U.S. patent application number 14/918419 was filed with the patent office on 2016-02-11 for formulations and uses of retinoic acid receptor selective agonists.
The applicant listed for this patent is QuRetino Therapeutics, Inc.. Invention is credited to Ferenc Makra.
Application Number | 20160038451 14/918419 |
Document ID | / |
Family ID | 47040824 |
Filed Date | 2016-02-11 |
United States Patent
Application |
20160038451 |
Kind Code |
A1 |
Makra; Ferenc |
February 11, 2016 |
FORMULATIONS AND USES OF RETINOIC ACID RECEPTOR SELECTIVE
AGONISTS
Abstract
The invention provides retinoic acid receptor (RAR) selective
agonists and formulations thereof for the treatment of disease or
for inducing a medically beneficial effect.
Inventors: |
Makra; Ferenc; (Palo Alto,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
QuRetino Therapeutics, Inc. |
Palo Alto |
CA |
US |
|
|
Family ID: |
47040824 |
Appl. No.: |
14/918419 |
Filed: |
October 20, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14286674 |
May 23, 2014 |
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14918419 |
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13253014 |
Oct 4, 2011 |
8772273 |
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14286674 |
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Current U.S.
Class: |
514/352 ;
514/510; 514/557 |
Current CPC
Class: |
A61K 31/44 20130101;
A61P 3/00 20180101; A61P 27/02 20180101; A61P 19/02 20180101; A61K
31/19 20130101; A61P 3/06 20180101; A61P 17/00 20180101; A61K 9/06
20130101; A61K 31/455 20130101; A61P 15/00 20180101; A61P 31/00
20180101; A61K 31/343 20130101; A61P 19/00 20180101; A61K 31/216
20130101; A61P 3/10 20180101; A61P 3/08 20180101; A61P 15/10
20180101; A61P 25/00 20180101; A61P 23/00 20180101; A61P 27/12
20180101; A61K 31/192 20130101; A61P 17/06 20180101; A61P 19/10
20180101; A61P 9/00 20180101; A61K 31/215 20130101; A61P 19/04
20180101; A61P 5/48 20180101; A61K 9/0014 20130101; A61P 9/10
20180101; A61P 17/10 20180101; A61P 25/04 20180101; A61P 1/02
20180101 |
International
Class: |
A61K 31/215 20060101
A61K031/215; A61K 31/19 20060101 A61K031/19; A61K 31/44 20060101
A61K031/44 |
Claims
1.-30. (canceled)
31. A method of treating a disease or a condition associated with
the disease in a subject, the method comprising: administering to a
subject a formulation comprising a single active ingredient,
wherein the active ingredient consists of a RAR selective agonist,
wherein the RAR selective agonist is not more than 0.005% of the
formulation, and wherein the RAR selective agonist has the
structure: ##STR00055## wherein the dotted bond is either present
and forms a double bond, or is absent; R.sup.1, R.sup.2, R.sup.3
and R.sup.4 are independently hydrogen or alkyl; n is 1, 2 or 3; X
is --C(R.sup.8)(R.sup.9)-- for n=1, 2 or 3; or X is oxygen for n=1;
wherein R.sup.8 and R.sup.9 are independently hydrogen or alkyl;
R.sup.5 is hydrogen, alkyl, alkoxy, alkoxy-alkyl-, alkylthio,
alkyl-NR.sup.10--, alkenyl, alkenyloxy, alkynyl, benzyl,
cycloalkyl-alkyl or phenyl-alkyl; wherein R.sup.10 is hydrogen or
alkyl; m is 0 when the dotted bond is present; or m is 1 when the
dotted bond is absent; wherein Ar is phenyl or a heteroarylic ring;
R.sup.6 is hydrogen, halogen, alkoxy or hydroxy; R.sup.7 is
hydrogen or alkyl; and Y is --COO--, --OCO--, --CONR.sup.10--,
--NR.sup.10CO--, --CH.dbd.CH--, --C.ident.C--, --COCH.dbd.CH--,
--CHOHCH.dbd.CH--, --CH.sub.2O--, --CH.sub.2S--, --CH.sub.2SO--,
--CH.sub.2SO.sub.2--, --CH.sub.2NR.sup.10--, --OCH.sub.2--,
--SCH.sub.2--, --SOCH.sub.2--, --SO.sub.2CH.sub.2-- or
--NR.sup.10CH.sub.2--, with the proviso that when Y is --OCO--,
--NR.sup.10CO--, --OCH.sub.2--, --SCH.sub.2--, --SOCH.sub.2--,
--SO.sub.2CH.sub.2-- or --NR.sup.10CH.sub.2--, R.sup.5 is hydrogen,
alkyl, alkoxy-alkyl-, alkenyl, alkynyl, benzyl, cycloalkyl-alkyl or
phenyl-alkyl; or a pharmaceutically active salt of carboxylic acids
of formula I.
32. The method of claim 31, wherein the RAR selective agonist is
administered by applying a cream, by applying an ointment, by
applying a lotion, by applying a liquid, by foam, orally or
intravenously comprising the RAR selective agonist.
33. The method of claim 31, wherein the disease or disease
condition is selected from the group consisting of a metabolic
disease or condition associated with a metabolic disease and a
carcinoma.
34. The method of claim 33, wherein the condition associated with
the metabolic disease is selected from hyperglycemia,
hyperinsulinemia, hyperlipidemia, impaired glucose metabolism,
diabetic retinopathy, macular degeneration, cataracts, diabetic
nephropathy, glomeruloscerosis, diabetic neuropathy, erectile
dysfunction, premenstrual syndrome, vascular restenosis, ulcerative
colitis, angina pectoris, myocardial infarction, stroke, skin or
connective tissue disorders, scar tissue repair, wrinkle treatment,
psoriasis, UV-damage skin, rosacea, metabolic acidosis, arthritis,
osteoporosis, conditions of impaired glucose tolerance, diabetic
ulcer, diabetes and cardiovascular disease.
35. The method of claim 33, wherein the carcinoma is selected from
the group consisting of basal cell carcinoma, squamous cell
carcinoma and leukemia.
36. The method of claim 31, wherein R.sup.8 and R.sup.9 are H.
37. The method of claim 31, wherein R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are alkyl.
38. The method of claim 31, wherein R.sub.1, R.sub.2, R.sub.3, and
R.sub.4 are each methyl, X.sub.n is --CH.sub.2--CH.sub.2--, R.sub.5
is --CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.3, Y is
--COO--, and R.sub.6 and R.sub.7 are each is H.
39. The method of claim 31, wherein R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are independently hydrogen or alkyl; n is 1 or 2; X is
--C(R.sup.8)(R.sup.9)-- for n=1 or 2; or X is oxygen for n=1;
wherein R.sup.8 and R.sup.9 are independently hydrogen or alkyl;
and R.sup.5 is hydrogen, alkyl, alkoxy, alkoxy-alkyl-, alkylthio,
alkyl-NR.sup.10--, alkenyl, alkenyloxy, alkynyl; wherein R.sup.10
is hydrogen or alkyl.
40. The method of claim 31, wherein R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are independently hydrogen or alkyl; n is 1 or 2; X is
--C(R.sup.8)(R.sup.9)-- for n=1 or 2; or X is oxygen for n=1;
wherein R.sup.8 and R.sup.9 are independently hydrogen or alkyl;
and R.sup.5 is hydrogen, alkyl, alkylthio, alkyl-NR.sup.10--,
alkenyl, alkynyl; wherein R.sup.10 is hydrogen or alkyl.
41. The method of claim 31, wherein R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are independently hydrogen or alkyl; n is 2; X is
--C(R.sup.8)(R.sup.9)-- for n=2; wherein R.sup.8 and R.sup.9 are
independently hydrogen or alkyl; and R.sup.5 is hydrogen, alkyl,
alkoxy, alkoxy-alkyl-, alkylthio, alkyl-NR.sup.10--, alkenyl,
alkenyloxy, alkynyl; wherein R.sup.10 is hydrogen or alkyl.
42. The method of claim 31, wherein R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are independently hydrogen or alkyl; n is 2; X is
--C(R.sup.8)(R.sup.9)-- for n=2; wherein R.sup.8 and R.sup.9 are
independently hydrogen or alkyl; and R.sup.5 is hydrogen, alkyl,
alkylthio, alkyl-NR.sup.10--, alkenyl, alkynyl; wherein R.sup.10 is
hydrogen or alkyl.
43. The method of claim 31, wherein R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are independently hydrogen or alkyl; n is 2; X is
--C(R.sup.8)(R.sup.9)-- for n=2; wherein R.sup.8 and R.sup.9 are
independently hydrogen or alkyl; R.sup.5 is hydrogen, alkyl,
alkoxy, alkoxy-alkyl-, alkylthio, alkyl-NR.sup.10--, alkenyl,
alkenyloxy, alkynyl; wherein R.sup.10 is hydrogen or alkyl; and Y
is --COO--, --OCO--, --CONR.sup.10--, --NR.sup.10CO--,
--CH.dbd.CH--, --C.ident.C--, --CH.sub.2O--, --CH.sub.2S--,
--CH.sub.2SO--, --CH.sub.2SO.sub.2--, --CH.sub.2NR.sup.10--,
--OCH.sub.2--, --SCH.sub.2--, --SOCH.sub.2--, --SO.sub.2CH.sub.2--
or --NR.sup.10CH.sub.2--, with the proviso that when Y is --OCO--,
--NR.sup.10CO--, --OCH.sub.2--, --SCH.sub.2--, --SOCH.sub.2--,
--SO.sub.2CH.sub.2-- or --NR.sup.10CH.sub.2--, R.sup.5 is hydrogen,
alkyl, alkoxy-alkyl-, alkenyl, alkynyl.
44. The method of claim 31, wherein R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are independently hydrogen or alkyl; n is 2; X is
--C(R.sup.8)(R.sup.9)-- for n=2; wherein R.sup.8 and R.sup.9 are
independently hydrogen or alkyl; and R.sup.5 is hydrogen, alkyl,
alkylthio, alkyl-NR.sup.10--, alkenyl, alkynyl; wherein R.sup.10 is
hydrogen or alkyl; and Y is --COO--, --OCO--, --CONR.sup.10--,
--NR.sup.10CO--, --CH.dbd.CH--, --C.ident.C--, --CH.sub.2O--,
--CH.sub.2S--, --CH.sub.2SO--, --CH.sub.2SO.sub.2--,
--CH.sub.2NR.sup.10--, --OCH.sub.2--, --SCH.sub.2--,
--SOCH.sub.2--, --SO.sub.2CH.sub.2-- or --NR.sup.10CH.sub.2--, with
the proviso that when Y is --OCO--, --NR.sup.10CO--, --OCH.sub.2--,
--SCH.sub.2--, --SOCH.sub.2--, --SO.sub.2CH.sub.2-- or
--NR.sup.10CH.sub.2--, R.sup.5 is hydrogen, alkyl, alkenyl,
alkynyl.
45. A method of treating acne vulgaris, the method comprising:
administering to a subject a topical formulation comprising a
single active ingredient, wherein the active ingredient consists of
a RAR selective agonist, wherein the RAR selective agonist is not
more than 0.05% of the formulation, and wherein the RAR selective
agonist has the structure: ##STR00056## wherein the dotted bond is
either present and forms a double bond, or is absent; R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 are independently hydrogen or alkyl; n
is 1, 2 or 3; X is --C(R.sup.8)(R.sup.9)-- for n=1, 2 or 3; or X is
oxygen for n=1; wherein R.sup.8 and R.sup.9 are independently
hydrogen or alkyl; R.sup.5 is hydrogen, alkyl, alkoxy,
alkoxy-alkyl-, alkylthio, alkyl-NR.sup.10--, alkenyl, alkenyloxy,
alkynyl, benzyl, cycloalkyl-alkyl or phenyl-alkyl; wherein R.sup.10
is hydrogen or alkyl; m is 0 when the dotted bond is present; or m
is 1 when the dotted bond is absent; wherein Ar is phenyl or a
heteroarylic ring; R.sup.6 is hydrogen, halogen, alkoxy or hydroxy;
R.sup.7 is hydrogen or alkyl; and Y is --COO--, --OCO--,
--CONR.sup.10--, --NR.sup.10CO--, --CH.dbd.CH--, --C.ident.C--,
--COCH.dbd.CH--, --CHOHCH.dbd.CH--, --CH.sub.2O--, --CH.sub.2S--,
--CH.sub.2SO--, --CH.sub.2SO.sub.2--, --CH.sub.2NR.sup.10--,
--OCH.sub.2--, --SCH.sub.2--, --SOCH.sub.2--, --SO.sub.2CH.sub.2--
or --NR.sup.10CH.sub.2--, with the proviso that when Y is --OCO--,
--NR.sup.10CO--, --OCH.sub.2--, --SCH.sub.2--, --SOCH.sub.2--,
--SO.sub.2CH.sub.2-- or --NR.sup.10CH.sub.2--, R.sup.5 is hydrogen,
alkyl, alkoxy-alkyl-, alkenyl, alkynyl, benzyl, cycloalkyl-alkyl or
phenyl-alkyl; or a pharmaceutically active salt of carboxylic acids
of formula I.
46. The method of claim 45, wherein the RAR selective agonist is
not more than 0.01% of the formulation.
47. The method of claim 45, wherein the RAR selective agonist is
administered by applying a cream, ointment, lotion or liquid
comprising the RAR selective agonist.
48. The method of claim 45, wherein R.sup.8 and R.sup.9 are H.
49. The method of claim 45, wherein R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are alkyl.
50. The method of claim 45, wherein R.sub.1, R.sub.2, R.sub.3, and
R.sub.4 are each methyl, X.sub.n is --CH.sub.2--CH.sub.2--, R.sub.5
is --CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.3, Y is
--COO--, and R.sub.6 and R.sub.7 are each is H.
51. The method of claim 45, wherein R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are independently hydrogen or alkyl; n is 1 or 2; X is
--C(R.sup.8)(R.sup.9)-- for n=1 or 2; or X is oxygen for n=1;
wherein R.sup.8 and R.sup.9 are independently hydrogen or alkyl;
and R.sup.5 is hydrogen, alkyl, alkoxy, alkoxy-alkyl-, alkylthio,
alkyl-NR.sup.10--, alkenyl, alkenyloxy, alkynyl; wherein R.sup.10
is hydrogen or alkyl.
52. The method of claim 45, wherein R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are independently hydrogen or alkyl; n is 1 or 2; X is
--C(R.sup.8)(R.sup.9)-- for n=1 or 2; or X is oxygen for n=1;
wherein R.sup.8 and R.sup.9 are independently hydrogen or alkyl;
and R.sup.5 is hydrogen, alkyl, alkylthio, alkyl-NR.sup.10--,
alkenyl, alkynyl; wherein R.sup.10 is hydrogen or alkyl.
53. The method of claim 45, wherein R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are independently hydrogen or alkyl; n is 2; X is
--C(R.sup.8)(R.sup.9)-- for n=2; wherein R.sup.8 and R.sup.9 are
independently hydrogen or alkyl; and R.sup.5 is hydrogen, alkyl,
alkoxy, alkoxy-alkyl-, alkylthio, alkyl-NR.sup.10--, alkenyl,
alkenyloxy, alkynyl; wherein R.sup.10 is hydrogen or alkyl.
54. The method of claim 45, wherein R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are independently hydrogen or alkyl; n is 2; X is
--C(R.sup.8)(R.sup.9)-- for n=2; wherein R.sup.8 and R.sup.9 are
independently hydrogen or alkyl; and R.sup.5 is hydrogen, alkyl,
alkylthio, alkyl-NR.sup.10--, alkenyl, alkynyl; wherein R.sup.10 is
hydrogen or alkyl.
55. The method of claim 45, wherein R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are independently hydrogen or alkyl; n is 2; X is
--C(R.sup.8)(R.sup.9)-- for n=2; wherein R.sup.8 and R.sup.9 are
independently hydrogen or alkyl; R.sup.5 is hydrogen, alkyl,
alkoxy, alkoxy-alkyl-, alkylthio, alkyl-NR.sup.10--, alkenyl,
alkenyloxy, alkynyl; wherein R.sup.10 is hydrogen or alkyl; and Y
is --COO--, --OCO--, --CONR.sup.10--, --NR.sup.10CO--,
--CH.dbd.CH--, --C.ident.C--, --CH.sub.2O--, --CH.sub.2S--,
--CH.sub.2SO--, --CH.sub.2SO.sub.2--, --CH.sub.2NR.sup.10--,
--OCH.sub.2--, --SCH.sub.2--, --SOCH.sub.2--, --SO.sub.2CH.sub.2--
or --NR.sup.10CH.sub.2--, with the proviso that when Y is --OCO--,
--NR.sup.10CO--, --OCH.sub.2--, --SCH.sub.2--, --SOCH.sub.2--,
--SO.sub.2CH.sub.2-- or --NR.sup.10CH.sub.2--, R.sup.5 is hydrogen,
alkyl, alkoxy-alkyl-, alkenyl, alkynyl.
56. The method of claim 45, wherein R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are independently hydrogen or alkyl; n is 2; X is
--C(R.sup.8)(R.sup.9)-- for n=2; wherein R.sup.8 and R.sup.9 are
independently hydrogen or alkyl; and R.sup.5 is hydrogen, alkyl,
alkylthio, alkyl-NR.sup.10--, alkenyl, alkynyl; wherein R.sup.10 is
hydrogen or alkyl; and Y is --COO--, --OCO--, --CONR.sup.10--,
--NR.sup.10CO--, --CH.dbd.CH--, --C.ident.C--, --CH.sub.2O--,
--CH.sub.2S--, --CH.sub.2SO--, --CH.sub.2SO.sub.2--,
--CH.sub.2NR.sup.10--, --OCH.sub.2--, --SCH.sub.2--,
--SOCH.sub.2--, --SO.sub.2CH.sub.2-- or --NR.sup.10CH.sub.2--, with
the proviso that when Y is --OCO--, --NR10CO--, --OCH2-, --SCH2-,
--SOCH2-, --SO2CH2- or --NR10CH2-, R5 is hydrogen, alkyl, alkenyl,
alkynyl.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/286,674, filed May 23, 2014, which is a
continuation of U.S. patent application Ser. No. 13/253,014, filed
Oct. 4, 2011, now U.S. Pat. No. 8,772,273, the disclosures of which
are incorporated herein by reference in its entirety for all
purposes.
FIELD OF THE INVENTION
[0002] This invention relates to retinoic acid receptor (RAR)
selective retinoid agonists and to the use of such retinoic acid
receptor agonists, particularly retinoic acid receptor .gamma.
(RAR.gamma.) selective agonists for the treatment of a disease and
for inducement of a medically beneficial effect.
BACKGROUND OF THE INVENTION
[0003] Retinoids are a class of compounds structurally related to
vitamin A, comprising natural and synthetic compounds. Several
series of retinoids have been found clinically useful in the
treatment of dermatological and oncological diseases. Retinoic acid
and its other naturally occurring retinoid analogs (9-cis retinoic
acid, all-trans 3,4-didehydro retinoic acid, 4-oxo retinoic acid
and retinol) are pleiotropic regulatory compounds that modulate the
structure and function of a wide variety of inflammatory, immune
and structural cells. They are important regulators of epithelial
cell proliferation, differentiation and morphogenesis in lungs.
Retinoids exert their biological effects through a series of
hormone nuclear receptors that are ligand inducible transcription
factors belonging to the steroid/thyroid receptor super family.
[0004] The retinoid receptors are classified into two families, the
retinoic acid receptors (RARs) and the retinoid X receptors (RXRs),
each consisting of three distinct subtypes (.alpha., .beta., and
.gamma.). Each subtype of the RAR gene family encodes a variable
number of isoforms arising from differential splicing of two
primary RNA transcripts. All-trans retinoic acid is the
physiological hormone for the retinoic acid receptors and binds
with approximately equal affinity to all the three RAR subtypes,
but does not bind to the RXR receptors for which 9-cis retinoic
acid is the natural ligand.
[0005] Retinoids have anti-inflammatory effects, alter the
progression of epithelial cell differentiation, and inhibit stromal
cell matrix production. These properties have led to the
development of topical and systemic retinoid therapeutics for
dermatological disorders such as psoriasis, acne, and hypertrophic
cutaneous scars. Other applications include the control of acute
promyelocytic leukemia, adeno- and squamous cell carcinoma, and
hepatic fibrosis.
[0006] A limitation in the therapeutic use of retinoids outside of
cancer has stemmed from the relative toxicity observed with the
naturally occurring retinoids, all-trans retinoic acid and 9-cis
retinoic acid. These natural ligands are non-selective and
therefore have pleiotropic effects throughout the body, which are
often toxic.
[0007] Recently various retinoids have been described that interact
selectively or specifically with the RAR or RXR receptors or with
specific subtypes (.alpha., .beta., .gamma.) within a class. For
example, Tom et al., Archives of Dermatology, 2005, 141: 1373-1377,
describe the efficacy and safety of short contact administration of
topical tretinoin on foot ulcers in patients with diabetes.
SUMMARY OF THE INVENTION
[0008] The invention provides novel formulations and uses of RAR
selective agonists. A RAR selective agonist, a pharmaceutically
acceptable salt of a RAR selective agonist or a formulation of
either of these may be used to treat a subject suffering from one
or more diseases disclosed herein or to induce a medically
beneficial effect in a subject. Exemplary RAR selective retinoid
agonists have a structure according to formula I:
##STR00001##
wherein the dotted bond is either present and forms a double bond,
or is absent; R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are
independently hydrogen or alkyl; n is 1, 2 or 3; X is
--C(R.sup.8)(R.sup.9)-- for n=1, 2 or 3; or X is oxygen for n=1;
R.sup.8 and R.sup.9 are independently hydrogen or alkyl; R.sup.5 is
hydrogen, alkyl, alkoxy, alkoxy-alkyl-, alkylthio,
alkyl-NR.sup.10--, alkenyl, alkenyloxy, alkynyl, benzyl,
cycloalkyl-alkyl, phenyl-alkyl, R.sup.10 is hydrogen or alkyl; m is
0 when the dotted bond is present; and m is 1 when the dotted bond
is absent; and A is a residue of formula:
##STR00002##
or of formula:
##STR00003##
wherein Ar is phenyl or a heteroarylic ring; R.sup.6 is hydrogen,
halogen, alkoxy or hydroxy; R.sup.7 is hydrogen or alkyl; and Y is
--COO--, --OCO--, --CONR.sup.10--, --NR.sup.10CO--, --CH.dbd.CH--,
--C.ident.C--, --COCH.dbd.CH--, --CHOHCH.dbd.CH--, --CH.sub.2O--,
--CH.sub.2S--, --CH.sub.2SO--, --CH.sub.2SO.sub.2--,
--CH.sub.2NR.sup.10--, --OCH.sub.2--, --SCH.sub.2--,
--SOCH.sub.2--, --SO.sub.2CH.sub.2-- or --NR.sup.10CH.sub.2--, with
the proviso that when Y is --OCO--, --NR.sup.10CO--, --OCH.sub.2--,
--SCH.sub.2--, --SOCH.sub.2--, --SO.sub.2CH.sub.2-- or
--NR.sup.10CH.sub.2--, R.sup.5 is hydrogen, alkyl, alkoxy-alkyl-,
alkenyl, alkynyl, benzyl, cycloalkyl-alkyl or phenyl-alkyl; and
pharmaceutically active salts of carboxylic acids of formula I.
Exemplary formulations of the RAR selective agonist are suitable
for topical or oral administration.
[0009] Also provided are devices containing the RAR selective
agonist or a formulation thereof for delivery of the compound.
[0010] The RAR selective agonists and formulations disclosed herein
may be used to treat a variety of diseases or to induce a variety
of medically beneficial effects. One advantage possessed by a
number of the embodiments disclosed herein is the lower toxicity
and fewer side effects experienced by subjects undergoing treatment
with the compounds and compositions as compared to the toxicity and
side effects engendered by other retinoids known in the art.
Various embodiments of the invention are more stable than known RAR
selective agonists and formulations and may also provide more cost
effective treatments in treating a disease.
DETAILED DESCRIPTION OF THE INVENTION
[0011] The present invention provides compounds and pharmaceutical
formulations suitable for administering one or more therapeutic
agents to a subject, pharmaceutical products containing the same,
processes of preparing such pharmaceutical formulations and
products, and methods of treating a subject employing such
pharmaceutical formulations and products.
Compounds
[0012] Various RAR selective agonists known in the art may be used
in the formulations and methods described herein. Exemplary
compounds useful in making the pharmaceutical formulations and in
practicing the methods of treatment and prevention disclosed herein
are RAR selective agonists having structures according to Formula I
and the various other compounds based on this structure, including
pharmaceutically acceptable salts thereof.
##STR00004##
wherein the dotted bond is either present and forms a double bond,
or is absent; R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are
independently hydrogen or alkyl; n is 1, 2 or 3; X is
--C(R.sup.8)(R.sup.9)-- for n=1, 2 or 3; or X is oxygen for n=1;
R.sup.8 and R.sup.9 are independently hydrogen or alkyl; R.sup.5 is
hydrogen, alkyl, alkoxy, alkoxy-alkyl-, alkylthio,
alkyl-NR.sup.10--, alkenyl, alkenyloxy, alkynyl, benzyl,
cycloalkyl-alkyl, phenyl-alkyl, R.sup.10 is hydrogen or alkyl; m is
0 when the dotted bond is present; and m is 1 when the dotted bond
is absent; and A is a residue of formula:
##STR00005##
or of formula:
##STR00006##
[0013] wherein Ar is phenyl or a heteroarylic ring; R.sup.6 is
hydrogen, halogen, alkoxy or hydroxy; R.sup.7 is hydrogen or alkyl;
and Y is --COO--, --OCO--, --CONR.sup.10--, --NR.sup.10CO--,
--CH.dbd.CH--, --C.ident.C--, --COCH.dbd.CH--, --CHOHCH.dbd.CH--,
--CH.sub.2O--, --CH.sub.2S--, --CH.sub.2SO--, --CH.sub.2SO.sub.2--,
--CH.sub.2NR.sup.10--, --OCH.sub.2--, --SCH.sub.2--,
--SOCH.sub.2--, --SO.sub.2CH.sub.2-- or --NR.sup.10CH.sub.2--, with
the proviso that when Y is --OCO--, --NR.sup.10CO--, --OCH.sub.2--,
--SCH.sub.2--, --SOCH.sub.2--, --SO.sub.2CH.sub.2-- or
--NR.sup.10CH.sub.2--, R.sup.5 is hydrogen, alkyl, alkoxy-alkyl-,
alkenyl, alkynyl, benzyl, cycloalkyl-alkyl or phenyl-alkyl; and
pharmaceutically active salts of carboxylic acids of formula I.
