U.S. patent application number 12/183359 was filed with the patent office on 2008-11-20 for low dosage forms of risedronate or its salts.
Invention is credited to David Ernest Burgio, JR., Richard John Dansereau.
Application Number | 20080287400 12/183359 |
Document ID | / |
Family ID | 46330326 |
Filed Date | 2008-11-20 |
United States Patent
Application |
20080287400 |
Kind Code |
A1 |
Dansereau; Richard John ; et
al. |
November 20, 2008 |
Low Dosage Forms Of Risedronate Or Its Salts
Abstract
Oral dosage forms comprising risedronate or a salt thereof, a
chelating agent, and means for effecting delayed release of the
risedronate (or salt) immediate release of the oral dosage form to
the small intestine of the mammal subject and pharmaceutically
effective absorption of the bisphosphonate with or without food or
beverages. The present invention substantially alleviates the
interaction between the risedronate (or salt) and food or
beverages, which interaction results in the active ingredient not
being available for absorption. The resulting oral dosage form may
thus be taken with or without food. Further, disclosed is delivery
of risedronate and the chelating agent to the small intestine,
substantially alleviating the upper GI irritation associated with
bisphosphonate therapies. These benefits simplify previously
complex treatment regimens and can lead to increased patient
compliance with bisphosphonate therapies.
Inventors: |
Dansereau; Richard John;
(Cincinnati, OH) ; Burgio, JR.; David Ernest;
(Liberty Township, OH) |
Correspondence
Address: |
THE PROCTER & GAMBLE COMPANY;Global Legal Department - IP
Sycamore Building - 4th Floor, 299 East Sixth Street
CINCINNATI
OH
45202
US
|
Family ID: |
46330326 |
Appl. No.: |
12/183359 |
Filed: |
July 31, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11286875 |
Nov 23, 2005 |
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12183359 |
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11106816 |
Apr 15, 2005 |
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11286875 |
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60573881 |
May 24, 2004 |
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Current U.S.
Class: |
514/89 |
Current CPC
Class: |
A61K 9/2059 20130101;
A61K 9/4891 20130101; A61P 19/08 20180101; A61P 19/10 20180101;
A61K 9/282 20130101; A61K 31/198 20130101; A61K 2300/00 20130101;
A61K 9/2054 20130101; A61K 9/2886 20130101; A61K 31/663 20130101;
A61K 31/198 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 31/663 20130101; A61K 9/2846 20130101; A61K 9/0053 20130101;
A61K 9/2866 20130101; A61K 31/675 20130101; A61K 45/06 20130101;
A61K 9/2013 20130101; A61K 31/675 20130101 |
Class at
Publication: |
514/89 |
International
Class: |
A61K 31/675 20060101
A61K031/675; A61P 19/10 20060101 A61P019/10 |
Claims
1. An oral dosage form comprising: (a) from about 50 mg to less
than 150 mg of a bisphosphonate selected from the group consisting
of risedronate and salts thereof; (b) from about 10 mg to about
1000 mg of a chelating agent; and (c) a delayed release mechanism
to immediately release the bisphosphonate and the chelating agent
in the small intestine.
2. The oral dosage form of claim 1 wherein the bisphosphonate is
risedronate sodium.
3. The oral dosage form of claim 2 wherein the chelating agent is
selected from the group consisting of sodium or disodium
ethylenediaminetetraacetate, citric acid, sodium hexametaphosphate,
salts thereof, and combinations thereof.
4. The oral dosage form of claim 3 wherein the chelating agent is
disodium EDTA.
5. The oral dosage form of claim 2 wherein the delayed release
mechanism is selected from the group consisting of pH triggered
delivery systems, time dependent delivery systems and mixtures
thereof.
6. The oral dosage form of claim 5 wherein the delayed release
mechanism is a pH triggered delivery system.
7. The oral dosage form of claim 6 wherein the pH triggered
delivery system comprises an enteric coating.
8. The oral dosage form of claim 4 wherein the delayed release
mechanism comprises methacrylic acid copolymer.
9. The oral dosage form of claim 4 comprising from about 55 mg to
about 500 mg of the disodium EDTA.
10. The oral dosage form of claim 9 comprising from about 75 mg to
about 250 mg of the disodium EDTA.
11. The oral dosage form of claim 10 comprising about 100 mg of the
risedronate sodium.
12. The oral dosage form of claim 10 wherein the delayed release
mechanism comprises a methacrylic acid copolymer.
13. The oral dosage form of claim 12 comprising about 100 mg of the
risedronate sodium.
14. The oral dosage form of claim 13 comprising about 100 mg of the
disodium EDTA.
15. A method for treating a disease characterized by abnormal
calcium and phosphate metabolism comprising administering to a
human or other mammal in need thereof the oral dosage form of claim
2.
16. The method of claim 15 wherein the disease is selected from the
group consisting of osteoporosis, Paget's disease,
hyperparathyroidism, hypercalcemia of malignancy, and osteolytic
bone metastasis, and combinations thereof.
17. The method of claim 16 comprising treatment of
osteoporosis.
18. The method of claim 17 wherein the oral dosage form is
administered continuously on a monthly basis.
19. The method of claim 18 wherein the oral dosage form is
administered with or without food.
20. The method of claim 18 wherein the oral dosage form comprises
about 100 mg of risedronate sodium.
21. The method of claim 20 wherein the oral dosage form comprises
about 100 mg of disodium EDTA.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation-in-part of U.S.
application Ser. No. 11/286,875, filed Nov. 23, 2005, which is a
continuation-in-part of U.S. application Ser. No. 11/106,816, filed
Apr. 15, 2005, which claims the benefit of U.S. Provisional
Application Ser. No. 60/573,881, May 24, 2004.
FIELD OF THE INVENTION
[0002] The present invention relates to oral dosage forms of
risedronate comprising risedronate, a chelating agent for enabling
administration of risedronate with food, and means for effecting
delayed release of risedronate and the chelating agent in the small
intestine. The oral dosage forms of the invention provide delivery
of the pharmaceutical composition to the small intestine of the
mammal subject and provide pharmaceutically effective absorption of
risedronate when administered with or without food or beverages.
The present invention further relates to a method of treating or
preventing diseases characterized by abnormal calcium and phosphate
metabolism comprising administering to a human or other mammal in
need thereof the oral dosage form described herein.
BACKGROUND OF THE INVENTION
[0003] Bisphosphonates were first developed to complex calcium in
hard water to improve detergent performance. Bisphosphonates have
since been found to be useful in the treatment and prevention of
diseases or conditions characterized by abnormal calcium and
phosphate metabolism. Such conditions may be divided into two broad
categories: [0004] 1. Conditions which are characterized by
anomalous mobilization of calcium and phosphate leading to general
or specific bone loss or excessively high calcium and phosphate
levels in the fluids of the body. Such conditions are sometimes
referred to herein as pathological hard tissue demineralization.
