U.S. patent application number 11/273470 was filed with the patent office on 2006-03-23 for method for inhibiting bone resorption.
Invention is credited to Anastasia G. Daifotis, Arthur C. II Santora, A. John Yates.
Application Number | 20060063740 11/273470 |
Document ID | / |
Family ID | 27368403 |
Filed Date | 2006-03-23 |
United States Patent
Application |
20060063740 |
Kind Code |
A1 |
Daifotis; Anastasia G. ; et
al. |
March 23, 2006 |
Method for inhibiting bone resorption
Abstract
Disclosed are methods for inhibiting bone resorption in mammals
while minimizing the occurrence of or potential for adverse
gastrointestinal effects. Also disclosed are pharmaceutical
compositions and kits for carrying out the therapeutic methods
disclosed herein.
Inventors: |
Daifotis; Anastasia G.;
(Westfield, NJ) ; Santora; Arthur C. II;
(Watchung, NJ) ; Yates; A. John; (Westfield,
NJ) |
Correspondence
Address: |
MERCK AND CO., INC
P O BOX 2000
RAHWAY
NJ
07065-0907
US
|
Family ID: |
27368403 |
Appl. No.: |
11/273470 |
Filed: |
November 14, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10244217 |
Sep 16, 2002 |
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11273470 |
Nov 14, 2005 |
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09376315 |
Aug 18, 1999 |
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10244217 |
Sep 16, 2002 |
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09134214 |
Aug 14, 1998 |
5994329 |
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09376315 |
Aug 18, 1999 |
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PCT/US98/14796 |
Jul 17, 1998 |
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09134214 |
Aug 14, 1998 |
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60053535 |
Jul 23, 1997 |
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60053351 |
Jul 22, 1997 |
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Current U.S.
Class: |
514/108 ;
514/102; 514/89 |
Current CPC
Class: |
A61K 31/66 20130101;
A61K 31/663 20130101; A61K 31/675 20130101 |
Class at
Publication: |
514/108 ;
514/102; 514/089 |
International
Class: |
A61K 31/675 20060101
A61K031/675; A61K 31/66 20060101 A61K031/66 |
Claims
1. A method for inhibiting bone resorption in a mammal, said method
comprising orally administering to said mammal a pharmaceutically
effective amount of a bisphosphonate as a unit dosage according to
a continuous schedule having a dosing interval selected from the
group consisting of once-weekly dosing, twice-weekly dosing,
biweekly dosing, and twice-monthly dosing.
2. A method according to claim 1 wherein said bisphosphonate is
selected from the group consisting of alendronate, cimadronate,
clodronate, tiludronate, etidronate, ibandronate, risedronate,
piridronate, pamidronate, zolendronate, pharmaceutically acceptable
salts thereof, and mixtures thereof.
3. A method according to claim 1 wherein said bisphosphonate is
selected from the group consisting of alendronate, pharmaceutically
acceptable salts thereof, and mixtures thereof.
4. A method according to claim 3 wherein said pharmaceutically
acceptable salt is alendronate monosodium trihydrate.
5. A method according to claim 4 wherein said mammal is a
human.
6. A method for treating osteoporosis in a mammal in need of such
treatment, said method comprising orally administering to said
mammal a pharmaceutically effective amount of a bisphosphonate as a
unit dosage according to a continuous schedule having a dosing
interval selected from the group consisting of once-weekly dosing,
twice-weekly dosing, biweekly dosing, and twice-monthly dosing.
7. A method according to claim 6 wherein said mammal is a
human.
8. A method according to claim 7 wherein said dosing interval is
once-weekly and said unit dosage comprises about 70 mg of
alendronate monosodium trihydrate, on an alendronic acid active
basis.
9. A method according to claim 7 wherein said dosing interval is
twice-weekly and said unit dosage comprises about 35 mg of
alendronate monosodium trihydrate, on an alendronic acid active
basis.
10. A method according to claim 7 wherein said dosing interval is
biweekly and said unit dosage comprises about 140 mg of alendronate
monosodium trihydrate, on an alendronic acid active basis.
11. A method according to claim 7 wherein said dosing interval is
twice-monthly and said unit dosage comprises about 140 mg of
alendronate monosodium trihydrate, on an alendronic acid active
basis.
12. A method for preventing osteoporosis in a mammal in need of
such treatment, said method comprising orally administering to said
mammal a pharmaceutically effective amount of a bisphosphonate as a
unit dosage according to a continuous schedule having a dosing
interval selected from the group consisting of once-weekly dosing,
twice-weekly dosing, biweekly dosing, and twice-monthly dosing.
13. A method according to claim 12 wherein said mammal is a
human.
14. A method according to claim 13 wherein said dosing interval is
once-weekly and said unit dosage comprises about 35 mg of
alendronate monosodium trihydrate, on an alendronic acid active
basis.
15. A method according to claim 13 wherein said dosing interval is
twice-weekly and said unit dosage comprises about 17.5 mg of
alendronate monosodium trihydrate, on an alendronic acid active
basis.
16. A method according to claim 13 wherein said dosing interval is
biweekly and said unit dosage comprises about 70 mg of alendronate
monosodium trihydrate, on an alendronic acid active basis.
17. A method according to claim 13 wherein said dosing interval is
twice-monthly and said unit dosage comprises about 70 mg of
alendronate monosodium trihydrate, on an alendronic acid active
basis.
18. A method for treating abnormal bone resorption in a human in
need of such treatment comprising orally administering to said
human a unit dosage of a bisphosphonate, said unit dosage
comprising from about 17.5 mg to about 140 mg, on an alendronic
acid basis, of a bisphosphonate selected from the group consisting
of alendronate, pharmaceutically acceptable salts thereof, and
mixtures thereof.
19. A method according to claim 18 wherein said unit dosage
comprises about 35 mg of the bisphosphonate.
20. A method according to claim 18 wherein said unit dosage
comprises about 70 mg of the bisphosphonate.
21. A method according to claim 20 wherein said unit dosage is
administered once-weekly.
22. A method according to claim 18 wherein said unit dosage
comprises about 140 mg of the bisphosphonate.
23. The method in accordance with claim 8, comprising orally
administering to said human a unit dosage of a bisphosphonate, said
unit dosage comprising from about 8.75 mg to about 70 mg, on an
alendronic acid basis, of a bisphosphonate selected from the group
consisting of alendronate, pharmaceutically acceptable salts
thereof, and mixtures thereof, on an alendronic acid active weight
basis.
24. A method according to claim 23 wherein said unit dosage
comprises about 17.5 mg of the bisphosphonate.
25. A method according to claim 23 wherein said unit dosage
comprises about 35 mg of the bisphosphonate.
26. A method according to claim 25 wherein said unit dosage is
administered once-weekly.
27. A method according to claim 23 wherein said unit dosage
comprises about 70 mg of the bisphosphonate.
28. (canceled)
29. (canceled)
30. A pharmaceutical composition comprising about 70 mg, on an
alendronic acid active basis, of a bisphosphonate selected from the
group consisting of alendronate, pharmaceutically acceptable salts
thereof, and mixtures thereof.
31. (canceled)
32. (canceled)
33. A method for inhibiting bone resorption in a mammal, said
method comprising orally administering to said mammal a
pharmaceutically effective amount of a bisphosphonate as a unit
dosage according to a continuous schedule having a periodicity from
about once every 3 days to about once every 16 days.
34. The method in accordance with claim 12, comprising orally
administering to said human about 70 mg of alendronate monosodium
trihydrate, on an alendronic acid active basis, as a unit dosage
according to a continuous schedule having a dosing interval of
once-weekly.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of PCT/US98/14796, filed
Jul. 17, 1998, and also claims priority to U.S. provisional
applications Ser. No. 60/053,535, filed Jul. 23, 1997, and
60/053,351, filed Jul. 22, 1997, both now abandoned, the contents
of all of the foregoing of which are hereby incorporated by
reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to oral methods for inhibiting
bone resorption in a mammal while minimizing the occurrence of or
potential for adverse gastrointestinal effects. These methods
comprise orally administering to a mammal in need thereof of a
pharmaceutically effective amount of a bisphosphonate as a unit
dosage according to a continuous schedule having a dosing interval
selected from the group consisting of once-weekly dosing,
twice-weekly dosing, biweekly dosing, and twice-monthly dosing. The
present invention also relates to pharmaceutical compositions and
kits useful for carrying out these methods.