[0014] The term "alkyl" as used herein denotes straight chain or
branched alkyl residues containing 1 to 10, preferably 1 to 7
carbon atoms, such as methyl, ethyl, isobutyl, pentyl, amyl and
3-pentyl, hexyl, heptyl, and the like; the alkyl chain may be
substituted by amino, hydroxy, halogen. Such groups are for example
hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl,
aminomethyl, 2-aminoethyl and the like.
[0015] As used herein, the term "alkoxy" refers to a straight or
branched chain hydrocarbonoxy group wherein the "alkyl" portion is
an alkyl group as defined above. Examples include methoxy, ethoxy,
n-propoxy and the like.
[0016] As used herein, the term "alkoxy-alkyl-" refers to a
dialkylether residue such as methoxymethyl, methoxyethyl,
methoxypropyl, ethoxymethyl, ethoxyethyl, methoxy-ethoxymethyl and
the like.
[0017] As used herein, the term "alkylthio" refers to a straight or
branched chain hydrocarbonthio group wherein the "alkyl" portion is
an alkyl group as defined above. Examples include methylthio,
ethylthio, propylthio, and the like.
[0018] As used herein the term "alkenyl" refers to a straight or
branched hydrocarbon chain radical having from 2 to 8 carbon atoms,
preferably from 2 to 4 carbon atoms, and having at least one
olefinic double bond, e.g. allyl, vinyl etc.
[0019] As used herein, the term "alkenyloxy" refers to a straight
or branched chain hydrocarbonoxy group wherein the "alkenyl"
portion is an alkenyl group as defined above. Examples include
allyloxy, 3-butenyloxy and the like.
[0020] As used herein the term "alkynyl" refers to a straight or
branched hydrocarbon chain radical having from 2 to 8 carbon atoms,
preferably from 2 to 4 carbon atoms, and having at least one triple
bond.
[0021] The term "cycloalkyl-alkyl" as used herein refers to alkyl
groups as defined above bearing a cycloalkyl group having 3 to 7
carbon atoms as for example cyclopropylmethyl, cyclobutylmethyl,
cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl,
cyclobutylethyl, cyclopentylethyl, cyclohexylethyl and the
like.
[0022] As used herein the term "phenyl-alkyl" refers to a alkyl
group as defined above having a phenyl group attached to the
terminal C-atom as benzyl, phenethyl, phenylpropyl and the like,
the phenyl group may unsubstituted or substituted by alkyl or
alkoxy.
[0023] The term "heteroarylic ring" as used herein refers to a 5 or
6-membered heteroaryl ring containing at least one hetero atom
selected from oxygen, sulfur, and nitrogen, for example, pyridinyl,
furanyl or thiophenyl. In formulae I, I-1 and IA-IH, "Ar"
surrounded by hexagon, also referred to as simply "Ar", can
indicate a heteroarylic ring having at least three ring carbon
atoms, in which case the heteroarylic ring is bonded to each of Y,
R.sup.6 and --C(O)OR.sup.7 via a different ring carbon atom.
Alternatively, Ar surrounded by hexagon can indicate phenyl, in
which case Y and --C(O)OR.sup.7 are para to each other.
[0024] The groups Y are shown in their orientation in the compound
of formula I. By way of illustration, when Y is --CONR.sup.10--,
the nitrogen is bonded directly to the group Ar.
[0025] For groups having acidic protons, an ionized or salt form is
equally contemplated. For example, --COOH also refers to
--COO.sup.- and --COOM, while --OH also refers to --O.sup.- and
--OM, where M is a cation.
[0026] The compounds of formula I, wherein R.sup.7 is hydrogen,
form salts with pharmaceutically acceptable bases such as alkali
salts, e.g. Na- and K-salts, and ammonium or substituted ammonium
salts such as trimethylammonium salts, which are within the scope
of this invention.
[0027] When n is 2 or 3 in the formulae given in this application,
each occurrence of R.sup.8 can be the same or different and each
occurrence of R.sup.9 can be the same or different. It is preferred
that all occurrences of R.sup.8 are the same as the others and that
all occurrences of R.sup.9 are the same as the others. When n is 1,
2 or 3, it is most preferred for each R.sup.8 and each R.sup.9 to
be hydrogen. In exemplary embodiments, n is 2.
[0028] In some embodiments, R.sup.1, R.sup.2, R.sup.3 and R.sup.4
are independently selected alkyl. In exemplary embodiments,
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are methyl.
[0029] In some embodiments, R.sup.5 is alkyl. In exemplary
embodiments, R.sup.5 is pentyl.
[0030] In exemplary embodiments, Ar surrounded by hexagon is
phenyl.
[0031] In exemplary embodiments, R.sup.6 is H. In exemplary
embodiments, R.sup.7 is H. In exemplary embodiments, R.sup.8 is H.
In exemplary embodiments, R.sup.9 is H.
[0032] In exemplary embodiments, Y is --C(O)(O)--.
[0033] An exemplary RAR selective agonist has the structure:
##STR00007##
wherein the dotted bond is present and forms a double bond, or is
absent; R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently
hydrogen or alkyl; n is 1, 2, or 3; X is --C(R.sup.8)(R.sup.9)--
for n=1, 2 or 3; or X is oxygen for n=1; R.sup.5 is hydrogen,
alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, benzyl,
cycloalkyl-alkyl or phenylalkyl; m is 0 when the dotted bond is
present; or m is 1 when the dotted bond is absent; Ar is phenyl or
heteroarylic ring; R.sup.6 is hydrogen, halogen, alkoxy or hydroxy;
R.sup.7 is hydrogen or alkyl; R.sup.8 and R.sup.9 are independently
hydrogen or alkyl; and Y is --COO--, --OCO--, --CONH--, --NHCO--,
--CH.dbd.CH--, --C.ident.C--, --COCH.dbd.CH--, --CHOHCH.dbd.CH--,
--CH.sub.2 O--, --CH.sub.2S-- or --CH.sub.2NH--; with the proviso
that when Y is --OCO-- or --NHCO--, R.sup.5 is hydrogen, alkyl,
alkenyl, alkynyl, benzyl, cycloalkyl-alkyl or phenylalkyl; or a
pharmaceutically active salt of Formula I-1.
[0034] A RAR selective agonist also refers to a pharmaceutically
active salt of Formula I or any subgenus or species thereof.
Exemplary salts are salts of a carboxylic acid of Formula I. The
terms "pharmaceutically acceptable salts" and "pharmaceutically
active salt", used interchangeably herein, are meant to include
salts of the compounds of the invention that are prepared with
nontoxic acids or bases, depending on the particular substituents
found on the compounds described herein. When compounds of the
present invention contain relatively acidic functionalities, base
addition salts can be obtained by contacting the neutral form of
such compounds with a sufficient amount of the desired base, either
neat or in a suitable inert solvent. Examples of pharmaceutically
acceptable base addition salts include sodium, potassium, calcium,
ammonium, organic amino, or magnesium salt, or a similar salt. When
compounds of the present invention contain relatively basic
functionalities, acid addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired acid, either neat or in a suitable inert solvent. Examples
of pharmaceutically acceptable acid addition salts include those
derived from inorganic acids like hydrochloric, hydrobromic,
nitric, carbonic, monohydrogencarbonic, phosphoric,
monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,
monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
as well as the salts derived from nontoxic organic acids like
acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,
suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,
p-tolylsulfonic, citric, tartaric, methanesulfonic and the like.
Also included are salts of amino acids such as arginate and the
like, and salts of organic acids like glucuronic or galactunoric
acids and the like. See, for example, Berge et al., Journal of
Pharmaceutical Science, 1977, 66: 1-19. Certain specific compounds
of the present invention contain both basic and acidic
functionalities that allow the compounds to be converted into
either base or acid addition salts.
[0035] Especially preferred are the compounds of formulas:
##STR00008## ##STR00009##
wherein the symbols are as defined above, X.sup.2 is oxygen or
--NH--, and Z is oxygen, sulfur or --NH--; and pharmaceutically
active salts of carboxylic acids of formulae IA-IH.
[0036] In exemplary embodiments, n is 2. In exemplary embodiments,
X.sup.2 is oxygen.
[0037] The double bond in compounds of formulae IB, IE and IF may
form an E/Z mixture or be E or Z configurated, preferably E
configurated. The zigzag line in these formulae above indicates
that the configuration can be E or Z.
[0038] Preferred compounds are those wherein X is
--C(R.sup.8)(R.sup.9)-- and n is an integer 1 or 2. In some
embodiments, R.sup.8 and R.sup.9 are the same. In exemplary
embodiments, R.sup.8 and R.sup.9 are H.
[0039] In some embodiments, R.sup.1, R.sup.2, R.sup.3 and R.sup.4
are independently selected alkyl. In exemplary embodiments,
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are methyl.
[0040] In some embodiments, R.sup.5 is alkyl. In exemplary
embodiments, R.sup.5 is pentyl.
[0041] In exemplary embodiments, Ar surrounded by hexagon is
phenyl.
[0042] In exemplary embodiments, R.sup.6 is H. In exemplary
embodiments, R.sup.7 is H. In exemplary embodiments, R.sup.8 is H.
In exemplary embodiments, R.sup.9 is H.
[0043] Especially preferred are compounds of formula IA wherein
X.sup.2 is oxygen and n is 2, for example: [0044] A
4,4,7,7-tetramethyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carboxylic
acid 4-carboxy-phenyl ester
[0044] ##STR00010## [0045] B
2,4,4,7,7-pentamethyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carboxylic
acid 4-carboxy-phenyl ester
[0045] ##STR00011## [0046] C
2-ethyl-4,4,7,7-tetramethyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carboxylic
acid 4-carboxy-phenyl ester
[0046] ##STR00012## [0047] D
4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carboxylic
acid 4-carboxy-phenyl ester
[0047] ##STR00013## [0048] E
2-benzyl-4,4,7,7-tetramethyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carboxylic
acid 4-carboxy-phenyl ester
[0048] ##STR00014## [0049]
2-propyl-4,4,7,7-tetramethyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carboxylic
acid 4-carboxy-phenyl ester; [0050]
2-butyl-4,4,7,7-tetramethyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carboxylic
acid 4-carboxy-phenyl ester; [0051]
2-hexyl-4,4,7,7-tetramethyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carboxylic
acid 4-carboxy-phenyl ester and [0052]
2-phenethyl-4,4,7,7-tetramethyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carboxy-
lic acid 4-carboxy-phenyl ester.
[0053] Further preferred are compounds of formula IA wherein Ar is
pyridine, i.e., [0054]
6-[(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carbon-
yl)-amino]-nicotinic acid
##STR00015##
[0055] Further preferred are compounds of formula IA wherein n is 1
and X is --C(R.sup.8)(R.sup.9)--: [0056]
4,4,6,6-tetramethyl-2-pentyl-1,2,3,4,5,6-hexahydro-pentalene-2-carboxylic
acid 4-carboxy-phenyl ester;
[0057] and compounds wherein n is 1 and X is oxygen: [0058]
1,1,3,3-tetramethyl-5-pentyl-3,4,5,6-tetrahydro-1H-cyclopenta[c]furan-5-c-
arboxylic acid 4-carboxy-phenyl ester.
[0059] A further group of preferred compounds are compounds
[0060] a) of formula IB: [0061]
4-[2-(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene-2-yl)--
vinyl]-benzoic acid;
##STR00016##
[0062] b) of formula IC: [0063]
4-(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene-2-ylethyn-
yl)-benzoic acid
##STR00017##
[0064] c) of formula ID, wherein Z is oxygen: [0065]
4-(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-inden-2-ylmethox-
y)-benzoic acid;
[0066] of formula ID, wherein Z is sulfur: [0067]
4-(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-inden-2-ylmethyl-
sulfanyl)-benzoic acid; and
[0068] of formula ID, wherein Z is --NH--: [0069]
4-[-(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-inden-2-ylmeth-
yl)-amino]-benzoic acid;
[0070] d) of formula IE: [0071]
4-[3-oxo-3-(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene--
2-yl)-propenyl]-benzoic acid; and
[0072] e) of formula IF: [0073]
4-[3-hydroxy-3-(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-ind-
en-2-yl)-propenyl]-benzoic acid.
[0074] Further preferred compounds of formula I are the compounds
of formula
##STR00018##
wherein the dotted bond is present and forms a double bond, or is
absent; R.sup.1, R.sup.2, R.sup.3, R.sup.4 are independently
hydrogen or alkyl; n is 1, 2 or 3; X is --C(R.sup.8)(R.sup.9)-- for
n=1, 2 or 3; or X is oxygen for n=1; R.sup.8 and R.sup.9 are
independently hydrogen or alkyl; R.sup.5 is hydrogen, alkyl,
alkoxy, alkenyl, alkenyloxy, alkynyl, benzyl, cycloalkyl-alkyl,
phenyl-alkyl; m is 0 when the dotted bond is present; or m is 1
when the dotted bond is absent; and R.sup.7 is hydrogen or alkyl;
and pharmaceutically active salts of carboxylic acids of formula
I-2.
[0075] Especially preferred compounds of formula I-2 are [0076]
(2E,4E,6E)-3-methyl-7-(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-
-1H-inden-2-yl)-hepta-2,4,6-trienoic acid
##STR00019##
[0076] and [0077]
(2Z,4E,6E)-3-methyl-7-(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-
-1H-inden-2-yl)-hepta-2,4,6-trienoic acid
##STR00020##
[0078] In some embodiments, a compound has the structure:
##STR00021##
wherein the dotted bond is either present and forms a double bond,
or is absent; R.sup.1, R.sup.2, R.sup.3, R.sup.4 are independently
hydrogen or alkyl; X is --C(R.sup.8)(R.sup.9)--; each R.sup.8 and
each R.sup.9 is independently hydrogen or alkyl; R.sup.5 is
hydrogen, alkyl, alkoxy, alkoxy-alkyl-, alkythio,
alkyl-NR.sup.10--, alkenyl, alkenyloxy, alkynyl, benzyl,
cycloalkyl-alkyl, or phenyl-alkyl; R.sup.10 is hydrogen or alkyl; m
is 0 when the dotted bond is present; and m is 1 when the dotted
bond is absent; and Ar surrounded by hexagon shown above is phenyl
and Y and --C(O)OR.sup.7 are para to each other; R.sup.6 is
hydrogen, halogen, alkoxy or hydroxy; R.sup.7 is hydrogen or alkyl;
and Y is --COO--, --OCO--, --CONR.sup.10--, --NR.sup.10CO--,
--CH.dbd.CH--, --C.ident.C--, --COCH.dbd.CH--, --CHOHCH.dbd.CH--,
--CH.sub.2O--, --CH.sub.2S--, --CH.sub.2SO--, --CH.sub.2SO.sub.2--,
--CH.sub.2NR.sup.10--, --OCH.sub.2--, --SCH.sub.2--,
--SOCH.sub.2--, --SO.sub.2CH.sub.2-- or --NR.sup.10CH.sub.2--, with
the proviso that when Y is --OCO--, --NR.sup.10CO--, --OCH.sub.2--,
--SCH.sub.2--, --SOCH.sub.2--, --SO.sub.2CH.sub.2-- or
--NR.sup.10CH.sub.2--, R.sup.5 is hydrogen, alkyl, alkoxy-alkyl-,
alkenyl, alkynyl, benzyl, cycloalkyl-alkyl or phenyl-alkyl; or
where R.sup.7 is hydrogen, a pharmaceutically active salt of the
compound.
[0079] In some embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.4 are
alkyl. In exemplary embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.4
are methyl.
[0080] In some embodiments, each R.sup.8 is the same and each
R.sup.9 is the same. In some embodiments, each R.sup.8 is hydrogen
and each R.sup.9 is hydrogen. In some embodiments, R.sup.5 is
hydrogen, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, benzyl,
cycloalkyl-alkyl or phenylalkyl; R.sup.10 is hydrogen; Y is
--COO--, --OCO--, --CONR.sup.10--, --NR.sup.10CO--, --CH.dbd.CH--,
--C.ident.C--, --COCH.dbd.CH--, --CHOHCH.dbd.CH--, --CH.sub.2O--,
--CH.sub.2S--, or --CH.sub.2NR.sup.10--, with the proviso that when
Y is --OCO-- or --NR.sup.10CO--, R.sup.5 is hydrogen, alkyl,
alkenyl, alkynyl, benzyl, cycloalkyl-alkyl or phenylalkyl. In some
embodiments, Y is --COO-- or --CONR.sup.10. In some embodiments, Y
is --COO--.
Synthesis
[0081] The compounds according to the invention can be prepared in
a manner known in the art. In particular, compounds of formula IA,
wherein X.sup.2 is oxygen or --NH-- may for example be prepared
according to scheme 1:
##STR00022##
wherein X, n, m and Ar are defined as above and R.sup.5 is
hydrogen, alkyl, alkoxy-alkyl-, alkenyl, alkynyl, benzyl,
cycloalkyl-alkyl, phenyl-alkyl; X.sup.1 is a halogen, preferably
bromide or iodide; X.sup.2' is --OH or NH.sub.2; X.sup.2 is oxygen
or --NH--; and R.sup.10 is R.sup.7 or a carboxylic acid protecting
group, preferably an allylic group. LDA is lithium
diisopropylamide; and DCC/DMAP is
dicyclohexylcarbodiimide/dimethylamino pyridine.
[0082] The acid 1, wherein the dotted line is absent and thus m is
1, can be alkylated with a suitable alkylhalogenide preferably an
alkylbromide or an alkyliodide, or with an alkyl sulfonate, e.g.
tosylate or mesylate, using a strong base, e.g. lithium
diisopropylamide or potassium tert-butylate, to give the alkylated
acid 2, which is condensed with a hydroxy- or aminoaryl carboxylic
acid ester 3 to give compound 4. In the alternative the alkylation
step is omitted for compounds of formula IA, wherein the dotted
bond is present and m is thus 0. As condensation agent
dicyclohexylcarbodiimide/4-dimethylaminopyridine can be used.
Alternatively the acid 2 (or 1, respectively) can be transformed
into the acid chloride (thionyl chloride, oxalyl chloride) and then
reacted with compounds 3 and in the presence of a base (pyridine,
triethylamine) R.sup.10 in compound 3 can be R.sup.7 when X.sup.2'
is NH.sub.2 or must be a carboxylic acid protecting group like
allyl-, .beta.-trimethylsilylethyl-, tert-butyl- or
4-(trimethylsilyl)-2-buten-1-yl- or benzyl, when X.sup.2' is --OH.
The carboxylic acid protecting group can be removed in the last
step without cleavage of the internal amide or ester bond with such
agents as Pd(0)/morpholine or Pd(0)/Bu.sub.3SnH for the allyl
group, Bu.sub.4NF for the .beta.-trimethylsilylethyl group, formic
acid for the tert-butyl group or Pd(0) for the
4-(trimethylsilyl)-2-buten-1-yl group or catalytic hydrogenation
for the benzyl group.
[0083] The acid 1, wherein the dotted line is absent and thus m is
1, used as starting material can be prepared in analogy to the
examples given in EP 0116277 and EP 0115274. The acid 1, wherein
the dotted line is present and forms a double bond are prepared as
depicted in scheme 1a below. Starting from the ester of formula 1a
which is transformed to the corresponding unsaturated compound 1b
as depicted in scheme 1a:
##STR00023##
wherein the symbols are as defined above, R.sup.7' is alkyl, LDA is
lithium diisopropylamide and Ph is phenyl.
[0084] Compounds of formula I, wherein Y is --CH.dbd.CH--, i.e.
compounds of formula IB may be prepared according to scheme 2:
##STR00024##
wherein the symbols are as defined above and Et signifies
ethyl.
[0085] The acid 2 can be reduced to the alcohol 5 (e.g. with
LiAlH.sub.4, or a borane complex), oxidized to the aldehyde 6 by a
Swern or a Dess-Martin oxidation or with pyridinium chlorochromate
and then condensed in a Wittig-Horner reaction with a suitable
phosphonate 7 using a strong base like NaH or
lithium-bis-(trimethylsilyl)-amide (LiHMDS) to give the olefinic
compounds of formula IB wherein R.sup.7 is different from hydrogen
and which can be hydrolyzed if desired to a compound of formula IB
wherein R.sup.7 is hydrogen. The double bond may be in a E/Z
mixture, or preferably in the E configuration. The Wittig-Horner
reaction is highly trans selective and Scheme 2 illustrates the
synthesis of the trans isomer. The corresponding cis isomer may be
prepared in accordance with Scheme 3, followed by Lindlar reduction
of the triple bond.
[0086] Compounds of formula I wherein Y is an acetylenic group
(--C.ident.C--), namely compounds of formula IC can be prepared
according to scheme 3:
##STR00025##
wherein the symbols are as defined above and X.sup.3 is halogen,
preferably bromine or iodine.
[0087] The aldehyde 6 can be transformed into the acetylenic
derivative 9 according to the method of Corey and Fuchs by reaction
with P(C.sub.6H.sub.5).sub.3/CBr.sub.4 and subsequently with
butyllithium. The lithiated product is then coupled with a bromo or
iodo substituted aromatic ester 8 in a Pd(0) catalyzed reaction to
give a compound of formula IC wherein R.sup.7 is different from
hydrogen and which can be hydrolyzed to the product wherein R.sup.7
is hydrogen if desired.
[0088] Compounds of formula I wherein Y is --CH.sub.2O--,
--CH.sub.2S-- or --CH.sub.2NR.sup.10--, i.e. compounds of formula
ID, wherein Z is --O--, --S-- or --NH--, can be synthesized
according to Scheme 4 by using an alcohol 5 as starting
material.
##STR00026##
wherein the symbols are as defined above and X.sup.2'' is --OH,
--SH or --NH.sub.2.
[0089] The hydroxy group of the alcohol 5 can be transformed to the
halogenated derivative 10 with PX.sub.3.sup.3 or
CX.sub.4.sup.3/(C.sub.6H.sub.5).sub.3P, wherein X.sup.3 is a
halogenide preferably a chloride or bromide, or to a sulfonate
using mesyl chloride or tosyl chloride followed by reaction with
compound 11 to give the product of formula ID, which may be
hydrolyzed to the product of formula ID wherein R.sup.7 is
hydrogen.
[0090] Compounds of formula ID, wherein Z is sulfur can be oxidized
to the sulfoxide or the sulfone with peroxides. An alternative
method for the synthesis of compounds of formula ID wherein Z is
oxygen or sulfur is according to Mitsunobu by reacting the alcohol
5 with compound 11 wherein X.sup.2'' is OH or SH.
[0091] Compounds of formula I, wherein Y is --COCH.dbd.CH--, i.e.
compounds of formula IE can be synthesized according to scheme
5.
##STR00027##
wherein the symbols are as defined above.
[0092] The ketone 12 can be alkylated at the higher substituted
position by using sodium hydride (NaH), potassium hydride (KH) or
potassium tert-butylate as a base to give compounds 13 wherein the
dotted bond is absent and m is 1. Aldol condensation of compounds
12 or 13, respectively, with formyl compound 14 in the presence of
catalytic amounts of sodium hydroxyde (NaOH), piperidine,
piperidinium acetate or piperidinium tosylate yields compounds of
formula IE wherein R.sup.7 is different from hydrogen which can be
transformed into the final product IE wherein R.sup.7 is hydrogen
by hydrolysis of the ester group.
[0093] Compound of formula I, wherein Y is --CHOHCH.dbd.CH--, i.e.
compounds of formula IF can be prepared according to scheme 6 by
reduction of a compound of formula IE with for example NaBH.sub.4
or with NaBH.sub.4/CeCl.sub.3.
##STR00028##
wherein the symbols are as defined above.
[0094] Compounds of formula IF wherein R.sup.7 is different from
hydrogen can be transformed into the product IF wherein R.sup.7 is
hydrogen by hydrolysis.
[0095] The compounds of formula I, wherein Y is --NR.sup.10CO--,
i.e. compounds of formula IG can be prepared according to scheme 7.
Various methods are known for the transformation of acid 2 into
amine 15 (Hofmann, Lossen, Curtius or Schmidt-rearrangement)
##STR00029##
wherein the symbols are as defined above.
[0096] The amine 15 for example can be reacted with a terephthalic
acid chloride derivative or a suitable acid chloride 16 in presence
of pyridine or triethyl amine to give the amide of formula IG
wherein R.sup.7 is different from hydrogen. Hydrolysis of the ester
group yields the product of formula IG wherein R.sup.7 is
hydrogen.
[0097] In the alternative the internal amide bond can also be
formed by reaction of the amine 15 with terephthalic acid half
ester and dicyclohexylcarbodiimide.
[0098] Compounds of formula I, wherein Y is --OCO--, i.e. compounds
of formula IH can be synthesized according to scheme 8.
[0099] Compound 12 can be oxidized according to Baeyer-Villiger
with a peroxyacid to give the hydroxy compound 17. Esterification
is performed using known methods as for example by reaction of an
acid chloride 16 and a base.
##STR00030##
wherein the symbols are as defined above.
[0100] Compounds of formula I-2 can be prepared according to the
method depicted in Scheme 9:
##STR00031##
wherein the symbols are as defined above.
[0101] The aldehyde 6 is reacted with the phosphonate 18 in a
Wittig-Horner reaction in presence of a strong base as for example
sodium hydride or lithium-bis-(trimethylsilyl)-amide (LiHMDS) in an
inert solvent as for example THF to the ester of formula I-2,
wherein R.sup.7 is alkyl. This ester may the subsequently be
hydrolyzed to the compound of formula I-2, wherein R.sup.7 is
hydrogen.
[0102] Compounds of formula I, wherein R.sup.5 is alkoxy, alkylthio
and alkyl-NR.sup.10-- and Y is different from --OCO--, --NHCO--,
--OCH.sub.2--, --SCH.sub.2--, --SOCH.sub.2--, --SO.sub.2CH.sub.2--
or --NR.sup.10CH.sub.2-- can be prepared by known methods for
example they may be prepared according to the methods depicted in
scheme 10.
