CA2085632A1 - Compositions comprising vitamin d precursors, analogs thereof and their use - Google Patents

Abstract

ABSTRACT OF THE INVENTION
Methods for providing active-type vitamin D
compounds to an individual are disclosed. The individuals are exposed to sunlight to produce vitamin D and analogs or derivatives thereof via the skin.
Pharmaceutical compositions comprising lumisterol and/or tachysterol and analogs or derivatives thereof are also disclosed.

Description

~ : ,,, TITLE OF T~E INV~NTION
CONPOSITIONS CONPRI~ING VITAMIN ~ PRECUR~OR~, ANALOGS ~HEREOF AND THEIR U~E
Field of the Invention The invention is in the field of cosmetics and medicinal chemistry. In particular, the present invention relates to topical compositions which provide vitamin D, deri~atives and analogs thereof throughout the year. In another aspect, the present invention relates to a method of producing previtamin D, derivatives and analogs thereof. The topical compositions of the invention allow a user in the high northern and southern latitudes to produce previtamin D, derivatives and analogs thereof in and on their skin even when exposed to Iow energy sunlight in the winter as well as in the morning and evening throughout the year. The method employs tachysterol and lumisterol, derivatives and analogs thereof which photoisomerize to previtamin D, derivatives and analogs therof, respectively, when exposed to low levels of ultraviolet radiation.

Backaround of the Invention Vitamin D3 is a derivative of provitamin D3 (7~
dehydrocholesterol), the immediate biological precursor of cholesterol. With adequate exposure to sunlight, dietary supplements are not normally r~quired. Holick et al. in Braunwald Harrison's Principles of Internal Medicine, 11th ed~
McGraw-Hill (1987), pp. 1857-69. However, not all ,3~

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individuals are exposed to the ad~quat~ levels of sunlight, especially in the winter.
When skin i8 expoRed to sunlight or artificial sources of ultraviolet (W) radiation, the UV
radiation penetrates the epidermi~ and cause~ a variety of biochemical reactionc. Included in these reactions are the transfor~ation of provitamin D3 to vitamin D3. The electromagnetic eneryy having wave-lengths between 290 and 315 nm i ab~orbed by pro~itamin D3 resultin~ in its fragmentation to previtamin D3. Althou~h previtamin D3 is biologically inert, it is thermally labile and spontaneously undergoes ~ temperature-dependent rearrangement to form the thermally stable vitamin D3. After biosyn-thesis, vitamin D3 i~ translocated from the epidermis into the circulation via a vitamin-D binding protein.
Holick et al. ~ SciPnce 211:590-593 (1981~; Holic~ et al. in Braunwald et al., Harrison1s Principles o~
Internal Medicine, 11th ed., McGraw-~ill (1987~, pp.
2~ 1857-69.
Factors that are frequently considered as affecting the cutaneous synthesis of vitamin D3 include age, altitude, geographical location t time o~ day and area of exposure to sunlight. Common to mo~t of theæe ~actor~ i~ the availa~ility of thQ reguisitP amount o~
ultraviolet radiation with energies b~tween 290 and 315 nm which is necessary to conv~rt provitamin D3 to vitamin D3. MacLaughlin et al., Scl.e~ce ~16:1001-1003 (1982~.
The av~ilability oP vitamin D precur~or in the skin and its photo-induced transfor~ation to previtamin ~3 and then to vitamin D3 is an ef~icient - , . . : ~

