CA1164345A - Anti-arthritic compositions containing gold salts and organophosphonates - Google Patents
Anti-arthritic compositions containing gold salts and organophosphonatesInfo
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- CA1164345A CA1164345A CA000392804A CA392804A CA1164345A CA 1164345 A CA1164345 A CA 1164345A CA 000392804 A CA000392804 A CA 000392804A CA 392804 A CA392804 A CA 392804A CA 1164345 A CA1164345 A CA 1164345A
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- acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/242—Gold; Compounds thereof
Abstract
ANTI-ARTHRITIC COMPOSITIONS CONTAINING
GOLD SALTS AND ORGANOPHOSPHONATES
Bennie L. Baker ABSTRACT OF THE DISCLOSURE
Compositions comprising pharmaceutically-acceptable gold salts and organophosphonates, especially the geminal diphosphonates, useful in the treatment of arthritic conditions, are disclosed. The method of treating arth-ritic conditions using these compositions is also dis-closed.
GOLD SALTS AND ORGANOPHOSPHONATES
Bennie L. Baker ABSTRACT OF THE DISCLOSURE
Compositions comprising pharmaceutically-acceptable gold salts and organophosphonates, especially the geminal diphosphonates, useful in the treatment of arthritic conditions, are disclosed. The method of treating arth-ritic conditions using these compositions is also dis-closed.
Description
4 3 '~ 5 ....
ANTX-ARTHRITIC COMPOSITIONS CONTAINING
GOLD SALTS A~D ORG.~NOPHOSPHONATES
Bennie L. Baker , .
. .
The present invention relates to pharmaceutical compositions used in the treatment of arthritic conditions, especially rheumatoid arthritis.
Rheumatic diseases are conditions in which pain and stiffness are prominent in portions of the musculo-skeletal system, including the connective tissuer Arthritis is the general name used for such conditions when the joints, themselves, are the major seat of the rheumatic 10 disease. Arthritis is one of the oldest known diseases.
Chronic arthritis of the spine is known to have been present in the ape man of 2 million years ago, as well as in the Java and Lansing Men of 500 thousand years ago, and Egypian mummies dating to 8,000 B.C. See Osgood, R. B., 15 Amer. _. Med. Sci., 200: 429~1940). The Romans buil~
extensive baths throughout their empire to aid in the treatment of arthritic diseases. Yetj in spite of this long history, the ~earch for a safe and effective therapy for arthritic conditions continues. The importance of such work is underscored by the fact that there are over 20 million persons in the United States, today, suffering fron some form of arthritis or related disease. Further, ~-arthritis and rheumatism result in 27 million lost work days yearly, second only to heart disease as a cause of chronic limitation of a~ilit~ to work.
Various gold salts have been recognized as an effective therapy for the treatment o~ rheumatoid arthritis.
See ~cCarty, D. J., Arthritis and ~llied Conditions, Lea & Febiger, 1979, pages 355-364. Gold was originally used to treat rheumatoid arthritis in the 192~'s; this use was based on the empirical belie that since gold was of ~ d~ . `
~ 3 ~3ll~
value in the treatment of tuberculosis, a chronic form of infectious disease, it might be ef~icacious in yet another chronic disorder suspected~ at the time, of having an ;`
infectious etiology. Early work in the treatment of 5 arthritic conditions using gold (Chrysotherapy) is sum-~arized in ~orestier, J., J. Lab. Clin. Med., 20: 827(1935).
. _ A major deterrent to the use of gold therapy is the frequent occurrence of side effects associated with such treatment; ~ome tests indicate that 25 t~ 40 ~ut of every 10 100 patients treated with gold salts will develop some degree of toxic reaction. One such side effect is renal toxicity, such as nephrosis. If renal toxicity side effects become apparent, it is necessary to discontinue the gold therapy and treat the side effect with corti-15 costeroids. Thus, the occurrence of such side effectsclearly curtails the usefulness of gold salt therapy in the treatment of arthritic conditions. Similar renal toxicity pro~lems can occur w~ere other metals are used to treat medical condltions, such as in the treatment of 20 depression using lithiu~ salts. ~rom the foregoing, it is clear that it would be desirable to be able to formulate an effective treatment regimen for arthritic conditions, incorporating the use o~ gold salts, while ~inimizin~ the potential renal toxicity side effects of suc~ treatment.
25 Gold salt therapy also tends to ~n~ one minerali-zation; a treatment regimen ~ic~ m~n~m~zes this effect would also ~e'highly desirable. See 3essop, Gold In the Treatment of Rheumatoid' Art ritis - ~hy, When and How?, J. Rhuematol. ~Su~p'l. 5~, 6: 12~17 ~197~I; Davis, ..... _ ....... _ . _ . . .......... .. . .
30 Undesira~le Effe_ts of Gold Salts, ~. Rheumatol.
~Sup ~ 5~, 6: 18-24 C19791; and ~artindale,''The Extra Pharmacopoeia, 26th Edition~ T~e P~armaceut~cal Press, London, 1975, pages 477~47~, ' Organophosp~on~te compounds are reported in t~e 35 literature as ~eing use~ul in t~e treatment o~ anomalous mobilization and deposition of calcium phosp~ate salts (bone mineral~ in humans and other animals; use o~ these 1 3 ~ ~
compounds in the treatment of arthritis is specifically disclosed. See especially, U~S. 3,683,080, Francis, granted August 8, 1972 U.S. Patent 4,234,645, Gunther and Fleisch, issued No~ember 18, 1980; and U.S. Patent 4,216,212, Flora and Francis, issue~ August 5, 1980.
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. ~es., 3: 109-121 (1972) discluses the use of a diphosphonate material in the treatment of arthritis in rats and mentions the use of phosphonates to inhibit inflammatory erosion in rat cartilage.
It is an object of the present invention to provide pharmaceutical composi~ions, comprising organophosphonates lS and gold salts, which are effective in the treatment of arthritic conditions while minimizing the renal toxicity and inhibition of bone mineralization which can accompany treatment with gold salts.
SUMMARY OF THE INVENTION
The present invention encompasses compositions and methods for treating arthritic conditions in animal tissue, especially in humans. The invention provides effective drvg combination compositions and therapy, and is based on the use of pharmacologically-active phosphon-ate compounds together with pharmaceutically-acceptable gold salts useful in the treatment of arthritic conditions.
In particular, the present invention relates to a pharmaceutical composition in unit dosage form comprising from about 50 mg. to about 500 mg. of an organophosphonate compound selected from the group consisting of R3 - C -R~
wherein R3 is hydrogen, alkyl containing from 1 to about 20 carbon atoms, alkenyl containing from 2 to about 20 carbon atoms, aryl, phenylethenyl, benzyl, halogen, amino, ., ~
'1 3 ~ 5 -- 4 ~
substituted amino, -CI-I2COOH, -CH~PO3H2, -C~I(PO3H2) (OH), or -CH2CH(PO3H2)2; R4 is hydrogen, lower alkyl amino, benzyl, halogen~ hydroxyl, -CH2COOH, -CH2PO3H2, or -CH2C~2PO3E~2, and the pharmaceutically-acceptable salts tllereof, and from about 1 mg. to about 200 mg. of a gold salt selected from the group consisting o gold sodium thiomalate, gold sodium thiosulfate, triethylphosphine goldr gold sodium thioglucose, and mixtures thereof~
The compounds act in concert to provide ef~ective treatment of the arthritic condition while minimizing or eliminating side effects, such as renal toxicity and the inhibition of bone mineralization, which frequently accompany therapy with gold salts.
DETAILED DESCRIPTION OF THE INVENTION
The compositions and treatment regimens of this inven-tion employ~ a safe and effective amount of a pharma ceutically-acceptable gold salt useful in the treatment of arthritic conditions; and (2) a safe and effective amount of a pharmaceutically-acceptable organophosphonate compound.
By "safe and effective amount of gold salt", as used herein, is meant sufficient gold salt compound to treat an arthritic condition, such as rheumatoid arthritis, at a reasonable benefit/risk ratio attendant with any medical treatment, when used in the manner of this invention.
Within the scope of sound medical judgment, the dosage of gold salt will vary with the particular condition being treated, the severity of the condition, the duration of the treatmentr the physical and medical characteristics of the patient, and the specific gold salt and phosphonate compounds employed.
By "safe and effective amount of phosphonate compound", as used herein, is meant a sufficient amount of the phos-phonate compound to effectively treat the bone erosion which accompanies arthritic conditions and, in addition, to minimize gold-induced renal abnormalities and ~`
~3~ 345 inhibition of bone mineralization, at a reasona~le benefit/
risk ratio attendant with any medical trea~nent. ~1ithin the scope of sound medical judgment, the dosage of phos-phonate will vary ~ith the particular condition being 5 treated, the severity of the condition, the duration of the -treatment, the physical and medical characteristics of the patient, and the specific phosphonates and gold salts employed.
By "pharmaceut7cally-acceptable", as used herein, is meant that the arug compounds and other ingredients used in the present compositions and methods of treabme~t are suitable for use in contact with the tissues of humans and lower animals without undue toxicityl irritation, allergic response, and the like, commensurate with a xeasonable benefit/risk ratio.
The term "administration" of the compounds and compositions herein includes systemic dosage, as by in-jection (especially parenterally), intravenous infusion, suppositories and oral administration thereof, as well as topical application of the compounds and compositions to the afflicted situs.
