CA1100874A - Topical pharmaceutical compositions for treating anomalous mobilization and deposition of bone mineral in humans and other animals - Google Patents

Abstract

Abstract of the Disclosure Compositions for topical application to the epidermis at an afflicted situs for the treatment of anomalous mobilization and deposition of calcium phosphate salts in the tissues of humans and other animals, are disclosed.
The compositions comprise: (i) from about 0.5% to about 20 of a pharmaceutically acceptable organophosphonate compound;
and (ii) a carrier which comprises from about 0.1% to about 15% of the composition of an organosulfoxide compound, wherein said organosulfoxide compound is a dialkylsulfoxide of the formula R'R"SO wherein group R' is a C6-C20 alkyl or substituted alkyl group and wherein group R" is a Cl-C3 alkyl or substituted alkyl group, the balance of said carrier comprising a pharmaceutically acceptable, compatible liquid, wherein the pH of aqueous solutions of the composition is from about 3.5 to about 10.

Description

BACKGROUND OF THE~ TION
The present invention relates to compositions and methods for treating the anomalous mobilization and deposition of calcium phosphate salts in animal tissues.
More specifically, organophosphonate compounds are combined with organosulfoxides to provide compositions especially adapted to be administered topically to the afflicted situs in subjects suffering from a variety of disease states involvin~ the abnormal metabolism of bone mineral.
A number o~ pathological conditions which can afflict warm-blooded animals involve abnormal calcium and phosphate metabolism. Such conditions are generally characterized by the anomalous mobilization of calci~m and phosphate leading to general or specific bone loss, and the anomalous deposition of calcium phosphate salts in body tissues, i.e., pathological calcification. Such disease states include osteoporosis, osteitis deformans, various other conditions wlth a calcification component such as myositis ossificans progressiva, scleroderma, calcification in the hip from introduction of a prosthetic '~

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device, and recalcification of an area following surgical removal of existing calcification, as well as afflictions such as arthritis, neuritis, bursitis, tendonitis, and other inflammatory conditions which predispose the involved tissue to the deposition of calcium phosphates. Frank deposition of bone mineral at joints, along the skeleton, and in soft tissues, with attendant pain and loss of function, is characteristic of these disease states. Such afflictions are usually progressively debilitating.
The systemic administration of organophosphonate compounds of the type described hereinafter has been reported to be an effective treatment for disease states involving abnormal metabolism of bone mineral and patho-logical calcification. sy the present invention, it hasbeen discovered that the organophosphonates can be caused to penetrate through the s'~in and soft ~issues directly to the site of pathological calcification. This desir-able penetration effect is obtained by the use of organosulfoxide compounds of the type disclosed hereinafter.
~ccordingly, direet treatment of the afflieted situs, with attendant diminution of potential side-effects caused by systemie administration of the organophosphonate eompounds, is now possible`.

RELATED REFERENCES
The use of solvent concentrations of dimethyl sulfoxide (DMS0) to promote skin penetration of certain drugs is known in the scientific and non-technical literature.
U.S. Patent 3,527,864, MacMillan and Lyness, issued September 8, 1970, discloses the use of the organosulfoxides used in this invention to promote the penetration of certain drug agents through the skin.
U.S. Patent 3,896,238, D. E. Smith, issued July 22, 1975, discloses the use of organosulfoxides in combination with sugar esters to promote the penetration of certain drug agents through the skin.
The phosphonate compounds used in the practice of this invention are reported in the literature as being useful in the treatment of anomalous mobilization and deposition of calcium phosphate salts tbone mineral) in humans and other animals. See especially the U.S. Patents of M.D. Francis: 3,683,080, granted August 8, 1972;
3,678,164, granted July 18, 1972; 3,662,066, granted May 9, 1972; 3,553,314, granted January 5, 1971; 3,553,315, granted January 5, 1971; 3,584,124, granted June 8, 1971;
3,584,125, granted June 8, 1971; and 3,641,246, granted February 8, 1972.
The article by Francis, Flora and King, entitled "The Effects of Disodium Ethane-l-Hydroxy-l,l-Diphosphonate on Adjuvant Induced Arthritis in Rats", appearing in Calc. Tiss Res. 9, 109-121 (1972) mentions the use of phosphonates to inhibit inflammatory erosion of cartilage in rats.

11~0874 Detergent compositions comprising organophosphonate materials to sequester water hardness cations and organo-sulfo~ides as the detersive surfactant are disclosed in several United States Patents, including: 3,502,585, 0. T. Quimby, March 24, 1970; 3,526,592, Quimby, September 1, 1970; 3,351,558, R. E. Zimmerer, November 7, 1967, and references cited therein.
In spite of the substantial body of literature relating to the components of the present invention, 10 . medicinal compositions which comprise combinations of organophosphonates and organosulfoxides and their utility as topical treatments to alleviate or prevent pathological calcification do not appear to have been appreciated heretofore.

