U.S. patent number 4,282,214 [Application Number 06/086,849] was granted by the patent office on 1981-08-04 for phenylacetate anti-inflammatory composition.
This patent grant is currently assigned to The Procter & Gamble Company. Invention is credited to Lawrence Flora, Marion D. Francis.
United States Patent |
4,282,214 |
Flora , et al. |
August 4, 1981 |
Phenylacetate anti-inflammatory composition
Abstract
The anti-inflammatory activity of fenoprofen, ketoprofen, MK-830
and other phenylacetic acid-based anti-inflammatory drugs is
enhanced by administration thereof in conjunction with a
phosphonate compound such as EHDP or Cl.sub.2 MDP.
Inventors: |
Flora; Lawrence (Hamilton,
OH), Francis; Marion D. (Cincinnati, OH) |
Assignee: |
The Procter & Gamble
Company (Cincinnati, OH)
|
Family
ID: |
26775218 |
Appl.
No.: |
06/086,849 |
Filed: |
October 22, 1979 |
Related U.S. Patent Documents
|
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
929476 |
Jul 31, 1978 |
|
|
|
|
801705 |
May 31, 1977 |
|
|
|
|
Current U.S.
Class: |
514/108;
514/107 |
Current CPC
Class: |
A61K
31/66 (20130101); A61K 31/66 (20130101); A61K
31/19 (20130101); A61K 31/66 (20130101); A61K
2300/00 (20130101) |
Current International
Class: |
A61K
31/66 (20060101); A61K 031/19 (); A61K 031/66 ();
A61K 031/195 () |
Field of
Search: |
;424/204,317,319 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Friedman; Stanley J.
Attorney, Agent or Firm: Goldstein; Steven J. Yetter; Jerry
J. Roth; Michael J.
Parent Case Text
This is a continuation of application Ser. No. 929,476 filed July
31, 1978 which is a continuation of application Ser. No. 801,705,
filed May 31, 1977, both now abandoned.
Claims
What is claimed is:
1. An anti-inflammatory composition, comprising: (1) from about 10
mg to about 500 mg of a phenylacetic acid-based compound selected
from the group consisting of fenoprofen, ketoprofen, MK-830 having
the formula ##STR5## and pharmaceutically-acceptable salts and
esters thereof; and (2) from about 50 mg. to about 250 mg. of an
organophosphonate compound selected from the group consisting of
geminal organophosphonates of the formula ##STR6## or
pharmaceutically acceptable salts thereof, wherein n is an integer
from 1 to about 10; R.sub.3 is selected from the group consisting
of H, --CH.sub.2 OH, C.sub.1 -C.sub.20 alkyl or cycloalkyl, C.sub.2
-C.sub.20 alkenyl, aryl, phenylethyl, benzyl, halogen, amino,
substituted amino, --CH.sub.2 COOH, --CH.sub.2 PO.sub.3 H.sub.2,
--CH(PO.sub.3 H.sub.2) (OH) or --CH.sub.2 CH(PO.sub.3
H.sub.2).sub.2 ; and R.sub.4 is selected from the group consisting
of H, lower alkyl, amino, benzyl, halogen, --OH, --CH.sub.2 COOH,
--CH.sub.2 PO.sub.3 H.sub.2 or --CH.sub.2 CH.sub.2 PO.sub.3
H.sub.2.
2. A composition according to claim 1 wherein the organophosphonate
compound is a member selected from the group consisting of
ethane-1-hydroxy-1,1-diphosphonic acid, dichloromethanediphosphonic
acid, methanediphosphonic acid, and the pharmaceutically-acceptable
salts and esters thereof.
3. A composition according to claim 1, comprising a safe and
effective amount of a member selected from the group consisting of
fenoprofen, ketoprofen, and MK-830, and a safe and effective amount
of dichloromethanediphosphonic acid, or the
pharmaceutically-acceptable salts or esters thereof.
4. A composition according to claim 3 in unit dosage form,
comprising: from about 10 mg to about 500 mg of a member selected
from the group consisting of fenoprofen and ketoprofen; and from
about 50 mg to about 250 mg of dichloromethanediphosphonic acid, or
a pharmaceutically-acceptable salt thereof.
5. A composition according to claim 1, comprising a safe and
effective amount of a member selected from the group consisting of
fenoprofen, ketoprofen, and MK-830, and a safe and effective amount
of ethane-1-hydroxy-1,1-diphosphonic acid, or the
pharmaceutically-acceptable salts thereof.
6. A composition according to claim 5 in unit dosage form
comprising: from about 10 mg to about 500 mg of a member selected
from the group consisting of fenoprofen and ketoprofen; and from
about 50 mg to about 250 mg of ethane-1-hydroxy-1,1-diphosphonic
acid, or the pharmaceutically-acceptable salts thereof.