By the term "comprising", as used herein, is meant that various other, compatible drugs and medicaments, as well as inert ingredients, can be conjointly employed in the compositions and processes of this invention, as long as the critical phosphonate compounds and gold salts are used in the manner disclosed.
By "compatible" herein is meant that the components of the compositions are capa~le o ~eing comingled without 3~ interacting in a manner which would substantially decrease the efficacy of the total compositions under ordinary use situations.
~ ;~ 6~3~ 5 By "carrier", as used herein, is meant a liquid, fluid or solid material which can optionally be used to provide finished compositions for systemic or topical administra-tion.
All percentages herein are by weight, unless otherwise specified.
Any pharmaceutically-acceptable gold salt, useful in the treatment of arthritic conditions, may be used in the present invention. A number of such gold compounds have been synthesized and are effective in the trea~ment o~
arthritic conditions; these include, but are not limited to, gold sodium thiomalate, gold sodium thiosulfate, triethylphosphine gold (e.g., Auranofi ~, which is especially adapted for oral administration, commercially available from Smith, Kline and French), gold sodium thioglucose, and mixtures of these components. The gold salts most commonly used in the United States for the treatment of arthritic conditions include gold sodium thiomalate, available commercially as Myochrysine~ from Merck Sharpe and Dohme as an aqueous solution of 50% gold for intramuscular injection, and Aurothioglucose~ (gold sodium thioglucose), commercially available as Solgana ~
from Schering as a wa~er-soluble 50~ gold preparation for intramuscular use prepared as a suspension in oil. Gold sodium thiomalate is especially preferred for use in the present invention.
Gold salts are generally administered to arthritic patients on a dosing schedule which retains the therapeutic benefits of the gold salts while minimizing the severity of potential toxic reactions. In such a dosing regimen, the initial dose is 10 milligrams of gold per week (e.g., by intramuscular injection), raised step wise over the next 2 to 3 weeks to 25 milligrams and then 50 milligrams. These small initial doses are used to identify patients who might be susceptible to gold toxicity. If there are no side eEfects, 50 milligram dosages are given weekly for the next 20 weeks. Treatment with the gold salts is generally continued for a prolonged period to prevent relapses. In the usual maintenance program, gold is given as 50 milli-gram injections at increasingly greater intexvals, initially every 2 weeks for 4 to 8 injections, then every 3 weeks for 4 to 6 injections, and monthly thereafter for 5 an indefinite period. If there is a return of symptoms, then weekly injectiolls of 50 milligrams are reinstitutedO
The applicability of this dosing program to particular cases depends upon numercus factors, including the medical and physical condition of the patient, the severity of the 10 illness, and the phosphonate materials being administered;
in general, the dosages can range ~rom 5 milligrams to 200 milligrams of gold salt per week, although the pre~erred dosages tend to ~e bet~een about 10 milligrams and 75 milligrams of gold salt per week. The compositions of the 15 present invention may contain from a~out 1 milligram to about 200 milligra~s, prefera~ly from about 2 to about 75 milligrams, of gold salt, depending upon the frequency with which the compositions are to be taken and how they are to be administered Ce.g~, orally, or by intramuscular 20 injection~.
The oxganophosphonate compounds Cor more succinctly, "phosphonates"l emplo~ed in the pxesent invention are characterîzed by the phosphonate moiety C-PO3M2, wherein M
represents X or a pharmaceutically-accepta~le cation or 25 ester group). The pho~phonates herein are organophos-phbnates, i.e., the phosphs'nate moiety is attached to a carbon atom ~y a cax~on-phospboxus ~ond tC-~ ~ondl. T~e carbon atom, in turn, can be konded to other hydrocarbyl groups, e.g, alkyl pho~phonates, or to ~drogen' atom5, 30 e.g., ~ethane phosphonates, ~a'logen atoms, e.g~, dichloro-methane diphosphonates, ox ta mixed h~drocar~yl gxoups, hydrogen atoms or oth~r $u~stituents, e.g., ~aloal~yl phosphonates. T~e h~dxocax~ xoups can ~e substituted or unsubstituted alkyl Cincluding c~cloalkyl~, aryl Cincluding 35 heteroaryl) and the'like~ Substitutent ~roups on the alkyl or aryl hydrocarbyl moiety can fie, ~or ~xa~ple, additional phosphonate moieties; halogensr especially chlorine;
3 ~ ~
carboxyl; esterified carboxyl; hydroxyl; amino; amido; and the like. Preferred for use herein are organophosphonates having more than one C~PO3M2 group; diphosphonates, especially geminal diphosphonates characterized by the group I
(M203P - C P03M2 ~
are most highly preferred.
In particular~ the phosphonate compounds useful herein are selected from those having the formula ,O3H2 3 C - R4 (geminal) ~03H2 wherein n is an integer ~rom l to about lO and the sub-stituent groups are H, alkyl, aryl, alkenyl, and the like.
Examples of Type (I) phosphonates are those wherein R, Rl and R2 are each hydrogen, alkyl, -CH2OH, or as noted ~or groups R3 and R4. Examples of Type (II) phosphonates are those wherein R3 is hydrogen, alkyl containing from l to about 20 carbon atoms, alkenyl containing from 2 to about 20 carbon atoms, aryl (e.g., phenyl or naphthyl), phenylethenyl, benzyl, halogen (e~g., chlorine, bromine, or fluorine), amino, substituted amino (e.2~22., dimethylamino, diethylamino, N-hydroxy-N-ethylaminor or acetylamino), ~ 2 J 1~3~5 -CH2COOH, -CH2P03H2, -CH(P03H2) (OH), or -CH2CH
(PO3H2)2; R~ is hydroyen, lower alkyl (e.g., methyl, ethyl, propyl, or butyl), amino, benzyl, halogen, (e.g., chlorine, bromine, or fluorine), hydroxyl, -CH2COOH, -CH2PO3H2, or -CH2CH2PO3H~, or a pharmaceutically-acceptable salt thereof, such as alkali metal (eOg., sodiuln or potassium)~
alkaline earth metal (e~g., calcium or magnesium), non-toxic heavy metal ~e.g., stannous or indium), and ammonium or low molecular weight, substituted ammonium (e.g. mono-, di-, or tri-ethanolammonium) salts. It will also be appreciated that groups R, Rl and R2 and groups R3 and R4 can be cycloalkyl, heterocyclic or can be joined in ring structures, said rings being carbocyclic or heterocyclic.
Among the operable phosphonates encompassed by the above formula are ethane-l-hydroxy-l,l-diphosphonic acid;
methane diphosphonic acid; methanehydroxydiphosphonic acid; ethane-1,1,2-triphosphonic acid; propane-1,1,3,3-tetraphosphonic acid; ethane-2-phenyl-1,1-diphosphonic acid; ethane-2-naphthyl-1,1-diphosphonic acid; methane-phenyldiphosphonic acid; ethane-l-amino-l,l-diphosphonic acid; dichloro-me~hanediphosphonic acid; nonane-5,5-diphosphonic acid; n-pentane~ diphosphonic acid;
methanedifluorodiphosphonic acid; methanedibromodiphos~
phonic acid; propane-2,2-diphosphonic acid; ethane-2-carbo~y-l,l-diphosphonic acid; propane-1-hydroxy-1,1,3-triphosphonic acid; ethane-2-hydroxy-1,1,2-triphosphonic acid; ethane-l-hydroxy-1,1,2-triphosphonic acid;
propane-1,3-diphenyl-2,2-diphosphonic acid; nonane-l, 3 ~ 5 -- ~o --l~diphosphonic acid hexadecane~ diphosphonic acid;
pent-4-ene-hydroxy-l,l-diphosphonic acid; octadec-9-ene-l-hydroxy-l,l-diphosphonic aeid; 3-phenyl~ diphosphono~
prop-2-ene; octane-l,l-diphosphonic acid; dodecane-l,l-diphosphonic acid; phenylaminomethane-diphosphonic acid;
naphthylaminomethanediphosphonic acid; N,N dimethylamino-methanediphosphonîc acid; N-(2-hydroxy-ethyl)-aminomethane diphosphonic acid; N-acetylaminomethane-diphosphonic acid;
aminomethanediphosphonic acid, and the pharmaceutically-acceptable salts of these acids, e.g., sodium, potassium, calcium, magnesium, stannous, indium, ammoniumj triethanol-ammoniun, 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 are most preferred for use herein; preferred members of this group include ethane-l-hydroxy-l,l-diphosphonic acid, dichloromethane diphosphonic acid, methanediphosphonic acid, pharmaceutically-acceptable salts of these acids, and mixtures thereof.
Ethane-l-hydroxy~ diphosphonic acid is a preferred geminal diphosphonate for use herein; its preparation is disclosed in U.S. Patent 3,400,149, Quimby, issued September 3, 19~8. This compound has the molecular formula CH3C(OH) (PO3H2)2 and according to nomenelature by radi-cals, the aeid may 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. Pre~erred salts for the purpose of this invention are the trisodium hydrogen salt, the disodium dihydrogen salt, and~or mixtures thereof.
