U.S. patent application number 10/420403 was filed with the patent office on 2003-10-30 for composition and dosage form for delayed gastric release of alendronate and/or other bis-phosphonates.
Invention is credited to Dahan, Mazal, Flashner-Barak, Moshe, Lerner, Yitzhak, Rosenberger, Vered.
Application Number | 20030203878 10/420403 |
Document ID | / |
Family ID | 27395916 |
Filed Date | 2003-10-30 |
United States Patent
Application |
20030203878 |
Kind Code |
A1 |
Flashner-Barak, Moshe ; et
al. |
October 30, 2003 |
Composition and dosage form for delayed gastric release of
alendronate and/or other bis-phosphonates
Abstract
The present invention provides a compacted pharmaceutical
composition for oral administration to a patient which expands upon
contact with gastric fluid to retain a dosage form in the patient's
stomach for an extended period of time, the formulation comprising
a non-hydrated hydrogel, a superdisintegrant and tannic acid. The
present invention further provides a pharmaceutical dosage form
containing an active ingredient, and the compacted pharmaceutical
composition. The invention further provides a dosage form suitable
for delivering a therapeutic bis-phosphonate such as alendronate to
the stomach of a patient over and extended period
Inventors: |
Flashner-Barak, Moshe;
(Petach Tikva, IL) ; Rosenberger, Vered;
(Jerusalem, IL) ; Dahan, Mazal; (Jerusalem,
IL) ; Lerner, Yitzhak; (Petach Tikva, IL) |
Correspondence
Address: |
KENYON & KENYON
ONE BROADWAY
NEW YORK
NY
10004
US
|
Family ID: |
27395916 |
Appl. No.: |
10/420403 |
Filed: |
April 22, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10420403 |
Apr 22, 2003 |
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10246502 |
Sep 16, 2002 |
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10246502 |
Sep 16, 2002 |
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09770898 |
Jan 26, 2001 |
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6476006 |
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60213832 |
Jun 23, 2000 |
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60260438 |
Jan 9, 2001 |
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Current U.S.
Class: |
514/89 ; 424/468;
514/102; 514/23 |
Current CPC
Class: |
A61K 9/2027 20130101;
A61K 9/205 20130101; A61K 9/286 20130101; A61P 19/08 20180101; A61P
19/10 20180101; A61K 31/663 20130101; A61K 9/2054 20130101; A61K
9/2059 20130101; A61P 19/00 20180101; A61K 9/284 20130101; A61K
9/2866 20130101; A61K 9/2077 20130101; A61P 3/14 20180101 |
Class at
Publication: |
514/89 ; 514/102;
424/468; 514/23 |
International
Class: |
A61K 031/685; A61K
031/675; A61K 031/7024; A61K 009/22 |
Claims
We claim:
1. A pharmaceutical dosage form for oral administration to a
patient which provides delayed gastric release of a therapeutically
effective amount of a therapeutic bis-phosphonate, the dosage form
comprising the bis-phosphonate and a drug delivery vehicle
comprising a non-hydrated hydrogel wherein upon contact with
gastric fluid or simulated gastric fluid the non-hydrated hydrogel
hydrates and the delivery vehicle expands.
2. The pharmaceutical dosage form of claim 1 wherein the drug
delivery vehicle further comprises a superdisintegrant.
3. The pharmaceutical dosage form of claim 2 wherein the drug
delivery vehicle further comprises tannic acid.
4. The pharmaceutical dosage form of claim 1 wherein release of
substantial amounts of the bis-phosphonate is delayed for a period
of two hours or more.
5. The pharmaceutical dosage form of claim 1 wherein release of
substantial amounts of the bis-phosphonate is delayed for a period
of three hours or more.
6. The pharmaceutical dosage form of claim 1 wherein release of
substantial amounts of the bis-phosphonate is delayed for a period
of four hours or more.
7. The pharmaceutical dosage form of claim 1 wherein the
bis-phosphonate is selected from the group consisting of alendronic
acid and its pharmaceutically acceptable salts and hydrates
thereof, residronate, etidronate and teludronate.
8. The pharmaceutical dosage form of claim 1 wherein the
bis-phosphonate is alendronic acid or one of its pharmaceutically
acceptable salts and hydrates thereof.
9. The pharmaceutical dosage form of claim 8 wherein the
bis-phosphonate is monosodium alendronate monohydrate.
10. The pharmaceutical dosage form of claim 8 wherein the
bis-phosphonate is monosodium alendronate trihydrate.
11. The pharmaceutical dosage form of claim 8 wherein the
bis-phosphonate is alendronic acid.
12. The pharmaceutical dosage form of claim 1 wherein the hydrogel
comprises hydroxypropyl methylcellulose.
13. The pharmaceutical dosage form of claim 12 wherein the hydrogel
further comprises hydroxypropyl cellulose.
14. The pharmaceutical dosage form of claim 13 wherein the hydrogel
comprises hydroxypropyl methylcellulose and hydroxypropyl cellulose
in a weight ratio of from about 1:3 to about 5:3.
15. The pharmaceutical dosage form of claim 2 wherein the
superdisintegrant is selected from the group consisting of
cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl
cellulose sodium and sodium starch glycolate.
16. The pharmaceutical dosage form of claim 15 wherein the
superdisintegrant is sodium starch glycolate.
17. The pharmaceutical dosage form of claim 15 wherein the
superdisintegrant is cross-linked carboxymethyl cellulose
sodium.
18. The pharmaceutical dosage form of claim 3 wherein tannic acid
comprises from about 5 weight percent to about 15 weight percent of
the drug delivery vehicle.
19. A method of treating bone disease in a human patient in need of
such treatment by administering to the patient the pharmaceutical
dosage form of claim 1.
20. The method of claim 19 wherein the bone disease is metastatic
bone disease.
21. The method of claim 19 wherein the bone disease is
osteoporosis.
22. The method of claim 19 wherein the bone disease is Paget's
disease.
23. A method of inhibiting bone resorption in a human patient in
need of such treatment by administering to the patient the
pharmaceutical dosage form of claim 1.
