U.S. patent application number 09/740338 was filed with the patent office on 2001-06-14 for combination of an agent that binds to the androgen receptor and a bisphosphonic acid in the prevention and/or treatment of diseases involving calcium or phosphate metabolism.
Invention is credited to Harada, Shun-Ichi, Rodan, Gideon, Schmidt, Azriel.
Application Number | 20010003745 09/740338 |
Document ID | / |
Family ID | 27487927 |
Filed Date | 2001-06-14 |
United States Patent
Application |
20010003745 |
Kind Code |
A1 |
Schmidt, Azriel ; et
al. |
June 14, 2001 |
Combination of an agent that binds to the androgen receptor and a
bisphosphonic acid in the prevention and/or treatment of diseases
involving calcium or phosphate metabolism
Abstract
The inhibition of natural bone formation experienced in the
prophylaxis and/or treatment of bone resorption disease with a
bisphosphonic acid or a pharmaceutically acceptable salt thereof is
overcome by the concommitant administration of an agent that binds
to the androgen receptor.
Inventors: |
Schmidt, Azriel; (Bryn mawr,
PA) ; Harada, Shun-Ichi; (North Wales, PA) ;
Rodan, Gideon; (Bryn Mawr, PA) |
Correspondence
Address: |
MERCK AND CO INC
P O BOX 2000
RAHWAY
NJ
070650907
|
Family ID: |
27487927 |
Appl. No.: |
09/740338 |
Filed: |
December 19, 2000 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
09740338 |
Dec 19, 2000 |
|
|
|
09038309 |
Mar 11, 1998 |
|
|
|
09038309 |
Mar 11, 1998 |
|
|
|
08972932 |
Nov 18, 1997 |
|
|
|
60031734 |
Nov 25, 1996 |
|
|
|
60032341 |
Dec 4, 1996 |
|
|
|
Current U.S.
Class: |
514/102 ;
514/171 |
Current CPC
Class: |
A61K 2300/00 20130101;
A61K 31/66 20130101; A61K 31/66 20130101 |
Class at
Publication: |
514/102 ;
514/171 |
International
Class: |
A61K 031/66; A61K
031/56 |
Claims
What is claimed is:
1. A method for the prevention and/or treatment of a disease
involving bone resorption which comprises the administration to a
patient in need thereof of an effective amount of a bisphosphonic
acid or a pharmaceutically acceptable salt thereof and an effective
amount of an agent that binds to the androgen receptor.
2. The method of claim 1 wherein the bone resorption disease being
treated is osteoporosis, Paget's disease, malignant hypercalcemia,
periodontal disease, joint prosthesis loosening or metastatic bone
disease.
3. The method of claim 2 wherein the bone resorption disease being
prevented and/or treated is osteoporosis.
4. The method of claim 1 wherein the bisphosphonic acid salt is
alendronate.
5. The method of claim 4 wherein the agent that binds to the
androgen receptor is testosterone.
6. The method of claim 2 wherein the bisphosphonic acid salt is
alendronate.
7. The method of claim 6 wherein the agent that binds to the
androgen receptor is testosterone.
8. The method of claim 3 wherein the bisphosphonic acid salt is
alendronate.
9. The method of claim 8 wherein the agent that binds to
theandrogen receptor is testosterone.
10. A pharmaceutical formulation comprising an effective amount of
a bisphosphonic acid or pharmaceutically acceptable salt thereof,
an effective amount of an agent that binds to the androgen receptor
and a pharmaceutically acceptable carrier.
11. The formulation of claim 7 wherein the bisphosphonic acid salt
is alendronate.
12. The formulation of claim 11 wherein the agent that binds to the
androgen receptor is testosterone.
13. A method of overcoming the inhibition of natural bone formation
during prophylaxis and/or treatment of bone resorption disease with
a bisphosphonic acid or pharmaceutically acceptable salt thereof
which comprises the concommitant administration of an agent that
binds to the androgen receptor.