physiological source of and mechani6m for the replenishment of vitamin D3. However, during the win$er in northern latitudes, sunlight does not contain enough high energy ultraYiolet radiation to convert provitamin D3 ~7-dehydrocholesterol) in hu~an Gkin to previtamin D3 (WQbb, Kline and Holick, ~ Clin.
L-inol ~e~ 67:373-37B (1988)). A~ a result, lndividuals in these latitudeq cannot make vitamin D3 in their skin, even when they are exposed to sunlight.
The lack of adequate exposure to ultraviolet radiation gives rise to the possibility of serious vitamin D
deficiency, a breakdown in blood calcium r~gulation with concomitant hypocalcemia and bone calcium wasting. . -The availability of the vitamin D precursor in the skin and its photo-induced transformation to preYitamin D3, and then to vitamin D3, is an e~ficient ~.
physiological ~ource of, and mechanism for the replenishmen~ of vita~in D3. Previously, it was thouyht that the only method o~ producing previtamin D3 was to transform provitamin D3. This transformation requires ~unlight or arti~icial W light in the region of 290-315 nm. There~ox~, in areas where the availabl~ light energy is below this range ~wavelengths greater than 316 nm), the transformation do~ not occur to any signi~icant extent. Kobayashi al., J._Nutr. Sci. Vitaminol. 19:123 ~1973~.
It has been disclosed (Holick, M., Tr~nsactions o~ the A~soci~ion o~ American ~y~lcians, 42:54-63 (1979); ~olecular Endoc~inolo~y; MacIntyre and Szelke, eds.; Elsevier/North Holland Biomedical Pr~ss (1979), pp.301-303~ $hat ~he topical application of hydroxylated metabolites of provita~in D compounds to the ~kin co~bined with U.V. phototherapy i~ a method for the sustained administration of vitamin D metabo-lites to patients who ~uffer vitamin D metabolic di~orders. When the hydroxylated proYitamin~ are applied and irradiated wi~h ultraviolet radiatlon, th~y convert ~o hy~roxylated previtamins w~ich then ther~ally i~omerize $o the hydroxylated vitamin D.
This worX i~ al~o di~closed in Holick et al., ~
Enaland ~ournal of Medicine 301:349-35~ (1980) and U.S. Patent No. 4,310,511 (Jan. 12, 1982).
1,25-Dihydroxyvitamin D3 and its analogs have been shown to be powerful antiproliferative agents which are e~fective for the treatment of the hyperproli~erative disorder p oriasi (DeLuca, ~. Fed, Proc. ~m. Soc. Biol. 2:224 236 (1988); ~olick in DeGroot t al., Endocrlnoloqy 2:so2-926, ~runP and Stratton, NoY~ ~ N.Y., (1988); Morimoto et al., Br. J~
Dermatol. 115:421_42~ (1986); ~olick, ~rc~ 5 125:1692-1697 (1989)~.
~ungaria~ Patent No. 102,939 discloses cosmetic creams containing provitamin D (~uch as rgoster~l) which, when irradiated with ultraviolet ray~, are transformed into vitamin D.
MacLaughlin et al., Science ~ 1001-1093 (1982), disclose the syn~hesi~ of previta~in D3 ~rom provitamin D3 in human skin and in an organic solvent after axposure to narrow-band radiation or ~imulated ~olar radiation. When human skin or an oryanlc 301Yent.
aontaining provitamin D3 were exposed to 295 nm radiation, up to 65% of the provitamin D3 was converted to previtamin D3. The authors ~urther disclose that , . ,: i., . - .

~ 2 the optimum wavelength for the production of previtamin D3 is ~etween 295 nm and 30Q nm.
Dauben et al., J. Am. Chem. soc~ 104:57~0-5781 (1982); J. ~. Chem. Soc. lQ4:355-356 (1982), di~close the effect of wavelength on the photochemistry of proYitamin D3 and the effect o~ wavelength on the production of previtamin D3. The authors found that whén provitamin D3 i exposed to light in the range o 254 nm, it i6 converted to a variety of photoproducts, the major portion being about 75~ tachysterol. This mixture was then exposed to either 300 ~m o~ light, broad-band 350 nm light or 355 nm light to give ,a build up of previ~amin D3. Dauben et al. conclude ~hat i~ provitamin D3 is ~irst irradiated at 0C with 254 nm light to give a quasi photostationary state of provitamin D3, previtamin D3, tachysterol and lumisterol, and the mixture is therea~ter irradiated (0C) with 350 nm light, a maximum of 83% previtamin D3 is produced.
Malatesta et al., J. Amer. Chem Soc. 103:6781-6783 (1981), disclose the e~ects o~ di~ferent UV
wavel~ngths on the relative quantities of photoproducts produced fro~ provitamin D3.
~olick et al. di~close that the photochemical conversion o~ previtamin D3 to lumi~terol and tachysterol i~ the major ~actor that prevents vitamin D3 ~ntoxication after ~ single prolonged expo~ure to the sun. Holick ~ , Sc ence ~ 590-592 (198~).
The corollary to this ~inding is ~hat lumisterol and tachys~erol are two biologically inert product~
thought to be ~loughed o~f the skin during ~he natural turnover of the epidermal cells.

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; ~ -Provitamin D2 (ergosterol) i~ the precursor of vitamin D2. Vitamin D2 is one of the ~ajor forms of vitamin D that is used to ~o~tify ~ood~ ~uch as milk ~nd ~ultivitamins. -, . .
SIJM~RY OF T~IE INV~SNTION

The present invention ie related to the discovery that topi~al ~ormula~ion~ comprising lumisterol and tachysterol, analogs and derivatives thereo~ ~re effective means o~ providing previtamin D, derivatives and analogs thereo~ to individuals. The present invention utiliz2s ~he low energy W photoconversion of l~misterol and tachysterol, analogs or derivatives thereof, to previtamin D, analogs or derivatives thereof, respectfully, as a method of producing vitamin D, analoys or derivatives thereo~ in ~he skin.
I~ is this novel ~inding that solYeS the pro~lem of producing vitamin D compounds via ~he skin in areas of ' low energy sunlight.
In particular, the inYention i5 directed to lumisterol and tachysterol, deriva~ives an~ analogs :~ thereof which are convertibl2 to vitamin D analogs in ' the presenc~ of low en~rgy W lighk. The invention is : also directed to pharmac~utical compositions containing an e~fective amount o~ lumisterol and/or tachy~terol, derivatives or analogs thereof, and a pharmaceutically e~ective carrier.
The invention is also directed to a method ~or providing vitamin D, analogs or derivatlves thereo~, to an individual by administering to the indivldual pharmaceutical composition of the invention.