BACKGROUND OF THE INVENTION
[0003] A variety of disorders in humans and other mammals involve
or are associated with abnormal bone resorption. Such disorders
include, but are not limited to, osteoporosis, Paget's disease,
periprosthetic bone loss or osteolysis, and hypercalcemia of
malignancy. The most common of these disorders is osteoporosis,
which in its most frequent manifestation occurs in postmenopausal
women. Osteoporosis is a systemic skeletal disease characterized by
a low bone mass and microarchitectural deterioration of bone
tissue, with a consequent increase in bone fragility and
susceptibility to fracture. Because osteoporosis, as well as other
disorders associated with bone loss, are chronic conditions, it is
believed that appropriate therapy will generally require chronic
treatment.
[0004] Multinucleated cells called osteoclasts are responsible for
causing bone loss through a process known as bone resorption. It is
well known that bisphosphonates are selective inhibitors of
osteoclastic bone resorption, making these compounds important
therapeutic agents in the treatment or prevention of a variety of
generalized or localized bone disorders caused by or associated
with abnormal bone resorption. See H. Fleisch, Bisphosphonates In
Bone Disease, From The Laboratory To The Patient, 2nd Edition,
Parthenon Publishing (1995), which is incorporated by reference
herein in its entirety.
[0005] At present, a great amount of preclinical and clinical data
exists for the potent bisphosphonate compound alendronate. Evidence
suggests that other bisphosphonates such as risedronate,
tiludronate, ibandronate and zolendronate, have many properties in
common with alendronate, including high potency as inhibitors of
osteoclastic bone resorption. An older bisphosphonate compound,
etidronate, also inhibits bone resorption. However, unlike the more
potent bisphosphonates, etidronate impairs mineralization at doses
used clinically, and may give rise to osteomalacia, a condition
resulting in an undesirable decrease in bone mineralization. See
Boyce, B. F., Fogelman, I., Ralston, S. et al. (1984) Lancet
1(8381), pp. 821-824 (1984), and Gibbs, C. J., Aaron, J. E.;
Peacock, M. (1986) Br. Med. J. 292, pp. 1227-1229 (1986), both of
which are incorporated by reference herein in their entirety.
[0006] Despite their therapeutic benefits, bisphosphonates are
poorly absorbed from the gastrointestinal tract. See B. J. Gertz et
al., Clinical Pharmacology of Alendronate Sodium, Osteoporosis
Int., Suppl. 3: S13-16 (1993) and B. J. Gertz et al., Studies of
the oral bioavailability of alendronate, Clinical Pharmacology
& Therapeutics, vol. 58, number 3, pp. 288-298 (September
1995), which are incorporated by reference herein in their
entirety. Intravenous administration has been used to overcome this
bioavailability problem. However, intravenous administration is
costly and inconvenient, especially when the patient must be given
an intravenous infusion lasting several hours on repeated
occasions.
[0007] If oral administration of the bisphosphonate is desired,
relatively high doses must be administered to compensate for the
low bioavailability from the gastrointestinal tract. To offset this
low bioavailability, it is generally recommended that the patient
take the bisphosphonate on an empty stomach and fast for at least
30 minutes afterwards. However, many patients find the need for
such fasting on a daily basis to be inconvenient. Moreover, oral
administration has been associated with adverse gastrointestinal
effects, especially those relating to the esophagus. See Fleisch,
Id. These effects appear to be related to the irritant potential of
the bisphosphonate in the esophagus, a problem which is exacerbated
by the presence of refluxed gastric acid. For example, the
bisphosphonate, pamidronate has been associated with esophageal
ulcers. See E. G. Lufkin et al., Pamidronate: An Unrecognized
Problem in Gastrointestinal Tolerability, Osteoporosis
International, 4: 320-322 (1994), which is incorporated by
reference herein in its entirety. Although not as common, the use
of alendronate has been associated with esophagitis and/or
esophageal ulcers. See P. C. De Groen, et al., Esophagitis
Associated With The Use Of Alendronate, New England Journal of
Medicine, vol. 335, no. 124, pp. 1016-1021 (1996), D. O. Castell,
Pill Esophagitis--The Case of Alendronate, New England Journal of
Medicine, vol. 335, no. 124, pp. 1058-1059 (1996), and U. A.
Liberman et al., Esophagitis and Alendronate, New England Journal
of Medicine, vol. 335, no. 124, pp. 1069-1070 (1996), which are
incorporated by reference herein in their entirety. The degree of
adverse gastrointestinal effects of bisphosphonates has been shown
to increase with increasing dose. See C. H. Chestnut et al.,
Alendronate Treatment of the Postmenopausal Osteoporotic Woman:
Effect of Multiple Dosages on Bone Mass and Bone Remodeling, The
American Journal of Medicine, vol. 99, pp. 144-152, (August 1995),
which is incorporated by reference herein in its entirety. Also,
these adverse esophageal effects appear to be more prevalent in
patients who do not take the bisphosphonate with an adequate amount
of liquid or who lie down shortly after dosing, thereby increasing
the chance for esophageal reflux.
[0008] Current oral bisphosphonate therapies generally fall into
two categories: (1) those therapies utilizing continuous daily
treatment, and (2) those therapies utilizing a cyclic regimen of
treatment and rest periods.
[0009] The continuous daily treatment regimens normally involve the
chronic administration of relatively low doses of the
bisphosphonate compound, with the objective of delivering the
desired cumulative therapeutic dose over the course of the
treatment period. However, continuous daily dosing has the
potential disadvantage of causing adverse gastrointestinal effects
due to the repetitive, continuous, and additive irritation to the
gastrointestinal tract. Also, because bisphosphonates should be
taken on an empty stomach followed by fasting and maintenance of an
upright posture for at least 30 minutes, many patients find daily
dosing to be burdensome. These factors can therefore interfere with
patient compliance, and in severe cases even require cessation of
treatment.
[0010] Cyclic treatment regimens were developed because some
bisphosphonates, such as etidronate, when given daily for more than
several days, have the disadvantage of actually causing a decline
in bone mineralization, i.e. osteomalacia. U.S. Pat. No. 4,761,406,
to Flora et al, issued Aug. 2, 1988, which is incorporated by
reference herein in its entirety, describes a cyclic regimen
developed in an attempt to minimize the decline in bone
mineralization while still providing a therapeutic anti-resorptive
effect. Generally, cyclic regimens are characterized as being
intermittent, as opposed to continuous treatment regimens, and have
both treatment periods during which the bisphosphonate is
administered and nontreatment periods to permit the systemic level
of the bisphosphonate to return to baseline. However, the cyclic
regimens, relative to continuous dosing, appear to result in a
decreased therapeutic antiresorptive efficacy. Data on risedronate
suggests that cyclic dosing is actually less effective than
continuous daily dosing for maximizing antiresorptive bone effects.
See L. Mortensen, et al., Prevention Of Early Postmenopausal Bone
Loss By Risedronate, Journal of Bone and Mineral Research, vol. 10,
supp. 1, p. s140 (1995), which is incorporated by reference herein
in its entirety. Furthermore, these cyclic regimens do not
eliminate or minimize adverse gastrointestinal effects, because
such regimens typically utilize periods of multiple daily dosing.
Also, the cyclic regimens are cumbersome to administer and have the
disadvantage of low patient compliance, and consequently
compromised therapeutic efficacy. U.S. Pat. No. 5,366,965, to
Strein, issued Nov. 22, 1994, which is incorpoated by reference
herein in its entirety, attempts to address the problem of adverse
gastrointestinal effects by administering a polyphosphonate
compound, either orally, subcutaneously, or intravenously,
according to an intermittent dosing schedule having both a bone
resorption inhibition period and a no-treatment rest period.
However, the regimen has the disadvantage of not being continuous
and regular, and requires nontreatment periods ranging from 20 to
120 days. PCT Application No. WO 95/30421, to Goodship et al,
published Nov. 16, 1995, which is,incorporated by reference herein
in its entirety, discloses methods for preventing prosthetic
loosening and migration using various bisphosphonate compounds.
Administration of a once weekly partial dose of the bisphosphonate
is disclosed. However, the reference specifically fails to address
the issue of adverse gastrointestinal effects or to disclose
administration of larger or multiple dosages.