##STR00032##
wherein the symbols are as defined above.
[0103] The ester 1a can be transformed into the ester enolate 1b in
presence of a strong, non-nucleophilic base like lithium
diisopropylamide; this enolate can then be reacted with:
[0104] a) MoO.sub.5-complex to give the corresponding
.alpha.-hydroxy compound which can then be alkylated with an
alkylhalogenide (R.sup.5X.sup.1) to form compound 19 which is then
transformed according to one of the reaction schemes above into the
desired compound of formula I;
[0105] b) a suitable disulfide alkyl-S--S-alkyl to give the
corresponding .alpha.-thioester 20;
[0106] c) a [NH.sub.2.sup..sym.]-synthon (for a review of such
synthons see G. Boche in Houben-Weyl, Methods of Organic Chemistry,
Vol. E21e, p. 5133 (1995) or D. Enders et al. in Tetrahedron 1998,
54, 10069).
[0107] Compounds of formula IA, wherein Y is --OCH.sub.2--,
--SCH.sub.2--, --SOCH.sub.2--, --SO.sub.2CH.sub.2-- or
--NR.sup.10CH.sub.2-- and R.sup.5 is alkyl, alkoxy-alkyl-, alkenyl,
alkynyl, benzyl, cycloalkyl-alkyl, phenyl-alkyl, can be prepared
according to the method depicted in scheme 11:
##STR00033##
wherein the symbols are as defined above.
[0108] The acid 22, synthesis described in example 11, can be
transformed in a Curtius reaction into the corresponding ketone 23
which will react with Lawesson reagent to the thioketone 24.
Addition of a Grignard reagent will lead to compounds 25 and 26,
respectively. Alkylation of compounds 15, 25 or 26 with bromomethyl
derivative 27 will give the desired products of formula IA, wherein
Y is --NHCH--, --OCH.sub.2-- or --SCH.sub.2--.
[0109] In some embodiments, the RAR selective agonist is selective
for RAR.beta. or RAR.gamma.. A RAR selective agonist is selective
for a target if it binds to the target with higher affinity
compared to binding with another molecule, such as a different RAR.
In exemplary embodiments, a RAR selective agonist is selective for
RAR.beta. over RAR.alpha. and/or RAR.gamma.. In exemplary
embodiments, a RAR selective agonist is selective for RAR.gamma.
over RAR.alpha. and/or RAR.beta.. Thus, a RAR selective agonist
tends to bind to a particular target with high binding affinity. In
some embodiments, a high binding affinity is given by a
dissociation constant K.sub.d of about 10.sup.-7 M or less. In
exemplary embodiments, a high binding affinity is given by a
dissociation constant K.sub.d of about 10.sup.-8 M or less, about
10.sup.-9 M or less, about 10.sup.-10 M or less, about 10.sup.-11 M
or less, about 10.sup.-12 M or less, about 10.sup.-13 M or less,
about 10.sup.-14 M or less or about 10.sup.-15 M or less.
[0110] Protocols for making various compounds of the invention are
described in U.S. Pat. No. 6,528,677 B1.
Formulations
[0111] In one aspect, the invention provides formulations of an
active agent such as a RAR selective agonist, with formulations for
topical or oral administration being an exemplary mode of delivery.
The formulations (sometimes referred herein to as a composition)
typically comprise an active agent (or a pharmaceutically
acceptable salt thereof) and a carrier medium.
[0112] An "active agent", "therapeutic agent" or "drug" refers to
any compound that is effective in treating a targeted disorder,
disease or condition or in inducing a medically beneficial effect.
Exemplary active agents include a RAR selective agonist disclosed
herein and a salt thereof.
[0113] A "carrier medium" or "carrier" refers to one or more
excipients, diluents, carriers, additives and combinations thereof
known in the art that may be combined with an active agent (such as
a RAR selective agonist disclosed herein) to enhance, facilitate or
enable the production, storage, administration, delivery or
effectiveness of the active compound. For topical formulations, a
carrier medium will be dermatologically acceptable, preferably
designed to reduce or avoid undue toxicity, incompatibility,
instability, allergic response and the like when applied to skin.
For oral formulations, a carrier medium will be orally acceptable,
preferably designed to reduce or avoid undue toxicity,
incompatibility, instability, allergic response and the like when
applied in the mouth.
[0114] Active agents in the formulations described herein should be
present in a therapeutically effective amount. A "therapeutically
effective amount" means the amount of a compound that, when
administered to a mammal for treating or preventing a disease, is
sufficient to effect such treatment or prevention of the disease or
to induce a medically beneficial effect. The therapeutically
effective amount will vary depending on the compound, the specific
nature of the disease and its severity and the age, weight or other
characteristic of the mammal to be treated. The dosage may be
delivered in a conventional pharmaceutical composition by a single
administration, by multiple applications, or via controlled
release, as needed to achieve the most effective results. Dosing
will continue for as long as is medically indicated, which
depending on the severity of the disease may range from a few weeks
to several months.
[0115] In some embodiments, the active agent will be present in an
amount of not more than about a percentage selected from 10%, 5%,
2%, 1%, 0.1%, 0.05%, 0.02%, 0.01%, 0.005%, 0.002%, 0.001%, 0.0005%,
0.0002%, 0.0001%, 0.00005%, 0.00002% and 0.00001% by weight based
on the total weight of the pharmaceutical formulation. In exemplary
embodiments, a formulation comprises an active agent (e.g. RAR
selective agonist) in amount that is about 0.005 wt %. In exemplary
embodiments, a formulation comprises an active agent (e.g. RAR
selective agonist) in amount that is about 0.01 wt %. In exemplary
embodiments, a formulation comprises an active agent (e.g. RAR
selective agonist) in amount that is about 0.05 wt %. In some
embodiments, a formulation comprises an active agent (e.g. RAR
selective agonist) in an amount that is about 0.005 wt % to about
0.05 wt %, preferably about 0.005 wt % to about 0.01 wt % or
preferably about 0.01 wt % to about 0.05 wt %. In some embodiments,
a formulation comprises an active agent (e.g. RAR selective
agonist) in an amount that is about 0.00001 wt % to about 1 wt %.
In exemplary embodiments, the dosage will range between about 0.005
and 0.05% active dose per component per application, preferably
from about 0.005 to about 0.05% of active dose. In non-limiting
embodiments, for example, a formulation comprises an active agent
(e.g. RAR selective agonist) in an amount that is or is at least
about a weight percentage (wt %) selected from 0.00001%, 0.00002%,
0.00003%, 0.00004%, 0.00005%, 0.00006%, 0.00007%, 0.00008%,
0.00009%, 0.0001%, 0.0002%, 0.0003%, 0.0004%, 0.0005%, 0.0006%,
0.0007%, 0.0008%, 0.0009%, 0.0010%, 0.0020%, 0.0030%, 0.0040%,
0.0050%, 0.0060%, 0.0070%, 0.0080%, 0.0090%, 0.0100%, 0.0110%,
0.0120%, 0.0130%, 0.0140%, 0.0150%, 0.0160%, 0.0170%, 0.0180%,
0.0190%, 0.0200%, 0.0210%, 0.0220%, 0.0230%, 0.0240%, 0.0250%,
0.0260%, 0.0270%, 0.0280%, 0.0290%, 0.0300%, 0.0310%, 0.0320%,
0.0330%, 0.0340%, 0.0350%, 0.0360%, 0.0370%, 0.0380%, 0.0390%,
0.0400%, 0.0410%, 0.0420%, 0.0430%, 0.0440%, 0.0450%, 0.0460%,
0.0470%, 0.0480%, 0.0490%, 0.0500%, 0.0525%, 0.0550%, 0.0575%,
0.0600%, 0.0625%, 0.0650%, 0.0675%, 0.0700%, 0.0725%, 0.0750%,
0.0775%, 0.0800%, 0.0825%, 0.0850%, 0.0875%, 0.0900%, 0.0925%,
0.0950%, 0.0975%, 0.1000%, 0.1250%, 0.1500%, 0.1750%, 0.2000%,
0.2250%, 0.2500%, 0.2750%, 0.3000%, 0.3250%, 0.3500%, 0.3750%,
0.4000%, 0.4250%, 0.4500%, 0.4750%, 0.5000%, 0.5250%, 0.0550%,
0.5750%, 0.6000%, 0.6250%, 0.6500%, 0.6750%, 0.7000%, 0.7250%,
0.7500%, 0.7750%, 0.8000%, 0.8250%, 0.8500%, 0.8750%, 0.9000%,
0.9250%, 0.9500%, 0.9750%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%,
1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%,
2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%,
3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%,
4.9% and 5.0%. Ranges incorporating any of these and other values
disclosed herein as endpoints may also be suitable.
[0116] The term "about" when used to qualify a percentage or amount
of a component herein can be interpreted to allow for minor
adjustments in the value of the percentage or amount while
maintaining the functionality of the component in the overall
formulation. In some embodiments, the term "about" when used to
qualify a percentage herein refers to a value that falls in a
range, inclusive of the endpoints, that is 5% above or below the
value of the percentage. Thus, in some embodiments, about 1% refers
to a value in the range of 0.95% to 1.05% and about 2% refers to a
value in the range of 1.9% to 2.1%. In some embodiments, the term
"about" when used to qualify a percentage herein refers to the
value of the percentage itself. Thus, in some embodiments, about 1%
refers to 1%.
[0117] In some embodiments, the methods disclosed herein also
include systemic administration of RAR agonists in simultaneous or
sequential combination with a further active agent or drug. Thus,
in some embodiments, a formulation further comprises an active
agent or a drug in addition to a RAR selective agonist, i.e., the
formulation further comprises a second active agent or a second
drug.
[0118] Second active agents that can be used with the present
invention include all drugs which can be delivered onto or through
the skin for either a local or systemic effect, among others. These
compounds include agents in all of the major therapeutic areas,
including, but not limited to, ACE inhibitors, adenohypophoseal
hormones, adrenergic neuron blocking agents, adrenocortical
steroids, inhibitors of the biosynthesis of adrenocortical
steroids, alphaadrenergic agonists, alpha-adrenergic antagonists,
selective alpha-two-adrenergic agonists, analgesics, antipyretics
and anti-inflammatory agents, androgens, local and general
anesthetics, antiaddictive agents, antiandrogens, antiarrhythmic
agents, antiasthmatic agents, anticholinergic agents,
anticholinesterase agents, anticoagulants, antidiabetic agents,
antidiarrheal agents, antidiuretic, antiemetic and prokinetic
agents, antiepileptic agents, antiestrogens, antifungal agents
(e.g., amphotericin B, clotrimazole, nystatin, ketoconazole,
miconazole, butocouazole, haloprogin, etc.), antihypertensive
agents, anti-inflammatory agents (e.g., steroidal compounds such as
dexamethasone, betamethasone, prednisone, prednisolone,
triamcinolone, hydrocortisone, alclometasone, amcinonide,
diflorasone, etc. as well as non-steroidal anti-inflammatories),
anti-itch and irritation-reducing compounds (e.g., antihistamines
such as diphenhydramine and psoriasis treatments), antimicrobial
agents, antimigraine agents, antimuscarinic agents, antineoplastic
agents, antiparasitic agents (e.g., lindane, anthralin, etc.),
antiparkinson's agents, antiplatelet agents, antiprogestins,
anticeptic agents (e.g., povidone-iodine, methylbenzethonium
chloride, etc.), antithyroid agents, antitussives, antiviral agents
(e.g., acyclovir and idoxuridine, etc.), atypical antidepressants,
azaspirodecanediones, barbituates, benzodiazepines,
benzothiadiazides, beta-adrenergic agonists, beta-adrenergic
antagonists, selective beta-one-adrenergic antagonists, selective
beta-two-adrenergic agonists, bile salts, burn relievers (e.g.,
o-amino-ptoluenesulfonamide, monoacetate, etc.), agents affecting
volume and composition of body fluids, butyrophenones, agents
affecting calcification, calcium channel blockers, cardiovascular
drugs, catecholamines and sympathomimetic drugs, cholinergic
agonists, cholinesterase reactivators, depigmenting agents (e.g.,
monobenzone), dermatological agents, diphenylbutylpiperidines,
diuretics, ergot alkaloids, ganglionic blocking agents, ganglionic
stimulating agents, hydantoins, agents for control of gastric
acidity and treatment of peptic ulcers, hematopoietic agents,
histamines, histamine antagonists, hormonal agents (e.g.,
estrogens, oestriol), 5-hydroxytryptamine antagonists, drugs for
the treatment of hyperlipoproteinemia, hypnotics and sedatives,
immunosupressive agents, laxatives, methylxanthines, monoamine
oxidase inhibitors, neuromuscular blocking agents, organic
nitrates, pancreatic enzymes, phenothiazines, progestins,
prostaglandins, agents for the treatment of psychiatric disorders,
retinoids, sodium channel blockers, agents for spasticity and acute
muscle spasms, succinimides, thioxanthines, thrombolytic agents,
thyroid agents, tricyclic antidepressants, inhibitors of tubular
transport of organic compounds, drugs affecting uterine motility,
vasodilators, vitamins and the like.
[0119] Representative drugs include, for example, bepridil,
diltiazem, felodipine, isradipine, nicardipine, nifedipine,
nimodipine, nitredipine, verapamil, dobutamine, isoproterenol,
carterolol, labetalol, levobunolol, nadolol, penbutolol, pindolol,
propranolol, sotalol, timolol, acebutolol, atenolol, betaxolol,
esmolol, metoprolol, albuterol, bitolterol, isoetharine,
metaproterenol, pirbuterol, ritodrine, terbutaline, alclometasone,
aldosterone, amcinonide, beclomethasone, dipropionate,
betamethasone, clobetasol, clocortolone, cortisol, cortisone,
corticosterone, desonide, desoximetasone, 11-desoxycorticosterone,
11-desoxycortisol, dexamethasone, diflorasone, fludrocortisone,
flunisolide, fluocinolone, fluocinonide, fluorometholone,
flurandrenolide, halcinonide, hydrocortisone, medrysone,
6.alpha.-methylprednisolone, mometasone, paramethasone,
prednisolone, prednisone, tetrahydrocortisol, triamcinolone,
benoxinate, benzocaine, bupivacaine, chloroprocaine, cocaine,
dibucaine, dyclonine, etidocaine, lidocaine, mepivacaine,
pramoxine, prilocaine, procaine, proparacaine, tetracaine,
alfentanil, choroform, clonidine, cyclopropane, desflurane, diethyl
ether, droperidol, enflurane, etomidate, halothane, isoflurane,
ketamine hydrochloride, meperidine, methohexital, methoxyflurane,
morphine, propofol, sevoflurane, thiamylal, thiopental,
acetaminophen, allopurinol, apazone, aspirin, auranofin,
aurothioglucose, colchicine, diclofenac, diflunisal, etodolac,
fenoprofen, flurbiprofen, gold sodium thiomalate, ibuprofen,
indomethacin, ketoprofen, meclofenamate, mefenamic acid,
meselamine, methyl salicylate, nabumetone, naproxen,
oxyphenbutazone, phenacetin, phenylbutazone, piroxicam,
salicylamide, salicylate, salicylic acid, salsalate, sulfasalazine,
sulindac, tolmetin, acetophenazine, chlorpromazine, fluphenazine,
mesoridazine, perphenazine, thioridazine, trifluorperazine,
triflupromazine, disopyramide, encainide, flecainide, indecainide,
mexiletine, moricizine, phenytoin, procainamide, propafenone,
quinidine, tocainide, cisapride, domperidone, dronabinol,
haloperidol, metoclopramide, nabilone, prochlorperazine,
promethazine, thiethylperazine, trimethobenzamide, buprenorphine,
butorphanol, dezocine, diphenoxylate, drocode, hydrocodone,
hydromorphone, levallorphan, levorphanol, loperamide, meptazinol,
methadone, nalbuphine, nalmefene, nalorphine, naloxone, naltrexone,
oxybutynin, pentazocine, isosorbide dinitrate, nitroglycerin,
theophylline, phenylephrine, ephidrine, pilocarpine, furosemide,
tetracycline, chlorpheniramine, ketorolac, bromocriptine,
guanabenz, prazosin, doxazosin, and flufenamid acid.
[0120] Still other representative drugs include benzodiazepines,
such as alprazolam, brotizolam, chlordiazepoxide, clobazam,
clonazepam, clorazepate, demoxepam, diazepam, flumazenil,
flurazepam, halazepam, lorazepam, midazolam, nitrazepam,
nordazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, and
the like; an antimuscarinic agent such as anisotropine, atropine,
clidinium, cyclopentolate, dicyclomine, flavoxate, glycopyrrolate,
hexocyclium, homatropine, ipratropium, isopropamide, mepenzolate,
methantheline, oxyphencyclimine, pirenzepine, propantheline,
scopolamine, telenzepine, tridihexethyl, tropicamide, and the like;
an estrogen such as chlorotrianisene, siethylstilbestrol, methyl
estradiol, estrone, estrone sodium sulfate, estropipate, mestranol,
quinestrol, sodium equilin sulfate, 17.beta.-estradiol (or
estradiol), semi-synthetic estrogen derivatives such as the esters
of natural estrogen, such as estradiol-17.beta.-enanthate,
estradiol-17.beta.-valerate, estradiol-3-benzoate,
estradiol-17.beta.-undecenoate, estradiol 16,17-hemisuccinate or
estradiol-17.beta.-cypionate, and the 17-alkylated estrogens, such
as ethinyl estradiol, ethinyl estradiol-3isopropylsulphonate, and
the like; an androgen such as danazol, fluoxymesterone,
methandrostenolone, methyltestosterone, nandrolone decanoate,
nandrolone phenpropionate, oxandrolone, oxymetholone, stanozolol,
testolactone, testosterone, testosterone cypionate, testosterone
enanthate, testosterone propionate, and the like; or a progestin
such as ethynodiol diacetate, gestodene, hydroxyprogesterone
caproate, levonorgestrel, medroxyprogesterone acetate, megestrol
acetate, norethindrone, norethindrone acetate, norethynodrel,
norgestrel, progesterone, and the like.
[0121] In some embodiments, the second active agent is an
antibiotic. Thus, in some embodiments, the formulation further
comprises an antibiotic. As used herein, an "antibiotic" refers to
any compound having activity against either Gram-positive or
Gram-negative organisms (i.e., inhibits the growth or destroys the
development of either Gram-positive or Gram-negative organisms).
Stedman's Medical Dictionary, Illustrated, (25th Ed.), Williams
& Wilkins: Baltimore (1990) and Mosby's Medical, Nursing, &
Allied Health Dictionary, (5th Ed.), Mosby: St. Louis (1998).
[0122] Any suitable antibiotic can be employed provided that the
antibiotic remains stable in the formulation. Preferably, the
stability is over a prolonged period of time, e.g., up to about 3
years, up to about 1 year, or up to about 6 months, typically
experienced in the manufacturing, packaging, shipping, and/or
storage of the composition. Suitable antibiotics are disclosed,
e.g., in Physician's Desk. Reference (PDR), Medical Economics
Company (Montvale, N.J.), (53rd Ed.), 1999; Mayo Medical Center
Formulary, Unabridged Version, Mayo Clinic (Rochester, Minn.),
January 1998; Merck Index, An Encyclopedia of Chemicals, Drugs, and
Biologicals, (11th Ed.), Merck & Co., Inc. (Rahway, N.J.),
1989; and references cited therein. Other topically-active
compounds are listed in Remington's Pharmaceutical Sciences, 17th
Ed., Merck Publishing Co., Easton, Pa. (1985).
[0123] Suitable classes of antibiotic include, e.g.,
.beta.-lactams, aminoglycosides, antifungal agents, and
combinations thereof. Suitable antibiotics include, e.g.,
cilastatin, clavulanic acid, folinic acid, probenecid, pyridoxine,
sulbactam, dapsone, ethambutol, isoniazid, pyrazinamide, rifampin,
streptomycin, capreomycin, ethionamide, para aminosalicylic acid,
cycloserine, ciprofloxacin, nalidixic acid, norfloxacin, ofloxacin,
imipenam, meropenem, cilistatin, cefadroxil, cefazolin, cephalexin,
cephalothin, cefaclor, cefamandole, cefonicid, cefoxitin,
cefuroxine, cefoperazone, cefotaxime, ceftazidime, ceftizoxime,
ceftriaxone, moxalactam, cefepine, bacitracin, vancomycin,
aztreonam, amoxicillin, clavulanic acid, benzathine, penicillin g,
penicillin v, ampicillin, carbenicillin. indamyl, carbenicillin,
mezlocillin, piperacillin, ticarcillin, cloxacillin, dicloxacillin,
floxacillin, methicillin, nafcillin, oxacillin, colistmethate,
polyrnixin b, trimethoprim, cotrimoxazole, mafenide, sulfadiazine,
sodium sulfacetamide, sulfacytine, sulfadiazine, sulfamethoxazole,
sulfapyridine, sulfasalazine, sulfisoxazole, chloramphenicol,
clindamycin, spectinomycin, azithromycin, clarithromycin,
erythrmoycin, erythromycin estolate, spiramycin, chlortetracycline,
demeclocycline, doxycycline, minocycline, oxytetracycline,
amikacin, kanamycin, neomycin, streptomycin, tobramycin,
nitrofurantoin, griseofulvin, potassium iodide, fluconazole,
itraconazole, ketoconazole, miconazole, clotrimazole, amphotericin
b, nystatin, niclosamide, nifurtimox, piperazine, praziquantel,
pyrantel pamoate, ascariasis, pinworm, thiabendazole, amodiaquine,
chloroquine, hydroxychloroquine, mefloquine, primaquine,
pyrimethamine, quinidine gluconate, fansidar, diloxanide furoate,
melarsoprol, nifurtimox, paromomycin, pentamidine, sodium
stibogluconate, suramin, metronidazole, foscarnet,
3-deoxythmidin-2-ene, dideoxycytosine, dideoxyinosine, lamivudine,
azidothymidine, indinavir, ritonavir, saquinavir, acyclovir,
idoxuridine, ribavirin, vidarabine, amantidine, rinantidine,
pharmaceutically acceptable salts thereof, and combinations
thereof
[0124] Specifically, the antibiotic can be at least one of
amphomycin, apramycin, avilamycin, azithromycin, bacitracin,
bactiracin zinc, clarithromycin, clindamycin, clindamycin
hydrochloride, clindamycin palmitate hydrochloride, clindamycin
phosphate, dirithromycin, erythromycin, erythromycin acistrate,
erthromycin estolate, erthryomycin ethlylsuccinate, erthryomycin
gluceptate, erythromycin lactobionate, erthromycin propionate,
erthromycin stearate, fosfomycin, fosfomycin tromethamine,
josamycin, kitasamycin, lexithromycin, lincomycin, limcomycin
hydrochloride, metronidazole hydrochloride, metronidazole
phosphate, mirincamycin hydrochloride, paldimycin, paulomycin,
pirlimycin hydrochloride, ranimycin, relomycin, roxithromycin,
spectinomycin hydrochloride, spiramycin, stallimycin hydrochloride,
tobramycin, vancomycin, vancomycin hydrochloride, zorbamycin,
mupirocin, mupirocin calcium, and parachlorophenol.
[0125] In some embodiments, the second active agent is an
analgesic. Thus, in some embodiments, a formulation further
comprises an analgesic. An analgesic is an agent that is capable of
reducing or eliminating pain. Various classes of analgesics include
nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., salicylates,
propionic acid derivatives, acetic acid derivatives, enolic acid
derivatives, fenamic acid derivatives, COX-2 inhibitors,
sulphonanilides, etc.) and opiates (e.g., morphine, codeine,
thebaine, papverine, etc.). Exemplary analgesics include
acetaminophen; alfentanil hydrochloride; aminobenzoate potassium;
aminobenzoate sodium; anidoxime; anileridine; anileridine
hydrochloride; anilopam hydrochloride; anirolac; antipyrine;
aspirin; benoxaprofen; benzydamine hydrochloride; bicifadine
hydrochloride; brifentanil hydrochloride; bromadoline maleate;
bromfenac sodium; buprenorphine hydrochloride; butacetin;
butixirate; butorphanol; butorphanol tartrate; carbamazepine;
carbaspirin calcium; carbiphene hydrochloride; carfentanil citrate;
ciprefadol succinate; ciramadol; ciramadol hydrochloride;
clonixeril; clonixin; codeine; codeine phosphate; codeine sulfate;
conorphone hydrochloride; cyclazocine; dexoxadrol hydrochloride;
dexpemedolac; dezocine; diflunisal; dihydrocodeine bitartrate;
dimefadane; dipyrone; doxpicomine hydrochloride; drinidene;
enadoline hydrochloride; epirizole; ergotamine tartrate; ethoxazene
hydrochloride; etofenamate; eugenol; fenoprofen; fenoprofen
calcium; fentanyl citrate; floctafenine; flufenisal; flunixin;
flunixin meglumine; flupirtine maleate; fluproquazone; fluradoline
hydrochloride; flurbiprofen; hydromorphone hydrochloride; ibufenac;
indoprofen; ketazocine; ketorfanol; ketorolac tromethamine;
letimide hydrochloride; levomethadyl acetate; levomethadyl acetate
hydrochloride; levonantradol hydrochloride; levorphanol tartrate;
lofemizole hydrochloride; lofentanil oxalate; lorcinadol;
lornoxicam; magnesium salicylate; mefenamic acid; menabitan
hydrochloride; meperidine hydrochloride; meptazinol hydrochloride;
methadone hydrochloride; methadyl acetate; methopholine;
methotrimeprazine; metkephamid acetate; mimbane hydrochloride;
mirfentanil hydrochloride; molinazone; morphine sulfate;
moxazocine; nabitan hydrochloride; nalbuphine hydrochloride;
nalmexone hydrochloride; namoxyrate; nantradol hydrochloride;
naproxen; naproxen sodium; naproxol; nefopam hydrochloride;
nexeridine hydrochloride; noracymethadol hydrochloride; ocfentanil
hydrochloride; octazamide; olvanil; oxetorone fumarate; oxycodone;
oxycodone hydrochloride; oxycodone terephthalate; oxymorphone
hydrochloride; pemedolac; pentamorphone; pentazocine; pentazocine
hydrochloride; pentazocine lactate; phenazopyridine hydrochloride;
phenyramidol hydrochloride; picenadol hydrochloride; pinadoline;
pirfenidone; piroxicam olamine; pravadoline maleate; prodilidine
hydrochloride; profadol hydrochloride; propiram fumarate;
propoxyphene hydrochloride; propoxyphene napsylate; proxazole;
proxazole citrate; proxorphan tartrate; pyrroliphene hydrochloride;
remifentanil hydrochloride; salcolex; salicylamide; salicylate
meglumine; salsalate; sodium salicylate; spiradoline mesylate;
sufentanil; sufentanil citrate; talmetacin; talniflumate;
talosalate; tazadolene succinate; tebufelone; tetrydamine; tifurac
sodium; tilidine hydrochloride; tiopinac; tonazocine mesylate;
tramadol hydrochloride; trefentanil hydrochloride; trolamine;
veradoline hydrochloride; verilopam hydrochloride; volazocine;
xorphanol mesylate; xylazine hydrochloride; zomepirac sodium; and
zucapsaicin. Other pharmaceutically acceptable forms, such as
alternative pharmaceutical salts, of these and other known
analgesics may also be combined with a RAR selective agonist
disclosed herein.
