation
of 86.5% less the percentage of API of isopropyl alcohol as a
solvent, 10% hexylene glycol as a humectant, 2.5%
ST-cyclomethicon-5 as a water repelling agent, and 1% HPC as a
viscosity increasing agent. Decreasing the quantity of viscosity
increasing agent in the formulation may allow for higher loadings
of API while maintaining acceptable organoleptic properties, such
as not feeling gritty. The quantity of API may be anywhere from
0.01% to 50% or any range therein, such as, but not limited to,
from 0.1% to 30% or from 2% to 20%. In certain embodiments the API
is a nitric oxide donor. In other embodiments, the API is
Nitricil.TM., a NO-releasing co-condensed silica, from Novan, Inc.
In some embodiments, the total nitric oxide loading in the topical
gel may be in a range from 0.01 to 30 wt/wt % or any range therein,
such as, but not limited to, 0.1 to 15 wt/wt %. In some
embodiments, the total nitric oxide loading in the topical gel is
in a range from 0.1 to 5 wt/wt % or any range therein. The total
nitric oxide loading in a topical gel may be measured by methods
known to those of skill in the art, including, but not limited to,
using a nitric oxide analyzer, such as a Sievers 280i Nitric Oxide
Analyzer.
[0069] For applications where the API is water reactive, such as a
nitric oxide-releasing particle that releases nitric oxide in the
presence of water, the inclusion of the water repelling agent may
increase the API storage stability of the topical gel. In some
embodiments, uniformly dispersing a water repellant with the API in
a ratio of API to water repellant of from 0.01:1 to 30:1 and, in
particular embodiments, 2 to 1, 4 to 1, 6 to 1, 8 to 1, 12 to 1 or
20 to 1, may, similarly, allow close association of the water
repellant with the API and, thereby, improve stability of the
topical gel.
[0070] For applications where the topical composition must absorb
water, dissociate when in contact with an aqueous environment (e.g.
on the surface of the skin), or utilize water as a mechanism for
initiating drug release/delivery, the inclusion of a humectant may
be used. For example, where the API is a diazeniumdiolated
co-condensed silica particle, the humectant may be provided in a
ratio of humectant to API of from 1:3 to 20:1 by weight to the API
and, in some embodiments at a ratio from 5 to 1, 5 to 3, 1 to 1, 1
to 1.2 or 1 to 2 to the API. Uniformly dispersing the humectant
with the API may allow for the close proximity of the humectant
with the API in the final topical gel and, thereby, provide
hydrophilic channels or access to moisture uptake in an anhydrous
topical gel.
[0071] In compositions with water sensitive APIs (i.e.,
diazeniumdiolate), cellulose polymers may be useful as viscosity
increasing agents because the crosslinking of the gel presents both
a physical barrier to moisture diffusion and a hydrogen bonding
network of water to protect it from getting to the water reactive
functional groups. However, the cellulose polymer may not inhibit
the release of nitric oxide in a moisture rich environment, such as
on the skin of a patient. The degree of stability enhancement may
be based on the weight percent of the cellulose polymer. Additional
factors affecting nitric oxide stability may include the molecular
weight of the cellulose. In some embodiments, the topical
compositions may be considered pharmaceutically acceptable. A
pharmaceutically acceptable composition, as defined herein, refers
to a composition that is suitable for application to a subject,
such as a human, without undue side effects such as toxicity or
irritation to the skin. Undue side effects are those that render
the composition unsuitable for application to a subject because the
harm from the side effects outweighs the benefits of the
composition.
[0072] In embodiments wherein the API includes a NO-releasing
compound, the NO-releasing compounds may be present in
pharmaceutically acceptable compositions according to embodiments
of the invention at any suitable concentration, but in some
embodiments, the NO-releasing compounds are present in the
compositions at a concentration sufficient to elicit an improvement
in, eliminate or prevent acne. In some embodiments, the
concentration of NO-releasing compounds ranges from 0.1% to 30% w/w
in the composition. In particular embodiments, the concentration of
the NO-releasing compounds is less than 20% w/w in the composition
or any range therein. In still further embodiments, the
concentration of the NO-releasing compounds is less than 10% w/w in
the composition or any range therein. In particular embodiments,
the concentration of the NO-releasing compounds is 1%, 2%, 4%, or
8% w/w in the composition.
[0073] While pharmaceutically acceptable compositions that may be
used in certain embodiments of the present inventive concept, in
particular embodiments, a topical gel is provided. Topical gels
according to the present inventive concept may be non-irritating to
the skin, may provide noticeable results in a relatively short
period of time, may be cosmetically elegant and/or may not bleach
or otherwise stain clothing and other items that contact the
product.
[0074] Additionally, to avoid a gritty feeling of the topical gel,
the maximum particle size for a the API may be less than 100 .mu.m,
or any range therein, and, in some embodiments, less than 20 .mu.m,
and in further embodiments, less than 10 .mu.m.
[0075] The topical vehicle and API may be readily spread by a
patient and, therefore, may have a viscosity of from 250 cP to
50000 cP or any range therein, such as, but not limited to, 500 cP
to 10000 cP or 1000 cP to 8000 cP. In some embodiments, the
viscosity of the topical gel is about 7000 cP. The viscosity of the
gel may be controlled by the amount of the viscosity increasing
agent added to the gel. Too much of the agent and the gel will
become too thick and difficult to spread.
[0076] The topical gel may also evaporate relatively quickly to
avoid a feeling of greasiness and, in some cases, to provide a
cooling sensation. Thus, the topical gel may have a relatively high
level of volatiles. In some embodiments, the percent of volatiles
by weight is greater than 55% or any range therein. In particular
embodiments, the percent of volatiles by weight is about 55%, 66%,
74%, 80%, or 86%.
[0077] Additionally, the topical gel may have a "leave-on" layer or
secondary formulation after evaporation of the volatiles that is
spread substantially uniformly when the topical gel is spread on
the skin. The percent non-volatiles may be from 2 to 45% by weight
to provide a suitable leave-on layer. In some embodiments, the
percent non-volatiles is about 14%, 17%, 23%, 31% or 41% by weight.
In some embodiments, the leave-on layer comprises nitric
oxide-releasing particles, hydroxypropylcellulose, and hexylene
glycol.
[0078] A topical gel of the present invention may have a pH from 5
to 12, or any range therein, such as, but not limited to, from 7 to
12, 8 to 11, or 10 to 11. In certain embodiments, a topical gel may
have a pH of about 5, 6, 7, 8, 9, 10, 11, or 12. In some
embodiments, such as, but not limited to, embodiments comprising a
water reactive API, the pH of a topical gel may change upon use
(e.g., contact with the skin of a subject) and/or upon contact with
water.
[0079] As described herein, selection of the ingredients may affect
the stability and, therefore, the release of the nitric oxide from
the API. Accordingly, the selected ingredients and their
proportions may be selected to provide a desired stability and
release profile for a given nitric oxide-releasing particle.
Furthermore, as described below, the processing of the API and
vehicle may also impact stability and release kinetics. For
diazeniumdiolate NO-releasing APIs, considerations in determining
the impact of the vehicle constituents and the processing include
rate of release of nitric oxide desired, including the release
profile desired, the type of ailment that the composition aims to
treat, other APIs included in the composition and the stability
desired.
Active Pharmaceutical Ingredients
[0080] Any suitable active pharmaceutical ingredient (API) or
combinations of APIs may be included in the compositions according
to embodiments of the invention. Examples of APIs include
antimicrobial agents, anti-acne agents, anti-inflammatory agents,
analgesic agents, anesthetic agents, antihistamine agents,
antiseptic agents, immunosuppressants, antihemorrhagic agents,
vasodilators, wound healing agents, anti-biofilm agents and
mixtures thereof.
[0081] Examples of antimicrobial agents include penicillins and
related drugs, carbapenems, cephalosporins and related drugs,
erythromycin, aminoglycosides, bacitracin, gramicidin, mupirocin,
chloramphenicol, thiamphenicol, fusidate sodium, lincomycin,
clindamycin, macrolides, novobiocin, polymyxins, rifamycins,
spectinomysin, tetracyclines, vanomycin, teicoplanin,
streptogramins, anti-folate agents including sulfonamides,
trimethoprim and its combinations and pyrimethamine, synthetic
antibacterials including nitrofurans, methenamine mandelate and
methenamine hippurate, nitroimidazoles, quinolones,
fluoroquinolones, isoniazid, ethambutol, pyrazinamide,
para-aminosalicylic acid (PAS), cycloserine, capreomycin,
ethionamide, prothionamide, thiacetazone, viomycin, eveminomycin,
glycopeptide, glyclyclycline, ketolides, oxazolidinone; imipenen,
amikacin, netilmicin, fosfomycin, gentamycin, ceftriaxone, Ziracin,
Linezolid, Synercid, Aztreonam, and Metronidazole, Epiroprim,
Sanfetrinem sodium, Biapenem, Dynemicin, Cefluprenam, Cefoselis,
Sanfetrinem celexetil, Cefpirome, Mersacidin, Rifalazil, Kosan,
Lenapenem, Veneprim, Sulopenem, ritipenam acoxyl, Cyclothialidine,
micacocidin A, carumonam, Cefozopran and Cefetamet pivoxil.
[0082] Examples of topical anti-acne agents include adapalene,
azelaic acid, benzoyl peroxide, clindamycin and clindamycin
phosphate, doxycycline, erythromycin, keratolytics such as
salicylic acid and retinoic acid (Retin-A''), norgestimate, organic
peroxides, retinoids such as isotretinoin and tretinoin,
sulfacetamide sodium, and tazarotene. Particular anti-acne agents
include adapalene, azelaic acid, benzoyl peroxide, clindamycin
(e.g., clindamycin phosphate), doxycycline (e.g., doxycycline
monohydrate), erythromycin, isotretinoin, norgestimate,
sulfacetamide sodium, tazarotene, etretinate and acetretin.
[0083] Examples of antihistamine agents include diphenhydramine
hydrochloride, diphenhydramine salicylate, diphenhydramine,
chlorpheniramine hydrochloride, chlorpheniramine maleate
isothipendyl hydrochloride, tripelennamine hydrochloride,
promethazine hydrochloride, methdilazine hydrochloride, and the
like. Examples of local anesthetic agents include dibucaine
hydrochloride, dibucaine, lidocaine hydrochloride, lidocaine,
benzocaine, p-buthylaminobenzoic acid 2-(die-ethylamino) ethyl
ester hydrochloride, procaine hydrochloride, tetracaine, tetracaine
hydrochloride, chloroprocaine hydrochloride, oxyprocaine
hydrochloride, mepivacaine, cocaine hydrochloride, piperocaine
hydrochloride, dyclonine and dyclonine hydrochloride.