7. A composition according to claim 1 comprising a safe and
effective amount of a member selected from the group consisting of
fenoprofen, ketoprofen, and MK-830, and a safe and effective amount
of methanediphosphonic acid, or the pharmaceutically-acceptable
salts thereof.
8. A composition according to claim 7 in unit dosage form,
comprising: from about 10 mg to about 500 mg of a member selected
from the group consisting of fenoprofen and ketoprofen; and from
about 50 mg to about 250 mg of methanediphosphonic acid, or a
pharmaceutically-acceptable salt thereof.
9. A composition according to claim 1 or 4 wherein the phenylacetic
acid-based compound is fenoprofen.
10. A method for treating or preventing pain and inflammation in
animal tissues, comprising administering to an animal in need of
such treatment: (1) from about 50 mg to about 6000 mg per day of a
phenylacetic acid-based compound selected from the group consisting
of fenoprofen, ketoprofen, MK-830 having the formula ##STR7## and
pharmaceutically-acceptable salts and esters thereof; and (2) from
about 200 mg to about 2000 mg per day of an organophosphonate
compound selected from the group consisting of geminal
organophosphonates of the formula ##STR8## or pharmaceutically
acceptable salts thereof, wherein n is an integer from 1 to about
10; R.sub.3 is selected from the group consisting of H, --CH.sub.2
OH, C.sub.1 -C.sub.20 alkyl or cycloalkyl, C.sub.2 -C.sub.20
alkenyl, aryl, phenylethyl, benzyl, halogen, amino, substituted
amino, --CH.sub.2 COOH, --CH.sub.2 PO.sub.3 H.sub.2, --CH(PO.sub.3
H.sub.2) (OH) or --CH.sub.2 CH(PO.sub.3 H.sub.2).sub.2 ; and
R.sub.4 is selected from the group consisting of H, lower alkyl,
amino, benzyl, halogen, --OH, --CH.sub.2 COOH, --CH.sub.2 PO.sub.3
H.sub.2 or --CH.sub.2 CH.sub.2 PO.sub.3 H.sub.2.
11. A method according to claim 10 wherein the organophosphonate
compound is a member selected from the group consisting of
ethane-1-hydroxy-1,1-diphosphonic acid, dichloromethanediphosphonic
acid, methanediphosphonic acid, and the pharmaceutically-acceptable
salts and esters thereof.
12. A method according to claim 10 wherein the animal is a
human.
13. A method according to claim 12 which employs a safe and
effective amount of fenoprofen or ketoprofen and a safe and
effective amount of dichloromethanediphosphonic acid, or the
pharmaceutically-acceptable salts or esters thereof.
14. A method according to claim 13 which employs: from about 50 mg
to about 6000 mg of fenoprofen or ketoprofen per day; and from
about 200 mg to about 2000 mg of dichloromethanediphosphonic acid,
or a pharmaceutically-acceptable salt thereof, per day.
15. A method according to claim 12 which employs a safe and
effective amount of fenoprofen or ketoprofen and a safe and
effective amount of ethane-1-hydroxy-1,1-diphosphonic acid, or the
pharmaceutically-acceptable salts or esters thereof.
16. A method according to claim 15 which employs: from about 50 mg
to about 6000 mg of fenoprofen or ketoprofen per day; and from
about 200 mg to about 2000 mg of ethane-1-hydroxy-1,1-diphosphonic
acid, or a pharmaceutically-acceptable salt thereof, per day.
17. A method according to claim 12 which employs a safe and
effective amount of fenoprofen or ketoprofen and a safe and
effective amount of methanediphosphonic acid, or the
pharmaceutically-acceptable salts or esters thereof.
18. A method according to claim 17 which employs: from about 50 mg
to about 6000 mg of fenoprofen or ketoprofen per day; and from
about 200 mg to about 2000 mg of methanediphosphonic acid, or a
pharmacutically-acceptable salt thereof, per day.
19. A method according to claim 10 or 14 which employs fenoprofen
as the phenylacetic acid-based compound.
Description
BACKGROUND OF THE INVENTION
The present invention relates to compositions and processes for
relieving inflammation. More specifically, phosphonate compounds
are administered in conjunction with well-recognized phenylacetic
acid-based antiinflammatory agents such as fenoprofen, ketoprofen,
MK-830, and derivatives thereof, to treat undesirable inflammation
of body tissues.
Inflammation, or the "inflammatory response", is the result of
complex interconnected physiological events, including increased
vascular permeability, fluid accumulation, and the migration of a
changing population of inflammatory cells into the inflamed area.