[0005] 2. Conditions which cause or result from deposition of
calcium and phosphate anomalously in the body. These conditions are
sometimes referred to herein as pathological calcifications.
[0006] The first category includes osteoporosis, a condition in
which bone hard tissue is lost disproportionately to the
development of new hard tissue. Essential quantities of cancellous
bone are lost, and marrow and bone spaces become larger, resulting
in reduced cancellous bone strength. Bone also becomes less dense
and fragile. Osteoporosis can be sub-classified as senile, drug
induced (e.g., adrenocorticoid, as can occur in steroid therapy),
disease induced (e.g., arthritic and tumor), etc., however the
manifestations are similar. Another condition in the first category
is Paget's disease (osteitis deformans). In this disease,
dissolution of normal bone occurs, which is then haphazardly
replaced by soft, poorly mineralized tissue such that the bone
becomes deformed from pressures of weight bearing, particularly in
the tibia and femur. Hyperparathyroidism, hypercalcemia of
malignancy, and osteolytic bone metastasis are conditions also
included in the first category.
[0007] The second category, involving conditions manifested by
anomalous calcium and phosphate deposition, includes myositis
ossificans progressiva, calcinosis universalis, and such
afflictions as arthritis, neuritis, bursitis, tendonitis, and other
inflammatory conditions which predispose involved tissue to
deposition of calcium phosphates.
[0008] Bisphosphonates tend to inhibit the resorption of bone
tissue, which is beneficial to patients suffering from excessive
bone loss. However, many of the early bisphosphonates, such as
ethane-1,1-diphosphonic acid (EHDP),
propane-3-amino-1-hydroxy-1,1-diphosphonic acid (APD), and
dichloromethane diphosphonic acid (Cl.sub.2MDP), have the
propensity of inhibiting bone mineralization when administered at
high dosage levels. Although more biologically potent
bisphosphonates exist, which can be administered at lower dosage
levels (such as
1-hydroxy-2-(3-pyridinyl)-ethylidene-1,1-bisphosphonic acid
(risedronate), alendronate, ibandronate, and zoledronate), oral
administration of bisphosphonates sometimes results in patient
complaints shortly after dosing. These complaints are usually
characterized by the patients as heartburn, esophageal burning,
pain and/or difficulty upon swallowing, and/or pain existing behind
and/or mid-sternum. It is hypothesized that this irritation results
from the bisphosphonate tablet adhering to epithelial and mucosal
tissues, resulting in the topical irritation thereof. In order to
avoid potential upper gastrointestinal irritation, patients taking
bisphosphonates are instructed to take their medication with a full
glass of water, and to remain upright for at least thirty minutes
after taking an oral dose of a bisphosphonate.
[0009] It is known that oral doses of bisphosphonates are poorly
absorbed (less than 1% of the oral dose) in the gastrointestinal
(GI) tract. See Ezra et al., Adv. Drug Del. Rev. 42: 175-95 (2000).
Several approaches have been suggested for increasing absorption of
oral bisphosphonates throughout the GI tract. These approaches
include modifying the permeability properties of the intestinal
mucosa (e.g., through the use of absorption enhancers), or altering
the physical or chemical properties of the bisphosphonate compounds
themselves (e.g., through prodrugs).
[0010] While the use of absorption enhancers, such as
ethylenediaminetetraacetic acid (EDTA), that increase intestinal
permeability at high doses, has been proposed as a means of
increasing absorption of oral bisphosphonates, the applicability of
EDTA as an agent in human pharmacotherapy has been thought to be
"impossible" in light of the effects of EDTA on mucosal integrity.
Ezra et al., Adv. Drug Del. Rev. 42: 185 (2000). Still others have
concluded that the high amount of EDTA required to effect an
increase in GI absorption would exclude the agent as a candidate
for use in oral bisphosphonate therapies. See Janner et al.,
Calcif. Tissue Int. 49: 280-83 (1991).
[0011] While the primary site of bisphosphonate absorption is the
small intestine, bisphosphonates such as risedronate have similar
absorption throughout the small intestine independent of where it
was delivered. See Mitchell et al., Pharm Res., Vol. 15, No. 2:
228-232 (1998). Thus targeted delivery of the bisphosphonate alone
to the small intestine would not increase absorption or efficacy of
the bisphosphonate. However, others have attempted to increase the
absorption of bisphosphonates by increasing the permeability of the
intestinal mucosa through delivery of microparticles of chelating
agents and bisphosphonate to the reported site of absorption
(BR2001-006601).
[0012] Bisphosphonates such as risedronate and alendronate have
been approved by a number of regulatory agencies as being effective
in the treatment of various bone pathologies. However, interactions
between bisphosphonates and foods and minerals (especially cations
like calcium, magnesium, aluminum, and iron-containing foods or
supplements) cause less of the bisphosphonate to be available for
absorption. For example, in Mitchell et. al., Br. J. Clin.
Pharmacol. 48: 536-542 (1999), it was demonstrated that
administration of risedronate within 30 minutes of a meal reduced
the amount absorbed by 50% compared to administration in the
fasting state. In order to reduce this food effect, the labeling of
oral bisphosphonate products instruct patients to take their
medication at least thirty minutes or in the case of ibandronate
sixty minutes, before the first food of the day, and are instructed
to take their calcium supplements at another time of the day, or on
a day when they are not taking an oral dose of a bisphosphonate.
These dosing instructions can seem complex and inconvenient to the
patient, which can lead to poor patient compliance.
[0013] There is an ongoing need to develop an oral dosage form of a
bisphosphonate which can be taken with or without food or beverages
(i.e., has pharmaceutically effective absorption regardless of food
or beverage intake), at the preference of the patient, and which
does not produce upper gastrointestinal irritation.
[0014] It has been found that an oral dosage form comprising
risedronate, a sufficient amount of chelating agent to bind the
ions and minerals in food, and a means for effecting delayed
release of risedronate and the chelating agent in the small
intestine is useful in providing immediate release of risedronate
to the small intestine, as well as pharmaceutically effective
absorption of risedronate when administered with or without food or
beverages. The oral dosage forms of the present invention may be
taken with or without food or beverages, thus simplifying the
bisphosphonate treatment therapy and leading to increased patient
compliance and convenience. Substantial reduction in the food
effect using the present invention may not only allow the new
formulation to be taken with or without food, but also achieve the
same clinical benefit at a lower dose relative to known products.
Further, the oral dosage forms of the invention provide for delayed
release of risedronate and the chelating agent in the small
intestine, which may alleviate the upper gastrointestinal
irritation experienced with other oral bisphosphonate dosage forms
and the need to remain upright for thirty minutes post-dose
administration.