[0084] Examples of antiseptic agents include alcohols, quaternary
ammonium compounds, boric acid, chlorhexidine and chlorhexidine
derivatives, iodine, phenols, terpenes, bactericides, disinfectants
including thimerosal, phenol, thymol, benzalkonium chloride,
benzethonium chloride, chlorhexidine, povidone iode,
cetylpyridinium chloride, eugenol and trimethylammonium
bromide.
[0085] Examples of anti-inflammatory agents include nonsteroidal
anti-inflammatory agents (NSAIDs); propionic acid derivatives such
as ibuprofen and naproxen; acetic acid derivatives such as
indomethacin; enolic acid derivatives such as meloxicam,
acetaminophen; methyl salicylate; monoglycol salicylate; aspirin;
mefenamic acid; flufenamic acid; indomethacin; diclofenac;
alclofenac; diclofenac sodium; ibuprofen; ketoprofen; naproxen;
pranoprofen; fenoprofen; sulindac; fenclofenac; clidanac;
flurbiprofen; fentiazac; bufexamac; piroxicam; phenylbutazone;
oxyphenbutazone; clofezone; pentazocine; mepirizole; tiaramide
hydrochloride; steroids such as clobetasol propionate,
bethamethasone dipropionate, halbetasol proprionate, diflorasone
diacetate, fluocinonide, halcinonide, amcinonide, desoximetasone,
triamcinolone acetonide, mometasone furoate, fluticasone
proprionate, betamethasone diproprionate, triamcinolone acetonide,
fluticasone propionate, desonide, fluocinolone acetonide,
hydrocortisone vlaerate, prednicarbate, triamcinolone acetonide,
fluocinolone acetonide, hydrocortisone and others known in the art,
predonisolone, dexamethasone, fluocinolone acetonide,
hydrocortisone acetate, predonisolone acetate, methylpredonisolone,
dexamethasone acetate, betamethasone, betamethasone valerate,
flumetasone, fluorometholone, beclomethasone diproprionate,
fluocinonide, topical corticosteroids, and may be one of the lower
potency corticosteroids such as hydrocortisone,
hydrocortisone-21-monoesters (e.g., hydrocortisone-21-acetate,
hydrocortisone-21-butyrate, hydrocortisone-21-propionate,
hydrocortisone-21-valerate, etc.), hydrocortisone-17,21-diesters
(e.g., hydrocortisone-17,21-diacetate,
hydrocortisone-17-acetate-21-butyrate,
hydrocortisone-17,21-dibutyrate, etc.), alclometasone,
dexamethasone, flumethasone, prednisolone, or methylprednisolone,
or may be a higher potency corticosteroid such as clobetasol
propionate, betamethasone benzoate, betamethasone dipropionate,
diflorasone diacetate, fluocinonide, mometasone furoate,
triamcinolone acetonide.
[0086] Examples of analgesic agents include alfentanil, benzocaine,
buprenorphine, butorphanol, butamben, capsaicin, clonidine,
codeine, dibucaine, enkephalin, fentanyl, hydrocodone,
hydromorphone, indomethacin, lidocaine, levorphanol, meperidine,
methadone, morphine, nicomorphine, opium, oxybuprocaine, oxycodone,
oxymorphone, pentazocine, pramoxine, proparacaine, propoxyphene,
proxymetacaine, sufentanil, tetracaine and tramadol.
[0087] Examples of anesthetic agents include alcohols such as
phenol; benzyl benzoate; calamine; chloroxylenol; dyclonine;
ketamine; menthol; pramoxine; resorcinol; troclosan; procaine drugs
such as benzocaine, bupivacaine, chloroprocaine; cinchocaine;
cocaine; dexivacaine; diamocaine; dibucaine; etidocaine;
hexylcaine; levobupivacaine; lidocaine; mepivacaine; oxethazaine;
prilocaine; procaine; proparacaine; propoxycaine; pyrrocaine;
risocaine; rodocaine; ropivacaine; tetracaine; and derivatives,
such as pharmaceutically acceptable salts and esters including
bupivacaine HCl, chloroprocaine HCl, diamocaine cyclamate,
dibucaine HCl, dyclonine HCl, etidocaine HCl, levobupivacaine HCl,
lidocaine HCl, mepivacaine HCl, pramoxine HCl, prilocaine HCl,
procaine HCl, proparacaine HCl, propoxycaine HCl, ropivacaine HCl,
and tetracaine HCl.
[0088] Examples of antihemorrhagic agents include thrombin,
phytonadione, protamine sulfate, aminocaproic acid, tranexamic
acid, carbazochrome, carbaxochrome sodium sulfanate, rutin and
hesperidin.
[0089] In some embodiments of the invention, the active
pharmaceutical ingredient (API) includes a compound that releases
nitric oxide (NO). Any suitable NO-releasing compound may be used.
In some embodiments, the NO-releasing compound includes a small
molecule compound that includes an NO donor group. Small molecule
compounds are defined herein as compounds having a molecular weight
of less than 500 daltons, and include organic and/or inorganic
small molecules. In some embodiments, the NO-releasing compound
includes a macromolecule that includes an NO donor group. A
macromolecule is defined herein as any compound that has a
molecular weight of 500 daltons or greater. Any suitable
macromolecule may be used, including crosslinked or non-crosslinked
polymers, dendrimers, metallic compounds, organometallic compounds,
inorganic-based compounds, and other macromolecular scaffolds. In
some embodiments, the macromolecule has a nominal diameter ranging
from 0.1 nm-100 .mu.m and may comprise the aggregation of two or
more macromolecules, whereby the macromolecular structure is
further modified with a NO donor group.
[0090] In some embodiments of the invention, the NO donor of the
NO-releasing compound releases nitric oxide upon exposure to an
external condition, such as light, heat, water, acid, base, and the
like. For example, in some embodiments, the NO-releasing compound
includes a diazeniumdiolate functional group as an NO donor. The
diazeniumdiolate functional group may produce nitric oxide under
certain conditions, such as upon exposure to water. As another
example, in some embodiments, the NO-releasing compound includes a
nitrosothiol functional group as the NO donor. The NO donor may
produce nitric oxide under certain conditions, such as upon
exposure to light. Examples of other NO donor groups include
nitrosamine, hydroxyl nitrosamine, hydroxyl amine and hydroxyurea.
Any suitable combination of NO donors and/or NO-releasing compounds
may also be used in the methods described herein. Additionally, the
NO donor may be incorporated into or onto the small molecule or
macromolecule through covalent and/or non-covalent
interactions.
[0091] In some embodiments of the invention, the NO-releasing
compounds may be in the form of NO-releasing particles, such as
those described in U.S. Publication No. 2009/0214618, the
disclosure of which is incorporated by reference herein in its
entirety. Such particles may be prepared by methods described
therein.
[0092] The NO-releasing compound may release nitric oxide by any
suitable mechanism, including via reaction with water and/or
thermal degradation. Examples of NO-releasing functional groups
that may be included in the NO-releasing compound include, but are
not limited to, diazeniumdiolate, nitrosamine, hydroxyl
nitrosamine, nitrosothiol, hydroxyl amine, hydroxyurea, and metal
nitrosyl complexes. Other NO-releasing functional groups that are
capable of releasing nitric oxide in a therapeutic manner, such as
acidified nitrite, may also be utilized.
[0093] The NO-releasing compound may be a small molecule compound,
an oligomer and/or a polymer and may be in any suitable physical
form, such as, but not limited to, a particle, coating, film,
liquid, solution and the like. In some embodiments, the nitric
oxide-releasing compound comprises diazeniumdiolate-functionalized
polysiloxane macromolecules as described above. Other non-limiting
examples of NO-releasing compounds include NO-releasing zeolites as
described in United States Patent Publication Nos. 2006/0269620 or
2010/0331968; NO-releasing metal organic frameworks (MOFs) as
described in United States Patent Application Publication Nos.
2010/0239512 or 2011/0052650; NO-releasing multi-donor compounds as
described in U.S. Provisional Patent Application Ser. No.
61/526,918 entitled "Tunable Nitric Oxide-Releasing Macromolecules
Having Multiple Nitric Oxide Donor Structures"; NO-releasing
dendrimers or metal structures as described in U.S. Publication No.
2009/0214618; nitric oxide releasing coatings as described in U.S.
Publication No. 2011/0086234; and compounds as described in U.S.
Publication No. 2010/0098733. The disclosures of each of the
references in this paragraph are incorporated herein by reference
in their entirety. Additionally, NO-releasing macromolecules may be
fabricated as described in International Application No.
PCT/US2012/022048 entitled "Temperature Controlled Sol-Gel
Co-Condensation" filed Jan. 20, 2012, the disclosure of which is
incorporated herein by reference in its entirety.
[0094] As an example, in some embodiments of the invention, the
NO-releasing particles include NO-loaded precipitated silica. The
NO-loaded precipitated silica may be formed from nitric oxide donor
modified silane monomers into a co-condensed siloxane network. In
one embodiment of the invention, the nitric oxide donor is an
N-diazeniumdiolate.
[0095] In some embodiments, the nitric oxide donor may be formed
from an aminoalkoxysilane by a pre-charging method, and the
co-condensed siloxane network may be synthesized from the
condensation of a silane mixture that includes an alkoxysilane and
the aminoalkoxysilane to form a nitric oxide donor modified
co-condensed siloxane network. As used herein, the "pre-charging
method" means that aminoalkoxysilane is "pretreated" or
"precharged" with nitric oxide prior to the co-condensation with
alkoxysilane. In some embodiments, the precharging nitric oxide may
be accomplished by chemical methods. In another embodiment, the
"pre-charging" method may be used to create co-condensed siloxane
networks and materials more densely functionalized with
NO-donors.
[0096] The co-condensed siloxane network may be silica particles
with a uniform size, a collection of silica particles with a
variety of size, amorphous silica, a fumed silica, a
nanocrystalline silica, ceramic silica, colloidal silica, a silica
coating, a silica film, organically modified silica, mesoporous
silica, silica gel, bioactive glass, or any suitable form or state
of silica.