The clinical manifestations of inflammation include swelling
(edema), increased local temperature, erythema, and pain. The
inflammatory response can be triggered by any of a number of
causative factors, including certain bacteria, radiation,
hypersensitivity to chemical agents, arthritis-like conditions, and
the like. The inflammatory response is generally believed to be a
primary defense mechanism in the body, but, unchecked, can become
excessive and can result in functional impairment.
The use of phenylacetic acid compounds such as fenoprofen,
ketoprofen, MK-830, and derivatives thereof, to combat inflammation
and attendant pain is accepted medical practice. The phenylacetate
agents are commonly employed to relieve pain and inflammation
associated with, for example, arthritis, bursitis, and the like. Of
course, it would be most desirable to potentiate the
anti-inflammatory response of any of the phenylacetic acid-based
agents to provide a more effective treatment regimen.
The use of pharmacologically-active phosphonate compounds to check
the anomalous mobilization and deposition of calcium phosphate
salts in the body, e.g., as a treatment for arthritis, is
known.
By the present invention, pharmacologically-active phosphonate
compounds are administered in conjunction with phenylacetic-acid
based anti-inflammatory agents to provide an improved therapy for
pain and inflammation, especially in the treatment of arthritis,
and like diseases.
RELATED REFERENCES
Various phenylacetate compounds are known for use in the treatment
of rheumatic and arthritic disorders; Nickander, et al. (1971) Fed.
Proc. Fed. Amer. Soc. Exp. Biol. 30, 563; Merck and Company,
Netherlands Patent Applications Nos. 65,07505 and 66,08311, Eire
Pat. Nos. 704/68 and 705/68 and Belgian Pat. No. 664,187, the
disclosures of which are incorporated herein by reference.
Analgesic abuse is often noted in patients with chronic
gastrointestinal or renal disease. Many such patients are in the
habit of taking analgesics for prolonged periods and usually in
excessive doses; Clin. Med., 1968, 75 (Aug.) 19; Lancet, ii/1969,
1233. A listing of references relating to phenylacetate-based
analgesics and anti-inflammatories and contraindications appears in
the text ANTIINFLAMMATORY AGENTS Chemistry and Pharmacology Vol. I,
Schemer and Whitehouse, Academic Press, New York, pp. 123-127.
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
(bone material) in humans and other animals. See especially the
U.S. Patents of M. D. Francis U.S. Pat. Nos.: 3,683,080, granted
Aug. 8, 1972; 3,678,164, granted July 18, 1972; 3,662,066, granted
May 9, 1972; 3,553,314, granted Jan. 5, 1971; 3,553,315, granted
Jan. 5, 1971; 3,584,124, granted June 8, 1971; 3,584,125, granted
June 8, 1971; and 3,641,246, granted Feb. 8, 1972.
The article by Francis, Flora and King, entitled "The Effects of
Disodium Ethane-1-Hydroxy-1,1-Diphosphonate on Adjuvant Induced
Artiritis in Rats", appearing in Calc. Tiss. Res. 9, 109-121 (1972)
mentions the use of phosphonates to inhibit inflammatory erosion of
cartilage in rats.
The copending application of L. Flora, entitled PHARMACEUTICAL
COMPOSITION, Ser. No. 705,650, filed July 15, 1976, discloses the
topical administration of phosphonate compounds of the type used
herein to humans to alleviate pathological calcification.
By the present invention, the anti-inflammatory activity of
phenylacetic acid compounds is potentiated by phosphonate
compounds. Thus, the invention encompasses a means whereby a
patient afflicted with pain and tissue inflammation can secure
relief without risking analgesic abuse due to over-use of
phenylacetic acid-based antiinflammatories.
SUMMARY OF THE INVENTION
The present invention encompasses compositions and means for
treating pain and inflammation in animal tissues, especially in
humans. The invention provides effective drug combination
compositions and therapy, and is based on the use of
pharmacologically-active phosphonate compounds in combination with
various phenylacetic acid-based anti-inflammatory agents such as
fenoprofen, ketoprofen, MK-830, and the like.
The compositions of this invention comprise an effective amount of
a phenylacetic acid-based antiinflammatory compound in combination
with an effective amount of a phosphonate compound. The compounds
act in concert to provide improved anti-inflammatory benefits.
The invention also encompasses treatment regimens comprising
administering an effective amount of the phenylacetic acid-based
anti-inflammatory agent and an effective amount of a phosphonate
compound to an animal, especially a human, suffering from tissue
inflammation.
