U.S. patent number RE39,050 [Application Number 10/375,274] was granted by the patent office on 2006-03-28 for methods of use for inhibiting bone loss and lowering serum cholesterol.
This patent grant is currently assigned to Eli Lilly and Company, Eli Lilly and Company. Invention is credited to Larry J. Black, Michael W. Draper.
United States Patent |
RE39,050 |
Draper , et al. |
March 28, 2006 |
Methods of use for inhibiting bone loss and lowering serum
cholesterol
Abstract
A method of inhibiting bone loss or resorption, or lowering
serum cholesterol, comprising administering to a human in need
thereof a compound having the formula ##STR00001## or a
pharmaceutically acceptable salt or solvate thereof, in a low
dosage amount. Also encompassed by the invention is a a
pharmaceutical formulation in unit dosage form comprising, per unit
dosage, a low dosage amount.
Inventors: |
Draper; Michael W. (Carmel,
IN), Black; Larry J. (Franklin, IN) |
Assignee: |
Eli Lilly and Company
(Indianapolis, IN)
|
Family
ID: |
22760425 |
Appl.
No.: |
10/375,274 |
Filed: |
February 27, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
Reissue of: |
08205012 |
Mar 2, 1994 |
05478847 |
Dec 26, 1995 |
|
|
Current U.S.
Class: |
514/443 |
Current CPC
Class: |
A61P
19/08 (20180101); A61K 31/4535 (20130101); A61P
3/06 (20180101); A61K 31/445 (20130101); A61P
43/00 (20180101); A61P 19/10 (20180101) |
Current International
Class: |
A01N
43/12 (20060101) |
Field of
Search: |
;514/333,422,578,443,448 |
References Cited
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4422193 |
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Feb 1994 |
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BR |
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2101356 |
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Jan 1994 |
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CA |
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0062505 |
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Oct 1982 |
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EP |
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0068563 |
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Jan 1983 |
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EP |
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0584952 |
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EP |
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EP |
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Oct 1995 |
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EP |
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2097788 |
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Nov 1982 |
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GB |
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9302163 |
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Jul 1994 |
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HU |
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0106450 |
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IL |
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NO |
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WO |
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Jun 1993 |
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WO |
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9305283 |
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Jan 1994 |
|
ZA |
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|
Primary Examiner: Webman; Edward J.
Attorney, Agent or Firm: Woodard, Emhardt, Moriarity, McNett
& Henry LLP
Claims
I claim:
1. A method of inhibiting .Iadd.post-menopausal .Iaddend.bone loss
.[.or bone resorption.]. .Iadd.in a post-menopausal woman in need
of treatment to prevent or to treat post-menopausal osteoporosis
.Iaddend.comprising administering to .[.a human.]. .Iadd.said woman
.Iaddend.in need .[.thereof.]. .Iadd.of said treatment .Iaddend.a
compound of formula I ##STR00003## or a pharmaceutically acceptable
salt or solvate thereof, in an amount of .[.about 50 to about 150
.]. .Iadd.55 to 65 .Iaddend.mg/day.
2. A method of claim 1 wherein .[.the human.]. .Iadd.said woman
.Iaddend.has been diagnosed as suffering from
.Iadd.post-menopausal.Iaddend.osteoporosis.
.[.3. A method of claim 1 wherein the human is a post-menopausal
female..].
.[.4. A method of claim 1 wherein the human is a male..].
5. A method of claim 1 wherein the compound is administered
prophylactically.
.[.6. A method of claim 1 wherein the compound of formula I is
administered in an amount of about 60 to about 150 mg/day..].
7. A method of claim 1 wherein the compound of formula I is
administered in an amount of 60 mg/day.
8. A method of claim 1 wherein the compound of formula I is
administered in an amount of .[.75.]. .Iadd.55 .Iaddend.mg/day.
9. A method of claim 1 wherein the compound of formula I is
administered in an amount of .[.100.]. .Iadd.65
.Iaddend.mg/day.
.[.10. A method of claim 1 wherein the compound of formula I is
administered in an amount of 125 mg/day..].
.[.11. A method of claim 1 wherein the compound of formula I is
administered in an amount of 150 mg/day..].
12. A method of claim 1 .[.wherein the compound is the.].
.Iadd.which comprises administering a .Iaddend.hydrochloride salt
.Iadd.of a compound of formula I.Iaddend..
.Iadd.13. A method of claim 12 wherein the hydrochloride salt is
administered in an amount of 60 mg/day..Iaddend.
.Iadd.14. A method of preventing post-menopausal osteoporosis in a
post-menopausal woman in need of treatment to prevent
post-menopausal osteoporosis comprising administering to said woman
a hydrochloride salt of a compound of Formula I ##STR00004## in an
amount of 60 mg/day..Iaddend.
.Iadd.15. A method of treating post-menopausal osteoporosis in a
post-menopausal woman in need of treatment for post-menopausal
osteoporosis comprising administering to said woman a hydrochloride
salt of a compound of Formula I ##STR00005## in an amount of 60
mg/day..Iaddend.
Description
FIELD OF THE INVENTION
This invention relates to methods for inhibiting bone loss and
lowering serum cholesterol using low dosage amounts of particular
2-phenyl-3-aroylbenzothiophenes.