[0097] In some embodiments, the alkoxysilane is a tetraalkoxysilane
having the formula Si(OR)4, wherein R is an alkyl group. The R
groups may be the same or different. In some embodiments the
tetraalkoxysilane is selected as tetramethyl orthosilicate (TMOS)
or tetraethyl orthosilicate (TEOS). In some embodiments, the
aminoalkoxysilane has the formula: R''--(NH--R')n-Si(OR)3, wherein
R is alkyl, R' is alkylene, branched alkylene, or aralkylene, n is
1 or 2, and R'' is selected from the group consisting of alkyl,
cycloalkyl, aryl, and alkylamine.
[0098] In some embodiments, the aminoalkoxysilane may be selected
from N-(6-aminohexyl)aminopropyltrimethoxysilane (AHAP3);
N-(2-aminoethyl)-3-aminopropyltrimethoxysilane (AEAP3);
(3-trimethoxysilylpropyl)di-ethylenetriamine (DET3);
(aminoethylaminomethyl)phenethyltrimethoxysilane (AEMP3);
[3-(methylamino)propyl]trimethoxysilane (MAP3);
N-butylamino-propyltrimethoxysilane(n-BAP3);
t-butylamino-propyltrimethoxysilane(t-BAP3);
N-ethylaminoisobutyltrimethoxysilane(EAiB3);
N-phenylamino-propyltrimethoxysilane (PAP3); and
N-cyclohexylaminopropyltrimethoxysilane (cHAP3).
[0099] In some embodiments, the aminoalkoxysilane has the formula:
NH [R'--Si(OR)3]2, wherein R is alkyl and R' is alkylene. In some
embodiments, the aminoalkoxysilane may be selected from
bis(3-triethoxysilylpropyl)amine,
bis-[3-(trimethoxysilyl)propyl]amine and
bis-[(3-trimethoxysilyl)propyl]ethylenediamine.
[0100] In some embodiments, as described herein above, the
aminoalkoxysilane is precharged for NO-release and the amino group
is substituted by a diazeniumdiolate. Therefore, in some
embodiments, the aminoalkoxysilane has the formula:
R''--N(NONO--X+)--R'--Si(OR)3, wherein R is alkyl, R' is alkylene
or aralkylene, R'' is alkyl or alkylamine, and X+ is a cation
selected from the group consisting of Na+, K+ and Li+.
[0101] The composition of the siloxane network, (e.g., amount or
the chemical composition of the aminoalkoxysilane) and the nitric
oxide charging conditions (e.g., the solvent and base) may be
varied to optimize the amount and duration of nitric oxide release.
Thus, in some embodiments, the composition of the silica particles
may be modified to regulate the half-life of NO release from silica
particles.
[0102] In another embodiment, the amino group of aminoalkoxysilane
is substituted with a diazeniumdiolate, and the aminoalkoxysilane
having a formula of R''--N(NONO--X+)--R'--Si(OR)3, wherein: R is
alkyl, R' is alkylene or aralkylene, R'' is alkyl or alkylamine,
and X+ is a cation selected from the group consisting of Na+ and
K+.
[0103] In some embodiments of the invention, the particle size of
the NO-releasing particles is in a range from 20 nm to 10 .mu.m.
The particle size may be tailored to minimize or prevent toxicity
and penetration through the epidermis (or compromised dermis) and
into the blood vessels. In particular embodiments, the particle
size is distributed around a mean particle size of less than 10
.mu.m, or any range therein, to allow the particle to enter a
follicle. In further embodiments, the particle size is distributed
around a mean particle size of less than 8 .mu.m, or any range
therein. In other embodiments, the particle size is distributed
around a mean particle size of greater than 10 .mu.m, or any range
therein, to prevent the particle from entering the follicle.
[0104] In still further embodiments, a mixture of particles with
mean particle sizes distributed around two or more mean particle
sizes may be provided. For example, a mixture of particles having a
particle size distributed around a mean particle size of less than
10 .mu.m to allow the particle to enter a follicle may be mixed
with particles having a particle size distributed around a mean
particle size of greater than 10 .mu.m to prevent the particle from
entering the follicle. The particles may have the same nitric oxide
release profiles or different nitric oxide release profiles. For
example, the smaller particles may have a release profile tailored
to enhance their ability to moderate sebum production and/or
abnormal keratinization and the larger particles may have a release
profile tailored to enhance their ability to kill bacteria, promote
wound healing, reduce scarring or other desirable therapeutic
effect provided by nitric oxide. Other combinations and multiple
combinations could also be provided.
Synthetic Methods and Apparatus
[0105] The compositions described herein may be made by any
suitable method. However, in some embodiments, the compositions may
be manufactured by a method described herein and in U.S.
Provisional Patent Application Ser. Nos. 61/504,626 and 61/610,179,
both entitled "Methods of Manufacturing Topical Compositions and
Apparatus For Same," filed Jul. 5, 2011 and Mar. 13, 2012,
respectively, which are hereby incorporated by reference herein in
their entirety.
[0106] In some embodiments, such methods include homogenizing a
first excipient composition that includes a viscosity increasing
agent and at least one solvent to form a first premix composition;
separately homogenizing at least one active pharmaceutical
ingredient (API) and a second excipient composition to form a
second premix composition; and combining the first premix
composition and the second premix composition to form the anhydrous
topical composition. The pre-mixing of constituents may increase
the stability of the API and provide uniformity of the dispersion
of the constituents throughout the final topical composition. In
some embodiments, the first excipient composition includes at least
one viscosity agent, at least one solvent and at least one
humectant, while the second excipient composition includes at least
one water repellant and at least one humectant. In some cases, the
humectant may be divided between the first excipient composition
and the second excipient composition so that the humectant may aid
in swelling of the viscosity increasing agent.
[0107] Any suitable homogenization mechanism may be used. Examples
of homogenization devices include mechanical overhead agitation
such as propeller, anchor, pitch blade, rotor-stator, rotating
blades, ultrasonic devices, in-line and high pressure homogenizers.
Any of these methods may be used, and multiple methods may be used
in combination in some embodiments. Homogenization of the premix
compositions may provide a final topical composition that has
desirable API stability and blend homogeneity. In some embodiments
of the present invention, an in-line homogenizer may be used.
Homogenization may be carried out continuously throughout out the
mixing of a composition and/or portion of a composition (e.g., a
first and/or second excipient composition). In some embodiments,
homogenization may be carried out intermittently throughout out the
mixing of a composition and/or portion of a composition (e.g., a
first and/or second excipient composition). In certain embodiments,
homogenization may be carried out intermittently in durations of
15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 minutes, or
any range therein, every 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4,
3, 2, 1 minutes, or any range therein.
[0108] In particular embodiments of the present invention, a
homogenization method and/or device may be used that maintains the
active pharmaceutical ingredient (e.g., a water reactive active
pharmaceutical ingredient) below a temperature at which the active
pharmaceutical ingredient could degrade. An active pharmaceutical
ingredient may degrade at a particular temperature if maintained at
that temperature for a specific duration of time. Accordingly, in
some embodiments of the present invention, the duration of time an
active pharmaceutical ingredient is maintained at a particular
temperature, is below the time period at which the active
ingredient could degrade at that temperature. In certain
embodiments of the present invention, for the entire homogenization
process, the active pharmaceutical ingredient is kept at a
temperature that does not exceed the temperature at which the
active pharmaceutical ingredient could degrade.
[0109] In some embodiments, homogenization is performed at a
temperature in a range from -15.degree. C. to 30.degree. C., or any
range therein, such as, but not limited to, -5.degree. C. to
25.degree. C., 0.degree. C. to 10.degree. C., 10.degree. C. to
20.degree. C., or 15.degree. C. to 25.degree. C. In some
embodiments, the homogenization is performed at room temperature.
In other embodiments, the homogenization is performed below room
temperature.
[0110] In some embodiments, homogenization is performed in a dry,
inert atmosphere, such that water and oxygen are substantially
absent from the homogenization vessel.
[0111] In some embodiments, homogenizing the first excipient
composition that includes the at least one viscosity increasing
agent and the at least one solvent includes adding the viscosity
increasing agent to the solvent at a relatively rapid rate, such as
at a rate in a range of 0.5 to 50 g of viscosity increasing agent
per min per liter solvent. In one embodiment, the rate is 15 g of
viscosity increasing agent per min per liter solvent. In some
embodiments where a humectant is added to the first excipient
composition, a portion of the humectant may be homogenized with the
at least one solvent, and then the at least one viscosity
increasing agent may be added to the mixture and the first
excipient composition may be homogenized. In other embodiments, a
portion of the humectant, at least one solvent, and at least one
viscosity increasing agent are added and homogenized together at
the same time. One or more portions of the humectant, such as 1, 2,
3, or more, may be added to the first excipient composition at
different times. Accordingly, when a humectant is added to the
first excipient composition, the humectant may be portioned into 2,
3, 4, or more equal and/or unequal portions, and one or more
portions of the humectant may be added to the first excipient
composition. For example, a humectant may be divided into three
equal and/or unequal portions, and two of the three portions may be
added to the first excipient composition at different times with
the remaining portion added to the second excipient
composition.
[0112] The rapid addition of a viscosity increasing agent such as
hydroxypropyl cellulose to the solvent is contrary to the typical
practice in the industry that would suggest slow addition of a
viscosity increasing agent such as hydroxypropyl cellulose to the
solvent to avoid clumping. In contrast, the present inventors have
found that by using the homogenization apparatus described herein
as a premixing vessel, the viscosity increasing agent may be
rapidly added. In fact, in some cases, rapid addition may result in
a more homogeneous mixture. In some embodiments, the homogenization
of the first excipient composition and the at least one solvent may
be performed at a rate of 2,500 to 10,000 RPM, for example, with an
IKA T-50 UltraTurax rotor stator device or equivalent mixing
conditions utilizing alternative homogenization devices.
[0113] In some embodiments, homogenizing the second excipient
composition is performed at a rate of 2500 to 10,000 rpm. In a
particular embodiment the rate is 7,500 RPM utilizing the rotor
stator configuration described above. Homogenization may be
achieved by using an apparatus described herein. In some
embodiments of the invention, the homogenization apparatus includes
a vessel and a rotor-stator therein. In some embodiments, the ratio
of the height of the reactive portion of the vessel to the width of
the vessel is in a range of 1:2 to 1:1. In some embodiments, the
widest portion of the rotor-stator has a diameter that is 5 to 50%
of the width of the vessel. The vessel may be temperature
controlled and may include an inlet and outlet for an inert gas.