14. The method of claim 13 wherein the bisphosphonic acid salt is
alendronate.
15. The method of claim 14 wherein the agent that binds to the
androgen receptor is testosterone.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation-in-part of Ser. No. 08/972,932, filed
Nov. 18, 1997, which in turn is a non-provisional application based
on provisional applications 60/031,734, filed Nov. 26, 1996, and
60/032,341, filed Dec. 4, 1996.
SUMMARY OF THE INVENTION
[0002] This invention is concerned with a novel method for the
prevention and/or treatment of diseases involving calcium or
phosphate metabolism. In particular it is concerned with the
prevention and/or treatment of diseases involving bone resorption,
especially osteoporosis, Paget's disease, malignant hypercalcemia,
periodontal disease, joint loosening and metastatic bone disease,
by the administration of an agent that binds to the androgen
receptor to produce a beneficial effect on bone and a bisphosphonic
acid or a pharmaceutically acceptable salt thereof either combined
in a single pharmaceutical formulation or as separate entities
administered more or less concurrently.
[0003] This invention is also concerned with a pharmaceutical
formulation in which an agent that binds to the androgen receptor
and a bisphosphonic acid or pharmaceutically acceptable salt
thereof are combined.
[0004] In the remainder of this specification the term
"bisphosphonic acid" is meant to refer to the acid or the
pharmaceutically acceptable salt thereof. Similarly, the
expression, "agent that binds to the androgen receptor" refers to
such agents that produce a beneficial effect on bone and includes
androgen antagonists, agonists and partial agonist/antagonist
agents.
BACKGROUND OF THE INVENTION
[0005] Several bisphosphonic acids are known in the art and known
to be effective in the treatment of diseases involving bone
resorption. Unfortunately they also inhibit overall bone formation.
Attempts have been made to stimulate bone formation that has been
inhibited by a bisphosphonic acid such as with injections of growth
hormone, IGF-1, parathyroid hormone or transforming growth factor
(TGF.sub.b) which is described in U.S. Pat. No. 5,118,667. None of
these attempts has been successful or widely used in patients and
have been only partially successful in animals. Most importantly
use of these agents involves daily injections with compounds that
have multiple effects. Combination of a bisphosphonic acid and a
growth hormone secretogogue also has been reported in
WO95/11029.
[0006] Combinations of estrogen, which is also known to prevent
bone resorption, and androgens to stimulate bone formation, have
been tried (Davis et al, 1996 Maturittas 21:227-236; Raisz et al.,
1996 J. Clin. Endocrinol. Metab. 81: 37-43; and Watts et al., 1995
Obstet-Gynecol. 85: 529-537). However, it is not obvious from the
results of these studies that androgens would stimulate the
formation of bone in the presence of a strong non-hormonal
inhibitor of bone formation. As a matter of fact, it has been
reported that the bisphosphonic acid, tiludronate, inhibits the
anabolic effect of parathyroid hormone (Delmas, Bone, 16(6),
603-610 (1995)).
[0007] Now, with the present invention there is provided a novel
method for the prevention and/or treatment of disease involving
bone resorption comprising the administration of a bisphosphonic
acid and an agent that binds to the androgen receptor whereby bone
resorption is prevented without compromising normal bone formation
induced by the androgen.
DETAILED DESCRIPTION OF THE INVENTION
[0008] The novel method of prevention and/or treatment of diseases
involving bone resorption of this invention comprises the
administration to a patient in need thereof of an effective amount
of a bisphosphonic acid and an effective amount of an agent that
binds to the androgen receptor.
[0009] The disease states involving bone resorption that can be
prevented and/or treated by the novel combination of this invention
are osteoporosis, Paget's disease, malignant hypercalcemia,
periodontal disease, joint prostheses loosening and metastatic bone
disease, especially osteoporosis.