SUMMARY OF THE INVENTION
[0015] The present invention relates to an oral dosage form
comprising: [0016] (a) from about 50 mg to less than 150 mg of a
bisphosphonate selected from the group consisting of risedronate
and salts thereof; [0017] (b) from about 10 mg to about 1000 mg of
a chelating agent; and [0018] (c) a delayed release mechanism to
immediately release the risedronate and the chelating agent in the
small intestine.
[0019] The dosage forms of the present invention provide an
immediate release of risedronate and the chelating agent to the
small intestine of the mammal subject and pharmaceutically
effective absorption of risedronate active ingredient when
administered with or without food or beverages.
[0020] The present invention substantially alleviates the
interaction between risedronate and food, which interaction results
in decreased absorption of risedronate. The resulting novel oral
dosage form may thus be taken with or without food or beverages,
which simplifies previously complex treatment regimens and can lead
to increased patient compliance with bisphosphonate therapies and
if the patients are compliant their disease can be better treated.
The invention further alleviates the potential for upper
gastrointestinal irritation associated with immediate release oral
dosage forms of bisphosphonates, by delaying release of the
bisphosphonate active ingredient until the bisphosphonate and the
chelating agent reach the small intestine.
[0021] The present invention further relates to a method of
treating or preventing diseases characterized by abnormal calcium
and phosphate metabolism comprising administering to a human or
other mammal in need thereof the oral dosage form described
herein.
[0022] The oral dosage form may be continuously administered on a
monthly basis, i.e., once every thirty days or once every calendar
month.
[0023] The invention further relates to a kit comprising one or
more oral dosage forms of the present invention and means for
facilitating compliance with methods of this invention.
DETAILED DESCRIPTION OF THE INVENTION
[0024] The term "immediate release" as used herein means
dissolution of the core tablet in less than 60 minutes, when
measured by standard USP definitions. For example, the USP
specifies that all tablets and capsules are subject, to a general
dissolution standard of not less than 75% of the core content is
dissolved in not more than 45 minutes in 900 mL of water, using the
apparatus, procedures, and interpretation presented in the United
States Pharmacopeia chapter, Dissolution, page 959. For this
purpose, 75% is Q, and conformance is demonstrated with either one
of Apparatus 1 at 100 rpm or Apparatus 2 at 50 rpm."
[0025] The terms "continuous" or "continuously," as used herein,
mean at regular specified intervals. For example, a continuous
schedule according to a dosing regimen of once monthly means that
the active is given one time per every thirty days or one time per
calendar month for an unspecified period of time or for as long as
treatment is necessary.
[0026] The term "delayed release or delayed delivery," as used
herein, refers to formulating the pharmaceutical composition
comprising risedronate and the chelating agent so that their
release will be accomplished at some generally predictable location
in the small intestine more distal to that which would have been
accomplished had there been no alteration in the delivery of the
risedronate and the chelating agent.
[0027] The term "nutrient," as used herein, means any nutritional
or dietary supplement including but not limited to vitamins,
minerals, amino acids, herbs or other botanicals, or concentrates,
metabolites, constituents, extracts, or combinations of the
same.
[0028] The term "pharmaceutical composition," as used herein, means
an oral dosage form comprised of a safe and effective amount of
risedronate and one or more pharmaceutically-acceptable excipients
including at least one chelating agent. The pharmaceutical
compositions described herein are comprised of from 0.5% to 75%,
preferably from 1% to 40% of risedronate and from 25% to 99.5%,
preferably from 60% to 99% of pharmaceutically-acceptable
excipients including at least one chelating agent.
[0029] The term "safe and effective amount," as used herein, means
an amount of a compound or composition high enough to significantly
positively modify the symptoms and/or condition to be treated, but
low enough to avoid serious side effects (at a reasonable risk
benefit ratio), within the scope of sound medical judgment. The
safe and effective amount of active ingredient for use in the
method of the invention herein will vary with the particular
condition being treated, the age and physical condition of the
patient to be treated, the severity of the condition, the duration
of the treatment, the nature of concurrent therapy, the particular
active ingredient being employed, the particular
pharmaceutically-acceptable excipients utilized, and like factors
within the knowledge and expertise of the attending physician.
[0030] The term "pharmaceutically effective absorption" as used
herein means an amount of a chelating compound high enough to
significantly bind the metal ions and minerals in food but low
enough not to significantly alter absorption of risedronate as
compared to absorption in the fasted state. That is, absorption is
similar with or without food. Given the high variability of
bisphosphonate absorption, fed exposure within about 50% of fasting
exposure is expected to be pharmaceutically effective
absorption.
[0031] The term "oral dosage form," as used herein, means any
pharmaceutical composition intended to be delivered or released to
the small intestine of a human or other mammal via the mouth of
said human or other mammal.
[0032] The term "unit dose" or "unit dosage" means a dosage form
containing an amount of pharmaceutical active or nutrient suitable
for administration in one single dose, according to sound medical
practice. The present invention is particularly useful for the
administration of unit doses in the form of tablets and
capsules.
[0033] The term "gastrointestinal tract" or "GI tract," as used
herein, relates to the alimentary canal, i.e., the
musculo-membranous tube about thirty feet in length, extending from
the mouth to the anus. The term "upper gastrointestinal tract," as
used herein, means the buccal cavity, the pharynx, the esophagus,
and the stomach. The term "lower gastrointestinal tract," as used
herein, means the small intestine and the large intestine.
[0034] The term "small intestine," as used herein, means the part
of the small intestine consisting of just distal to the stomach
(the duodenum, the jejunum, and the ileum), i.e., that portion of
the intestinal tract just distal to the duodenal sphincter of the
fundus of the stomach and proximal to the large intestine. The term
"large intestine," as used herein, means the part of the lower
gastrointestinal tract including the ascending colon, the
transverse colon, the descending colon, the sigmoid colon, and the
rectum
Risedronate
[0035] The terms "bisphosphonate" and "diphosphonate," as used
herein, include acids, salts, esters, hydrates, polymorphs,
hemihydrates, solvates, and derivatives thereof. The
bisphosphonates of the present invention include those forms of
1-hydroxy-2-(3-pyridinyl)-ethylidene-1,1-bisphosphonic acid
(risedronate) as described in U.S. Pat. No. 5,583,122, to Benedict
et al., issued Dec. 10, 1996; U.S. Pat. No. 6,410,520 B2, to Cazer
et al., issued Jun. 25, 2002
[0036] Non-limiting examples of salts useful herein include those
selected from the group consisting of alkali metal, alkaline metal,
ammonium, and mono-, di-, tri-, or
tetra-C.sub.1-C.sub.30-alkyl-substituted ammonium. Preferred salts
are those selected from the group consisting of sodium, potassium,
and ammonium salts.