1~)0~74 S~l.~RY OF THE INVE~JTION
The present invention is directed to compositions and methods for treating anomalous mobilization and deposition of calcium phosphate salts (bone mineral) and attendant inflammation and pain in the tissues of humans and lower animals. Disease states such as Paget's - Disease tosteitis deformans), myositis ossificans progressiva, osteoporosis, arthritis, bursitis, and other maladies involving heterotopic calcification can be treated in the manner of this invention. In contrast with prior art treatments with organophosphonates which involve systemic administration of the drug, the present invention employs a penetrating carrier for the organo-phosphonate drug which allows direct, topical application to the afflicted situs.

The present invention encompasses liquid compositions for topical application to the epidermis at an afflicted situs for the treatment of anomalous mobilization and deposition of calcium phosphate salts in the tissues of humans and lower animals, comprising:
ti) from about 0.5% to about 20% of a pharmaceutically acceptable phosphonate compound; and (ii) a carrier which comprises from about 0.1% to about 15~ of the composition of an organosulfoxide compound wherein said organosulfoxide compound is a dialkylsulfoxide of the formula R'R"SO wherein group R' is a C6-C20 alkyl or substituted alkyl group and wherein group R" is a Cl-C3 alkyl or substituted alkyl group, the balance of said carrier comprising a pharmaceutically acceptable, compatible liquid, wherein the pH of aqueous solutions of the - composition is from about 3.5 to about 10.

, lV~74 The present invention also encompasses a method for treating or preventing the anomalous mobilization and deposition of calcium phosphate salts in the tissues of humans and lower animals in need of such treatment, comprising topically applying thereto, at the afflicted situs, a safe and effective amount of a composition of the foregoing type.

' -5a-` 110~)87~

DETAILED DESCRIPTION OF THE INVLNTION
The compositions herein comprise a safe and effective amount of an organophosphonate compound in combination with a carrier ~hich comprises a safe and effective amount of an orqanosulfoxide compound. The carrier and organophosphonate compound are selected from pharmaceutically-acceptable, compatible materials which, when combined, provide penetrating liquid compositions especially adapted for topical application to an afflicted situs.
By "safe and effective amount of organophosphonate compound" herein is meant a sufficient amount of the organophosphonate compound to alleviate pathological calcification at a reasonable benefit/risk ratio attendant with any medical treatment. Within the scope of sound medical judgment, the dosage of organophosphonate will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, and the specific organophosphonate employed.
By "carrier" herein is meant a liquid or fluid material comprising the organosulfoxide dissolved therein or therewith, which dissolves the organophosphonate compound and remains in the liquid or fluid state.
By "safe and effective amount of organosulfoxide compound" herein is meant sufficient organosulfoxide compound to provide penetration of the organophosphonate compound through the epidermal barrier to the afflicted situs without unacceptable side effects.

110~874 By "pharmaceutically-acceptable" herein is meant that the ingredients are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio.
By "compatible" herein is meant that the eomponents of the eompositions are capable of being eommingled without interacting in a manner w~lich would substantially deerease the effieacy of the total compositions under ordinary use situations.
By "topical application" herein is meant directly laying on or spreading on epidermal tissue (including outer skin and oral, gingival, nasal, ete. tissue).
By "afflieted situs" herein is meant the localized area of pathological calcification, and the immediate surrvunding dred.
All pereentages herein are by weight, unless otherwise specified.
The organophosphonate eompounds and organosulfoxide eompounds eritieal to the praetiee of this invention are diselosed more fully hereinafter. Optional ingredients whieh ean be ineluded in the eompositions to provide aesthetic and eosmetie benefits, but which are not eritieal to the praetiee of the invention, are also diselosed hereinafter.

liO~874 The organophosphonate compounds (or, more succinctly, "phosphonates") employed in the manner of this invention are of the type disclosed hereina~ter.
The phosphonate compounds which can be employed in the present invention are characterized by the phosphonate moiety (-P03M2, wherein M represents H or a pharmaceutically-acceptable cation or ester group). The phosphonates herein are organophosphonates, i.e., the phosphonate moiety is attached to a carbon atom by a carbon-phosphorus bond (C-P bond). The carbon atom, in turn, is bonded to other hydrocarbyl groups, e.g., alkyl phosphonates, or to hydrogen atoms, e.g., methane phosphonates, or to mixed hydrocarbyl groups, hydrogen atoms or other substituents, e.g., haloalkyl phosphonates. The hydrocarbyl groups can be substituted or non-substituted alkyl (inc]uding cycloalkyl), aryl (including heteroaryl) and the like.
Substituent groups on the alkyl or aryl hydrocarbyl moiety can be, for example, additional phosphonate moieties; halogens, especially chlorine; carboxyl;
esterified carboxyl; hydroxyl; amino; amido; and the like. Preferred ~or use herein are organophosphonates having more than one C-P03M2 group; diphosphonates, especially geminal diphosphonates characterized by the grouping ' - ' ~ ~' , 110~874 (M203P-- C P3M2 ) .