[0126] In some embodiments, the second active agent is an
anesthetic. Thus, in some embodiments, a formulation further
comprises an anesthetic. An anesthetic is an agent that reversibly
depresses neuronal function, producing total or partial loss of
sensation. Exemplary anesthetics include aliflurane; articaine;
benoxinate hydrochloride; benzocaine; biphenamine hydrochloride;
bupivacaine hydrochloride; butamben; butamben picrate;
chloroprocaine hydrochloride; cocaine; cocaine hydrochloride;
cyclopropane; desflurane; dexivacaine; diamocaine cyclamate;
dibucaine; dibucaine hydrochloride; dyclonine hydrochloride;
enflurane; ether; ethyl chloride; etidocaine; etoxadrol
hydrochloride; euprocin hydrochloride; fluroxene; halothane;
isobutamben; isoflurane; ketamine hydrochloride; levobupivacaine;
levoxadrol hydrochloride; lidocaine; lidocaine hydrochloride;
mepivacaine hydrochloride; methohexital sodium; methoxyflurane;
midazolam hydrochloride; midazolam maleate; minaxolone; norflurane;
octodrine; oxethazaine; phencyclidine hydrochloride; pramoxine
hydrochloride; prilocaine hydrochloride; procaine hydrochloride;
propanidid; proparacaine hydrochloride; propofol; propoxycaine
hydrochloride; pyrrocaine; risocaine; rodocaine; roflurane;
ropivacaine; salicyl alcohol; sevoflurane; teflurane; tetracaine;
tetracaine hydrochloride; thiamylal; thiamylal sodium; thiopental
sodium; tiletamine hydrochloride; and zolamine hydrochloride. Other
pharmaceutically acceptable forms, such as alternative
pharmaceutical salts, of these and other known anesthetics may also
be combined with a RAR selective agonist disclosed herein.
[0127] The compounds that can be used in the present invention,
including the compounds listed above, are meant to include all
pharmaceutically acceptable salts and conjugates.
Topical Administration
[0128] In one aspect, the invention provides a formulation
comprising an active agent, such as a RAR selective agonist, and a
carrier medium, wherein the formulation is suitable for topical
administration. "Topical administration" means the application or
spreading of a composition onto the surface of keratinous tissue.
Keratinous tissue includes keratin-containing layers disposed as
the outermost protective covering of mammals and includes, but is
not limited to, skin, hair and nails. A "topical formulation"
includes compositions suitable for topical administration on
keratinous tissue. Such compositions are typically
dermatologically-acceptable in that they do not have undue
toxicity, incompatibility, instability, allergic response and the
like, when applied to skin. Topical formulations of the present
invention can have a selected viscosity to avoid significant
dripping or pooling after application to skin.
[0129] An active agent may also be formulated for transdermal
delivery. The term "transdermal delivery" refers to the diffusion
of an agent across the barrier of the skin, nail, hair, claw or
hoof resulting from topical administration or other application of
a formulation. The stratum corneum acts as a barrier and few
pharmaceutical agents are able to penetrate intact skin. In
contrast, the epidermis and dermis are permeable to many solutes
and absorption of drugs therefore occurs more readily through skin,
nail, hair, claw or hoof that is abraded or otherwise stripped of
the stratum corneum to expose the epidermis. Transdermal delivery
includes injection or other delivery through any portion of the
skin, nail, hair, claw or hoof or mucous membrane and
absorption.
[0130] The formulations of the present invention can be
incorporated into all types of vehicles. Non-limiting examples of
suitable vehicles include liquids, emulsions (e.g., water-in-oil,
water-in-oil-in-water, oil-in-water, oil-in-water-in-oil,
oil-in-water-in-silicone emulsions), creams, lotions, solutions
(both aqueous and hydro-alcoholic), anhydrous bases (such as
lipsticks and powders), gels, ointments and any combination of the
forgoing as would be known to one of ordinary skill in the art. See
for example, Remington's Pharmaceutical Sciences (Mack Pub. Co.
1995). The formulations of the present invention can also be used
in many products including, but not limited to, sunscreen products,
sunless skin tanning products, hair products, finger nail products,
moisturizing creams, skin benefit creams and lotions, softeners,
day lotions, foundations, night creams, lipsticks, cleansers,
toners, masks, or other known applications. Additionally, the
products can be formulated as leave-on or rinse-off products. In
some embodiments, the formulations can be oil-free, substantially
anhydrous, and/or anhydrous. In some embodiments, the formulations
comprise water. Variations and other appropriate vehicles will be
apparent to the skilled artisan and are appropriate for use in the
present invention. In certain aspects, it is important that the
concentrations and combinations of the compounds, ingredients, and
agents be selected in such a way that the combinations are
chemically compatible and do not form complexes that precipitate
from the finished product.
[0131] In exemplary embodiments, an active agent such as a RAR
selective agonist is in the form of a cream, ointment or gel. Such
forms are particularly useful for topical administration. In the
context of the present invention, an ointment includes any
chemically suitable cream known in the art of retinoid agonists as
applicable for administration to a subject. Examples of
conventional ointment known in the art include the lipophilic
ointment dispersed in a hydrophilic phase. For intranasal
administration, useful forms include a nasal emulsion.
[0132] A lotion or cream may include a relatively large aqueous
phase and a relatively small oil phase. Furthermore, the lotions
and creams of the invention may include the active compound
"all-in-solution" in the oil phase so that substantially none of
the active compound crystallizes out at room temperature. In one
embodiment, the lotion or cream may comprise a biphasic system,
that is, a system wherein a portion (from about 30 to about 75% by
weight) of the active compound is in solution in the oil phase and
the remainder is in suspension in the aqueous phase.
[0133] Gel formulations can also be used in connection with the
present invention. As will be appreciated by the skilled
practitioner, gels are semisolid. Single-phase gels contain organic
macromolecules distributed substantially uniformly throughout the
carrier liquid, which is typically aqueous, but also may be a
solvent or solvent blend. In various embodiments, conventional
gelling agents can be used. In an exemplary embodiment, cellulose
or its derivatives are used. In an exemplary embodiment,
hydroxypropyl methyl cellulose, such as Methocel E4M, is used.
Other gelling agents include methyl cellulose, hydroxypropyl
cellulose, hydroxypropyl methyl cellulose, cellulose acetate, ethyl
cellulose, methyl hydroxy ethyl cellulose, hydroxy ethyl cellulose
and cellulose gum. Cellulose based gelling agents, particularly
hydroxymethylcellulose and hydroxypropyl methyl cellulose, are also
useful in some embodiments. In some embodiments, cross-linked
acrylic polymers including Carbopol may be used.
[0134] In one embodiment, the formulation of the invention is
viscous enough to form a firm gel. In one embodiment, the viscosity
is in the range of 25,000-300,000 cps (centipoise) or
75,000-200,000 cps, based on Brookfield (LV) analysis.
[0135] Ointments, which are semisolid preparations, are typically,
though not always, based on petrolatum or other petroleum
derivatives. The specific ointment base to be used is typically one
that provides for optimum delivery for the active agent chosen for
a given formulation and preferably provides for other desired
characteristics as well, e.g., emolliency or the like. As with
other carriers or vehicles, an ointment base should be inert,
stable, nonirritating and non-sensitizing. As explained in
Remington: The Science and Practice of Pharmacy, 19th Ed. (Easton,
Pa.: Mack Publishing Co., 1995), at pages 1399-1404, ointment bases
may be grouped in four classes: oleaginous bases; emulsifiable
bases; emulsion bases; and water-soluble bases. Oleaginous ointment
bases include, for example, vegetable oils, fats obtained from
animals, and semisolid hydrocarbons obtained from petroleum.
Examples of oleaginous ointment bases include White Ointment USP,
Yellow Ointment NF, Oleic Acid USP, Olive Oil USP, Paraffin USP,
Petrolatum NF, White Petrolatum USP, Spermaceti Wax USP, Synthetic
Spermaceti NF, Starch Glycerite NF, White Wax USP, and Yellow Wax
USP. Emulsifiable ointment bases, also known as absorbent ointment
bases, contain little or no water and include, for example,
hydroxystearin sulfate, anhydrous lanolin and hydrophilic
petrolatum. Emulsion ointment bases are either water-in-oil (W/O)
emulsions or oil-in-water (O/W) emulsions, and include, for
example, cetyl alcohol, glyceryl monostearate, lanolin and stearic
acid. Preferred water-soluble ointment bases are prepared from
polyethylene glycols of varying molecular weight. See Remington:
The Science and Practice of Pharmacy, supra, for further
information.
[0136] Liquid formulations for topical administration may contain
as excipients sterile water or saline, alkylene glycols such as
propylene glycol, polyalkylene glycols such as polyethylene glycol,
oils of vegetable origin, hydrogenated naphthalenes and the like.
They may employ slightly acidic buffers in pH ranges of about 4 to
about 6. Suitable buffers include acetate, ascorbate and citrate at
concentrations ranging from about 5 mM to about 50 mM.
[0137] Any conventional carrier medium can be employed in the
vehicles described herein. The carrier medium can be any organic or
inorganic carrier material, such as water, gelatin, gum arabic,
lactose, starch, magnesium stearate, talc, polyalkylene glycols,
petroleum jelly and the like, sorbic acid and corn oil. A carrier
medium suitable for use in a pharmaceutical formulation according
to the present invention may be selected from the group consisting
of one or more glycerides, such as, for example, one or more
glycerol esters of saturated fatty acids or one or more
polyglycolysed glycerides, cocoa butter, theobroma or the like, one
or more high molecular weight polyethylene glycol, one or more
polyoxyethylene, lanolin and derivatives thereof, one or more fatty
acids, fatty alcohols, fatty esters (including, for example,
caprylic acid, caprylic triglyceride or the like), and one or more
organic oil (including, for example, hydrogenated vegetable oils)
or the like.
[0138] The CTFA International Cosmetic Ingredient Dictionary and
Handbook (2004 and 2008) describes a wide variety of non-limiting
ingredients that can be used in the context of the present
invention. Examples of these ingredient classes include: fragrances
(artificial and natural), dyes and color ingredients (e.g., Blue 1,
Blue 1 Lake, Red 40, titanium dioxide, D&C blue no. 4, D&C
green no. 5, D&C orange no. 4, D&C red no. 17, D&C red
no. 33, D&C violet no. 2, D&C yellow no. 10, and D&C
yellow no. 11), adsorbents, lubricants, solvents, moisturizers
(including, e.g., emollients, humectants, film formers, occlusive
agents, and agents that affect the natural moisturization
mechanisms of the skin), water-repellants, UV absorbers (physical
and chemical absorbers such as paraminobenzoic acid ("PABA") and
corresponding PABA derivatives, titanium dioxide, zinc oxide,
etc.), essential oils, vitamins (e.g. A, B, C, D, E, and K), trace
metals (e.g. zinc, calcium and selenium), anti-irritants (e.g.
steroids and non-steroidal anti-inflammatories), botanical extracts
(e.g. aloe vera, chamomile, cucumber extract, ginkgo biloba,
ginseng, and rosemary), anti-microbial agents, antioxidants (e.g.,
BHT and tocopherol), chelating agents (e.g., disodium EDTA and
tetrasodium EDTA), preservatives (e.g., methylparaben and
propylparaben), pH adjusters (e.g., sodium hydroxide and citric
acid), absorbents (e.g., aluminum starch octenylsuccinate, kaolin,
corn starch, oat starch, cyclodextrin, talc, and zeolite), skin
bleaching and lightening agents (e.g., hydroquinone and niacinamide
lactate), humectants (e.g., sorbitol, urea, and manitol),
exfoliants, waterproofing agents (e.g., magnesium/aluminum
hydroxide stearate), skin conditioning agents (e.g., aloe extracts,
allantoin, bisabolol, ceramides, dimethicone, hyaluronic acid, and
dipotassium glycyrrhizate). Other additional ingredients include
one or more penetration enhancers (which may be surfactants,
alcohols, esters, glycols or the like or any other suitable
penetration enhancer), surfactants (which may be cationic,
non-ionic, anionic or polymeric), emulsifiers, clays, anti-foaming
agents, spreading agents, barriers, solubilizing agents for the
therapeutic agent and the like.
[0139] Non-limiting examples of some of these ingredients are
provided in the following subsections.
a. UV Absorption Agents
[0140] UV absorption agents that can be used in combination with
the compositions of the present invention include chemical and
physical sunblocks. Non-limiting examples of chemical sunblocks
that can be used include para-aminobenzoic acid (PABA), PABA esters
(glyceryl PABA, amyldimethyl PABA and octyldimethyl PABA), butyl
PABA, ethyl PABA, ethyl dihydroxypropyl PABA, benzophenones
(oxybenzone, sulisobenzone, benzophenone, and benzophenone-1
through 12), cinnamates (octyl methoxycinnamate, isoamyl
pmethoxycinnamate, octylmethoxy cinnamate, cinoxate, diisopropyl
methyl cinnamate, DEA-methoxycinnamate, ethyl diisopropylcinnamate,
glyceryl octanoate dimethoxycinnamate and ethyl methoxycinnamate),
cinnamate esters, salicylates (homomethyl salicylate, benzyl
salicylate, glycol salicylate, isopropylbenzyl salicylate, etc.),
anthranilates, ethyl urocanate, homosalate, octisalate,
dibenzoylmethane derivatives (e.g., avobenzone), octocrylene, octyl
triazone, digalloy trioleate, glyceryl aminobenzoate, lawsone with
dihydroxyacetone, ethylhexyl triazone, dioctyl butamido triazone,
benzylidene malonate polysiloxane, terephthalylidene dicamphor
sulfonic acid, disodium phenyl dibenzimidazole tetrasulfonate,
diethylamino hydroxybenzoyl hexyl benzoate, bis diethylamino
hydroxybenzoyl benzoate, bis benzoxazoylphenyl ethylhexylimino
triazine, drometrizole trisiloxane, methylene bis-benzotriazolyl
tetramethylbutylphenol, and bis-ethylhexyloxyphenol
methoxyphenyltriazine, 4-methylbenzylidenecamphor, and isopentyl
4-methoxycinnamate. Non-limiting examples of physical sunblocks
include, kaolin, talc, petrolatum and metal oxides (e.g., titanium
dioxide and zinc oxide). Compositions of the present invention can
have UVA and UVB absorption properties. The compositions can have
an sun protection factor (SPF) of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90 or
more, or any integer therein.
[0141] In some embodiments, a formulation comprises a UV absorption
agent in an amount of about 0.05 to about 15 wt %, preferably from
about 0.5 to about 5.0 wt %.
b. Moisturizing Agents
[0142] Non-limiting examples of moisturizing agents that can be
used with the formulations of the present invention include amino
acids, chondroitin sulfate, diglycerin, erythritol, fructose,
glucose, glycerin, glycerol polymers, glycol, 1,2,6-hexanetriol,
honey, hyaluronic acid, hydrogenated honey, hydrogenated starch
hydrolysate, inositol, lactitol, maltitol, maltose, mannitol,
natural moisturizing factor, PEG-15 butanediol, polyglyceryl
sorbitol, salts of pyrollidone carboxylic acid, potassium PCA,
propylene glycol, sodium glucuronate, sodium PCA, sorbitol,
sucrose, trehalose, urea, and xylitol.
[0143] Other examples include acetylated lanolin, acetylated
lanolin alcohol, alanine, algae extract, aloe barbadensis,
aloe-barbadensis extract, aloe barbadensis gel, althea officinalis
extract, apricot (prunus armeniaca) kernel oil, arginine, arginine
aspartate, arnica montana extract, aspartic acid, avocado (persea
gratissima) oil, barrier sphingolipids, butyl alcohol, beeswax,
behenyl alcohol, beta-sitosterol, birch (betula alba) bark extract,
borage (borago officinalis) extract, butcherbroom (ruscus
aculeatus) extract, butylene glycol, calendula officinalis extract,
calendula officinalis oil, candelilla (euphorbia cerifera) wax,
canola oil, caprylic/capric triglyceride, cardamon (elettaria
cardamomum) oil, carnauba (copernicia cerifera) wax, carrot (daucus
carota sativa) oil, castor (ricinus communis) oil, ceramides,
ceresin, ceteareth-5, ceteareth-12, ceteareth-20, cetearyl
octanoate, ceteth-20, ceteth-24, cetyl acetate, cetyl octanoate,
cetyl palmitate, chamomile (anthemis nobilis) oil, cholesterol,
cholesterol esters, cholesteryl hydroxystearate, citric acid, clary
(salvia sclarea) oil, cocoa (theobroma cacao) butter,
coco-caprylate/caprate, coconut (cocos nucifera) oil, collagen,
collagen amino acids, corn (zea mays) oil, fatty acids, decyl
oleate, dimethicone copolyol, dimethiconol, dioctyl adipate,
dioctyl succinate, dipentaerythrityl hexacaprylate/hexacaprate,
DNA, erythritol, ethoxydiglycol, ethyl linoleate, eucalyptus
globulus oil, evening primrose (oenothera biennis) oil, fatty
acids, geranium maculatum oil, glucosamine, glucose glutamate,
glutamic acid, glycereth-26, glycerin, glycerol, glyceryl
distearate, glyceryl hydroxystearate, glyceryl laurate, glyceryl
linoleate, glyceryl myristate, glyceryl oleate, glyceryl stearate,
glyceryl stearate SE, glycine, glycol stearate, glycol stearate SE,
glycosaminoglycans, grape (vitis vinifera) seed oil, hazel (corylus
americana) nut oil, hazel (corylus avellana) nut oil, hexylene
glycol, hyaluronic acid, hybrid safflower (carthamus tinctorius)
oil, hydrogenated castor oil, hydrogenated coco-glycerides,
hydrogenated coconut oil, hydrogenated lanolin, hydrogenated
lecithin, hydrogenated palm glyceride, hydrogenated palm kernel
oil, hydrogenated soybean oil, hydrogenated tallow glyceride,
hydrogenated vegetable oil, hydrolyzed collagen, hydrolyzed
elastin, hydrolyzed glycosaminoglycans, hydrolyzed keratin,
hydrolyzed soy protein, hydroxylated lanolin, hydroxyproline,
isocetyl stearate, isocetyl stearoyl stearate, isodecyl oleate,
isopropyl isostearate, isopropyl lanolate, isopropyl myristate,
isopropyl palmitate, isopropyl stearate, isostearamide DEA,
isostearic acid, isostearyl lactate, isostearyl neopentanoate,
jasmine (jasminum officinale) oil, jojoba (buxus chinensis) oil,
kelp, kukui (aleurites moluccana) nut oil, lactamide MEA,
laneth-16, laneth-10 acetate, lanolin, lanolin acid, lanolin
alcohol, lanolin oil, lanolin wax, lavender (lavandula
angustifolia) oil, lecithin, lemon (citrus medica limonum) oil,
linoleic acid, linolenic acid, macadamia ternifolia nut oil,
maltitol, matricaria (chamomilla recutita) oil, methyl glucose
sesquistearate, methylsilanol PCA, mineral oil, mink oil,
mortierella oil, myristyl lactate, myristyl myristate, myristyl
propionate, neopentyl glycol dicaprylate/dicaprate, octyldodecanol,
octyldodecyl myristate, octyldodecyl stearoyl stearate, octyl
hydroxystearate, octyl palmitate, octyl salicylate, octyl stearate,
oleic acid, olive (olea europaea) oil, orange (citrus aurantium
dulcis) oil, palm (elaeis guineensis) oil, palmitic acid,
pantethine, panthenol, panthenyl ethyl ether, paraffin, PCA, peach
(prunus persica) kernel oil, peanut (arachis hypogaea) oil, PEG-8
C12-18 ester, PEG-15 cocamine, PEG-150 distearate, PEG-60 glyceryl
isostearate, PEG-5 glyceryl stearate, PEG30 glyceryl stearate,
PEG-7 hydrogenated castor oil, PEG-40 hydrogenated castor oil,
PEG-60 hydrogenated castor oil, PEG-20 methyl glucose
sesquistearate, PEG40 sorbitan peroleate, PEG-5 soy sterol, PEG-10
soy sterol, PEG-2 stearate, PEG-8 stearate, PEG-20 stearate, PEG-32
stearate, PEG-40 stearate, PEG-50 stearate, PEG-100 stearate,
PEG-150 stearate, pentadecalactone, peppermint (mentha piperita)
oil, petrolatum, phospholipids, polyamino sugar condensate,
polyglyceryl-3 diisostearate, polyquaternium-24, polysorbate 20,
polysorbate 40, polysorbate 60, polysorbate 80, polysorbate 85,
potassium myristate, potassium palmitate, propylene glycol,
propylene glycol dicaprylate/dicaprate, propylene glycol
dioctanoate, propylene glycol dipelargonate, propylene glycol
laurate, propylene glycol stearate, propylene glycol stearate SE,
PVP, pyridoxine dipalmitate, retinol, retinyl palmitate, rice
(oryza sativa) bran oil, RNA, rosemary (rosmarinus officinalis)
oil, rose oil, safflower (carthamus tinctorius) oil, sage (salvia
officinalis) oil, sandalwood (santalum album) oil, serine, serum
protein, sesame (sesamum indicum) oil, shea butter (butyrospermum
parkii), silk powder, sodium chondroitin sulfate, sodium
hyaluronate, sodium lactate, sodium palmitate, sodium PCA, sodium
polyglutamate, soluble collagen, sorbitan laurate, sorbitan oleate,
sorbitan palmitate, sorbitan sesquioleate, sorbitan stearate,
sorbitol, soybean (glycine soja) oil, sphingolipids, squalane,
squalene, stearamide MEA-stearate, stearic acid, stearoxy
dimethicone, stearoxytrimethylsilane, stearyl alcohol, stearyl
glycyrrhetinate, stearyl heptanoate, stearyl stearate, sunflower
(helianthus annuus) seed oil, sweet almond (prunus amygdalus
dulcis) oil, synthetic beeswax, tocopherol, tocopheryl acetate,
tocopheryl linoleate, tribehenin, tridecyl neopentanoate, tridecyl
stearate, triethanolamine, tristearin, urea, vegetable oil (e.g.,
corn oil), water, waxes, wheat (triticum vulgare) germ oil and
ylang ylang (cananga odorata) oil.
[0144] In some embodiments, a formulation comprises a moisturizing
agent in an amount of about 0.05 to about 20 wt %, preferably about
1.0 to about 10 wt %, preferably about 0.1 to about 3.0 wt %, more
preferably about 0.5, about 1.0, about 2.0 or about 2.5 wt %.
c. Antioxidants
[0145] Non-limiting examples of antioxidants that can be used with
the compositions of the present invention include acetyl cysteine,
ascorbic acid polypeptide, ascorbyl dipalmitate, ascorbyl
methylsilanol pectinate, ascorbyl palmitate, ascorbyl stearate,
butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),
t-butyl hydroquinone, cysteine, cysteine HCl, diamylhydroquinone,
di-t-butylhydroquinone, dicetyl thiodipropionate, dioleyl
tocopheryl methylsilanol, disodium ascorbyl sulfate, distearyl
thiodipropionate, ditridecyl thiodipropionate, dodecyl gallate,
erythorbic acid, esters of ascorbic acid, ethyl ferulate, ferulic
acid, gallic acid esters, hydroquinone, isooctyl thioglycolate,
kojic acid, magnesium ascorbate, magnesium ascorbyl phosphate,
methylsilanol ascorbate, natural botanical anti-oxidants such as
green tea or grape seed extracts, nordihydroguaiaretic acid, octyl
gallate, phenylthioglycolic acid, potassium ascorbyl tocopheryl
phosphate, potassium sulfite, propyl gallate, quinones, rosmarinic
acid, sodium ascorbate, sodium bisulfate, sodium erythorbate,
sodium metabisulfite, sodium sulfite, superoxide dismutase, sodium
thioglycolate, sorbityl furfural, thiodiglycol, thiodiglycolamide,
thiodiglycolic acid, thioglycolic acid, thiolactic acid,
thiosalicylic acid, tocophereth-5, tocophereth-10, tocophereth-12,
tocophereth-18, tocophereth-50, tocopherol, tocophersolan,
tocopheryl acetate, tocopheryl linoleate, tocopheryl nicotinate,
tocopheryl succinate, and tris(nonylphenyl)phosphite. In an
exemplary embodiment, a formulation comprises BHT.
[0146] In some embodiments, a formulation comprises an antioxidant
in amount of about 0.001 to about 1.0 wt %, preferably about 0.05
to about 0.75 wt % and more preferably about 0.1 wt % to about 0.5
wt %.
d. Structuring Agents
[0147] In some embodiments, a formulation comprises a structuring
agent. In some embodiments, a structuring agent assists in
providing rheological characteristics to the composition to
contribute to the composition's stability. In other embodiments, a
structuring agent can also function as an emulsifier or surfactant.
Non-limiting examples of structuring agents include stearic acid,
palmitic acid, stearyl alcohol, cetyl alcohol, behenyl alcohol,
stearic acid, palmitic acid, the polyethylene glycol ether of
stearyl alcohol having an average of about 1 to about 21 ethylene
oxide units, the polyethylene glycol ether of cetyl alcohol having
an average of about 1 to about 5 ethylene oxide units, and mixtures
thereof.
[0148] In some embodiments, a formulation comprises a structuring
agent in amount of about 0.5 to about 15.0 wt %, preferably about
1.0 to about 10.0 wt %, more preferably about 2.0 to about 5.0 wt
%.
e. Emulsifiers
[0149] In some embodiments, a formulation comprises an emulsifier.