[0037] Mixed nomenclature is currently in use by those of ordinary
skill in the art, for example reference to a specific weight or
percentage of a bisphosphonate active ingredient is on an anhydrous
monosodium salt basis for risedronate. As an example, the phrase
"about 100 mg of risedronate, pharmaceutically acceptable salts
thereof, and mixtures thereof, on an anhydrous monosodium salt
basis" means that the amount of the risedronate compound selected
is calculated based on about 100 mg of anhydrous risedronate
monosodium salt.
[0038] As is discovered herein, substantial reduction in the food
effect using the present invention may not only allow the new
formulation to be taken with or without food, but also achieve the
same clinical benefit at a lower dose relative to known products.
The oral dosage form contains from about 50 mg to less than 150 mg
of the risedronate, alternatively from about 75 to about 125 mg of
the risedronate, and alternatively about 100 mg of the risedronate
(all on a risedronate anhydrous monosodium salt basis).
Chelating Agent
[0039] The term "chelating agent," as used herein, means a molecule
containing two or more electron donor atoms that can form
coordinate bonds to a single metal ion. The term "chelating agent"
is understood to include the chelating agent as well as salts
thereof. For example, the term "chelating agent" includes citric
acid as well as its salt forms.
[0040] The most common and widely used chelating agents coordinate
to metal atoms through oxygen or nitrogen donor atoms, or both.
Other less common chelating agents coordinate through sulfur in the
form of --SH (thiol or mercapto) groups. After the first coordinate
bond is formed, each successive donor atom that binds creates a
ring containing the metal atom. A chelating agent may be bidentate,
tridentate, tetradentate, etc., depending upon whether it contains
two, three, four, or more donor atoms capable of binding to the
metal atom. See Kirk-Othmer Encyclopedia of Chemical Technology
(4th ed. 2001).
[0041] In homogeneous dilute solutions, the equilibrium constant
for the formation of the complex from the solvated metal ion (e.g.,
calcium) and the chelating agent in its fully dissociated form is
called the formation or stability constant, K. The practical
significance of formation constants is that a high log K value
means a large ratio of chelated to unchelated (or free) metal ion,
when equivalent amounts of metal ion and chelating agent are
present. Higher ratios (or difference if K is expressed in log
units) of the chelating agent and the bisphosphonate complexation
constants are preferred in order to have nearly all of the metal
ion complexed to the chelating agent instead of the bisphosphonate.
For example, for equal molar amounts of both bisphosphonate and the
chelating agent, in order for the metal ions to be 99% complexed to
the chelating agent, the chelating agent must have a log K which is
at least 4 units higher than the bisphosphonate-metal ion complex.
The other technique which can be used to favor the chelating
agent-metal ion complex over that of the bisphosphonate-metal ion
complex is to add a molar excess of the chelating agent which
relies on the law of mass action to favor formation of the
chelating agent-metal ion complex.
[0042] Although pH and solution concentration can affect the
formation constant, in general, the log K of the chelating agent is
preferably at least equal to that of the bisphosphonate. In other
instances the log K of the chelating agent is 2 to 5 units higher
than that of the bisphosphonate. In other instances, the chelating
agent is present at a molar excess to that of the bisphosphonate.
The chelating agent in such instances is present in at least a 2:1
molar ratio of the chelating agent to bisphosphonate.
[0043] In one embodiment, the chelating agent is selected from the
group consisting of sodium or disodium EDTA, citric acid, malic
acid, tartaric acid, lactic acid, adipic acid, succinic acid,
lysine, sodium hexametaphosphate, and combinations thereof. In
another embodiment, the chelating agent is sodium or disodium EDTA,
citric acid, or sodium hexametaphosphate.
[0044] The amount of chelating agent present in the oral dosage
form of the present invention will depend on the particular
chelating agent or agents (i.e., mixtures of chelating agents)
selected, the amount of bisphosphonate active ingredient present in
the oral dosage form, and the specific portion of the small
intestine where delivery and release of the chelating agent and/or
bisphosphonate active ingredient is desired. After the ingestion of
milk, it has been shown in the art that the concentration of
calcium decreases over the length of the lower GI tract, beginning
with the small intestine and proceeding through to the end of the
small intestine. Mahe, J. et al., Gastroileal nitrogen and
electrolyte movements after bovine milk ingestion in humans, Am. J.
Clin. Nutr. 56: 410-16 (1992).
[0045] The concentration of calcium in the stomach is approximately
10-fold higher than that of the concentration in the jejunum and
approximately 40 times that in the ileum. Thus if the risedronate
and chelating agent were released in the stomach (with food), the
amount of chelating agent would be insufficient to overcome the
effect of calcium on drug absorption. The concentration of calcium
in the jejunum and ileum are lower and by targeting release of the
dosage form in these regions where the amount of calcium is lower,
the chelating agent is more effective at binding most or all of the
calcium than if released in the stomach. It is also desirable to
target release of the tablet in the small intestine and after the
coating dissolves and releases the chelating agent and risedronate
from the core tablet in an immediate release fashion. This will
maximize the local concentration of the chelant in relationship to
that of the calcium in the small intestine. Slow or prolonged
delivery of the chelating agent in the small intestine is not
anticipated to achieve the desired local concentration of the
chelating agent and this type of delivery will not overcome the
food effect.
[0046] Generally, the oral dosage forms of the present invention
will contain a safe and effective amount of a chelating agent
suitable for achieving the desired chelating effect, that is,
chelating the residual metal ions that are present in the
gastrointestinal tract from food at the site of delivery without
significantly affecting the absorption of the bisphosphonate had no
food been present. In one embodiment, the oral dosage form contains
from about 10 mg to about 100 mg of a chelating agent. In another
embodiment, the oral dosage forms contain from about 10 mg to about
500 mg of a chelating agent. When the chelating agent is disodium
EDTA, an optional range is from about 55 mg to about 500 mg,
alternatively from about 75 mg to about 250 mg, alternatively from
about 75 mg to about 150 mg, alternatively about 100 mg. When the
chelating agent is citric acid, an optional range is from about 100
mg to about 970 mg, alternatively from about 250 mg to about 500 mg
per unit dose.
Delayed Delivery to the Small Intestine
[0047] The ultimate site of and/or the rate of delivery in the
small intestine can be satisfactorily controlled by one skilled in
the art, by manipulating any one or more of the following: [0048]
(a) the active ingredient proper; [0049] (b) the type and level of
disintegrant; [0050] (c) the type of coating, the type and level of
excipients added to the coating and the concomitant desirable
thickness and permeability (swelling properties) of the coating;
[0051] (d) the time dependent conditions of the coating itself
and/or within the coated tablet, particle, bead, or granule; [0052]
(e) the particle size of the granulated active ingredient; [0053]
(f) the pH dependent conditions of the coating itself and/or within
the coated tablet, particle, bead, or granule; [0054] (g) the
particle size or solubility of the chelating agent; [0055] (h) the
dissolution rate of the coating; [0056] (j) size or shape of the
tablet.