BACKGROUND OF THE INVENTION
I. Bone Loss
The current major disease or conditions of bone which are of public
concern include post-menopausal osteoporosis, ovariectomy patients,
senile osteoporosis, patients undergoing long-term treatment of
corticosteroids, side effects from glucocorticoid or steroid
treatment, patients suffering from Cushing's syndrome, gonadal
dysgensis, periarticular erosions in rheumatoid arthritis,
osteoarthritis, Paget's disease, osteohalisteresis, osteomalacia,
hypercalcemia of malignancy, osteopenia due to bone metastases,
periodontal disease, and hyperparathyroidism. All of these
conditions are characterized by bone loss, resulting from an
imbalance between the degradation of bone (bone resorption) and the
formation of new healthy bone. This turnover of bone continues
normally throughout life and is the mechanism by which bone
regenerates. However, the conditions stated above will tip the
balance towards bone loss such that the amount of bone resorbed is
inadequately replaced with new bone, resulting in net bone
loss.
One of the most common bone disorders is post-menopausal
osteoporosis which affects an estimated 20 to 25 million women in
the United States alone. Women after menopause experience an
increase in the rate of bone turnover with resulting net loss of
bone, as circulating estrogen levels decrease. The rate of bone
turnover differs between bones and is highest in sites enriched
with trabecular bone, such as the vertebrae and the femoral head.
The potential for bone loss at these sites immediately following
menopause is 4-5% per year. The resulting decrease in bone mass and
enlargement of bone spaces leads to increased fracture risk, as the
mechanical integrity of bone deteriorates rapidly.
At present, there are 20 million people with detectable vertebral
fractures due to osteoporosis and 250,000 hip fractures per year
attributable to osteoporosis in the U.S. The latter case is
associated with a 12% mortality rate within the first two years and
30% of the patients will require nursing home care after the
fracture. Therefore, bone disorders are characterized by a
noticeable mortality rate, a considerable decrease in the
survivor's quality of life, and a significant financial burden to
families.
Essentially all of the conditions listed above would benefit from
treatment with agents which inhibit bone resorption. Bone
resorption proceeds by the activity of specialized cells called
osteoclasts. Osteoclasts are unique in their ability to resorb both
the hydroxyapatite mineral and organic matrix of bone. They are
identical with the cartilage resorbing cells, previously termed
chondroclasts. It is for this reason that potent inhibitors of
osteoclastic bone resorption will also inhibit the cell-mediated
degradation of cartilage observed in rheumatoid arthritis and
osteoarthritis.
Therapeutic treatments to impede net bone loss include the use of
estrogens. Estrogens have been shown clearly to arrest the bone
loss observed after menopause and limit the progression of
osteoporosis; .Iadd. .Iaddend.but patient compliance has been poor
because of estrogen side-effects. These side effects include
resumption of menses, mastodynia, increase in the risk of uterine
cancer, and possibly an increase in the risk of breast cancer.
Alternatively, calcitonin has been used to treat osteoporotic
patients. Salmon calcitonin has been shown to directly inhibit the
resorption activity of mammalian osteoclasts and is widely
prescribed in Italy and Japan. However, calcitonins are
prohibitively expensive to many and appear to be short-lived in
efficacy. That is, osteoclasts are able to "escape" calcitonin
inhibition of resorption by down-regulating calcitonin receptors.
Therefore, recent clinical data suggest that chronic treatment with
calcitonin may not have long term effectiveness in arresting the
post-menopausal loss of bone.
II. Serum Cholesterol
All mammalian cells require cholesterol as a structural component
off their cell membranes and for non-sterol end products.
Cholesterol is also required for steroid hormone synthesis. The
very property, however, that makes cholesterol useful in the cell
membranes, its insolubility in water, also makes it potentially
lethal. When cholesterol accumulates in the wrong place, for
example within the wall of an artery, it cannot be readily
mobilized and its presence leads to the development of an
atherosclerotic plaque. Elevated concentrations of serum
cholesterol associated with low density lipoproteins have been
demonstrated to be a major contributing factor in the development
and progression of atherosclerosis.
In mammals, serum lipoprotein is composed of cholesterol together
with cholesteryl esters, triglycerides, phospholipids and
apoproteins. Serum or plasma lipoprotein is comprised of several
fractions. The major fractions or classes of plasma lipoproteins
are very low density lipoprotein (VLDL), low density lipoprotein
(LDL), intermediate density lipoprotein (IDL), and high density
lipoprotein (HDL). These classes differ from one another in size,
density and in the relative proportions of triglycerides and
cholesteryl esters in the core, and in the nature of the
apoproteins on the surface.
In mammals, serum cholesterol is derived from exogenous dietary
sources as well as through endogenous synthesis. Endogeneous
synthesis of cholesterol involves a complex set of enzyme-catalyzed
reactions and regulatory mechanisms generally termed the mevalonate
pathway. Cells face a complex problem in regulating mevalonate
synthesis because cholesterol, the bulk end product of mevalonate
metabolism, is derived from plasma low density lipoprotein which
enters the cell by receptor-mediated endocytosis, as well as from
synthesis within the cell. Each cell must balance these external
and internal sources so as to sustain mevalonate synthesis while
avoiding sterol over accumulation. This balance is achieved through
feedback regulation of at least two sequential enzymes in
mevalonate synthesis, 3-hydroxy-3-methylglutaryl coenzyme A
(HMG-CoA) synthase and HMG-CoA reductase and also of LDL receptors.