The vessel may be made of any suitable material, including, for
example, glass, stainless steel, polytetrafluoroethylene, and other
non-reactive materials. Particular embodiments of the
homogenization apparatus will be described in detail below.
[0114] Once the two premix compositions are prepared, they may be
combined and mixed. In some embodiments, the premix compositions
are mixed at a rate in a range of 10 to 50 RPM. In addition to
mixing the two premix compositions, the combined composition may be
homogenized, for example, under high shear using IKA Labor Pilot
2000/4 in-line homogenizer operating at a rate in a range of 2,000
to 24,000 RPM, allowing material to be recirculated at a rate of up
to 4 gallons per minute, or equivalent conditions with alternative
homogenization devices. Such a homogenization process may smooth,
deagglomerate, reduce particle size, increase blend uniformity of
excipient and active pharmaceutical ingredients, improve viscosity
uniformity, reduce segregation of suspended particulates, and/or
improve API stability.
[0115] Process parameters for an exemplary homogenization process
are provided in Table 1.
TABLE-US-00001 TABLE 1 Exemplary process parameters Process
Parameter Setting/Range Pre-mixing vessel temperature 18.degree. C.
to 22.degree. C. Main vessel temperature 18.degree. C. to
22.degree. C. Inert gas flow rate about 0.2 liters per minute Rate
of addition for hydroxypropyl 1 minute or less cellulose
Mixer/agitator speed setting for the 75 Hz to 90 Hz main vessel
Mixing time for the first excipient 30 minutes or more composition
In-line homogenization time for the first homogenize in about 5
minute excipient composition durations every 5 to 10 minutes
throughout the mixing time for the first excipient composition
Rotor-stator homogenization time for 2 minutes or more the second
excipient composition Mixing time for the composition 30 minutes or
more In-line homogenization time for the homogenize in about 2
minute composition durations every 5 to 10 minutes throughout the
mixing time for the composition
Exemplary Methods and Apparatus for Manufacturing Topical
Compositions
[0116] FIG. 1 is a detailed drawing of a system 100 for the
manufacture of formulations according to some embodiments of the
present invention. As seen in FIG. 1, the system 100 includes a
pre-mixing vessel 105 that is provided by a rotor-stator
homogenizer 110 in a single jacketed vessel 120 that is connected
to a circulator 130 for temperature control. The jacketed vessel
120 may be operated under an blanket of inert gas, such as argon,
with a rotameter 230 used to control the rate of inert gas addition
by controlling the flow from one of the two outputs of a three-way
valve. A vent line 150 is also present to exhaust excess inert gas.
Raw materials are introduced from holding vessels 50 to the
pre-mixing vessel 105.
[0117] The pre-mixing vessel 105 is used for two primary purposes
in the system 100: (1) to provide a forced wetting mechanism for
excipients such as, but not limited to, viscosity increasing agents
such as hydroxypropyl cellulose (HPC) in a suspension consisting of
solvents and excipients to produce a gel, ointment or cream; and
(2) to disperse an active pharmaceutical ingredient, such as those
described herein, in a suspension of the active pharmaceutical
ingredient and solvents or excipients. The pre-mixing vessel 105
has an oversize valve 125 to prevent blockages during transfer of
suspensions to a mixing vessel (kettle) 160. For example, the
mixing vessel 160 may be a 15 Liter top driven mixing vessel
available from Lee Industries. The transfer of suspensions between
the pre-mixing vessel 105 and the mixing vessel 160 is carried out
by using a peristaltic pump 155 at a controlled rate. The
peristaltic pump may, for example, be a Masterflex LS available
from Cole-Parmer, or similar. The transfer rate of excipients into
the system 100 for pre-mixing may also be important to compounding
in the mixing vessel 160.
[0118] The mixing vessel 160 includes kettle 161, a motor 170 to
drive an overhead anchor agitator with paddles 180 and has an
in-line homogenizer 190 that is connected to the bottom ball valve
165 of the mixing vessel 160. The in-line homogenizer 190 may, for
example, be a Labor Pilot 2000/4available from IKA-Werk, or
similar. The mixing vessel 160 includes a jacket 200 that is
connected to a circulator 210 to maintain temperature control. The
mixing vessel 160 also has a RTD sensor 166 to monitor temperature
in the kettle 161 and is recorded automatically using a recorder
220, such as a Honeywell chart recorder. The contents of the kettle
161 may also be under an inert gas blanket with a rotometer 230
used to control the rate of inert gas addition. A vent line 167 is
also present on the mixing vessel 160 to exhaust excess inert gas.
The in-line homogenizer 190 is used for process intensification
from an enhanced mixing perspective, particularly during
semi-solids compounding. Semi-solids products may also be
discharged via the use of the in-line homogenizer 190 through the
use of a three-way valve 240.
[0119] Additionally, as illustrated in FIG. 1, optional in-line
processing/analysis equipment 245 may be provided. For example, the
in-line processing/analysis equipment 245 may include a viscometer
to measure viscosity, a Ramen spectrometer, a pH meter, lighting
devices to pre-age or otherwise process a composition, a
colorimeter to measure the color and/or uniformity of the gel or
other such in-line analysis equipment.
[0120] The system 100 may allow for excipients to be dispersed
uniformly without agglomeration and lumping. A homogeneous
solution, suspension, gel, ointment, emulsion, and cream, or other
pharmaceutical composition, may be manufactured using this device.
Furthermore, the system 100 using the homogenizer allows for active
pharmaceutical ingredients to be dispersed in a suspension to
improve blend uniformity and thus prevent agglomeration formation
and potential segregation. The in-line homogenizer 190 may be used
to further aid the formation of a semi-solid formulation that is
homogenous and uniform in terms of excipient and active
pharmaceutical ingredient distribution. In some embodiments, it may
be desirable to use an inert gas environment in both the pre-mixing
vessel 105 and mixing vessel 160 is to prevent moisture from
entering. As such, such an apparatus may be useful for making
moisture-sensitive, or otherwise anhydrous, formulations.
[0121] Operation of the system 100 will now be described with
reference to an exemplary manufacturing process for producing a
topical composition. FIG. 2 is a flowchart illustration of
steps/operations that may be carried out according to some
embodiments of the present invention. As seen in FIG. 2, the first
excipient composition is premixed in the pre-mixing vessel 100
(block 1000) and transferred to the mixing vessel 160 (block 1010),
for example, by the peristaltic pump 155. The forced wetting of the
viscosity increasing agent with the homogenizer 110 of the
pre-mixing vessel 105 may allow for the rapid combination of
materials which, otherwise, would take substantially longer to mix.
The contents of the mixing vessel 160 are mixed and periodically
homogenized (block 1020), for example, by recirculating the
contents of the mixing vessel 160 through the in-line homogenizer
190.
[0122] In block 1030, the API and the second excipient composition
are premixed and homogenized in the homogenizer 110. Premixing
these constituents may improve the uniformity of them in the final
gel as well as closely associating the API with excipients such as
the humectant and the water repelling agent which, in the case of a
water reactive API, may improve the stability of the API in the
final topical composition. The pre-mixed contents of the
homogenizer 110 are then transferred to the mixing vessel 160 via
the peristaltic pump 155 (block 1040) and the contents mixed in the
mixing vessel 160 (block 1050). The premix homogenizer 110 is then
rinsed with the solvent and the contents transferred to the mixing
vessel 160 (block 1060). The contents of the mixing vessel are then
mixed until the desired uniformity is obtained (block 1070).
[0123] FIG. 3 is a more detailed flowchart of operations for a
particular system 100 according to some embodiments of the present
inventive concept. As seen in FIG. 3, operations begin by
dispensing raw materials for use in the process (block 2100). In
particular embodiments for the exemplary system of FIG. 1, the raw
materials may be dispensed as multiple portions of the same raw
material. Such portions may be based on the batch size and the
dimensions of the particular equipment utilized. Thus, what is
described herein with reference to multiple sub-processes could be
combined into fewer sub-process or more sub-processes depending on
the particular equipment utilized and batch size. In some
embodiments, for the initial mixing operations, the dispensed raw
materials are ethyl alcohol and/or isopropyl alcohol as the solvent
and Klucel.RTM. hydroxypropyl cellulose as the viscosity increasing
agent.
[0124] The temperature of the pre-mixing vessel 105 and the mixing
vessel 160 are set to 20.degree. C.+/-2.degree. C. via the jacket
120 and the recirculation system 130 and the jacket 200 and
recirculating system 210 (block 2110). The pre-mixing vessel 105
and mixing vessel 160 are blanketed with argon gas and the flow set
through the valve 140 to provide about 0.2 liters of argon per
minute (block 2120). The alcohol is added to the pre-mixing vessel
105 (block 2130) optionally with a portion of the humectant
hexylene glycol (block 2135) and then the homogenization rate of
the homogenizer 110 is set and begun (block 2140). In the present
example, the homogenizer rate is set to 7500 revolutions per minute
to provide a high shear homogenization. After beginning
homogenization of the alcohol, the hydroxypropyl cellulose is
rapidly added to the pre-mixing vessel 105 (block 2150). In
particular, the hydroxypropyl cellulose may be added in less than 2
minutes or any range therein, in some cases, in less than 1 minute
and, in some cases, in about 30 seconds. In some embodiments, at
least one humectant, such as hexylene glycol, is added with the
hydroxypropyl cellulose. For example, in some embodiments, a
portion of the total humectant in the gel is added in the first
excipient mixture while the remaining humectant is added with the
second excipient composition. Any suitable amount of humectant may
be added to the first excipient composition, but in some
embodiments, the amount of humectant included in the first
composition is that which is needed to swell the viscosity
increasing agent.
[0125] After the hydroxypropyl cellulose is added to the pre-mixing
vessel 105, the homogenization rate is reduced and the mixture is
pumped through the peristaltic pump 155 to the mixing vessel 160
(block 2160) at a rate of at least 250 mL/min to avoid gelation
during the transfer process. In particular, the mixture may be
pumped at a rate of 500 mL/min. The mixing vessel 160 is set to mix
the contents with a mixer speed of 10 to 50 RPM, and in particular
at about 40 rpm. In the present example, the homogenizer rate is
reduced to 4000 revolutions per minute. After transferring the
mixed ethyl alcohol and hydroxypropyl cellulose to the mixing
vessel 160, the homogenizer rate may be reset to the higher rate
and the process begun again if more batches of material are
required (block 2170). In the present example, the operations of
block 2100 through 2170 are repeated three times. The pre-mixing
vessel 105 is then rinsed with alcohol for 5 minutes and the
contents transferred to the mixing vessel 160 through the
peristaltic pump 155 at a flow rate of 500 mL/min (block 2175).
