US2004147492A1PendingUtilityA1
Methods of treating acne
Est. expiryApr 5, 2021(expired)· nominal 20-yr term from priority
Inventors:Robert Ashley
A61K 31/135A61K 31/65D06M 16/00A61K 9/0053A61P 17/10
66
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Claims
Abstract
A method of treating acne in a human in need thereof comprising administering systemically to said human a tetracycline compound in an amount that is effective to treat acne but has substantially no antibiotic activity, without administering a bisphosphonate compound.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of treating acne in a human in need thereof comprising administering systemically to said human a tetracycline compound in an amount that is effective to treat acne but has substantially no antibiotic activity, without administering a bisphosphonate compound.
2 . A method according to claim 1 , wherein said acne is acne vulgaris, cystic acne, acne atrophica, bromide acne, chlorine acne, acne conglobata, acne cosmetica, acne detergicans, epidemic acne, acne estivalis, acne fulminans, halogen acne, acne indurata, iodide acne, acne keloid, acne mechanica, acne papulosa, pomade acne, premenstral acne, acne pustulosa, acne rosacea, acne scorbutica, acne scrofulosorum, acne urticata, acne varioliformis, acne venenata, propionic acne, acne excoriee, gram negative acne, steroid acne, or nodulocystic acne.
3 . A method according to claim 1 , wherein said tetracycline compound is an antibiotic tetracycline compound administered in an amount which is 10-80% of the antibiotic amount.
4 . A method according to claim 1 , wherein said tetracycline compound is doxycycline administered twice a day in a dose of 20 mg.
5 . A method according to claim 1 , wherein said tetracycline compound is minocycline administered once a day in a dose of 38 mg.
6 . A method according to claim 1 , wherein said tetracycline compound is minocycline administered twice a day in a dose of 38 mg.
7 . A method according to claim 1 , wherein said tetracycline compound is minocycline administered three times a day in a dose of 38 mg.
8 . A method according to claim 1 , wherein said tetracycline compound is minocycline administered four times a day in a dose of 38 mg.
9 . A method according to claim 1 , wherein said tetracycline compound is tetracycline administered once a day in a dose of 60 mg/day.
10 . A method according to claim 1 , wherein said tetracycline compound is tetracycline administered twice a day in a dose of 60 mg/day.
11 . A method according to claim 1 , wherein said tetracycline compound is tetracycline administered three times a day in a dose of 60 mg/day.
12 . A method according to claim 1 , wherein said tetracycline compound is tetracycline administered four times a day in a dose of 60 mg/day.
13 . A method according to claim 1 , wherein said tetracycline compound is an antibiotic tetracycline compound administered in an amount which results in a serum concentration which is 10-80% of the minimum antibiotic serum concentration.
14 . A method according to claim 1 , wherein said tetracycline compound is doxycycline administered in an amount which results in a serum concentration which is 1.0 μg/ml.
15 . A method according to claim 1 , wherein said tetracycline compound is minocycline administered in an amount which results in a serum concentration which is 0.8 μg/ml.
16 . A method according to claim 1 , wherein said tetracycline compound is tetracycline administered in an amount which results in a serum concentration which is 0.5 μg/ml.
17 . A method according to claim 3 or 13 , wherein said antibiotic tetracycline compound is doxycycline, minocycline, tetracycline, oxytetracycline, chlortetracycline, demeclocycline or pharmaceutically acceptable salts thereof.
18 . A method according to claim 17 , wherein said antibiotic tetracycline compound is doxycycline.
19 . A method according to claim 18 , wherein said doxycycline is administered in an amount which provides a serum concentration in the range of about 0.1 to about 0.8 μg/ml.
20 . A method according to claim 18 , wherein said doxycycline is administered in an amount of 20 milligrams twice daily.
21 . A method according to claim 19 , wherein said doxycycline is administered by sustained release over a 24 hour period.
22 . A method according to claim 21 , where said doxcycline is administered in an amount of 40 milligrams.
23 . A method according to claim 1 , wherein said tetracycline compound is a non-antibiotic tetracycline compound.
24 . A method according to claim 23 , wherein said non-antibiotic tetracycline compound is:
4-de(dimethylamino)tetracycline (CMT-1), tetracyclinonitrile (CMT-2), 6-demethyl-6-deoxy-4-de(dimethylamino)tetracycline (CMT-3), 4-de(dimethylamino)-7-chlorotetracycline (CMT-4), tetracycline pyrazole (CMT-5) 4-hydroxy-4-de(dimethylamino)tetracycline (CMT-6), 4-de(dimethylamino)-12α-deoxytetracycline (CMT-7), 6-α-deoxy-5-hydroxy-4-de(dimethylamino)tetracycline (CMT-8), 4-de(dimethylamino)-12α-deoxyanhydrotetracycline (CMT-9), or 4-de(dimethylamino)minocycline (CMT-10).