In the absence of LDL, mammalian cells maintain high activities of
the two enzymes, thereby synthesizing mevalonate for
.[.product:ion.]. .Iadd.production .Iaddend.of cholesterol as well
as the non-sterol products. When LDL is present, from exogenous
sources, HMG-CoA synthase and reductase activity is repressed and
the cells produce smaller amounts of mevalonate for the non-sterol
end products.
Abundant evidence indicates that treatment of hyperlipoproteinemia
will diminish or prevent atherosclerotic complications. In addition
to a diet that maintains a normal body weight and minimizes
concentrations of lipids in plasma, therapeutic Strategies include
elimination of factors that exacerbate hyperlipoproteinemia and the
administration of therapeutic agents that lower plasma
concentrations of lipoproteins, either by diminishing the
production of lipoproteins or by enhancing the efficiency of their
removal from plasma.
The most promising class of drugs currently available for the
treatment of hypercholesterolemia act by inhibiting HMG-CoA
reductase, the rate-limiting enzyme of endogenous cholesterol
synthesis. Drugs of this class competitively inhibit the activity
of the enzyme. Eventually, this lowers the endogenous synthesis of
cholesterol and, by normal homeostatic mechanisms, plasma
cholesterol is taken up by LDL receptors to restore the
intracellular cholesterol balance.
Relative to other cells in the body, liver cells play a critical
role in maintaining serum cholesterol homeostasis by both releasing
precursors of LDL and through receptor mediated LDL uptake from the
serum. In both man and animal models an inverse correlation appears
to exist between liver LDL receptors and LDL-associated serum
cholesterol levels. In general, higher hepatocyte receptor numbers
result in lower LDL-associated serum cholesterol levels.
Cholesterol released into hepatocytes can be stored as cholesterol
esters, converted into bile acids and released into the bile duct,
or enter into an oxycholesterol pool. It .[.ms.]. .Iadd.is
.Iaddend.this oxycholesterol pool that is believed to be involved
in end product repression of both the genes of the LDL receptor and
enzymes involved in the cholesterol synthetic pathway.
Transcription of the LDL receptor gene is known to be repressed
when cells have an excess supply of cholesterol, probably in the
form of oxycholesterol. A DNA sequence in the LDL receptor promoter
region, known as the sterol response element, appears to confer
this sterol end product repression. This element has been
extensively studied (Brown, Goldstein and Russell, U.S. Pat. Nos.
4,745,060 and 4,935,363) and appears to consist of a 16 base pair
sequence that occurs 5' of the LDL receptor coding region. The
sterol response element can be inserted into genes that normally do
not respond to cholesterol, conferring sterol end product
repression on the chimeric gene. The exact mechanism of this
repression is not understood. There is, however, abundant evidence
that polar intermediates in cholesterol biosynthesis and naturally
occurring as well as synthetic hydroxysterols repress genes
containing the sterol response element.
It has been suggested that a hydroxycholesterol binding protein
serves as a receptor. When the receptor is bound to an oxysterol it
acts on the sterol response element to control transcription
through a mechanism that is similar to the action of members of the
steroid hormone receptor super gene family.
In populations where coronary heart disease is a major health
problem, the incidence of the disease is markedly lower in women
than in men. This is particularly true in younger age groups, such
as men and women between 35 and 44 years of age.
Generally, plasma lipoprotein metabolism is influenced by the
circulating concentrations of gonadal steroids. Changes in serum
estrogen and androgen concentrations, resulting from alterations in
gonadal status or from the administration of exogenous gonadal
steroids are associated with changes in serum lipoprotein levels.
The changes effected by estrogens and androgens generally support
the proposition that sex differences in lipoproteins are due to
hormonal differences between men and women.
The generally accepted relationship between gonadal steroids and
plasma lipoproteins is that androgens lower HDL concentrations and
increase LDL, thus contributing to the low HDL and high LDL levels
observed in men when compared to women. Estrogens are held to have
opposite effects on lipoproteins: that is HDL is raised and LDL is
lowered. These sex steroid-induced differences in lipoprotein
concentrations are thought to contribute to the lower incidence of
cardiovascular disease in women compared to men. After the
menopause, the protective effect of estrogens in women is lost and
the incidence of cardiovascular disease increases towards the male
levels. Postmenopausal women who take estrogens generally have
lower rates of cardiovascular disease than women of a similar age
who do not. Estrogen, particularly when taken orally, lowers plasma
levels of LDL and raises those of HDL.
The mechanisms by which estrogen lowers levels of LDL and raises
those of HDL are not known. In general, changes in the plasma
concentration of a lipoprotein result from changes in the rate of
its synthesis or the rate of its catabolism. For example, estrogen
may lower LDL levels by increasing the clearance of LDL from
plasma, since estrogen increases the number of hepatic LDL
receptors in animals.
Although estrogens have beneficial effects on serum LDL, given even
at very low levels, long-term estrogen therapy has been implicated
in a variety of disorders, including an increase in the risk of
uterine cancer and possibly breast cancer, causing many women to
avoid this treatment. Recently suggested therapeutic regimens,
which seek to lessen the cancer risk, such as administering
combinations of progestogen and estrogen, cause the patient to
experience regular bleeding, which is unacceptable to most older
women. Furthermore, combining progesterone with estrogen seems to
blunt the serum cholesterol lowering effects of estrogen. Concerns
over the significant undesirable effects associated with estrogen
therapy, support the need to develop alternative therapies for
hypercholesterolemia that generates the desirable effects on serum
LDL but does not cause undesirable effects.