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The invention is also directed to a ~thod o~
trea~ing hyperproliferati~e disorders of the ~kin : including psoriasis, healing wounds and inhibiting car forma ion with the pharmaceutica:l compositions of ~- 5the inventionq The invention is also directed to the treatment o~ ulcers such as diabetic ulcer,s o~ the feet, .. ~ decubitus ulcers (bed sores), genito-urinary ulcers, - and ulcerative keratitis with ~he pharmaceutlcal i 10compositions of the invention.
,~
.BRIEF DESCRIPTION OF THE DRAWINGS
"~
- Figure 1 illustrates the photochemical conversion :of provitamin D to vitamin D and the concomitant 15production of lumisterol and tachysterol. ~hen the bond between C-22 ~nd C-23 is a single covalent bond ~:~ and X is hydrogen, the compounds belong to the D3 ~` family, e.y. vitamin D3. Where the bond between C-22 .; and C-23 is a double covalent bond and X is methyl, 20the compounds belong to the D2 f~mily, e.g, vitamin D2.
" Figure 2 depicts an HPLC trace of a control : solution of provitamin D3 (A) and a solution of ; provitamin ~3 exposed ~o sunligh~ on a day during the ;~ winter (B).
2 5Fiqure 3 depicte an HPLC trace of a control BolUtlon of tachysterol (A) and a solution o~
~.' tachysterol exposed to sunlight on a day during the i~: winter (~J.
Fiyure 4 depicts an HPLC trace of a control 30solution of lumisterol (A~ and a ~olution o~

~ ' :~ -1 l :
" .
1, .,,' , :

:- -8- ~:
,~ ~
lumi terol exposed to sunlight on a day during the :~ winter (B). ~:
,, :
~ D~SCRIPTION OF THE P~EF~R~ OD~ENTS
: ::
The ack~ve compounds utilized in the present invention are tachysterol r lumisterol ancl derivati1ves thereo~, either alone or in combination. The tachysterol and lumisterol derivatives have the following ~ormulae (I) and (II), respectively:

:~ ' ' CH ~1 ;ii 3~ J ~

R ~ -O ~ ~-R 1 ,.................. .

;, ~'' ~, , ~; (I) ~II) ~, 10 wherein the bond between C-22 and C-23 is a single or double bond;
X is hydrogen, methyl or ethyl; and ,. , .

. ~
: ` :

i3~: ~
~.
:, :, R1 is hydrogen or a Rtraight or branched chain glycosidic residue containing 1-20 glyco~idic units per residue, or R1 is an orthoester glyco~ide moiety of -~ the Formula (III):

", ~ ~5< X ~ ~3 :.
,~
^ 5 (III~

- where A represent~ a gluco~uranosyl or a ~lucopyranosyl ring;
' R2 is hydrogen, lower (Cl-Ch) alkyl, C7-C~ aralkyl, '~!, or C6-C10 aryl; and ' 10 R3 is hydrogen or a ~traight or branch chain '~ glycosidic residue containing 1-20 glycosidic units -~
per residu~
' These comp~unds are photoisomers of pr vitamin D, :, th~ precursor of biologically active vitamin D.
`~ 15 Tachysterol and lumisterol may be pr~pared by phokvisomerization and i~olation as disclosed by Holick et a~ Lo hem. 18:1003-1008 (1979). Analogous , methods ~or making the corresponding glycosidic and :': ortho~ster glycoside derivatives are taught, ~or ~:
~xample, by Holick ~ , U.S. Patent Nos. 4,410,515 ~: and 4,521,410, the disclosures of which are fully incorporated by re~erence herein.

' .
:
~.......................................................................... .

:
.

The tachysterol and lumisterol analogs of the present invention have the ~ollowing Formulae ~IV) and (V), respectiv~ly: -~,V~Q~
Q~ ~:
; w,V ~,ab ~ ,~
UX~V~ 1 $
~ 0 ~ 1 x t ',:
" .
,, .

' ' ; ( IV) ~V) wherein the bond between carbons C-22 and C-23 l~
- ~ingle or dou~le bond;
y1 is hydrogen, ~, CH3~ ~H2CH3 or X1;

' ~1" j ~ 3 ~3 U is hydrogen, -OH or -O-(C2-C4 alkyl)-OH;
Z1 is F, H or X1;
Q~ is CF3 or C~2X1;
Qb i~ CF3 or CH3;
wherein x1 i3 selected from the group consisting of hydrogen, -OH and oR1; :
wherein R7 is hydrogen or a straight or ~ranched chain glycosidic residue containing l-20 glycosidi~ units per residue~ or R1 is an orthoester glyco~ide moiety of the Formula (III):

R~< DX

(II~) wherein A represents a gluco~urano~yl or glucopyranosyl ring;
R2 is hydrogen, lower C1-C4 alkyl or aryl, with the proviso that aryl i~ phanyl or phenyl ~ub-sti~uted by chloro, fluoro, bromo, iodo, lower C1-C4 alkyl, C7-C4 alkoxy; or naphthyl; and ~3 ia hydrogen or a straight or branched cha:in glycosidic residue containing l 20 ylycosidic unit~ per residue;
W is ~'}I-C~3 01~ 0;