25 . A method according to claim 23 , wherein the non-antibiotic tetracycline compound is selected from the group consisting of:
wherein:
R7 is selected from the group consisting of hydrogen, amino, nitro, mono(lower alkyl)amino, halogen, di(lower alkyl)amino, ethoxythiocarbonylthio, azido, acylamino, diazonium, cyano, and hydroxyl;
R6-a is selected from the group consisting of hydrogen and methyl;
R6 and R5 are selected from the group consisting of hydrogen and hydroxyl;
R8 is selected from the group consisting of hydrogen and halogen;
R9 is selected from the group consisting of hydrogen, amino, azido, nitro, acylamino, hydroxy, ethoxythiocarbonylthio, mono(lower alkyl)amino, halogen, diazonium, di(lower alkyl)amino and RCH(NH 2 )CO;
R is hydrogen or lower alkyl; and pharmaceutically acceptable salts thereof; with the following provisos:
when either R7 and R9 are hydrogen then R8 must be halogen; and
when R6-a, R6, R5 and R9 are all hydrogen and R7 is hydrogen, amino, nitro, halogen, dimethylamino or diethylamino, then R8 must be halogen; and
when R6-a is methyl, R6 and R9 are both hydrogen, R5 is hydroxyl, and R7 is hydrogen, amino, nitro, halogen or diethylamino, then R8 is halogen; and
when R6-a is methyl, R6 is hydroxyl, R5, R7 and R9 are all hydrogen, then R8 must be halogen; and
when R6-a, R6 and R5 are all hydrogen, R9 is methylamino and R7 is dimethylamino, then R8 must be halogen; and
when R6-a is methyl, R6 is hydrogen, R5 is hydroxyl, R9 is methylamino and R7 is dimethylamino, then R8 must be halogen; and
when R6-a is methyl, R6, R5 and R9 are all hydrogen and R7 is cyano, then R8 must be halogen.
26 . A method according to claim 23 , wherein the non-antibiotic tetracycline compound is selected from the group consisting of:
wherein:
R7 is selected from the group consisting of hydrogen, amino, nitro, mono(lower alkyl)amino, halogen, and di(lower alkyl)amino, ethoxythiocarbonylthio, azido, acylamino, diazonium, cyano, and hydroxyl;
R6-a is selected from the group consisting of hydrogen and methyl;
R6 and R5 are selected from the group consisting of hydrogen and hydroxyl;
R4 is selected from the group consisting of NOH, N—NH-A, and NH-A, where A is a lower alkyl group;
R8 is selected from the group consisting of hydrogen and halogen;
R9 is selected from the group consisting of hydrogen, amino, azido, nitro, acylamino, hydroxy, ethoxythiocarbonylthio, mono(lower alkyl)amino, halogen, di(lower alkyl)amino and RCH(NH 2 )CO;
R is hydrogen or lower alkyl; and
pharmaceutically acceptable salts thereof; with the following provisos:
when R4 is NOH, N—NH-alkyl or NH-alkyl and R7, R6-a, R6, R5, and R9 are all hydrogen, then R8 must be halogen; and
when R4 is NOH, R6-a is methyl, R6 is hydrogen or hydroxyl, R7 is halogen, R5 and R9 are both hydrogen, then R8 must be halogen; and
when R4 is N—NH-alkyl, R6-a is methyl, R6 is hydroxyl and R7, R5, R9 are all hydrogen, then R8 must be halogen; and
when R4 is NH-alkyl, R6-a, R6, R5 and R9 are all hydrogen, R7 is hydrogen, amino, mono(lower alkyl)amino, halogen, di(lower alkyl)amino or hydroxyl, then R8 must be halogen; and
when R4 is NH-alkyl, R6-a is methyl, R6 and R9 are both hydrogen, R5 is hydroxyl; and R7 is mono(lower alkyl)amino or di(lower alkyl)amino, then R8 must be halogen; and
when R4 is NH-alkyl, R6-a is methyl, R6 is hydroxy or hydrogen and R7, R5, and R9 are all be hydrogen, then R8 must be halogen.