are most highly preferred.
Typical phosphonate compounds useful herein are of the formula S (I) Rl- (C)n- R2; and (II) R3 - (I)n R4 P3H2 ~ 3 2 . (vicinal) (geminal) wherein n is an integer from 1 to about 10 and the sub-stituent groups are H, alkyl, aryl, alkenyl, and the like.
Examples of type I phosphonates are those wherein R, R

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110(~1374 and R2 are each hydrogen, alkyl, -CH20H or are as noted for groups R3 and R4. Examples of type II phosphonates are those wherein R3 is hydrogen, alkyl containin~ from 1 to about 20 carbon atoms, alkenyl containing from 2 to about 20 carbon atoms, aryl (e.g., phenyl and naphthyl), phenylethenyl, benzyl, halogen (e.g., chlorine, bromine, and fluorine), amino, substituted amino (e.g., dimethyl-amino, diethylamino, N-hydroxy-N-ethylamino, acetylamino), -CH2COO~I, -CH2PO3H2~ -CH(PO3H2)(OH) or -C~I2CH(P03H2)2;
R4 is hydrogen, lower alkyl (e.g., methyl, ethyl, propyl, and butyl), amino, benzyl, halogen (e.g., chlorine, bromine and fluorine), hydroxyl, -CH2COOH, -CH2P03EI2, or -C112C~2P03I~2, or a pharmaceutically-acceptable salt thereof such as alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., calcium and magnesium), non-toxic heavy metal (e.g., stannous and indi~m), and ammQnium or low molecular weight substituted ammonium (e.g., mono-, di-, and tri-ethanolammonium) salts. It will be appreciated that groups R, Rl and R2 and groups R3 and R4 can be cyclo-alkyl, heterocyclic or can be joined in ring structures,said rings being carbocyclic or heterocyclic.
The above described organophosphonic acids and their pharmaceutically-acceptable salts and esters are commonly referred to collectively as "phosphonates", "diphosphonates"
or "polyphosphonat:es".
Operable phosphonates of the above formula (I) include propane-l, 2, 3-triphosphonic acid; butane-l, 2,3,4-tetraphosphonic acid; hexane-l, 2,3, 4,5,6-he~aphosphonic acid; hexane-l-hydroxy-2,3,4,5,6-pentaphosphonic acid;
hexane-1,6-dihydroxy-2,3,4,5-tetraphosphonic acid;
pentane-1,2,3,4,5-pentaphosphonie acid; heptane-1,2,3,4,5, 6,7-heptaphosphonic acid; octane-1,2,3,4,S,6,7,8-octa-phosphonic acid; nonane-].,2,3,4,5,6,7,8,9-nonaphosphonic acid; decane-L,2,3,4,5,6,7,8,9,10-decaphosphonic acid;
and the pharmaceutically acceptable salts of these acids, e.g., sodium, potassium, calcium, magnesium, ammonium, triethanolammonium, diethanolammonium, and monoethanol-1~ ammonium salts.
Among the operable phosphonates encompassed by the above formula (II) are ethane-l-hydroxy-l,l-diphosphonic acid; methanediphosphonic aci.d; methanehydroxydiphosphoni.c acid; ethane-1,1,2-tripllosphonic acid; propane-1,1,3,3-tetraphosphonic acid; ethane-2-phenyl-1,1-diphosphonie aeid; ethane-2-naphthyl-1,1-diphosphonic acid; methane-phenyldiphosphonie aeid; ethane-l-amino-l,l-diphosphonic acid; methanediehlorodiphosphonie aeid (diehloromethylene diphosphonic aeid); nonane-5,5-diphosphonie aeid; n-pentane-l,l-di.phosphonie aeid; methanedifluorodiphosphonie acid;
methanedibromodiphosphonie aeid; propane-2,2-diphosphonie aeid; ethane-2-earboxy-1,1-diphosphonie aeid; propane-l-hydroxy-1,1,3-triphosphonic acid; ethane-2-hydroxy-1,1,2-triphosphonic acid; ethane-l-hydroxy-1,1,2-triphosphonie acid; propane-1,3-diphenyl-2,2-diphosphonic aeid; nonane-l,l-diphosphonic aeid; hexadecane-l,l-diphosphonic acid;
pent-4-ene-1-hydroxy-1,1-diphosphonic acid; octadee-9-ene-l-hydroxy-l,l-diphosphonic acid; 3-phenyl-1,1-diphosphono-prop-2-ene; octane-l,l-diphosphonic acid; dodecane-l,l-110(~874 diphosphonic acid; phenylaminomethanediphosphonic acid;
maphthylaminomethanediphosphonic acid; N,N-dimethylamino-methanediphosphonic acid; N-(2-hydroxyethyl)-aminomethane-diphosphonic acid; N-acetylaminomethanediphosphonic acid;
aminomethanediphosphonic acid; and the pharmaceutically-acceptable salts of these acids, e.g., sodium, potassium, calcium, magnesium, stannous, indium, ammonium, triethanol-ammonium, diethanolammonium, and monoethanolammonium salts.
Mixtures of any of the foregoing phosphonic acids and/or salts can be used in the practice of this invention.
The geminal diphosphonates of formula (II) are most preferred for use herein.
Ethane-l-hydroxy-l,l-diphosphonic acid, an especially preferred geminal phosphonate, has the molecular formula CIl3C(OH)(P03H2)2 (according to nomenclature by radicals, the acid might also be named l-hydroxyethylidene diphosphonic acid). The most readily crystallizable salt - of this acid is obtained when two or three of the acid hydrogens are replaced by sodium. Preferred salts for the purpose of this invention are the trisodium hydrogen salt which has the structure:

l ~ .
CH3 - C - OH 3Na 11~0874 and the disodium dihydrogen salt.
The trisodium hydrogen salt normally crystallizes as the hexahydrate which loses some water during air-drying to yield a mixture of the hexa- and monohydrate averaging 3 to 4 molecules of water of hydration.
While any pharmaceutically-acceptable salt of ethane-l-hydroxy-l,l-diphosphonic acid can be used in the practice of this invention, the tetrasodium salt, the trisodium hydrogen salt, the disodium dihydrogen salt, the monosodium trihydrogen salt, and the mixtures thereof are preferred. The other sodium, potassium, ammonium, and mono-, di-, and tri-ethanolammonium salts and mixtures thereof are also suitable, provided caution is observed in regulating the total intake of cation species in the salt composition. These compounds can be prepared by - any suitable method; however, an especially preferred method is disclosed in U.S. Patent 3,400,149, granted September 3, 1968.
Methanehydroxydiphosphonic acid and related compounds operable herein can be prepared, for example, by the reaction of phosgene with an alkali metal dialkylphosphite. A complete description of these compounds and the method for preparing same is found in U.S. Patent 3,422,137 of O.T. Quimby.
Methanediphosphonic acid and related compounds useful herein are described in detail in U.S. Patent 3,213,030, granted October 19, 1965; a preferred method of preparing such compounds is disclosed in U.S. Patent 3,251,907, granted May 17, 1966.

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11~)()874 Ethane-1,1,2-triphosphonic acid and related compounds which can be used in this invention, as well as a method for their preparation, are fully described in U.S. Patent 3,551,339, of O.T. Quimby.
Propane-1,1,3,3-tetraphosphonic acid and related com-pounds useful herein, and a method for preparing same are fully disclosed in U.S. Patent 3,400,176, of O. T. Quimby.
Pentane-2,2-diphosphonic acid and related compounds can be prepared in accordance with the method described by G.M.
Kosolopoff in J. Amer. Chem. Soc. 75, 1500 (1953).
Propane-1,2,3-triphosphonic acid and salts thereof can be prepared by a process disclosed in U.S. Patent 3,743,668 of D. Allan Nicholson and Darrel Campbell, granted October 24, 1972.
Butane-1,2,3,4-tetraphosphonic acid and salts thereof can be prepared by a process disclosed in U.S. Patent 3,775,504 of D. Allan Nicholson and Darrel Campbell, granted August 25, 1973.
The higher aliphatic vicinal polyphosphonates and salts thereof can be prepared by the process disclosed in U.S. Patent 3,584,035, of Nicholson and Campbell.
Substituted ethane diphosphonic acids and salts and esters thereof are disclosed in U.S. Patent 3,940,436, issued February 24, 1976, to A.F. Kerst.

llOU874 U.S. Patent 3,944,599, to the same inventor, discloses geminal diphosphonate compounds having halogen and hydroxyl substituent groups, and the means for preparing same.
Phosphonobutane tri- and tetra-oarboxylic acid compounds and their preparation are disclosed in U.S. Patents 3,886,204 and 3,886,205, both issued May 27, 1975, to Geffers, et al.
German Specificaion 2360798, June 26, 1975, to Henkel &
Cie CmbH discloses pharmaceutical and cosmetic preparations for influencing the deposition of poorly soluble calcium salts, said preparations comprising polymethylene phosphonic acid compounds.
This publication, described the preparation of the phosphonate materials in detail.
The preparation and pharmacological properties of various amino phosphonate compounds are described in German Specifica-tion 2343 146 (March 6, 1975); Belgian Patent 822,930 (June 4, 1975); Belgian Patent 822,929 (December 6, 1973); German Spec-ification (2360 711 (June 12, 1975); German Specification 2360 719 (June 6, 1975); Belgian Patent 819,187 (February 26, 1975);
Belgian Patent 819,188 (February 26, 1975); and Belgian Patent 819,189 (February 26, 1975).

