Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
1100874
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
'~
--1--
...., ;,
-
110~87~
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`.
1100874
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
P3H2
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
, ~ ~
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
-- 10 --
74
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:
- P03 - -3
l ~ .
CH3 - C - OH 3Na
03H
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.
- 13 -
~D :
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.
- 14 -
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).
- 15 -
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.
, . . .
_l .. _. _ _ ._ . _. . .. ._ _ . . . . . .. _.. .. .... _.. . ... . ._ __ . . . .. ....
ib
.
.
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
- 18 -
74
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.
-- 19 --
-..
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
- 20 -
1100874
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
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)874
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' 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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874
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.
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1100874
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
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~ i - localized areas of pathological calcification in humans
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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.
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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
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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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U874
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.
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)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
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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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