Preferred phenylacetic acid-based treatment regimens and
compositions herein employ a member selected from the group
consisting of fenoprofen, ketoprofen, and MK-830, or the
pharmaceutically-acceptable salts and esters thereof, or mixtures
thereof, and, as the phosphonate compound, a member selected from
the group consisting of ethane-1-hydroxy-1,1-diphosphonic acid, and
the pharmaceutically-acceptable salts and esters thereof;
dichloromethanediphosphonic acid, and the
pharmaceutically-acceptable salts and esters thereof; and
methanediphosphonic acid, and the pharmaceutically-acceptable salts
and esters thereof. Mixtures of said phosphonates can also be
used.
DETAILED DESCRIPTION OF THE INVENTION
The compositions and treatment regimens of this invention employ:
(1) a safe and effective amount of a pharmaceutically-acceptable
phenylacetic acid-based anti-inflammatory compound; and (2) a safe
and effective amount of a pharmaceutically-acceptable phosphonate
compound. These compounds are administered to alleviate
inflammation in a patient in need of such treatment.
By "safe and effective amount of phenylacetic acid-based
anti-inflammatory compound" herein is meant sufficient phenylacetic
acid compound to alleviate tissue inflammation, 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 phenylacetic acid compound will vary with
the particular condition being treated, the severity of the
condition, the duration of the treatment, and the specific
phenylacetic acid and phosphonate compounds employed.
By "safe and effective amount of phosphonate compound" herein is
meant a sufficient amount of the phosphonate compound to potentiate
the anti-inflammatory effect of the phenylacetic acid compound, at
a reasonable benefit/risk ratio attendant with any medical
treatment. Within the scope of sound medical judgment, the dosage
of phosphonate will vary with the particular condition being
treated, the severity of the condition, the duration of the
treatment, and the specific phosphonate and phenylacetic acid
compounds employed.
By "pharmaceutically-acceptable" herein is meant that the drug
compounds and other ingredients used in the present compositions
and processes 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.
The term "administration" of the compounds and compositions herein
includes systemic use, as by injection (especially parenterally),
intravenous infusion, suppositories and oral administration
thereof, as well as topical application of the compounds and
compositions to the afflicted situs.
By "topical application" herein is meant directly laying on or
spreading the compounds and compositions on epidermal tissue
(including outer skin and oral, gingival, nasal, etc., tissue).
By "afflicted situs" herein is meant a localized area of
inflammation, and the immediate surrounding area.
The process of the present invention is most conveniently carried
out by administering compositions comprising both a phosphonate
compound and a compatible phenylacetic acid compound and,
optionally, compatible carrier materials.
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 phenylacetic acid-based anti-inflammatory compounds
are used in the manner disclosed. The term "comprising" thus
encompasses and includes the more restrictive terms "consisting of"
and "consisting essentially of" which characterize the use of the
essential phosphonate compounds and phenylacetic acid
compounds.
By "compatible" herein is meant that the components of the
compositions are capable of being commingled without interacting in
a manner which would substantially decrease the efficacy of the
total compositions under ordinary use situations.
By "carrier" herein is meant a liquid, fluid or solid material
which can optionally be used to provide finished compositions for
systemic or topical administration of the drug compounds.
All percentages herein are by weight, unless otherwise
specified.
The phosphonate compounds and phenylacetic acid compounds critical
to the practice of this invention are disclosed more fully
hereinafter. Optional ingredients which can be included in the
compositions to provide aesthetic, cosmetic, and convenience
benefits, but which are not critical to the practice of the
invention, are also disclosed.
The compounds used herein are derivatives of phenylacetic acid; the
salts and esters of such derivatives can also be used. The parent
acid is represented by the formula ##STR1##
As is well known in the art, phenylacetic acid can be derivatized
on the ring or .alpha.-methyl group to provide various
pharmacologically active compounds which exhibit analgesic and/or
anti-inflammatory activity. The phenylacetic acid-based compounds
employed in the practice of this invention are all well known in
the medical arts for use in the treatment of arthritis and like
disease states.
Various phenylacetic acid-based compounds, their
pharmaceutically-acceptable esters, and their
pharmaceutically-acceptable salts, are used herein. Typical
examples of such materials are those represented by the formula
##STR2## wherein: X can be, for example, H, --CH.sub.3, CH.sub.2,
--C.sub.2 H.sub.5 or other lower alkyl substituents; Y can be, for
example, H, Cl, F, CH.sub.3 O.sup.-, --OH, CH.sub.3 S.sup.-, or the
like; and R can be, for example, phenyl, substituted phenyl wherein
the substituents are, for example, those recited for Y, phenoxy,
substituted phenoxy wherein the substituents are, for example,
those recited for Y, cyclohexyl, substituted cyclohexyl wherein the
substituents are, for example, those recited for Y, benzoyl,
substituted benzoyl wherein the substituents are, for example,
those recited for Y, butoxy, 1-propenoxy, and the like. A listing
of such materials appears in the text ANTIINFLAMMATORY AGENTS
Chemistry and Pharmacology Vol. I, cited hereinabove, pp. 93-99,
the disclosures of which are incorporated herein by reference. The
syntheses of these known materials can be carried out using
procedures well known in the art.