[0010] Examples of the bisphosphonic acids that may be used as an
active ingredient in the novel method and formulation of this
invention include:
[0011] 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;
[0012] N-methyl-4-amino-1-hydroxybutylidene-1 , 1-bisphosphonic
acid;
[0013] 4-(N,N-dimethylamino)-1-hydroxybutylidene-1,1-bisphosphonic
acid;
[0014] 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid;
[0015] 3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic
acid;
[0016]
1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic
acid;
[0017] (dichloromethyene)-bisphosphonic acid;
[0018] [1-hydroxy-3-(1-pyrrolidinyl)-propylidene] bisphosphonic
acid;
[0019] (1-hydroxyyethylidene)-bisphosphonic acid;
[0020] [(cycloheptylamino) methylene] bisphosphonic acid;
[0021] (6-amino-1-hydroxyhexylidene) bisphosphonic acid;
[0022] [[(4-chloropheny) thio] methylene] bisphosphonic acid;
[0023] [1-hydroxy-2-imidazo-(1,2a) pyridin-3-ylethylidene]
bisphosphonic acid;
[0024] [1-hydroxy-2-(1H-imidazole-1-yl) ethyledene] bisphosphonic
acid;
[0025] 1-hydroxy-2-[3-pyridyl]ethylidene-1,1-bisphosphonic acid;
and
[0026] 4-(hydroxymethylene-1,1-bisphosphonic acid)piperidine; or
their pharmaceutically acceptable salts.
[0027] Methods for the preparation of bisphosphonic acids may be
found in, e.g., U.S. Pat. No. 3,962,432: U.S. Pat. No. 4,054,598:
U.S. Pat. No. 4,267,108: U.S. Pat. No. 4,327,039: U.S. Pat. No.
4,407,761: U.S. Pat. No. 4,621,077: U.S. Pat. No. 4,624,947: U.S.
Pat. No. 4,746,654: U.S. Pat. No. 4,922,077: and EPO Pat. Pub. No.
0,252,504. In particular, methods for the preparation of
4-amino-1-hydroxybutylidene-1,1-bisphospho- nic acid and
4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salt
trihydrate may be found in U.S. Pat. No. 4,407,761 and U.S. Pat.
No. 4,922,077, respectively.
[0028] The pharmaceutically acceptable salts of bisphosphonic acids
may also be employed in the instant invention. Examples of basic
salts of bisphosphonic acids include ammonium salts, alkali metal
salts such as potassium and sodium (including mono-, di- and
tri-sodium) salts (which are preferred), alkaline earth metal salts
such as calcium and magnesium salts, salts with organic bases such
as dicyclohexylamine salts, N-methyl-D- glucamine, and salts with
amino acids such as arginine, lysine, and so forth. The non-toxic,
physiologically acceptable salts are preferred. The salts may be
prepared by methods known in the art, such as in U.S. Pat. No.
4,922,077.
[0029] In the present invention it is preferred that the
bisphosphonic acid is 4-amino-1-hydroxybutylidene-1,1-bisphosphonic
acid. It is even more preferred that the bisphosphonic acid is a
sodium salt of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid,
in particular, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid
monosodium salt trihydrate.
[0030] Examples of agents that bind to the androgen receptor that
may be used as an active ingredient in the novel method and
formulation of this invention include but not limited to danazol,
5a-dihydrotestosterone, testosterone, nandrolane decanoate,
methyltestosterone, methanadrostenolone, stanozolol,
fluoxymesterone, oxymetholone, oxandrolone, oxymethol,
norethandrolone, ethylestranol, 4-androsten-19-al-3,17-dione,
19-nortestosterone, norethandrone, norethisterone,
dehydroepiandrosterone, epiandrosterone sulfate, androstenedione
and androstenediol, testosterone propionate, testosterone
cytpionate, and testosterone enanthate, preferably
testosterone.