~ C 3 V is CH2 or 0;
: with the proviso that both W and V are not both 0; and i8 either a single bond between Q3 and QP or a hydrogen atom on Q~ and Qb.
Th se co~pounds are photoisomer~ o previtamin D
analogs, the precursor o~ biologically active vitamin D analo~s.
~xamples of particular vitamin D analogs are taught, for example, by ~olick et alO, U.S. Patent No.
4,310,511 (Jan. 12, ~g82); Partridge et al., U.s.
Patent No. 4,634,692 ~1987); Yamada, JP Publication NoO J5 5111-460; DeLuca et al., U.S. Patent No.
4,719,205 (19B83; Holick et al., U.s. Patent No.
4,410,515 (1983); Hslick et al., U.S. Patent No.
4,521,410 ~1985~; Holick et al., U.5. Patent No.
4,230,701; and Shiina t al., Arch. Bi~chem. 8iQP-hvs~
220:90 (1983), the disclosures of which are fully incorporated by reference herein. Methods ~or ~aking the corresponding glycosidic and orthoes~er glycoside vitamin D analogs are taught, for example, by Holick et al., U.S. Patent Nos. 4,410,515 and 4,521,410, the disclosures of which are ~ully incorporated by . referPnce herein.
:. The tachysterol and lumisterol analogs may be prepared by photoisomerization of the re~ui~ite ! provita~in D analog according to the method disclosed by Holick et al., Biochem. 1~:1003-1008 (1979).
: By administering an e~ective amount o~
tachysterol, lumlsterol and a~alogs or deriv~tiYes thereof in topical compositions according to this invention, it is pos6ible for the ~irst time to provide a method which allows individuals living in q~

:: ~
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regions of low energy sunlight to produce vitamin D
compounds via their skin, thus preventing harmful Yitamin D3 depletion. The compositions o~ the present invention may be used, therefore, in methods of S treating or preventing os~eomal~cia due to vitamin de~iciency, and calcium disorders re~ulting from a lack o~ vitamin D ~a lack of vita~in D lead~ ~o de~icient intestinal ab~orp~ion of calcium which ' results in hypocalcemia), ~lucocorticoid-induced ; 10 decrease in calcium ab~orption, osteoporosis, senile decrease in calcium absorption, hypoparathyxoidism, milk ~eYer disease, turkey weak leg diseaset ~tc.
The present invention also provides ~or a ~ethod of healing wounds and inhibiting scar formation and trea~ing hyperproliferative disorders of the skin including psoriasis by administering an effective amount of a tachysterol or luminsterol analog of the invention. Wounds to the external epithelium include cut~, punctures and lacerations, including corneal ,!~ 20 lacerations. The invention al o provides for the treatment of ulcers such as diabetic ulcers of the ~eet, decubitus ulcers (bed sores), genito urinary ulcers, and ulcerative keratitis by administering an ef~ectiv0 amount of a tachysterol or luminster~Dl analog of the invention. Ulcerative keratitis- i5 cau~ed, for example, by extended wear of conta,ct len~es.
Genito-urinary ulC2XS treatable with the tachysterol and lumisterol analogs of t~e invention include thos~ cau~ed by, for example, herpes sim~lex virus as well as other viral, fungal and bacterial infections. See Harrison's PrinciPles o~ Internal t~
r~

Me~icine, E. Braunwald et al. (eds.); ~cGraw-Hill Book Co., New York, N.Y., 1987, pp. 514-516.
Examples of tachysterol and lumlstero1 analogs include 1-hydroxytachysterol2, 1-hydroxytachysterol3, 1-hydroxylumisterol2, 1-hydroxylumi~terol3~ 1,24-dihydroxytachy~terolz, 1,24-dihydroxytachyst2rol3, 1,24-dihydroxylumisterol2, 1,24-dihydroxylumisterol3, 1,25-dihydroxytachysterol2, 1,25-dihydroxy~achy~terol3, 1,25 dihydroxylumisterol2, 1,25-dihydroxylumisterol3, 24,25-dihydroxytachyst~rol2, 24,25-dihydroxy-tachysterol3, 24,25-dihydroxylumi~terol2, 24,25-dihydroxylumisterol3, 25,26-dihydroxytachysterol2, 25,26-dihydroxytachysterol3, 25,26-dihydrox-ylumisterol2, 25,26-dihydroxylumisterol3~ 1,24,25-trihydroxytachysterol2, 1,24,25-trihydroxytachysterol3, 1,24,25-trihydroxylumisterol2, 1,24,25-trihydroxy-lumisterol3, 2-B-~3-hydroxypropoxy)-1 alpha,25-dihydroxytachysterol2, 2-~-(3-hydroxypropoxy)-1 alpha,25-dihydroxytachysterol3, 2-B-(3-hydroxypropoxy)-1 alpha,25-dihydroxylumisterol~, 2-B-(3-hydroxy-propoxy)-1 alpha,25-dihydroxylumisterol3, as well as the side chain ~luoro derivative6 of 1,25-dihydroxytachysterol2, 1,25-dihydroxytachysterol3, 1,25-dihydroxylumistexolz, 1,25-dihydroxylumisterol3, l-hydroxytachysterolz, 1-hydroxytachysterol3, 1-hydroxylumisterol2, and 1-hydroxylumisterol3. Al~;o included are the 20- and 22-oxa tachyskerol and lumi~terol derivatives including 20-OX2l-la(OH)tachy~terol2, 20-oxa-l~(OH~tachysterD13, 20-oxa-la(OH~lumisterol~, 20-oxa l~(~H)lumis~erol3, 20-oxa-1~,25~OH~2tachysterol2, 20-oxa 1~,25(0H)2tachy6terol3, 20-oxa-1~,25(0~1)21umisteroli!, 20-oxa-1~,25(0H)2-. ., ~