24. A method of treating hypercalcemia in a human patient in need
of such treatment by administering to the patient the
pharmaceutical dosage form of claim 1.
25. A method of treating malignancy in bone of a human patient in
need of such treatment by administering to the patient the
pharmaceutical dosage form of claim 1.
26. The pharmaceutical dosage form of claim 1 wherein the drug
delivery vehicle comprises of from about 50 wt. % to about 80 wt. %
of a hydrogel, of from about 10 wt. % to about 30 wt. % of a
superdisintegrant, and of from about 5 wt. % to about 10 wt. %
tannic acid.
27. The pharmaceutical dosage form of claim 26 capable of being
retained in the stomach of a human patient for a period of at least
two hours.
28. The pharmaceutical dosage form of claim 26 capable of being
retained in the stomach of a human patient for a period of at least
three hours.
29. The pharmaceutical dosage form of claim 26 wherein the dosage
form swells by a factor of five or more within about fifteen
minutes of contacting aqueous solution.
30. The pharmaceutical dosage form of claim 29 wherein the dosage
form swells by a factor of eight or more within about fifteen
minutes of contacting aqueous solution.
31. The pharmaceutical dosage form of claim 29 wherein the dosage
form swells by a factor of five or more within about five minutes
of contacting aqueous solution.
32. The pharmaceutical dosage form of claim 26 further comprising a
substance that emits gas upon contact with acid.
33. The pharmaceutical dosage form of claim 32 wherein the
substance that emits gas upon contact with acid is sodium
bicarbonate.
34. The pharmaceutical dosage form of claim 26 wherein the hydrogel
comprises hydroxypropyl methylcellulose.
35. The pharmaceutical dosage form of claim 34 wherein the hydrogel
further comprises hydroxypropyl cellulose.
36. The pharmaceutical dosage form of claim 35 wherein the hydrogel
comprises hydroxypropyl methylcellulose and hydroxypropyl cellulose
in a weight ratio of from about 1:3 to about 5:3.
37. The pharmaceutical dosage form of claim 26 wherein the
superdisintegrant is selected form the group consisting of
cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl
cellulose sodium and sodium starch glycolate.
38. A coated pharmaceutical dosage form comprising a core which
contains a therapeutic bis-phosphonate and optionally other
pharmaceutical excipients and a coating around the core, wherein
the coating comprises a hydrogel, a superdisintegrant and tannic
acid.
39. The coated pharmaceutical dosage form of claim 38 from about 50
wt. % to about 80 wt. % of a hydrogel, from about 10 wt. % to about
30 wt. % of a superdisintegrant, and from about 5 wt. % to about 10
wt. % tannic acid.
40. A coated pharmaceutical dosage form having a core comprising
about 18 wt. % sodium alendronate monohydrate, about 48 wt. %
microcrystalline cellulose and about 32 wt. % lactose, the core
having a coating thereon which comprises about 17 wt. % HPMC, about
10 wt. % tannic acid, about 50 wt. % HPC and about 22 wt. %
crosslinked carboxymethyl cellulose sodium.
41. A coated pharmaceutical dosage form having a core comprising
about 18 wt. % sodium alendronate monohydrate, about 41 wt. %
microcrystalline cellulose and about 41 wt. % lactose, the core
having a coating thereon which comprises about 17 wt. % HPMC, about
10 wt. % tannic acid, about 50 wt. % HPC and about 22 wt. %
crosslinked carboxymethyl cellulose sodium.
42. A method of making the dosage form of claim 40 or 41 comprising
the steps of mixing powdered sodium alendronate monohydrate,
microcrystalline cellulose and lactose, tableting the mixed powders
to make a core, dry mixing the HPMC, tannic acid, HPC and
cross-linked carboxymethyl sodium to produce a coating mix,
embedding the core in the coating mix and compacting the coating
mix to produce the dosage form.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 10/246,502, filed Sep. 16, 2002, which is a
continuation of U.S. patent application Ser. No. 09/770,898, filed
Jan. 26, 2001, now U.S. Pat. No. 6,476,006, and claims the benefit
under 35 U.S.C. .sctn.119(e) of U.S. provisional applications
Serial No. 60/213,832, filed Jun. 23, 2000 and Serial No.
60/260,438, filed Jan. 9, 2001, the contents of all of which are
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to gastric retention systems
and to pharmaceutical dosage forms that use them to release a drug
in a patient's stomach or duodenum. More particularly, the
invention relates to gastric retention systems suitable for use
with bis-phosphonates such as alendronic acid and its
pharmaceutically acceptable salts and hydrates thereof to release
these drugs in a controlled manner.
BACKGROUND OF THE INVENTION
[0003] After discovery of a new drug for treatment of a human
disease further investigation must be undertaken to determine
whether it is most effective to administer the drug to a patient
intravenously, transdermally, subcutaneously or orally. Orally
administered drugs are easy to administer and therefore are often
favored whenever an oral route is feasible. However, compliance
problems sometimes occur with orally administered drugs when the
dosage form is inconvenient to take or must be taken frequently or
at inconvenient times. Orally administered drugs are often
presented to a patient in such dosage forms as tablets, pills,
lozenges and capsules. Most orally administered drugs are absorbed
into the bloodstream from the patient's gastrointestinal tract,
excepting inhalants which are absorbed by the lungs and
sinuses.
[0004] Orally-administered drugs may be absorbed more readily by
the gastrointestinal ("GI") tract through either the stomach wall
or the intestine wall. Few drugs are efficiently absorbed by the
colon. Tablets that are designed to carry drugs that are more
readily absorbed through the intestine wall are sometimes covered
with a coating that is resistant to the acidic conditions of the
stomach but which decomposes under the basic conditions of the
intestine. This enteric coating allows the tablet to transit the
stomach without releasing the active ingredient until it reaches
the portion of the GI tract where it is most readily absorbed. This
enteric-coating strategy is also effective when the drug is caustic
to the lining of the stomach or decomposes under acidic
conditions.