Emulsifiers can reduce the interfacial tension between phases and
improve the formulation and stability of an emulsion. The
emulsifiers can be nonionic, cationic, anionic, and zwitterionic
emulsifiers. See, e.g., 2010 McCutcheon's Emulsifiers &
Detergents North American edition (Mccutcheon's Emulsifiers and
Detergents) (McCutcheon's Publications Apr. 1, 2010); and U.S. Pat.
Nos. 5,011,681; 4,421,769 and 3,755,560. Topical formulations may
include emulsifiers that act as stabilizers to enhance stability of
the active agent or of the formulation itself. Non-limiting
examples include esters of glycerin, esters of propylene glycol,
fatty acid esters of polyethylene glycol, fatty acid esters of
polypropylene glycol, esters of sorbitol, esters of sorbitan
anhydrides, carboxylic acid copolymers, esters and ethers of
glucose, ethoxylated ethers, ethoxylated alcohols, alkyl
phosphates, polyoxyethylene fatty ether phosphates, fatty acid
amides, acyl lactylates, soaps, TEA stearate, DEA oleth-3
phosphate, polyethylene glycol 20 sorbitan monolaurate (polysorbate
20), polyethylene glycol 5 soya sterol, steareth-2, steareth-20,
steareth-21, ceteareth-20, PPG-2 methyl glucose ether distearate,
ceteth-10, polysorbate 80, cetyl phosphate, potassium cetyl
phosphate, diethanolamine cetyl phosphate, polysorbate 60, glyceryl
stearate, PEG-100 stearate, and mixtures thereof. An exemplary
emulsifier or surfactant is polyoxyl stearate (e.g., polyoxyl 40
stearate).
[0150] In some embodiments, a formulation comprises an emulsifying
agent in amount from about 0.5 to about 2.5 wt %, preferably 0.5 to
2.0%, more preferably 1.0% or 1.8%.
f. Silicone Containing Compounds
[0151] In some embodiments, a formulation includes a silicone
containing compound, i.e., any member of a family of polymeric
products whose molecular backbone is made up of alternating silicon
and oxygen atoms with side groups attached to the silicon atoms. By
varying the --Si--O-- chain lengths, side groups, and crosslinking,
silicones can be synthesized into a wide variety of materials. They
can vary in consistency from liquid to gel to solids.
[0152] The silicone containing compounds that can be used in the
context of the present invention include those described in this
specification or those known to a person of ordinary skill in the
art. Non-limiting examples include silicone oils (e.g., volatile
and non-volatile oils), gels, and solids. In certain aspects, the
silicon containing compounds includes a silicone oils such as a
polyorganosiloxane. Non-limiting examples of polyorganosiloxanes
include dimethicone, cyclomethicone, polysilicone-11, phenyl
trimethicone, trimethylsilylamodimethicone,
stearoxytrimethylsilane, or mixtures of these and other
organosiloxane materials in any given ratio in order to achieve the
desired consistency and application characteristics depending upon
the intended application (e.g., to a particular area such as the
skin, hair, or eyes). A "volatile silicone oil" includes a silicone
oil have a low heat of vaporization, i.e. normally less than about
50 cal per gram of silicone oil. Non-limiting examples of volatile
silicone oils include: cyclomethicones such as Dow Corning 344
Fluid, Dow Corning 345 Fluid, Dow Corning 244 Fluid, and Dow
Corning 245 Fluid, Volatile Silicon 7207 (Union Carbide Corp.,
Danbury, Conn.); low viscosity dimethicones, i.e. dimethicones
having a viscosity of about 50 cst or less (e g, dimethicones such
as Dow Corning 200-0.5 cst Fluid). The Dow Corning Fluids are
available from Dow Corning Corporation, Midland, Mich.
Cyclomethicone and dimethicone are described in the Third Edition
of the CTFA Cosmetic Ingredient Dictionary (incorporated by
reference) as cyclic dimethyl polysiloxane compounds and a mixture
of fully methylated linear siloxane polymers end-blocked with
trimethylsiloxy units, respectively. Other non-limiting volatile
silicone oils that can be used in the context of the present
invention include those available from General Electric Co.,
Silicone Products Div., Waterford, N.Y. and SWS Silicones Div. of
Stauffer Chemical Co., Adrian, Mich.
[0153] In some embodiments, a formulation comprises a silicone
containing compound in an amount from about 0.1 to 15 wt %,
preferably 0.1 to about 3.0 wt %, more preferably about 0.5, 1.0,
or 2.5 wt %.
g. Essential Oils
[0154] In some embodiments, a formulation comprises an essential
oil. Essential oils include oils derived from herbs, flowers,
trees, and other plants. Such oils are typically present as tiny
droplets between the plant's cells, and can be extracted by several
method known to those of skill in the art (e.g., steam distilled,
enfleurage (i.e., extraction by using fat), maceration, solvent
extraction, or mechanical pressing). When these types of oils are
exposed to air they tend to evaporate (i.e., a volatile oil). As a
result, many essential oils are colorless, but with age they can
oxidize and become darker. Essential oils are insoluble in water
and are soluble in alcohol, ether, fixed oils (vegetal), and other
organic solvents. Typical physical characteristics found in
essential oils include boiling points that vary from about
160.degree. C. to 240.degree. C. and densities ranging from about
0.759 to about 1.096.
[0155] Essential oils typically are named by the plant from which
the oil is found. For example, rose oil or peppermint oil are
derived from rose or peppermint plants, respectively. Non-limiting
examples of essential oils that can be used in the context of the
present invention include sesame oil, macadamia nut oil, tea tree
oil, evening primrose oil, Spanish sage oil, Spanish rosemary oil,
coriander oil, thyme oil, pimento berries oil, rose oil, anise oil,
balsam oil, bergamot oil, rosewood oil, cedar oil, chamomile oil,
sage oil, clary sage oil, clove oil, cypress oil, eucalyptus oil,
fennel oil, sea fennel oil, frankincense oil, geranium oil, ginger
oil, grapefruit oil, jasmine oil, juniper oil, lavender oil, lemon
oil, lemongrass oil, lime oil, mandarin oil, marjoram oil, myrrh
oil, neroli oil, orange oil, patchouli oil, pepper oil, black
pepper oil, petitgrain oil, pine oil, rose otto oil, rosemary oil,
sandalwood oil, spearmint oil, spikenard oil, vetiver oil,
wintergreen oil, or ylang ylang. Other essential oils known to
those of skill in the art are also contemplated as being useful
within the context of the present invention.
[0156] In some embodiments, a formulation comprises an essential
oil in amount of about 0.1 to about 15.0 wt %, preferably about 1.0
to about 10.0 wt % or preferably about 2.0 to about 5.0 wt %.
h. Thickening Agents
[0157] In some embodiments, a formulation comprises a thickening
agent. Thickening agents, including thickener or gelling agents,
include substances which that can increase the viscosity of a
composition. Thickeners include those that can increase the
viscosity of a composition without substantially modifying the
efficacy of the active ingredient within the composition. Topical
formulations may include thickening agents that act as stabilizers
to enhance stability of the active agent or of the formulation
itself. In certain aspects of the present invention, thickeners
include hydrogenated polyisobutene or trihydroxystearin, or a
mixture of both. One exemplary thickening agent is xanthan gum.
[0158] Non-limiting examples of additional thickening agents that
can be used in the context of the present invention include
carboxylic acid polymers, crosslinked polyacrylate polymers,
polyacrylamide polymers, polysaccharides and gums. Examples of
carboxylic acid polymers include crosslinked compounds containing
one or more monomers derived from acrylic acid, substituted acrylic
acids, and salts and esters of these acrylic acids and the
substituted acrylic acids, wherein the crosslinking agent contains
two or more carbon-carbon double bonds and is derived from a
polyhydric alcohol (see U.S. Pat. Nos. 5,087,445; 4,509,949;
2,798,053; CTFA International Cosmetic Ingredient Dictionary,
Fourth edition, 1991, pp. 12 and 80). Examples of commercially
available carboxylic acid polymers include carbomers, which are
homopolymers of acrylic acid crosslinked with allyl ethers of
sucrose or pentaerytritol (e.g., Carbopol.TM. 900 series from B. F.
Goodrich).
[0159] In some embodiments, a formulation comprises a thickening
agent in an amount of about 0.1 to about 20.0 wt %, preferably
about 0.25 to about 10.0 wt %, more preferably from about 0.5 to
about 5.0 wt %.
i. Hardeners and Plasticizers
[0160] In some embodiments, a formulation comprises a hardeners
(also called a "stiffener") and/or a plasticizer or the like.
Suitable hardeners include, for example, beeswax, an alcohol (e.g.,
cetyl alcohol, stearyl alcohol, myristyl alcohol), stearic acid,
aluminium monostearate, bentonite or the like. Suitable
plasticizers include, for example, glyceryl monostearate,
polysorbate 80, propylene glycol or the like.
[0161] In some embodiments, a formulation comprises a hardener or a
plasticizer in an amount of about 0.1 to about 15.0 wt %,
preferably about 1.0 to about 10.0 wt %, more preferably about 2.0
to about 5.0 wt %
j. Preservatives
[0162] In some embodiments, a formulation comprises a preservative.
Useful preservatives known in the art include benzalkonium
chloride, benzethonium, chlorohexidine, phenol, m-cresol, benzyl
alcohol, methylparaben, propylparaben and other parabens,
chlorobutanol, o-cresol, p-cresol, chlorocresol, phenylmercuric
nitrate, thimerosal, benzoic acid, sorbic acid and various mixtures
thereof. See, e.g., Wallhausser, K.-H., Develop. Biol. Standard,
24:9-28 (1974) (S. Krager, Basel). Preferably, the preservative is
selected from methylparaben, propylparaben and mixtures
thereof.
[0163] In some embodiments, a formulation comprises a preservative
in an amount of about 0.01 to about 1.0 wt %, preferably from about
0.1 to 0.5 wt %, more preferably from about 0.03 to about 0.15 wt
%. When alcohol is used as a preservative, the amount is usually
about 15.0 to about 20.0%.
[0164] In some embodiments, a formulation comprises an active
agent, a hardener, a structuring agent, a moisturizer, an
emulsifier or surfactant, an antioxidant, a thickening agent, a
preservative and a solvent. In some embodiments, a formulation
comprises an active agent, a solvent and any combination of a
hardener, a structuring agent, a moisturizer, an emulsifier, a
surfactant, an antioxidant, a thickening agent and a preservative.
In some embodiments, a formulation comprises an active agent, an
emulsifier, a hardener, a thickening agent, an antioxidant, a
thickening agent (or stabilizer), a preservative and a solvent, and
in exemplary embodiments, the formulation further comprises more
than one of any of these components. In exemplary embodiments, the
solvent is water.
[0165] In some embodiments, a formulation comprises a RAR selective
agonist, stearyl alcohol, stearic acid, isopropylmyristate,
butylated hydroxytoluene, gum xanthan, polyoxyl stearate, sorbic
acid, oil, and water. This formulation is particularly useful for
making ointments.
Oral Administration
[0166] In one aspect, the invention provides an formulation
comprising an active agent, such as a RAR selective agonist and a
carrier medium, wherein the formulation is suitable for oral
administration. Such oral formulations can be a solid, semisolid or
liquid. Example dosage forms include tablets, lozenges, troches,
pills, aqueous or oily suspensions, solid dispersions, granules,
powders, emulsions, capsules, syrups, elixirs, gargle, sprays and
gums. Pharmaceutically common capsules include gelatin hard
capsules, soft gelatin capsules, starch capsules. The capsules may
be filled with powders, granulates, pellets, tablets or a filling.
The carrier medium in an oral formulation comprises one or more
excipients, diluents, carriers, additives and combinations thereof
known in the art that may be combined with an active agent (such as
a RAR selective agonist disclosed herein) to enhance, facilitate or
enable the production, storage, administration, delivery or
effectiveness of the active compound.
[0167] An oral formulation typically comprises a carrier medium in
the range of from about 70% to about 99.9% (w/w), preferably from
about 80% to about 95% (w/w) of the formulation. In some
embodiments, a RAR selective agonist is present in a range selected
from about 1 mg/mL to about 200 mg/mL, about 10 mg/mL to about 175
mg/mL, about 20 mg/mL to about 150 mg/mL, about 30 mg/mL to about
125 mg/mL, about 40 mg/mL to about 100 mg/mL and about 50 mg/mL to
about 75 mg/mL. In one embodiment, a formulation comprises a RAR
selective agonist at a concentration selected from about 1 mg/mL,
about 2 mg/mL, about 2.5 mg/mL, about 5 mg/mL, about 10 mg/mL,
about 15 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL,
about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL,
about 55 mg/mL, about 60 mg/mL, about 75 mg/mL, about 80 mg/mL,
about 90 mg/mL, about 100 mg/mL, about 120 mg/mL, about 125 mg/mL,
about 150 mg/mL, about 175 mg/mL and about 200 mg/mL.
[0168] In some embodiments, a RAR selective agonist is present in a
range selected from about 1 mg/g to about 250 mg/g, or optionally
about 20 mg/g to about 200 mg/g, or about 40 mg/g to about 180
mg/g, or about 60 mg/g to about 160 mg/g, or about 80 mg/g to about
130 mg/g, or about 50 mg/g to about 100 mg/g. In one embodiment, a
formulation comprises a RAR selective agonist at a concentration of
about 133 mg/g, about 185 mg/g, about 200 mg/g, and about 250 mg/g.
Exemplary amounts of RAR selective agonist include, without
limitation, about 20 mg/g, about 50 mg/g, about 75 mg/g, about 100
mg/g, about 120 mg/g, about 130 mg/g, about 140 mg/g, about 150
mg/g, about 175 mg/g and about 200 mg/g.
[0169] In some embodiments, the formulation comprises an excipient.
Excipients commonly used to formulate such dosage forms include
encapsulating materials or formulation additives such as absorption
accelerators, antioxidants, binders, buffers, coating agents,
coloring agents, diluents, disintegrating agents, emulsifiers,
extenders, fillers, flavoring agents, humectants, lubricants,
preservatives, propellants, releasing agents, sterilizing agents,
sweeteners, solubilizers and mixtures thereof. Examples of specific
excipients include agar, alginic acid, aluminum hydroxide, benzyl
benzoate, 1,3-butylene glycol, castor oil, cellulose, cellulose
acetate, cocoa butter, corn starch, corn oil, cottonseed oil,
ethanol, ethyl acetate, ethyl carbonate, ethyl cellulose, ethyl
laureate, ethyl oleate, gelatin, germ oil, glucose, glycerol,
groundnut oil, isopropanol, isotonic saline, lactose, magnesium
hydroxide, magnesium stearate, malt, olive oil, peanut oil,
potassium phosphate salts, potato starch, propylene glycol, talc,
tragacanth, water, safflower oil, sesame oil, sodium carboxymethyl
cellulose, sodium lauryl sulfate, sodium phosphate salts, soybean
oil, sucrose, tetrahydrofurfuryl alcohol, and mixtures thereof.
[0170] In some embodiments, the formulation comprises a diluent.
Suitable diluents illustratively include, either individually or in
combination, lactose, including anhydrous lactose and lactose
monohydrate; lactitol; maltitol; mannitol; sorbitol; xylitol;
dextrose and dextrose monohydrate; fructose; sucrose and
sucrose-based diluents such as compressible sugar, confectioner's
sugar and sugar spheres; maltose; inositol; hydrolyzed cereal
solids; starches (e.g., corn starch, wheat starch, rice starch,
potato starch, tapioca starch, etc.), starch components such as
amylose and dextrates, and modified or processed starches such as
pregelatinized starch; dextrins; celluloses including powdered
cellulose, microcrystalline cellulose, silicified microcrystalline
cellulose, food grade sources of .alpha.- and amorphous cellulose
and powdered cellulose, and cellulose acetate; calcium salts
including calcium carbonate, tribasic calcium phosphate, dibasic
calcium phosphate dihydrate, monobasic calcium sulfate monohydrate,
calcium sulfate and granular calcium lactate trihydrate; magnesium
carbonate; magnesium oxide; bentonite; kaolin; sodium chloride; and
the like. Such diluents, if present, typically constitute in total
about 5% to about 95%, for example about 20% to about 90%, or about
50% to about 85%, by weight of the composition. The diluent or
diluents selected preferably exhibit suitable flow properties and,
where tablets are desired, compressibility.
[0171] In some embodiments, the formulation comprises disintegrant.
Suitable disintegrants include, either individually or in
combination, starches including pregelatinized starch and sodium
starch glycolate; clays; magnesium aluminum silicate;
cellulose-based disintegrants such as powdered cellulose,
microcrystalline cellulose, methylcellulose, low-substituted
hydroxypropylcellulose, carmellose, carmellose calcium, carmellose
sodium and croscarmellose sodium; alginates; povidone;
crospovidone; polacrilin potassium; gums such as agar, guar, locust
bean, karaya, pectin and tragacanth gums; colloidal silicon
dioxide; and the like. One or more disintegrants, if present,
typically constitute in total about 0.2% to about 30%, for example
about 0.5% to about 20%, or about 1% to about 10%, by weight of the
composition.
[0172] In some embodiments, the formulation comprises a binding
agent or adhesive. Binding agents or adhesives are useful
excipients, particularly where the composition is in the form of a
tablet. Such binding agents and adhesives should impart sufficient
cohesion to the blend being tableted to allow for normal processing
operations such as sizing, lubrication, compression and packaging,
but still allow the tablet to disintegrate and the composition to
be absorbed upon ingestion. Suitable binding agents and adhesives
include, either individually or in combination, acacia; tragacanth;
glucose; polydextrose; starch including pregelatinized starch;
gelatin; modified celluloses including methylcellulose, carmellose
sodium, hydroxypropylmethylcellulose (HPMC),
hydroxypropylcellulose, hydroxyethylcellulose and ethylcellulose;
dextrins including maltodextrin; zein; alginic acid and salts of
alginic acid, for example sodium alginate; magnesium aluminum
silicate; bentonite; polyethylene glycol (PEG); polyethylene oxide;
guar gum; polysaccharide acids; polyvinylpyrrolidone (povidone or
PVP), for example povidone K-15, K-30 and K-29/32; polyacrylic
acids (carbomers); polymethacrylates; and the like. One or more
binding agents and/or adhesives, if present, typically constitute
in total about 0.5% to about 25%, for example about 1% to about
15%, or about 1.5% to about 10%, by weight of the composition.
[0173] In some embodiments, the formulation comprises a wetting
agent. Wetting agents are normally selected to maintain the drug in
close association with water, a condition that can improve
bioavailability of the composition. Non-limiting examples of
surfactants that can be used as wetting agents include, either
individually or in combination, quaternary ammonium compounds, for
example benzalkonium chloride, benzethonium chloride and
cetylpyridinium chloride; dioctyl sodium sulfosuccinate;
polyoxyethylene alkylphenyl ethers, for example nonoxynol 9,
nonoxynol 10 and octoxynol 9; poloxamers (polyoxyethylene and
polyoxypropylene block copolymers); polyoxyethylene fatty acid
glycerides and oils, for example polyoxyethylene (8)
caprylic/capric mono- and diglycerides, polyoxyethylene (35) castor
oil and polyoxyethylene (40) hydrogenated castor oil;
polyoxyethylene alkyl ethers, for example ceteth-10, laureth-4,
laureth-23, oleth-2, oleth-10, oleth-20, steareth-2, steareth-10,
steareth-20, steareth-100 and polyoxyethylene (20) cetostearyl
ether; polyoxyethylene fatty acid esters, for example
polyoxyethylene (20) stearate, polyoxyethylene (40) stearate and
polyoxyethylene (100) stearate; sorbitan esters, for example
sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate
and sorbitan monostearate; polyoxyethylene sorbitan esters, for
example polysorbate 20 and polysorbate 80; propylene glycol fatty
acid esters, for example propylene glycol laurate; sodium lauryl
sulfate; fatty acids and salts thereof, for example oleic acid,
sodium oleate and triethanolamine oleate; glyceryl fatty acid
esters, for example glyceryl monooleate, glyceryl monostearate and
glyceryl palmitostearate; .alpha.-tocopherol polyethylene glycol
(1000) succinate (TPGS); tyloxapol; and the like. One or more
wetting agents, if present, typically constitute in total about
0.1% to about 15%, for example about 0.2% to about 10%, or about
0.5% to about 7%, by weight of the composition.
[0174] Nonionic surfactants, more particularly poloxamers, are
examples of wetting agents that can be useful herein.
Illustratively, a poloxamer such as Pluronic.TM. F127, if present,
can constitute about 0.1% to about 10%, for example about 0.2% to
about 7%, or about 0.5% to about 5%, by weight of the
composition.
[0175] In some embodiments, the formulation comprises a lubricant.
Lubricants reduce friction between a tableting mixture and
tableting equipment during compression of tablet formulations.
Suitable lubricants include, either individually or in combination,
glyceryl behenate; stearic acid and salts thereof, including
magnesium, calcium and sodium stearates; hydrogenated vegetable
oils; glyceryl palmitostearate; talc; waxes; sodium benzoate;
sodium acetate; sodium fumarate; sodium stearyl fumarate; PEGs
(e.g., PEG 4000 and PEG 6000); poloxamers; polyvinyl alcohol;
sodium oleate; sodium lauryl sulfate; magnesium lauryl sulfate; and
the like. One or more lubricants, if present, typically constitute
in total about 0.05% to about 10%, for example about 0.1% to about
5%, or about 0.2% to about 2%, by weight of the composition. Sodium
stearyl fumarate is a particularly useful lubricant.
[0176] In some embodiments, the formulation comprises an
anti-adherent. Anti-adherents reduce sticking of a tablet
formulation to equipment surfaces. Suitable anti-adherents include,
either individually or in combination, talc, colloidal silicon
dioxide, starch, DL-leucine, sodium lauryl sulfate and metallic
stearates. One or more anti-adherents, if present, typically
constitute in total about 0.05% to about 10%, for example about
0.1% to about 7%, or about 0.2% to about 5%, by weight of the
composition. Colloidal silicon dioxide is a particularly useful
anti-adherent.
[0177] In some embodiments, the formulation comprises a glidant.
Glidants improve flow properties and reduce static in a tableting
mixture. Suitable glidants include, either individually or in
combination, colloidal silicon dioxide, starch, powdered cellulose,
sodium lauryl sulfate, magnesium trisilicate and metallic
stearates. One or more glidants, if present, typically constitute
in total about 0.05% to about 10%, for example about 0.1% to about
7%, or about 0.2% to about 5%, by weight of the composition.
Colloidal silicon dioxide is a particularly useful glidant.
[0178] Other excipients such as buffering agents, stabilizers,
antioxidants, antimicrobials, colorants, flavors and sweeteners are
known in the pharmaceutical art and can be used in the present
embodiments. Tablets can be uncoated or can comprise a core that is
coated, for example with a nonfunctional film or a
release-modifying or enteric coating. Capsules can have hard or
soft shells comprising, for example, gelatin (in the form of hard
gelatin capsules or soft elastic gelatin capsules), starch,
carrageenan and/or HPMC, optionally together with one or more
plasticizers.
[0179] In some embodiments, the formulation comprises an agent for
enhancing palatability, such as masking agents. A masking agent may
include one or more organic acids, including amino acids. Organic
acids of interest include, but are not limited to: glycolic acid,
lactic acid, methyl lactic acid, palycarobxlyic acids, e.g., malic
acid, citric acid, tartronic acid, tartaric acid, succinic acidetc.
Amino acids of interest include, but are not limited to: glycine,
alanine, valine, leucine, isoleucine, serine, threonine, cysteine,
cystine, methionine, aspartic acid, asparagine, glutamic acid,
glutamine, arginine, lysine, 5-hydroxylysine, histidine,
phenylalanine, tyrosine, tryptophan, 3-hydroxyproline,
4-hydroxyproline, proline, homocysteine, homocystine, homoserine,
ornithine, citrulline, creatine, asparaginic acid, 3-aminopropanoic
acid, theanine, 2-aminobutanoic acid, 4-aminobutanoic acid,
2-amino-2-methylpropanoic acid, 2-methyl-3-aminopropanoic acid,
2,6-diaminopimelic acid, 2-amino-3-phenylbutanoic acid,
phenylglycine, canavanine, canaline, 4-hydroxyarginine,
4-hydroxyornithine, homoarginine, 4-hydroxyhomoarginine,
.beta.-lysine, 2,4-diaminobutanoic acid, 2,3-diaminopropanoic acid,
2-methylserine, 3-phenylserine betaine, sulfur-containing amino
acids, such as taurine, cysteinesulfinic acid, methionine sulfoxide
and methionine sulfone. A masking agent can also be a saccharide or
polysaccharide, such as cyclodextrin. A formulation may also
comprise a sweetening agent such as fructose, aspartame or
saccharin; flavoring agents such as peppermint, oil of wintergreen,
or cherry coloring agents and preserving agents, to provide a
pharmaceutically palatable preparation.
[0180] In some embodiments, a formulation is a capsule comprising a
capsule shell and a filling. In exemplary embodiments, the filling
comprises, in any combination, a dispersing agent (e.g., cellulose
and its derivatives, such as carboxymethylcellulose and natural
gums); a solubilizing/oral absorption promoter agent (e.g.,
cyclodextrins, ethanol, triacetin, propylen glycol, glycerides,
medium and long chain fatty acid, polyoxyethylene hydrogenated or
non-hydrogenated vegetable oils derivatives); a surfactant (e.g.,
poloxamers, medium chain triglycerides, ethoxylated esters,
polyglycerol esters, polyoxyethylene alkyl ethers, sorbitan esters,
polyoxyethylene sorbitan fatty acid esters); and a viscosity
modifier (hydrogenated or non-hydrogenated vegetable oils, glycerol
esters, polyglycerol esters and propylene glycol esters). The
filling may also optionally contain chemical stabilizing-promoting
agents such as antioxidants and chelating agents.
[0181] In various embodiments, a formulation (especially a tablet,
pill or capsule) comprises a coating. The coating can be formulated
in order to control delivery of the active, whether rapid or slow,
sustained release is desired. In some embodiments, the oral
formulation is a tablet, pill or capsule coated to delay
disintegration and absorption in the gastrointestinal tract,
thereby providing a sustained action over an extended period of
time. Selectively permeable membranes surrounding an osmotically
active driving compound are also suitable for orally administered
compounds. In these later platforms, fluid from the environment
surrounding the capsule is imbibed by the driving compound, which
swells to displace the agent or agent composition through an
aperture. These delivery platforms can provide an essentially zero
order delivery profile as opposed to the spiked profiles of
immediate release formulations. A time delay material such as
glycerol monostearate or glycerol stearate may also be used.