27 . A method according to claim 23 wherein the non-antibiotic tetracycline compound is selected from the group consisting of:
wherein: R7, R8, and R9 taken together in each case, have the following meanings:
R7
R8
R9
azido
hydrogen
hydrogen
dimethylamino
hydrogen
azido
hydrogen
hydrogen
amino
hydrogen
hydrogen
azido
hydrogen
hydrogen
nitro
dimethylamino
hydrogen
amino
acylamino
hydrogen
hydrogen
hydrogen
hydrogen
acylamino
amino
hydrogen
nitro
hydrogen
hydrogen
(N,N-dimethyl)glycylamino
amino
hydrogen
amino
hydrogen
hydrogen
ethoxythiocarbonylthio
dimethylamino
hydrogen
acylamino
dimethylamino
hydrogen
diazonium
dimethylamino
chloro
amino
hydrogen
chloro
amino
amino
chloro
amino
acylamino
chloro
acylamino
amino
chloro
hydrogen
acylamino
chloro
hydrogen
monoalkylamino
chloro
amino
nitro
chloro
amino
dimethylamino
chloro
acylamino
dimethylamino
chloro
dimethylamino
hydrogen
hydrogen
dimethylamino
dimethylamino
hydrogen
hydrogen
and
wherein: R7, R8, and R9 taken together in each case, have the following
meanings:
azido
hydrogen
hydrogen
dimethylamino
hydrogen
azido
hydrogen
hydrogen
amino
hydrogen
hydrogen
azido
hydrogen
hydrogen
nitro
dimethylamino
hydrogen
amino
acylamino
hydrogen
hydrogen
hydrogen
hydrogen
acylamino
amino
hydrogen
nitro
hydrogen
hydrogen
(N,N-dimethyl)glycylamino
amino
hydrogen
amino
hydrogen
hydrogen
ethoxythiocarbonylthio
dimethylamino
hydrogen
acylamino
hydrogen
hydrogen
diazonium
hydrogen
hydrogen
dimethylamino
diazonium
hydrogen
hydrogen
ethoxythiocarbonylthio
hydrogen
hydrogen
dimethylamino
chloro
amino
amino
chloro
amino
acylamino
chloro
acylamino
hydrogen
chloro
amino
amino
chloro
hydrogen
acylamino
chloro
hydrogen
monoalkylamino
chloro
amino
nitro
chloro
amino
and
wherein: R8 is hydrogen or halogen and R9 is selected from the group
consisting of nitro, (N,N-dimethyl)glycylamino, and
ethoxythiocarbonylthio; and
wherein: R7, R8, and R9 taken together in each case, have the following
meanings:
amino
hydrogen
hydrogen
nitro
hydrogen
hydrogen
azido
hydrogen
hydrogen
dimethylamino
hydrogen
azido
hydrogen
hydrogen
amino
hydrogen
hydrogen
azido
hydrogen
hydrogen
nitro
bromo
hydrogen
hydrogen
dimethylamino
hydrogen
amino
acylamino
hydrogen
hydrogen
hydrogen
hydrogen
acylamino
amino
hydrogen
nitro
hydrogen
hydrogen
(N,N-dimethyl)glycylamino
amino
hydrogen
amino
diethylamino
hydrogen
hydrogen
hydrogen
hydrogen
ethoxythiocarbonylthio
dimethylamino
hydrogen
methylamino
dimethylamino
hydrogen
acylamino
dimethylamino
chloro
amino
amino
chloro
amino
acylamino
chloro
acylamino
hydrogen
chloro
amino
amino
chloro
hydrogen
acylamino
chloro
hydrogen
monoalkylamino
chloro
amino
nitro
chloro
amino
and pharmaceutically acceptable salts thereof.
28 . A method according to claim 23 , wherein the non-antibiotic tetracycline compound is selected from the group consisting of:
wherein:
R7 is selected from the group consisting of hydrogen, amino, nitro, mono(lower alkyl)amino, halogen, di(lower alkyl)amino, ethoxythiocarbonylthio, azido, acylamino, diazonium, cyano, and hydroxyl;
R6-a is selected from the group consisting of hydrogen and methyl;
R6 and R5 are selected from the group consisting of hydrogen and hydroxyl;
R8 is selected from the group consisting of hydrogen and halogen;
R9 is selected from the group consisting of hydrogen, amino, azido, nitro, acylamino, hydroxy, ethoxythiocarbonylthio, mono(lower alkyl)amino, halogen, diazonium, di(lower allyl)amino and RCH(NH 2 )CO;
R is hydrogen or lower alkyl;
R a and R b are selected from the group consisting of hydrogen, methyl, ethyl, n-propyl and 1-methylethyl with the proviso that R a and R b cannot both be hydrogen;
R c and R d are, independently, (CH 2 ) n CHR e wherein n is 0 or 1 and R e is selected from the group consisting of hydrogen, alkyl, hydroxy, lower(C 1 -C 3 )alkoxy, amino, or nitro; and,
W is selected from the group consisting of (CHR e ) m wherein m is 0-3 and said R e is as above, NH, N(C 1 -C 3 ) straight chained or branched alkyl, 0, S and N(C 1 -C 4 ) straight chain or branched alkoxy; and,
pharmaceutically acceptable salts thereof.