[0031] The bisphosphonic acid and the agent that binds to the
androgen receptor can be administered combined in a single dosage
form, which forms another aspect of the present invention, or as
separate entities administered more or less concurrently. In either
method of administration, the active ingredients are provided in
doses that are the same as would be administered if given as sole
medicament. In the case of the bisphosphonic acid, oral doses of
2.5 to 100 mg/day are approprate. Prophylactically, doses of about
2.5 to about 10 mg/day, and especially about 5 mg/day should be
employed. For the treatment of bone disease involving bone
resorption daily doses of about 5 to 20 mg/day may be used,
especially about 10 mg/day. In the case of the agent that binds to
the androgen receptor, doses of about 0.1-100 mg/day are
recommended and preferably about 0.1-10 mg/day, depending on the
potency of the agent.
[0032] In the combination of the present invention the
bisphosphonic acid and the agent binds to the adrogen receptor may
be administered separately or in combination. In addition, the
administration of one element may be prior to, concurrently with,
or subsequent to the administration of the other agent.
[0033] The active ingredients of the combination of the present
invention may be administered by oral, parenteral (e.g.,
intramuscular, intraperitoneal, intravenous or subcutaneous
injection, or implant), nasal, vaginal, rectal, sublingual, or
topical routes of administration and may be formulated, alone or
together, in suitable dosage unit formulations containing
conventional non-toxic pharmaceutically acceptable carriers,
adjuvants and vehicles appropriate for each route of
administration.
[0034] The pharmaceutical compositions for the administration of
the compounds of this invention may conveniently be presented in
dosage unit form and may be prepared by any of the methods well
known in the art of pharmacy. All methods include the step of
bringing the active ingredient into association with the carrier
which constitutes one or more accessory ingredients. In general,
the pharmaceutical compositions are prepared by uniformly and
intimately bringing the active ingredient into association with a
liquid carrier or a finely divided solid carrier or both, and then,
if necessary, shaping the product into the desired formulation. In
the pharmaceutical composition the active ingredient(s) is included
in an amount sufficient to produce the desired effect upon the
process or condition of the disease.
[0035] The pharmaceutical compositions containing the active
ingredient(s) suitable for oral administration may be in the form
of discrete units such as hard or soft capsules, tablets, troches
or lozenges, each containing a predetermined amount of the active
ingredient(s); in the form of a dispersible powder or granules; in
the form of a solution or a suspension in an aqueous liquid or
non-aqueous liquid; in the form of syrups or elixirs; or in the
form of an oil-in-water emulsion or a water-in-oil emulsion.
Compositions intended for oral use may be prepared according to any
method known to the art for the manufacture of pharmaceutical
compositions and such compositions may contain one or more agents
selected from the group consisting of sweetening agents, flavoring
agents, coloring agents and preserving agents in order to provide
pharmaceutically elegant and palatable preparation.
[0036] Solid dosage forms for oral administration include capsules,
tablets, pills, powders and granules. In such solid dosage forms,
the active compounds are admixed with at least one inert
pharmaceutically acceptable carrier such as sucrose, lactose, or
starch. Such dosage forms can also comprise, as is normal practice,
additional substances other than inert diluents, e.g., lubricating
agents such as magnesium stearate. In the case of capsules, tablets
and pills, the dosage forms may also comprise buffering agents.
[0037] Tablets containing the active ingredient in admixture with
non-toxic pharmaceutically acceptable excipients may also be
manufactured by known methods. The excipients used may be for
example, (1) inert diluents such as calcium carbonate, lactose,
calcium phosphate or sodium phosphate; (2) granulating and
disintegrating agents such as corn starch, or alginic acid; (3)
binding agents such as starch, gelatin or- acacia; and (4)
lubricating agents such as magnesium stearate, stearic acid or
talc. The tablets may be uncoated or they may be coated by known
techniques to delay disintegration and absorption in the
gastroinestinal tract and thereby provide a sustained action over a
longer period. For example, a time delay material such as glyceryl
monostearate or glyceryl disearate may be employed. They may also
be coated by the techniques described in the U.S. Pat. Nos.