15~
:, lumisterol3, 22 oxa-l~(OH)tachysterol2, ~2-oxa-l~(O~)tachysterol3, 22-oxa-1~(OH)lumi~terol2, 22~oxa-l~(OH)lumisterol3, 22-oxa-1~,25(0H)2tachysterolz, 22~
oxa-1~,25(OH)2tachysterol3, 22-oxa-1~,25(0H~21umisterol2 and 22-oxa-1~,25(0H)21umisterol3. Also in luded within the 6cope o~ the present invention are 25, 26 cyclopropyl c:ompounds including 1,24-dihydroxy-25,26-dehydrotachystsrol3, 17 24-dihydroxy-25,.26-dehydrotachysterol2, 1,24-dihydroxy-25,26-dehydrolumisterol3, and 1,24-dihydroxy-25,26-dehydrolumist~rol2.
Foremost among the individuals which may be treated with the compositions of the invention are humans, although the invention is not intended to be 50 limited. Any animal which may benefit Prom treatment with the compositions o~ the invention are within the spirit and scope o~ the present inYention.
By using tachysterol and lumisterol analogs in topiral compositions according to this invention, it i~ possible ~or the first time ts provide a method which allows individuals living in regl~ns of low unlight to produce vitamin D analoys via their skin.
The compositions of the present invention may be used, therefore, in ~ethod~ o~ treating decubitus and diabetic foot ulcers; ulcerative keratitis; treati~g psoriasis; wound healing; inhibiting ~car formation;
treatiny or preventing osteodystrophy due to an acquired or inherited disorder in ~itamin D
: metaboli~m; glucocorticoid-induced decrea~e in calcium absorption; o~teoporosis; ~enile decrease in calcium absorption; hypoparathyroidism; milk fever di ease;
and turkey weak leg disease.

, ~.

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The compounds 9~ the present invention can be administered in any appropriate pharmacological carrier for topical or lntravenou~ admlnistration.
The dosage a~ministered will be depen~ent on the age, health and weight of the recipient~ and the nature o~
the effect desired.
The topi6al compositions of the invention may be applie~ so that at least 0.1 microgram, pxeferably at least about 10 micrograms to about 100 mg of the vitamin D precur~or/gm carrier is administered to the skin. A preferred range is between about 1 microgram to about 1 milligram of tachysterol, lumisterol or analog or derivative thereof/gm carrier.
The compositions of the invention formulated for intravenou administration may comprise at least about 0.1 micrvgram, preferably at least about 1.0 microgram to about 100 mg of th~ vitamin D precu~sor or analog precursor per ml o~ physiologically acceptable solution. A most preferred range is about 1.0 micro-grams ~o about 100 micrograms of tachy~terol, lumi terol or analog or derivative thereof per ml of solution.
The compounds can be employed $n a pharmacolog-ically inert topical carrier such as ne comprising a gel, an ointment or a cream, includiny such carriers as water, glycerol, alcohol, propylene glycoll ~atty alcohols, txiglycerides, Patty acid esters or mineral oils. Other possible carriers are liquid pe~rolatum, isopropylpalmitate, polyethylene glycol e~hanol 95%, polyoxye~ylene monolaurate 5~ in water, sodium lauryl ~ulfate 5~ in wat~r, and the like. Minerals such as J, . . . , :~' ' , ~ ' ' ' ' ~ ,.` ' , .