[0005] It is sometimes desirable that a drug be released in a
patient's stomach rather than in the intestine. One such instance
is when it is therapeutically advantageous to release the drug over
several hours. The average residence time of solid food in the
small intestine is about three hours. A controlled release
pharmaceutical dosage form may pass through the stomach and
intestine and into the colon before the active ingredient has been
completely released. However, if the dosage form is retained in the
stomach, complete release occurs upstream of the small intestine
and the active ingredient will enter the intestine in an unbound
state in which it can be readily absorbed before reaching the
colon.
[0006] It is also desirable to release a drug in the stomach when
it is unstable to the basic conditions of the intestine. A
composition that is formulated to dissolve upon contact with any
aqueous solution will at least partially dissolve in the stomach
because it reaches the stomach before it reaches the intestine.
However, the average residence time of food in the stomach is only
about 1 to 3 hours. Unless the drug is very rapidly absorbed, or
the residence time is increased, some of the drug will pass to the
intestine. An unstable drug will at least partially decompose to a
product compound that either is not absorbed or, if absorbed, may
not exert the desired therapeutic effect. Accordingly,
decomposition of a base sensitive drug that passes into the
intestine reduces the effectiveness of the dosage and, as well,
introduces an uncontrollable factor that is detrimental to accurate
dosing.
[0007] For the foregoing reasons, formulation chemists have
developed strategies to increase the retention time of oral dosages
in the stomach. One of the general strategies, involves using an
intragastric expanding dosage form that swells upon contact with
stomach juices, preventing its passage through the pylorus.
Intragastric expanding dosage forms use hydrogels which expand upon
contact with water to expand the dosage form to sufficient size to
prevent its passage through the pylorus. An example of such a
dosage form is described in U.S. Pat. No. 4,434,153. The '153
patent discloses a device for executing a therapeutic program after
oral ingestion, the device having a matrix formed of a non-hydrated
hydrogel and a plurality of tiny pills containing a drug dispersed
throughout the matrix.
[0008] As reviewed by Hwang, S. et al. "Gastric Retentive
Drug-Delivery Systems," Critical Reviews in Therapeutic Drug
Carrier Systems, 1998, 15, 243-284, one of the major problems with
intragastric expanding hydrogels is that it can take several hours
for the hydrogel to become fully hydrated and to swell to
sufficient size to obstruct passage through the pylorus. Since food
remains in the stomach on average from about 1 to 3 hours, there is
a high probability that known expanding dosage forms like that of
the '153 patent will pass through the pylorus before attaining a
sufficient size to obstruct passage.
[0009] The rate-limiting factor in the expansion of ordinary
hydrogels is the rate of delivery of water to non-surfacial
hydrogel material in the dosage form. Conventional non-hydrated
hydrogels are not very porous when dry and ingress of water into
the hydrogel is slowed further by the formation of a low
permeability gelatinous layer on the surface after initial contact
with water. One approach to solving this problem uses so-called
superporous hydrogels. Superporous hydrogels have networks of pores
of 100 .mu. diameter or more. Pores of that diameter are capable of
efficient water transport by capillary action. Water reaches the
non-surfacial hydrogel material quickly resulting in a rapid
expansion of the superporous hydrogel to its full extent. However,
there are also shortcomings attendant to the use of superporous
hydrogels. They tend to be structurally weak and some are unable to
withstand the mechanical stresses of the natural contractions that
propel food out of the stomach and into the intestine. The
superporous hydrogels tend to break up into particles too small to
be retained.
[0010] Non-superporous hydrogels do not suffer from mechanical
strength problems to as great an extent as superporous hydrogels.
An additional advantage of using conventional hydrogels is that
their degradation/erosion rates are well studied. The blended
composition of the present invention should be compared with the
superporous hydrogels described in Chen, J. and Park, K. Journal of
Controlled Release 2000, 65, 73-82, wherein the mechanical strength
of superporous hydrogels is improved by the polymerization of
precursor hydrogel monomers in the presence of several
superdisintegrants. The result of the polymerization described by
Chen and Park is a new substance having interconnecting
cross-linking networks of polyacrylate and, e.g. cross-linked
carboxymethyl cellulose sodium. Such interconnecting networks are
not expected to have the same degradation rates as conventional
hydrogels made from the same precursor hydrogel monomers.
[0011] Many disease therapies can benefit from improvements in
controlled gastric release technology, such as osteoporosis and
Paget's disease. Bis-phosphonates such as alendronate, residronate,
etidronate and teludronate are commonly prescribed drugs for
treatment of these diseases. Despite their benefits,
bis-phosphonates suffer from very poor oral bioavailability (Gert,
B. J.; Holland, S. D.; Kline, W. F.; Matuszewski, B. K.; Freeman,
A.; Quan, H.; Lasseter, K. C.; Mucklow, J. C.; Porras, A. G.;
Studies of the oral bioavailablity of alendronate, Clinical
Pharmacology & Therapeutics (1995) 58, 288-298), serious
interference of absorption by foods and beverages other than water
(ibid.), and side effects that consist of irritation of the upper
gastrointestinal mucosa (Liberman, U. A.; Hirsch, L. J.;
Esophagitis and alendronate, N. Engl. J. Med. (1996) 335, 1069-70)
with the potential for this irritation leading to more serious
conditions (Physicians' Desk Reference, Fosamax, Warnings).
[0012] To overcome these limitations, the bis-phosphonates, such as
alendronate, have been given in relatively large doses in a fasting
condition while maintaining an upright position for at least a half
an hour after dosing (Physicians' Desk Reference, Fosamax, Dosage
and Administration). Since bis-phosphonates are not metabolized,
dosing also can be lowered to once a week instead of daily (70 mg
per dose once a week in place of 10 mg per dose daily) by
administering very large sustained-release doses of the drug,
(Daifotis, A. G.; Santora II, A. C.; Yates, A. G.; Methods for
inhibiting bone resorption, U.S. Pat. No. 5,994,329).