[0057] In addition the pharmacodynamic effect of the tablets, after
multiple dosing, should be within at least 75% of the comparable
immediate release tablet.
Delayed Release in the Small Intestine
[0058] A human or other mammal suffering from diseases or disorders
involving calcium and phosphate metabolism can be successfully
treated by the delivery of risedronate to the small intestine of
said human or other mammal. The novel dosage forms described herein
effect an immediate release to the small intestine, and prohibit
the undesired release of risedronate in the mouth, pharynx,
esophagus, and/or stomach, thereby prohibiting the erosion,
ulceration, or other like irritation of the epithelial or mucosal
layers of these tissues.
[0059] The chelant and risedronate are released rapidly and as
close to simultaneously as possible. This causes the local
concentration of chelating agent to be higher in relationship to
the metal ions in the food. The higher local concentration of
chelating agent in the environment where the active is released may
more effectively complex the metals in the food and facilitate
absorption of the bisphosphonate. This can be conveniently achieved
from a single tablet.
[0060] Various means for targeting release of risedronate and the
chelating agent in the small intestine are suitable for use in the
present invention. Non-limiting examples of means for delivery to
the small intestine include pH triggered delivery systems and time
dependent delivery systems.
pH Triggered Delivery Systems
[0061] One embodiment of the present invention involves coating (or
otherwise encapsulating) the risedronate and the chelating agent(s)
with a substance which is not broken down, by the gastrointestinal
fluids to release the risedronate and the chelating agent until a
specific desired point in the intestinal tract is reached. In one
embodiment, delayed release of the pharmaceutical composition is
achieved by coating the tablet, capsule, particles, or granules, of
the risedronate and the chelating agent with a substance which is
pH dependent, i.e., broken down or dissolves at a pH which is
generally present in the small intestine, but not present in the
upper GI tract (i.e., the mouth, buccal cavity, pharynx, esophagus,
or stomach) or lower GI tract.
[0062] In some cases, it may be desirable that the risedronate and
the chelating agent are released at a particular location in the
small intestine. In other cases, it may be desirable to release the
risedronate and the chelating agent independently at different
locations within the small intestine. For example, it may be
desirable to release the chelating agent in the, jenunum and the
risedronate in the ileum When targeted release of the risedronate
and the chelating agent together or separately in particular
locations within the small intestine is desired, the selection of
the coating material and/or the method of coating or otherwise
combining the risedronate and the chelating agent with the selected
coating material or other pharmaceutically-acceptable excipients
may be varied or altered as is described herein, or by any method
known to one skilled in the art.
[0063] Solubility, acidity, and susceptibility to hydrolysis of the
different risedronate active ingredients, such as acid addition
salts, salts formed with the phosphonic group (e.g., alkali metal
salts, alkaline earth metal salts, etc.), and esters (e.g., alkyl,
alkenyl, aryl, arylalkyl) may be used as guidelines for the proper
choice of coating. In addition, suitable pH conditions might be
established within the coated tablets, particles, or granules by
adding a suitable buffer to the active ingredient in accordance
with the desired release pattern.
[0064] One embodiment of the present invention is delivered to the
small intestine utilizing a pH dependent enteric coating material
made from a partly methyl esterified methacrylic acid polymer. The
oral dosage form can be in the form of an enteric coated compressed
tablet made of granules or particles of active ingredient.
[0065] Any enteric coating which is insoluble at a pH below 5.5
(i.e., that generally found in the mouth, pharynx, esophagus, and
stomach), but soluble between about pH 5.5 and about pH 6.5 (i.e.,
that present in the small intestine) can be used in the practice of
the present invention. Accordingly, when it is desired to effect
delivery of the bisphosphonate and the chelating agent to the small
intestine, any enteric coating is suitable which is wholly- or
partially-insoluble at a pH below 5.5 and soluble at about a pH 5.5
to about pH 6.5.
[0066] The enteric coating must be applied to the compressed
tablet, or capsule (e.g., gelatin, starch, or
hydroxypropylmethylcellulose) in a sufficient thickness so that the
entire coating does not dissolve in gastrointestinal fluids at a pH
below 5.5, but does dissolve at a pH above about 5.5 and below pH
about 6.5 The dissolution or disintegration of the excipient
coating generally does not occur until the entry of the coated
dosage form into the small intestine.
[0067] It is expected that any anionic polymer exhibiting the
requisite pH-dependent solubility profile can be used as an enteric
coating in the practice of the present invention to achieve
delivery of the bisphosphonate and chelating agent to the small
intestine. The coating chosen must be compatible with the
particular risedronate active ingredient selected. The preferred
polymers for use in the present invention are anionic carboxylic
polymers. It is particularly preferred that the polymers are
acrylic polymers, more preferably partly methyl-esterified
methacrylic acid polymers, in which the ratio of free anionic
carboxyl groups to ester groups is about 1:1.
[0068] A particularly suitable methacrylic acid copolymer is
Eudragit L.RTM., particularly Eudragit L 30 D-55.RTM. and Eudragit
L 100-55.RTM., manufactured by Rohm Pharma GmbH and Co. KG,
Darmstadt, Germany. In Eudragit L 30 D-55.RTM., the ratio of free
carboxyl groups to ester groups is approximately 1:1. Further, said
copolymer is known to be insoluble in GI fluids having a pH below
5.5, generally 1.5-5.5, i.e., that generally present in the fluid
of the upper GI tract, but readily soluble at pH above 5.5, i.e.,
that generally present in the fluid of the small intestine.
[0069] The coating can, and usually will, contain a plasticizer and
possibly other coating excipients such as coloring agents,
surfactant, talc, and/or magnesium stearate, many of which are well
known in the coating art. In particular, anionic carboxylic acrylic
polymers usually will contain 10-25% by weight of a plasticizer,
especially triethyl citrate, tributyl citrate, acetyltriethyl
citrate, dibutyl phthalate, diethyl phthalate, polyethylene glycol,
acetylated monoglycerides propylene glycol, and triacetin.
Conventional coating techniques such as fluid-bed or pan coating
are employed to apply the coating. Coating thickness must be
sufficient to ensure that the oral dosage form remains essentially
intact until the desired site of delivery in the small intestine is
reached.
[0070] The solid oral dosage form may be in the form of a coated
compressed tablet which contains particles or granules of the
bisphosphonate active ingredient and the chelating agent, or of a
soft or hard capsule (e.g., gelatin, starch, or
hydroxypropylmethylcellulose), coated or uncoated, which contains
beads or particles of the bisphosphonate active ingredient and the
chelating agent, which themselves are enterically coated. In an
embodiment of the invention the tablets are compressed and the
tablet is enteric coated.