3~ ~ ~

anti-oxidants, humectants, viscosity ~tabilizers and the like may b~ added, i~ necessary.
Alterna~ively, the csmpDunds may be employed as part o~ a ~un screen lotion which ~electively screens the harm~ul high energy W radia~ion ~below 3$5 nm) but which allow~ ~edium and low energy UV radiation (above 315 nm~ to pass which is o~ sufficient energy to photoisomerize lumisterol, tachy~terol ~nd the analogs or derivatives thereof to previtamin D or the analogs or derivatives thereo~. Alternatively, the compounds of the invention may be added to broad range sun screens that absorb radia~ion with e~ergies of up to 360 nm. Such sun screen lotions may comprise any of those well known to those of ordinary skill in the art, for exampl~, ethyl ~-aminobenzoate (benzocaine), ~-aminobenzoic acid (PABA~, octyl methoxy~innamate (PARASOLRMCX~, butyl methoxydib~nzoylmethan SPARASOL~
178~), phenyl ~alicylate (salcol~, 2-ethsxyethyl ~
methoxycinnamate, glyceryl ~-aminobenzoate, 2,4-dibenzoyl resorcinol~ octyl dimethyl PABA, oxybenzone, benzophenones, methyl anthranilate, cinoxate, amyldimethyl PABA, homomenthyl salicylate, digalloyl trioleate, ethyl-~-ylycosylimido benzoate, and red v~terinary petrolatum. For other examples, ~e~ Algra i 25 ~ 31~, Int J. Der~ 17:628-634 (1978), Sayre, R.~.
et alL, Photochem~Photobiol. ~2:559-566 (1979).
Preparations ~or parenteral administration include sterile or agueous or non-aqueoUs solu~ions~
suspension~, and emulsions. Examples o~ non-aqueous ~olvents ar0 prspylene glycol, polyethylene glycol, vegetable oils such as olive oil~ and injectable organic esters such as ethyl oleate. Aqueous carriQrs ., ~ - - - ;, ~ . i , . . .

-., ~ . . ~ , . . - ~ .

. . . . .. . . .. , . , . . , - .. - .. ....

3~ ~

include water, alcoholic/aqueous solution~, emulsions or ~uspensions, including ~aline and ~uf~ered ~edia.
Parenteral vehicles include ~odium chloride solution, Ringer'~ dextroee, dextrose and sodium chloride, lactat2d Ringer'~, or ~ixed oils. In~r~venous vehicles include fluid and nutrient replenishers, electrolyte replenisher~, such as those based on Ringer's dextrose, and the like~ Preservatives and oth~r additives may also be present, such as, for j 10 example, antimicrobials, anti-oxidants, chelating agents, inert gases and the like. See, generally, Remington's Pharmaceutical _Science, 16th Ed., M~ck Eds., 1980.
:~ The compositions comprising tachysterol and/or lumisterol and analogs or derivatives thereof which are formulated for parenteral administration may be utilized to provide an individual with these vitamin D analsg precursors so as ko allow the production of vitamin D analogs or derivatives in the skin in the presence of medium and low energy ~Y radiation.
The invention further rPlates to ~olutions comprising the tachysterol and lumisterol, analogs and derivatives thsreof which may be exposed to W
radiation to allow the preparation of a ~olution comprising an active vitamin D compound as desir~ed just before administration to the individual. This : method avoids the decomposition of vitamin D and analogs thereof which occurs in solution. Solutions which may comprise compounds of the invention ~ay include the above-listed parenter~l ~olukions. 0~
; cour~e, the 301utions comprisin~ th2 lumisterol and tachysterol analogs must be stored in an opaque ,:

: .
.
~.............. .. : . - : . ..

,. --1 9--container to avoid prema~ure conversion of tachysterol and lumisterol analog~ to the corresponding vitamin D
~nalog.
Ha~ing now generally de~cribed thi~ i~vention, the same will be understood by reference to an example ,I which is provided herQin for purposes o~ illustration only and i5 not intending to be limited unle~s otherwi~e specified.

- ~xamp~le 1 Crystalline provitamin D; was dissolved in methanol at a concentration of 10 micrograms/ml. Ten ! ml of thiæ solution was placed in quartz test tubes.
one test tube containing pro~itamin D3 in methanol was exposed to direct sunlight in ~oston during November, 1989 between 9 AM and 10 AM (Fig. 2B3 while a similar sample remained in the dark o~er the ~me period of time (Tig. 2A) O At the end o~ the exposure, a small aliquot was taken from each test tube and chromatographed on a high per~ormance liquid chromatograph according to MacLaughlin et al., Science 216:1001-1003 (1982). Similar studies were conducted with lumisterol (Fig. 4) and tachysterol (Fig. 3) that were prepared a~ pre~iously described ~HolicX et al., ~iochem. 18:1003-1008 (1979~. The analysis of all ~he chromatogram~ in Figs. 2-4 revealed that when tachysterol and lumisterol w~re exposed to sunlight in : November between 9 and 10 AM, they underwent photoisomerlzation to previtamin D3 (Flgs. 3B, 4B). In contrast, provitamin D3 exposed tv khe same dlrect sunlight did not convert to previtamin D3 (Fig. 2B).
All samples that were kept in the dark for the ~ame .

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~ime did not convert to previtamin D3 ~Figs. 2A, 3A, 4A).
It is ~xpected that the tarhy6terol and lumi8t~rol analog5 of the present invention, upon S irradiation with the same low intensity and energy W
light, will give th~ corre6ponding analogs.
Haviny nsw generally described thi3 invention, it will be apparent to one o~ ordinary ~kill in the art that the same can be carried out in a variety of 1~ embodiments and variations which are equivalent . without affecting the spirit or scope of the invention or any embodiments thereof.