[0011] It is seen from current teachings that both daily and cyclic
treatment regimens have shortcomings, and that there is a need for
development of a dosing regimen to overcome these shortcomings.
[0012] In the present invention, it is found that the adverse
gastrointestinal effects that can be associated with daily or
cyclic dosing regimens can be minimized by administering the
bisphosphonate at a relatively high unit dosage according to a
continuous schedule having a dosing interval selected from the
group consisting of once-weekly dosing, twice-weekly dosing,
biweekly dosing, and twice-monthly dosing. In other words, it is
found that the administration of a bisphosphonate at a high
relative dosage at a low relative dosing frequency causes less
adverse gastrointestinal effects, particularly esophageal effects,
compared to the administration of a low relative dosage at a high
relative dosing frequency. This result is surprising in view of the
teachings suggesting that adverse gastrointestinal effects would be
expected to increase as a function of increasing bisphosphonate
dosage. Such administration methods of the present invention would
be especially beneficial in treating patients that have been
identified as suffering from or are susceptible to upper
gastrointestinal disorders, e.g. gastrointestinal reflux disease
(i.e. "GERD"), esophagitis, dyspepsia (i.e. heatburn), ulcers, and
other related disorders. In such patients conventional
bisphosphonate therapy could potentially exacerbate or induce such
upper gastrointestinal disorders.
[0013] From a patient lifestyle standpoint, the methods of the
present invention would also be more convenient than daily or
cyclic dosing regimens. Patients would be subjected less frequently
to the inconvenience of having to take the drug on an empty stomach
and having to fast for at least 30 minutes after dosing. Also,
patients would not need to keep track of a complex dosing regimen.
The methods of the present invention are likely to have the
advantage of promoting better patient compliance, which in turn can
translate into better therapeutic efficacy.
[0014] It is an object of the present invention to provide methods
for inhibiting bone resorption and the conditions associated
therewith.
[0015] It is another object of the present invention to provide
methods for treating abnormal bone resorption and the conditions
associated therewith
[0016] It is another object of the present invention to provide
methods for preventing abnormal bone resorption and the conditions
associated therewith.
[0017] It is another object of the present invention to provide
methods which are oral methods.
[0018] It is another object of the present invention to provide
such methods in humans.
[0019] It is another object of the present invention to provide
such methods in patients that have been identified as suffering
from or are susceptible to upper gastrointestinal disorders, e.g.
gastrointestinal reflux disease (i.e. "GERD"), esophagitis,
dyspepsia (i.e. heatburn), ulcers, and other related disorders.
[0020] It is another object of the present invention to provide
such methods while minimizing the occurrence of or potential for
adverse gastronintestinal effects.
[0021] It is another object of the present invention to provide
such methods comprising a continuous dosing schedule having a
dosing interval selected from the group consisting of weekly
dosing, twice-weekly dosing, biweekly dosing, and twice-monthly
dosing.
[0022] It is another object of the present invention to provide
such methods comprising a continuous dosing schedule having a
dosing periodicity ranging from about once every 3 days to about
once every 16 days.
[0023] It is another object of the present invention to provide
such methods wherein the continuous dosing schedule is maintained
until the desired therapeutic effect is achieved.
[0024] It is another object of the present invention to treat or
prevent abnormal bone resorption in an osteoporotic mammal,
preferably an osteoporotic human.
[0025] It is another object of the present invention to provide
pharmaceutical compositions and kits useful in the methods
herein.
[0026] These and other objects will become readily apparent from
the detailed description which follows.
SUMMARY OF THE INVENTION
[0027] The present invention relates to methods for inhibiting bone
resorption in a mammal in need thereof, while minimizing the
occurrence of or potential for adverse gastrointestinal effects,
said method comprising orally administering to said mammal a
pharmaceutically effective amount of a bisphosphonate as a unit
dosage according to a continuous schedule having a dosing interval
selected from the group consisting of once-weekly dosing,
twice-weekly dosing, biweekly dosing, and twice-monthly dosing,
wherein said continuous schedule is maintained until-the desired
therapeutic effect is achieved for said mammal.
[0028] In other embodiments, the present invention relates to
methods comprising a continuous dosing schedule having a dosing
periodicity ranging from about once every 3 days to about once
every 16 days.
[0029] In other embodiments, the present invention relates to
methods for treating abnormal bone resorption in a mammal in need
of such treatment.
[0030] In other embodiments, the present invention relates to
methods for preventing abnormal bone resorption in a mammal in need
of such prevention.
[0031] In other embodiments, the present invention relates to such
methods useful in humans.
[0032] In other embodiments, the present invention relates to such
methods useful in humans indentified as having or being susceptible
to upper gastrointestinal disorders.
[0033] In other embodiments, the present invention relates to
methods for treating or preventing osteoporosis in a mammal.
[0034] In other embodiments, the present invention relates to
methods for treating or preventing osteoporosis in a human.
[0035] In other embodiments, the present invention relates to
methods for inhibiting bone resorption, or treating or preventing
abnormal bone resorption in a human comprising administering to
said human from about 8.75 mg to about 140 mg, on an alendronic
acid active basis, of a bisphosphonate selected from the group
consisting of alendronate, pharmaceutically acceptable salts
thereof, and mixtures thereof.
[0036] In other embodiments the present invention relates to a
pharmaceutical composition comprising from about 8.75 mg to about
140 mg, on an alendronic acid active basis, of a bisphosphonate
selected from the group consisting of alendronate, pharmaceutically
acceptable salts thereof, and mixtures thereof.
[0037] All percentages and ratios used herein, unless otherwise
indicated, are by weight. The invention hereof can comprise,
consist of, or consist essentially of the essential as well as
optional ingredients, components, and methods described herein.
BRIEF DESCRIPTION OF THE FIGURES
[0038] FIG. 1 is a photomicrograph (total magnification 270.times.)
of canine esophagus tissue (paraffin embedded and stained with
hematoxylin and eosin) from an animal sacrificed immediately after
infusion of the last of five separate dosages of 50 mL of simulated
gastric juice administered on five consecutive days.
[0039] FIG. 2 is a photomicrograph (total magnification 270.times.)
of canine esophagus tissue (paraffin embedded and stained with
hematoxylin and eosin) from an animal sacrificed immediately after
infusion of the last of five separate dosages of 50 mL of 0.20
mg/mL alendronate in simulated gastric juice administered on five
consecutive days.
[0040] FIG. 3 is a photomicrograph (total magnification 270.times.)
of canine esophagus tissue (paraffin embedded and stained with
hematoxylin and eosin) from an animal sacrificed 24 hours after
infusion with a single dosage of 50 mL of 0.80 mg/mL alendronate in
simulated gastric juice.
[0041] FIG. 4 is a photomicrograph (total magnification 270.times.)
of canine esophagus tissue (paraffin embedded and stained with
hematoxylin and eosin) from an animal sacrificed 7 days after
infusion with a single dosage of 50 mL of 0.80 mg/mL alendronate in
simulated gastric juice.
[0042] FIG. 5 is a photomicrograph (total magnification 270.times.)
of canine esophagus tissue (paraffin embedded and stained with
hematoxylin and eosin) from an animal sacrified 7 days after
infusion of the last of 4 separate dosages of 50 mL of 0.80 mg/mL
alendronate in simulated gastric juice administered once per week,
i.e. once every 7 days.
[0043] FIG. 6 is a photomicrograph (total magnification 270.times.)
of canine esophagus tissue (paraffin embedded and stained with
hematoxylin and eosin) from an animal sacrified 4 days after
infusion of the last of 8 separate dosages of 50 mL of 0.40 mg/mL
alendronate in simulated gastric juice administered twice per week,
i.e. once every 3-4 days.
[0044] FIG. 7 is a photomicrograph (total magnification 270.times.)
of canine esophagus tissue (paraffin embedded and stained with
hematoxylin and eosin) from an animal sacrificed immediately after
infusion of the last of five separate dosages of 50 mL of 0.20
mg/mL risedronate in simulated gastric juice administered on five
consecutive days.
[0045] FIG. 8 is a photomicrograph (total magnification 270.times.)
of canine esophagus tissue (paraffin embedded and stained with
hematoxylin and eosin) from an animal sacrificed immediately after
infusion of the last of five separate dosages of 50 mL of 4.0 mg/mL
tiludronate in simulated gastric juice administered on five
consecutive days.