[0071] Suitable enteric coating materials include Eudragit
L-100.RTM., Eudragit L 30 D-55.RTM., cellulose acetate phthalate,
shellac, or any enteric coating material that dissolves at about pH
5.5 to about 6.5. The enteric coating is applied using various
spray techniques known to one skilled in the art. The enteric
coating may further comprise one or more
pharmaceutically-acceptable excipients including, but not limited
to, talc, triethyl citrate, polyethylene glycol, Tween 80.RTM.
(polyoxyethylene sorbitan monooleate, available from Sigma Chemical
CO., St. Louis, Mo.), castor oil. The enteric coating is applied to
the tablet core to provide a weight gain of 2.5% to 40%.
[0072] The tablet core comprises a bisphosphonate active
ingredient, a chelating agent, and may contain one or more
pharmaceutically-acceptable excipients. Suitable excipients
include, but are not limited to, crystalline cellulose, lactose,
calcium hydrogen phosphate, polyvinylpyrrolidone, magnesium
stearate, sucrose, starch, magnesium oxide, sodium starch glycolate
and sodium lauryl sulfate.
Time Dependent Delivery Systems
[0073] In another embodiment of the invention, delivery of the
risedronate and the chelating agent to the small intestine is
achieved through the use of a time dependent delivery system. Given
established transit times after gastric emptying, drug and/or
chelating agent release can be targeted to the various segments of
the small intestine. Approaches to time dependent delivery systems
suitable for use in the present invention include, but are not
limited to, such devices as the Pulsincap.TM. (Scherer DDS,
Strathclyde, U.K.), the Time Clock.TM. (Zambon Group, Milan,
Italy), and SyncroDose.TM. (Penwest, Patterson, N.Y.), as well as
various coatings which degrade over time to release tablet contents
such as hydroxypropylmethylcellulose, hydroxypropylcellulose, or
any suitable hydrogel.
[0074] In one embodiment of the invention, the time-dependent
device Pulsincap.TM. is used to target delivery of the active
ingredient and the chelating agent to the small intestine. The
active ingredient and other excipients, including the chelating
agent, are contained inside the Pulsincap.TM. water-insoluble
capsule by means of a hydrogel plug which is covered by a
water-soluble cap. The entire dose form is optionally coated in an
enteric-coating material to protect the dose form from degradation
while in transit through the upper GI tract. When the patient
swallows the Pulsincap.TM. dosage form, the water-soluble cap
dissolves and exposes the hydrogel plug to gastric and/or
intestinal fluids. The hydrogel cap then swells, and eventually
pops out of the capsule body, thus releasing the capsule contents.
Release of the capsule contents can be targeted to specific regions
of the small intestine by modifying the hydrogel plug properties.
Watts, Peter J. & Illum, Lisbeth, Drug Dev. and Indus. Pharm.,
23(9): 893-917 (1997).
[0075] In one embodiment of the invention, a time dependent coating
is applied over a compressed tablet and then an enteric coating is
applied over the time dependent coating. This is used to target
delivery of the active ingredient and the chelating agent to the
small intestine. The active ingredient and other excipients,
including the chelating agent, are contained inside the core
tablet. The entire dose form is coated with a time dependent
coating and then an enteric coating. The enteric-coating material
is to protect the dose form from degradation while in transit
through the upper GI tract. When the patient swallows the dosage
form the enteric coating dissolves after the dosage form leaves the
stomach and then the core tablet starts to swell. Eventually, at a
predetermined time in the small intestine fluids, the time
dependent coating will rupture and releases the contents of the
core tablet in the small intestine. Release of the core tablet
contents can be targeted to specific regions of the small intestine
by modifying the core tablet, time dependent coating and/or the
enteric coating.
Pharmaceutically-Acceptable Excipients
[0076] Pharmaceutically-acceptable excipients include, but are not
limited to, polymers, resins, plasticizers, fillers, lubricants,
diluents, binders, disintegrants, solvents, co-solvents,
surfactants, buffer systems, preservatives, sweetener agents,
flavoring agents, pharmaceutical-grade dyes or pigments, chelating
agents, viscosity agents, and combinations thereof.
Pharmaceutically-acceptable excipients can be used in any component
in making the oral dosage form, i.e. core tablet or coating.
[0077] Flavoring agents and dyes and pigments among those useful
herein include but are not limited to those described in Handbook
of Pharmaceutical Excipients (4th Ed., Pharmaceutical Press
2003).
[0078] Suitable co-solvents include, but are not limited to,
ethanol, isopropanol, and acetone.
[0079] Suitable surfactants include, but are not limited to,
polyoxyethylene sorbitan fatty acid esters, polyoxyethylene
monoalkyl ethers, sucrose monoesters, simethicone emulsion, sodium
lauryl sulfate, Tween 80.RTM., and lanolin esters and ethers.
[0080] Suitable preservatives include, but are not limited to,
phenol, alkyl esters of parahydroxybenzoic acid, benzoic acid and
the salts thereof, boric acid and the salts thereof, sorbic acid
and the salts thereof, chlorbutanol, benzyl alcohol, thimerosal,
phenylmercuric acetate and nitrate, nitromersol, benzalkonium
chloride, cetylpyridinium chloride, methyl paraben, and propyl
paraben.
[0081] Suitable fillers include, but are not limited to, starch,
lactose, sucrose, maltodextrin, and microcrystalline cellulose.
[0082] Suitable plasticizers include, but are not limited to,
triethyl citrate, polyethylene glycol, propylene glycol, dibutyl
phthalate, castor oil, acetylated monoglycerides, and
triacetin.
[0083] Suitable polymers include, but are not limited to,
ethylcellulose, cellulose acetate trimellitate,
hydroxypropylmethylcellulose phthalate, cellulose acetate
phthalate, polyvinyl acetate phthalate, and Eudragit.RTM. L 30-D,
Eudragit.RTM. L 100-55, (Rohm Pharma GmbH and Co. KG, Darmstadt,
Germany), and Acryl-EZE.RTM. and Sureteric.RTM. (Colorcon, Inc.,
West Point, Pa.).
[0084] Suitable lubricants include, but are not limited to,
magnesium stearate, stearic acid, and talc.
Methods of Use
[0085] The present invention further relates to a method of
treating or preventing diseases characterized by abnormal calcium
and phosphate metabolism comprising administering to a human or
other mammal in need thereof a safe and effective amount of a
pharmaceutical composition delivered to said human or other mammal
via the oral dosage forms described herein.