Excipients and solvents are dosed either manually or through
automated methods.
[0126] When the pre-mixing vessel 105 has been rinsed and
transferred to the mixing vessel 106, the mixing vessel 160 mix
rate is increased to about 45 RPM and the contents mixed for about
45 minutes (block 2180). Every 10 to 20 minutes or any range
therein (block 2200), the contents of the mixing vessel 160 are
recirculated through the valve 165, the in-line homogenizer 190,
the valve 240 and optionally, the in-line analysis equipment 245
(block 2190) for about 3 minutes but not so long as to cause an
undesirable temperature increase resulting from the high shear
homogenization.
[0127] In block 2210, the pre-mixing of the API begins by adding
the humectant hexylene glycol (in which in some embodiments, the
remaining portion of the humectant is added--for example, one half
of the total humectant concentration may optionally have been
included in the first excipient composition (block 2135)) and
ST-cyclomethicone-5 to the pre-mixing vessel 105. The
homogenization rate of the homogenizer 110 is set and begun (block
2220). In the present example, the homogenizer rate is set to 4000
revolutions per minute. The materials are homogenized for about 5
minutes and the API (in this example, Nitricil.TM., a nitric
oxide-releasing co-condensed silica) is added to the pre-mixing
vessel 105 (block 2230). The homogenizer rate is reduced to 2500
revolutions per minute and the contents of the pre-mixing vessel
105 homogenized for about 10 minutes. The mixture in the pre-mixing
vessel 105 is then pumped through the peristaltic pump 155 to the
mixing vessel 160 (block 2240), for example at a rate of 500
mL/min. The pre-mixing vessel 105 is then rinsed with ethyl alcohol
for about 5 minutes at a homogenization rate of 4000 revolutions
per minute (blocks 2260 and 2270). After 5 minutes, the rate of the
homogenizer 110 is reduced to 2500 revolutions per minute and the
contents transferred to the mixing vessel 160 through the
peristaltic pump 155, for example at a rate of 500 mL/min (block
2270). The combined contents of the mixing vessel 160 are mixed at
a mixing rate of about 45 RPM for about an additional 90 minutes
(block 2280). The mixed material may then be stored in any suitable
container that avoids contact with moisture or may be pumped to a
packaging system as described herein.
[0128] As will be appreciated by one of skill in the art in light
of the present disclosure, the step/operations illustrated in may
be carried out of sequence or concurrently or steps/operations may
be combined while still falling within the scope of the present
inventive concept. For example, if multiple rotor/stator
homogenizing vessels are utilized what is illustrated in the
Figures as a sequence of steps may be carried out simultaneously.
Furthermore, operations which are illustrated as batch operations
could be modified to provide continuous process operations.
Accordingly, the flowchart illustrations should not be construed as
limiting the scope of the present invention.
[0129] FIG. 4A is a cross section drawing of a pre-mixing vessel
105 suitable for use in the system 100. FIG. 4B is a drawing of the
lid and FIG. 4C is a drawing of the rotar-stator for the
homogenizer 110. As seen in FIG. 4A, the pre-mixing vessel 105
includes a homogenizer vessel 110 with a jacket 120 for passing
heating/cooling media around the homogenizer vessel 110. The
heating/cooling media enters and exits the jacket 120 through the
inlet/outlet ports 111, 112. The homogenizer vessel 110 has a drain
port 113 with a drain valve 114 that is a zero clearance valve so
as to not leave any dead space in the homogenizer vessel 110 where
ingredients could collect. Furthermore, the drain port 113 and
drain valve 114 are large enough to provide for the rapid removal
of material from the pre-mixing vessel 105 and so that it will not
clog with the gel. The pre-mixing vessel 105 may be made of any
suitable material but, in some embodiments, it is made of
glass.
[0130] FIG. 4B illustrates the lid 115 of the pre-mixing vessel
105. The lid 115 includes three openings 116, 117, 118 that may be
sealed and allow access to the homogenizer vessel 110. The largest
opening 116 is for the rotor/stator 119 of the homogenizer. The
middle opening 117 is for the inert gas. The smallest opening is
for a temperature probe 118. The rotor/stator 119 illustrated in
FIG. 4C allows for a seal where the shaft goes through the lid
115.
[0131] In a particular embodiment, the dimension PN is 170 mm, L1
is 200 mm, ID is 170 mm and L2 is 300 mm. The drain valve 114 is 20
mm. The opening 116 is 30 mm in diameter, the opening 117 is 20 mm
in diameter and the opening 118 is 8 mm in diameter. The
rotor/stator 119 is model number T50 from IKA-Werk. The use of the
rotor/stator 119 allows for the placement of the opening 116
centered or off center in the lid 115.
[0132] While embodiments of the present inventive subject matter
have been described with reference to particular configurations of
a processing system and specific processing conditions variations
to these systems and conditions may be made while still falling
within the scope of the present inventive subject matter. For
example, the processing system may include solid powder metering
systems for raw materials, such as the Klucel and the API.
Similarly, additional systems could be incorporated to prevent
oxidation of the materials. For example, processing could be
carried out under vacuum to remove oxygen and carbon dioxide,
solutions could be degassed via vacuum or bubbling, the materials
could be protected from light (e.g. if a nitrosothiol NO releasing
donor is utilized) or light could be used to either photo-age the
topical gel or eliminate photodecomposition of the topical gel or
its components.
Packaging and Delivery of Topical Compositions
[0133] Returning to FIG. 1, also illustrated is a packaging system
300. As seen in FIG. 1, the packaging system 300 includes a hopper
310 for receiving the product to be packaged and a tube filler 320,
such as an Arencomatic 1000 from Norden, for taking the product
from the hopper 310, dispensing the product into a tube and sealing
the tube. Argon gas is provided in the hopper 310 and to the tube
filler 320 with the rate of flow being controlled by the tube
filler 320 or a flow meter 330. A blanket of argon gas is provided
in the hopper 310 and the hopper 310 filled from the bottom so that
the product is not exposed to moisture in the air. The tube filler
320 fills preformed tubes with argon gas and then fills the tubes
from the bottom to displace the gas and, thereby, reduce the
likelihood that the product will be exposed to moisture.
[0134] In some embodiments, a nitric oxide-releasing topical
therapeutic may be provided in sealed single dose tubes (e.g., 2 g
tubes) that are oxygen impermeable to prevent moisture from
reaching the topical therapeutic and causing release of the nitric
oxide. The patient would then puncture the tube at the time of
application and apply the product to their skin. The product could
also be refrigerated until use to thereby further reduce the
likelihood of premature release of the nitric oxide.
[0135] In addition to being oxygen impermeable, the coatings and
adhesives of the tubes should not contaminate the topical gel in
the tubes. In particular, the adhesive at the crimped end of the
tube should not contain a cold seal. Adhesives such as Darex.TM.
and related synthetic rubber and latex compounds, which could have
an adverse reaction and subsequently could contaminate the topical
gel such as initiating release of nitric oxide, changing the color
of the gel or other undesirable result. In some embodiments,
packaged nitric oxide-releasing topical gels may be provided with a
shelf life of at least about one week.
[0136] In further embodiments, the packaged nitric oxide-releasing
topical gels have a shelf life of at least about four weeks, at
least about 12 weeks, at least about 26 weeks, or at least about 52
weeks. In still further embodiments, the packaged nitric
oxide-releasing topical gels have a shelf life of from at least 12
to at least 104 weeks, or any range therein. As used herein, the
term "shelf life" refers to the length of time a product (i.e., a
topical gel of the present invention) maintains the ability to
release a therapeutically effective amount of nitric oxide in an
unopened package stored under recommended storage conditions. The
shelf life may, for example, be evidenced by the "use by" or "best
if used by" date for the product, the manufacturer's expiration
date of the product and/or the actual product characteristics after
the specified period of time. Accordingly, the term "shelf life" as
used herein should be construed as including both an "actual" shelf
life of the product and a "predicted" shelf life of the product
unless stated otherwise. As one skilled in the art will recognize,
the rate of release of nitric oxide in a topical gel under packaged
and/or stored conditions may be different (i.e., faster or slower)
than the rate of release of nitric oxide when the topical gel is in
use. In certain embodiments, the rate of release of nitric oxide
may be faster when a topical gel is in use compared to the rate of
release of nitric oxide when the topical gel was packaged and/or
stored.
[0137] In some embodiments, the shelf life of the product is the
time that the product maintains the ability to release at least 50%
of the initial amount of nitric oxide that the product may release
when packaged. In further embodiments, the shelf life of the
product is the time that the product maintains the ability to
release at least 70%, at least 80%, at least 90%, at least 95%, or
at least 98% of the initial amount of nitric oxide that the product
may release when packaged. In some embodiments, the recommended
storage conditions are room temperature. In some embodiments, the
recommended storage conditions are refrigerated storage conditions.
In particular embodiments, the refrigerated storage conditions are
between 1.degree. C.-12.degree. C., or any range therein.
[0138] Further embodiments may provide packaged nitric
oxide-releasing topical gels that have a useful life of at least
about 7 days after opening the package. In further embodiments, the
useful life is at least about 30 days, at least about 60 days or at
least about 90 days. In still further embodiments, the packaged
nitric oxide-releasing topical gels have a useful life of from at
least about 60 days to at least about 730 days. As used herein, the
term "useful life" refers to the length of time that the product
maintains the ability to release a therapeutically effective amount
of nitric oxide from an opened packaged when applied as recommended
and when stored under recommended storage conditions. The useful
life may, for example, be evidenced by the manufacturer's
recommended time to dispose of the product after opening or
measurements of the products characteristics after opening.
[0139] Accordingly, the term "useful life" as used herein should be
construed as including both an "actual" useful life of the product
or a "predicted" useful life of the product unless stated
otherwise. In some embodiments, the useful life of the product is
the time that the product maintains the ability to release at least
50% of the initial amount nitric oxide that the product may release
when the package is opened. In further embodiments, the shelf life
of the product is the time that the product maintains the ability
to release at least 70%, at least 80%, at least 90%, at least 95%,
or at least 98% of the initial amount nitric oxide that the product
may release when the package is opened. In some embodiments, the
recommended storage conditions after opening are room temperature.
In particular embodiments, the recommended storage conditions after
opening are refrigerated conditions.