DESCRIPTION OF THE INVENTION
[0046] The present invention relates to a method, preferably an
oral method, for inhibiting bone resorption in a mammal in need
thereof, while minimizing the occurrence of or potential for
adverse gastrointestinal effects. The present invention relates to
methods of treating or preventing abnormal bone resorption in a
mammal in need of such treatment or prevention. The methods of the
present invention comprise orally administering to a mammal a
pharmaceutically effective amount of a bisphosphonate as a unit
dosage, wherein said dosage is administered according to a
continuous schedule having a dosing interval selected from the
group consisting of once-weekly dosing, twice-weekly dosing,
biweekly dosing, and twice-monthly dosing. In other embodiments,
the present invention relates to methods comprising a continuous
dosing schedule having a dosing periodicity ranging from about once
every 3 days to about once every 16 days. Typically, the continuous
dosing schedule is maintained until the desired therapeutic effect
is achieved for the mammal.
[0047] The present invention utilizes higher unit dosages of the
bisphosphonate at each dosing point than has heretofore been
typically administered, yet because of the dosing schedule chosen,
the potential for adverse gastrointestinal effects are minimized.
Moreover, the method is more convenient because the disadvantages
associated with daily dosing are minimized.
[0048] The methods of the present invention are generally
administered to mammals in need of bisphosphonate therapy.
Preferably the mammals are human patients, particularly human
patients in need of inhibiting bone resorption, such as patients in
need of treating or preventing abnormal bone resorption.
[0049] The administration methods of the present invention are
especially useful in administering bisphosphonate therapy to human
patients that have been identified as suffering from or are
susceptible to upper gastrointestinal disorders, e.g. GERD,
esophagitis, dyspepsia, ulcers, etc. In such patients conventional
bisphosphonate therapy could potentially exacerbate or induce such
upper gastrointestinal disorders.
[0050] The term "pharmaceutically effective amount", as used
herein, means that amount of the bisphosphonate compound, that will
elicit the desired therapeutic effect or response when administered
in accordance with the desired treatment regimen. A preferred
pharmaceutically effective amount of the bisphosphonate is a bone
resorption inhibiting amount.
[0051] The term "minimize the occurrence of or potential for
adverse gastrointestinal effects", as used herein, means reducing,
preventing, decreasing, or lessening the occurrence of or the
potential for incurring unwanted side effects in the
gastrointestinal tract, i.e. the esophagus, stomach, intestines,
and rectum, particularly the upper gastrointestinal tract, i.e. the
esophagus and stomach. Nonlimiting adverse gastrointestinal effects
include, but are not limited to GERD, esophagitis, dyspepsia,
ulcers, esophageal irritation, esophageal perforation, abdominal
pain, and constipation.
[0052] The term "abnormal bone resorption", as used herein means a
degree of bone resorption that exceeds the degree of bone
formations either locally, or in the skeleton as a whole.
Alternatively, "abnormal bone resorption" can be associated with
the formation of bone having an abnormal structure.
[0053] The term "bone resorption inhibiting", as used herein, means
treating or preventing bone resorption by the direct or indirect
alteration of osteoclast formation or activity. Inhibition of bone
resorption refers to treatment or prevention of bone loss,
especially the inhibition of removal of existing bone either from
the mineral phase and/or the organic matrix phase, through direct
or indirect alteration of osteoclast formation or activity.
[0054] The terms "continuous schedule" or "continuous dosing
schedule", as used herein, mean that the dosing regimen is repeated
until the desired therapeutic effect is achieved. The continuous
schedule or continuous dosing schedule is distinguished from
cyclical or intermittent administration.
[0055] The term "until the desired therapeutic effect is achieved",
as used herein, means that the bisphosphonate compound is
continuously administered, according to the dosing schedule chosen,
up to the time that the clinical or medical effect sought for the
disease or condition is observed by the clinician or researcher.
For methods of treatment of the present invention, the
bisphosphonate compound is continuously administered until the
desired change in bone mass or structure is observed. In such
instances, achieving an increase in bone mass or a replacement of
abnormal bone structure with more normal bone structure are the
desired objectives. For methods of prevention of the present
invention, the bisphosphonate compound is continuously administered
for as long as necessary to prevent the undesired condition. In
such instances, maintenance of bone mass density is often the
objective. Nonlimiting examples of administration periods can range
from about 2 weeks to the remaining lifespan of the mammal. For
humans, administration periods can range from about 2 weeks to the
remaining lifespan of the human, preferably from about 2 weeks to
about 20 years, more preferably from about 1 month to about 20
years, more preferably from about 6 months to about 10 years, and
most preferably from about 1 year to about 10 years.
METHODS OF THE PRESENT INVENTION
[0056] The present invention comprises methods for inhibiting bone
resorption in mammals. The present invention also comprises
treating abnormal bone resorption in mammals. The present invention
also comprises methods for preventing abnormal bone resorption in
mammals. In preferred embodiments of the present invention, the
mammal is a human.
[0057] The methods of the present invention do not have the
disadvantages of current methods of treatment which can cause or
increase the potential for adverse gastrointestinal effects or
which require cumbersome, irregular, or complicated dosing
regimens.
[0058] The present invention comprises a continuous dosing schedule
whereby a unit dosage of the bisphosphonate is regularly
administered according to a dosing interval selected from the group
consisting of once-weekly dosing, twice-weekly dosing, biweekly
dosing, and twice-monthly dosing.
[0059] By once-weekly dosing is meant that a unit dosage of the
bisphosphonate is administered once a week, i.e. one time during a
seven day period, preferably on the same day of each week. In the
once-weekly dosing regimen, the unit dosage is generally
administered about every seven days. A nonlimiting example of a
once-weekly dosing regimen would entail the administration of a
unit dosage of the bisphosphonate every Sunday. It is preferred
that the unit dosage is not administered on consecutive days, but
the once-weekly dosing regimen can include a dosing regimen in
which unit dosages are administered on two consecutive days falling
within two different weekly periods.
[0060] By twice-weekly dosing is meant that a unit dosage of the
bisphosphonate is administered twice a week, i.e. two times during
a seven day period, preferably on the same two days of each weekly
period. In the twice-weekly dosing regimen, each unit dosage is
generally administered about every three to four days. A
nonlimiting example of a twice-weekly dosing regimen would entail
the administration of a unit dosage of the bisphosphonate every
Sunday and Wednesday. It is preferred that the unit dosages are not
administered on the same or consecutive days, but the twice-weekly
dosing regimen can include a dosing regimen in which unit dosages
are administered on two consecutive days within a weekly period or
different weekly periods.
[0061] By biweekly dosing is meant that a unit dosage of the
bisphosphonate is administered once during a two week period, i.e.
one time during a fourteen day period, preferably on the same day
during each two week period. In the twice-weekly dosing regimen,
each unit dosage is generally administered about every fourteen
days. A nonlimiting example of a biweekly dosing regimen would
entail the administration of a unit dosage of the bisphosphonate
every other Sunday. It is preferred that the unit dosage is not
administered on consecutive days, but the biweekly dosing regimen
can include a dosing regimen in which the unit dosage is
administered on two consecutive days within two different biweekly
periods.
[0062] By twice-monthly dosing is meant that a unit dosage of the
bisphosphonate is administered twice, i.e. two times, during a
monthly calendar period. With the twice-monthly regimen, the doses
are preferably given on the same two dates of each month. In the
twice-monthly dosing regimen, each unit dosage is generally
administered about every fourteen to sixteen days. A nonlimiting
example of a biweekly dosing regimen would entail dosing on or
about the first of the month and on or about the fifteenth, i.e.
the midway point, of the month. It is preferred that the unit
dosages are not administered on the same or consecutive days but
the twice-monthly dosing regimen can include a dosing regimen in
which the unit dosages are administered on two consecutive days
within a monthly period, or different monthly periods. The
twice-monthly regimen is defined herein as being distinct from, and
not encompassing, the biweekly dosing regimen because the two
regimens have a different periodicity and result in the
administration of different numbers of dosages over long periods of
time. For example, over a one year period, a total of about twenty
four dosages would be administered according to the twice-monthly
regimen (because there are twelve calendar months in a year),
whereas a total of about twenty six dosages would be administered
according to the biweekly dosing regimen (because there are about
fifty-two weeks in a year).
[0063] In further embodiments or descriptions of the present
invention, the unit dosage is given with a periodicity ranging from
about once every 3 days to about once every 16 days.