l~L0~874 ' As can be seen from the foregoing, the preparation of the phosphonates used in the practice of this invention can be accomplished using well-known methods, or by simple modifications of various art-disclosed procedures. Only those organophosphonates which are pharmaceutically-~ acceptable (i.e., provide a satisfactory benefit/ris~
! ratio) are contemplated for use herein. The well-known toxicity of some type (I) monophosphonates (n=l) disclosed I in the structural formulas above precludes their use ¦ 10 herein. However, such materials are known in the art ~¦ and are easily avoided in the practice of this invention.
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110~874 The organosulfoxide compounds of the type used herein can be represented by the formula R'R"SO

wherein R' and R" can be: alkyl; substituted alkyl;
hydrocarbyl aryl; substituted hydrocarbyl aryl; heteroaryl;
substituted heteroaryl; alkenyl; substituted alkenyl;
alkynyl; substituted alkynyl; cyclo-alkyl, alkenyl or alkyoyl; substituted cyclo-alkyl, alkenyl or alkyoyl;
hetero-alkyl, alkenyl or alkynyl; or substituted hetero-alkyl, alkenyl or alkynyl groups. The substituent groupscan be, -for example, hydroxyl, alkoxyl, halogen, and the like.
Selection of specific organosulfoxides for use with specific organophosphonates can be made using the Skin Penetration Test described more fully hereinafter.
This test measures the enhanced penetration of the organo-phosphonates through the epidermal barrier caused by the organosulfoxides.
Preferred compositions herein are those wherein water comprises a major portion of the penetrating carrier.
Accordingly, in sùch preferred compositions the organo-sulfoxide must be selected from those which are water-soluble at the intended use concentrations. In general, organosulfoxides wherein R' and R" are each Cl-C20 alkyl or substituted alkyl groups (i.e., "dialkyl sulfoxides") exhibit substantial solubility in water and are especially preferred in such water-based carriers.

110~874 Lower dialkyl organosulfoxides (i.e., R' and R"
each about Cl-C6 hydrocarbyl or substituted hydrocarbyl) are known to promote skin penetration when used at solvent concentrations (50%, or more). Such high con-centrations can cause undesirable systemic effects.
Accordingly, while useful penetrants, the lower dialkyl sulfoxides are not preferred for use herein.
The dialkyl organosulfoxides wherein group R' is a ca. C6, or higher, alkyl or substituted alkyl group and wherein group R" is a Cl-C3 alkyl (especially methyl) or substituted alkyl group are preferred herein, since they can be used in less than solvent concentrations.
More preferred are dialkyl organosulfoxides wherein group R' is a C8, or higher, alkyl or substituted alkyl group and group R" is Cl-C3 alkyl (especially methyl) or substituted alkyl, since these can be used at 10,', or less, to provide excellent penetration and are water-soluble at typical use concentrations.
Most preferred herein are the organosulfoxides wherein R' is a C8-C12 alkyl or substituted alkyl group and wherein R" is methyl. Such materials are highly water-solub]e and can be used at concentrations in the range of about 0.1% to about 10% in the compositions herein to provide excellent penetration of the organophosphonate to the site o~ pathological calcification.
The sulfoxide compounds disclosed herein can be used singly or in combination for the purpose o~ this invention. ~lese compounds are readily obtainable by well known methods. For example, most can be prepared by the conventional method of first preparing the corresponding thioether and then oxidizing to the sulfoxide. The methods of carrying out these steps have recently been reviewed by A. Schc;berl and A. Wasner [Methoden Orsanischen Che~ie (Houben-Weyl), 4th ed., Georg Thieme Verlag, Stuttgart, Vol. IX, pp. 97-143, 211-218 (1955)~. Further methods for preparing sulfoxide compounds are disclosed in U.S. Patents 3,288,858;
3,288,859; and 3,288,860, granted November 29, 1966 .

Non-limiting exampl~s of preferred sulfoxides for use herein include: decyl methyl sulfoxide; octyl hydroxyisopropyl sulfoxide; nonyl ethyl sulfoxide; nonyl methyl sulfoxide; ~-hydroxyundecyl methyl sulfoxide; and dodecyl methyl sulfoxide. Decyl methyl sulfoxide is most preferred.
Compositions in accordance with this invention can be formulated with a wide variety of optional dermatologically acceptable ingredien~s and in a n~mber of liquid or fluid forms. For example, such compositions can be in low viscosity liquid or higher viscosity cream form and can be either solutions, emulsions, or dispersicns.
The organophosphonate and organosulfoxide ingredients are dissol~red in a water-dispersible, dermatologically acceptable vehicle. Such vehicles are well known in the pharmaceutical and cosmetic arts and their choice is not critical to the efficacy of the pharmacolosically active substance and the organosulroxide penetration enhancing agent as long as they are water-miscible.