,~
Dichloromethanediphosphonic acid is an especially preferred geminal diphosphonate for use hereinD This com-pound has the molecular formula C12C(PO3H2~2, and is abbreviated C12MDP. The dichloromethanediphosphonates, especially the sodium salts of C12MDP, are readily prepared and are most preferred for use in the practice of this invention. Methanediphosphonic acid and its salts are also preferred for use herein; the compounds and the methods for preparing those compounds are described in detail in U.S. Patent 3l213,030, Diehl, granted October 19, 1965 and U.S. Patent 3,251,907, Roy, Granted May 17, 1966.
Other phosphonate compounds, examples of which are given below, are well-known in the art. Thus, methane-hydroxydiphosphonic acid and related compounds are described in U.S. Patent 3l422,137, Quimbly, issued January 14, 1969; ethane-lrl,2-triphosphonic acid and related compounds are described in U.S. Patent 3,551,339, Quimbly, issued December 29, 1970; propane-1,1,3~3-tetra-phosphonic acid and related compounds are described in U.S. Patent 3,400,176, Quimby, issued September 3, 1968;
pentane-2,2-diphosphonic acid and related compounds are described in Ko$olopoff, Ju Amer. Chem. Soc., 75: 1500 (1953); propane-1,2,3-triphosphonic acid and salts thereof are described in U.S. Patent 3,743,688, Nicholson and Campbell, issued July 3, 1973; butane-1,2,3,4-tetraphos-phonic acid and salts thereof are described in U.S. Patent 3,755,504, Nicholson and Campbell, issued August 28, 1973;
the higher aliphatic vicinal polyphosphonates and salts thereof are described in U.S Patent 3,584,035, Nicholson and Campbell, issued June 8, 1971; substituted ethane diphosphonic acids and salts and esters thereof are des-cribed in U.S. Patent 3,940,436, Kerst, issued February 24, 1976; halogenated and hydroxylated geminal diphosphonates are disclosed in U.S. Patent 3,944,599, Kerst; phosphono-butane tri~ and tetracarboxylic acid are disclosed in U.S.
Patent 3,886,204, Geffers, et alO, and varlous amino ~ 7~3~5 phosphonate compounds are described in German specification
ANTX-ARTHRITIC COMPOSITIONS CONTAINING
GOLD SALTS A~D ORG.~NOPHOSPHONATES
Bennie L. Baker , .
. .
The present invention relates to pharmaceutical compositions used in the treatment of arthritic conditions, especially rheumatoid arthritis.
Rheumatic diseases are conditions in which pain and stiffness are prominent in portions of the musculo-skeletal system, including the connective tissuer Arthritis is the general name used for such conditions when the joints, themselves, are the major seat of the rheumatic 10 disease. Arthritis is one of the oldest known diseases.
Chronic arthritis of the spine is known to have been present in the ape man of 2 million years ago, as well as in the Java and Lansing Men of 500 thousand years ago, and Egypian mummies dating to 8,000 B.C. See Osgood, R. B., 15 Amer. _. Med. Sci., 200: 429~1940). The Romans buil~
extensive baths throughout their empire to aid in the treatment of arthritic diseases. Yetj in spite of this long history, the ~earch for a safe and effective therapy for arthritic conditions continues. The importance of such work is underscored by the fact that there are over 20 million persons in the United States, today, suffering fron some form of arthritis or related disease. Further, ~-arthritis and rheumatism result in 27 million lost work days yearly, second only to heart disease as a cause of chronic limitation of a~ilit~ to work.
Various gold salts have been recognized as an effective therapy for the treatment o~ rheumatoid arthritis.
See ~cCarty, D. J., Arthritis and ~llied Conditions, Lea & Febiger, 1979, pages 355-364. Gold was originally used to treat rheumatoid arthritis in the 192~'s; this use was based on the empirical belie that since gold was of ~ d~ . `
~ 3 ~3ll~
value in the treatment of tuberculosis, a chronic form of infectious disease, it might be ef~icacious in yet another chronic disorder suspected~ at the time, of having an ;`
infectious etiology. Early work in the treatment of 5 arthritic conditions using gold (Chrysotherapy) is sum-~arized in ~orestier, J., J. Lab. Clin. Med., 20: 827(1935).
. _ A major deterrent to the use of gold therapy is the frequent occurrence of side effects associated with such treatment; ~ome tests indicate that 25 t~ 40 ~ut of every 10 100 patients treated with gold salts will develop some degree of toxic reaction. One such side effect is renal toxicity, such as nephrosis. If renal toxicity side effects become apparent, it is necessary to discontinue the gold therapy and treat the side effect with corti-15 costeroids. Thus, the occurrence of such side effectsclearly curtails the usefulness of gold salt therapy in the treatment of arthritic conditions. Similar renal toxicity pro~lems can occur w~ere other metals are used to treat medical condltions, such as in the treatment of 20 depression using lithiu~ salts. ~rom the foregoing, it is clear that it would be desirable to be able to formulate an effective treatment regimen for arthritic conditions, incorporating the use o~ gold salts, while ~inimizin~ the potential renal toxicity side effects of suc~ treatment.
25 Gold salt therapy also tends to ~n~ one minerali-zation; a treatment regimen ~ic~ m~n~m~zes this effect would also ~e'highly desirable. See 3essop, Gold In the Treatment of Rheumatoid' Art ritis - ~hy, When and How?, J. Rhuematol. ~Su~p'l. 5~, 6: 12~17 ~197~I; Davis, ..... _ ....... _ . _ . . .......... .. . .
30 Undesira~le Effe_ts of Gold Salts, ~. Rheumatol.
~Sup ~ 5~, 6: 18-24 C19791; and ~artindale,''The Extra Pharmacopoeia, 26th Edition~ T~e P~armaceut~cal Press, London, 1975, pages 477~47~, ' Organophosp~on~te compounds are reported in t~e 35 literature as ~eing use~ul in t~e treatment o~ anomalous mobilization and deposition of calcium phosp~ate salts (bone mineral~ in humans and other animals; use o~ these 1 3 ~ ~
compounds in the treatment of arthritis is specifically disclosed. See especially, U~S. 3,683,080, Francis, granted August 8, 1972 U.S. Patent 4,234,645, Gunther and Fleisch, issued No~ember 18, 1980; and U.S. Patent 4,216,212, Flora and Francis, issue~ August 5, 1980.
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. ~es., 3: 109-121 (1972) discluses the use of a diphosphonate material in the treatment of arthritis in rats and mentions the use of phosphonates to inhibit inflammatory erosion in rat cartilage.
It is an object of the present invention to provide pharmaceutical composi~ions, comprising organophosphonates lS and gold salts, which are effective in the treatment of arthritic conditions while minimizing the renal toxicity and inhibition of bone mineralization which can accompany treatment with gold salts.
SUMMARY OF THE INVENTION
The present invention encompasses compositions and methods for treating arthritic conditions in animal tissue, especially in humans. The invention provides effective drvg combination compositions and therapy, and is based on the use of pharmacologically-active phosphon-ate compounds together with pharmaceutically-acceptable gold salts useful in the treatment of arthritic conditions.
In particular, the present invention relates to a pharmaceutical composition in unit dosage form comprising from about 50 mg. to about 500 mg. of an organophosphonate compound selected from the group consisting of R3 - C -R~
wherein R3 is hydrogen, alkyl containing from 1 to about 20 carbon atoms, alkenyl containing from 2 to about 20 carbon atoms, aryl, phenylethenyl, benzyl, halogen, amino, ., ~
'1 3 ~ 5 -- 4 ~
substituted amino, -CI-I2COOH, -CH~PO3H2, -C~I(PO3H2) (OH), or -CH2CH(PO3H2)2; R4 is hydrogen, lower alkyl amino, benzyl, halogen~ hydroxyl, -CH2COOH, -CH2PO3H2, or -CH2C~2PO3E~2, and the pharmaceutically-acceptable salts tllereof, and from about 1 mg. to about 200 mg. of a gold salt selected from the group consisting o gold sodium thiomalate, gold sodium thiosulfate, triethylphosphine goldr gold sodium thioglucose, and mixtures thereof~
The compounds act in concert to provide ef~ective treatment of the arthritic condition while minimizing or eliminating side effects, such as renal toxicity and the inhibition of bone mineralization, which frequently accompany therapy with gold salts.
DETAILED DESCRIPTION OF THE INVENTION
The compositions and treatment regimens of this inven-tion employ~ a safe and effective amount of a pharma ceutically-acceptable gold salt useful in the treatment of arthritic conditions; and (2) a safe and effective amount of a pharmaceutically-acceptable organophosphonate compound.
By "safe and effective amount of gold salt", as used herein, is meant sufficient gold salt compound to treat an arthritic condition, such as rheumatoid arthritis, at a reasonable benefit/risk ratio attendant with any medical treatment, when used in the manner of this invention.
Within the scope of sound medical judgment, the dosage of gold salt will vary with the particular condition being treated, the severity of the condition, the duration of the treatmentr the physical and medical characteristics of the patient, and the specific gold salt and phosphonate compounds employed.
By "safe and effective amount of phosphonate compound", as used herein, is meant a sufficient amount of the phos-phonate compound to effectively treat the bone erosion which accompanies arthritic conditions and, in addition, to minimize gold-induced renal abnormalities and ~`
~3~ 345 inhibition of bone mineralization, at a reasona~le benefit/
risk ratio attendant with any medical trea~nent. ~1ithin the scope of sound medical judgment, the dosage of phos-phonate will vary ~ith the particular condition being 5 treated, the severity of the condition, the duration of the -treatment, the physical and medical characteristics of the patient, and the specific phosphonates and gold salts employed.