The organophosphonate compounds (or, more succinctly,
"phosphonates") employed in the manner of this invention are of the
following type.
The phosphonate compounds which can be employed in the present
invention are characterized by the phosphonate moiety (--PO.sub.3
M.sub.2, 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, can be bonded to other hydrocarbyl groups, e.g.,
alkyl phosphonates, or to hydrogen atoms, e.g., methane
phosphonates, halogen atoms, e.g., dichloromethanediphosphonates,
or to mixed hydrocarbyl groups, hydrogen atoms or other
substituents, e.g., haloalkyl phosphonates. The hydrocarbyl groups
can be substituted or non-substituted alkyl (including 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 for use herein are organophosphonates having more than
one C--PO.sub.3 M.sub.2 group; diphosphonates, especially geminal
diphosphonates characterized by the grouping ##STR3## are most
highly preferred.
Typical phosphonate compounds useful herein are of the formula
##STR4## wherein n is an integer from 1 to about 10 and the
substituent groups are H, alkyl, aryl, alkenyl, and the like.
Examples of Type (I) phosphonates are those wherein R, R.sub.1 and
R.sub.2 are each hydrogen, alkyl, --CH.sub.2 OH, or are as noted
for groups R.sub.3 and R.sub.4. Examples of Type (II) phosphonates
are those wherein R.sub.3 is hydrogen, alkyl containing 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., dimethylamino, diethylamino, N-hydroxy-N-ethylamino,
acetylamino), --CH.sub.2 COOH, --CH.sub.2 PO.sub.3 H.sub.2,
--CH(PO.sub.3 H.sub.2)(OH) or --CH.sub.2 CH(PO.sub.3 H.sub.2).sub.2
; R.sub.4 is hydrogen, lower alkyl (e.g., methyl, ethyl, propyl,
and butyl), amino, benzyl, halogen (e.g., chlorine, bromine and
fluorine), hydroxyl, --CH.sub.2 COOH, --CH.sub.2 PO.sub.3 H.sub.2,
or --CH.sub.2 CH.sub.2 PO.sub.3 H.sub.2, or a
pharmaceutically-acceptable salt thereof such as alkali metal
(e.g., sodium and potassium) alkaline earth metal (e.g., calcium
and magnesium), nontoxic heavy metal (e.g., stannous and indium),
and ammonium or low molecular weight substituted ammonium (e.g.,
mono-, di-, and tri-ethanolammonium) salts. It will be appreciated
that groups R, R.sub.1 and R.sub.2 and groups R.sub.3 and R.sub.4
can be cycloalkyl, 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 "phosphonoates", "diphosphonates" or
"polyphosphonates".
Non-limiting examples of phosphonates of the above Type (I) include
propane-1,2,3-triphosphonic acid; butane-1,2,3,4-tetraphosphonic
acid; hexane-1,2,3,4,5,6-hexaphosphonic acid;
hexane-1-hydroxy-2,3,4,5,6-pentaphosphonic acid;
hexane-1,6-dihydroxy-2,3,4,5-tetraphosphonic acid;
pentane-1,2,3,4,5-pentaphosphonic acid;
heptane-1,2,3,4,5,6,7-heptaphosphonic acid;
octane-1,2,3,4,5,6,7,8-octaphosphonic acid;
nonane-1,2,3,4,5,6,7,8,9-nonaphosphonic acid;
decane-1,2,3,4,5,6,7,8,9,10-decaphosphonic acid; and the
pharmaceutically-acceptable salts of these acids, e.g., sodium,
potassium, calcium, magnesium, ammonium, triethanolammonium,
diethanolammonium, and monoethanolammonium salts.
Among the operable phosphonates encompassed by the above Type (II)
are ethane-1-hydroxy-1,1-diphosphonic acid; methanediphosphonic
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; methanephenyldiphosphonic
acid; ethane-1-amino-1,1-diphosphonic acid;
dichloromethanediphosphonic acid (a.k.a.