-..

8'~4 E~.amples o. ~ .er-dispersible derm2tologically acceptable vehicles are ~"ater (highly ?referred); water-soluDle alcohols (monohvdric and polyhydrlc alcohols, particularlv lower Cl-C8 alcohols, e.g., ethanol, propanol, glycerol, sorbitol, 2-methoxyethar.ol, diethylene-glycol, monomethyl or diethyl ether of ethylene glycol, hexylene glycol, mannitol, propylene glycol); polyethylene glycols ar.d methoxypolyoxyethvlenes (macrogols having molecul2r weight ranging from 200 to 20,000); glyceryl monolaurate, monopalmit2te or monostearate; polyo~y-ethylene glycerols; olyo~yethylene sorbitols; and glucose. When alcohols or their derivatives a~e used, some water is preferably included since such materials are usually hygroscopic.
Although the vehicle is preferably water-~iscible as stated a~ove, petrole~ based oint..ents and the like can also be used. Por example, such substances as mineral oil, petroleum jelly, stearoyl diacetin, lanolin, pararfin and beeswax. ~lthough thev ma~ tend to slow absorption, they can be used, especially if there is sufficie~t water-dispersible vehicle present to provide a medi~m for absorption by animal tissue. Emulsific2tion of such substances also ~rovides a means for their use. Oil-in-water emulsions such as cold crezm bases can also be used.
Since the co.~positions of this lnver.tion 2re to be toplcall~ ap~liad .o animal tissue, the-~ should be formu-lated so that thev have a pH in 2~ueous solu'ion or not less than about 3.5 nor more th2n 2bout 10Ø Irritation can be encountered at pH's lower than about 3.5 and the stabi]lty of various ingredients can be adversely affected at pH's higher than about 10Ø
The usual buffering materials can be used to adjust the pH to the desired range. Examples of such buffers are: glycine, citric acid, disodium hydrogen phosphate, potassium hydrogen tartrate, potassium hydrogen tartrate, potassium hydrogen phthalate, and sodium hydrogen succinate. When the salt forms of the organophosphonates are used, buffers generally need not be employed.
The following constitutes a description of the preferred embodiments herein, but various changes and modifications can be made without departing from the spirit and scope of the invention.
Preferred compositions herein comprise from about 0.5% to about 20%, more preferably from about 3% to about 12%, of the organophosphonate compound dissolved in the carrier.
Preferred compositions herein are those wherein the carrier comprises from about 0.1% to about 15%, more preferably 0.2% to about 10%, of the organosulfoxide com-pound, the balance of said carrier comprising a pharmaceutically-accèptable, compatible liquid.
Water is the preferred liquid for dissolving the organosulfoxide to provide the carrier which, in turn, dissolves the organophosphonate compound.
Compositions wherein the organophosphonate compound is a member selected from the group consisting of:

llOIU874 ethane-l-hydroxy~ diphosphonic acid, and the pharma-ceutically-acceptable salts and esters thereof;
methanediphosphonic acid, and the pharmaceutically-acceptable salts and esters thereof; and methanedichloro-S diphosphonic acid, and the pharmaceutically-acceptable salts and esters thereof, and wherein the organosulfoxide compound is a member selected from the group consisting of: decyl methyl sulfoxide; octyl hydroxyisopropyl sulfoxide; nonyl ethyl sulfoxide; nonyl methyl sulfoxide;
~-hydroxyundecyl methyl sulfoxide; and dodecyl methyl sulfoxide, and formulated in the compositional ranges disclosed above are generally preferred for topical application to skin.
Highly preferred compositions herein are homo-geneo~us solutions which consist essentially of fromabout 0.1% to about 10% decyl methyl sulfoxide, from about 5% to about 15% by weight of ethane-l-hydroxy-l,l-diphosphonate, sodium salt form, or methanedichlorophos-phonate, sodium salt form, the balance comprising water or water and a water-miscible cosmetic vehicle.
Treatment regimens according to the practice of this invention comprise applying the compositions herein directly to the skin at the situs of pathological calcifica-tion. The rate of application and duration of treatment will, of course, depend on the severity of the condition, the response of the particular patient, and such factors as require the sound medical judgment of the attending physician. In general, using the compositions within the compositional ranges noted above, application rates of )874 : i ' from about 0.0005 g/cm2 to about O.lO,gm/cm2 of afflicted , ,situs per day are used. Application can be done once, or preferably several times daily for periods of a week, or more, to relieve or prevent pathological calcification.
The following Skin Penetration Test demonstrates ~, the penetration of the epidermal barrier by the organo-~- I sulfoxide/organophosphonate compositions herein. The organosulfoxide used is the highly preferred n-decyl - , methyl sulfoxide.
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Skin Penetration Test The ability of organophosphonates to diffuse through the epidermal barrier when applied thereto in compositions falling within the scope of this invention can be measured in vitro by various means. A complete description and diagram of suitable apparatus for carrying out such Skin Penetration Tests are fully disclosed in U.S. Patent 3,527,864, MacMillan and Lyness, entitled COMPOSITIO~S FOR TOPICAL APPLICATION TO A~ L