By "pharmaceut7cally-acceptable", as used herein, is meant that the arug compounds and other ingredients used in the present compositions and methods of treabme~t are suitable for use in contact with the tissues of humans and lower animals without undue toxicityl irritation, allergic response, and the like, commensurate with a xeasonable benefit/risk ratio.
The term "administration" of the compounds and compositions herein includes systemic dosage, as by in-jection (especially parenterally), intravenous infusion, suppositories and oral administration thereof, as well as topical application of the compounds and compositions to the afflicted situs.
By the term "comprising", as used herein, is meant that various other, compatible drugs and medicaments, as well as inert ingredients, can be conjointly employed in the compositions and processes of this invention, as long as the critical phosphonate compounds and gold salts are used in the manner disclosed.
By "compatible" herein is meant that the components of the compositions are capa~le o ~eing comingled without 3~ interacting in a manner which would substantially decrease the efficacy of the total compositions under ordinary use situations.
~ ;~ 6~3~ 5 By "carrier", as used herein, is meant a liquid, fluid or solid material which can optionally be used to provide finished compositions for systemic or topical administra-tion.
All percentages herein are by weight, unless otherwise specified.
Any pharmaceutically-acceptable gold salt, useful in the treatment of arthritic conditions, may be used in the present invention. A number of such gold compounds have been synthesized and are effective in the trea~ment o~
arthritic conditions; these include, but are not limited to, gold sodium thiomalate, gold sodium thiosulfate, triethylphosphine gold (e.g., Auranofi ~, which is especially adapted for oral administration, commercially available from Smith, Kline and French), gold sodium thioglucose, and mixtures of these components. The gold salts most commonly used in the United States for the treatment of arthritic conditions include gold sodium thiomalate, available commercially as Myochrysine~ from Merck Sharpe and Dohme as an aqueous solution of 50% gold for intramuscular injection, and Aurothioglucose~ (gold sodium thioglucose), commercially available as Solgana ~
from Schering as a wa~er-soluble 50~ gold preparation for intramuscular use prepared as a suspension in oil. Gold sodium thiomalate is especially preferred for use in the present invention.
Gold salts are generally administered to arthritic patients on a dosing schedule which retains the therapeutic benefits of the gold salts while minimizing the severity of potential toxic reactions. In such a dosing regimen, the initial dose is 10 milligrams of gold per week (e.g., by intramuscular injection), raised step wise over the next 2 to 3 weeks to 25 milligrams and then 50 milligrams. These small initial doses are used to identify patients who might be susceptible to gold toxicity. If there are no side eEfects, 50 milligram dosages are given weekly for the next 20 weeks. Treatment with the gold salts is generally continued for a prolonged period to prevent relapses. In the usual maintenance program, gold is given as 50 milli-gram injections at increasingly greater intexvals, initially every 2 weeks for 4 to 8 injections, then every 3 weeks for 4 to 6 injections, and monthly thereafter for 5 an indefinite period. If there is a return of symptoms, then weekly injectiolls of 50 milligrams are reinstitutedO
The applicability of this dosing program to particular cases depends upon numercus factors, including the medical and physical condition of the patient, the severity of the 10 illness, and the phosphonate materials being administered;
in general, the dosages can range ~rom 5 milligrams to 200 milligrams of gold salt per week, although the pre~erred dosages tend to ~e bet~een about 10 milligrams and 75 milligrams of gold salt per week. The compositions of the 15 present invention may contain from a~out 1 milligram to about 200 milligra~s, prefera~ly from about 2 to about 75 milligrams, of gold salt, depending upon the frequency with which the compositions are to be taken and how they are to be administered Ce.g~, orally, or by intramuscular 20 injection~.
The oxganophosphonate compounds Cor more succinctly, "phosphonates"l emplo~ed in the pxesent invention are characterîzed by the phosphonate moiety C-PO3M2, wherein M
represents X or a pharmaceutically-accepta~le cation or 25 ester group). The pho~phonates herein are organophos-phbnates, i.e., the phosphs'nate moiety is attached to a carbon atom ~y a cax~on-phospboxus ~ond tC-~ ~ondl. T~e carbon atom, in turn, can be konded to other hydrocarbyl groups, e.g, alkyl pho~phonates, or to ~drogen' atom5, 30 e.g., ~ethane phosphonates, ~a'logen atoms, e.g~, dichloro-methane diphosphonates, ox ta mixed h~drocar~yl gxoups, hydrogen atoms or oth~r $u~stituents, e.g., ~aloal~yl phosphonates. T~e h~dxocax~ xoups can ~e substituted or unsubstituted alkyl Cincluding c~cloalkyl~, aryl Cincluding 35 heteroaryl) and the'like~ Substitutent ~roups on the alkyl or aryl hydrocarbyl moiety can fie, ~or ~xa~ple, additional phosphonate moieties; halogensr especially chlorine;
3 ~ ~
carboxyl; esterified carboxyl; hydroxyl; amino; amido; and the like. Preferred for use herein are organophosphonates having more than one C~PO3M2 group; diphosphonates, especially geminal diphosphonates characterized by the group I
(M203P - C P03M2 ~
are most highly preferred.
In particular~ the phosphonate compounds useful herein are selected from those having the formula ,O3H2 3 C - R4 (geminal) ~03H2 wherein n is an integer ~rom l to about lO and the sub-stituent groups are H, alkyl, aryl, alkenyl, and the like.
Examples of Type (I) phosphonates are those wherein R, Rl and R2 are each hydrogen, alkyl, -CH2OH, or as noted ~or groups R3 and R4. Examples of Type (II) phosphonates are those wherein R3 is hydrogen, alkyl containing from l to about 20 carbon atoms, alkenyl containing from 2 to about 20 carbon atoms, aryl (e.g., phenyl or naphthyl), phenylethenyl, benzyl, halogen (e~g., chlorine, bromine, or fluorine), amino, substituted amino (e.2~22., dimethylamino, diethylamino, N-hydroxy-N-ethylaminor or acetylamino), ~ 2 J 1~3~5 -CH2COOH, -CH2P03H2, -CH(P03H2) (OH), or -CH2CH
(PO3H2)2; R~ is hydroyen, lower alkyl (e.g., methyl, ethyl, propyl, or butyl), amino, benzyl, halogen, (e.g., chlorine, bromine, or fluorine), hydroxyl, -CH2COOH, -CH2PO3H2, or -CH2CH2PO3H~, or a pharmaceutically-acceptable salt thereof, such as alkali metal (eOg., sodiuln or potassium)~
alkaline earth metal (e~g., calcium or magnesium), non-toxic heavy metal ~e.g., stannous or indium), and ammonium or low molecular weight, substituted ammonium (e.g. mono-, di-, or tri-ethanolammonium) salts. It will also be appreciated that groups R, Rl and R2 and groups R3 and R4 can be cycloalkyl, heterocyclic or can be joined in ring structures, said rings being carbocyclic or heterocyclic.
Among the operable phosphonates encompassed by the above formula are ethane-l-hydroxy-l,l-diphosphonic acid;
methane diphosphonic acid; methanehydroxydiphosphonic acid; ethane-1,1,2-triphosphonic acid; propane-1,1,3,3-tetraphosphonic acid; ethane-2-phenyl-1,1-diphosphonic acid; ethane-2-naphthyl-1,1-diphosphonic acid; methane-phenyldiphosphonic acid; ethane-l-amino-l,l-diphosphonic acid; dichloro-me~hanediphosphonic acid; nonane-5,5-diphosphonic acid; n-pentane~ diphosphonic acid;
methanedifluorodiphosphonic acid; methanedibromodiphos~
phonic acid; propane-2,2-diphosphonic acid; ethane-2-carbo~y-l,l-diphosphonic acid; propane-1-hydroxy-1,1,3-triphosphonic acid; ethane-2-hydroxy-1,1,2-triphosphonic acid; ethane-l-hydroxy-1,1,2-triphosphonic acid;
propane-1,3-diphenyl-2,2-diphosphonic acid; nonane-l, 3 ~ 5 -- ~o --l~diphosphonic acid hexadecane~ diphosphonic acid;
pent-4-ene-hydroxy-l,l-diphosphonic acid; octadec-9-ene-l-hydroxy-l,l-diphosphonic aeid; 3-phenyl~ diphosphono~
prop-2-ene; octane-l,l-diphosphonic acid; dodecane-l,l-diphosphonic acid; phenylaminomethane-diphosphonic acid;
naphthylaminomethanediphosphonic acid; N,N dimethylamino-methanediphosphonîc acid; N-(2-hydroxy-ethyl)-aminomethane diphosphonic acid; N-acetylaminomethane-diphosphonic acid;
aminomethanediphosphonic acid, and the pharmaceutically-acceptable salts of these acids, e.g., sodium, potassium, calcium, magnesium, stannous, indium, ammoniumj triethanol-ammoniun, 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 are most preferred for use herein; preferred members of this group include ethane-l-hydroxy-l,l-diphosphonic acid, dichloromethane diphosphonic acid, methanediphosphonic acid, pharmaceutically-acceptable salts of these acids, and mixtures thereof.