4,256,108; 4,160,452; and 4,265,874 to form osmotic therapeutic
tablets for controlled release.
[0038] In some cases, formulations for oral use may be in the form
of hard gelatin capsules wherein the active ingredient is mixed
with an inert solid diluent, for example calcium carbonate, calcium
phosphate or kaolin. They may also be in the form of soft gelatin
capsules wherein the active ingredient is mixed with water or an
oil medium, for example peanut oil, liquid paraffin, or olive
oil.
[0039] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs containing inert diluents commonly used in the
art, such as water. Besides such inert diluents, compositions can
also include adjuvants, such as wetting agents, emulsifying and
suspending agents, and sweetening, flavoring, and perfuming
agents.
[0040] Aqueous suspensions normally contain the active materials in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients may be
[0041] 1) - suspending agents such as sodium
carboxymethyl-cellulose, methylcellulose,
hydroxypropylmethyl-cellulose, sodium alginate,
polyvinyl-pyrrolidone, gum tragacanth and gum acacia;
[0042] 2) dispersing or wetting agents which may be
[0043] (a) a naturally-occuring phosphatide such as lecithin,
[0044] (b) a condensation product of an alkylene oxide with a fatty
acid, for example, polyoxyethylene sterate,
[0045] (c) a condensation product of ethylene oxide with a long
chain aliphatic alcohol, for example,
heptadecaethyleneoxycetanol,
[0046] (d) a condensation product of ethylene oxide with a partial
ester derived from a fatty acid and a hexitol such as
polyoxyethylene sorbitol monooleate, or
[0047] (e) a condensation product of ethylene oxide
[0048] with a partial ester derived from a fatty acid and a hexitol
anhydride, for example polyoxyethylene sorbitan monooleate.
[0049] The aqueous suspensions may also contain one or more
preservatives, for example, ethyl or n-propyl p-hydroxybenzoate;
one or more coloring agents; one or more flavoring agents; and one
or more sweetening agents such as sucrose or saccharin.
[0050] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
and flavoring agents may be added to provide a palatable oral
preparation. These compositions may be prepared by the addition of
an antioxidant such as ascorbic acid.
[0051] Dispersible powders and granules are suitable for the
preparation of an aqueous suspension. They provide the active
ingredient in admixture with a dispersing or wetting agent, a
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example, those
sweetening, flavoring and coloring agents described above may also
be present.
[0052] The pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions. The oily phase may be a
vegatable oil such as olive oil or arachis oil, or a mineral oil
such as liquid paraffin or a mixture thereof. Suitable emulsifying
agents may be (1) naturally-occuring gums such as gum acacia and
gum tragacanth, (2) naturally-occuring phosphatides such as soy
bean and lecithin, (3) esters or partial esters derived from fatty
acids and hexitol anhydrides, for example, sorbitan monooleate, (4)
condensation products of said partial esters with ethylene oxide,
for example polyoxyethylene sorbitan monooleate. The emulsions may
also contain sweetening and flavoring agents.
[0053] Syrups and elixirs may be formulated with sweetening agents,
for example, glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative and
flavoring and coloring agents.
[0054] The pharmaceutical compositions may be in the form of a
sterile injectable aqueous or oleagenous suspension or solution.
The suspension may be formulated according to known methods using
those suitable dispersing or wetting agents and suspending agents
which have been mentioned above. The sterile injectable preparation
may also be a sterile injectable solution or suspension in a
non-toxic parenterally-acceptable diluent or solvent, for example
as a solution in 1,3-butane diol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution and
isotonic sodium chloride solution. In addition, sterile, fixed oils
are conventionally employed as a solvent or suspending medium. For
this purpose any bland fixed oil may be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid find use in the preparation of injectables.