Attempts to fill this need by the use of compounds commonly known
as antiestrogens, which interact with the estrogen receptor and/or
bind what has been termed the antiestrogen binding site (AEBS),
have had limited success, perhaps due to the fact that these
compounds generally display a mixed agonist/antagonist effect. That
is, although these compounds can antagonize estrogen interaction
with the receptor, the compounds themselves may cause estrogenic
responses in those tissues having estrogen receptors such as the
uterus. Therefore some antiestrogens, such as tamoxifen, are
subject to some of the same adverse effects associated with
estrogen therapy.
SUMMARY OF THE INVENTION
The invention provides a method of inhibiting bone resorption and
bone loss comprising administering to a human in need thereof a
compound of the formula ##STR00002## and pharmaceutically
acceptable salts and solvates thereof, in an amount of about 50 to
about 150 mg/day.
The invention also encompasses a method for lowering serum
cholesterol comprising administering a compound of formula I in an
amount of about 50 to about 150 mg/day.
The invention also .[.encompases.]. .Iadd.encompasses
.Iaddend.pharmaceutical formulations in dosage unit form,
comprising, per dosage with an amount of about 50 to about 150 mg
of a compound of formula I.
DESCRIPTION OF THE INVENTION
The current invention concerns the discovery that compounds of
formula I are useful for lowering serum cholesterol levels and
inhibiting bone resorption and bone loss at dosages of about 50
.Iadd. .Iaddend.to about 150 mg/day. The methods provided by this
invention are practiced by administering to a human in need thereof
a dose of a compound of formula I or a pharmaceutically acceptable
salt or solvate thereof in the amount of about 50 to about 150
mg/day, to lower serum cholesterol level, or inhibit bone loss or
resorption.
The term "inhibit" is defined to include its generally accepted
meaning which includes preventing, prohibiting, restraining, and
slowing, stopping or reversing progression, or severity, and
holding in check and/or treating existing characteristics. The
present method includes both medical therapeutic and/or
prophylactic treatment, as appropriate.
Generally, the compound is formulated with common excipients,
diluents or carriers, and compressed into tablets, or formulated as
elixirs or solutions for convenient oral administration, or
administered by the intramuscular or intravenous routes. The
compounds can be administered transdermally, and are well suited to
formulation as sustained release dosage forms and the like.
The method of the present invention is useful in men as well as
women. The substantial absence of estrogenic response should allow
men to employ the method of the present invention without
evidencing the feminizing response of estrogen or estrogen agonists
such as gynecomastia. Preferably, however, the methods of the
present invention are useful in women, more preferably estrogen
deficient women.
The 2-phenyl-3-aroylbenzothiophene compounds that are the active
component in the methods of this invention were first developed by
C. David Jones and Tulio Suarez as anti-fertility agents (U.S. Pat.
No. 4,133,814, issued Jan. 9, 1979). Certain compounds in the group
were found to be useful in suppressing the growth of mammary
tumors.
Jones later found a group of related compounds to be useful for
antiestrogen and antiandrogen therapy, especially in the treatment
of mammary and prostatic tumors (U.S. Pat. No. 4,418,068, issued
Nov. 29, 1983). One of these compounds, the hydrochloride salt form
of the compound of formula I, was clinically tested for a brief
time for the treatment of breast cancer. That compound is called
raloxifene, formerly keoxifene.
Raloxifene is currently undergoing human clinical trials for use in
.[.osteoporsis.]. .Iadd.osteoporosis .Iaddend.and lipid lowering.
Draper et al. ("Effects of Raloxifene on Biochemical Markers of
Bone and Lipid Metabolism in Healthy Post-Menopausal Women," Fourth
International Symposium on Osteoporosis, Hong Kong, Mar. 29, 1993)
discussed certain positive findings of raloxifene's usefulness in
inhibiting bone resorption and lowering serum cholesterol. The
dosages tested were 200 mg/day and 600 mg/day. .[.As evidenced by
EPO Publication EP-A-584952, published Mar. 2, 1994, (corresponding
to.]. U.S. application Ser. No. 07/920,933 filed Jul. 28, 1992
(docket X-7947).[.).]. , .Iadd.similarly lists .Iaddend.the
preferred range .[.is listed.]. as 200 mg to 600 mg/day. While this
dosing range of 200-600 mg/day does provide sufficient response and
is pharmaceutically acceptable it has now been found that a lower
dosage range of raloxifene of about 50 mg/day to about 150 mg/day
surprisingly results in providing equivalent benefits as compared
to the higher range.
Raloxifene has been shown to bind to the estrogen receptor and was
originally thought to be a molecule whose function and pharmacology
was that of an anti-estrogen in that it blocked the ability of
estrogen to activate uterine tissue and estrogen dependent breast
cancers. Indeed, raloxifene does block the action of estrogen in
some cells; however in other cell types, raloxifene activates the
same genes as estrogen does and displays the same pharmacology,
e.g., osteoporosis, hyperlipidemia. The unique profile which
raloxifene displays and differs from that of estrogen is now
thought to be due to the unique activation and/or suppression of
various gene functions by the raloxifene-estrogen receptor complex
as opposed to the activation and/or suppression of genes by the
estrogen-estrogen receptor complex. Therefore, although raloxifene
and estrogen utilize and compete for the same receptor, the
pharmacological outcome from gene regulation of the two is not
easily predicted and is unique to each.