Ethane-l-hydroxy~ diphosphonic acid is a preferred geminal diphosphonate for use herein; its preparation is disclosed in U.S. Patent 3,400,149, Quimby, issued September 3, 19~8. This compound has the molecular formula CH3C(OH) (PO3H2)2 and according to nomenelature by radi-cals, the aeid may 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. Pre~erred salts for the purpose of this invention are the trisodium hydrogen salt, the disodium dihydrogen salt, and~or mixtures thereof.
,~
Dichloromethanediphosphonic acid is an especially preferred geminal diphosphonate for use hereinD This com-pound has the molecular formula C12C(PO3H2~2, and is abbreviated C12MDP. The dichloromethanediphosphonates, especially the sodium salts of C12MDP, are readily prepared and are most preferred for use in the practice of this invention. Methanediphosphonic acid and its salts are also preferred for use herein; the compounds and the methods for preparing those compounds are described in detail in U.S. Patent 3l213,030, Diehl, granted October 19, 1965 and U.S. Patent 3,251,907, Roy, Granted May 17, 1966.
Other phosphonate compounds, examples of which are given below, are well-known in the art. Thus, methane-hydroxydiphosphonic acid and related compounds are described in U.S. Patent 3l422,137, Quimbly, issued January 14, 1969; ethane-lrl,2-triphosphonic acid and related compounds are described in U.S. Patent 3,551,339, Quimbly, issued December 29, 1970; propane-1,1,3~3-tetra-phosphonic acid and related compounds are described in U.S. Patent 3,400,176, Quimby, issued September 3, 1968;
pentane-2,2-diphosphonic acid and related compounds are described in Ko$olopoff, Ju Amer. Chem. Soc., 75: 1500 (1953); propane-1,2,3-triphosphonic acid and salts thereof are described in U.S. Patent 3,743,688, Nicholson and Campbell, issued July 3, 1973; butane-1,2,3,4-tetraphos-phonic acid and salts thereof are described in U.S. Patent 3,755,504, Nicholson and Campbell, issued August 28, 1973;
the higher aliphatic vicinal polyphosphonates and salts thereof are described in U.S Patent 3,584,035, Nicholson and Campbell, issued June 8, 1971; substituted ethane diphosphonic acids and salts and esters thereof are des-cribed in U.S. Patent 3,940,436, Kerst, issued February 24, 1976; halogenated and hydroxylated geminal diphosphonates are disclosed in U.S. Patent 3,944,599, Kerst; phosphono-butane tri~ and tetracarboxylic acid are disclosed in U.S.
Patent 3,886,204, Geffers, et alO, and varlous amino ~ 7~3~5 phosphonate compounds are described in German specification
2,343,146 (March 6r 1975), German specification 2,360,711 (June 12, 1975), German specification 2,360,719 (June 6, 1975).
While any pharmace~tically-acceptable salt o~ the phos-phonates can be used in the practice of this invention, the sodium salts are preferred. Various pharmaceutical cations such as potassium, ammonium, mono-, di-, and tri-ethanolam~onium, a~d mixtures ther~of, are also suit-able for use as counterions in the salts, provided caution is observed in regulating the total intake of cation species in the salt eompositions. Sueh salts ean be prepared by any suitable method involving neutralization of the parent phosphonic acid.
The present invention in most eonveniently practiced by administering a single composition which comprises a mixture of gold salt and phosphonateO In an alternative mode, the dosage regimen can consist of separate adminis-tration of the two agents this latter approach is less convenient, but may be desirable based on the pharmaco-logieal properties of the partieular compounds administered or the needs oE a partieular patient.
Compositions eomprising the gold salt and phosphonate components ean be administered parenterally in aqueous solution by subeutaneous, intradermal, intramuscular or intravenous injeetion.
When administered orally, the phosphonate eompounds herein are only about 10% absorbed through the gut, the rest being excreted. Aeeordingly, oral eompositions typieally contain an exeess of the phosphonate material over that which ean be effeetively used in an injectable form to aceount Eor the low absorption. Dosage forms of the present invention will, generally, eontain ~rom about 50 milligrams to about 500 milligrams of the phosphonate compound, preferably, a geminal diphosphonate, sueh as ~ .
~ 7 ~
dichloromethanediphosph~nic acid, ethane-l-llydroxy 1,1~
diphosphonic acld, methanediphosphonic acid, or a phar-maceutically-acceptable salt of these materials. Of course, the total dosage of the compositions herein will be 5 decided by the attending physician and will be determined by such factors as the type and severity of the arthritic condition being treated, the age and weight of the patient, the medical history of the patient, and like ~actors well known in the medical art. In general, treatment regimens 10 according to the present invention will call for the admini~tration of ~rom about 200 milligrams to about 2000 milligrams per day of the diphosphonate ~aterials.
For purposes of oral administration, compositions can be formulated as capsules, tablets or granules. For 15 treatment of non-human animals, compositions are preferably incorporated in animal feeds, ~eed supplemen-~s or Ieea concentrates.
Compositions comprising the gold salts and phos-phonate materials can be administered, per se, or, more 20 preferably, in com~ination ~it~ a solid or li~uid filler, diluent or encapsulatlng substance as a pharmaceutical carrier, e.g., materials commonly used in a manufacture of tablets, capsules, elixirs, and the li~e. Some examples of the substances which can serve as pharmaceutically-25 acceptable carriers include pyrogen-free water; water~
alcohol mix~ures; saline; suga~s, such as lactose, glucose and sucrose; starches, suc~ ac corn starch and potato starch; cellulose and its derivatives, such as sodium car~oxymethyl cellulose, ~thyl cellulose, and cellulose 30 acetate; po~dered gumsi malt; gelatin; stearic acid;
calcium sulfate; ve~etable oils, such as peanut oil and cottonseed oil; mineral oili polyols, such as prop~lene glycol, slycerin, sorhitol, mannitol, and pol~ethylene glycol; agar, alginic acid; as ~ell as other non-toxic, 35 compatible substances used in pharmaceutical formulations.
~ ~fi~3~
- 14 ~
Wetting agents and lubricants, such as sodium :lauryl sulfate, as well as coloring agents, flavoring agents and preservatives can also be present~
Renal toxicity side effects may also be present when 5 metal salts, aside from gold, are used in the treabment of medical conditions. Thus, when lithium salts, such as lithium carbonate, lithium chloride, lithium citrate, lithium sulfate, and mixtures of these materials, are used in the treatment o~ manic depressive conditions renal 10 to~icity can result. The administration of organophos-phonate compounds together ~ith these li-thium salts reduces the renal toxicity side effects which may accompany such treatment. Compositions comprising a safe and effective amount of the pharmaceutically-acceptable lithium salts 15 together with organophosphonate compounds, particularly geminal diphosphonates, in an amount safe and effective to minimize or eliminate the renal toxicity side effects, would be used in this manner.
The compositions herein can be prepared by standard 20 formulation and tableting techniques used in the phar-maceu.ical industry. The following examples illustrate the present compositions and their use, but are not intended to be limiting o~ the scope of the invention.
EXAM LE I
Capsules, having the ~ollowing formulati~n, are prepared by conventional methods. j~
.. .. . ..
Ingredient mg. per Capsule Ethane~l-hydroxy~ 00 diphosphonic acid Triethyl phosphine gold (e.g., 7 Auranofin) A capsule of the type above is administered orally once daily and is effective in treating patients having 35 rheumatoid arthritis w~ile minimizing the renal toxicity
While any pharmace~tically-acceptable salt o~ the phos-phonates can be used in the practice of this invention, the sodium salts are preferred. Various pharmaceutical cations such as potassium, ammonium, mono-, di-, and tri-ethanolam~onium, a~d mixtures ther~of, are also suit-able for use as counterions in the salts, provided caution is observed in regulating the total intake of cation species in the salt eompositions. Sueh salts ean be prepared by any suitable method involving neutralization of the parent phosphonic acid.
The present invention in most eonveniently practiced by administering a single composition which comprises a mixture of gold salt and phosphonateO In an alternative mode, the dosage regimen can consist of separate adminis-tration of the two agents this latter approach is less convenient, but may be desirable based on the pharmaco-logieal properties of the partieular compounds administered or the needs oE a partieular patient.
Compositions eomprising the gold salt and phosphonate components ean be administered parenterally in aqueous solution by subeutaneous, intradermal, intramuscular or intravenous injeetion.
When administered orally, the phosphonate eompounds herein are only about 10% absorbed through the gut, the rest being excreted. Aeeordingly, oral eompositions typieally contain an exeess of the phosphonate material over that which ean be effeetively used in an injectable form to aceount Eor the low absorption. Dosage forms of the present invention will, generally, eontain ~rom about 50 milligrams to about 500 milligrams of the phosphonate compound, preferably, a geminal diphosphonate, sueh as ~ .
~ 7 ~
dichloromethanediphosph~nic acid, ethane-l-llydroxy 1,1~
diphosphonic acld, methanediphosphonic acid, or a phar-maceutically-acceptable salt of these materials. Of course, the total dosage of the compositions herein will be 5 decided by the attending physician and will be determined by such factors as the type and severity of the arthritic condition being treated, the age and weight of the patient, the medical history of the patient, and like ~actors well known in the medical art. In general, treatment regimens 10 according to the present invention will call for the admini~tration of ~rom about 200 milligrams to about 2000 milligrams per day of the diphosphonate ~aterials.