Methods of Using Anhydrous Topical Compositions
[0140] A composition described herein may be used to treat a
dermatological ailment. For example, a composition of the present
invention may be used to treat acne. In certain embodiments, the
composition comprises at least one API, such as a NO-releasing API.
In other embodiments, the composition comprises a vehicle and thus
does not comprise an API. A composition described herein may be
applied to the skin at a concentration sufficient to treat a
dermatological ailment such as acne. As such, in some embodiments,
a topical composition described herein may decrease, eliminate or
prevent acne, decrease abnormal keratinization, reduce microbial
colonization, reduce inflammation and/or decrease sebum production.
Decrease of acne may be detected by a visual reduction in the
amount or severity of the acne and/or by decrease in pain or
discomfort associated with the acne, as identified by the
subject.
[0141] In particular embodiments of the present invention, a
topical composition described herein is non-drying and/or
non-irritating to the skin of a subject. Dryness and/or irritation
of the skin may be detected visually and/or as identified by a
subject.
[0142] In some embodiments, an anhydrous topical composition
according to embodiments of the invention is applied topically to
the skin of the subject. Any portion of the subject's skin may be
treated. However, in some embodiments, the subject's face is
treated by a method described herein. Furthermore, in some
embodiments, the subject's trunk is treated by a method described
herein. The subject may have acne or a pharmaceutical composition
described herein may be used to prevent acne from forming.
[0143] Subjects suitable to be treated with a method of the
invention include, but are not limited to, avian and mammalian
subjects. Mammals of the present invention include, but are not
limited to, canines, felines, bovines, caprines, equines, ovines,
porcines, rodents (e.g. rats and mice), lagomorphs, primates,
humans, and the like, and mammals in utero. Any mammalian subject
in need of being treated according to the present invention is
suitable. Human subjects of both genders and at any stage of
development (i.e., neonate, infant, juvenile, adolescent, adult)
may be treated according to the present invention.
[0144] Illustrative avians according to the present invention
include chickens, ducks, turkeys, geese, quail, pheasant, ratites
(e.g., ostrich) and domesticated birds (e.g., parrots and
canaries), and birds in ovo.
[0145] The invention may also be carried out on animal subjects,
particularly mammalian subjects such as mice, rats, dogs, cats,
livestock and horses for veterinary purposes, and for drug
screening and drug development purposes.
[0146] In some embodiments, a method of treating acne, decreasing
abnormal keratinization, reducing microbial colonization, reducing
inflammation and/or decreasing sebum production may include using a
method described herein in combination with another therapeutic
regimen and/or in combination with another API, such as those that
have antimicrobial, anti-inflammatory, pain-relieving,
immunosuppressant, vasodilating properties, and/or anti-acne
properties. For example, other anti-acne agents such as retenoids,
may be used in conjunction (prior, concurrently or after) with the
application of the nitric oxide. As such, in some embodiments of
the invention, a patient may be treated with nitric oxide, at least
one NO releasing compound and/or a composition described herein in
combination with an additional therapeutic agent when the
additional therapeutic agent is not in the same composition. For
example, in some embodiments, an additional therapeutic agent may
be administered (e.g., topically, systemically, parenterally,
orally, buccally, subcutaneously, via inhalation, intratracheally,
surgically, transdermally, etc.), either concurrently and/or
sequentially with application of nitric oxide, at least one nitric
oxide source and/or a pharmaceutically acceptable composition that
includes at least one nitric oxide source.
[0147] In some embodiments of the invention, a pharmaceutically
acceptable composition described herein may be administered to the
skin via spray delivery. A non-aqueous delivery propellant may be
used for water sensitive NO-releasing compounds including
diazeniumdiolate-modified compounds. Further, in some embodiments,
particular components of the medicaments may be separated at some
point prior to application of the medicament. For example, a water
reactive NO-releasing compound may be stored separately from an
aqueous component or propellant until application (e.g., via
spraying or applying a gel). In some embodiments, the NO-releasing
compounds may be combined with an aqueous constituent prior to
application or the NO-releasing compounds and an aqueous
constituent may be applied to the skin sequentially.
[0148] While some embodiments of the present inventive concept may
be suitable for treating acne so as to moderate production of
sebum, moderate abnormal keratinization, reduce inflammation and/or
reduce microbial colonization, some embodiments may promote healing
of a wound associated with the dermatological condition, affect a
biofilm associated with the dermatological condition and/or reduce
scarring from a wound associated with the dermatological condition.
Additionally, embodiments of the present inventive concept may also
treat the dermatological condition without significant side
effects.
[0149] Accordingly, particular embodiments of the present inventive
concept provide a method of treating a dermatological condition by
topically administering a nitric oxide releasing topical
composition in an amount effective to actively promote healing of a
wound associated with the dermatological condition. Some
embodiments provide a method of treating a dermatological condition
by topically administering a nitric oxide releasing composition in
an amount effective to affect a biofilm associated with the
dermatological condition. Still further embodiments provide a
method of treating a dermatological condition by topically
administering a nitric oxide releasing composition in an amount
effective to reduce scarring from a wound associated with the
dermatological condition. Some embodiments provide a method of
treating a dermatological condition by topically administering a
nitric oxide releasing composition in an amount effective to treat
the dermatological condition without significant side effects.
[0150] Wound healing may be effected through prolonged low
concentrations of nitric oxide administration whereby nitric oxide
acts as a signaling molecule in a number of wound healing cascades.
An intermediate NO-releasing composition may mitigate the
inflammatory phase. High levels of NO-released may be necessary to
effect antimicrobial activity, using the rapid burst of nitric
oxide to kill microorganisms through oxidative/nitrosative
intermediates. In some embodiments, provided is a kit for the
topical treatment of dermatological ailments that includes at least
one composition that includes at least one viscosity increasing
agent, at least one organic solvent, at least one humectant and at
least one water repellant. In some embodiments, a kit includes a
first composition that releases low concentrations of nitric oxide;
and a second composition that releases a higher level of nitric
oxide. Additional APIs may be included in some or all of the
compositions to increase efficacy.
[0151] While embodiments of the present invention have been
described as providing a topical composition that includes an API,
in some embodiments, a topical composition according to the present
invention may be used to treat a condition and, in particular, a
dermatological condition as described herein, such as acne, without
the inclusion of an API. In such embodiments of the present
invention, the "vehicle" may be used to treat the dermatological
condition. Accordingly, therapeutic applications of a topical
composition of the present invention include application of a
topical composition with and/or without an API included in the
topical composition.
EXAMPLES
Example 1: Examples of Topical Gels
TABLE-US-00002 [0152] TABLE 1 Nitricil .TM. Gel, 0.2% Quality %
Component Supplier Standard Function w/w Ethyl alcohol, anhydrous,
Koptec USP Solvent 85.3 200 proof, USP or or BDH Isopropyl alcohol,
USP Hexylene glycol, 99% Fluka/ Reagent Co-solvent/ 10.0 Sigma
Humectant Cyclomethicone, NF Dow NF Water- 2.5 ST-Cyclomethicone-5
Corning repelling agent Hydroxypropyl cellulose, NF Ashland NF
Viscosity- 2.0 Klucel MF Pharm modifying agent Nitricil .TM. Novan
N/A API 0.2 Total 100.0
TABLE-US-00003 TABLE 2 Nitricil .TM. Gel, 0.5% Quality % Component
Supplier Standard Function w/w Ethyl alcohol, anhydrous, Koptec USP
Solvent 85.0 200 proof, USP or or BDH Isopropyl alcohol, USP
Hexylene glycol, 99% Fluka/ Reagent Co-solvent/ 10.0 Sigma
Humectant Cyclomethicone, NF Dow NF Water- 2.5 ST-Cyclomethicone-5
Corning repelling agent Hydroxypropyl cellulose, NF Ashland NF
Viscosity- 2.0 Klucel MF Pharm modifying agent Nitricil .TM. Novan
N/A API 0.5 Total 100.0
TABLE-US-00004 TABLE 3 Nitricil .TM. Gel, 1% Quality % Component