[0013] Alendronate is best absorbed from the upper GI tract
(duodenum and jejunum) (Lin, J. H.; Bisphosphonates: a review of
their pharmacokinetic properties, Bone (1996), 18, 75-85. Porras,
A. G.; Holland, S. D.; Gertz, B. J.; Pharmacokinetics of
Alendronate, Clin Pharmacokinet (1999) 36, 315-328), and is better
absorbed at a pH of .about.6 (Gert, B. J.; Holland, S. D.; Kline,
W. F.; Matuszewski, B. K.; Freeman, A.; Quan, H.; Lasseter, K. C.;
Mucklow, J. C.; Porras, A. G. ; Studies of the oral bioavailablity
of alendronate, Clinical Pharmacology & Therapeutics (1995) 58,
288-298). Only gastric retention with controlled release allows for
the extended delivery of a drug to the duodenum. Controlled release
of the drug to the duodenum and jejunum parts of the intestine
should allow an improvement in bioavailability, thus allowing a
lowering of the total dose of the drug.
SUMMARY OF THE INVENTION
[0014] We have now found a rapidly expanding oral dosage form that
swells rapidly in the gastric juices of a patient, thereby
increasing the likelihood that an active ingredient carried by the
form will be released in the stomach. This oral dosage form employs
a blend of a superdisintegrant, tannic acid and one or more
conventional hydrogels. The dosage forms of the present invention
swell rapidly, yet because they do not require superporous
hydrogels, do not have their associated mechanical strength
problems.
[0015] The present invention further provides compacted
pharmaceutical compositions for oral administration to a patient
which expand upon contact with gastric fluid to retain a dosage
form in the patient's stomach for an extended period of time, the
formulation comprising a blend of a non-hydrated hydrogel, a
superdisintegrant and tannic acid.
[0016] The present invention further provides a pharmaceutical
dosage form containing an active ingredient and the compacted
pharmaceutical composition.
[0017] Yet further, the present invention provides compositions and
dosage forms for delayed release of bis-phosphonates. The dosage
forms release the bis-phosphonates into the stomach of a patient
suffering from osteoporosis or Paget's disease The dosage forms
include a drug delivery vehicle which retains the dosage form in
the patient's stomach for an extended period of time. In some
embodiments of the invention, the drug delivery vehicle further
provides a means to slow the release of the bis-phosphonate.
Bis-phosphonate is released into the stomach over at least a
portion of the period that the dosage form is retained in the
stomach.
DETAILED DESCRIPTION OF THE INVENTION
[0018] The present invention provides a carrier composition for a
pharmaceutically active ingredient and dosage forms containing the
carrier composition and the active ingredient. Tablets containing
the inventive composition swell rapidly on contact with aqueous
solution, such as the gastric juices of a patient and simulated
gastric fluid. Rapid swelling is achieved by a novel combination of
hydrogel, superdisintegrant and tannic acid.
[0019] The preferred hydrogel of the present invention is
hydroxypropylmethylcellulose, either alone or in combination with
hydroxypropyl cellulose and/or a cross-linked acrylate polymer.
Suitable cross-linked acrylate polymers include polyacrylic acid
crosslinked with allyl sucrose commercially available under the
trade name Carbopol.RTM. (BF Goodrich Chemical Ltd.) and
polyacrylic acid cross linked with divinyl glycol. As further
illustrated by Examples 5 and 8, below, a preferred hydrogel of the
invention is a mixture of hydroxypropyl methylcellulose and
hydroxypropyl cellulose. The most preferred hydrogel of the present
invention is a combination of hydroxypropyl methylcellulose and
hydroxypropyl cellulose in a weight ratio of from about 1:3 to
about 5:3. The molecular weight of the hydrogels is not critical to
practice of the invention.
[0020] The inventive composition also includes a superdisintegrant.
Superdisintegrants are pharmaceutical excipients within a larger
class of excipients known as disintegrants. Disintegrants are
typically hydrophilic polymers of either natural or synthetic
origin. Superdisintegrants are disintegrants that swell upon
contact with water. Preferred superdisintegrants of the present
invention swell to at least double their non-hydrated volume on
contact with water. Exemplary of these superdisintegrants are
cross-linked polyvinyl pyrollidone (a.k.a. crospovidone),
cross-linked carboxymethyl cellulose sodium (a.k.a. croscarmelose
sodium) and sodium starch glycolate. Crospovidone is commercially
available from BASF Corp. under the tradename Kollidon.RTM. CL and
from International Specialty Chemicals Corp. under the tradename
Polyplasdone.RTM.. Croscarmellose sodium is commercially available
from FMC Corp. under the tradename Ac-Di-Sol.RTM. and from Avebe
Corp. under the tradename Primellose.RTM.. Sodium starch glycolate
is commercially available from Penwest Pharmaceuticals Co. under
the tradename Explotab.RTM. and from Avebe Corp. under the
tradename Primojel.RTM.. The most preferred superdisintegrant is
sodium starch glycolate.
[0021] The inventive composition further includes tannic acid.
Tannic acid, also called tannin, gallotannin and gallotannic acid,
is a naturally occurring constituent of the bark and fruit of many
trees. The term "tannins" conventionally refers to two groups of
compounds, "condensed tannins" and "hydrolyzable tannins." Merck
Index monograph No. 8828 (9th ed. 1976). The hydrolyzable tannins
are sugars that are esterified with one or more (polyhydroxylarene)
formic acids. One common polyhydroxylarene formic acid is galloyl
(i.e. 3,4,5-trihydroxybenzoyl). Another common polyhydroxylarene
formic acid substituent of tannins is meta-digallic acid. A common
sugar moiety of tannins is glucose. The tannic acid of the present
invention is selected from the hydrolyzable tannins, and especially
glucose tannins in which one or more of the hydroxyl groups of
glucose is esterified with gallic acid and/or meta-digallic
acid.
[0022] The novel expanding composition of the present invention
comprises hydroxypropyl methylcellulose, optionally in combination
with other hydrogel polymers, a superdisintegrant and tannic acid.
These excipients are preferably combined in a weight ratio,
exclusive of any other excipients that may be present, of from
about 20 wt. % to about 80 wt. % hydrogel, from about 10 wt. % to
about 75 wt. % superdisintegrant and from about 2 wt. % to about 15
wt. % tannic acid. A preferred composition comprises from about 30
wt. % to about 55 wt. % superdisintegrant, about 5 wt. % (.+-.2 wt.
