Vitamin D3 and analogs thereof for treating alopecia

Patent metadata

Field	Value
Publication number	US-9901637-B2
Application number	US-85343110-A
Country	US
Kind code	B2
Filing date	Aug 10, 2010
Priority date	Aug 14, 2009
Publication date	Feb 27, 2018
Grant date	Feb 27, 2018

Abstract

The invention provides methods and pharmaceutical compositions for preventing or treating alopecia, such as chemotherapy-induced alopecia (CIA). The pharmaceutical compositions of the invention comprises an effective amount of a vitamin D compound in a formulation that topically delivers the vitamin D compound to the epidermis layer but substantially avoids the dermis layer. In chemotherapy patients, the pharmaceutical compositions of the invention can be administered either before or concurrent with the chemotherapy medication.

First claim

The invention claimed is:

1. A method of treating chemotherapy-induced alopecia in an individual, comprising topically administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a vitamin D compound and a carrier; wherein the carrier consists of propylene glycol and anhydrous absolute ethanol at a % (w/w) ratio of propylene glycol to ethanol selected from the group consisting of 20:80; 25:75; 30:70; 35:65; 36:64; 37:63; 38:62; 39:61; 40:60; 41:59; 42:58; 43:57; 44:56; and 45:55; and wherein the vitamin D compound is represented by Formula (I):

wherein
a and b are each independently a single or double bond;
X is —CH 2 when a is a double bond, or X is hydrogen or a hydroxyl substituted alkyl when a is a single bond;
R 1 is hydrogen, hydroxyl, alkoxyl, tri-alkyl silyl or alkyl, optionally substituted with one to three halogen, hydroxyl, cyano or —NR′R″ moieties;
R 2 is hydrogen, hydroxyl, —O-trialkyl silyl, or alkyl, alkoxyl or alkenyl, optionally substituted with one to three halogen, hydroxyl, cyano or —NR′R″ moieties;
R 3 is absent when b is a double bond or R 3 is hydrogen, hydroxyl or alkyl, or R 3 and R 1 together with the carbon atoms to which they are attached may be linked to form 5-7 membered carbocyclic ring when b is a single bond;
R 4 is absent when b is a double bond or hydrogen, halogen or hydroxyl when b is a single bond;
R 5 is absent when a is a double bond or R 5 is hydrogen, halogen or hydroxyl when a is a single bond;
R 6 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclicyl, alkyl-O-alkyl, alkyl-CO 2 -alkyl optionally substituted with one to five, hydroxyl, oxo, halogen, alkoxyl, aryl, heteroaryl, cyano, nitro or —NR′R″ moieties;
R 7 is alkyl optionally substituted with one to three hydroxyl, halogen, alkoxyl, aryl, heteroaryl, cyano, nitro or —NR′R″ moieties;
R′ and R″ are each, independently, hydrogen, hydroxyl, halogen, alkyl or alkoxyl;
the alkyl group is a fully saturated branched or unbranched having 1 to 20 carbon atoms;
the alkoxy group has 1-7 carbon atoms;
the alkenyl group is selected from the group consisting of vinyl, prop-1-enyl, allyl, butenyl, isopropenyl and isobutenyl;
the alkynyl group is selected from the group consisting of ethynyl, prop-1-ynyl (propargyl), butynyl, isopropynyl and isobutynyl;
the cycloalkyl group is a saturated or an unsaturated monocyclic, bicyclic, or tricyclic hydrocarbon group of 3-12 carbon atoms;
the aryl group is a monocyclic or bicyclic aromatic hydrocarbon group having 6-20 carbon atoms in the ring portion;
the heteroaryl group is a monocyclic or bicyclic aryl group, containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms selected from O, N or S; and
the heterocyclyl is a 4-, 5-, 6-, or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic or 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system, in which contains at least one heteroatom selected from O, S and N, where the N and S can also optionally be oxidized to various oxidation states, and pharmaceutically acceptable salts thereof, thereby treating chemotherapy-induced alopecia in the individual.

2. The method of claim 1 , wherein the vitamin D compound is 1,25-dihydroxyvitamin D3.

3. The method of claim 1 or 2 , wherein the individual is a primate.

4. The method of claim 1 or 2 , wherein the individual is a human.

5. The method of claim 1 or 2 , wherein alopecia has not commenced in the individual.

6. The method of claim 1 or 2 , wherein the individual is undergoing or about to undergo chemotherapy.

7. The method of claim 6 , wherein the pharmaceutical composition does not substantially reduce the efficacy of the chemotherapy.