[0055] Preparations according to this invention for parenteral
administration include sterile aqueous or non-aqueous solutions,
suspension, or emulsions. Examples of non-aqueous solvents or
vehicles are propylene glycol, polyethylene glycol, vegetable oils,
such as olive oil and corn oil, gelatin, and injectable organic
esters such as ethyl oleate. Such dosage forms may also contain
adjuvants such as preserving, wetting, emulsifying, and dispersing
agents. They may be sterilized by, for example, filtration through
a bacteria-retaining filter, by incorporating sterilizing agents
into the compositions, by irradiating the compositions, or by
heating the compositions. They can also be manufactured in the form
of sterile solid compositions which can be dissolved in sterile
water, or some other sterile injectable medium immediately before
use.
[0056] The active ingredient(s) of this invention may also be
administered in the form of suppositories for rectal
administration. This composition can be prepared by mixing the drug
with a suitable non-irritating excipient which is solid at ordinary
temperatures but liquid at body temperature and will therefore melt
in the rectum to release the drug. Such materials are cocoa butter
and polyethylene gylcols.
[0057] Compositions for nasal or sublingual administration are also
prepared with standard excipients well known in the art.
[0058] For topical administration the active ingredient(s) of this
invention may be formulated in liquid or semi-liquid preparations
such as liniments or lotions; oil-in-water or water-in-oil
emulsions such as creams, ointments, jellies or pastes, including
tooth-pastes; or solutions or suspensions such as drops, and the
like.
[0059] The pharmaceutical composition and method of the present
invention may further comprise other therapeutically active
compounds usually applied in the treatment of the above mentioned
pathological conditions, for instance vitamin D.sub.2 and D.sub.3
and hydroxylated derivatives, e.g. 1a-hydroxy-vitamin D.sub.3,
1a-hydroxy-vitamin D.sub.2, 1a-25-dihydroxy-vitamin D.sub.3,
1a-25-dihydroxy-vitamin D.sub.2, calcitonin (human, porcine or
salmon), mitramycin, sodium fluoride, and non-steroid
antiinflammatory drugs, such as acetylsalicyclic acid,
indomethacin, naprosyn, and timegadine.
[0060] The amount of active ingredient(s) in the formulations of
this invention may be varied. However, it is convenient for the
unit dose, such as a tablet, to contain the amount of active
ingredient(s) that would be administered in the prophylaxis or
therapy of a particular bone resorption disease. Accordingly,
formulations comprising 2.5 mg, 5.0 mg and 10 mg of the
bisphosphonic acid and 0.125-2.5 mg, 0.25-5.0 mg and 0.5-10 mg
respectively, of the androgen would be appropriate.
EXAMPLE
[0061]
1 Formulation Comprising Alendronate and Androgen Ingredients Per
Tablet Per 4.000 Tablets Alendronate (monosodium 6.55 mg 26.2 g
salt trihydrate) Agent that binds to the Androgen Receptor 0.25-5
mg 1-20 g Anhydrous Lactose, NF 110.45 mg 441.8 g Microcrystalline
80.0 mg 320.0 g Cellulose, NF Magnesium Stearate 1.00 mg 4.0 g
Impalpable Powder, NF Croscarmellose Sodium 2.00 mg 8.0 g NF, Type
A
[0062] The active ingredients (equivalent to 5.0 mg of
bisphosphonate anhydrous free acid per tablet) are premixed with
1/3of the microcrystalline cellulose and 1/2of the anhydrous
lactose in a ribbon blender for 5 minutes at 20 rpm. To the premix
is added the remaining 2/3of the microcrystalline cellulose and the
remaining 1/2of the anhydrous lactose and blended for 10 minutes at
20 rpm. The croscarmellose sodium is added to the blended powders
and mixed for 5 minutes at 20 rpm. Finally the magnesium stearate
is added to the mixture by passing it through a 90 mesh screen and
blended for an additional 5 minutes at 20 rpm. The lubricated
mixture is compressed to provide tablets with the equivalent of 5
mg of alendronate anhydrous free acid and 0.25-5 mg of agent that
binds to the androgen receptor.
* * * * *