Vitamin D3 and analogs thereof for treating alopecia

Patent metadata

Field	Value
Publication number	US-11305016-B2
Application number	US-201815872669-A
Country	US
Kind code	B2
Filing date	Jan 16, 2018
Priority date	Aug 14, 2009
Publication date	Apr 19, 2022
Grant date	Apr 19, 2022

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 pharmaceutical composition comprising a vitamin D compound and a carrier; wherein the carrier consists of propylene glycol and ethanol at a % (w/w) ratio of propylene glycol to ethanol 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; 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, wherein the pharmaceutical composition comprises 3-100 μg/mL of the vitamin D compound.

2. The pharmaceutical composition 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.

3. The pharmaceutical composition of claim 1 , wherein the vitamin D compound is 1,25-dihydroxyvitamin D3; 1,25-dihydroxy-16-ene-23-yne-cholecalciferol; 1α-hydroxyvitamin D3; 1α,24-dihydroxyvitamin D3; or MC 903.

4. The pharmaceutical composition of claim 1 , wherein the vitamin D compound is 1,25-dihydroxyvitamin D3.

5. The pharmaceutical composition of claim 1 , wherein the vitamin D compound modulates the expression of HSPA2 , HSF4, HSPB1 or DNAJC6 in normal keratinocytes.

6. The pharmaceutical composition of claim 1 , wherein the vitamin D compound modulates the expression of SLC1A1, KCNB2, KCNN4 or SLC1A3 in normal keratinocytes.

7. The pharmaceutical composition of claim 1 , wherein the vitamin D compound decreases the expression of one or more proteins selected from the group consisting of Crk II, Growth Factor Independence 1, Serine Threonine Protein Phosphatase 1b, Cathepsin D, Transforming Growth Factor b pan, WAVE, Protein Tyrosine Phosphatase PEST, and CD40 by at least about 2-fold.

8. The pharmaceutical composition of claim 1 , wherein the vitamin D compound induces overexpression of one or more proteins selected from the group consisting of BACH1, CENPE, cMyc, C-src tryosine kinase (Csk), CtBP1, Dimethyl Histone H3 diMeLys4, Dimethyl Histone H3 diMeLys9, Estrogen Receptor, FKHRL1 (FOXO3a), FOXP2, HDAC2, HDAC6, MAP Kinase Activated Protein Kinase 2 (MAPKAPK2), MAP Kinase ERK1, Melanocortin 3 Receptor, Proliferating Cell Protein Ki67, S100, SHPTP2, Sin3A, ARTS, ASAP1 Centaurin b4, Cofilin, Connexin 32, Dystrophin, Focal Adhesion Kinase pp125FAK, gTubulin, Myosin IX Myr5, Neurofilament 200, p120ctn, PAD14, Par4 Prostate Apoptosis Response 4, ROCK1, Uvomorulin ECadherin, Vitronectin, Bclx, BclxL, BID, Bmf, DcR2, ERK5, Integrin-linked kinase (ILK), Protein Kinase Ba, PUMA bbc3, Amyloid Precursor Protein, Presenilin1, Glutamic Acid Decarboxylase 65, Glutamic Acid Decarboxylase 67, Nitric Oxide Synthase (bNOS), Substance P Receptor, Synaptopodin, Tumor Necrosis Factor a, and Ubiquitin C-terminal Hydrolase L1 by at least about 2-fold.

9. The pharmaceutical composition of claim 1 , wherein the vitamin D compound induces overexpression in normal keratinocytes of one or more of: Glutathione S-transferase (GST), Keratin 1, Keratin 17, Galectin 1, S100 A9 (Calprotectin), and S100 A13.

10. The pharmaceutical composition of claim 1 , wherein the % (w/w) ratio of propylene glycol to ethanol is 40:60.

11. A pharmaceutical composition comprising a vitamin D compound and a carrier, wherein the carrier consists of propylene glycol, ethanol and ethoxydiglycol or 2-(2-ethoxyethoxy)ethanol; wherein propylene glycol is present at about 30% (w/w), ethanol is present at about 60% (w/w), and ethoxydiglycol or 2-(2-ethoxyethoxy)ethanol is present at about 10% (w/w); 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

Assignees

• Berg Llc

Inventors

• Jimenez Joaquin J
• Narain Niven Rajin
• Mccook John Patrick

Classifications

• A61Q7/00

  Preparations for affecting hair growth · CPC title

• A61K31/593 Primary

  9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3 · CPC title

• A61P39/02

  Antidotes · CPC title

• A61K31/592

  9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2 · CPC title

• A61K2800/74

  Biological properties of particular ingredients · CPC title