%) tannic acid, plus an amount of hydrogel sufficient to bring the
total to 100 wt. %.
[0023] One especially preferred embodiment of the present invention
is a rapidly expanding pharmaceutical composition comprising from
about 10 wt. % to about 20 wt. % hydroxypropyl methyl cellulose,
from about 45 wt. % to about 50 wt. % hydroxypropyl cellulose,
about 25 wt. % to about 35 wt. % sodium starch glycolate and about
4 wt. % to about 6 wt. % tannic acid. A second especially preferred
embodiment of the present invention is a rapidly expanding
pharmaceutical composition comprising from about 20 wt. % to about
30 wt. % hydroxypropyl methyl cellulose, from about 10 wt. % to
about 20 wt. % hydroxypropyl cellulose, about 45 wt. % to about 55
wt. % sodium starch glycolate and about 4 wt. % to about 6 wt. %
tannic acid.
[0024] The novel composition of the invention can be prepared
conventionally by dry blending. In order to form a structurally
resilient mass upon contact with water or gastric fluid, the
blended composition is compacted prior to hydration.
[0025] One object of the invention is to provide a dosage form such
as a tablet that is retained in the stomach for an extended period
of time by swelling to a size that prevents passage through the
pylorus upon contact with gastric juices. Over time the swollen
tablet degrades or erodes into particles that are sufficiently
small to traverse the pylorus. The tablet may be compacted
following conventional dry granulation or direct compression
techniques.
[0026] The pharmaceutical dosage forms of the present invention
comprise the compacted expanding composition of the invention and
an active ingredient. Active ingredients that may be carried by
these dosage forms include, but are in no way limited to,
bis-phosphonates such as alendronic acid and its pharmaceutically
acceptable salts and hydrates, levodopa, carbidopa,
methylphenidate, diltiazem, irinotecan and etoposide. Preferably,
the pharmaceutical dosage forms are retained in the stomach for
three hours or more, more preferably about five hours or more. In
order to obstruct passage through the pylorus, the dosage form
preferably swells by a factor of five or more, more preferably
about eight or more, within about fifteen minutes of contacting
gastric fluid. Yet more preferably, such swelling is reached within
about five minutes.
[0027] The novel composition of the invention can be prepared
conventionally by dry blending. In order to form a structurally
resilient mass upon contact with water or gastric fluid, the
blended composition is compacted prior to hydration. The
composition may be compacted following conventional dry granulation
or direct compression techniques.
[0028] For instance, the blended composition may be compacted into
a slug or a sheet and then comminuted into compacted granules. The
compacted granules may be compressed subsequently into a final
dosage form. It will be appreciated that the processes of slugging
or roller compaction, followed by comminution and recompression
render the hydrogel, superdisintegrant and tannic acid
intragranular in the final dosage form. The active ingredient of
the pharmaceutical may also be provided intragranularly by blending
it with the expanding composition prior to compaction.
Alternatively the active ingredient may be added after comminution
of the compacted composition, which results in the active
ingredient being extragranular.
[0029] As an alternative to dry granulation, the blended
composition may be compressed directly into the final
pharmaceutical dosage form using direct compression techniques.
Direct compression produces a more uniform tablet without granules.
Thus the active ingredient and any other desired excipients are
blended with the composition prior to direct compression tableting.
Such additional excipients that are particularly well suited to
direct compression tableting include microcrystalline cellulose,
spray dried lactose, dicalcium phosphate dihydrate and colloidal
silica. An additional alternative to dry granulation is wet
granulation. The blend of excipients may be granulated using water
or an alcohol as a granulation solvent by standard granulation
techniques known in the art followed by drying.
[0030] In addition to the above-described excipients, the rapidly
expanding pharmaceutical composition and dosage form may further
include any other excipients. One factor that must be taken into
account in formulating a pharmaceutical composition is the
mechanical process which the composition undergoes to be
transformed into a dosage form, such as a tablet or capsule. Some
excipients are added to facilitate this mechanical processing, such
as glidants and tablet lubricants. Glidants improve the flow
properties of the composition in powder or granule form while
lubricants ease ejection of a tablet from the tableting dye in
which it is formed by compression. Silicon dioxide is a common
glidant, while magnesium is a common tablet lubricant. Thus, for
example, the present inventive composition may further include
silicon dioxide and magnesium stearate. Other excipients which may
be mentioned are binders, that are added to prevent flaking and
other types of physical disintegration of the tablet prior to
ingestion by a patient. Yet other excipients are diluents whose
presence causes the tablet to be larger and thus easier for a
patient to handle.
[0031] Further increase in retention times can be realized by the
addition of a compound that produces gas when contacted with acid,
such as sodium bicarbonate. Sodium bicarbonate may be provided by
blending into the expanding composition of the invention or may be
an extragranular constituent of a tablet prepared by dry
granulation. Sodium bicarbonate is preferably used at low
concentration, of from about 0.5 wt % to about 5 wt. % of expanding
composition.
[0032] In addition to the above-described use of the expanding
composition in tablets prepared by dry or wet granulation and
compression, there are many other embodiments in which the
expanding composition could be used to retain a drug delivery
vehicle in the stomach. For instance, the expanding composition can
be used to coat a smaller tablet (this is a preferred construction
of a gastric retention dosage form of alendronate, described
below). The expanding composition can be used advantageously in
this way in sustained delivery of a drug. After contact with
aqueous fluid and swelling, the composition is highly porous. Thus,
the release rate of a sustained release dosage form like a coated
tablet or slowly disintegrating tablet is substantially unaffected
by a coating of the expanding composition.