Claims (57)

1. A composition comprising a pharmaceutically acceptable carrier and a compound of the formula wherein the bond between C-22 and C-23 is a single or double bond;
X is hydrogen, methyl or ethyl; and R1 is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue, or R1 is an orthoester glycoside moiety of the formula:

where A represents a glucofuranosyl or a glucopyranosyl ring;

R2 is hydrogen, lower (C1-C4) alkyl, C7-C10 aralkyl, or C6-C10 aryl; and R3 is hydrogen or a straight or branch chain glycosidic residue containing 1-20 glycosidic units per residue;
wherein said compound is presentin an amount effective to provide vitamin D3 when said composition is administered to an individual.

2. The composition of claim 1, wherein said compound is lumisterol3.

3. The composition of claim 1, wherein said carrier is effective for topical administration.

4. The composition of claim 3, further comprising one or more sun screen agents.

5. The composition of claim 1, wherein said carrier is effective for parenteral administration.

6. The composition of claim 1, wherein said compound is present in an amount of 0.00001 to 10% by weight.

7. The composition of claim 1, wherein said compound is present in an amount of 0.0001 to 0.01% by weight.

8. A composition a pharmaceutically acceptable carrier and a compound having the formula:

wherein the bond between C-22 and C-23 is a single or double bond;
X is hydrogen, methyl or ethyl; and R1 is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue, or R1 is an orthoester glycoside moiety of the formula:

where A represents a glucofuranosyl or a glucopyranosyl ring;
R2 is hydrogen, lower (C1-C4) alkyl, C7-C10 aralkyl, or C6-C10 aryl; and R3 is hydrogen or a straight or branch chain glycosidic residue containing 1-20 glycosidic units per residue;
wherein said compound is present in an amount effective to provide vitamin D3 when said composition is administered to an individual.

9. The composition of claim 8, wherein said compound is tachysterol3.

10. The composition of claim 8, wherein said carrier is effective for topical administration.

11. The composition of claim 10, further comprising one or more sun screen agents.

12. The composition of claim 8, wherein said carrier is effective for parenteral administration.

13. The composition of claim 8, wherein said compound is present in an amount of 0.00001 to 10% by weight.

14. The composition of claim 8, wherein said compound is present in an amount of 0.0001 to 0.01% by weight.

15. A composition comprising lumisterol and tachysterol and a pharmaceutically acceptable carrier wherein said lumisterol and tachysterol are present in an amount effective to provide vitamin D3 when said composition is administered to an individual.

16. The composition of claim 15, wherein said carrier is effective for topical administration.

17. The composition of claim 15, wherein said carrier is effective for parenteral administration.

18. The composition of claim 15, wherein said lumisterol and tachysterol are individually present in an amount of from 0.00001 to 10% by weight.

19. The composition of claim 15, wherein said lumisterol and tachysterol are individually present in an amount of from 0.001 to 0.01% by weight.

20. A method for providing vitamin D3 to an individual which comprises administering to said individual the pharmaceutical composition of any one of claims 1, 8 and 15 and exposing said individual to UV radiation.

21. The method of claim 20, wherein said composition is administered by topical means.

22. The method of claim 21, wherein said composition further comprises one or more sun screen agents.

23. The method of claim 20, wherein said composition is administered by intravenous means.

24. The method of claim 20, wherein said UV
radiation is provided by sunlight of insufficient intensity and wavelength to effect the conversion of provitamin D to vitamin D.

25. The method of claim 24, wherein said UV
radiation has a wavelength above 315 nm.

26. A method for treating or preventing osteomalacia due to vitamin D deficiency or a calcium disorder resulting from a lack of vitamin D, glucocorticoid-induced decrease in calcium absorption, osteoporosis, senile decrease in calcium absorption, hypoparathyroidism, milk fever disease, or turkey weak leg disease in an individual which comprise ad-ministering to said individual the pharmaceutical composition of any one of claims 1, 8 and 15 and exposing said individual to low energy UV radiation.

27. The method of claim 26, wherein said composition is administered by topical means.

28. The method of claim 27, wherein aid composition further comprises one or more sun screen agents.

29. The method of claim 26, wherein said composition is administered by intravenous means.

30. The method of claim 26, wherein said UV
radiation is provided by sunlight of insufficient intensity and wave-length to effect the conversion of provitamin D to vitamin D.

31. The method of claim 30, wherein said UV
radiation has a wavelength above 315 nm.

32. A composition comprising a pharmaceutically acceptable carrier and a compound of the formula wherein the bond between carbons C-22 and C 23 is single or double bond;
Y1 is hydrogen, F, CH3, CH2CH3 or X1;
U is hydrogen, -OH or -O-(C2-C4 alkyl)-OH;
Z1 is F, H or X1, Qa is CF3 or CH2X1;
Qb is CF3 or CH3;
wherein x1 is selected from the group consisting of hydrogen, -OH and OR1;

wherein R1 is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue, or R1 is an orthoester glycoside moiety of the formula:

wherein A represents a glucofuranosyl or glucopyranosyl ring;
R2 is hydrogen, lower alkyl, or aryl, with the proviso that aryl is phenyl or phenyl substituted by chloro, fluoro, bromo, iodo, lower C1-C4 alkyl, C1-C4 alkoxy; or naphthyl; and R3 is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue;
W is CH-CH3 or O;
V is CH2 or O;
with the proviso that both W and V are not both O; and "===" is either a single bond between Qa and Qb or a hydrogen atom on Qa and Qb;
wherein said compound is present in an amount effective to provide a vitamin D analog when said composition is administered to an individual.