TISS~ AND MæT~OD OF E~ 7CI~G P~TRATION THEREOF, issued~September 8, 1970, In general terms, a section of skin is placed in a continuous flow apparatus comprising an inner cylindrical chamber mounted wi~hin a larser outer cylindrical chamber and sealed thereon with set screws such that water of constant temperature can be introduced into the space between said inner and outer cylindrical chambers and flow around the inner cylindrical chamber and out the constant temperature water outlet. The composition to be tested is placed in the inner chamber in contact with the freshly sectioned piece of skin affixed to the bottom of said inner chamber and resting upon a stainless steel screen support and sealed to a base chamber with a neoprene ring.

Ringer's Solution is introduced into the base chamber and is agitated with a magnetic stirring bar which is in contact with the sXin. The effluent Ringer's Solution is collected at intervals and measured for penet-2nts which have diffused through the skin from the test solution.

.

Permeability constants between test (added organosulfoxide penetrant) and control (no organosulfoxide penetrant) can be calculated by methods similar to those employed by Treherne, J. Invest. Derm., 45:249, 1965, and compared to determine the effect of the organosulfoxide on the penetration of the epidermal barrier by the organophos-phonate.
In in v tro skin penetration tests, a typical organosulfoxide, decyl methyl sulfoxide, was found to enhance the penetration of a typical organophosphonate, ethane-l-hydroxy-l,l-diphosphonate, some 6-fold over a control.
It will be appreciated from the foregoing that the improved delivery of the organophosphonates through skin prouides a novel means for directly treating . ~, . .
~ i - localized areas of pathological calcification in humans .: . .
and lower animals 1n need of such treatment. The follow-- ing in vivo Animal Study supports the effectiveness of this mode of treatment.
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lliOV874 Animal Study The followiny experiment was carried out to measure the effectiveness of a typical organophosphonate compound, disodium ethane-l-hydroxy-l,l-diphosphonate (EHDP) used in combination with a penetrating carrier comprising a typical organosulfoxide compound, decyl methyl sulfoxide, on dihydrotachysterol (DHT) induced calcification when applied topically.
In general terms, the experiment comprised inducing calciphylaxis in rats by an oral gavage of DHT (10 mg/kg) in a corn oil vehicle (2 mg DHT/ml). ~fter induction of calciphylaxis, subcutaneous administration of ferrous gluconate was used to induce skin calcification. The EHDP composition (10% EHDP, 0.25% decyl methyl sulfoxide, balance water) was topically applied twice daily to the ferrous gluconate injected area at a volume of 0.2 ml/appli-cation. Topical application of the EHDP solution was continued on a daily basis for seven days. The animals were then sacrificed and skin samples were submitted for calcium and phosphorus analysis. The percent skin calcium was taken as a measure of the effectiveness of the topical EHDP treatment.
In an animal test of the foregoing type, the base-line control animals without induced calciphylaxis had a percentage skin calcium level of 0.035. In the same test, animals~with induced calciphylaxis and saline treatment exhibited a percentage skin calcium of 2.026.
In the same test, animals treated with EHDP dissolved in the penetrating carrier vehicle described above had a percentage skin calcium of 0.067.

r ll~Q874 On the basis of the foregoing, it must be concluded that the topical application of E~P in the penetrating organosulfoxide carrier to the.afflicted situs of the animals substantially reduced the patho-~ 5 logical calcification, as compared with control animals..1 The following examples further illustrate the practice of this inventlon, but are not intended to be . limiting thereof.
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110~J874 EXAMPLE I

Inqredient % by wt.
Decyl methyl sulfoxide 0.25 EHDP 10.0 Water Balance J

When topically applied to the joints of horses three times daily, the composition of Example I sub-stantially reduces pathological calcification associated with arthritis-like conditions associated with stress !

at the joints.
In the composition of Example I, the EHDP is replaced by an equivalent amount of the trisodium salt o~ ethane-l-hydroxy-l,l-diphosphonic acid and equivalent results are secured.