8. The method of claim 6 , wherein the chemotherapy is systemic chemotherapy.

9. The method of claim 6 , wherein the chemotherapy includes one or more of: Anthracyclines, 5-FU, Tamoxifen, Irinotecan, Paclitaxel, Carboplatin, Etoposide, Cyclophosphamide, Erlotinib, Gemcitabine, Staurosporin, Vincristine, Imatinib, Gefitinib, Sorafenib, Dasatinib, Dactinomycin, Hexamethamelamine, Ifosfamide, bleomycin, methotrexate, Docetaxel, Vindesine, Vinorelbine, Topotecan, Amsacrine, Cytarabine, Busulphan, Melphalan, Vinblastine, Lomustine, Thiotepa, Gemcitabine, Carmustine, Mitroxantrone, Mitomycin C, Procarbazine, 6-Mercaptopurine, Sreptozotocin, Fludarabine, Raltitrexed and Capecitabine.

10. The method of claim 9 , wherein the chemotherapeutic agent is Doxorubicin, Daunorubicin, Epirubicin, Idarubicin or Valrubicin.

11. The method of claim 1 or 2 , wherein the pharmaceutical composition is administered to the individual prior to administration of chemotherapy or concurrent with administration of chemotherapy to the individual.

12. The method of claim 1 or 2 , wherein the pharmaceutical composition is administered to the individual after the commencement of administration of chemotherapy to the individual, but prior to the commencement of alopecia in the individual.

13. The method of claim 1 or 2 , wherein the vitamin D compound is topically administered to the individual at a dosage volume equivalent to about 0.1 μg of calcitriol/cm 2 .

14. The method of claim 1 or 2 , wherein the therapeutically effective amount of the vitamin D compound is equivalent to about 2-100 μg of calcitriol per 75 kg body weight.

15. The method of claim 1 or 2 , wherein said vitamin D compound, when topically administered to the individual at the effective concentration of:
(1) about 50 μg/mL, does not cause toxicity after at least about 25 consecutive days of drug administration; or
(2) about 100 μg/mL, does not cause toxicity after at least about 7 consecutive days of drug administration.

16. The method of claim 1 or 2 , wherein the % (w/w) ratio of propylene glycol to anhydrous absolute ethanol is selected from the group consisting of 35:65; 36:64; 37:63; 38:62; 39:61; 40:60; 41:59; 42:58; 43:57; 44:56; and 45:55.

17. The method of claim 16 , wherein the % (w/w) ratio of propylene glycol to anhydrous absolute ethanol is 40:60.

18. The method of claim 1 or 2 , wherein the therapeutically effective amount is 0.4 to 25 μg of the vitamin D compound per 75 kg body weight.

19. The method of claim 1 , wherein the vitamin D compound is represented by Formula (II):

wherein
c is a single or double bond;
R 1a is hydrogen or alkyl, optionally substituted with one to three halogen, hydroxyl, cyano or —NR′R″ moieties;
R 2a is hydrogen, hydroxyl, —O-trialkyl silyl, or alkyl, alkoxyl or alkenyl, optionally substituted with one to three halogen, hydroxyl, cyano or —NR′R″ moieties;
R 3a and R 4a are absent when c is a double bond, or are each independently hydrogen, hydroxyl, halogen, alkoxyl or alkyl optionally substituted with one to three hydroxyl or halogen moieties when c is a single bond; and
R 3b , R 4b , R 5a , R 6a , R 7a and R 8a are each, independently, hydrogen, hydroxyl, halogen, alkoxyl or alkyl optionally substituted with one to three hydroxyl or halogen moieties, or any two of R 6a , R 7a and R 8a may be linked to form a 3-7 membered carbocyclic ring, and pharmaceutically acceptable salts thereof.

20. The method of claim 1 , wherein the vitamin D compound is 1,25-dihydroxyvitamin D3; 1,25-dihydroxy-16-ene-23-yne-cho

Assignees

• Jimenez Joaquin
• Narain Niven Rajin
• Mccook John Patrick
• Berg Llc

Inventors

• Jimenez Joaquin
• Narain Niven Rajin
• Mccook John Patrick

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P39/02

  Antidotes · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/02

  Nutrients, e.g. vitamins, minerals · CPC title

• A61P17/14

  for baldness or alopecia · CPC title