[0064] The methods and compositions of the present invention are
useful for inhibiting bone resorption and for treating and
preventing abnormal bone resorption and conditions associated
therewith. Such conditions include both generalized and localized
bone loss. Also, the creation of bone having an abnormal structure,
as in Paget's disease, can be associated with abnormal bone
resorption. The term "generalized bone loss" means bone loss at
multiple skeletal sites or throughout the skeletal system. The term
"localized bone loss" means bone loss at one or more specific,
defined skeletal sites.
[0065] Generalized boss loss is often associated with osteoporosis.
Osteoporosis is most common in post-menopausal women, wherein
estrogen production has been greatly diminished. However,
osteoporosis can also be steroid-induced and has been observed in
males due to age. Osteoporosis can be induced by disease, e.g.
rheumatoid arthritis, it can be induced by secondary causes, e.g.,
glucocorticoid therapy, or it can come about with no identifiable
cause, i.e. idiopathic osteoporosis. In the present invention,
preferred methods include the treatment or prevention of abnormal
bone resorption in osteoporotic humans.
[0066] Localized bone loss has been associated with periodontal
disease, with bone fractures, and with periprosthetic osteolysis
(in other words where bone resorption has occured in proximity to a
prosthetic implant).
[0067] Generalized or localized bone loss can occur from disuse,
which is often a problem for those confined to a bed or a
wheelchair, or for those who have an immobilized limb set in a cast
or in traction.
[0068] The methods and compositions of the present invention are
useful for treating and or preventing the following conditions or
disease states: osteoporosis, which can include post-menopausal
osteoporosis, steroid-induced osteoporosis, male osteoporosis,
disease-induced osteoporosis, idiopathic osteoporosis; Paget's
disease; abnormally increased bone turnover; periodontal disease;
localized bone loss associated with periprosthetic osteolysis; and
bone fractures.
[0069] The methods of the present invention are intended to
specifically exclude methods for the treatment and/or prevention of
prosthesis loosening and prosthesis migration in mammals as
described in PCT application WO 95/30421, to Goodship et al,
published Nov. 16, 1995, which is incorporated by reference herein
in its entirety.
Bisphosphonates
[0070] The methods and compositions of the present invention
comprise a, bisphosphonate. The bisphosphonates of the present
invention correspond to the chemical formula ##STR1## wherein
[0071] A and X are independently selected from the group consisting
of H, OH, halogen, NH.sub.2, SH, phenyl, C1-C30 alkyl, C1-C30
substituted alkyl, C1-C10 alkyl or dialkyl substituted NH.sub.2,
C1-C10 alkoxy, C1-C10 alkyl or phenyl substituted thio, C1-C10
alkyl substituted phenyl, pyridyl, furanyl, pyrrolidinyl,
imidazonyl, and benzyl.
[0072] In the foregoing chemical formula, the alkyl groups can be
straight, branched, or cyclic, provided sufficient atoms are
selected for the chemical formula. The C1-C30 substituted alkyl can
include a wide variety of substituents, nonlimiting examples which
include those selected from the group consisting of phenyl,
pyridyl, furanyl, pyrrolidinyl, imidazonyl, NH.sub.2, C1-C10 alkyl
or dialkyl substituted NH.sub.2, OH, SH, and C1-C10 alkoxy.
[0073] In the foregoing chemical formula, A can include X and X can
include A such that the two moieties can form part of the same
cyclic structure.
[0074] The foregoing chemical formula is also intended to encompass
complex carbocyclic, aromatic and hetero atom structures for the A
and/or X substituents, nonlimiting examples of which include
naphthyl, quinolyl, isoquinolyl, adamantyl, and
chlorophenylthio.
[0075] Preferred structures are those in which A is selected from
the group consisting of H, OH, and halogen, and X is selected from
the group consisting of C1-C30 alkyl, C1-C30 substituted alkyl,
halogen, and C1-C10 alkyl or phenyl substituted thio.
[0076] More preferred structures are those in which A is selected
from the group consisting of H, OH, and Cl, and X is selected from
the group consisting of C1-C30 alkyl, C1-C30 substituted alkyl, Cl,
and chlorophenylthio.
[0077] Most preferred is when A is OH and X is a 3-aminopropyl
moiety, so that the resulting compound is a
4-amino-1-hydroxybutylidene-1,1-bisphosphonate, i.e.
alendronate.
[0078] Pharmaceutically acceptable salts and derivatives of the
bisphosphonates are also useful herein. Nonlimiting examples of
salts include those selected from the group consisting alkali
metal, alkaline metal, ammonium, and mono-, di, tri-, or
tetra-C1-C30-alkyl-substituted ammonium. Preferred salts are those
selected from the group consisting of sodium, potassium, calcium,
magnesium, and ammonium salts. Nonlimiting examples of derivatives
include those selected from the group consisting of esters,
hydrates, and amides.
[0079] "Pharmaceutically acceptable" as used herein means that the
salts and derivatives of the bisphosphonates have the same general
pharmacological properties as the free acid form from which they
are derived and are acceptable from a toxicity viewpoint.
[0080] It should be noted that the terms "bisphosphonate" and
"bisphosphonates", as used herein in referring to the therapeutic
agents of the present invention are meant to also encompass
diphosphonates, biphosphonic acids, and diphosphonic acids, as well
as salts and derivatives of these materials. The use of a specific
nomenclature in referring to the bisphosphonate or bisphosphonates
is not meant to limit the scope of the present invention, unless
specifically indicated. Because of the mixed nomenclature currently
in use by those or ordinary skill in the art, reference to a
specific weight or percentage of a bisphosphonate compound in the
present invention is on an acid active weight basis, unless
indicated otherwise herein. For example, the phrase "about 70 mg of
a bone resorption inhibiting bisphosphonate selected from the group
consisting of alendronate, pharmaceutically acceptable salts
thereof, and mixtures thereof, on an alendronic acid active weight
basis" means that the amount of the bisphosphonate compound
selected is calculated based on 70 mg of alendronic acid.
[0081] Nonlimiting examples of bisphosphonates useful herein
include the following:
[0082] Alendronic acid,
4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid.
[0083] Alendronate (also known as alendronate sodium or monosodium
trihydrate), 4-amino- 1-hydroxybutylidene-1,1-bisphosphonic acid
monosodium trihydrate.
[0084] Alendronic acid and alendronate are described in U.S. Pat.
No. 4,922,007, to Kieczykowski et al., issued May 1, 1990, and U.S.
Pat. No. 5,019,651, to Kieczykowski, issued May 28, 1991, both of
which are incorporated by reference herein in their entirety.
[0085] Cycloheptylaminomethylene-1,1-bisphosphonic acid, YM 175,
Yamanouchi (cimadronate), as described in U.S. Pat. No. 4,970,335,
to Isomura et al., issued Nov. 13, 1990, which is incorporated by
reference herein in its entirety.
[0086] 1,1-dichloromethylene-1,1-diphosphonic acid (clodronic
acid), and the disodium salt (clodronate, Procter and Gamble), are
described in Belgium Patent 672,205 (1966) and J. Org Chem 32, 4111
(1967), both of which are incorporated by reference herein in their
entirety.
[0087] 1-hydroxy-3-(1-pyrrolidinyl)-propylidene-1,1-bisphosphonic
acid (EB-1053).
[0088] 1-hydroxyethane-1,1-diphosphonic acid (etidronic acid).
[0089]
1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic
acid, also known as BM-210955, Boehringer-Mannheim (ibandronate),
is described in U.S. Pat. No. 4,927,814, issued May 22, 1990, which
is incorporated by reference herein in its entirety.
[0090] 6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid
(neridronate).
[0091] 3-(dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic
acid (olpadronate).
[0092] 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid
(pamidronate).
[0093] [2-(2-pyridinyl)ethylidene]-1,1-bisphosphonic acid
(piridronate) is described in U.S. Pat. No. 4,761,406, which is
incorporated by reference in its entirety.
[0094] 1-hydroxy-2-(3-pyridinyl)-ethylidene-1,1-bisphosphonic acid
(risedronate).
[0095] (4-chlorophenyl)thiomethane-1,1-disphosphonic acid
(tiludronate) as described in U.S. Pat. No. 4,876,248, to Breliere
et al., Oct. 24, 1989, which is incorporated by reference herein in
its entirety.