Polymeric materials that can be used for sustained release include
but are not limited to, sodium carboxymethylcellulose,
hydroxypropylcellulose, hydroxypropylmethylcellulose and
hydroxyethylcellulose (preferably, hydroxypropyl methylcellulose).
Coating materials for sustained release include polymers with a
pH-dependent solubility (i.e., pH-controlled release), polymers
with a slow or pH-dependent rate of swelling, dissolution or
erosion (i.e., time-controlled release), polymers that are degraded
by enzymes (i.e., enzyme-controlled release) and polymers that form
firm layers that are destroyed by an increase in pressure (i.e.,
pressure-controlled release).
[0182] In some embodiments, a formulation is a rapid release oral
formulation. In these embodiments, the formulation comprises a
coating that either dissolves independently of the pH value or is
removed from the solid oral formulation upon contact with digestive
juice. In this way, relatively rapid disintegration of the drug
form and release of the active substance within a short period of
time are ensured, whereby high local concentrations of the active
substance are achieved. The coating may be applied using methods
such as film coating, press coating, tablet coating, encapsulating
or micro-encapsulating. The release of active substance from the
appropriately coated solid administration forms for oral
application, such as film tablets, coated tablets, laminated
tablets, capsules, or microcapsules, takes place more rapidly as
compared to the gastric juice-resistant administration forms.
Film-forming agents (i.e., coatings) for coating tablets include
those derived from, e.g., the groups of cellulose derivatives,
dextrins, starches and starch derivatives, polymers based on other
carbohydrates and derivatives thereof, natural gums such as gum
arabic, xanthans, alginates; polyacrylic acid, polyvinyl alcohol,
polyvinyl acetate, polyvinylpyrrolidone, polymethacrylates and
derivatives thereof (Eudragit.RTM.), chitosan and derivatives
thereof, shellac and derivatives thereof. In addition to these
film-forming agents, substances from the class of wax and fat
substances may be used to produce the coatings according to the
invention. In some embodiments, the cellulose derivative is
selected from soluble alkyl- or hydroxyalkylcellulose derivatives
such as methylcellulose, hydroxymethylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose,
methylhydroxyethylcellulose, methylhydroxypropylcellulose, or
sodium carboxymethylcellulose. In exemplary embodiments,
methylhydroxypropylcellulose is employed. The usual cellulose
derivatives suitable for pharmaceutical purposes, with varying
degrees of substitution and/or varying molecular weights
corresponding to varying viscosity levels of the aqueous solutions,
may be used as suitable film-forming agents on the basis of
cellulose. Likewise, insoluble cellulose derivatives such as
ethylcellulose may be employed.
[0183] If required, the films may contain additional adjuvants such
as plasticizers, pore-forming agents, filling agents, colorants,
pigments, antifoam agents, antistick agents, and the like. The
various polymers, adjuvants, excipients and additives described
through the present disclosure may be used in this respect. In
addition, all the pharmaceutically common or physiologically
tolerable adjuvants which are suited to form a closed coat by press
coating on the drug forms to be covered may be used. In particular,
these include adjuvants as are common in conventional tabletting,
specifically filling agents from the group of carbohydrates such as
lactose, saccharose, glucose and other sugars, microcrystalline
cellulose, starches and starch derivatives, sugar alcohols such as
mannitol, sorbitol, xylitol, inorganic filling agents such as
phosphates and carbonates. Other adjuvants as required in the
production of conventional tablets, such as binding agents,
disintegrants, flow agents, release agents, taste improvers,
pigments, and coloring agents may be contained in addition to the
filling agents.
[0184] In some embodiments, the formulation comprises a stabilizer.
Examples include those selected from lecithins; phospholipids;
pharmaceutical acceptable oils, e.g. soybean oils and the like,
polyethylenglycols and saturated or insaturated mono-, di- or
triglicerides. Other stabilizers disclosed herein may also be
used.
[0185] In some embodiments, the formulation comprises a RAR
selective agonist and a carrier, wherein the drug is in solution in
the carrier. This will be understood to mean that substantially all
of the drug is in solution, i.e., no substantial portion, for
example no more than about 2%, or no more than about 1%, of the
drug is in solid (e.g., crystalline) form, whether dispersed, for
example in the form of a suspension, or not. In practical terms,
this means that the drug must normally be formulated at a
concentration below its limit of solubility in the carrier. It will
be understood that the limit of solubility can be
temperature-dependent, thus selection of a suitable concentration
should take into account the range of temperatures to which the
composition is likely to be exposed in normal storage, transport
and use.
[0186] In some embodiments, the formulation comprises water.
[0187] In some embodiments, the formulation comprises an organic
solvent. Among preferred water-soluble organic solvents are
ethanol, benzyl alcohol, dimethylacetamide, PVP, PG and PEG
compounds such as: PEG 300, PEG 400, or PEG 400 monolaurate. The
PEG compound in the present compositions is provided in an amount
of about 5% to about 100%, or about 5% to about 60%, or about 10%
to about 90%, or about 20% to about 80%, or 30% to about 70%, or
about 40% to about 60%, all concentrations being a percentage of
volume/volume (v/v). PG may be present at a concentration of about
2.5% to about 100% (v/v).
[0188] The concentration of the PEG compounds in the present
compositions can vary depending on what other solubilizers or
diluents or excipients are also present. For example, the PEG 300,
PEG 400 or PEG 400 monolaurate of the present invention can be at a
concentration of about 5%, about 10%, about 12.5%, about 15%, about
20%, about 25%, about 30%, about 35%, about 40%, about 45%, about
50%, about 55%, about 60%, about 65%, about 70%, about 75%, about
80%, about 85%, about 90%, or about 95%, all such concentrations
being given as a percentage of volume/volume (v/v).
[0189] In some embodiments, the formulation is substantially
non-aqueous, i.e., having no water, or having an amount of water
that is small enough to be, in practical terms, essentially
non-deleterious to performance or properties of the composition.
Typically, the carrier comprises zero to less than about 5% by
weight water. It will be understood that certain ingredients useful
herein can bind small amounts of water on or within their molecules
or supramolecular structures; such bound water if present does not
affect the "substantially non-aqueous" character of the carrier as
defined herein. Suitable examples of long chain triglycerides
include any pharmaceutically acceptable vegetable oil, for example
canola, coconut, corn, cottonseed, flaxseed, olive, palm, peanut,
safflower, sesame, soy and sunflower oils, and mixtures of such
oils. Oils of animal, particularly marine animal, origin can also
be used, including for example fish oil.
[0190] In some embodiments, the formulation comprises one or more
glyceride materials. Suitable glyceride materials include, without
limitation, medium to long chain mono-, di- and triglycerides. The
term "medium chain" herein refers to hydrocarbyl chains
individually having no less than about 6 and less than about 12
carbon atoms, including for example C.sub.8 to C.sub.10 chains.
Thus glyceride materials comprising caprylyl and capryl chains,
e.g., caprylic/capric mono-, di- and/or triglycerides, are examples
of "medium chain" glyceride materials herein. The term "long chain"
herein refers to hydrocarbyl chains individually having at least
about 12, for example about 12 to about 18, carbon atoms, including
for example lauryl, myristyl, cetyl, stearyl, oleyl, linoleyl and
linolenyl chains. Medium to long chain hydrocarbyl groups in the
glyceride materials can be saturated, mono- or polyunsaturated.
[0191] In some embodiments, a formulation comprises a phospholipid
or mixture of phospholipids. In general such phospholipids are
phosphoric acid esters that yield on hydrolysis phosphoric acid,
fatty acid(s), an alcohol and a nitrogenous base. Pharmaceutically
acceptable phospholipids can include without limitation
phosphatidylcholines, phosphatidylserines and
phosphatidylethanolamines. In one embodiment the composition
comprises phosphatidylcholine, derived for example from natural
lecithin. Any source of lecithin can be used, including animal
sources such as egg yolk, but plant sources are generally
preferred. Soy is a particularly rich source of lecithin that can
provide phosphatidylcholine for use in the present invention.
[0192] Illustratively, a suitable amount of phospholipid is about
15% to about 75%, for example about 30% to about 60%, by weight of
the carrier, although greater and lesser amounts can be useful in
particular situations.
[0193] In some embodiments, a formulation comprises a glycol.
Generally, glycols tend to be suitable only for non-encapsulated
formulations or where a soft capsule shell is to be used, and tend
to be incompatible with hard shells such as hard gelatin shells.
Suitable glycols include propylene glycol and polyethylene glycols
(PEGs) having molecular weight of about 200 to about 1,000 g/mol,
e.g., PEG-400, which has an average molecular weight of about 400
g/mol. Such glycols can provide relatively high solubility of the
drug; however the potential for oxidative degradation of the drug
can be increased when in solution in a carrier comprising such
glycols, for example because of the tendency of glycols to produce
superoxides, peroxides and/or free hydroxyl radicals. The higher
the glycol content of the carrier, the greater may be the tendency
for degradation of a chemically unstable drug. In one embodiment,
therefore, one or more glycols are present in a total glycol amount
of at least about 1% but less than about 50%, for example less than
about 30%, less than about 20%, less than about 15% or less than
about 10% by weight of the carrier. In another embodiment, the
carrier comprises substantially no glycol.
[0194] Glycolides are glycols such as propylene glycol or PEG
esterified with one or more organic acids, for example medium- to
long-chain fatty acids. Suitable examples include propylene glycol
monocaprylate, propylene glycol monolaurate and propylene glycol
dilaurate products such as, for example. Capmul PG8.TM., Capmul
PG12.TM. and Capmul PG-2L.TM. respectively of Abitec Corp. and
products substantially equivalent thereto.
[0195] Suitable glyceride materials for use together with a
phospholipid include, without limitation, those mentioned above.
Glyceride materials such as medium chain and/or long chain mono-,
di- and triglycerides, more typically medium-chain mono-, di- and
triglycerides, can be present in a total glyceride amount of about
5% to about 70%, for example about 15% to about 60% or about 25% to
about 50%, by weight of the carrier, although greater and lesser
amounts can be useful in particular situations. In one embodiment,
the encapsulated liquid comprises about 7% to about 30%, for
example about 10% to about 25%, by weight medium-chain
triglycerides and about 7% to about 30%, for example about 10% to
about 25%, by weight medium-chain mono- and diglycerides.
[0196] Additional solubilizing agents that are other than glycols,
glycolides or glyceride materials can be included if desired. Such
agents, for example N-substituted amide solvents such as
dimethylformamide (DMF) and N,N-dimethylacetamide (DMA), can, in
specific cases, assist in raising the limit of solubility of the
drug in the carrier, thereby permitting increased drug loading.
However, the carriers useful herein generally provide adequate
solubility of small-molecule drugs of interest herein without such
additional agents.
[0197] In some embodiments, the formulation comprises a viscosity
reducing agent. An example of such an agent is an alcohol, more
particularly ethanol, which is preferably introduced in a form that
is substantially free of water, for example 99% ethanol, dehydrated
alcohol USP or absolute ethanol. Excessively high concentrations of
ethanol should, however, generally be avoided. This is particularly
true where, for example, the drug-carrier system is to be
administered in a gelatin capsule, because of the tendency of high
ethanol concentrations to result in mechanical failure of the
capsule. In general, suitable amounts of ethanol are 0% to about
25%, for example about 1% to about 20% or about 3% to about 15%, by
weight of the carrier. Glycols such as propylene glycol or PEG and
medium-chain mono- and diglycerides (for example caprylic/capric
mono- and diglycerides) can also be helpful to lower viscosity;
where the drug-carrier system is to be encapsulated in a hard
capsule such as a hard gelatin capsule, medium-chain mono- and
diglycerides are particularly useful in this regard.
[0198] In some embodiments, the formulation comprises a
non-phospholipid surfactant. Such a surfactant can serve various
functions, including for example enhancing dispersion of the
encapsulated liquid upon release from the capsule in the aqueous
environment of the gastrointestinal tract. Thus in one embodiment
the non-phospholipid surfactant is a dispersing and/or emulsifying
agent that enhances dispersion and/or emulsification of the capsule
contents in real or simulated gastrointestinal fluid.
Illustratively, a surfactant such as a polysorbate (polyoxyethylene
sorbitan ester), e.g., polysorbate 80 (available for example as
Tween 80.TM. from Uniqema), can be included in an amount of 0% to
about 30%, for example about 7% to about 30% or about 10% to about
25%, by weight of the carrier. In some embodiments such a
surfactant is included in an amount of 0% to about 5%, for example
0% to about 2% or 0% to about 1%, by weight of the carrier.
[0199] Other surfactants may be suitable and include, either
individually or in combination, quaternary ammonium compounds, for
example benzalkonium chloride, benzethonium chloride and
cetylpyridinium chloride; dioctyl sodium sulfosuccinate;
polyoxyethylene alkylphenyl ethers, for example nonoxynol 9,
nonoxynol 10 and octoxynol 9; poloxamers (polyoxyethylene and
polyoxypropylene block copolymers), for example poloxamer 188 and
poloxamer 237; polyoxyethylene fatty acid glycerides and oils, for
example polyoxyethylene (8) caprylic/capric mono- and diglycerides,
polyoxyethylene (35) castor oil and polyoxyethylene (40)
hydrogenated castor oil; polyoxyethylene alkyl ethers, for example
ceteth-10, laureth-4, laureth-23, oleth-2, oleth-10, oleth-20,
steareth-2, steareth-10, steareth-20, steareth-100 and
polyoxyethylene (20) cetostearyl ether; polyoxyethylene fatty acid
esters, for example polyoxyethylene (20) stearate, polyoxyethylene
(40) stearate and polyoxyethylene (100) stearate; sorbitan esters,
for example sorbitan monolaurate, sorbitan monooleate, sorbitan
monopalmitate and sorbitan monostearate; polyoxyethylene sorbitan
esters, for example polysorbate 20 and polysorbate 80; propylene
glycol fatty acid esters, for example propylene glycol laurate;
sodium lauryl sulfate; fatty acids and salts thereof, for example
oleic acid, sodium oleate and triethanolamine oleate; glyceryl
fatty acid esters, for example glyceryl monooleate, glyceryl
monostearate and glyceryl palmitostearate; .alpha.-tocopheryl
polyethylene glycol succinate (TPGS); tyloxapol; and the like. In
one embodiment, the at least one surfactant is a poloxamer or
mixture of poloxamers. Poloxamer 188 is a specific example. One or
more surfactants typically constitute in total about 10 to about
100 mg/ml of the suspension. In the case of poloxamer 188, an
illustratively suitable amount is about 10 to about 100 mg/ml, for
example about 15 to about 60 mg/ml, of the suspension. The
surfactant can be present in any desired effective amount, such as
at a concentration of about 1% (v/v) to about 100% (v/v),
preferably about 9% (v/v) to about 80% (v/v), and more preferably,
about 10% (v/v) to about 50% (v/v). As specific examples, preferred
concentrations of a non-ionic surfactant are Tween.RTM. 20 at a
concentration of about 9% (v/v) to about 100% (v/v) and Tween.RTM.
80 of about 33% (v/v) to about 100% (v/v). All percentages of the
surfactant are volume percentages (v/v).
[0200] In some embodiments, the formulation comprises a
cyclodextrin. The cyclodextrins herein may be .alpha.-cyclodextrin,
.beta.-cyclodextrin, .gamma.-cyclodextrin, and the modified
cyclodextrins may include HP-.beta.-CD and SBE-.beta.-CD, for
example. In one embodiment, the present composition contains a
modified cyclodextrin in a concentration of about 5% to about 80%,
or about 10% to about 70%, or about 20% to about 60%, or about 30%
to about 50%, all such concentrations being given as a percentage
of weight/volume (w/v).
[0201] In some embodiments, the formulation comprises a modified
cellulose, such as EC, HPMC, MC and CMC. The modified cellulose can
be present in any desired effective amount, such as a concentration
of about 0.1% to about 25%, or about 0.5% to about 7.5%, or about
1.0% to about 5%. As specific examples, EC may be present at a
concentration of about 5% to about 20%; HPMC may be present at a
concentration of about 0.5% to about 1%; MC may be present at a
concentration of about 1% to about 3%; and CMC may be present at a
concentration of about 1% to about 4%. The percentages of modified
cellulose are in weight per volume (w/v).
[0202] In another embodiment, the formulation comprise a
water-insoluble lipid, such as an oil, fat emulsion or wax. The
water-insoluble lipid carriers can be present in any desired
effective amount, such as a concentration of about 10% to about
100%, or about 15% to about 85%, or about 25% to about 75%.
Non-limiting examples of oils include corn oil, olive oil,
peppermint oil, soy bean oil, sesame seed oil, mineral oil and
glycerol. In one embodiment, the oil is present at a concentration
of about 10% (v/v) to about 100% (v/v). Mixed fat emulsion
compositions are available, such as Intralipid.RTM. emulsion, as
described above. In various embodiments, mixed fat emulsions may be
present at a concentration of about 10% (w/v) to about 30% (w/v);
and preferably about 20% (w/v). Non-limiting examples of suitable
waxes are beeswax and carnuba wax. In one embodiment, the wax is
present at a concentration of about 5% (w/w) to about 50%
(w/w).
[0203] In some embodiments, the formulation is a solid dispersion.
Solid dispersions comprise a RAR selective agonist in an
essentially non-crystalline or amorphous form, which is usually
more soluble than the crystalline form. The term "solid dispersion"
herein encompasses systems having small solid-state particles of
one phase dispersed in another solid-state phase. More
particularly, the present solid dispersions comprise one or more
active ingredients dispersed in an inert carrier or matrix in solid
state, and can be prepared by melting or solvent methods or by a
combination of melting and solvent methods.
[0204] The major component of the matrix of a solid dispersion
product is a polymer that is hydrophilic or water-soluble at least
in a part of the pH scale, more particularly at a pH occurring in
the gastrointestinal (GI) tract, or a combination of such polymers.
A polymer or polymer mixture useful herein is solid at ambient
temperature and, in the interests of good storage stability at a
range of temperatures, should remain solid even at the highest
temperatures typically experienced during storage, transport and
handling of the product. A useful property of a polymer determining
its usefulness herein is therefore its glass transition temperature
(T.sub.g). Suitable water-soluble polymers include, but are not
limited to, those having a T.sub.g of at least about 50.degree. C.,
more particularly about 80.degree. C. to about 180.degree. C.
Methods for determining T.sub.g values of organic polymers are
described for example in Sperling, ed. (1992) Introduction To
Physical Polymer Science, 2nd edition, John Wiley & Sons, Inc.
Exemplary polymers include homopolymers and copolymers of N-vinyl
lactams, especially homopolymers and copolymers of N-vinyl
pyrrolidone, e.g., the homopolymer polyvinylpyrrolidone (PVP or
povidone) and copolymers such as those comprising monomers of
N-vinyl pyrrolidone and vinyl acetate (copovidone) or N-vinyl
pyrrolidone and vinyl propionate; cellulose esters and cellulose
ethers, in particular methylcellulose, ethylcellulose,
(hydroxyalkyl)celluloses such as hydroxypropylcellulose,
(hydroxyalkyl)alkyl-celluloses such as hydroxypropylmethylcellulose
(HPMC or hypromellose), cellulose phthalates and succinates such as
cellulose acetate phthalate, hydroxypropylmethylcellulose
phthalate, hydroxypropylmethylcellulose succinate and
hydroxypropylmethylcellulose acetate succinate (HPMC-AS); high
molecular weight polyalkylene oxides such as polyethylene oxide,
polypropylene oxide and copolymers of ethylene oxide and propylene
oxide (poloxamers); polyacrylates and polymethacrylates such as
methacrylic acid/ethyl acrylate copolymers, methacrylic acid/methyl
methacrylate copolymers, butyl methacrylate/2-dimethylaminoethyl
methacrylate copolymers, poly(hydroxyalkyl acrylates) and
poly(hydroxyalkyl methacrylates); polyacrylamides; vinyl acetate
polymers such as copolymers of vinyl acetate and crotonic acid,
partially hydrolyzed polyvinyl acetate (also referred to as
partially saponified "polyvinyl alcohol") and polyvinyl alcohol;
oligo- and polysaccharides such as carrageenans, galactomannans and
xanthan gum; and mixtures of two or more thereof.
[0205] The dispersion, and other formulations, may further comprise
a non-ionic surfactant as disclosed herein.
[0206] As can be appreciated by one of skill in the art, an
excipient, carrier, diluent or additive that is suitable for
topical formulations may also in some instances be suitable for
oral formulations, and an excipient, carrier, diluent or additive
that is suitable for oral formulations may also in some instances
be suitable for topical formulations.
[0207] In one aspect, the invention provides a RAR selective
agonist as disclosed herein for treating a disease in a subject. In
one aspect, the invention provides a formulation of a RAR selective
agonist as disclosed herein for treating a disease in a subject. In
one aspect, the invention provides a RAR selective agonist as
disclosed herein for use in manufacturing a medicament for treating
a disease in a subject. In one aspect, the invention provides a
formulation of a RAR selective agonist as disclosed herein for use
in manufacturing a medicament for treating a disease in a
subject.
[0208] In one aspect, the invention provides a RAR selective
agonist as disclosed herein for preventing a disease in a subject.
In one aspect, the invention provides a formulation of a RAR
selective agonist as disclosed herein for preventing a disease in a
subject. In one aspect, the invention provides a RAR selective
agonist as disclosed herein for use in manufacturing a medicament
for preventing a disease in a subject. In one aspect, the invention
provides a formulation of a RAR selective agonist as disclosed
herein for use in manufacturing a medicament for preventing a
disease in a subject.
[0209] In one aspect, the invention provides a RAR selective
agonist as disclosed herein for inducing a medically beneficial
effect in a subject. In one aspect, the invention provides a
formulation of a RAR selective agonist as disclosed herein for
inducing a medically beneficial effect in a subject. In one aspect,
the invention provides a RAR selective agonist as disclosed herein
for use in manufacturing a medicament for inducing a medically
beneficial effect in a subject. In one aspect, the invention
provides a formulation of a RAR selective agonist as disclosed
herein for use in manufacturing a medicament for inducing a
medically beneficial effect in a subject.
Devices
[0210] In one aspect, the invention provides a medical device
comprising a RAR selective agonist or a formulation thereof. In
exemplary embodiments, the medical device is a stent. A variety of
stents known in the art can be used in the present invention, and
the underlying structure of the stent can be virtually any stent
design, whether of the self-expanding type or of the
balloon-expandable type and whether metal or polymeric. The stent
could be made of virtually any bio-compatible material having
physical properties suitable for the design. For example, tantalum
and stainless steel have been proven suitable for many such designs
and could be used in the present invention. Also, stents made with
biostable or bioabsorbable polymers such as poly(ethylene
terephthalate), polyacetal, poly(lactic acid), poly(ethylene
oxide)/poly(butylene terephthalate) copolymer could be used in the
present invention. Although the stent surface should be clean and
free from contaminants that may be introduced during manufacturing,
the stent surface requires no particular surface treatment in order
to retain the coating applied in the present invention. Both the
inner and outer surfaces of the stent may be provided with the
coating according to the present invention.
[0211] Particularly useful stents include those that are suitable
for controlled-release of a drug, such as a RAR selective agonist.
In exemplary embodiments, a stent comprises, in addition to the
drug, a carrier, such as a coating carrier, or a matrix. Some
materials suitable for the coating carrier are presently in
clinical use for the slow release of drugs, for example, from
capsules, tablets, powders, or other galenic preparations after
internal application into the gastrointestinal tract, such as
gelatin, cellulose and methacrylic acid. Synthetic polymers have
been developed which are degradable within the body, for use as
drug carriers. Incorporating drugs into carrier substances, and
using powders and micro-beads for timed, continuous release, have
been described.
[0212] The coating carrier can include a solvent and a synthetic or
naturally occurring polymer. The polymer chosen must be a polymer
that is biocompatible and minimizes irritation to the vessel wall
when the stent is implanted. The polymer may be either a biostable
or a bioabsorbable polymer depending on the desired rate of release
or the desired degree of polymer stability. Bioabsorbable polymers
that could be used include poly(L-lactic acid), polycaprolactone,
poly(lactide-co-glycolide), poly(hydroxybutyrate),
poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,
polyanhydride, poly(glycolic acid), poly(D,L-lactic acid),
poly(glycolic acid-co-trimethylene carbonate), polyphosphoester,
polyphosphoester urethane, poly(amino acids), cyanoacrylates,
poly(trimethylene carbonate), poly(iminocarbonate),
copoly(ether-esters) (e.g. PEO/PLA), polyalkylene oxalates,
polyphosphazenes and biomolecules such as fibrin, fibrinogen,
cellulose, starch, collagen and hyaluronic acid. Also, biostable
polymers with a relatively low chronic tissue response such as
polyurethanes, silicones, and polyesters could be used and other
polymers could also be used if they can be dissolved and cured or
polymerized on the stent such as polyolefins, polyisobutylene and
ethylene-alphaolefin copolymers; acrylic polymers and copolymers,
vinyl halide polymers and copolymers, such as polyvinyl chloride;
polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene
halides, such as polyvinylidene fluoride and polyvinylidene
chloride; polyacrylonitrile, polyvinyl ketones; polyvinyl
aromatics, such as polystyrene, polyvinyl esters, such as polyvinyl
acetate; copolymers of vinyl monomers with each other and olefins,
such as ethylene-methyl methacrylate copolymers,
acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl
acetate copolymers; polyamides, such as Nylon 66 and
polycaprolactam; alkyd resins; polycarbonates; polyoxymethylenes;
polyimides; polyethers; epoxy resins, polyurethanes; rayon;
rayon-triacetate; cellulose, cellulose acetate, cellulose butyrate;
cellulose acetate butyrate; cellophane; cellulose nitrate;
cellulose propionate; cellulose ethers; and carboxymethyl
cellulose. In some embodiments, the polymer is biodegradable and
will disintegrate, with consequent slow release of drugs
incorporated therein, while in contact with blood or other body
fluids. The active period of the coated stent may be adjusted by
varying the thickness of the coating, the specific type of material
selected for the carrier, and the time release characteristics of
specific substances incorporated into the carrier.