[0086] Diseases characterized by abnormal calcium and phosphate
metabolism include, but are not limited to, osteoporosis, Paget's
disease (osteitis deformans), hyperparathyroidism, hypercalcemia of
malignancy, osteolytic bone metastasis, myositis ossificans
progressiva, calcinosis universalis, and such afflictions as
arthritis, neuritis, bursitis, tendonitis, and other inflammatory
conditions which predispose involved tissue to deposition of
calcium phosphates.
[0087] The oral dosage forms of the present invention are suitable
for administration to a patient according to a continuous monthly
dosing interval.
Kits
[0088] The present invention further comprises kits that are
particularly useful for administering the oral dosage forms
described herein according to a monthly continuous dosing schedule.
Such kits comprise one or more oral dosage forms comprising
risedronate (or salt) and a chelating agent and a means for
facilitating compliance with methods of this invention. Such kits
provide a convenient and effective means for assuring that the
subject to be treated takes the appropriate oral dosage form in the
correct dosage and in the correct manner. The compliance means of
such kits includes any means which facilitates administering the
active according to a method of this invention. Such compliance
means includes instructions, packaging, and dispensing means, and
combinations thereof. The kits can also comprise a means for aiding
the memory, including but not limited to a listing of the days of
the week, numbering, illustrations, arrows, Braille, calendar
stickers, reminder cards, or other means specifically selected by
the patient. Examples of packaging and dispensing means are well
known in the art, including those described in U.S. Pat. No.
4,761,406, Flora et al., issued Aug. 2, 1988; and U.S. Pat. No.
4,812,311, Uchtman, issued Mar. 14, 1989.
[0089] Optionally, the kits can comprise at least one oral dosage
form comprising a risedronate and a chelating agent and at least
one oral dosage form of an accompanying nutrient. Preferred
nutrients are calcium and/or vitamin D. Oral forms of calcium
suitable for use in the present invention include capsules,
compressed tablets, chewable tablets, and the like. Typical salt
forms of calcium suitable for use in the present invention include
but are not limited to calcium carbonate, calcium citrate, calcium
malate, calcium citrate malate, calcium glubionate, calcium
gluceptate, calcium gluconate, calcium lactate, dibasic calcium
phosphate, and tribasic calcium phosphate. In one embodiment, kits
of the present invention may include tablets comprising 400 mg to
1500 mg calcium.
[0090] The term "vitamin D," as used herein, refers to any form of
vitamin D that may be administered to a mammal as a nutrient.
Vitamin D is metabolized in the body to provide what is often
referred to as "activated" forms of vitamin D. The term "vitamin D"
can include activated and non-activated forms of vitamin D, as well
as precursors and metabolites of such forms. Precursors of these
activated forms include vitamin D.sub.2 (ergocalciferol, produced
in plants) and vitamin D.sub.3 (cholecalciferol, produced in skin
and found in animal sources and used to fortify foods). Vitamins
D.sub.2 and D.sub.3 have similar biological efficacy in humans.
Non-activated metabolites of vitamins D.sub.2 and D.sub.3 include
hydroxylated forms of vitamins D.sub.2 and D.sub.3. Activated
vitamin D analogs cannot be administered in large doses on an
intermittent schedule, due to their toxicity in mammals. However,
non-activated vitamin D.sub.2, vitamin D.sub.3, and their
metabolites may be administered in larger doses than "active" forms
of vitamin D on an intermittent basis, without toxicity. In one
embodiment, kits of the present invention may include tablets
comprising 100 IU to 10,000 IU of vitamin D.
[0091] In another embodiment, kits of the present invention may
include one or more nutrient tablets comprising both calcium and
vitamin D. In a further embodiment, the unit dose of nutrient
comprises about 600 mg calcium and about 400 IU vitamin D.
[0092] The following non-limiting examples illustrate the
formulations, processes, and uses of the present invention.
EXAMPLES
Example I
Enteric-Coated Tablets Containing Risedronate and EDTA
[0093] Enteric-coated tablets containing risedronate and EDTA are
made by preparing a coating composition and compressed tablets
containing risedronate and EDTA, and then applying said coating
composition to said tablets.
[0094] An enteric coating composition is prepared in the form of a
lacquer containing the following excipients, per tablet:
TABLE-US-00001 A. Enteric Coating Suspension Ingredients: Eudragit
L 30 D-55 .RTM. (wet basis) 73.65 mg (manufactured by Rohm Pharma
GmbH and Co. KG, Darmstadt, Germany) Triethylcitrate 2.21 mg Talc
16.57 mg Yellow Iron Oxide 0.03 mg Simethicone 0.07 mg Polysorbate
80 0.22 mg Purified Water 113.2 mg
[0095] The enteric coating is prepared using the following
method:
[0096] A pigment suspension is prepared by adding polysorbate 80,
ground ferric oxide, and talc to approximately three-quarters of
the purified water while mixing. The suspension is mixed for at
least 60 minutes. The simethicone and the remaining water are added
to the pigment suspension and mixed for at least 60 minutes. The
Eudragit L 30 D-55 is screened then combined with triethyl citrate
and mixed for at least 45 minutes. The pigment suspension is then
added to the Eudragit solution and mixed for 30 to 60 minutes. The
resulting coating suspension is mixed throughout the coating
process. The core tablets are transferred to the coating pan and
preheated with occasional jogging. Tablets are coated, using a
typical pan coating process until the required quantity of coating
solution has been applied. Tablets are then cooled and collected in
suitable containers.
[0097] A coating weight gain of 10% (total solids) is applied by
spraying the above composition onto compressed tablets containing
risedronate and EDTA, prepared in Part B below.
TABLE-US-00002 B. Compressed Tablets Containing Risedronate and
EDTA The enteric coating suspension prepared in Part A above is
sprayed onto 75 mg risedronate tablets, each tablet weighing 390 mg
and each containing: Active Ingredients: Risedronate Sodium 75 mg*
Chelant: Disodium EDTA 100 mg Excipients Prosolv SMCC 90 181.8 mg
Sodium starch glycolate 9.7 mg Stearic acid 19.5 mg Magnesium
stearate 3.9 mg *This amount is calculated on a risedronate
anhydrous monosodium salt basis.
[0098] Tablets having the composition set forth above are prepared
as follows:
[0099] Pass the edetate disodium, risedronate sodium, and ProSolv
SMCC 90 through a mill and transfer to a blender equipped with an
intensifier bar. Blend with intensifier bar on for 10 minutes. Pass
the sodium starch glycolate through a mill and add to the blender.
Blend for 8 minutes with the intensifier bar off. The stearic acid
and magnesium stearate are screened and added to the blender. The
blend is mixed for approximately 3 minutes with the intensifier bar
off. The blend is compressed into tablets using a suitable tablet
press.
Example II
Enteric-Coated Tablets Containing Risedronate and EDTA
[0100] Enteric-coated tablets containing risedronate and EDTA are
made by preparing a coating composition and compressed tablets
containing risedronate and EDTA, and then applying said coating
composition to said tablets.