[0096] 1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic
acid (zolendronate).
[0097] Preferred are bisphosphonates selected from the group
consisting of alendronate, cimadronate, clodronate, tiludronate,
etidronate, ibandronate, risedronate, piridronate, pamidronate,
zolendronate, pharmaceutically acceptable salts thereof, and
mixtures thereof.
[0098] More preferred is alendronate, pharmaceutically acceptable
salts thereof, and mixtures thereof.
[0099] Most preferred is alendronate monosodium trihydrate.
Pharmaceutical Compositions
[0100] Compositions useful in the present invention comprise a
pharmaceutically effective amount of a bisphosphonate. The
bisphosphonate is typically administered in admixture with suitable
pharmaceutical diluents, excipients, or carriers, collectively
referred to herein as "carrier materials", suitably selected with
respect to oral administration, i.e. tablets, capsules, elixirs,
syrups, effervescent compositions, powders, and the like, and
consistent with conventional pharmaceutical practices. For example,
for oral administration in the form of a tablet, capsule, or
powder, the active ingredient can be combined with an oral,
non-toxic, pharmaceutically acceptable inert carrier such as
lactose, starch, sucrose, glucose, methyl cellulose, magnesium
stearate, mannitol, sorbitol, croscarmellose sodium and the like;
for oral administration in liquid form, e.g., elixirs and syrups,
effervescent compositions, the oral drug components can be combined
with any oral, non-toxic, pharmaceutically acceptable inert carrier
such as ethanol, glycerol, water and the like. Moreover, when
desired or necessary, suitable binders, lubricants, disintegrating
agents, buffers, coatings, and coloring agents can also be
incorporated. Suitable binders can include starch, gelatin, natural
sugars such a glucose, anhydrous lactose, free-flow lactose,
beta-lactose, and corn sweeteners, natural and synthetic gums, such
as acacia, guar, tragacanth or sodium alginate, carboxymethyl
cellulose, polyethylene glycol, waxes, and the like. Lubricants
used in these dosage forms include sodium oleate, sodium stearate,
magnesium stearate, sodium benzoate, sodium acetate, sodium
chloride and the like. A particularly preferred tablet formulation
for alendronate monosodium trihydrate is that described in U.S.
Pat. No. 5,358,941, to Bechard et al, issued Oct. 25, 1994, which
is incorporated by reference herein in its entirety. The compounds
used in the present method can also be coupled with soluble
polymers as targetable drug carriers. Such polymers can include
polyvinylpyrrolidone, pyran copolymer,
polyhydroxylpropyl-methacrylamide, and the like.
[0101] The precise dosage of the bisphonate will vary with the
dosing schedule, the oral potency of the particular bisphosphonate
chosen, the age, size, sex and condition of the mammal or human,
the nature and severity of the disorder to be treated, and other
relevant medical and physical factors. Thus, a precise
pharmaceutically effective amount cannot be specified in advance
and can be readily determined by the caregiver or clinician.
Appropriate amounts can be determined by routine experimentation
from animal models and human clinical studies. Generally, an
appropriate amount of bisphosphonate is chosen to obtain a bone
resorption inhibiting effect, i.e. a bone resorption inhibiting
amount of the bisphosphonate is administered. For humans, an
effective oral dose of bisphosphonate is typically from about 1.5
to about 6000 .mu.g/kg body weight and preferably about 10 to about
2000 .mu.g/kg of body weight.
[0102] For human oral compositions comprising alendronate,
pharmaceutically acceptable salts thereof, or pharmaceutically
acceptable derivatives thereof, a unit dosage typically comprises
from about 8.75 mg to about 140 mg of the alendronate compound, on
an alendronic acid active weight basis.
[0103] For once-weekly dosing, an oral unit dosage comprises from
about 17.5 mg to about 70 mg of the alendronate compound, on an
alendronic acid active weight basis. Examples of weekly oral
dosages include a unit dosage which is useful for osteoporosis
prevention comprising about 35 mg of the alendronate compound, and
a unit dosage which is useful for treating osteoporosis comprising
about 70 mg of the alendronate compound.
[0104] For twice-weekly dosing, an oral unit dosage comprises from
about 8.75 mg to about 35 mg of the alendronate compounds on an
alendronic acid active weight basis. Examples of twice-weekly oral
dosages include a unit dosage which is useful for osteoporosis
prevention comprising about 17.5 mg of the alendronate compound,
and a unit dosage which is useful for osteoporosis treatment,
comprising about 35 mg of the alendronate compound.
[0105] For biweekly or twice-monthly dosing, an oral unit dosage
comprises from about 35 mg to about 140 mg of the alendronate
compound, on an alendronic acid active weight basis. Examples of
biweekly or twice-monthly oral dosages include a unit dosage which
is useful for osteoporosis prevention comprising about 70 mg of the
alendronate compound, and a unit dosage which is useful for
osteoporosis treatment, comprising about 140 mg of the alendronate
compound.
[0106] Nonlimiting examples of oral compositions comprising
alendronate, as well as other bisphosphonates, are illustrated in
the Examples, below.
Sequential Administration of Histamine H2 Receptor Blockers and/or
Proton Pump Inhibitors with Bisphosphonates
[0107] In further embodiments, the methods and compositions of the
present invention can also comprise a histamine H2 receptor blocker
(i.e. antagonist) and/or a proton pump inhibitor. Histamine H2
receptor blockers and proton pump inhibitors are well known
therapeutic agents for increasing gastric pH. See L. J. Hixson, et
al., Current Trends in the Pharmacotherapy for Peptic Ulcer
Disease, Arch. Intern. Med., vol. 152, pp. 726-732 (April 1992),
which is incorporated by reference herein in its entirety. It is
found in the present invention that the sequential oral
administration of a histamine H2 receptor blocker and/or a proton
pump inhibitor, followed by a bisphosphonate can help to further
minimize adverse gastrointestinal effects. In these embodiments,
the histamine H2 receptor blocker and/or proton pump inhibitor is
administered from about 30 minutes to about 24 hours prior to the
administration of the bisphosphonate. In more preferred
embodiments, the histamine H2 receptor blocker and/or proton pump
inhibitor is administered from about 30 minutes to about 12 hours
prior to the administration of the bisphonate.
[0108] The dosage of the histamine H2 receptor blocker and/or
proton pump inhibitor will depend upon the particular compound
selected and factors associated with the mammal to be treated, i.e.
size, health, etc.
[0109] Nonlimiting examples of histamine H2 receptor blockers
and/or proton pump inhibitors include those selected from the group
consisting of cimetidine, famotidine, nizatidine, ranitidine,
omprazole, and lansoprazole.
Treatment Kits
[0110] In further embodiments, the present invention relates to a
kit for conveniently and effectively carrying out the methods in
accordance with the present invention. Such kits are especially
suited for the delivery of solid oral forms such as tablets or
capsules. Such a kit preferably includes a number of unit dosages.
Such kits can include a card having the dosages oriented in the
order of their intended use. An example of such a kit is a "blister
pack". Blister packs are well known in the packaging industry and
are widely used for packaging pharmaceutical unit dosage forms. If
desired, a memory aid can be provided, for example in the form of
numbers, letters, or other markings or with a calendar insert,
designating the days in the treatment schedule in which the dosages
can be administered. Alternatively, placebo dosages, or calcium or
dietary supplements, either in a form similar to or distinct from
the bisphosphonate dosages, can be included to provide a kit in
which a dosage is taken every day. In those embodiments including a
histamine H2 receptor and/or proton pump inhibitor, these agents
can be included as part of the kit.
EXAMPLES
[0111] The following examples further describe and demonstrate
embodiments within the scope of the present invention. The examples
are given solely for the purpose of illustration and are not to be
construed as limitations of the present invention as many
variations thereof are possible without departing from the spirit
and scope of the invention.
Example 1
Esophageal Irritation Potential
[0112] The esophageal irritation potential of the bisphosphonates
is evaluated using a dog model.
[0113] The experiments demonstrate the relative irritation
potential of the following dosing regimens: placebo (Group 1), a
single high concentration dosage of alendronate monosodium
trihydrate (Group 2), a low concentration dosage of alendronate
monosodium trihydrate administered for five consecutive days
(Groups 3 and 4), a high concentration dosage of alendronate
monosodium trihydrate administered once per week for four weeks
(Group 5), a mid-range concentration dosage of alendronate
monosodium trihydrate administered twice per week for four weeks
(Group 6), a low dosage of risedronate sodium administered for five
consecutive days (Group 7), and a low dosage of tiludronate
disodium administered for five consecutive days (Group 8).