For purposes of oral administration, compositions can be formulated as capsules, tablets or granules. For 15 treatment of non-human animals, compositions are preferably incorporated in animal feeds, ~eed supplemen-~s or Ieea concentrates.
Compositions comprising the gold salts and phos-phonate materials can be administered, per se, or, more 20 preferably, in com~ination ~it~ a solid or li~uid filler, diluent or encapsulatlng substance as a pharmaceutical carrier, e.g., materials commonly used in a manufacture of tablets, capsules, elixirs, and the li~e. Some examples of the substances which can serve as pharmaceutically-25 acceptable carriers include pyrogen-free water; water~
alcohol mix~ures; saline; suga~s, such as lactose, glucose and sucrose; starches, suc~ ac corn starch and potato starch; cellulose and its derivatives, such as sodium car~oxymethyl cellulose, ~thyl cellulose, and cellulose 30 acetate; po~dered gumsi malt; gelatin; stearic acid;
calcium sulfate; ve~etable oils, such as peanut oil and cottonseed oil; mineral oili polyols, such as prop~lene glycol, slycerin, sorhitol, mannitol, and pol~ethylene glycol; agar, alginic acid; as ~ell as other non-toxic, 35 compatible substances used in pharmaceutical formulations.
~ ~fi~3~
- 14 ~
Wetting agents and lubricants, such as sodium :lauryl sulfate, as well as coloring agents, flavoring agents and preservatives can also be present~
Renal toxicity side effects may also be present when 5 metal salts, aside from gold, are used in the treabment of medical conditions. Thus, when lithium salts, such as lithium carbonate, lithium chloride, lithium citrate, lithium sulfate, and mixtures of these materials, are used in the treatment o~ manic depressive conditions renal 10 to~icity can result. The administration of organophos-phonate compounds together ~ith these li-thium salts reduces the renal toxicity side effects which may accompany such treatment. Compositions comprising a safe and effective amount of the pharmaceutically-acceptable lithium salts 15 together with organophosphonate compounds, particularly geminal diphosphonates, in an amount safe and effective to minimize or eliminate the renal toxicity side effects, would be used in this manner.
The compositions herein can be prepared by standard 20 formulation and tableting techniques used in the phar-maceu.ical industry. The following examples illustrate the present compositions and their use, but are not intended to be limiting o~ the scope of the invention.
EXAM LE I
Capsules, having the ~ollowing formulati~n, are prepared by conventional methods. j~
.. .. . ..
Ingredient mg. per Capsule Ethane~l-hydroxy~ 00 diphosphonic acid Triethyl phosphine gold (e.g., 7 Auranofin) A capsule of the type above is administered orally once daily and is effective in treating patients having 35 rheumatoid arthritis w~ile minimizing the renal toxicity
3 ~ 5 and bone mineralization inhibition side effects which can accompany gold salt therapy.
The composition of Example I may also be rormulated as a tablet, using conventional ta~leting techniques and agents.
In the composition of ~xample I, the ethane-1-hydroxy-l,l-diphosphonic acid is replaced, in whole or in part, by equivalent amounts o~ ethane~l-hydroxy-l,l-diphosphonic acid, sodium salt form; dichloromethanedi-phosphonic acid or the sodium salts thereof; methanedi-phosphonic acid or the sodium salts thereof, and equivalent results are secured. The compositions are also usefully formulated using 200 mg or S00 mg of the phosphonate com-ponent per capsule.
In the capsules of Example I, the gold sodium thiomalate is replaced, in whole or in part, by equivalent amounts of gold sodium thiosulfate, gold sodium thiomalate, or gold sodium thioglucose, in a form suitable fox oral administration, and equivalent results are secured.
EX~PLE rI
Capsules , having t~e co~position gi~en ~elow, are prepared ~y conventional method~, .... . ..
Ingredient- mg per Caps le Dichloromethanediphosphonic2QQ
acid Triethylphosphine gold ~e~g., 4 Auranofinl A capsule ~ this t~pe is adm~nistered or~ t~ice daily, and is effective in t~e t~eatment o~ axt~xitic 30 conditions~
In the composit~on o~ Example II r the dichlQro-methanediphosphonic acid ls replaced, ~n ~ole or in part, by an equivalent amount o~ dichlo~omethaned~phosphonic acid, sodiu~ salt ~orm, and equivalent results are secured.
~ 3~3~5 The compositions are also usefully formulated usiny 40~ mg or 500 mg or the phosphonate component per capsule.
In the capsules of Example II, the triethylphos- `.
phine gold is replaced, in whole or in part, by gold sodium thiomalate, gold sodium thiosulfate, gold sodium thioglucose, in a form suitable for oral administration and equivalent results are secured.
EXAMP.LE III
A composition for intramuscular injection is pre-pared by blending the following ingredients:
Ingredient m~. per Dose '.-.
Dichloromethanediphosphoni.c 500 acid, disodium salt Gold sodium ~hiomalate 50 15 Pyrogen-free water Balance Thè compositi.on of Example III is administered by intramuscular injection once a week to a patient having rheumatoid arthriti~. Over the course o~ treatment, the bone ercsive activity associated ~rit~ t~e arthritic con-dition decreases, the ~one does not tend to demineralize,and no renal toxicity side e~ects are seen~
In the composition o~ Example III, the diphosphonate material is replaced, in whole or in par~, ~y an equivalent amount o~ ethane-l-hydroxy-l,l-diphosphonic acid, methane-diphosphonic acid, or pharmaceutically-acceptable salts o~
these compounds, and equiy~lent results are o~t~ined.
In the composit~on ~ Exa~ple III, t~e gold sodium thiomalate is replaced, in ~hole or in part, ~ eq~tivalent amounts of ~old s.odium thi.~sul~ate, txiet~lphosp~ine gold, or gold sodium thioglucose and e~uiv~lent results are securedO
Th.e unit dosage composition o~ Exampl~ I~I may also be formulated with ~xiation~ in the d~phosp~onate or gold salt levels included, depending upon t~e particular dosages to ~e administered at a given time in the course of treat-ment.
3 ~ ~
EX~PLE IV
.
A patient having rheumatoid arthritis is given one intramuscular injection containing 50 mg of gold sodium-thiomalate per week and one tablet containing 500 mg of dichloromethane diphosphonic acid (disodium salt) daily. This course of treatment is continued for six months and the gold salt dosage is then reduced to main-tenance levels. The bone erosive ac~ivity associated with the arthritic condition is found to decrease; further, no bone demineralization activity or renal toxicity is seen.
- ~XA~PL~ ~
The effect of the present invention on renal toxi-city was demonstrated in the following manner. 135 Male Charles Rivers CD (Sprague-Dawleyl rats, each weig~ing between 125 and 175 grams ~ere divided, at random, into 9 groups o~ equal size. Each group was placed undex a treat-ment regimen as described in the t~ble ~elow ~or a 91 day period. The dichloromethanediphosphon3te (C12MDP~, sodium salt~ was administered ~y subcutaneous ventral ~lank in-jections, while the gold sodium thiom~late ~GST~ was ad-ministered ~y intramuscular lnjections, alternating each week ~etween the left and right t~igh muscle.
Grou~ - Tre~tment -~
.~
1 Vehicle control ca . s% ~enzyl ~lconol ~ sterile isotonic s~linel 2 2 mg/kg C12MDR ~ Q.5% ~enz~l alco~ol 3 10 mg/k~ C12~DP ~ Q.5~ ~enzy-l ~lcohol
The composition of Example I may also be rormulated as a tablet, using conventional ta~leting techniques and agents.
In the composition of ~xample I, the ethane-1-hydroxy-l,l-diphosphonic acid is replaced, in whole or in part, by equivalent amounts o~ ethane~l-hydroxy-l,l-diphosphonic acid, sodium salt form; dichloromethanedi-phosphonic acid or the sodium salts thereof; methanedi-phosphonic acid or the sodium salts thereof, and equivalent results are secured. The compositions are also usefully formulated using 200 mg or S00 mg of the phosphonate com-ponent per capsule.
In the capsules of Example I, the gold sodium thiomalate is replaced, in whole or in part, by equivalent amounts of gold sodium thiosulfate, gold sodium thiomalate, or gold sodium thioglucose, in a form suitable fox oral administration, and equivalent results are secured.
EX~PLE rI
Capsules , having t~e co~position gi~en ~elow, are prepared ~y conventional method~, .... . ..
Ingredient- mg per Caps le Dichloromethanediphosphonic2QQ
acid Triethylphosphine gold ~e~g., 4 Auranofinl A capsule ~ this t~pe is adm~nistered or~ t~ice daily, and is effective in t~e t~eatment o~ axt~xitic 30 conditions~
In the composit~on o~ Example II r the dichlQro-methanediphosphonic acid ls replaced, ~n ~ole or in part, by an equivalent amount o~ dichlo~omethaned~phosphonic acid, sodiu~ salt ~orm, and equivalent results are secured.
~ 3~3~5 The compositions are also usefully formulated usiny 40~ mg or 500 mg or the phosphonate component per capsule.
In the capsules of Example II, the triethylphos- `.
phine gold is replaced, in whole or in part, by gold sodium thiomalate, gold sodium thiosulfate, gold sodium thioglucose, in a form suitable for oral administration and equivalent results are secured.
EXAMP.LE III
A composition for intramuscular injection is pre-pared by blending the following ingredients:
Ingredient m~. per Dose '.-.