[0101] An enteric coating composition is prepared in the form of a
lacquer containing the following excipients, per tablet:
TABLE-US-00003 A. Enteric Coating Suspension Ingredients: Eudragit
L 30 D-55 .RTM. (wet basis) 77.34 mg (manufactured by Rohm Pharma
GmbH and Co. KG, Darmstadt, Germany) Triethylcitrate 2.32 mg Talc
17.4 mg Yellow Iron Oxide 0.03 mg Simethicone 0.07 mg Polysorbate
80 0.23 mg Purified Water 118.88 mg
[0102] The enteric coating is prepared using the following
method:
[0103] A pigment suspension is prepared by adding polysorbate 80,
ground ferric oxide, and talc to approximately three-quarters of
the purified water while mixing. The suspension is mixed for at
least 60 minutes. The simethicone and the remaining water are added
to the pigment suspension and mixed for at least 60 minutes. The
Eudragit L 30 D-55 is screened then combined with triethyl citrate
and mixed for at least 45 minutes. The pigment suspension is then
added to the Eudragit solution and mixed for 30 to 60 minutes. The
resulting coating suspension is mixed throughout the coating
process. The core tablets are transferred to the coating pan and
preheated with occasional jogging. Tablets are coated, using a
typical pan coating process until the required quantity of coating
solution has been applied. Tablets are then cooled and collected in
suitable containers.
[0104] A coating weight gain of 10% (total solids) is applied by
spraying the above composition onto compressed tablets containing
risedronate and EDTA, prepared in Part B below.
TABLE-US-00004 B. Compressed Tablets Containing Risedronate and
EDTA The enteric coating suspension prepared in Part A above is
sprayed onto 100 mg risedronate tablets, each tablet weighing 440
mg and each containing: Active Ingredients: Risedronate Sodium 100
mg* Chelant: Disodium EDTA 100 mg Excipients Prosolv SMCC 90 202.6
mg Sodium starch glycolate 11 mg Stearic acid 22 mg Magnesium
stearate 4.4 mg *This amount is calculated on a risedronate
anhydrous monosodium salt basis.
[0105] Tablets having the composition set forth above are prepared
as follows:
[0106] Pass the edetate disodium, risedronate sodium, and ProSolv
SMCC 90 through a mill and transfer to a blender equipped with an
intensifier bar. Blend with intensifier bar on for 10 minutes. Pass
the sodium starch glycolate through a mill and add to the blender.
Blend for 8 minutes with the intensifier bar off. The stearic acid
and magnesium stearate are screened and added to the blender. The
blend is mixed for approximately 3 minutes with the intensifier bar
off. The blend is compressed into tablets using a suitable tablet
press.
Example III
Enteric-Coated Tablets Containing Risedronate and EDTA
[0107] Enteric-coated tablets containing risedronate and EDTA are
made by preparing a coating composition and compressed tablets
containing risedronate and EDTA, and then applying said coating
composition to said tablets.
[0108] An enteric coating composition is prepared in the form of a
lacquer containing the following excipients, per tablet:
TABLE-US-00005 A. Enteric Coating Suspension Ingredients: Eudragit
L 30 D-55 .RTM. (wet basis) 77.34 mg (manufactured by Rohm Pharma
GmbH and Co. KG, Darmstadt, Germany) Triethylcitrate 2.32 mg Talc
17.4 mg Yellow Iron Oxide 0.03 mg Simethicone 0.07 mg Polysorbate
80 0.23 mg Purified Water 118.88 mg
[0109] The enteric coating is prepared using the following
method:
[0110] A pigment suspension is prepared by adding polysorbate 80,
ground ferric oxide, and talc to approximately three-quarters of
the purified water while mixing. The suspension is mixed for at
least 60 minutes. The simethicone and the remaining water are added
to the pigment suspension and mixed for at least 60 minutes. The
Eudragit L 30 D-55 is screened then combined with triethyl citrate
and mixed for at least 45 minutes. The pigment suspension is then
added to the Eudragit solution and mixed for 30 to 60 minutes. The
resulting coating suspension is mixed throughout the coating
process. The core tablets are transferred to the coating pan and
preheated with occasional jogging. Tablets are coated, using a
typical pan coating process until the required quantity of coating
solution has been applied. Tablets are then cooled and collected in
suitable containers.
[0111] A coating weight gain of 10% (total solids) is applied by
spraying the above composition onto compressed tablets containing
risedronate and EDTA, prepared in Part B below.
TABLE-US-00006 B. Compressed Tablets Containing Risedronate and
EDTA The enteric coating suspension prepared in Part A above is
sprayed onto 125 mg risedronate tablets, each tablet weighing 495
mg and each containing: Active Ingredients: Risedronate Sodium 125
mg* Chelant: Disodium EDTA 100 mg Excipients Prosolv SMCC 90 227.9
mg Sodium starch glycolate 12.35 mg Stearic acid 24.75 mg Magnesium
stearate 4.95 mg *This amount is calculated on a risedronate
anhydrous monosodium salt basis.
[0112] Tablets having the composition set forth above are prepared
as follows:
[0113] The risedronate sodium, edetate disodium, sodium starch
glycolate, and ProSolv SMCC 90 are passed through a mill and added
to a blender equipped with an intensifier bar. The mixture is
blended for approximately ten minutes with the intensifier bar on.
The stearic acid and magnesium stearate are screened and added to
the blender. The blend is mixed for approximately 3 minutes with
the intensifier bar off. The blend is compressed into tablets using
a suitable tablet press.
Example IV
[0114] A 65 kg woman diagnosed with postmenopausal osteoporosis is
prescribed the enteric-coated oral dosage form of Example I, to be
taken once monthly.
Example V
[0115] A 70 kg man diagnosed with prostate cancer and high bone
turnover is prescribed the enteric-coated oral dosage form of
Example II, to be taken once monthly. The patient takes the oral
dosage form once per month, immediately before going to sleep. The
patient does not experience upper GI irritation or discomfort.
Example VI
[0116] A group of women diagnosed with postmenopausal osteoporosis
are prescribed the enteric-coated oral dosage form of Example III,
to be taken once monthly, comprising 100 mg risedronate sodium. The
patients take the oral dosage form with breakfast once per
month.
[0117] All documents cited are, in relevant part, incorporated
herein by reference; the citation of any document is not to be
construed as an admission that it is prior art with respect to the
present invention.
[0118] While particular embodiments of the present invention have
been illustrated and described, it would be obvious to those
skilled in the art that various other changes and modifications can
be made without departing from the spirit and scope of the
invention. It is therefore intended to cover in the appended claims
all such changes and modifications that are within the scope of
this invention.
* * * * *