Generally, the compound is formulated with common excipients,
diluents or carriers, and compressed into tablets, or formulated as
elixirs or solutions for convenient oral administration, or
administered by the intramuscular or intravenous routes. The
compounds can be administered transdermally or intravaginaly, and
may be formulated as sustained release dosage forms and the
like.
The compounds used in the methods of the current invention can be
made according to established procedures, such as those detailed in
U.S. Pat. Nos. 4,133,814, 4,418,068, and 4,380,635 all of which are
incorporated by reference herein. In general, the process starts
with a benzo[b]thiophene having a 6-hydroxyl group and a
2-(4-hydroxyphenyl) group. The hydroxyl groups of the starting
compound are protected, the three position is acylated, and the
product deprotected to form the formula I compounds. Examples of
the preparation of such compounds are provided in the U.S. patents
discussed above.
The compounds used in the methods of this invention form
pharmaceutically acceptable acid and base addition salts with a
wide variety of organic and inorganic acids and bases and include
the physiologically acceptable salts which are often used in
pharmaceutical chemistry. Such salts are also part of this
invention. Typical inorganic acids used to form such salts include
hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric,
phosphoric, hypophosphoric and the like. Salts derived from organic
acids such as aliphatic mono and dicarboxylic acids, phenyl
substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic
acids, aromatic acids, aliphatic and aromatic sulfonic acids, may
also be used. Such pharmaceutically acceptable salts thus include
acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate,
benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate,
methoxybenzoate, methylbenzoate, o-acetoxybenzoate,
naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate,
.beta.-hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate,
caprate, caprylate, chloride, cinnamate, citrate, formate,
fumarate, glycollate, heptanoate, hippurate, lactate, malate,
maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate,
isonicotinate, nitrate, oxalate, phthalate, teraphthalate,
phosphate, monohydrogenphosphate, dihydrogenphosphate,
metaphosphate, pyrophosphate, propiolate, propionate,
phenylpropionate, salicylate, sebacate, succinate, suberate,
sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate,
benzene-sulfonate, p-bromobenzenesulfonate, chlorobenzenesulfonate,
ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate,
naphthalene-1-sulfonate, naphthalene-2-sulfonate,
p-toluenesulfonate, xylenesulfonate, tartarate, and the like. A
preferred salt is the hydrochloride salt.
The pharmaceutically acceptable acid addition salts are typically
formed by reacting a compound of formula I with an equimolar or
excess amount of acid. The reactants are generally combined in a
mutual solvent such as diethyl ether or benzene. The salt normally
precipitates out of solution within about one hour to 10 days and
can be isolated by filtration or the solvent can be stripped off by
conventional means.
Bases commonly used for formation of salts include ammonium
hydroxide and alkali and alkaline earth metal hydroxides,
carbonates, as well as aliphatic and primary, secondary and
tertiary amines, aliphatic diamines. Bases especially useful in the
preparation of addition salts include sodium hydroxide, potassium
hydroxide, ammonium hydroxide, potassium carbonate, methylamine,
diethylamine, ethylene diamine and cyclohexylamine.
The pharmaceutically acceptable salts generally have enhanced
solubility characteristics compared to the compound from which they
are derived, and thus are often more amenable to formulation as
liquids or emulsions.
Pharmaceutical formulations can be prepared by procedures known in
the art. For example, the compounds can be formulated with common
excipients, diluents, or carriers, and formed into tablets,
capsules, suspensions, powders, and the like. Examples of
excipients, diluents and carriers that are suitable for such
formulations include the following: fillers and extenders such as
starch, sugars, mannitol, and silicic derivatives; binding agents
such as carboxymethyl cellulose and other cellulose derivatives,
alginates, gelatin, and polyvinyl pyrrolidone; moisturizing agents
such as glycerol; disintegrating agents such as calcium carbonate
and sodium bicarbonate; agents for retarding dissolution such as
paraffin; resorption accelerators such as quaternary ammonium
compounds; surface active agents such as cetyl alcohol, glycerol
monostearate; adsorptive carriers such as kaolin and bentonite; and
lubricants such as talc, calcium and magnesium stearate, and solid
polyethyl glycols.
The compounds can also be formulated as elixirs or solutions for
convenient oral administration or as solutions appropriate for
parenteral administration, for instance by intramuscular,
subcutaneous or intravenous routes. Additionally, the compounds are
well suited to formulation as sustained release dosage forms and
the likes. The formulations can be so constituted that they release
the active ingredient only or preferably in a particular part of
the intestinal tract, possibly over a period of time. The coatings,
envelopes, and protective matrices may be made, for example, from
polymeric substances or waxes.
The dosage range for the invention is about 50 to about 150 mg/day,
and preferably 60 to 150 mg/day, and most preferably 60 to 100
mg/day. Particular dosages within the range of the invention were
50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120,
125, 130, 135, 140, 145, and 150 mg/day.