dichloromethylenediphosphonic acid and methanedichlorodiphosphonic
acid); nonane-5,5-diphosphonic acid; n-pentane-1,1-diphosphonic
acid; methanedifluorodiphosphonic acid; methanedibromodiphosphonic
acid; propane-2,2-diphosphonic acid;
ethane-2-carboxy-1,1-diphosphonic acid;
propane-1-hydroxy-1,1,3-triphosphonic acid;
ethane-2-hydroxy-1,1,2-triphosphonic acid;
ethane-1-hydroxy-1,1,2-triphosphonic acid;
propane-1,3-diphenyl-2,2-diphosphonic acid; nonane-1,1-diphosphonic
acid; hexadecane-1,1-diphosphonic acid;
pent-4-ene-1-hydroxy-1,1-diphosphonic acid;
octadec-9-ene-1-hydroxy-1,1-diphosphonic acid;
3-phenyl-1,1-diphosphonoprop-2-ene; octane-1,1-diphosphonic acid;
dodecane-1,1-diphosphonic acid; phenylaminomethanediphosphonic
acid; nephthylaminomethanediphosphonic acid;
N,N-dimethylaminomethanediphosphonic acid;
N-(2-hydroxyethyl)-aminomethanediphosphonic acid;
N-acetylaminomethanediphosphonic acid; aminomethanediphosphonic
acid; and the pharmaceutically-acceptable salts of these acids,
e.g., sodium, potassium, calcium, magnesium, stannous, indium,
ammonium, triethanolammonium, 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 Type (II) are most preferred for use
herein.
Ethane-1-hydroxy-1,1-diphosphonic acid is a preferred geminal
diphosphonate for use herein. This compound has the molecular
formula CH.sub.3 C(OH)(PO.sub.3 H.sub.2).sub.2 (according to
nomenclature by radicals, the acid may also be named
1-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 and the
disodium dihydrogen salt, and/or mixtures thereof.
Dichloromethanediphosphonic acid is an especially preferred geminal
diphosphonate for use herein. This compound has the molecular
formula Cl.sub.2 C(PO.sub.3 H.sub.2).sub.2, abbreviated Cl.sub.2
MDP. The dichloromethanediphosphonates, especially the sodium salts
of Cl.sub.2 MDP, are readily prepared and are most preferred for
use in the practice of this invention.
The preparation of typical phosphonate compounds of the type
disclosed for use herein is found in standard references and
publications, especially the following.
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.
Pat. No. 3,422,137, O. T. Quimby, incorporated herein by
reference.
Ethane-1-hydroxy-1,1-diphosphonic acid can be prepared as disclosed
in U.S. Pat. No. 3,400,149, incorporated herein by reference.
Methanediphosphonic acid and related compounds useful herein are
described in detail in U.S. Pat. No. 3,213,030, granted Oct. 19,
1965; a preferred method of preparing such compounds is disclosed
in U.S. Pat. No. 3,251,907, granted May 17, 1966, incorporated
herein by reference.
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. Pat. No. 3,551,339, O. T. Quimby,
incorporated herein by reference.
Propane-1,1,3,3-tetraphosphonic acid and related compounds useful
herein, and a method for preparing same are fully disclosed in U.S.
Pat. No. 3,400,176, O. T. Quimby, incorporated herein by
reference.
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), incorporated herein by
reference.
Propane-1,2,3-triphosphonic acid and salts thereof can be prepared
by a process disclosed in U.S. Pat. No. 3,743,688, D. Allan
Nicholson and Darrel Campbell, incorporated herein by
reference.
Butane-1,2,3,4-tetraphosphonic acid and salts thereof can be
prepared by a process disclosed in U.S. Pat. No. 3,755,504, D.
Allan Nicholson and Darrel Campbell, incorporated herein by
reference.
The higher aliphatic vicinal polyphosphonates and salts thereof can
be prepared by the process disclosed in U.S. Pat. No. 3,584,035,
Nicholson and Campbell, incorporated herein by reference.
Substituted ethane diphosphonic acids and salts and esters thereof
are disclosed in U.S. Pat. No. 3,940,436, issued Feb. 24, 1976, to
A. F. Kerst, the disclosures of which are incorporated herein by
reference. U.S. Pat. No. 3,944,599, to the same inventor, discloses
geminal diphosphonate compounds having halogen and hydroxyl
substituent groups, and the means for preparing same. The
disclosures of this patent are also incorporated herein by
reference.
Phosphonobutane tri- and tetra-carboxylic acid compounds and their
preparation are disclosed in U.S. Pat. Nos. 3,886,204 and
3,886,205, both issued May 27, 1975, to Geffers, et al., the
disclosures of which are incorporated herein by reference.
German Pat. No. 2360-798, June 26, 1975, to Henkel & Cie GmbH
discloses pharmaceutical and cosmetic preparations for influencing
the deposition of poorly soluble calcium salts, said preparations
comprising polymethylene phosphonic acid compounds. This
publication, the disclosures of which are incorporated herein by
reference, describes the preparation of the phosphonate materials
in detail.