29 . A method according to claim 16 , wherein the non-antibiotic tetracycline compound selected from the group consisting of structures S-Z has the following provisos:
when either R7 and R 9 are hydrogen then R8 must be halogen; and when R6-a, R6, R5 and R9 are all hydrogen and R7 is hydrogen, amino, nitro, halogen, dimethylamino or diethylamino, then R8 must be halogen; and when R6-a is methyl, R6 and R9 are both hydrogen, R5 is hydroxyl, and R7 is hydrogen, amino, nitro, halogen or diethylamino, then R8 is halogen; and when R6-a is methyl, R6 is hydroxyl, R5, R7 and R9 are all hydrogen, then R8 must be halogen; and when R6-a, R6 and R5 are all hydrogen, R9 is methylamino and R7 is dimethylamino, then R8 must be halogen; and when R6-a is methyl, R6 is hydrogen, R5 is hydroxyl, R9 is methylamino and R7 is dimethylamino, then R8 must be halogen; and when R6-a is methyl, R6, R5 and R9 are all hydrogen and R7 is cyano, then R8 must be halogen.
30 . A method according to claim 1 , wherein said tetracycline compound has a photoirritancy factor of less than the photoirritancy factor of doxycycline.
31 . A method according to claim 1 , wherein said tetracycline compound has a photoirritancy factor from about one to about two.
32 . A method according to claim 31 , wherein said tetracycline compound has a general formula:
wherein R7, R8, and R9 taken together are, respectively, hydrogen, hydrogen and dimethylamino.
33 . A method according to claim 1 , wherein said tetracycline compound has a photoirritancy factor from about 1.0 to about 1.2.
34 . A method according to claim 33 , wherein said tetracycline compound is selected from the group consisting of:
R7
R8
R9
wherein R7, R8, and R9 taken together in each case, have the following
meanings:
hydrogen
hydrogen
amino
hydrogen
hydrogen
palmitamide
and
wherein R7, R8, and R9 taken together in each case, have the following
meanings:
hydrogen
hydrogen
acetamido
hydrogen
hydrogen
dimethylaminoacetamido
hydrogen
hydrogen
nitro
hydrogen
hydrogen
amino
and
wherein R8, and R9 taken together are, respectively, hydrogen and nitro.
35 . A method according to claim 1 , wherein said systemic administration is oral administration, intravenous injection, intramuscular injection, subcutaneous administration, transdermal administration or intranasal administration.
36 . A method of treating acne in a human in need thereof comprising administering to said human an effective amount of a non-antibiotic tetracycline compound without administering a bisphosphonate compound.
37 . A method according to claim 36 , wherein said administration is topical administration.
38 . A method according to claim 36 , wherein said administration is systemic administration.
39 . A method for reducing the number of comedones in a human in need thereof comprising administering systemically to said human a tetracycline compound in an amount that is effective to reduce the number of comedones but has substantially no antibiotic activity.
40 . A method according to claim 39 , wherein said tetracycline compound is doxycycline.
41 . A method according to claim 40 , wherein said doxycycline is administered in a daily amount of from about 30 to about 60 milligrams but maintains a concentration in human plasma below the threshold for a significant antibiotic effect.
42 . A method according to claim 40 , wherein said doxycycline is administered in an amount of approximately 20 milligrams twice daily.
43 . A method according to claim 39 , wherein said tetracycline compound is administered without administering a bisphosphonate.
44 . A method for inhibiting oxidation of melanin in a human in need thereof comprising administering systemically to said human a tetracycline compound in an amount that is effective to inhibit oxidation of melanin but has substantially no antibiotic activity.
45 . A method for inhibiting lipid-associated abnormal follicular differentiation in a human in need thereof comprising administering systemically to said, human a tetracycline compound in an amount that is effective to inhibit lipid-associated abnormal follicular differentiation but has substantially no antibiotic activity.Join the waitlist — get patent alerts
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