The compositions are preferably formulated in a unit dosage form
each dosage containing about 50 to about 150 mg, and more
preferably the amounts listed above. The term "unit dosage form"
refers to physically discrete units, such as tablets and capsules,
suitable as unitary dosages, particularly as unitary daily dosages,
for human subjects and other mammals, each unit containing a
predetermined quantity of active material calculated to produce the
desired therapeutic effect, in association with a suitable
pharmaceutical excipient.
The term or period of time of administration to a human subject of
the dosage of about 50 to about 150 mg/day will vary depending upon
severity of the condition, patient health, and related factors
which will be decided upon by the attending physician. A course of
treatment is expected to be at least for a period of six months,
more normally at least one year, and .[.preferrably.].
.Iadd.preferably .Iaddend.on a continual basis.
Examples of formulations using the dosage range follow:
TABLE-US-00001 Formulations Ingredient Quantity (mg/capsule)
Formulation 1: Gelatin Capsules Hard gelatin capsules are prepared
using the following: Raloxifene 50-150 Starch, NF 0-650 Starch
flowable powder 0-650 Silicone fluid 350 centistokes 0-15 The
ingredients are blended, passed through a No. 45 mesh U.S. sieve,
and filled into hard gelatin capsules. Examples of capsule
formulations include those shown below: Formulation 2: Raloxifene
capsule Raloxifene 60 Starch, NF 112 Starch flowable powder 225.3
Silicone fluid 350 centistokes 1.7 Formulation 3: Raloxifene
capsule Raloxifene 75 Starch, NF 108 Starch flowable powder 225.3
Silicone fluid 350 centistokes 1.7 Formulation 4: Raloxifene
capsule Raloxifene 100 Starch, NF 103 Starch flowable powder 225.3
Silicone fluid 350 centistokes 1.7 Formulation 5: Raloxifene
capsule Raloxifene 125 Starch, NF 150 Starch flowable powder 397
Silicone fluid 350 centistokes 3.0 Formulation 6: Raloxifene
capsule Raloxifene 150 Starch, NF 150 Starch flowable powder 397
Silicone fluid 350 centistokes 3.0
The specific formulations above may be changed in compliance with
the reasonable variations provided.
A tablet formulation is prepared using the ingredients below:
TABLE-US-00002 Tablets Ingredient Quantity (mg/tablet) Formulation
7: Raloxifene 60 Cellulose, microcrystalline 0-650 Silicon dioxide,
fumed 0-650 Stearate acid 0-15 Formulation 8: Raloxifene 75
Cellulose, microcrystalline 0-650 Silicon dioxide, fumed 0-650
Stearate acid 0-15 Formulation 9: Raloxifene 100 Cellulose,
microcrystalline 0-650 Silicon dioxide, fumed 0-650 Stearate acid
0-15 Formulation 10: Raloxifene 125 Cellulose, microcrystalline
0-650 Silicon dioxide, fumed 0-650 Stearate acid 0-15 Formulation
11: Raloxifene 150 Cellulose, microcrystalline 0-650 Silicon
dioxide, fumed 0-650 Stearate acid 0-15
The components are blended and compressed to form tablets.
Alternatively, tablets each containing 50 to 150 mg of active
ingredient are made up as follows:
TABLE-US-00003 Tablets Ingredient Quantity (mg/tablet) Formulation
12: Raloxifene 60 Starch 45 Cellulose, microcrystalline 35
Polyvinylpyrrolidone 4 (as 10% solution in water) Sodium
carboxymethyl cellulose 4.5 Magnesium stearate 0.5 Talc 1
Formulation 13: Raloxifene 75 Starch 45 Cellulose, microcrystalline
35 Polyvinylpyrrolidone 4 (as 10% solution in water) Sodium
carboxymethyl cellulose 4.5 Magnesium stearate 0.5 Talc 1
Formulation 14: Raloxifene 100 Starch 45 Cellulose,
microcrystalline 35 Polyvinylpyrrolidone 4 (as 10% solution in
water) Sodium carboxymethyl cellulose 4.5 Magnesium stearate 0.5
Talc 1 Formulation 15: Raloxifene 125 Starch 45 Cellulose,
microcrystalline 35 Polyvinylpyrrolidone 4 (as 10% solution in
water) Sodium carboxymethyl cellulose 4.5 Magnesium stearate 0.5
Talc 1 Formulation 16: Raloxifene 150 Starch 45 Cellulose,
microcrystalline 35 Polyvinylpyrrolidone 4 (as 10% solution in
water) Sodium carboxymethyl cellulose 4.5 Magnesium stearate 0.5
Talc 1
The active ingredient, starch, and cellulose are passed through a
No. 45 mesh U.S. sieve and mixed thoroughly. The solution of
polyvinylpyrrolidone is mixed with the resultant powders which are
then passed through a No. 14 mesh U.S. sieve. The granules so
produced are dried at 50.degree.-60.degree. C. and passed through a
No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium
stearate, and talc, previously passed through a No. 60 U.S. sieve,
are then added to the granules which, after mixing, are compressed
on a tablet machine to yield tablets.