The preparation and pharmacological properties of various amino
phosphonate compounds are described in German Pat. No. 2343-146
(Mar. 6, 1975); Belgian Pat. No. 822-930 (June 4, 1975); Belgian
Pat. No. 822-929 (June 4, 1975); German Pat. No. 2360-711 (June 12,
1975); German Pat. No. 2360-719 (June 12, 1975); Belgian Pat. No.
819-187 (Feb. 26, 1975); Belgian Pat. No. 819-188 (Feb. 26, 1975);
and Belgian Pat. No. 819-189 (Feb. 26, 1975), the disclosures of
said publications being incorporated herein by reference.
Other amino phosphonates useful herein include the well-known
"EDTA-analogs", i.e.,
and the like.
While any pharmaceutically-acceptable salt of the phosphonates 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- ethanolammonium, and mixtures
thereof, are also suitable for use as counterions in the salts,
provided caution is observed in regulating the total intake of
cation species in the salt composition. Such salts can be prepared
by any suitable method involving neutralization of the parent
phosphonic acid.
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:risk ratio) are contemplated for use herein. The well-known
toxicity of some Type (I) monophosphonates (n=1) disclosed in the
structural formulas above precludes their use herein. However, such
materials are known in the art and are easily avoided in the
practice of this invention.
The present invention is most conveniently practiced by
administering compositions which comprise mixtures of the
phenylacetic acid-based anti-inflammatory agent and the phosphonate
agent. In an alternate mode, a dosage regimen can consist of
separate administration of the two types of agents, but this is
less convenient.
Compositions comprising the phenylacetic acid-based
anti-inflammatory agent and the phosphonate compound can be
administered parenterally in aqueous solution by subcutaneous,
intradermal, intramuscular or intravenous injection.
When administered orally, the phosphonate compounds herein are only
about 10% absorbed through the gut, the rest being excreted.
Accordingly, oral compositions typically contain an excess of the
phosphonate material over that which can be effectively used in an
injectable form to account for the low absorption.
Especially useful compositions herein for oral administration
comprise, in unit dosage form, from about 10 mg to about 500 mg of
fenoprofen(preferred), ketoprofen or MK-830 and from about 50 mg to
about 250 mg of dichloromethanediphosphonic acid, or a
pharmaceutically-acceptable salt thereof. Similarly, oral
compositions in unit dosage form comprising from about 10 mg to
about 500 mg of fenoprofen, ketoprofen or MK-830 and from about 50
mg to about 250 mg of ethane-1-hydroxy-1,1-diphosphonic acid, or a
pharmaceutically-acceptable salt thereof, or methanediphosphonic
acid, or a pharmaceutically-acceptable salt thereof, are useful in
the practice of the invention.
Of course, the total daily usage of the compositions herein will be
decided by the attending physician and will be determined by such
factors as the type of inflammation being treated, the age and
weight of the patient, the severity of the inflammation, and like
factors well known in the medical arts. In general, treatment
regimens according to the present invention comprise administering
to an animal in need of such treatment from about 50 mg to about
6000 mg (preferably 100-1000 mg) of phenylacetic acid-based
compound per day and from about 200 mg to about 2000 mg per day of
the diphosphonates herein, especially dichloromethanediphosphonic
acid, ethane-1-hydroxy-1,1-diphosphonic acid, methanediphosphonic
acid, or the pharmaceutically-acceptable salts or esters of these
respective acids; the dichloromethanediphosphonates are
particularly useful herein due to their safety and efficacy.
For purposes of oral administration, compositions can be formulated
as capsules, tablets or granules. For treatment of non-human
animals, compositions are preferably incorporated in animal feeds,
feed supplements or feed concentrates.
Compositions comprising the phenylacetic acid-based
anti-inflammatory agent and phosphonate can be administered per se
or, more preferably, in combination with a solid or liquid filler,
diluent or encapsulating substance as a pharmaceutical carrier,
e.g., materials commonly used in the manufacture of tablets,
capsules, elixirs, and the like. Some examples of the substances
which can serve as pharmaceutical carriers herein include
pyrogen-free water; water-alcohol mixtures; saline; sugars such as
lactose, glucose and sucrose; starches such as corn starch and
potato starch; cellulose and its derivatives, such as sodium
carboxymethylcellulose, ethylcellulose, cellulose acetate; powdered
gums; malt; gelatin; stearic acid; calcium sulfate; vegetable oils,
such as peanut oil and cottonseed oil; mineral oil; polyols such as
propylene glycol, glycerin, sorbitol, mannitol and polyethylene
glycol, agar; alginic acid; as well as other non-toxic, compatible
substances used in pharmaceutical formulations. Wetting agents and
lubricants such as sodium lauryl sulfate, as well as coloring
agents, flavoring agents and preservatives can also be present.