[0114] The following solutions are prepared: [0115] (1) simulated
gastric juice (pH about 2), i.e. the control solution. [0116] (2)
simulated gastric juice (pH about 2) containing about 0.20 mg/mL of
alendronate monosodium trihydrate on an alendronic acid active
basis. [0117] (3) simulated gastric juice (pH about 2) containing
about 0.80 mg/mL of alendronate monosodium trihydrate on an
alendronic acid active basis. [0118] (4) simulated gastric juice
(pH about 2) containing about 0.40 mg/mL of alendronate monosodium
trihydrate on an alendronic acid active basis. [0119] (5) simulated
gastric juice (pH about 2) containing about 0.20 mg/mL of
risedronate sodium on a risedronic acid active basis. [0120] (6)
simulated gastric juice (pH about 2) containing about 4.0 mg/mL of
tiludronate disodium on a tiludronic acid active basis. The
simulated gastric juice is prepared by dissolving about 960 mg of
pepsin (L-585,228000B003, Fisher Chemical) in about 147 mL of 0.90
(wt %) NaCl (aqueous), adding about 3 mL of 1.0 M HCl (aqueous),
and adjusting the volume to about 300 mL with deionized water. The
pH of the resulting solution is measured and if necessary is
adjusted to about 2 using 1.0 M HCl (aqueous) or 1.0 M NaOH
(aqueous).
[0121] The animals used in the experiments are anesthetized and
administered about 50 mL of the appropriate solution over about 30
minutes by infusion into the esophagus using an infusion pump and a
rubber catheter. The following treatment experiments are run:
[0122] Group 1: This control group contains four animals. Each
animal is administered a dosage of about 50 mL of simulated gastric
juice [solution (1)] on each of five consecutive days. The animals
are sacrificed immediately after the last dose is administered.
[0123] Group 2: This group contains four animals. Each animal is
administered a dosage of about 50 mL of simulated gastric juice
containing about 0.20 mg/mL of alendronate [solution (2)] on each
of five consecutive days. The animals are sacrificed immediately
after the last dose is administered. [0124] Group 3: This group
contains five animals. Each animal is administered a dosage of
about 50 mL of simulated gastric juice containing about 0.80 mg/mL
of alendronate [solution (3)] on a single treatment day. The
animals are sacrificed about 24 hours after the dose is
administered. [0125] Group 4: This group contains five animals.
Each animal is administered a dosage of about 50 mL of simulated
gastric juice containing about 0.80 mg/mL of alendronate [solution
(3)] on a single treatment day. The animals are sacrificed about 7
days after the dose is administered. [0126] Group 5: This group
contains six animals. Each animal is administered a dosage of about
50 mL of simulated gastric juice containing about 0.80 mg/mL of
alendronate [solution (3)] once per week, i.e. every seven days,
for four weeks. The animals are administered a total of four
dosages. The animals are sacrificed about 7 days after the last
dose is administered. [0127] Group 6: This group contains six
animals. Each animal is administered a dosage of about 50 mL of
simulated gastric juice containing about 0.40 mg/mL of alendronate
[solution (4)] twice per week, i.e. every three to four days, for
four weeks. The animals are administered a total of eight dosages.
The animals are sacrificed about four days after the last dose is
administered. [0128] Group 7: This group contains eight animals.
Each animal is administered a dosage of about 50 mL of simulated
gastric juice containing about 0.20 mg/mL of risedronate [solution
(5)] on each of five consecutive days. The animals are sacrificed
immediately after the last dose is administered. [0129] Group 8:
This group contains four animals. Each animal is administered a
dosage of about 50 mL of simulated gastric juice containing about
4.0 mg/mL of tiludronate [solution (6)] on each of five consecutive
days. The animals are sacrificed immediately after the last dose is
administered.
[0130] The esophagus from each sacrificed animal is removed and
prepared for histopathology using standard techniques by embedding
the tissue in paraffin, staining with hematoxylin and eosin. The
sections are examined microscopically. The histopathology results
are summarized in Table 1.
[0131] For the Group 1 animals (control group), the
photomicrographs show that the esophagus is normal with an intact
epithelium and absence of inflammatory cells in the submucosa. FIG.
1 is a representative photomicrograph from a Group 1 animal.
[0132] For the Group 2 animals, the photomicrographs show that the
esophagus exhibits deep ulceration of the epithelial surface and
marked submucosal inflammation and vacuolation. FIG. 2 is a
representative photomicrograph from a Group 2 animal.
[0133] For the Group 3 animals, the photomicrographs show that the
esophagus has an intact epithelial surface with very slight
submucosal inflammation and vacuolation. FIG. 3 is a representative
photomicrograph from a Group 3 animal.
[0134] For the Group 4 animals, the photomicrographs show that the
esosphagus has an intact epithelium with either minimal
inflammation (two of the five animals) or no inflammation (three of
the five animals) and no vacuolation. FIG. 4 is a representative
photomicrograph from a Group 4 animal exhibiting minimal
inflammation.
[0135] For the Group 5 animals, the photomicrographs show that the
esophagus is normal with an intact epithelium and absence of
inflammatory cells in the submucosa. FIG. 5 is a representative
photomicrograph from a Group 5 animal.
[0136] For the Group 6 animals, the photomicrographs show that the
esophagus exhibits deep ulceration of the epithelial surface and
marked submucosal inflammation and vacuolation. FIG. 6 is a
representative photomicrograph from a Group 6 animal.
[0137] For the Group 7 animals, the photomicrographs show that the
esophagus exhibits deep ulceration of the epithelial surface and
marked submucosal inflammation and vacuolation. FIG. 7 is a
representative photomicrograph from a Group 7 animal.
[0138] For the Group 8 animals, the photomicrographs show that the
esophagus exhibits slight ulceration of the epithelial surface and
slight submucosal inflammation and vacuolation. FIG. 8 is a
representative photomicrograph from a Group 8 animal.
[0139] These experiments demonstrate that considerably less
esophageal irritation (comparable to control Group 1)is observed
from the administration of a single high concentration dosage of
alendronate (Groups 3 and 4) versus administration of low
concentration dosages on consecutive days (Group 2). These
experiments also demonstrate consideraly less esophageal irritation
is observed from the administration of a single high concentration
of alendronate on a weekly basis (Group 5) or twice-weekly basis
(Group 6) versus administration of low concentration dosages on
consecutive days (Group 2). These experiments also demonstrate that
when other bisphosphonates such as risedronate (Group 7) or
tiludronate (Group 8) are administered at low dosages on
consecutive days that the esophageal irritation potential is high.
TABLE-US-00001 TABLE 1 Esophageal Irritation Potential Studies
Active Agent Dosing Sacrifice Group mg/mL Schedule Time
Histo-pathology 1 0 1X daily immediately Normal. Intact (n = 4) for
5 days after epithelium and last absence of dosing inflammatory
cells in the submucosa. 2 Alendronate 1X daily immediately Deep
ulceration of (n = 4) 0.20 for 5 days after epithelial surface.
last Marked submucosal dosing inflammation and vacuolation. 3
Alendronate 1X 24 hours Intact epithelial (n = 5) 0.80 after
surface with very dosing slight submucosal inflammation and
vacuolation. 4 Alendronate 1X 7 days Intact epithelium (n = 5) 0.80
after with either minimal dosing inflammation (2 of 5 animals) or
no inflammation (3 of 5 animals) and no vacuolation. 5 Alendronate
1X 7 days Intact epithelium (n = 6) 0.80 weekly after last with no
for a total dosing inflammation and no of 4 doses vacuolation. 6
Alendronate 2X immediately Deep ulceration of (n = 6) 0.40 weekly
after epithelial surface. for 4 last Marked submucosal weeks dosing
inflammation and vacuolation. 7 Risedronate 1X daily immediately
Deep ulceration of (n = 8) 0.20 for 5 days after epithelial surface
(4 last of 8 animals). dosing Marked submucosal inflammation and
vacuolation. 8 Tiludronate 1X daily 24 hours Slight submucosal (n =
4) 4.0 for 5 days after last inflammation and dosing vacuolation (3
of 4 animals, including 1 of these animals with slight
ulceration).