Suspensions each containing 50-150 mg of medicament per 5 mL dose
are made as follows:
TABLE-US-00004 Suspensions Ingredient Quantity (mg/5 ml)
Formulation 17: Raloxifene 60 mg Sodium carboxymethyl cellulose 50
mg Syrup 1.25 mg Benzoic acid solution 0.10 mL Flavor q.v. Color
q.v. Purified water to 5 mL Formulation 18: Raloxifene 75 mg Sodium
carboxymethyl cellulose 50 mg Syrup 1.25 mg Benzoic acid solution
0.10 mL Flavor q.v. Color q.v. Purified water to 5 mL Formulation
19: Raloxifene 100 mg Sodium carboxymethyl cellulose 50 mg Syrup
1.25 mg Benzoic acid solution 0.10 mL Flavor q.v. Color q.v.
Purified water to 5 mL Formulation 20: Raloxifene 125 mg Sodium
carboxymethyl cellulose 50 mg Syrup 1.25 mg Benzoic acid solution
0.10 mL Flavor q.v. Color q.v. Purified water to 5 mL Formulation
21: Raloxifene 150 mg Sodium carboxymethyl cellulose 50 mg Syrup
1.25 mg Benzoic acid solution 0.10 mL Flavor q.v. Color q.v.
Purified water to 5 mL
The medicament is passed through a No. 45 mesh U.S. sieve and mixed
with the sodium carboxymethyl cellulose and syrup to form a smooth
paste. The benzoic acid solution, flavor, and color are
diluted.[.:.]. .Iadd. .Iaddend.with some of the water and added,
with stirring. Sufficient water is then added to produce the
required volume.
The following examples illustrate the preparation of the compounds
used in the invention.
EXAMPLE 1
6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thi-
ophene
A 4 g. portion of
6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidinoeth-
oxy)-benzoyl]benzo[b]thiophene, hydrochloride, was combined with
100 ml. of denatured alcohol and 10 ml. of 5 N sodium hydroxide,
and stirred under reflux for 1.5 hours under a nitrogen atmosphere.
The reaction mixture was then evaporated to dryness under vacuum,
and the residue was dissolved in 200 ml. of water and washed with
300 ml. of diethyl ether. The water layer was degassed under
vacuum, and then nitrogen was bubbled through it to remove all
traces of ether. The mixture Was then acidified with 1 N
hydrochloric acid, and then made basic with excess sodium
bicarbonate. The precipitate Was collected by filtration and washed
with cold water to obtain 2.4 g. of crude product. It was purified
on a 2.times.30 cm. column of silica gel, eluting first with 700
ml. of 55 methanol in chloroform, followed by 1 liter of 10%
methanol in chloroform. The impurities came off first, and the
product-containing fractions were combined and evaporated under
vacuum to obtain 1.78 g. of yellow oil. The oil was dissolved in 6
m. of acetone, seeded and chilled in a freezer to obtain 1.2 g. of
purified product, m.p. 143.degree.-147.degree. C. The identity of
the product was confirmed as follows:
nmr spectrum (100 mHz in dmso-d.sub.6).delta.1.20-1.65(6H, m,
N(CH.sub.2CH.sub.2).sub.2CH.sub.2); 2.30-2.45 (4H, m,
N(CH.sub.2CH.sub.2).sub.2CH.sub.2); 2.60 (2H, t, J=6 Hz,
OCH.sub.2CH.sub.2N); 4.06(2H, t, J=6Hz, OCH.sub.2CH.sub.2N); 6.68
(2H, d, J=9H, aromatic o to OH); 6.85 (1H, q, J.sub.H4-H5=9 Hz,
J.sub.H5-H7=2 Hz, H5 of benzothiophene ring); 6.90(2H, d, J=9 Hz,
aromatic o to OCH.sub.2CH.sub.2N); 7.18 (2H, d, J=9 Hz, aromatic m
to OH); 7.25 (1H, d, J=9z, H4 of benzothiophene ring); 7.66 (2H, d,
J=9 Hz, aromatic o to CO); 9.72(2H, broad s, OH). Ultraviolet
spectrum in ethanol; .lamda..sub.max (.epsilon.): 290 nm. (34,000).
Electron impact mass Spectrum M.sub.f at m/e 473.
EXAMPLE 2
6-hydroxy-2-(4-hydoxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thio-
phene
A 3.6 g. portion of
6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidinoeth-
oxy)-benzoyl]benzo[b]thiophene was dissolved in 100 ml. of
tetrahydrofuran and 40 ml. of methanol, and 10 ml. of 5 N sodium
hydroxide was added. The mixture was stirred for 16 hours at
ambient temperature, and was then worked up by the procedure of
Example 1 above to obtain 3.5 g of a yellow solid. The impure
product was purified by column chromatography on silica gel,
eluting with a gradient solvent from 5% methane in chloroform to
30% methanol in chloroform. The product-containing fractions were
evaporated to obtain 1.85 g. of oily product, which was
recrystallized from acetone to obtain 1.25 g. of purified product,
m.p. 141.degree.-144.degree. C.