Dichloromethanediphosphoni.c 500 acid, disodium salt Gold sodium ~hiomalate 50 15 Pyrogen-free water Balance Thè compositi.on of Example III is administered by intramuscular injection once a week to a patient having rheumatoid arthriti~. Over the course o~ treatment, the bone ercsive activity associated ~rit~ t~e arthritic con-dition decreases, the ~one does not tend to demineralize,and no renal toxicity side e~ects are seen~
In the composition o~ Example III, the diphosphonate material is replaced, in whole or in par~, ~y an equivalent amount o~ ethane-l-hydroxy-l,l-diphosphonic acid, methane-diphosphonic acid, or pharmaceutically-acceptable salts o~
these compounds, and equiy~lent results are o~t~ined.
In the composit~on ~ Exa~ple III, t~e gold sodium thiomalate is replaced, in ~hole or in part, ~ eq~tivalent amounts of ~old s.odium thi.~sul~ate, txiet~lphosp~ine gold, or gold sodium thioglucose and e~uiv~lent results are securedO
Th.e unit dosage composition o~ Exampl~ I~I may also be formulated with ~xiation~ in the d~phosp~onate or gold salt levels included, depending upon t~e particular dosages to ~e administered at a given time in the course of treat-ment.
3 ~ ~
EX~PLE IV
.
A patient having rheumatoid arthritis is given one intramuscular injection containing 50 mg of gold sodium-thiomalate per week and one tablet containing 500 mg of dichloromethane diphosphonic acid (disodium salt) daily. This course of treatment is continued for six months and the gold salt dosage is then reduced to main-tenance levels. The bone erosive ac~ivity associated with the arthritic condition is found to decrease; further, no bone demineralization activity or renal toxicity is seen.
- ~XA~PL~ ~
The effect of the present invention on renal toxi-city was demonstrated in the following manner. 135 Male Charles Rivers CD (Sprague-Dawleyl rats, each weig~ing between 125 and 175 grams ~ere divided, at random, into 9 groups o~ equal size. Each group was placed undex a treat-ment regimen as described in the t~ble ~elow ~or a 91 day period. The dichloromethanediphosphon3te (C12MDP~, sodium salt~ was administered ~y subcutaneous ventral ~lank in-jections, while the gold sodium thiom~late ~GST~ was ad-ministered ~y intramuscular lnjections, alternating each week ~etween the left and right t~igh muscle.
Grou~ - Tre~tment -~
.~
1 Vehicle control ca . s% ~enzyl ~lconol ~ sterile isotonic s~linel 2 2 mg/kg C12MDR ~ Q.5% ~enz~l alco~ol 3 10 mg/k~ C12~DP ~ Q.5~ ~enzy-l ~lcohol
4 2 m~k~ G~T ~ stexile isotonic saline 10 mg~kg G$T ~ stexile isQtonic ~aline 6 ~ mg~kg Cl2~DR ~ 2 m~g GST
7 2 mg/ky C12~D~ ~ lQ mg~g GST
8 10 mg/kg C12MDP ~ 2 m~k~ GST
9 10 mg~kg C12~1Dp ~ lQ m~kg G~T
At the end of the treatmenf period, the rats were sacrificed, necropsied, and the effects of the treatment on the rats' kidneys were evaulated in terms of tubular degeneration and the presence of megalocytes. Me~alocytes
7 2 mg/ky C12~D~ ~ lQ mg~g GST
8 10 mg/kg C12MDP ~ 2 m~k~ GST
9 10 mg~kg C12~1Dp ~ lQ m~kg G~T
At the end of the treatmenf period, the rats were sacrificed, necropsied, and the effects of the treatment on the rats' kidneys were evaulated in terms of tubular degeneration and the presence of megalocytes. Me~alocytes
5 are a -egenerative phenomenGn associated with heavy metal nephroto~ici~y. The severity of lesions observed was noted and graded on a scale of 1-4. These results are summarized in Tables 1 and 2, below.
Table 1 10 TUbular Degeneration ~animals/lesion severity) for Various Combinations of Cl MDP and_GST r .~
Dose of Cl MDP Dose of GST (mg/kg?_ (mg~kg~- _- O - 2 lQ
0 15/NC 15/NC 9/1,6~3 2 15/NC 15/NC 13/NC, 2/1 13/NC,1/1,1/2 14/NC,1/1 6/NC,3~ ,3/2,3/3 T~ble 2 Megalocytes ~animals/lesion severity~
for Various Combi ations of_C12MDP and GST
. .
Dose o~ C1 MDP ~ose of GST (mg/kg) -- (mg~kq~ - 0 2 lQ
0 15~C 3~2, 12~3 4/2, 11/3 2 15~NC 14~2, 1~3 9/~, 6~3 2S 10 15~NC 8~2, 7~3 3~2, 12~3 le~ion se~erity; l-min~m~l, 2~mild, 3=moderate, 4=marked; NC-indicated change not observed The data su~maxized a~ove indicate that the com-binations of the t~ a~ents exhi~t a positi~e interaction on ~ST related renal damage. Ta~les 1 and 2 ~ho~ that increasing doses of GST increases the number of incidents and the severit~ of renal tu~ular de~eneration and mega-locytosis, respectivel~. C12MDP treatments on the other 3 ~ ~ ¢
hand, had no significant effect on these parameters. When C12MDP and GST treatments were administered concurrently, both the number of instances and the severity of GST-induced renal toxicity, especially in terms of megalo-cytosis, were reduced.
Tibias from animals in each of the groups, described above, were isolated and analyzed to determine their fat-free dry weights, ash weights, and calcium and phosphorus contents. The calcium and phosphorous levels of these bones are summarized in the tables, below.
Table 3 Mean Percent Calcium for ~arious Combinations of Cl MDP and GST
Dose of C12MDP Dose of GST (m~/kg) (mg/kg~_ O 2 10 0 24.3 23.8-~ 23.8~
2 24.7* 24.6* 2~.5*
24.5 24.8* 24.8*
Ta~le 4 Mean Percent Phosphorus for Various Combinations of Cl~MDP and GST
.. _ . . ,".. _ _ .. _ ~
Dose of C12MDP Dose of GST '~mg/k~~ :
(m~/ g) _ _ O 2 10 ~' 0 1~.5 12.2~ 12.2 ~ 12.5 12.6* 12.4*
12~4 1~.4* 12.3*
* Statistically dif~exent f~om ~roup ~ith no C12MDP at thQ given GST dcse level + Statisticall~ different ~rom grou~ with no GST at the'given Cl~MD~ dose level.
The a~o~e data îndicate that the combination therapy of the present invent~on exhibited a positive interaction on the calciu~ and phosphorus content of the 3 ~ ~
bone. In the absence of C12MDP, GST treatment caused a statistically significant lower calcium and phosphorus content in bone. However, when C12MDP and GST treatment were administered concurrently, changing lev~ls of GST ha~
no statistically significant effect on the calcium or phosphorus content.
W~AT IS CLAIMED IS~
Table 1 10 TUbular Degeneration ~animals/lesion severity) for Various Combinations of Cl MDP and_GST r .~
Dose of Cl MDP Dose of GST (mg/kg?_ (mg~kg~- _- O - 2 lQ
0 15/NC 15/NC 9/1,6~3 2 15/NC 15/NC 13/NC, 2/1 13/NC,1/1,1/2 14/NC,1/1 6/NC,3~ ,3/2,3/3 T~ble 2 Megalocytes ~animals/lesion severity~
for Various Combi ations of_C12MDP and GST
. .
Dose o~ C1 MDP ~ose of GST (mg/kg) -- (mg~kq~ - 0 2 lQ
0 15~C 3~2, 12~3 4/2, 11/3 2 15~NC 14~2, 1~3 9/~, 6~3 2S 10 15~NC 8~2, 7~3 3~2, 12~3 le~ion se~erity; l-min~m~l, 2~mild, 3=moderate, 4=marked; NC-indicated change not observed The data su~maxized a~ove indicate that the com-binations of the t~ a~ents exhi~t a positi~e interaction on ~ST related renal damage. Ta~les 1 and 2 ~ho~ that increasing doses of GST increases the number of incidents and the severit~ of renal tu~ular de~eneration and mega-locytosis, respectivel~. C12MDP treatments on the other 3 ~ ~ ¢
hand, had no significant effect on these parameters. When C12MDP and GST treatments were administered concurrently, both the number of instances and the severity of GST-induced renal toxicity, especially in terms of megalo-cytosis, were reduced.
Tibias from animals in each of the groups, described above, were isolated and analyzed to determine their fat-free dry weights, ash weights, and calcium and phosphorus contents. The calcium and phosphorous levels of these bones are summarized in the tables, below.
Table 3 Mean Percent Calcium for ~arious Combinations of Cl MDP and GST
Dose of C12MDP Dose of GST (m~/kg) (mg/kg~_ O 2 10 0 24.3 23.8-~ 23.8~
2 24.7* 24.6* 2~.5*
24.5 24.8* 24.8*
Ta~le 4 Mean Percent Phosphorus for Various Combinations of Cl~MDP and GST
.. _ . . ,".. _ _ .. _ ~
Dose of C12MDP Dose of GST '~mg/k~~ :
(m~/ g) _ _ O 2 10 ~' 0 1~.5 12.2~ 12.2 ~ 12.5 12.6* 12.4*
12~4 1~.4* 12.3*
* Statistically dif~exent f~om ~roup ~ith no C12MDP at thQ given GST dcse level + Statisticall~ different ~rom grou~ with no GST at the'given Cl~MD~ dose level.