33. The composition of claim 32, wherein said compound is lalpha,25-dihydroxylumisterol3, lalpha,25-dihydroxylumisterol2, lalpha-hydroxylumisterol3, lalpha-hydroxylumisterol2,24,25-dihydroxylumisterol3, 24,25-dihydroxylumisterol2, 1,24-dihydroxylumisterol3, 1,24-dihydroxylumisterol2, and 1,24-dihydroxy-25,26-dehydrolumisterol3.

34. The composition of claim 34, wherein said carrier is effective for topical administration.

35. The composition of claim 32, further comprising one or more sun screen agents.

36. The composition of claim 32, wherein said carrier is effective for parenteral administration.

37. The composition of claim 32, wherein said compound is present in an amount of 0.00001 to 10% by weight.

38. The composition of claim 32, wherein said compound is present in an amount of 0.0001 to 0.01% by weight.

39. A composition comprising a pharmaceutically acceptable carrier and a compound having the formula:

wherein the bond between carbons C-22 and C-23 is single or double bond;
Y1 is hydrogen, F, CH3, CH2CH3 or X1;
U is hydrogen, -OH or -O-(C2-C4 alkyl)-OH;
Z1 is F, H or X1;
Qa is CF3 or CH2X1;
Qb is CF3 or CH3;
wherein X1 is selected from the group consisting of hydrogen, -OH and OR1;
wherein R1 is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue, or R1 is an orthoester glycoside moiety of the Formula (III):

wherein A represents; a glucofuranosyl or glucopyranosyl ring;
R2 is hydrogen, lower alkyl, aralkyl, or aryl, with the proviso that aryl is phenyl or phenyl substituted by chloro, fluoro, bromo, iodo, lower C1-C4 alkyl, C1-C4 alkoxy; or naphthyl; and R3 is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue;
W is CH-CH3 or O;

V is CH2 or O;
with the proviso that both W and V are not both O; and "===" is either a single bond between Qa and Qb or a hydrogen atom on Qa and Qb;
wherein said compound is present in an amount effective to provide a vitamin D analog when said composition is administered to an individual.

40. The composition of claim 39, wherein said compound is lalpha,25-dihydroxytachysterol3, lalpha,25-dihydroxytachysterol2, lalpha-hydroxytachysterol3, lalpha-hydroxytachysterol2, 24,25-dihydroxytachy-sterol3, 24,25-dihydroxytachysterol2, 1,24-dihydroxytachysterol3, 1,24-dihydroxytachysterol2, and 1,24-dihydroxy-25,26-dehydrotachysterol3.

41. The composition of claim 39, wherein said carrier is effective for topical administration.

42. The composition of claim 41, further comprising one or more sun screen agents.

43. The composition of claim 39, wherein said carrier is effective for parenteral administration.

44. The composition of claim 39, wherein said compound is present in an amount of 0.00001 to 10% by weight.

45. The composition of claim 39, wherein said compound is present in an amount of 0.0001 to 0.01% by weight.

46. A method for providing a vitamin D analog to an individual which comprises administering to said individual the composition of claim 32 or 39 and exposing said individual to UV radiation.

47. The method of claim 46, wherein said composition is administered by topical means.

48. The method of claim 47, wherein said composition further comprises one or more sun screen agents.

49. The method of claim 46, wherein said composition is administered by intravenous means.

50. The method of claim 46, wherein said UV
radiation is provided by sunlight of insufficient intensity and wavelength to effect the conversion of the corresponding provitamin D analog to the vitamin D analog.

51. The method of claim 46, wherein said UV
radiation has a wavelength above 315 nm.

52. A method for treating decubitus or diabetic foot ulcers; ulcerative keratitis; psoriasis; wounds;
inhibiting scar formation; glucocorticoid-induced decrease in calcium absorption; osteoporosis; senile decrease in calcium absorption; hypoparathyroidism;
milk fever disease; turkey weak leg disease or treating or preventing osteodystrophy due to an acquired or inherited defect in the metabolism of vitamin D; which comprises administering to said individual the composition of claim 32 or 39 and exposing said individual to UV radiation.

53. The method of claim 52, wherein said composition is administered by topical means.

54. The method of claim 53, wherein said composition further comprises one or more sun screen agents.

55. The method of claim 52, wherein said composition is administered by intravenous means.

56. The method of claim 52, wherein said UV
radiation is provided by sunlight of insufficient intensity and wave-length to effect the conversion of the corresponding provitamin D analog to the vitamin D analog.

57. The method of claim 56, wherein said UV
radiation has a wavelength above 315 nm.