[0213] The ratio of therapeutic substance to polymer in the
solution will depend on the efficacy of the polymer in securing the
therapeutic substance onto the stent and the rate at which the
coating is to release the therapeutic substance to the tissue of
the blood vessel. More polymer may be needed if it has relatively
poor efficacy in retaining the therapeutic substance on the stent
and more polymer may be needed in order to provide an elution
matrix that limits the elution of a very soluble therapeutic
substance. The weight proportion of drug relative to the
combination of drug and carrier can range from about 90% to about
1%. Other useful proportions include about 5%, about 10%, about
20%, about 30%, about 40%, about 50%, about 60%, about 70% and
about 80%.
[0214] Olejnik, US 20080213338 A1, describes an implant stent with
a retinoid for improved biocompatibility, and similar structures
may be useful for constructing stents comprising a RAR selective
agonist or a formulation thereof as disclosed herein.
Uses
[0215] The retinoids according to the invention possess RAR agonist
activity. RAR.gamma. receptor is expressed in highest level in
skin. The RAR.gamma. agonist selectivity of a compound can be
determined by routine ligand binding assays known to one of skill
in the art such as described in C. Apfel et al. Proc. Nat. Sci.
Acad. (USA), 89:7129-7133 (1992); M. Teng et al., J. Med. Chem.,
40:2445-2451 (1997); and PCT Publication WO1996030009.
[0216] RAR agonists disclosed herein may be used for promoting the
repair of damaged tissue, reduce inflammation, increase dermal
homeostasis, increase fibro proliferation and decrease
microvascular dysfunction. Treatment with RAR agonists,
particularly, RAR.gamma. selective agonist is useful to promote
repair of elastin deposition and tissue repair. RAR selective
agonists may also be administered to modulate cell proliferation
and cellular differentiation; promote deposition of collagen;
activate bone collagen and bone union; stimulate fibroblast
activation; stimulate neovascularization; promote elastin
formation; up-regulate the plasminogen activator system; increase
epidermal proliferation and thickness; increase pro-collagen
synthesis; decrease matrix metalloproteinase activity; induce
corneal tissue healing; improve functioning of the upper-digestive
system; and treat chronically damaged or atrophic skin.
[0217] RAR selective agonists may also promote the formation of
granulation tissue, collagen deposition and lesion contraction
leading to enhanced rate of healing and increased tensile strength
of abrasion.
[0218] RAR selective agonists may also be useful for treating
wrinkling as an incident of aging and actinic damage, normalization
of the production of sebum, the reduction of enlarged pores,
promoting the rate of wound healing, limiting of scar tissue
formation during healing and the like.
[0219] In certain embodiments, compositions of the present
invention can decrease the amount of internal oxidation and/or
external oxidative damage in a cell. In other aspects, the
compositions can increase collagen synthesis in a cell. The
compositions can also reduce skin inflammation, such as by reducing
inflammatory cytokine production in a cell. Non-limiting examples
of such cells include human epidermal keratinocyte, human
fibroblast dermal cell, human melanocytes, three dimensional human
cell-derived in vitro tissue equivalents comprising human
keratinocytes, human fibroblasts, or human melanocytes, or any
combination thereof (e.g., combination of human keratinocytes and
human fibroblasts or a combination of human keratinocytes and human
melanocytes).
[0220] The method can also include topically applying an amount
effective to: increase the stratum corneum turnover rate of the
skin; increase collagen synthesis in fibroblasts; increase cellular
anti-oxidant defense mechanisms (e.g., exogenous additions of
antioxidants can bolster, replenish, or prevent the loss of
cellular antioxidants such as catalase and glutathione in skin
cells (e.g., keratinocytes, melanocytes, langerhans cells, etc.)
which will reduce or prevent oxidative damage to the skin,
cellular, proteins, and lipids); inhibit melanin production in
melanocytes; reduce or prevent oxidative damage to skin (including
reducing the amount lipid peroxides and/or protein oxidation in the
skin).
[0221] In one aspect, the invention provides a method of treating a
disease in a subject comprising administering to the subject a
therapeutically effective amount of a RAR selective agonist as
disclosed herein. In one aspect, the invention provides a method of
treating a disease in a subject comprising administering to the
subject a formulation comprising a therapeutically effective amount
of a RAR selective as disclosed herein.
[0222] In some embodiments, a method of treating a disease in a
subject comprises (a) diagnosing the subject as experiencing the
disease and (b) administering to the subject a therapeutically
effective amount of a RAR selective agonist as disclosed herein. In
some embodiments, the invention provides a method of treating a
disease in a subject comprising (a) diagnosing the subject as
experiencing the disease and (b) administering to the subject a
formulation comprising a therapeutically effective amount of a RAR
selective agonist as disclosed herein. In exemplary embodiments,
the disease is treated.
[0223] In some embodiments, a method of preparing a medicament
comprises (a) measuring in vitro the quantity of a marker for a
disease in a sample derived from a subject experiencing the disease
and (b) preparing a RAR selective agonist as disclosed herein in an
amount effective for treating (or preventing) the disease. In some
embodiments, a method of preparing a medicament comprises (a)
measuring in vitro the quantity of a marker for a disease in a
sample derived from a subject experiencing the disease and (b)
preparing a formulation comprising a RAR selective agonist as
disclosed herein in an amount effective for treating (or
preventing) the disease. The amount effective for treating the
disease may be based on the quantity of the marker that was
measured.
[0224] In another aspect, the invention provides use of a RAR
selective agonist in the manufacture of a medicament for the
treatment of a disease. In another aspect, the invention provides
use of a formulation comprising a RAR selective agonist in the
manufacture of a medicament for the treatment of a disease.
[0225] In another aspect, the invention provides use of a RAR
selective agonist in the manufacture of a medicament for the
prevention of a disease. In another aspect, the invention provides
use of a formulation comprising a RAR selective agonist in the
manufacture of a medicament for the prevention of a disease.
[0226] In one aspect, the invention provides a method of inducing a
medically beneficial effect in a subject comprising administering
to the subject a therapeutically effective amount of a RAR
selective agonist as disclosed herein. In one aspect, the invention
provides a method of inducing a medically beneficial effect in a
subject comprising administering to the subject a formulation
comprising a therapeutically effective amount of a RAR selective
agonist as disclosed herein.
[0227] In some embodiments, a method of inducing a medically
beneficial effect in a subject comprises (a) diagnosing the subject
as needing or being capable of benefiting from the medically
beneficial effect and (b) administering to the subject a
therapeutically effective amount of a RAR selective agonist as
disclosed herein. In some embodiments, the invention provides a
method of inducing a medically beneficial effect in a subject
comprising (a) diagnosing the subject as needing or being capable
of benefiting from the medically beneficial effect and (b)
administering to the subject a formulation comprising a
therapeutically effective amount of a RAR selective agonist as
disclosed herein.
[0228] In some embodiments, a method of preparing a medicament
comprises (a) measuring in vitro the quantity of a marker for a
medical state in a sample derived from a subject needing or being
capable of benefiting from a medically beneficial effect and (b)
preparing a RAR selective agonist as disclosed herein in an amount
effective for inducing the medically beneficial effect. In some
embodiments, the invention provides a method of treating a disease
in a subject comprising (a) measuring in vitro the quantity of a
marker for a medical state in a sample derived from a subject
needing or being capable of benefiting from a medically beneficial
effect and (b) preparing a formulation of a RAR selective agonist
as disclosed herein in an amount effective for inducing the
medically beneficial effect. The amount effective for inducing the
medically beneficial effect may be based on the quantity of the
marker that was measured. The medical state may one demonstrating
that a subject needs or is capable of benefiting from a medically
beneficial effect.
[0229] In another aspect, the invention provides use of a RAR
selective agonist in the manufacture of a medicament for inducing a
medically beneficial effect. In another aspect, the invention
provides use of a formulation of a RAR selective agonist in the
manufacture of a medicament for inducing a medically beneficial
effect.
[0230] The diseases referred to in the compositions and methods
described herein herein can be any disease that is effectively
treated or prevented by administering a RAR selective agonist or
formulation thereof to a subject experiencing the disease. The
subject may exhibit one or more symptoms of the disease, including
changed levels of biomarkers whose varied concentration compared to
concentrations in subjects not experiencing the disease provide an
indication that the subject may benefit from a RAR selective
agonist or formulation thereof. Exemplary diseases are described
below and throughout the present disclosure. In some embodiments,
the disease is not diabetic ulcer.
[0231] In some embodiments, the disease is a metabolic disease. In
some embodiments, the disease is a metabolic disease other than
diabetic ulcer. In some embodiments, the metabolic disease is
metabolic syndrome. Metabolic syndrome is a complex disease,
characterized by the American Heart Association by the following
abnormalities: abdominal obesity, atherogenic dyslipidemia,
hypertension, insulin resistance with or without glucose
intolerance, proinflammatory state and prothrombotic state (Grundy
et al., Circulation, 2004, 109: 433-438). It is generally
recognized in the art that people with three or more of the above
symptoms can be considered to have metabolic syndrome. People with
the metabolic syndrome are at increased risk of a cardiovascular
disease, such as coronary heart disease or other diseases related
to plaque buildups in artery walls (e.g., stroke and peripheral
vascular disease) and/or Type II diabetes. The term "metabolic
syndrome" as used herein refers to a disease characterized by at
least three of the following abnormalities: abdominal obesity,
atherogenic dyslipidemia, hypertension, insulin resistance with or
without glucose intolerance, proinflammatory or inflammation state
and prothrombotic state. The treatment or prevention of metabolic
syndrome by administration of a RAR selective agonist or a
formulation thereof can be achieved by treating or preventing any
one or more of these abnormalities or by treating or preventing any
one or more symptoms or conditions associated with metabolic
syndrome. Exemplary symptoms and conditions associated with
metabolic syndrome include hyperglycemia, hyperinsulinemia,
hyperlipidemia, impaired glucose metabolism, diabetic retinopathy,
macular degeneration, cataracts, diabetic nephropathy,
glomeruloscerosis, diabetic neuropathy, erectile dysfunction,
premenstrual syndrome, vascular restenosis, and/or ulcerative
colitis, angina pectoris, myocardial infarction, stroke, skin
and/or connective tissue disorders, metabolic acidosis, arthritis,
osteoporosis and conditions of impaired glucose tolerance. In some
embodiments, the symptom or condition associated with metabolic
syndrome is diabetes or cardiovascular disease.
[0232] In some embodiments, the disease is diabetes. Diabetes is
characterized by high blood sugar, and may result from the body's
failure to produce insulin (Type 1) or from insulin resistance, a
condition in which cells fail to use insulin properly, sometimes
combined with an absolute insulin deficiency (Type 2). Any known
method can be used diagnose diabetes, including, for example,
measurement of glucose levels in the blood during an overnight fast
and measurement of the body's ability to appropriately handle the
excess sugar presented after drinking a high glucose drink.
[0233] In some embodiments, the disease is a diabetic complication.
A diabetic complication refers to a pathological process or event
occurring during diabetes that is not an essential part of the
disease. In some embodiments, it may result from the disease, and
in some embodiments, it may result from independent causes. In
exemplary embodiments, the diabetic complication affects the skin
but is not an ulcer. Examples include a bacterial infection, fungal
infection, itching, diabetic dermopathy, necrobiosis lipoidica
diabeticorum, atherosclerosis, diabetic blisters, eruptive
xanthomatosis, digital sclerosis, disseminated granuloma annulare,
acathosis nigricans and calluses. Other diabetic complications
include diabetic angiopathy and diabetic neuropathy. In some
embodiments, the disease is not a diabetic complication. In some
embodiments, the disease is not a diabetic ulcer. In some
embodiments, the disease is not a foot ulcer, in particular, not a
diabetic foot ulcer. In some embodiments, the disease is not a leg
ulcer, in particular, not a diabetic leg ulcer. In some
embodiments, the disease is a metabolic disease other than diabetic
ulcer.
[0234] In some embodiments, the disease is a carcinoma. A carcinoma
refers to a cancer that begins in a tissue that lines a surface of
the body and is generally tumor tissue derived from epithelial
cells. Carcinoma growths tend to infiltrate the surrounding tissues
and give rise to metastases.
[0235] In some embodiments, the disease is a basal cell carcinoma.
BCC arises from the basal cells of the epidermis and its
appendages. It is characterised by slow local growth capable of
causing extensive tissue damage resulting in loss of organ function
and disfigurement. The most common etiological factor in BCC is
exposure to ultraviolet light (UV). Consequently, areas of skin
with high levels of UV exposure, such as the head or neck, are most
commonly affected. A number of factors can lead to the development
of multiple basal cell carcinoma (MBCC) including conditions such
as nevoid basal cell carcinoma syndrome (NBCCS, also referredto as
basal cell nevoid syndrome (BCNS) and Gorlin-Goltz syndrome),
xeroderma pigmentosum, immunosuppression due to intensive
immunosuppressive therapy administered after organ transplant, or
radiation exposure at a young age particularly for the treatment of
acne. A RAR selective agonist or formulation thereof can be used to
treat or prevent basal cell carcinoma. In some embodiments, the
basal cell carcinoma is selected from nodular basal-cell carcinoma
(classic basal-cell carcinoma), cystic basal-cell carcinoma,
cicatricial basal-cell carcinoma (morpheaform basal-cell carcinoma,
morphoeic basal-cell carcinoma), Infiltrative basal-cell carcinoma,
micronodular basal-cell carci.noma, superficial basal-cell
carcinoma (superficial multicentric basal-cell carcinoma),
pigmented basal-cell carcinoma, rodent ulcer (Jacobi ulcer),
fibroepithelioma of Pinkus, polypoid basal-cell carcinoma,
pore-like basal-cell carcinoma and aberrant basal-cell
carcinoma.
[0236] In some embodiments, the disease is a squamous cell
carcinoma. Squamous cell carcinoma arises from the epidermis and
resembles the squamous cells that comprise most of the upper layers
of skin. Squamous cell cancers may occur on all areas of the body
including the mucous membranes, but are most common in areas
exposed to the sun. Metastasing squamous cell carcinomas most often
arise on sites of chronic inflammatory skin conditions or on the
mucous membranes or lips. It has been reported that in patients
with psoriasis treated with psoralen-UVA, systemic retinoid use
reduced SCC risk but did not significantly alter basal cell
carcinoma incidence. Nijsten et al., J Am Acad Dermatol 2003, 49:
644-50. Thus, a RAR selective agonist or formulation thereof can be
used to treat or prevent squamous cell carcinoma. In some
embodiments, the squamous cell carcinoma is selected from papillary
carcinoma, verrucous squamous cell carcinoma, papillary squamous
cell carcinoma, squamous cell carcinoma, large cell keratinizing
squamous cell carcinoma, large cell keratinizing squamous cell
carcinoma, small cell keratinizing squamous cell carcinoma, spindle
cell squamous cell carcinoma, adenoid/pseudoglandular squamous cell
carcinoma, intraepidermal squamous cell carcinoma and
lymphoepithelial carcinoma.
[0237] In some embodiments, the disease is leukemia. Leukemia is a
form of cancer that begins in the blood-forming cells of the bone
marrow and is associated with an excess of abnormal white blood
cells in the blood. Acute leukemia is a rapidly progressing disease
that results in the massive accumulation of immature, functionless
cells (blasts) in the marrow and blood. Chronic leukemia, by
contrast, progresses more slowly and leads to unregulated
proliferation and hence marked overexpansion of a spectrum of
mature (differentiated) cells. RAR selective agonist or formulation
thereof can be used to treat or prevent leukemia. In some
embodiments, leukemia is selected from myeloid leukemia,
lymphocytic leukemia, chronic leukemia (both chronic myeloid
leukemia (CML) and chronic lymphocytic leukemia (CLL)),
erythroleukemia, thrombocythemia, myelodysplastic syndromes (MDS),
acute myeloid leukemia (AML) and acute lymphocytic leukemia
(ALL).
[0238] In some embodiments, the disease is a cardiovascular
disease. The term "cardiovascular disease" includes any disease,
disorder or pathological state or condition that involves the heart
and/or blood vessels, arteries and veins (vascular disease). A
cardiovascular disorder can be caused by an imbalance in arterial
pressure, a malfunction of the heart, or an occlusion of a blood
vessel, e.g., by a thrombus. A cardiovascular disorder includes,
but is not limited to disorders such as arterial disease, atheroma,
arteriosclerosis, atherosclerosis, stroke, cardiac hypertrophy,
ischemia reperfusion injury, restenosis, arterial inflammation,
vascular wall remodeling, ventricular remodeling, rapid ventricular
pacing, coronary microembolism, tachycardia, bradycardia, pressure
overload, aortic bending, coronary artery ligation, vascular heart
disease, valvular disease, including but not limited to, valvular
degeneration caused by calcification, rheumatic heart disease,
endocarditis, or complications of artificial valves; atrial
fibrillation, long-QT syndrome, congestive heart failure, sinus
node dysfunction, angina, heart failure, hypertension, atrial
fibrillation, atrial flutter, pericardial disease, including but
not limited to, pericardial effusion and pericarditis;
cardiomyopathies, e.g., dilated cardiomyopathy or idiopathic
cardiomyopathy, myocardial infarction, coronary artery disease,
coronary heart disease, coronary artery spasm, ischemic disease,
transient ischemic attack (TIA), arrhythmia, sudden cardiac death,
and cardiovascular developmental disorders (e.g., arteriovenous
malformations, arteriovenous fistulae, raynaud's syndrome,
neurogenic thoracic outlet syndrome, causalgia/reflex sympathetic
dystrophy, hemangioma, aneurysm (e.g., aortic aneurysm), cavernous
angioma, aortic valve stenosis, atrial septal defects,
atrioventricular canal, coarctation of the aorta, ebsteins anomaly,
hypoplastic left heart syndrome, interruption of the aortic arch,
mitral valve prolapse, ductus arteriosus, patent foramen ovale,
partial anomalous pulmonary venous return, pulmonary atresia with
ventricular septal defect, pulmonary atresia without ventricular
septal defect, persistance of the fetal circulation, pulmonary
valve stenosis, single ventricle, total anomalous pulmonary venous
return, transposition of the great vessels, tricuspid atresia,
truncus arteriosus, ventricular septal defects),
cardiopericarditis, peripheral vascular disease, venous
thromoembolism and pulmonary embolism, infection or inflammation of
the heart and/or blood vessels, arteries and veins, as well as
valvular, vascular and clotting problems, insufficiencies and
disorders.
[0239] In some embodiments, the disease is an endocrine disease. An
endocrine disease is typically characterized by disregulated
hormone release (a productive pituitary adenoma), inappropriate
response to signaling (hypothyroidism), lack of a gland (diabetes
mellitus type 1, diminished erythropoiesis in chronic renal
failure), or structural enlargement in a critical site such as the
thyroid (toxic multinodular goitre). Hypofunction of endocrine
glands can occur as a result of loss of reserve, hyposecretion,
agenesis, atrophy, or active destruction. Hyperfunction can occur
as a result of hypersecretion, loss of suppression, hyperplastic or
neoplastic change, or hyperstimulation. Endocrinopathies are
classified as primary, secondary, or tertiary. Primary endocrine
disease inhibits the action of downstream glands. Secondary
endocrine disease is indicative of a problem with the pituitary
gland. Tertiary endocrine disease is associated with dysfunction of
the hypothalamus and its releasing hormones. Endocrine diseases
generally affect the system of glands that secrete hormones
directly into the bloodstream. Organs such as the kidney, liver,
heart and gonads have secondary endocrine functions, and thus
certain endocrine diseases may also involve disorders of these
organs. Classes of endocrine diseases may include, for example,
adrenal disorders, glucose homeostasis disorders, calcium
homeostasis disorders, metabolic bone disease, pituitary gland
disorders, sex hormone disorders and endocrine gland tumors.
Examples of endocrine disease include conditions such as adrenal
insufficiency (e.g., Addison's disease, mineralocorticoid
deficiencies), adrenal hormone excess (e.g., Conn's syndrome,
Cushing's syndrome, GRA/Glucocorticoid remediable aldosteronism,
pheochromocytoma), congenital adrenal hyperplasia (adrenogenital
syndrome), adrenocortical carcinoma, diabetes mellitus (e.g., type
1 diabetes, type 2 diabetes, gestational diabetes, mature onset
diabetes), hypoglycemia (e.g., idiopathic hypoglycemia,
insulinoma), glucagonoma, thyroiditis (e.g., Hashimoto's
thyroiditis), thyroid cancer, parathyroid gland disorders (e.g.,
primary hyperparathyroidism, secondary hyperparathyroidism,
tertiary hyperparathyroidism, hypoparathyroidism,
pseudohypoparathyroidism), osteoporosis, osteitis deformans
(Paget's disease of bone), rickets and osteomalacia, posterior
pituitary disorder (e.g., diabetes insipidus), anterior pituitary
disorder (e.g., hypopituitarism or panhypopituitarism, pituitary
tumors (such as pituitary adenomas, prolactinoma or
hyperprolactinemia, acromegaly, gigantism, Cushing's disease), sex
development or intersex disorders (e.g., hermaphroditism, gonadal
dysgenesis, androgen insensitivity syndromes, hypogonadism
(gonadotropin deficiency), Kallmann syndrome, Klinefelter syndrome,
Turner syndrome, ovarian failure (also known as premature
menopause), testicular failure, gender identity disorder, disorders
of puberty (e.g., delayed puberty, precocious puberty), menstrual
function or fertility disorders (e.g., amenorrhea, polycystic ovary
syndrome), multiple endocrine neoplasia (e.g., MEN type 1, MEN type
2a, MEN type 2b) and carcinoid syndrome, thyroid disease, and
obesity.
[0240] In some embodiments, the disease is a neurological disease.
In exemplary embodiments, the disease is Alzheimer's disease.
Alzheimer's disease is characterized by plaques containing
amyloid-.beta. (A.beta.) peptide and neuronal tangles. It has been
hypothesized that late onset Alzheimer's disease (AD) is influenced
by the availability in brain of retinoic acid (RA), the final
product of the vitamin A (retinoid) metabolic cascade. Goodman
& Pardee, Proc Natl Acad Sci USA, 2003 March 4; 100: 2901-2905.
The retinoid signalling pathway is mediated by retinoic acid (RA)
receptors (RARs) and retinoid X receptors (RXRs), both of which
have three types, .alpha., .beta. and .gamma., and various
isoforms. Bastien & Rochette-Egly, Gene, 2004, 328: 1-16.
Jarvis et al., European Journal of Neuroscience, 2010, 32:
1246-1255, have reported that RAR.alpha. agonists have therapeutic
potential for the treatment of AD. A RAR selective agonist or
formulation thereof as disclosed herein may thus be administered to
a subject in order to treat or prevent Alzheimer's disease.
[0241] In some embodiments, the disease is heterotrophic
ossification. In subjects suffering from heterotrophic
ossification, ectopic bone forms within muscles and connective
tissues and near blood vessels or nerves. The pathogenesis of this
disease is not completely understood, but it is thought that
inciting events, such as trauma, surgery (especially invasive
surgery such as knee replacement), deep burns or protracted
immobilization, induce local inflammation, which is followed by the
recruitment of skeletal progenitor cells that differentiate into
chondrocytes, undergo hypertrophy and are replaced by endochondral
bone. Shimono et al., Nature Medicine, 2011, 17: 454-461. Shimono
et al. have reported that heterotopic ossification was essentially
prevented in mice receiving a nuclear retinoic acid
receptor-.gamma. (RAR-.gamma.) agonist. Accordingly, a RAR
selective agonist or formulation thereof as disclosed herein may
thus be administered to a subject in order to treat or prevent
heterotrophic ossification.
[0242] In some embodiments, the disease is a topical disease other
than diabetic ulcer. In some embodiments, the topical disease is
selected from dermal atrophy, hyperpigmentation, hypopigmentation,
dermal hypoplasia, epidermal hypoplasia, kerotoses, ichthyoses,
follicular disorders, benign epithelial tumors, perforated
dematoses, keratinization disorders and chronic lesion caused by
reduced RAR.gamma. expression.
[0243] In some embodiments, the disease is a skin condition.
Non-limiting examples of skin conditions include pruritus, sun
damaged skin, dermatitis (including, but not limited to seborrheic
dermatitis, nummular dermatitis, contact dermatitis, atopic
dermatitis, exfoliative dermatitis, perioral dermatitis, and stasis
dermatitis), psoriasis, folliculitis, rosacea, acne, impetigo,
erysipelas, erythrasma, eczema, and other inflammatory skin
conditions. In certain non-limiting aspects, the skin condition can
be caused by exposure to UV light, age, irradiation, chronic sun
exposure, environmental pollutants, air pollution, wind, cold,
heat, chemicals, disease pathologies, smoking, or lack of
nutrition.
[0244] In some embodiments, the disease is an ocular surface
disease. It is well established that the cornea and the conjunctiva
have an absolute requirement for vitamin A (retinol), which acts
through its metabolites such as retinaldehyde, which forms the
visual chromophore, and retinoic acids, which regulate gene
expression. Nezzar et al., Molecular Vision, 2007, 13: 1641-1650.
Diseases such as keratinization, xerophthalmia, keratomalacia,
ulceration, epithelial squamous metaplasia and a deficiency of
conjunctival goblet cells may result from abnormal differentiation
of the ocular surface due to vitamin A deficiency. A RAR selective
agonist or formulation thereof (particularly a topical formulation)
as disclosed herein may thus be administered to a subject in order
to treat or prevent any of these ocular surface diseases, and
additionally may be useful for the treatment or prevention of dry
eye or corneal epithelial wounds.
[0245] In some embodiments, the disease targeted by the methods,
compounds and formulations described herein is a disease selected
from skin lesion, acne vulgaris, cystic acne, psoriasis, ichthyoses
(e.g., ichthyosis hystrix, epidermolytic hyperkeratosis, and
lamellar ichthyosis), follicular disorders (e.g.,
pseudofolliculites, senile comedones, nevus comidonicas, and
trichostatis spinulosa), benign epithelial tumors (e.g., flat
warts, trichoepithelioma, and molluscum contagiosum), perforated
dematoses (e.g., elastosis perforans seripiginosa and Kyrles
disease), and disorders of keratinization (e.g., Dariers disease,
keratoderma, hyperkeratosis plantaris, pityriasis rubra pilaris,
lichen planus acanthosis nigricans, and psoriasis).