Supplier Standard Function w/w Ethyl alcohol, anhydrous, Koptec USP
Solvent 84.5 200 proof, USP or or BDH Isopropyl alcohol, USP
Hexylene glycol, 99% Fluka/ Reagent Co-solvent/ 10.0 Sigma
Humectant Cyclomethicone, NF Dow NF Water- 2.5 ST-Cyclomethicone-5
Corning repelling agent Hydroxypropyl cellulose, NF Ashland NF
Viscosity- 2.0 Klucel MF Pharm modifying agent Nitricil .TM. Novan
N/A API 1.0 Total 100.0
TABLE-US-00005 TABLE 4 Nitricil .TM. Gel, 2% Quality Component
Supplier Standard Function % w/w Ethyl alcohol, anhydrous, Koptec
USP Solvent 83.5 200 proof, USP or or BDH Isopropyl alcohol, USP
Hexylene glycol, 99% Fluka/ Reagent Co-solvent/ 10.0 Sigma
Humectant Cyclomethicone, NF Dow NF Water-repelling 2.5
ST-Cyclomethicone-5 Corning agent Hydroxypropyl Ashland NF
Viscosity- 2.0 cellulose, NF modifying Klucel MF Pharm agent
Nitricil .TM. Novan N/A API 2.0 Total 100.0
TABLE-US-00006 TABLE 5 Nitricil .TM. Gel, 3% Quality Component
Supplier Standard Function % w/w Ethyl alcohol, anhydrous, Koptec
USP Solvent 82.5 200 proof, USP or or BDH Isopropyl alcohol, USP
Hexylene glycol, 99% Fluka/ Reagent Co-solvent/ 10.0 Sigma
Humectant Nitricil .TM. Novan N/A API 3.0 Cyclomethicone, NF Dow NF
Water-repelling 2.5 ST-Cyclomethicone-5 Corning agent Hydroxypropyl
Ashland NF Viscosity- 2.0 cellulose, NF modifying Klucel MF Pharm
agent Total 100.0
TABLE-US-00007 TABLE 6 Nitricil .TM. Gel, 4% Quality Component
Supplier Standard Function % w/w Ethyl alcohol, anhydrous, Koptec
USP Solvent 81.5 200 proof, USP or or BDH Isopropyl alcohol, USP
Hexylene glycol, 99% Fluka/ Reagent Co-solvent/ 10.0 Sigma
Humectant Nitricil .TM. Novan N/A API 4.0 Cyclomethicone, NF Dow NF
Water-repelling 2.5 ST-Cyclomethicone-5 Corning agent Hydroxypropyl
Ashland NF Viscosity- 2.0 cellulose, NF modifying Klucel MF Pharm
agent Total 100.0
TABLE-US-00008 TABLE 7 Nitricil .TM. Gel, 5% Quality Component
Supplier Standard Function % w/w Ethyl alcohol, anhydrous, Koptec
USP Solvent 80.5 200 proof, USP or or BDH Isopropyl alcohol, USP
Hexylene glycol, 99% Fluka/ Reagent Co-solvent/ 10.0 Sigma
Humectant Nitricil .TM. Novan N/A API 5.0 Cyclomethicone, NF Dow NF
Water-repelling 2.5 ST-Cyclomethicone-5 Corning agent Hydroxypropyl
Ashland NF Viscosity- 2.0 cellulose, NF modifying Klucel MF Pharm
agent Total 100.0
TABLE-US-00009 TABLE 8 Nitricil .TM. Gel, 6% Quality Component
Supplier Standard Function % w/w Isopropyl alcohol, USP Koptec USP
Solvent 80.5 or BDH Hexylene glycol, 99% Fluka/ Reagent Co-solvent/
10.0 Sigma Humectant Nitricil .TM. Novan N/A API 6.0
Cyclomethicone, NF Dow NF Water-repelling 2.5 ST-Cyclomethicone-5
Corning agent Hydroxypropyl Ashland NF Viscosity- 1.0 cellulose, NF
modifying Klucel MF Pharm agent Total 100.0
TABLE-US-00010 TABLE 9 Nitricil .TM. Gel, 12% Quality Component
Supplier Standard Function % w/w Isopropyl alcohol, USP Koptec USP
Solvent 74.5 or BDH Hexylene glycol, 99% Fluka/ Reagent Co-solvent/
10.0 Sigma Humectant Nitricil .TM. Novan N/A API 12.0
Cyclomethicone, NF Dow NF Water-repelling 2.5 ST-Cyclomethicone-5
Corning agent Hydroxypropyl Ashland NF Viscosity- 1.0 cellulose, NF
modifying Klucel MF Pharm agent Total 100.0
TABLE-US-00011 TABLE 10 Nitricil .TM. Gel, 20% Quality Component
Supplier Standard Function % w/w Isopropyl alcohol, USP Koptec USP
Solvent 66.5 or BDH Hexylene glycol, 99% Fluka/ Reagent Co-solvent/
10.0 Sigma Humectant Nitricil .TM. Novan N/A API 20 Cyclomethicone,
NF Dow NF Water-repelling 2.5 ST-Cyclomethicone-5 Corning agent
Hydroxypropyl Ashland NF Viscosity- 1.0 cellulose, NF modifying
Klucel MF Pharm agent Total 100.0
TABLE-US-00012 TABLE 11 Nitricil .TM. Gel, 30% Quality Component
Supplier Standard Function % w/w Isopropyl alcohol, USP Koptec USP
Solvent 56.5 or BDH Hexylene glycol, 99% Fluka/ Reagent Co-solvent/
10.0 Sigma Humectant Nitricil .TM. Novan N/A API 30.0
Cyclomethicone, NF Dow NF Water-repelling 2.5 ST-Cyclomethicone-5
Corning agent Hydroxypropyl Ashland NF Viscosity- 1.0 cellulose, NF
modifying Klucel MF Pharm agent Total 100.0
TABLE-US-00013 TABLE 12 Placebo Gel Quality Component Supplier
Standard Function % w/w Ethyl alcohol, anhydrous, Koptec USP
Solvent 85.5 200 proof, USP or or BDH Isopropyl alcohol, USP
Hexylene glycol, 99% Fluka/ Reagent Co-solvent/ 10.0 Sigma
Humectant Cyclomethicone, NF Dow NF Water-repelling 2.5
ST-Cyclomethicone-5 Corning agent Hydroxypropyl Ashland NF
Viscosity- 2.0 cellulose, NF modifying Klucel MF Pharm agent Total
100.0
Example 2: NO-Releasing Topical Gels P. acne Time Kill
[0153] A 2% API loaded anhydrous gel of a specific embodiment
described herein, wherein the API is a nitric oxide releasing
macromolecule, was tested for efficacy in the reduction of P.
acnes, using ASTM E-2315. In this test, Propionibacterium acnes
ATCC 6919 (10.sup.6 CFU/ml) were incubated with 250 mg of gel
vehicle or 250 mg of active gel containing Nitricil.TM. (4 mg/ml)
in 37.degree. C. phosphate buffered saline (PBS). After 30 minutes,
2 hours, and 4 hours of incubation, aliquots from each tube were
removed, neutralized with letheen broth, serially diluted, and
plated to obtain viable colony counts.
TABLE-US-00014 TABLE 13 Control Blank Time, hrs Time, hrs Control 0
0.5 1 2 Control 0 0.5 1 2 1 2.10E+06 1.60E+06 2.00E+06 1.60E+06 1
.32 .20 .30 .20 2 2.20E+06 1.60E+06 1.80E+06 1.90E+06 2 .34 .20 .26
.28 Average 2.15E+06 1.60E+06 1.90E+06 1.75E+06 Average .33 .20 .28
.24 STDERR 3.54E+04 0.00E+00 7.07E+04 1.06E+05 STDERR .01 .00 .02
.03 % 0 26 12 19 Log .00 .13 .05 .09 Reduction Reduction vs ctrl vs
Ctrl
TABLE-US-00015 TABLE 14 Gel vehicle by itself Gel Time, hrs Gel
Time, hrs Vehicle 0 0.5 1 2 Vehicle 0 0.5 1 2 1 2.30E+06 1.80E+06
1.80E+06 2.90E+05 1 .36 .26 .26 .46 2 2.10E+06 2.00E+06 2.10E+06
3.30E+05 2 .32 .30 .32 .52 Average 2.20E+06 1.90E+06 1.95E+06
3.10E+05 Average .34 .28 .29 .49 STDERR 7.07E+04 7.07E+04 1.06E+05
1.41E+04 STDERR .01 .02 .02 .02 % -2 12 9 86 Log 0.01 .05 .04 .84
Reduction Reduction vs ctrl vs Ctrl
TABLE-US-00016 TABLE 15 Gel vehicle with Nitricil .TM. 2% 2%
Nitricil .TM. Nitricil .TM. Gel Time, hrs Gel Time, hrs 11-9-37 0
0.5 1 2 11-9-37 0 0.5 1 2 1 1.90E+06 2.10E+03 1.00E+01 1.00E+01 1
.28 .32 .00 .00 2 1.80E+06 2.10E+03 1.00E+01 1.00E+01 2 .26 .32 .00
.00 Average 1.85E+06 2.10E+03 1.00E+01 1.00E+01 Average .27 .32 .00
.00 STDERR 3.54E+04 0.00E+00 0.00E+00 0.00E+00 STDERR .01 .00 .00
.00 % 14 99.90 99.9995 99.9995 Log .07 .01 .33 .33 Reduction
Reduction vs ctrl vs Ctrl
TABLE-US-00017 TABLE 16 Summary of Data Time, hrs Time, hrs %
Reduction 0 0.5 1 2 Log Reduction 0 0.5 1 2 Control 6 12 19 Control
.00 .13 .05 .09 Gel Vehicle 2 2 9 86 Gel Vehicle 0.01 .05 .04 .84
2% Nitricil .TM. 4 9.90 >99.999 >99.999 2% Nitricil .TM. .07
.01 5.33 5.33 Gel Gel
[0154] The data in Tables 13-16 is also shown graphically in FIG.
5. As can be seen from Table 16 and FIG. 5, a NO-releasing
composition according to an embodiment of the invention can be
effective to kill P. acnes.
Example 3
[0155] The NO release profile for 2% Nitricil.TM. in anhydrous gel,
as tested in Example 1 and made by the process described herein, is
shown in FIG. 6. At a pH of 6.0 that may be encountered in the
stratum corneum, the maximum flux of nitric oxide exceeded 0.5 nmol
NO per mg gel per second and a half-life of about 160 seconds.
Example 4
[0156] Stability data for 2% Nitricil.TM. in anhydrous gel, as
tested in Example 1 and made by the process described herein, are
shown in FIG. 7
Example 5--Macromolecular Nitric Oxide Releasing Compound
[0157] A nitric oxide releasing macromolecular compound comprising
MAP3 was fabricated as described in United States Patent
Application Publication No. 2009/0214618 and in PCT Patent
Application Number PCT/US12/22048, filed Jan. 20, 2012, entitled
"Temperature Controlled Sol-Gel Co-Condensation," the disclosures
of which are incorporated herein by reference as if set forth in
their entirety. The resulting macromolecular particles were ball
milled to provide an average particle size of from 8 to 10 .mu.m to
provide an active pharmaceutical ingredient (API).
Example 6--Topical Gel with Active Pharmaceutical Ingredient
[0158] Topical gel incorporating the API of Example 5 ("Active")
was fabricated as described in U.S. Provisional Patent Application
Ser. No. 61/504,628 entitled "Topical Compositions and Methods of
Using Same to Treat Acne," and U.S. Provisional Patent Application
Ser. No. 61/504,626, entitled "Methods of Manufacturing Topical
Compositions and Apparatus for Same," both of which were filed Jul.
5, 2011 and are incorporated herein as if set forth in their
entirety. In particular, the Active had the formulation of:
TABLE-US-00018 TABLE 17 Active Gel Quality Component Standard
Function % w/w Ethyl alcohol, anhydrous, USP Solvent 83.5 200
proof, USP Hexylene glycol, 99% Reagent Co-solvent/ 10.0 Humectant
Cyclomethicone, NF NF Water-repelling 2.5 ST-Cyclomethicone-5 agent
Hydroxypropyl cellulose, NF NF Viscosity- 2.0 Klucel MF Pharm
modifying agent Nitricil .TM. N/A API 2.0
Example 7--Topical Gel with Masking Agent
[0159] Topical gel incorporating titanium dioxide as a masking
agent ("Vehicle") was fabricated as described in U.S. Provisional
Patent Application Ser. No. 61/504,628 entitled "Topical
Compositions and Methods of Using Same to Treat Acne," and U.S.