The a~o~e data îndicate that the combination therapy of the present invent~on exhibited a positive interaction on the calciu~ and phosphorus content of the 3 ~ ~
bone. In the absence of C12MDP, GST treatment caused a statistically significant lower calcium and phosphorus content in bone. However, when C12MDP and GST treatment were administered concurrently, changing lev~ls of GST ha~
no statistically significant effect on the calcium or phosphorus content.
W~AT IS CLAIMED IS~
Claims (2)
1. A pharmaceutical composition in unit dosage form comprising from about 50 mg. to about 500 mg. of an organophosphonate compound selected from the group consisting of wherein R3 is hydrogen, alkyl containing from 1 to about 20 carbon atoms, alkenyl containing from 2 to about 20 carbon atoms, aryl, phenylethenyl, benzyl, halogen, amino, substituted amino, -CH2COOH, -CH2PO3H2, -CH(PO3H2) (OH), or -CH2CH(PO3H2)2; R4 is hydrogen, lower alkyl amino, benzyl, halogen, hydroxyl, -CH2COOH, -CH2PO3H2, or -CH2CH2PO3H2, and the pharmaceutically-acceptable salts thereof, and from about 1 mg. to about 200 mg. of a gold salt selected from the group consisting of gold sodium thiomalate, gold sodium thiosulfate, triethylphosphine gold, gold sodium thioglucose, and mixtures thereof.
2. A composition according to claim 1 wherein the organo-phosphonate compound is selected from the group consisting of dichloromethanediphosphonic acid, ethane-1-hydroxy-1, 1-diphosphonic acid, methanediphosphonic acid, and the pharmaceutically-acceptable salts of these acids.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US219,052 | 1980-12-22 | ||
| US06/219,052 US4330530A (en) | 1980-12-22 | 1980-12-22 | Anti-arthritic compositions and method using gold salts and organophosphonates |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1164345A true CA1164345A (en) | 1984-03-27 |
Family
ID=22817643
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000392804A Expired CA1164345A (en) | 1980-12-22 | 1981-12-21 | Anti-arthritic compositions containing gold salts and organophosphonates |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US4330530A (en) |
| EP (1) | EP0054997B1 (en) |
| JP (1) | JPS57171922A (en) |
| CA (1) | CA1164345A (en) |
| DE (1) | DE3174098D1 (en) |
| ES (1) | ES508185A0 (en) |
Families Citing this family (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1201087B (en) * | 1982-04-15 | 1989-01-27 | Gentili Ist Spa | PHARMACOLOGICALLY ACTIVE BIPPHOSPHONES, PROCEDURE FOR THEIR PREPARATION AND RELATED PHARMACEUTICAL COMPOSITIONS |
| FR2531088B1 (en) * | 1982-07-29 | 1987-08-28 | Sanofi Sa | ANTI-INFLAMMATORY PRODUCTS DERIVED FROM METHYLENEDIPHOSPHONIC ACID AND THEIR PREPARATION METHOD |
| IT1187828B (en) * | 1985-05-24 | 1987-12-23 | Gentili Ist Spa | PHARMACEUTICAL COMPOSITION BASED ON DIPHOSPHONATES FOR THE TREATMENT OF ARETROSIS |
| IL84731A0 (en) * | 1986-12-19 | 1988-05-31 | Norwich Eaton Pharma | Heterocycle-substituted diphosphonic acids and salts and esters and pharmaceutical compositions containing them |
| US4877603A (en) * | 1987-12-18 | 1989-10-31 | The Procter & Gamble Company | Oral compositions |
| JPH01165526A (en) * | 1987-12-21 | 1989-06-29 | Smith Kline Fujisawa Kk | Auranofin suppository |
| NZ228367A (en) * | 1988-03-23 | 1992-02-25 | Smithkline Beecham Corp | Topical composition containing a gold compound for treating inflammatory conditions |
| FR2629716B1 (en) * | 1988-04-07 | 1991-07-19 | Sanofi Sa | PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION BASED ON A DIPHOSPHONIC ACID DERIVATIVE |
| HUT72437A (en) * | 1992-06-30 | 1996-04-29 | Procter & Gamble Pharma | Compositions for the treatment of arthritis containing phosphonates and nsaids |
| US6274552B1 (en) | 1993-03-18 | 2001-08-14 | Cytimmune Sciences, Inc. | Composition and method for delivery of biologically-active factors |
| US20010055581A1 (en) * | 1994-03-18 | 2001-12-27 | Lawrence Tamarkin | Composition and method for delivery of biologically-active factors |
| US5652227A (en) * | 1995-01-30 | 1997-07-29 | Teronen; Olli Pekka | Inhibition of the degradation of connective tissue matrix protein components in mammals |
| US6407218B1 (en) | 1997-11-10 | 2002-06-18 | Cytimmune Sciences, Inc. | Method and compositions for enhancing immune response and for the production of in vitro mabs |
| US7229841B2 (en) * | 2001-04-30 | 2007-06-12 | Cytimmune Sciences, Inc. | Colloidal metal compositions and methods |
| AU2001221607A1 (en) * | 2000-11-20 | 2002-05-27 | Ecole Polytechnique Federale De Lausanne (Epfl) | Endosseous implant |
| CN1925843A (en) * | 2003-12-02 | 2007-03-07 | 细胞免疫科学公司 | Methods and compositions for the production of monoclonal antibodies |
| AU2005209318B2 (en) * | 2004-01-28 | 2010-02-11 | Cytimmune Sciences, Inc. | Functionalized colloidal metal compositions and methods |
| US8771750B2 (en) * | 2006-12-14 | 2014-07-08 | Savannah River Nuclear Solutions, Llc | Delivery or removal of metals from biological systems |
| EP2200932A4 (en) * | 2007-09-21 | 2014-09-10 | Cytimmune Sciences Inc | Nanotherapeutic colloidal metal compositions and methods |
| US20110014118A1 (en) * | 2007-09-21 | 2011-01-20 | Lawrence Tamarkin | Nanotherapeutic colloidal metal compositions and methods |
| EP2219458B1 (en) | 2007-11-08 | 2015-07-15 | Cytimmune Sciences, Inc. | Compositions and methods for generating antibodies |
| US11690856B2 (en) * | 2017-10-23 | 2023-07-04 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Compounds for treating CMV related diseases |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE463805C (en) * | 1925-06-23 | 1928-08-03 | Leopold Cassella & Co G M B H | Process for the preparation of durable, sterilizable solutions which contain phosphorus in organic bonds and bound gold |
| US3553314A (en) * | 1968-12-23 | 1971-01-05 | Procter & Gamble | Oral compositions for calculus retardation |
| US3584125A (en) * | 1968-12-23 | 1971-06-08 | Procter & Gamble | Compositions for inhibiting anomalous deposition and mobilization of calcium phosphate in animal tissue |
| US3584124A (en) * | 1968-12-24 | 1971-06-08 | Procter & Gamble | Compositions for inhibiting anomalous deposition and mobilization of calcium phosphate in animal tissue |
| US3553315A (en) * | 1968-12-24 | 1971-01-05 | Procter & Gamble | Oral compositions for calculus retardation |
| US3678164A (en) * | 1969-02-12 | 1972-07-18 | Procter & Gamble | Compositions for inhibiting anomalous deposition and mobilization of calcium phosphate in animal tissue |
| US3641246A (en) * | 1970-01-14 | 1972-02-08 | Procter & Gamble | Compositions for inhibiting anomalous deposition and mobilization of calcium phcosphate in animal tissue |
| US3662066A (en) * | 1970-03-04 | 1972-05-09 | Procter & Gamble | Compositions for inhibiting anomalous deposition and mobilization of calcium phosphate in animal tissue |
| US3683080A (en) * | 1970-08-28 | 1972-08-08 | Procter & Gamble | Compositions for inhibiting anomalous deposition and mobilization of calcium phosphate in animal tissue |
| US4096247A (en) * | 1977-02-16 | 1978-06-20 | Smithkline Corporation | Gold thio glucopyranoside compounds and method of use |
| US4216212A (en) * | 1978-06-08 | 1980-08-05 | The Procter & Gamble Company | Pyrazolidine anti-inflammatory composition and methods of use |
-
1980
- 1980-12-22 US US06/219,052 patent/US4330530A/en not_active Expired - Lifetime
-
1981
- 1981-12-11 DE DE8181201349T patent/DE3174098D1/en not_active Expired
- 1981-12-11 EP EP81201349A patent/EP0054997B1/en not_active Expired
- 1981-12-21 ES ES508185A patent/ES508185A0/en active Granted
- 1981-12-21 CA CA000392804A patent/CA1164345A/en not_active Expired
- 1981-12-22 JP JP56206322A patent/JPS57171922A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| EP0054997A1 (en) | 1982-06-30 |
| DE3174098D1 (en) | 1986-04-17 |
| ES8307495A1 (en) | 1983-08-01 |
| EP0054997B1 (en) | 1986-03-12 |
| US4330530A (en) | 1982-05-18 |
| ES508185A0 (en) | 1983-08-01 |
| JPS57171922A (en) | 1982-10-22 |
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