[0033] The expanding composition is also suited for the retention
of drugs in the stomach when such drugs are contained in tablets
that are either partially embedded in the expanding composition or
attached thereto by an adhesive. These tablets can be of a slow
release nature giving slow or controlled release for an extended
period of time in the stomach. These tablets can further be of a
delayed pulse release nature. The expanding composition of this
invention will retain these forms in the stomach until the delay
time has passed whereupon the drug will be released in a burst or
pulse fashion. Attaching, or partially embedding, several such
tablets, each timed with a different relay to release, to the
composition of this invention, allows versatile dosing schemes from
one taken dose. For example, one could deliver three (or more)
timed doses in a pulse fashion while the patient needs to take the
dose only once. The three doses would mimic taking three doses of
the drug at the prescribed times, with the drug being absorbed from
the stomach with each dose. Such dosing allows for improved
compliance to dosage schedules and in many cases will lead thereby
to improved therapy.
[0034] Delayed dosage forms that are not coupled to gastric
retention will deliver each such dose in a different part of the GI
tract with different absorption profiles for each of the doses.
Such therapy would not be equivalent to taking three doses of the
drug at the prescribed times, wherein the drug would have been
absorbed from the stomach in each case.
[0035] The present invention provides a delayed release dosage form
containing the delivery vehicle/composition of the invention and a
therapeutic bis-phosphonate that is capable of delivering the
bis-phosphonate to the stomach of a patient several hours after
administration.
[0036] Suitable bis-phosphonates include alendronic acid and its
pharmaceutically acceptable salts and hydrates thereof, as well as
residronate, etidronate and teludronate.
[0037] The bis-phosphonate drug delivery vehicle may be formed from
the afore-described hydrogel, superdisintegrant and tannic acid by
blending or granulating. Regardless of the method by which the
hydrogel, superdisintegrant and tannic acid are combined, they are
preferably combined in a weight ratio, exclusive of the
bis-phosphonate and any other excipients that may be present, of
from about 50 wt. % to about 80 wt. % hydrogel, from about 10 wt. %
to about 30 wt. % superdisintegrant and from about 5 wt. % to about
15 wt. % tannic acid. A yet more preferred drug delivery vehicle
comprises from about 15 wt. % to about 25 wt. % superdisintegrant,
about 10 wt. % (.+-.2 wt. %) tannic acid, plus an amount of
hydrogel sufficient to bring the total to 100 wt. %. One especially
preferred bis-phosphonate delivery vehicle comprises from about 15
wt. % to about 20 wt. % hydroxypropyl methyl cellulose, from about
45 wt. % to about 55 wt. % hydroxypropyl cellulose, about 20 wt. %
to about 25 wt. % carboxy methyl cellulose sodium and about 8 wt. %
to about 12 wt. % tannic acid.
[0038] Dosage forms containing the drug delivery vehicle and
bis-phosphonate swell rapidly on contact with aqueous solution,
e.g. water, gastric fluid and acidic solutions like simulated
gastric fluid. In order to obstruct passage through the pylorus,
the drug delivery vehicle preferably swells by a factor of five or
more, more preferably about eight or more, within about fifteen
minutes of contacting gastric fluid. Yet more preferably, such
swelling is reached within about five minutes. Preferably, the
swelling causes retention of the pharmaceutical dosage forms in the
stomach for three hours or more, more preferably about four hours
or more, after which time the drug delivery vehicle either
dissolves or degrades into fragments small enough to pass through
the pylorus.
[0039] The invention further relates to specific pharmaceutical
dosage forms containing a therapeutic bis-phosphonate and the drug
delivery vehicle. These forms may have (a) a monolithic
construction, such as a tablet made by conventional direct
compression or granulation techniques wherein the active is
dispersed in the drug delivery vehicle, (b) a layered construction
wherein the active, alone or in mixture with any other excipients,
form a layer that is bonded, e.g. by compression, to another layer
formed of the drug delivery vehicle, (c) an encapsulated
construction wherein either of the (a) or (b) type constructions
are encapsulated, (d) a coated construction wherein a core
containing the actives is coated with the drug delivery vehicle,
and (e) a construction whereby the drug is incorporated in an
optionally coated matrix tablet, said tablet being partially
embedded in the drug delivery vehicle, or attached externally to
the drug delivery vehicle by an adhesive.
[0040] A monolithic dosage form can be prepared by the direct
compression and granulation methods previously described. The
monolithic dosage form may be made in any shape desired, but it has
been found that an ovoid or elliptical shape is advantageous for
retaining the dosage form in the stomach. An ovoid or elliptical
dosage form preferably is sized at between about 4 mm and 8 mm in
two dimensions and between about 10 mm and 20 mm in the third
dimension, more preferably about 6.times.6.times.16 mm. Monolithic
dosage forms slow the release of the actives due to the diffusional
barrier created by the surrounding swelled hydrogel. The diffusion
may slow to the point that release occurs by erosion of the drug
delivery vehicle.
[0041] In a monolithic dosage form, delayed release of the actives
may be provided by coating the actives with a delay release coating
according to methods known to the art. Thus, where the foregoing
description of the present invention has described mixing,
blending, granulating, compressing, etc. of the actives, it will be
appreciated by those skilled in the art that the actives may
previously be coated with a coating that erodes slowly in gastric
fluid to provide a delay in release of the actives. In particular,
a monolithic dosage form may contain microgranules, microcapsules
or coated beads containing the actives.
[0042] A particularly preferred bis-phosphonate dosage form is a
coated construction wherein the drug delivery vehicle coats a core
containing the active. This construction is illustrated in detail
with Examples 9-12, below. A coated construction delays the release
of the active by providing a diffusional barrier through which the
active must pass before it is released. As illustrated in the
Examples, a coated construction can provide either a delayed/rapid
release or a delayed/extended release of the active depending upon
the formulation of the core.
[0043] A preferred layered construction is one which contains the
drug delivery vehicle in one layer and the actives in another
layer. Preferred dimensions for this embodiment are about
14.times.8 mm. A layered construction may be prepared by
conventional multilayer compression techniques. A layered dosage
form comprising two layers, one comprising the drug delivery
vehicle and the other comprising the actives and any other desired
excipients, may be made to delay release of the actives by coating
only the actives-containing layer with a conventional coating
resistant to gastric fluids. A further method of achieving a delay
in the release is to formulate the drug containing layer as a
matrix that delays diffusion and erosion or by incorporating the
active substances in microcapsules or coated beads within the drug
containing layer.