EXAMPLE 3
6-hydroxy-2-(4-hydroxyphenyl)-3[4-(2-piperidinoethoxy)benzoyl]benzo[b]thio-
phene, hydrochloride
Under a nitrogen blanket, a mixture of 3 g. of
4-(2-piperidinoethoxy) benzoic acid, hydrochloride, 2 drops of
dimethylformamide, 2.5 ml. of thionyl chloride and 40 ml. of
chlorobenzene was heated at 70.degree.-75.degree. C. for about one
hour. The excess thionyl chloride and 15-20 ml. of solvent were
then distilled off. The remaining suspension was cooled to ambient
temperature, and to it were added 100 ml. of dichloromethane, 2.7
g. of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene and 10 g. of
aluminum chloride. The solution was stirred for about one hour, 7.5
ml. of ethanethiol was added, and the mixture was stirred for 45
minutes more. Then 40 ml. of tetrahydrofuran was added, followed by
15 ml. of 20% hydrochloric acid, with an exotherm to reflux. Fifty
ml. of water and 25 ml. of saturated aqueous sodium chloride were
added. The mixture was stirred and allowed to cool to ambient
temperature. The precipitate was collected by filtration and washed
successively with 30 ml of water, 40 ml of 25% aqueous
tetrahydrofuran, and 35 ml. of water. The solids were then dried at
40.degree. C. under vacuum to obtain 5.05 g. of product, which was
identified by nmr.
.delta.1.7(6H, m, N(CH.sub.2CH.sub.2).sub.2CH.sub.2); 2.6-3.1 (2H,
m, NCH2); 3.5-4.1 (4H, m, NCH.sub.2); 4.4 (2H, m, OCH.sub.2);
6.6-7.4 (9H, m, aromatic); 7.7 (2H, d, aromatic o to CO); 9.8(2H,
m, OH).
Test Results
An 8-week parallel, double-blind, placebo study in approximately
160 healthy post-menopausal women was completed. The doses of
raloxifene used in this study were 10, 50, and 200 mg. The 10 mg
dose had no significant activity with either bone marker. (See
Table I) Because of development over time seen with many bone
markers, a raloxifene dose of 50 mg/day will likely be fully active
when evaluated during a study of longer duration.
TABLE-US-00005 TABLE I Baseline Values and Mean (.+-.SEM) Group
Changes from Baseline to Endpoint in Markers of Bone Metabolism
(GGGC) Raloxifene Raloxifene Raloxifene Placebo 10 mg 50 mg 200 mg
Marker (n = 42) (n = 42) (n = 42) (n = 41) Serum alkaline
phosphatase (U/L) Baseline 77.31 78.71 73.86 79.07 (.+-.3.53)
(.+-.3.12) (.+-.2.69) (.+-.2.77) Change -1.10 0.21 -4.78 -5.93*
(.+-.2.08) (.+-.1.56) (.+-.1.52) (.+-.1.48) Serum osteocalcin
(ng/mL) Baseline 3.94 3.86 3.65 4.21 (.+-.0.21) (.+-.0.19)
(.+-.0.21) (.+-.0.21) Change -0.63 -0.27 -0.81 -1.21* (.+-.0.16)
(.+-.0.13) (.+-.0.15) (.+-.0.18) Abbreviations: n = greatest number
of subjects tested for any one marker; SEM = standard error of the
mean. *Statistically significantly (p < 0.051) different from
placebo (two-tailed comparison).
Serum lipid levels were affected by raloxifene doses of 50 and 200
mg (Table II). Decreases in LDL cholesterol were observed in
raloxifene.[.-.]. .Iadd. .Iaddend.treated subjects at 50 mg with a
comparable decrease in the 200 mg patients. Raloxifene-treated
subjects showed no changes in HDL levels. Statistically significant
decreases in HDL:LDL ratios and the total serum cholesterol levels
were observed in raloxifene-treated subjects at both the 50 and 200
mg doses.
TABLE-US-00006 TABLE II Baseline Values and Mean (.+-.SEM) Group
Changes from Baseline to Endpoint in Serum Lipids (GGGC) Raloxifene
Raloxifene Raloxifene Placebo 10 mg 50 mg 200 mg Variable (n = 42)
(n = 42) (n = 42) (n = 41) LDL-C (mmol/L) Baseline 3.67 4.11# 3.55
3.68 (.+-.0.11) (.+-.0.17) (.+-.0.16) (.+-.0.13) Change 0.02 0.05
-0.23* -0.17 (.+-.0.08) (.+-.0.10) (.+-.0.06) (.+-.0.07) HDL-C
(mmol/L) Baseline 1.41 1.41 1.35 1.32 (.+-.0.06) (.+-.0.06)
(.+-.0.05) (.+-.0.05) Change -0.03 0.01 0.04 0.02 (.+-.0.03)
(.+-.0.02) (.+-.0.02) (.+-.0.02) HDL-C:LDL-C ratio Baseline 0.40
0.37 0.42 0.38 (.+-.0.02) (.+-.0.03) (.+-.0.03) (.+-.0.02) Change
-0.01 0.00 0.03* 0.03* (.+-.0.01) (.+-.0.01) (.+-.0.01) (.+-.0.01)
Toal cholesterol (mmol/L) Baseline 5.69 6.18# 5.82 5.71 (.+-.0.12)
(.+-.0.19) (.+-.0.21) (.+-.0.14) Change 0.10 0.01 -0.23* -0.15
(.+-.0.09) (.+-.0.10) (.+-.0.08) (.+-.0.08) Abbreviations: LDL-C =
low-density lipoprotein cholesterol; HDL-C = high-density
lipoprotein cholesterol; n = greatest number of subjects tested for
any one marker; SEM = standard error of the mean. #Statistically
significantly (p < 0.050) larger than all other treatments
(two-tailed comparison). *Statistically significantly (p <0.050)
different from placebo (two-tailed comparison).
* * * * *