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XAMPLE II

Inqredient % by wt.

Methanedichlorodiphosphonic 12 acid, dis~dium salt Decyl methyl sulfoxide Water Balance The composition of Example II is topically applied to a situs of pathological calcification in a patient suffering from osteitis deformans. Two mls. of the composition are applied three times daily fox a period of one month to alleviate the pathological calcification.
In the composition of Example II, the methane-dichlorodiphosphonic acid, disodium sa]t, is replaced by an equivalent amount of EHDP; methanediphosphonic acid, disodium salt; and methanedichlorophosphonic acid, dimethyl ester; respectively, and equivalent results are secured.
In the composition of Example II the decyl methyl sulfoxide is replaced by an equivalent amount of octyl hydroxyisopropyl sulfoxide, nonyl ethyl sulfoxide, nonyl methyl sulfoxide, ~-hydroxyundecyl methyl sulfoxide and dodecyl methyl sulfoxide, respectively, and excellent penetration of the organophosphonate active ingredient - through the skin and to the calcified site is secured.

The compositions of Example II are typically applied at the rate of ca. 0.002 g on a circular area havin~ a 2 cm. diameter.

_ ~9 _ ( )0874 EXAMPLE III

Inqredient % bY wt.
Dodecyl methyl sulfoxide 10.0 EHDP 10.0 Ethyl alcohol 10.0 Stearyl alcohol 3.0 Lanolin 6.0 Water ~ Balance '. . . .
, The composition of Example III provides a cream base penetrating carrier having dissolved therein the organosulfoxide and organophosphonate compounds. The - enhanced penetration of the phosphonate compound through the epidermal bàrrier by virtue of the presence of the ? oxganosulfoxide is seen when the penetration of a similarly formulated product without organosulfoxide is compared therewith.
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Claims (13)

The embodiments of the invention in which an ex-clusive property or privilege is claimed are defined as follows:

1. A liquid composition for topical application to the epidermis at an afflicted situs for the treatment of anomalous mobilization and deposition of calcium phosphate salts in the tissues of humans and lower animals, comprising:

(i) from about 0.5% to about 20% of a pharmaceutically acceptable phosphonate compound; and (ii) a carrier which comprises from about 0.1% to about 15% of the composition of an organosulfoxide compound wherein said organosulfoxide compound is a dialkylsulfoxide of the formula R'R"SO wherein group R' is a C6-C20 alkyl or substituted alkyl group and wherein group R" is a Cl-C3 alkyl or substituted alkyl group, the balance of said carrier comprising a pharmaceutically acceptable, compatible liquid, wherein the pH of aqueous solutions of the composition is from about 3.5 to about 10.

2. A composition according to Claim 1 wherein the organophosphonate compound is characterized by more than one phosphonate moiety.

3. A composition according to Claim 2 wherein the organophosphonate compound is a diphosphonate.

4. A composition according to Claim 3 wherein the organophosphonate compound is a geminal diphosphonate.

5. A composition according to Claim 1 wherein the organosulfoxide compound is a dialkyl sulfoxide wherein group R" is methyl.

6. A composition according to Claim 5 wherein R' is a C8, -C20 alkyl or substituted alkyl group.

7. A composition according to Claim 6 wherein R' is a C8-C12 alkyl or substituted alkyl group.

8. A composition according to Claim 1 wherein the organophosphonate compound is a member selected from the group consisting of:
i) ethane-1-hydroxy-1,1-diphosphonic acid, and the pharmaceutically-acceptable salts and esters thereof;

ii) methanediphosphonic acid, and the pharma-ceutically-acceptable salts and esters thereof; and iii) methanedichlorodiphosphonic acid, and the pharmaceutically-acceptable salts and esters thereof.

9. A composition according to Claim 8 wherein the organosulfoxide compound is a member selected from the group consisting of: decyl methyl sulfoxide; octyl hydroxyisopropyl sulfoxide; nonyl ethyl sulfoxide; nonyl methyl sulfoxide; .beta.-hydroxyundecyl methyl sulfoxide; and dodecyl methyl sulfoxide.

10. A composition according to Claim 9 wherein the organosulfoxide compound is decyl methyl sulfoxide.

11. A composition according to Claim 1, 8 or 9 wherein the pharmaceutically acceptable, compatible liquid is water.

12. A composition according to Claim 1, 8 or 9 wherein the pharmaceutically acceptable, compatible liquid comprises a water-soluble alcohol.

13. A composition according to Claim 1, which consists essentially of from about 0.1% to about 10% by weight of decyl methyl sulfoxide, from about 5% to about 15% by weight of ethane-l-hydroxy-l,l-diphosphonate, sodium salt form, or methanedichloro phosphonate, sodium salt form, the balance comprising water or water and a water-miscible cosmetic vehicle.