Example 2
Once-Weekly Dosing Regimen.
Treatment of Osteoporosis.
[0140] Alendronate tablets or liquid formulations containing about
70 mg of alendronate, on an alendronic acid active basis, are
prepared (see EXAMPLES 7 and 8). The tablets or liquid formulations
are orally administered to a human patient once-weekly, i.e.
preferably about once every seven days (for example, every Sunday),
for a period of at least one year. This method of administration is
useful and convenient for treating osteoporosis and for minimizing
adverse gastrointestinal effects, particularly adverse esophageal
effects. This method is also useful for improving patient
acceptance and compliance.
Prevention of Osteoporosis.
[0141] Alendronate tablets or liquid formulations containing about
35 mg of alendronate, on an alendronic acid active basis, are
prepared (see EXAMPLES 7 and8). The tablets or liquid formulations
are orally administered to a human patient once-weekly, i.e.
preferably about once every seven days (for example, every Sunday),
for a period of at least one year. This method of administration is
useful and convenient for preventing osteoporosis and for
minimizing adverse gastrointestinal effects, particularly adverse
esophageal effects. This method is also useful for improving
patient acceptance and compliance.
Example 3
Twice-Weekly Dosing Regimen.
Treatment of Osteoporosis.
[0142] Alendronate tablets or liquid formulations containing about
35 mg of alendronate, on an alendronic acid active basis, are
prepared (see EXAMPLES 7 and 8). The tablets or liquid formulations
are orally administered to a human patient twice-weekly, preferably
about once every three or four days (for example, every Sunday and
Wednesday), for a period of at least one year. This method of
administration is useful and convenient for treating osteoporosis
and for minimizing adverse gastrointestinal effects, particularly
adverse esophageal effects. This method is also useful for
improving patient acceptance and compliance.
Prevention of Osteoporosis.
[0143] Alendronate tablets or liquid formulations containing about
17.5 mg of alendronate, on-an alendronic acid active basis, are
prepared (see EXAMPLES 7 and8). The tablets or liquid formulations
are orally administered to a human patient twice-weekly, preferably
about once every three or four days (for example, every Sunday and
Wednesday), for a period of at least one year. This method of
administration is useful and convenient for preventing osteoporosis
and for minimizing adverse gastrointestinal effects, particularly
adverse esophageal effects. This method is also useful for
improving patient acceptance and compliance.
Example 4
Biweekly Dosing Regimen
Treatment of Osteoporosis.
[0144] Alendronate tablets or liquid formulations containing about
140 mg of alendronate, on an alendronic acid active basis, are
prepared (see EXAMPLES 7 and 8). The tablets or liquid formulations
are orally administered to a human patient biweekly, i.e.
preferably about once every fourteen days (for example, on
alternate Sundays), for a period of at least one year. This method
of administration is useful and convenient for treating
osteoporosis and for minimizing adverse gastrointestinal effects,
particularly adverse esophageal effects. This method is also useful
for improving patient acceptance and compliance.
Prevention of Osteoporosis.
[0145] Alendronate tablets or liquid formulations containing about
70 mg of alendronate, on an alendronic acid active basis, are
prepared (see EXAMPLES 7 and 8). The tablets or liquid formulations
are orally administered to a human patient biweekly, i.e.
preferably about once every fourteen days (for example, on
alternate Sundays), for a period of at least one year. This method
of administration is useful and convenient for preventing
osteoporosis and for minimizing adverse gastrointestinal effects,
particularly adverse esophageal effects. This method is also useful
for improving patient acceptance and compliance.
Example 5
Twice-Monthly Dosing Regimen.
Treatment of Osteoporosis.
[0146] Alendronate tablets or liquid formulations containing about
140 mg of alendronate, on an alendronic acid active basis, are
prepared (see EXAMPLES 7 and 8). The tablets or liquid formulations
are orally administered to a human twice-monthly, i.e. preferably
about once every fourteen to sixteen days (for example, on about
the first and fifteenth of each month), for a period of at least
one year. This method of administration is useful and convenient
for treating osteoporosis and for minimizing adverse
gastrointestinal effects, particularly adverse esophageal effects.
This method is also useful for improving patient acceptance and
compliance.
Prevention of Osteoporosis.
[0147] Alendronate tablets or liquid formulations containing about
70 mg of alendronate, on an alendronic acid active basis, are
prepared (see EXAMPLES 7 and 8). The tablets or liquid formulations
are orally administered to a human patient biweekly, i.e.
preferably once every fourteen to sixteen days (for example, on
about the first and fifteenth of each month), for a period of at
least one year. This method of administration is useful and
convenient for preventing osteoporosis and for minimizing adverse
gastrointestinal effects, particularly adverse esophageal effects.
This method is also useful for improving patient acceptance and
compliance.
Example 6
[0148] In further embodiments, alendronate tablets or liquid
formulations are orally dosed, at the desired dosage, according to
the dosing schedules of EXAMPLES 2-5, for treating or preventing
other disorders associated with abnormal bone resorption.
[0149] In yet further embodiments, other bisphosphonate compounds
are orally dosed, at the desired dosage, according to the dosing
schedules of EXAMPLES 2-5, for treating or preventing osteoporosis
or for treating or preventing other conditions associated with
abnormal bone resorption.
Example 7
Bisphosphonate Tablets.
[0150] Bisphosphonate containing tablets are prepared using
standard mixing and formation techniques as described in U.S. Pat.
No. 5,358,941, to Bechard et al., issued Oct. 25, 1994, which is
incorporated by reference herein in its entirety.
[0151] Tablets containing about 35 mg of alendronate, on an
alendronic acid active basis, are prepared using the following
relative weights of ingredients. TABLE-US-00002 Ingredient Per
Tablet Per 4000 Tablets Alendronate Monosodium 45.68 mg 182.72 g
Trihydrate Anhydrous Lactose, NF 71.32 mg 285.28 g Microcrystalline
Cellulose, 80.0 mg 320.0 g NF Magnesium Stearate, NF 1.0 mg 4.0 g
Croscarmellose Sodium, NF 2.0 mg 8.0 g
[0152] The resulting tablets are useful for administration in
accordance with the methods of the present invention for inhibiting
bone resorption.
[0153] Similarly, tablets comprising other relative weights of
alendronate, on an alendronic acid active basis are prepared: e.g.,
about 8.75, 17.5, 70, and 140 mg per tablet. Also, tablets
containing other bisphosphonates at appropriate active levels are
similarly prepared: e.g., cimadronate, clodronate, tiludronate,
etidronate, ibandronate, risedronate, piridronate, pamidronate,
zolendronate, and pharmaceutically acceptable salts thereof. Also,
tablets containing combinations of bisphosphonates are similarly
prepared.
Example 8
Liquid Bisphosphonate Formulation.
[0154] Liquid bisphosphonate formulations are prepared using
standard mixing techniques.
[0155] A liquid formulation containing about 70 mg of alendronate
monosodium trihydrate, on an alendronic acid active basis, per
about 75 mL of liquid is prepared using the following relative
weights of ingredients. TABLE-US-00003 Ingredient Weight
Alendronate Monosodium 91.35 mg Trihydrate Sodium Propylparaben
22.5 mg Sodium Butylparaben 7.5 mg Sodium Citrate Dihydrate 1500 mg
Citric Acid Anhydrous 56.25 mg Sodium Saccharin 7.5 mg Water qs 75
mL 1 N Sodium Hydroxide (aq) qs pH 6.75
[0156] The resulting liquid formulation is useful for
administration as a unit dosage in accordance with the methods of
the present invention for inhibiting bone resorption.
[0157] Similarly, liquid formulations comprising other relative
weights of alendronate, on an alendronic acid active basis, per
unit dosage are prepared: e.g., about 8.75, 17.5, 35, and 140 mg
per 75 mL volume. Also, the liquid formulations are prepared to
provide other volumes for the unit dosage, e.g. about 135 mL. Also,
the liquid formulations are prepared containing other
bisphosphonates at appropriate active levels: e.g., cimadronate,
clodronate, tiludronate, etidronate, ibandronate, risedronate,
piridronate, pamidronate, zolendronate, and pharmaceutically
acceptable salts thereof. Also, liquid formulations containing
combinations of bisphosphonates are similarly prepared.
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