Provisional Patent Application Ser. No. 61/504,626, entitled
"Methods of Manufacturing Topical Compositions and Apparatus for
Same," both of which were filed Jul. 5, 2011 and are incorporated
herein as if set forth in their entirety. In particular, the
Vehicle had the formulation of:
TABLE-US-00019 TABLE 18 Vehicle Gel Quality Component Standard
Function % w/w Ethyl alcohol, anhydrous, USP Solvent 85.45 200
proof, USP Hexylene glycol, 99% Reagent Co-solvent/ 10.0 Humectant
Cyclomethicone, NF NF Water-repelling 2.5 ST-Cyclomethicone-5 agent
Hydroxypropyl cellulose, NF NF Viscosity- 2.0 Klucel MF Pharm
modifying agent Titanium dioxide N/A 0.05
All clinical trial materials were packaged in single use 2 g tubes
on an Arencomatic 1000 automated packaging system from Norden. The
2 g tubes were stored at 5.degree. C. until dispensing to trial
subjects. The tubes packaged into 2 week kits.
Example 8--Clinical Study Protocol
[0160] A single-center, double-blind, randomized,
vehicle-controlled, parallel group study was conducted in 70
intent-to-treat (ITT) subjects with moderate to severe acne
vulgaris. The study included male and female subjects between the
ages of 12 and 40 (inclusive) with moderate to severe acne
vulgaris, defined as at least 20 but no more than 40 inflammatory
lesions (papules and pustules), 20 to 60 non-inflammatory lesions
(open and closed comedones), no more than 2 nodules, and an
Investigator Global severity Assessment of 3 or 4. Subjects who
satisfied the entry criteria at the Baseline visit were randomized
to either Active or Vehicle in a 1:1 ratio. Tolerability and safety
assessments included cutaneous tolerability evaluation, physical
exams, collection of vital signs, blood pressure monitoring, urine
pregnancy tests (UPTs), blood methemoglobin monitoring and adverse
event collection. Efficacy assessments included inflammatory and
noninflammatory lesion counts and an Investigator global severity
assessment (IGA). Subjects returned for post-baseline evaluation at
Weeks 2, 4, 6 and 8. Of the 70 ITT subjects enrolled in the study,
60 subjects completed the study per the study protocol. The
subjects were provided kits with a two week supply of the 2 g tubes
at each visit and instructed to maintain the tubes under
refrigerated conditions until use.
Example 9--Tolerability and Safety Results
[0161] Cutaneous tolerability results of the study are shown in
Table 19 for the Active and Table 20 for the Vehicle.
TABLE-US-00020 TABLE 19 Summary of Cutaneous Tolerability at
Baseline and Week 8 - Active Baseline Pre- Application Maximum
Severity Week 8 Mild Mod Severe Mild Mod Severe Mild Mod Severe
Erythema 1 0 0 4 2 0 1 0 0 (2.9) % (12.1) % (5.7%) (3.0) % Scaling
0 0 0 2 2 0 0 1 0 (5.7%) (5.7%) (3.0) % Dryness 0 0 0 0 0 0 0 0 0
Itching 3 2 0 4 2 0 2 2 0 (8.6%) (5.7%) (11.8%) (6.1%) (6.1%)
(6.1%) Burning/ 0 0 0 1 1 0 1 0 0 Stinging (3.0)% (3.0%) (3.0)
%
TABLE-US-00021 TABLE 20 Summary of Cutaneous Tolerability at
Baseline and Week 8 - Vehicle Baseline End of Treatment
Pre-Application Maximum Severity (Wk 8) Mild Mod Severe Mild Mod
Severe Mild Mod Severe Erythema 1 0 0 2 0 0 0 0 0 (2.9) % (5.7%)
Scaling 0 0 0 1 0 0 0 0 0 (2.9%) Dryness 0 0 0 0 0 0 0 0 0 Itching
6 1 0 1 0 0 0 0 0 (17.1%) (2.9%) (2.9%) Burning/ 0 0 0 1 0 0 1 0 0
Stinging (2.9%) (3.6%)
[0162] Methemoglobin results were obtained by pulse co-oximeter
from Masimo. The results at baseline, 2 weeks and 8 weeks are shown
in Table 21.
TABLE-US-00022 TABLE 21 Methemoglobin Levels as Measured by Pulse
Co-Oximetry Baseline 2 Weeks 8 Weeks Active N 35 35 34 Mean 0.9 1.1
0.9 STD 0.3 0.3 0.3 Vehicle N 35 34 31 Mean 0.7 1.0 0.8 STD 0.3 0.3
0.4
As seen in Table 21, the methemoglobin levels for Active and
Vehicle subjects were will within acceptable ranges and did not
differ significantly.
Example 10--Shelf Life
[0163] Tubes of the clinical supplies were maintained under
controlled conditions at 5.degree. C. and periodically evaluated
for nitric oxide content. Tubes were also maintained at a
controlled storage facility at 5.degree. C. by the packager/labeler
that prepared the kits and evaluated for nitric oxide content.
Unused materials distributed to and retrieved from the clinical
study site in the Dominican Republic were also evaluated for nitric
oxide content. The results of the evaluation for remaining nitric
oxide are shown in Table 22.
TABLE-US-00023 TABLE 22 Shelf Life Stability of 2% Topical Gel in 2
gram Tubes Active Gel % Recovery vs Initial NO Relative Std
5.degree. C. Loading Dev 6 month Stability @ Storage 96.6% N/A
Facility (n = 2) Retained Clinical Materials 100% 0.5% (n = 3)
Material Retuned from 93.1% 4.6% Clinical Trial (n = 4)
Example 11--NO Recovery Over Time
[0164] Tubes of a 2% anhydrous gel were stored at 5.degree. C.,
25.degree. C./60% relative humidity (R.H.), 30.degree. C./65% R.H.,
and 40.degree. C./75% R.H. At 2, 4, 8, 12 and 16 weeks, the gel in
the tubes was evaluated for nitric oxide content. FIG. 8 shows the
nitric oxide recovery for the 2% anhydrous gels in 2 gram tubes
over a time. The results of the stability study are provided in
Table 23.
TABLE-US-00024 TABLE 23 Stability of 2% anhydrous gel at various
temperatures over 26 weeks Temperature/ % NO % NO % NO % NO % NO
Relative Recovered at Recovered at Recovered at Recovered at
Recovered Humidity Week 2 Week 4 Week 8 Week 12 at Week 26
5.degree. C. 98.27586 100 86.2069 94.82759 96.55172 25.degree.
C./60% R.H. 81.03448 74.13793 58.62069 65.51724 53.44828 30.degree.
C./65% R.H. 74.13793 67.24138 53.44828 48.27586 25.86207 40.degree.
C./75% R.H. 50 37.93103 20.68966 13.7931 6.896552
Example 12--Activity of Vehicle for P. Acnes in Healthy
Patients
[0165] Topical Gel Vehicle with titanium dioxide was produced as
described in Example 7. Topical Gel Vehicle without titanium
dioxide was produced as described in Example 7 except the titanium
dioxide was replaced with additional ethyl alcohol. These
formulations were evaluated to determine if the Vehicle in the
clinical study had antimicrobial activity. A vehicle with
antimicrobial activity could mask the effectiveness of an active
ingredient in a clinical study.
[0166] Topical Gel Vehicle with titanium dioxide and Topical Gel
Vehicle without titanium dioxide were evaluated in vivo to
determine the effects on P. acnes and cutaneous tolerability.
Thirty-one healthy adult males and females 18 years of age and
older were enrolled in the study after meeting eligibility
requirements at screening, 7-10 days prior to baseline. Subjects
were carefully screened to ensure that none were using any
prohibited topical or systemic antibiotics within 4 weeks prior to
enrollment. The panelists were instructed not to use any
antimicrobial topical products (e.g., soaps, medicated shampoos,
acne preparations) during the study. The volunteers were selected
for the study based on a high degree of fluorescence of the facial
skin under a Wood's lamp indicating the presence of high levels of
P. acnes. Baseline P. acnes counts were at least 10,000 colonies
per cm.sup.2 on the facial skin.
[0167] Subjects were treated for four weeks with either Topical Gel
Vehicle with titanium dioxide or Topical Gel Vehicle without
titanium dioxide. Each volunteer was treated once daily on the
central forehead under supervision by a technician at the site
beginning on the Thursday following acceptance into the study.
Topical Gel Vehicle was also applied by the subjects (unsupervised)
at home once daily on Saturdays and Sundays. At each visit, a
sufficient amount of the test product (pea-sized amount) was
applied and rubbed in for about 30 seconds.
[0168] Quantitative bacteriologic cultures were obtained from the
test site at Baseline (0) and at Weeks 2 and 4. During the study,
cutaneous tolerability assessments were made at Baseline and Weeks
1, 2, 3 and 4. Each of the local signs and symptoms, erythema,
dryness, scaling, stinging/burning and itching were assessed on a
four point scale where 0=none, 1=mild, 2=moderate, and 3=severe.
Thirty-one patients were enrolled and 30 patients completed the
study. One patient was discontinued prematurely by the Investigator
for non-compliance.
[0169] Table 24 includes the P. acnes counts for the 4 week study.
As seen in Table 24, neither of the formulations tested achieved
significant reductions in P. acnes.
TABLE-US-00025 TABLE 24 Total P. acnes Total P. acnes
(Log/cm.sup.2) Topical Gel Topical Gel Vehicle without Vehicle with
titanium dioxide titanium dioxide Mean .+-. Std over Mean .+-. Std
over Baseline 6.75.+-. N/A 6.72.+-. N/A Week 2 6.66.+-. 0.0180
6.69.+-. 0.0000 Week 4 6.64.+-. 0.0037 6.67.+-. 0.0000 Net Change
from Baseline Week 2 -0.08 .+-. 0.12 N/A -0.05.+-. N/A Week 4 -0.11
.+-. 0.12 N/A -0.07.+-. N/A
[0170] With regard to the cutaneous tolerability assessment, there
was no erythema, scaling or itching observed/reported during the
study with either formulation. There was only one report of mild
(score=1) burning/stinging at Week 1 with the topical gel without
titanium dioxide and one report of mild (score=1) dryness with the
topical gel with titanium dioxide at Week 4.
[0171] Many modifications and other embodiments of the inventions
set forth herein will come to mind to one skilled in the art to
which these inventions pertain having the benefit of the teachings
presented in the foregoing descriptions and the associated
drawings. Therefore, it is to be understood that the inventions are
not to be limited to the specific embodiments disclosed and that
modifications and other embodiments are intended to be included
within the scope of the appended claims. Although specific terms
are employed herein, they are used in a generic and descriptive
sense only and not for purposes of limitation.
* * * * *