[0044] The drug delivery vehicle is also suited for the retention
of the actives in the stomach when the actives are contained in
tablets that are either partially embedded in the drug delivery
vehicle or attached thereto by an adhesive. In addition to being of
sustained release nature, these tablets can further be of a delayed
pulse release nature or a delayed sustained release nature. The
expanding composition of this invention will retain these forms in
the stomach until the delay time has passed whereupon the drug will
be released in a burst or pulse fashion or in a sustained fashion.
Attaching, or partially embedding, several such tablets, each timed
with a different delay to release, to the composition of this
invention, allows versatile dosing schemes from one taken dose. For
example, one could deliver three (or more) timed doses in a pulse
fashion while the patient needs to take the dose only once. The
three doses would mimic taking three doses of the drug at the
prescribed times, with the drug being absorbed from the stomach
with each dose. Such dosing allows for improved compliance to
dosage schedules and in many cases will lead thereby to improved
therapy. Delayed dosage forms that are not coupled to gastric
retention will deliver each such dose in a different part of the GI
tract with different absorption profiles for each of the doses.
Such therapy would not be equivalent to taking three doses of the
drug at the prescribed times, wherein the drug would have been
absorbed from the stomach in each case.
[0045] In addition to the above-described dosage forms, there are
many other dosage forms in which the drug delivery vehicle could be
used to deliver a therapeutic bis-phosphonate over a sustained
period in the stomach.
[0046] Having thus described the invention with reference to
certain preferred embodiments, other embodiments will become
apparent to one skilled in the art from consideration of the
specification and examples. It is intended that the specification,
including the examples, is considered exemplary only, with the
scope and spirit of the invention being indicated by the claims
which follow.
EXAMPLES
EXAMPLES 1-8
[0047] Materials:
[0048] The HPMC used was HPMC K-15PM. The hydroxypropyl cellulose
used was Kluce.RTM. HF NF, available from Hercules. The sodium
croscarmellose used was Ac-Di-Sol.RTM. obtained from Avebe Corp.
The crosslinked polyacrylic acid was Carbopol.RTM. 974P obtained
from B. F. Goodrich Chemical Ltd. All materials were of
pharmaceutical grade.
[0049] Preparation of Tablets:
[0050] The compositions of each of the tablets are summarized in
Table 1. All the compositions contain hydroxypropyl methyl
cellulose, tannic acid, a superdisintegrant and 1% magnesium
stearate. All of the excipients, except for magnesium stearate,
were mixed simultaneously and thoroughly blended by hand. Magnesium
stearate was then added at a level of 1% w/w and the blend was
further mixed by hand until the magnesium stearate was uniformly
distributed throughout the composition. The amount of each
composition needed to produce a 5 mm thick tablet was determined
and then that amount was compressed into 5 mm thick tablets on a
Manesty f3 single punch tableting machine with a 10 mm diameter
punch and die. Tablets ranged in weight from 350-400 mg and each
had a hardness within the range of 5-7 KP as tested in an Erweka
hardness tester.
1 TABLE 2 Example No. (wt. %) Excipient 1 2 3 4 5 6 7 8
Hydroxypropyl 23.8 32.7 30.3 23.8 26.7 38.5 34.8 15.9
methylcellulose Hydroxypropyl cellulose 0.0 0.0 0.0 0.0 16.0 19.2
0.0 47.6 Cros-linked 0 0.0 0.0 0.0 0.0 0.0 8.7 0.0 polyacrylic acid
Total Hydrogel 23.8% 32.7% 30.3% 23.8% 42.7% 57.7% 43.5% 63.5%
Sodium starch glycolate 71.4 65.4 60.6 0.0 53.3 38.5 52.2 31.7
Sodium Croscarmellose 0.0 0.0 0.0 71.4 0.0 0.0 0.0 0.0 Tannic Acid
4.8 2.0 9.1 4.8 4.0 3.8 4.3 4.8 100% 100% 100% 100% 100% 100% 100%
100%
[0051] Swelling tests:
[0052] The tablets were added to 40 ml of 0.1M HCl contained in a
50 ml beaker and maintained at 37.+-.2.degree. C. The tablets were
removed after fifteen minutes with a tweezers and measured with a
caliper. Gel strength was assessed qualitatively with the
tweezers.
[0053] Results:
[0054] The results of the swelling tests are summarized in Table 2.
Swelling of the hydrogel was enhanced using either sodium
croscarmellose or sodium starch glycolate. The formulation can
optionally and advantageously contain a mixture of two hydrogel
polymers as demonstrated by the incorporation hydroxypropyl
cellulose and carbopol in the formulations of Examples 5, 6 and 8.
The tablet that expanded the most (36 times in volume) contained
tannic acid at 5% with sodium croscarmellose as the disintegrant.
The tablet with the second highest expansion (18.times.) also
contained tannic acid at 5% but used sodium starch glycolate. Both
of those gels were qualitatively weak compared to those of examples
5-8. The best performing tablets in terms of a high degree of
expansion and good mechanical strength are those of Examples 5 and
8, which contained tannic acid at 5 wt. %, used both hydroxypropyl
methylcellulose and hydroxypropyl cellulose hydrogel polymers and
contained sodium starch glycolate as disintegrant.
2TABLE 2 Example No. Degree of Swelling.sup.a Strength 1 18.1
moderate 2 12.7 moderate 3 7.2 moderate 4 36 moderate 5 10.4 strong
6 2 strong 7 4.5 strong 8 9.7 strong .sup.aratio of hydrated tablet
volume to dry tablet volume
EXAMPLE 9
[0055] Sodium alendronate monohydrate was formulated into an
immediate release tablet of 5-mm diameter with the composition of
Table 3 by mixing the powders and direct compression in a standard
rotary tablet press. Tablet hardness was between 7 and 12 kP.