For topical application directly to the afflicted situs, the
compositions herein are preferably formulated as solutions in a
liquid or semi-liquid carrier. Carriers which promote penetration
of the present compositions into and through the skin to the
subdermal, inflamed tissues are preferred in such topical
compositions. The organic sulfoxides and phosphine oxides and
mixtures thereof with sugar esters, and liquid and semi-liquid
carriers comprising same, which are preferred for use with the
present compositions, are fully described in U.S. Pat. Nos.
3,903,256 and 3,839,566, MacMillan and Lyness, and U.S. Pat. Nos.
3,896,238 and 3,952,099, Smith, the disclosures of which are
incorporated herein by reference.
Topical compositions herein generally comprise from about 1% to 20%
of the phenylacetic acid-based compound, from about 1% to about 20%
of the phosphonate compound, the balance comprising a compatible
carrier, usually a liquid or cream. Especially effective carriers
comprise a C.sub.10, or higher, organic sulfoxide compound to
enhance skin penetration by the active drug agents. Decyl methyl
sulfoxide (0.1%-10% of the topical composition) is especially
useful for enhancing penetration of the drug agents through
skin.
The compositions herein can be prepared by standard formulation and
tableting techniques used in the pharmaceutical industry.
The following examples illustrate the present compositions and
their use, but are not intended to be limiting of the scope of the
invention.
EXAMPLE I
Capsules are prepared by conventional methods, as follows:
______________________________________ Ingredient Mg. per capsule
______________________________________ Ethane-1-hydroxy-1,1- 200
diphosphonic acid Fenoprofen 25
______________________________________
A capsule of the above type is administered orally 2-4 times daily
to substantially reduce the pain and inflammation associated with
arthritis, rheumatism, bursitis and lumbago.
In the composition of Example I, the
ethane-1-hydroxy-1,1-diphosphonic acid is replaced by
ethane-1-hydroxy-1,1-diphosphonic acid, sodium salt form, and
equivalent results are secured.
In the capsules of Example I, the fenoprofen is replaced by an
equivalent amount of ketoprofen or MK-830, and equivalent results
are secured.
EXAMPLE II
Capsules are prepared by conventional methods, as follows:
______________________________________ Ingredient Mg. per capsule
______________________________________ Dichloromethanediphos- 200
phonic acid Fenoprofen 200
______________________________________
A capsule of the above type is administered orally 2-4 times daily
to substantially reduce the pain and inflammation associated with
arthritis, rheumatism, bursitis and lumbago.
In the composition of Example II, the dichloromethanediphosphonic
acid is replaced by dichloromethanediphosphonic acid, sodium salt
form, and equivalent results are secured.
In the capsules of Example II, the fenoprofen is replaced by an
equivalent amount of ketoprofen or MK-830, and equivalent results
are secured.
In the composition of Example II, the dichloromethanediphosphonic
acid is replaced by an equivalent amount of (H.sub.2 O.sub.3
PCH.sub.2).sub.2 N--CH.sub.2 --CH.sub.2 --N(CH.sub.2 PO.sub.3
H.sub.2).sub.2 and excellent results are secured.
EXAMPLE III
A topical composition is prepared by blending the following
ingredients:
______________________________________ Ingredient % by weight
______________________________________ Decyl methyl sulfoxide 0.5
Ethane-1-hydroxy-1,1- 5.0 diphosphonic acid, disodium salt
Fenoprofen 10.0 Water Balance
______________________________________
The composition of Example III is applied topically to the joints
of animals and humans to reduce pathological calcification
associated with arthritis like conditions caused by stress at the
joints.
In the composition of Example III, the diphosphonate material is
replaced by an equivalent amount of dichloromethanediphosphonic
acid, disodium salt, and equivalent results are secured.
In the topical composition of Example III, the fenoprofen is
replaced by an equivalent amount of ketoprofen or MK-830, and
equivalent results are secured.
EXAMPLE IV
A suppository suitable for human or animal use is prepared from the
following ingredients:
______________________________________ Ingredient % by weight
______________________________________ Fenoprofen 10.0
Dichloromethanediphosphonic 10.0 acid, disodium salt Cocoa butter
Balance ______________________________________
The composition of Example IV is prepared by melting the cocoa
butter at a temperature of ca. 39.degree. C. and adding the
diphosphonate and fenoprofen materials to the melt, with blending,
to provide a homogeneous system. The cocoa
butter/phosphonate/fenoprofen melt is poured into molds of
appropriate dimensions and allowed to solidify. The resulting
product is a lubricious suppository, or the like, which melts at
body temperature to release the phosphonate and fenoprofen drug
agents to provide improved antiinflammatory benefits.
An injectable composition is prepared by replacing the cocoa butter
of Example IV with sterile, pyrogen-free water.
* * * * *