[0246] In some embodiments, the treatment or prevention of certain
diseases is excluded. Any disease disclosed herein may be excluded.
For example, in some embodiments, the disease is not one or more
diseases selected from an epithelial lesion; light- and age-damaged
skin; skin lesion; acne (e.g., acne vulgaris, cystic acne);
psoriasis; a tumor or precancerous change of the mucous membrane in
the mouth, tongue, larynx, esophagus, bladder, cervix or colon; and
emphysema and associated pulmonary diseases. In some embodiments,
the treatment of a trauma or of an induced wound is excluded;
examples include burns and surgical wounds.
[0247] In one aspect, the invention provides a method of inducing a
medically beneficial effect (such as inducing bone collagen
formation) in a subject comprising administering to the subject a
therapeutically effective amount of a RAR selective agonist or a
formulation comprising a RAR selective agonist. RAR selective
agonists can thus be administered to subjects who are not suffering
from disease.
[0248] In a particular embodiment, there is disclosed a method of
reducing the appearance of a nonpathological skin condition
comprising topically applying any one of the compositions described
in this specification to the skin condition, wherein topical
application of the composition to skin condition reduces the
appearance of the skin condition. In some embodiments, the skin
condition is a fine line or wrinkle, uneven skin tone, or an age
spot. The skin condition can be located on facial skin, arm skin,
leg skin, chest skin, abdomen skin, back skin etc.
[0249] In yet another embodiment, there is disclosed a method of
increasing the firmness of skin comprising topically applying any
one of the compositions described in this specification to skin in
need thereof (a non-limiting example of which can be sagging skin,
aged skin, skin that has reduced elasticity, skin that has skin
cells having inadequate amounts of collage, fibronectin, or laminin
or all of such proteins, etc.), wherein topical application of the
composition to skin increases the firmness of skin. The composition
can be used on facial skin, arm skin, leg skin, chest skin, abdomen
skin, back skin, etc.
[0250] In still another embodiment there is disclosed a method of
increasing collagen, fibronectin, or laminin production in a skin
cell comprising topically applying any one of the compositions
disclosed in this specification to a skin cell that is in need of
collagen, fibronectin, or laminin production, wherein the topical
application of the composition to the skin cell increases collagen,
fibronectin, or laminin production in the skin cell. In certain
aspects, collagen, fibronectin, and laminin production are
increased in the skin cell.
[0251] In one aspect, the invention provides a method of inducing
bone collagen formation in a subject, the method comprising
administering to the subject a RAR selective agonist. In one
aspect, the invention provides a method of inducing bone collagen
formation in a subject, the method comprising administering to the
subject formulation comprising a RAR selective agonist. The effect
of retinoic acid on development and healing of osseous tissues, as
well as on maintenance of normal skeletal growth and remodeling,
has been well established. Sela et al., Inflamm. Res., 2000, 49:
679-683. Physiological doses of retinoic acid induce collagen gene
expression in approximately one third of the cells treated with it,
and increase alkaline phosphatase levels. Pacifici et al., Exper.
Cell Res., 1991, 195: 38-46. Studies have suggested that retinoic
acid either directly increases the synthesis of collagen, or
reduces degradation of certain types of pro-collagen. Sela, supra.
Accordingly, a RAR selective agonist or formulation thereof as
disclosed herein may thus be administered to a subject in order to
induce bone collagen formation.
[0252] A "subject" in the context of the present invention is an
animal, preferably a mammal. The mammal can be a human, non-human
primate, mouse, rat, dog, cat, horse, or cow, but are not limited
to these examples. In various exemplary embodiments, a subject is
human and may be referred to as a "patient". Mammals other than
humans can be advantageously used as subjects that represent animal
models of a disease or for veterinarian applications. A subject can
be one who has been previously diagnosed or identified as having a
disease, and optionally has already undergone, or is undergoing, a
therapeutic intervention for a disease. Alternatively, a subject
can also be one who has not been previously diagnosed as having a
disease. For example, a subject can be one who exhibits one or more
risk factors for a disease, or one who does not exhibit a disease
risk factor, or one who is asymptomatic for a disease. A subject
can also be one who is suffering from or at risk of developing a
disease. In certain embodiments, the subject can be already
undergoing therapy or can be a candidate for therapy. In exemplary
embodiments, the subject is generally one in need of treatment for
a disease or has been determined to be in need for treatment of a
disease.
[0253] Thus, the methods disclosed herein can further comprise
identifying a subject as in need of treatment of a disease
disclosed herein.
[0254] The term "sample" used herein refers to a specimen or
culture obtained from a subject and includes fluids, gases and
solids including, for example, tissue. In various exemplary
embodiments, the sample comprises blood. A sample could be a fluid
obtained from a subject including, for example, whole blood or a
blood derivative (e.g. serum, plasma, or blood cells), ovarian cyst
fluid, ascites, lymphatic, cerebrospinal or interstitial fluid,
saliva, mucous, sputum, sweat, urine, or any other secretion,
excretion, or other bodily fluids. As will be appreciated by those
in the art, virtually any experimental manipulation or sample
preparation steps may have been done on the sample. For example,
wash steps may be applied to a sample.
[0255] The terms "treatment" and "treating" refer to the reduction
of the progression, severity and/or duration of a disease or
amelioration of one or more symptoms thereof, wherein such
reduction and/or amelioration result from the administration of one
or more therapies (e.g., a RAR selective agonist or a formulation
thereof).
[0256] In some aspects, a RAR selective agonist or a formulation
thereof is administered for preventing a disease or is used in
manufacturing or preparing a medicament for preventing a disease.
Such methods may include the same steps performed in methods of
treating the disease.
[0257] Administration of a RAR selective agonist include topical
application of the compound or a formulation thereof to a portion
of skin in need of such compound or formulation, wherein topical
application reduces or prevents a skin condition when compared to
skin that has a skin condition and that has not been treated with
the composition, or wherein topical application increases bone
collagen formation. The skin can be facial skin or non-facial skin
(e.g., arms, legs, hands, chest, back, feet, etc.). Administration
of a RAR selective agonist also includes oral administration.
[0258] Delivery of the compounds of the present invention to the
subject over prolonged periods of time, for example, for periods of
one week to one year, may be accomplished by a single
administration of a controlled release system containing sufficient
active ingredient for the desired release period. Various
controlled release systems, such as transdermal patches, devices
and alternative dosage forms may be utilized for this purpose.
Localization at the site to which delivery of the active ingredient
is desired is an additional feature of some controlled release
devices, which may prove beneficial in the treatment of certain
disorders.
EXAMPLES
[0259] The Examples below provide a number of exemplary
formulations. In some embodiments, the formulation comprises any of
the indicated components at about the weight percentage shown.
Example 1
[0260] Table 1 provides exemplary concentrations of ingredients
suitable for formulating an ointment.
TABLE-US-00001 TABLE 1 Ingredient Wt/wt % RAR selective agonist
0.005% stearyl alcohol 1% stearic acid 4% isopropylmyristate 13%
BHT 0.01% gum xanthan 1.5% polyoxyl 40 stearate 2% sorbic acid 0.1%
corn oil 0.045% filtered water 78.34%
Example 2
[0261] Table 2 provides exemplary concentrations of ingredients
suitable for formulating an ointment.
TABLE-US-00002 TABLE 2 Ingredient Wt/wt % RAR selective agonist
0.01% stearyl alcohol 1% stearic acid 4% isopropylmyristate 13% BHT
0.01% gum xanthan 1.5% polyoxyl 40 stearate 2% sorbic acid 0.1%
corn oil 0.045% filtered water 78.335%
Example 3
[0262] Table 3 provides exemplary concentrations of ingredients
suitable for formulating an ointment.
TABLE-US-00003 TABLE 3 Ingredient Wt/wt % RAR selective agonist
0.05% stearyl alcohol 1% stearic acid 4% isopropylmyristate 13% BHT
0.01% gum xanthan 1.5% polyoxyl 40 stearate 2% sorbic acid 0.1%
corn oil 0.045% filtered water 78.295%
Example 4
[0263] The following are exemplary embodiments.
Embodiment 1
[0264] A method of treating a metabolic disease or a condition
associated with the metabolic disease in a subject, wherein the
metabolic disease is other than diabetic ulcer, the method
comprising: administering to the subject a therapeutically
effective amount of a RAR selective agonist, wherein the RAR
selective agonist has the structure:
##STR00034## [0265] wherein the dotted bond is either present and
forms a double bond, or is absent; [0266] R.sup.1, R.sup.2, R.sup.3
and R.sup.4 are independently hydrogen or alkyl; [0267] n is 1, 2
or 3; [0268] X is --C(R.sup.8)(R.sup.9)-- for n=1, 2 or 3; or X is
oxygen for n=1; [0269] wherein R.sup.8 and R.sup.9 are
independently hydrogen or alkyl; [0270] R.sup.5 is hydrogen, alkyl,
alkoxy, alkoxy-alkyl-, alkylthio, alkyl-NR.sup.10--, alkenyl,
alkenyloxy, alkynyl, benzyl, cycloalkyl-alkyl or phenyl-alkyl;
[0271] wherein R.sup.10 is hydrogen or alkyl; [0272] m is 0 when
the dotted bond is present; or m is 1 when the dotted bond is
absent; [0273] A is a residue of formula:
[0273] ##STR00035## [0274] or of formula:
[0274] ##STR00036## [0275] wherein Ar is phenyl or a heteroarylic
ring; [0276] R.sup.6 is hydrogen, halogen, alkoxy or hydroxy;
[0277] R.sup.7 is hydrogen or alkyl; and [0278] Y is --COO--,
--OCO--, --CONR.sup.10--, --NR.sup.10CO--, --CH.dbd.CH--,
--C.ident.C--, --COCH.dbd.CH--, --CHOHCH.dbd.CH--, --CH.sub.2O--,
--CH.sub.2S--, --CH.sub.2SO--, --CH.sub.2SO.sub.2--,
--CH.sub.2NR.sup.10--, --OCH.sub.2--, --SCH.sub.2--,
--SOCH.sub.2--, --SO.sub.2CH.sub.2-- or --NR.sup.10CH.sub.2--,
[0279] with the proviso that when Y is --OCO--, --NR.sup.10CO--,
--OCH.sub.2--, --SCH.sub.2--, --SOCH.sub.2--, --SO.sub.2CH.sub.2--
or --NR.sup.10CH.sub.2--, R.sup.5 is hydrogen, alkyl,
alkoxy-alkyl-, alkenyl, alkynyl, benzyl, cycloalkyl-alkyl or
phenyl-alkyl; [0280] or a pharmaceutically active salt of
carboxylic acids of formula I.
Embodiment 2
[0281] The method of embodiment 1 wherein the condition associated
with the metabolic disease is selected from hyperglycemia,
hyperinsulinemia, hyperlipidemia, impaired glucose metabolism,
diabetic retinopathy, macular degeneration, cataracts, diabetic
nephropathy, glomeruloscerosis, diabetic neuropathy, erectile
dysfunction, premenstrual syndrome, vascular restenosis, ulcerative
colitis, angina pectoris, myocardial infarction, stroke, skin or
connective tissue disorders, metabolic acidosis, arthritis,
osteoporosis, conditions of impaired glucose tolerance, diabetes
and cardiovascular disease.
Embodiment 3
[0282] A method of treating a topical disease in a subject, wherein
the topical disease is selected from skin lesion, acne vulgaris,
cystic acne and psoriasis; [0283] the method comprising:
administering to the subject a topical formulation comprising a RAR
selective agonist, [0284] wherein the RAR selective agonist is
about 0.00001% to about 1% wt/wt of the formulation, and [0285]
wherein the RAR selective agonist has the structure:
[0285] ##STR00037## [0286] wherein the dotted bond is either
present and forms a double bond, or is absent; [0287] R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 are independently hydrogen or alkyl;
[0288] n is 1, 2 or 3; [0289] X is --C(R.sup.8)(R.sup.9)-- for n=1,
2 or 3; or X is oxygen for n=1; [0290] wherein R.sup.8 and R.sup.9
are independently hydrogen or alkyl; [0291] R.sup.5 is hydrogen,
alkyl, alkoxy, alkoxy-alkyl-, alkylthio, alkyl-NR.sup.10--,
alkenyl, alkenyloxy, alkynyl, benzyl, cycloalkyl-alkyl or
phenyl-alkyl; [0292] wherein R.sup.10 is hydrogen or alkyl; [0293]
m is 0 when the dotted bond is present; or m is 1 when the dotted
bond is absent; [0294] A is a residue of formula:
[0294] ##STR00038## [0295] or of formula:
[0295] ##STR00039## [0296] wherein Ar is phenyl or a heteroarylic
ring; [0297] R.sup.6 is hydrogen, halogen, alkoxy or hydroxy;
[0298] R.sup.7 is hydrogen or alkyl; and [0299] Y is --COO--,
--OCO--, --CONR.sup.10--, --NR.sup.10CO--, --CH.dbd.CH--,
--C.ident.C--, --COCH.dbd.CH--, --CHOHCH.dbd.CH--, --CH.sub.2O--,
--CH.sub.2S--, --CH.sub.2SO--, --CH.sub.2SO.sub.2--,
--CH.sub.2NR.sup.10--, --OCH.sub.2--, --SCH.sub.2--,
--SOCH.sub.2--, --SO.sub.2CH.sub.2-- or --NR.sup.10CH.sub.2--,
[0300] with the proviso that when Y is --OCO--, --NR.sup.10CO--,
--OCH.sub.2--, --SCH.sub.2--, --SOCH.sub.2--, --SO.sub.2CH.sub.2--
or --NR.sup.10CH.sub.2--, R.sup.5 is hydrogen, alkyl,
alkoxy-alkyl-, alkenyl, alkynyl, benzyl, cycloalkyl-alkyl or
phenyl-alkyl; [0301] or a pharmaceutically active salt of
carboxylic acids of formula I.
Embodiment 4
[0302] A method of inducing bone collagen formation in a subject,
the method comprising: administering to the subject a RAR selective
agonist having the structure:
##STR00040## [0303] wherein the dotted bond is either present and
forms a double bond, or is absent; [0304] R.sup.1, R.sup.2, R.sup.3
and R.sup.4 are independently hydrogen or alkyl; [0305] n is 1, 2
or 3; [0306] X is --C(R.sup.8)(R.sup.9)-- for n=1, 2 or 3; or X is
oxygen for n=1; [0307] wherein R.sup.8 and R.sup.9 are
independently hydrogen or alkyl; [0308] R.sup.5 is hydrogen, alkyl,
alkoxy, alkoxy-alkyl-, alkylthio, alkyl-NR.sup.10--, alkenyl,
alkenyloxy, alkynyl, benzyl, cycloalkyl-alkyl or phenyl-alkyl;
[0309] wherein R.sup.10 is hydrogen or alkyl; [0310] m is 0 when
the dotted bond is present; or m is 1 when the dotted bond is
absent; [0311] A is a residue of formula:
[0311] ##STR00041## [0312] or of formula:
[0312] ##STR00042## [0313] wherein Ar is phenyl or a heteroarylic
ring; [0314] R.sup.6 is hydrogen, halogen, alkoxy or hydroxy;
[0315] R.sup.7 is hydrogen or alkyl; and [0316] Y is --COO--,
--OCO--, --CONR.sup.10--, --NR.sup.10CO--, --CH.dbd.CH--,
--C.ident.C--, --COCH.dbd.CH--, --CHOHCH.dbd.CH--, --CH.sub.2O--,
--CH.sub.2S--, --CH.sub.2SO--, --CH.sub.2SO.sub.2--,
--CH.sub.2NR.sup.10--, --OCH.sub.2--, --SCH.sub.2--,
--SOCH.sub.2--, --SO.sub.2CH.sub.2-- or --NR.sup.10CH.sub.2--,
[0317] with the proviso that when Y is --OCO--, --NR.sup.10CO--,
--OCH.sub.2--, --SCH.sub.2--, --SOCH.sub.2--, --SO.sub.2CH.sub.2--
or --NR.sup.10CH.sub.2--, R.sup.5 is hydrogen, alkyl,
alkoxy-alkyl-, alkenyl, alkynyl, benzyl, cycloalkyl-alkyl or
phenyl-alkyl; [0318] or a pharmaceutically active salt of
carboxylic acids of formula I.
Embodiment 5
[0319] The method of any of embodiments 1, 2 and 4 wherein the RAR
selective agonist is in a formulation comprising: [0320] (a) the
RAR selective agonist and [0321] (b) a carrier medium comprising
one or more excipients, [0322] wherein the formulation is suitable
for topical administration to the subject.
Embodiment 6
[0323] The method of any preceding embodiment wherein the RAR
selective agonist is administered by applying a cream, ointment,
lotion or liquid comprising the RAR selective agonist.
Embodiment 7
[0324] The method of any preceding embodiment wherein the RAR
selective agonist is in a formulation comprising: [0325] (a) the
RAR selective agonist and [0326] (b) a carrier medium comprising
one or more excipients, [0327] wherein the RAR selective agonist is
about 0.00001 wt % to about 1 wt % of the formulation.
Embodiment 8
[0328] The method of any of embodiments 5 and 7 wherein the carrier
medium comprises [0329] (a) an alcohol; [0330] (b) stearic acid;
[0331] (c) isopropylmyristate; [0332] (d) polyoxyl stearate; [0333]
(e) butylated hydroxytoluene; [0334] (f) xanthan gum; [0335] (g)
sorbic acid; [0336] (h) an oil; and [0337] (i) water.
Embodiment 9
[0338] The method of embodiment 8 wherein the alcohol is about 0.5
wt % to about 1.5 wt % of the formulation; [0339] the stearic acid
is about 2 wt % to about 7 wt % of the formulation; [0340] the
isopropylmyristate is about 6 wt % to about 16 wt % of the
formulation; and [0341] the polyoxyl stearate is about 1 wt % to
about 6 wt % of the formulation.
Embodiment 10
[0342] The method of any of embodiments 8 and 9 [0343] wherein the
alcohol is about 1 wt % of the formulation; [0344] the stearic acid
is about 4 wt % of the formulation; [0345] the isopropylmyristate
is about 13 wt % of the formulation; [0346] the butylated
hydroxytoluene is about 0.01 wt % of the formulation; [0347] the
xanthan gum is about 1.5 wt % of the formulation; [0348] the
polyoxyl stearate is about 2 wt % of the formulation; [0349] the
sorbic acid is about 0.1 wt % of the formulation; [0350] the oil is
about 0.045 wt wt % of the formulation; and [0351] the water is
about 78.34 wt % of the formulation.
Embodiment 11
[0352] The method of any of embodiments 8-10 wherein the alcohol is
stearyl alcohol; the polyoxyl stearate is polyoxyl 40 stearate; or
the oil is corn oil.
Embodiment 12
[0353] The method of any of embodiments 1, 2 and 4 wherein the RAR
selective agonist is in a formulation comprising: [0354] (a) the
RAR selective agonist and [0355] (b) a carrier medium comprising
one or more excipients, [0356] wherein the formulation is suitable
for oral administration to the subject.
Embodiment 13
[0357] The method of any preceding embodiment wherein the RAR
selective agonist has the structure:
##STR00043##
Embodiment 14
[0358] The method of any preceding embodiment wherein the RAR
selective agonist has the structure
##STR00044## [0359] wherein X.sup.2 is oxygen or --NH--.
Embodiment 15
[0360] The method of embodiment 14 wherein X.sup.2 is oxygen and n
is 2.
Embodiment 16
[0361] The method of any preceding embodiment wherein R.sup.8 and
R.sup.9 are H.
Embodiment 17
[0362] The method of any preceding embodiment wherein R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 are alkyl.
Embodiment 18
[0363] A composition comprising: [0364] (a) a RAR selective
agonist; and [0365] (b) an analgesic, an anesthetic or an
antibiotic, [0366] wherein the RAR selective agonist has the
structure:
[0366] ##STR00045## [0367] wherein the dotted bond is either
present and forms a double bond, or is absent; [0368] R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 are independently hydrogen or alkyl;
[0369] n is 1, 2 or 3; [0370] X is --C(R.sup.8)(R.sup.9)-- for n=1,
2 or 3; or X is oxygen for n=1; [0371] wherein R.sup.8 and R.sup.9
are independently hydrogen or alkyl; [0372] R.sup.5 is hydrogen,
alkyl, alkoxy, alkoxy-alkyl-, alkylthio, alkyl-NR.sup.10--,
alkenyl, alkenyloxy, alkynyl, benzyl, cycloalkyl-alkyl or
phenyl-alkyl; [0373] wherein R.sup.10 is hydrogen or alkyl; [0374]
m is 0 when the dotted bond is present; or m is 1 when the dotted
bond is absent; [0375] A is a residue of formula:
[0375] ##STR00046## [0376] or of formula:
[0376] ##STR00047## [0377] wherein Ar is phenyl or a heteroarylic
ring; [0378] R.sup.6 is hydrogen, halogen, alkoxy or hydroxy;
[0379] R.sup.7 is hydrogen or alkyl; and [0380] Y is --COO--,
--OCO--, --CONR.sup.10--, --NR.sup.10CO--, --CH.dbd.CH--,
--C.ident.C--, --COCH.dbd.CH--, --CHOHCH.dbd.CH--, --CH.sub.2O--,
--CH.sub.2S--, --CH.sub.2SO--, --CH.sub.2SO.sub.2--,
--CH.sub.2NR.sup.10--, --OCH.sub.2--, --SCH.sub.2--,
--SOCH.sub.2--, --SO.sub.2CH.sub.2-- or --NR.sup.10CH.sub.2--,
[0381] with the proviso that when Y is --OCO--, --NR.sup.10CO--,
--OCH.sub.2--, --SCH.sub.2--, --SOCH.sub.2--, --SO.sub.2CH.sub.2--
or --NR.sup.10CH.sub.2--, R.sup.5 is hydrogen, alkyl,
alkoxy-alkyl-, alkenyl, alkynyl, benzyl, cycloalkyl-alkyl or
phenyl-alkyl; [0382] or a pharmaceutically active salt of
carboxylic acids of formula I.
Embodiment 19
[0383] The composition of embodiment 18 wherein the RAR selective
agonist has the structure:
##STR00048##
Embodiment 20
[0384] The composition of any of embodiments 18 and 19 wherein the
RAR selective agonist has the structure
##STR00049## [0385] wherein X.sup.2 is oxygen or --NH--.
Embodiment 21
[0386] The composition of embodiment 20 wherein X.sup.2 is oxygen
and n is 2.
Embodiment 22
[0387] The composition of any of embodiments 18-21 wherein R.sup.8
and R.sup.9 are H.
Embodiment 23
[0388] The composition of any of embodiments 18-22 wherein R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 are alkyl.
Embodiment 24
[0389] The composition of any of embodiments 18-23 further
comprising a carrier medium, wherein the composition is a
pharmaceutically acceptable formulation.
Embodiment 25
[0390] A stent comprising a RAR selective agonist having the
structure:
##STR00050## [0391] wherein the dotted bond is either present and
forms a double bond, or is absent; [0392] R.sup.1, R.sup.2, R.sup.3
and R.sup.4 are independently hydrogen or alkyl; [0393] n is 1, 2
or 3; [0394] X is --C(R.sup.8)(R.sup.9)-- for n=1, 2 or 3; or X is
oxygen for n=1; [0395] wherein R.sup.8 and R.sup.9 are
independently hydrogen or alkyl; [0396] R.sup.5 is hydrogen, alkyl,
alkoxy, alkoxy-alkyl-, alkylthio, alkyl-NR.sup.10--, alkenyl,
alkenyloxy, alkynyl, benzyl, cycloalkyl-alkyl or phenyl-alkyl;
[0397] wherein R.sup.10 is hydrogen or alkyl; [0398] m is 0 when
the dotted bond is present; or m is 1 when the dotted bond is
absent; [0399] A is a residue of formula:
[0399] ##STR00051## [0400] or of formula:
[0400] ##STR00052## [0401] wherein Ar is phenyl or a heteroarylic
ring; [0402] R.sup.6 is hydrogen, halogen, alkoxy or hydroxy;
[0403] R.sup.7 is hydrogen or alkyl; and [0404] Y is --COO--,
--OCO--, --CONR.sup.10--, --NR.sup.10CO--, --CH.dbd.CH--,
--C.ident.C--, --COCH.dbd.CH--, --CHOHCH.dbd.CH--, --CH.sub.2O--,
--CH.sub.2S--, --CH.sub.2SO--, --CH.sub.2SO.sub.2--,
--CH.sub.2NR.sup.10--, --OCH.sub.2--, --SCH.sub.2--,
--SOCH.sub.2--, --SO.sub.2CH.sub.2-- or --NR.sup.10CH.sub.2--,
[0405] with the proviso that when Y is --OCO--, --NR.sup.10CO--,
--OCH.sub.2--, --SCH.sub.2--, --SOCH.sub.2--, --SO.sub.2CH.sub.2--
or --NR.sup.10CH.sub.2--, R.sup.5 is hydrogen, alkyl,
alkoxy-alkyl-, alkenyl, alkynyl, benzyl, cycloalkyl-alkyl or
phenyl-alkyl; [0406] or a pharmaceutically active salt of
carboxylic acids of formula I.
Embodiment 26
[0407] The stent of embodiment 25 wherein the RAR selective agonist
has the structure:
##STR00053##
Embodiment 27
[0408] The stent of any of embodiments 25 and 26 wherein the RAR
selective agonist has the structure
##STR00054## [0409] wherein X.sup.2 is oxygen or --NH--.
Embodiment 28
[0410] The stent of embodiment 27 wherein X.sup.2 is oxygen and n
is 2.
Embodiment 29
[0411] The stent of any of embodiments 25-28 wherein R.sup.8 and
R.sup.9 are H.
Embodiment 30
[0412] The stent of any of embodiments 25-29 wherein R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 are alkyl.
DEFINITION AND INCORPORATION BY REFERENCE
[0413] The articles "a," "an" and "the" as used herein do not
exclude a plural number of the referent, unless context clearly
dictates otherwise. The conjunction "or" is not mutually exclusive,
unless context clearly dictates otherwise. The term "include"
refers to nonexhaustive examples.
[0414] All references, publications, patent applications, issued
patents, accession records, databases, websites and document urls
cited herein are incorporated by reference in their entirety for
all purposes.
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