3 TABLE 3 Component Weight (mg) Sodium alendronate monohydrate 11.6
mg.sup.a Microcrystalline cellulose 30 mg Lactose for direct
compression 20 mg Magnesium stearate 0.5 mg .sup.aequivalent to 10
mg alendronic acid
[0056] This tablet was embedded into 800 mg of gastric retention
delivery system (GRDS) matrix of formulation of Table 4 formed by
dry mixing of the components and compression in a Kilian RUD-20
press coat machine. The outer tablet is of oval shape with
dimensions approximately 17.times.7.times.9 mm.
4 TABLE 4 GRDS Component weight % HPMC (Methocel .RTM. K-15M) 17
Tannic acid 10 HPC (Klucel .RTM. HF) 50 Croscarmelose (aci-di-sol
.RTM.) 22 Magnesium stearate 1
[0057] The tablet was tested in a USP apparatus 2 dissolution
tester at 37.degree. C. in 500 ml 0.1N HCl to simulate gastric
conditions. The tablet expanded in about 15 minutes to dimensions
of 22.times.10.times.23 mm, large enough to effect gastric
retention since the tablet in its swollen state will not fit
through the pylorus. The results of the release of the alendronate
are given in Table 5. Essentially no alendronate was released
during the first three hours. The drug was then released at a
relatively fast rate from the disintegrating inner tablet through
the GRDS matrix.
5 TABLE 5 Time (h) Cumulative % release 0 0 1 0 2 0 3 3 4 50 5
100
EXAMPLE 10
[0058] Sodium alendronate monohydrate was formulated into an
extended release tablet of 5-mm diameter with a composition shown
in Table 6 by mixing the powders and direct compression in a
standard rotary tablet press. Tablet hardness was between 7 and 12
kP.
6 TABLE 6 Component Weight (mg) Sodium alendronate monohydrate 11.6
mg.sup.a Microcrystalline cellulose 25 mg Lactose 25 mg Magnesium
stearate 0.5 mg .sup.aequivalent to 10 mg alendronic acid
[0059] This tablet was embedded into 800 mg of Gastric Retention
Delivery System (GRDS) matrix of formulation of Table 7 formed by
dry mixing of the components and compression in a Kilian RUD-20
press coat machine. The outer tablet is of oval shape with
dimensions about 17.times.7.times.9 mm.
7 TABLE 7 Component weight % HPMC (Methocel K-15M) 17 Tannic acid
10 HPC (Klucel HF) 50 Croscarmelose (aci-di-sol) 22 Magnesium
stearate 1
[0060] The tablet was tested in a USP apparatus 2 dissolution
tester at 37.degree. C. in 500 ml 0.1N HCl to simulate gastric
conditions. The tablet expanded in 15 minutes to dimensions of
22.times.10.times.23 mm, sufficiently large to cause gastric
retention. The results of the release of the alendronate are given
in Table 8. Essentially no alendronate was released during the
first three hours. The drug was then released at a slow extended
release profile.
8 TABLE 8 Time (h) Cumulative % release 0 0 1 0 2 0 3 2 4 9 5 15 6
21 7 27 8 32 9 36
EXAMPLE 11
[0061] Sodium alendronate monohydrate (11.6 mg) was formulated into
a tablet of 5-mm diameter with 50 mg of the GRDS composition shown
in Table 6 above by mixing the powders and direct compression in a
standard rotary tablet press. Tablet hardness was between 7 and 12
kP. This tablet is embedded into 800 mg of Gastric Retention
Delivery System (GRDS) matrix formulation of Table 7 formed by dry
mixing of the components and compression in a Kilian RUD-20 press
coat machine. The outer tablet was of oval shape with dimensions
about 17.times.7.times.9 mm.
[0062] The tablets were tested in a USP apparatus 2 dissolution
tester at 37.degree. C. in 500 ml 0.1N HCl to simulate gastric
conditions. The tablet expanded in about 15 minutes to dimensions
of 22.times.10.times.23 mm, large enough to effect gastric
retention. The results of the release of the alendronate are given
in Table 9.
[0063] Essentially no alendronate was released during the first
three hours. The drug was then released at a relatively constant
pace from the inner tablet through the GRDS matrix
9 TABLE 9 Time (h) Cumulative % release 0 0 1 0 2 0 3 5 4 15 5 30 6
50 7 65 8 75 9 80 12 100
EXAMPLE 12
[0064] Sodium alendronate monohydrate was granulated with 0.5% HPC
(Klucel HF) in ethanol. The granulate was dried and milled to a
free flowing powder. This granulate was mixed with the GRDS matrix
formulation of Table 7 in a ratio of 11.8 mg alendronate granulate
to 850 mg GRDS matrix such that the alendronate matrix was
dispersed homogeneously in the matrix. Tablets were pressed in a
standard rotary press using oval tooling to give tablets with an
approximate size of 17.times.7.times.8 mm. 500 Grams of these
tablets were coated in a perforated pan coater with 5% HPMC
suspended in ethanol under the following conditions to give tablets
with a coating level of 15% w/w.
10 Coating conditions: Bed temperature: 40.degree. C. Solution flow
rate: 7.5 ml/min Coating time: about 20 minutes
[0065] The tablets were tested in a USP apparatus 2 dissolution
tester at 37.degree. C. in 500 ml 0.1N HCl to simulate gastric
conditions. The tablet expands quickly, but slower than in the
previous examples (in about 45 minutes) to dimensions of
20.times.8.times.20 mm which is large enough to effect gastric
retention. The results of the release of the alendronate are given
in Table 10. A low level of alendronate was released during the
first three hours. The drug was then released at a relatively
constant pace from the GRDS matrix.
11 TABLE 10 Time (h) Cumulative % release 0 0 1 1 2 3 3 5 4 25 5 45
6 65 7 85 8 100
EXAMPLE 13
[0066] Tablets from example 11 were administered to 3 beagle dogs
in a crossover design versus an immediate release alendronate
formulation. Urine samples were collected for 48 hours and an
overall AUC for alendronate was determined. The average
bioavailability of the alendronate from the immediate release
formulation was calculated to be .about.1.5% while the
bioavailability of the gastric retention alendronate was found to
be greater than 3%.
* * * * *