Note: Descriptions are shown in the official language in which they were submitted.
WO 95/05173 2 ~ 6 9 7 3 ~ PCTIUS94/09204
Description
ORAL COMPOSITIONS OF H2 - ANTAGONISTS
This invention relates to pharmaceutically elegant
compositions of therapeutic compounds having H2-antagonist
activity especially adapted for convenient oral
administration.
Background of the Invention
Magnesium aluminum silicates have been known in the
pharmaceutical art to be useful to mask the bitter taste
of a variety of medicinal agents. U.S. Patent No.
3,140,978 (M. R. Zentner), together with related patents
such as 3,248,290, 3,337,402, 3,337,403, as well as U.S.
Patent No. 4,711,774 (J. Denick Jr.), together with
4,716,033, 4,717,565, 4,758,424, 4,758,425 and 4,761,274,
describe the adsorption of medications of many therapeutic
classes onto magnesium aluminum silicates as well as the
suspensions, granulations, lozenges, chewable tablets and
the like prepared from the resulting complexes using
standard formulation methods. None of these mention the
use of H2-antagonists as the active therapeutic agent.
Other specific applications of magnesium alllm;nl~m
silicates to formulation procedures are disclosed in U.S.
Patent Nos. 3,432,593 (M. Shepard), 3,567,819 and
4,753,800. These also are of a specific aim and are
believed cumulative as well to the two basic references of
Zentner and Denick mentioned above.
U.S. Patent No. 4,719,228 (D. Rawlins) discloses the
use of selected synthetic silicas to form free flowing
powder products of a number of therapeutic classes of
drugs including antiulcer drugs. No reference to H2-
antagonists is made here.
The scientific literature contains studies of the use
of silicate clays in formulating various drugs of
different chemical types and the nature of the binding
forces involved. In general, the release of the active
ingredient from such formulations is uncertain but is
WO95/05173 PCT/US94/09204--
2i~9~ 3~
often retarded by clay admixture, J.W. McGinity et al., J.
Pharm. Sc. 65, 896; J.T. Carstensen et al., J. Pharm. Sc.
60 733. Certain electrolytes such as sodium and magnesium
chloride are reported to facilitate the release of
antibiotics from clay adsorbates, J.W. McGinity et al., J.
Pharm. Sc. 64, 1567.
An effervescent tablet containing ranitidine as the
active H2-antagonist agent has been reported. This
pharmaceutical form, which contains sodium acid
pyrophosphate, an acid salt, demonstrated substantial
reduced bioavailability of the active ingredient (54%).
K.M. Koch et al., Pharm. Res. 10 1027 (1993).
U.S. Patent No. 5,219,563 (S.J. Douglas) reports
adsorbates of ranitidine on synthetic ion exchange resin.
Disclosure of the Invention
This invention relates to pharmaceutical oral
compositions cont~;n;ng one or more H2-antagonist drugs.
These compositions do not exhibit a bitter taste in the
mouth and distribute the active ingredient substantially
in the gastrointestinal tract. The composition contains,
as essential ingredients, an H2-antagonist - magnesium
aluminum silicate complex and calcium carbonate. The
dosage unit form is any which would normally expose the
bitter H2-antagonist to the taste of the patient but is
preferably a chewable tablet. For larger doses, it may be
a sachet, lozenge or packaged flavored granules.
Best Mode for Carrying Out the Invention
Most drugs which have H2-antagonist activity, and are
thereby useful for treating various gastrointestinal
disorders such as ulcers, dyspepsia or gastrointestinal
reflux indications, have a bitter taste. The H2-compounds
are preferably administered orally. For the usual
prescription use, the oral product forms of these
compounds are capsules or coated tablets. Certain
segments of the patient population prefer more easily
ingested product forms. This is most evident in the over-
the-counter market. One of the most useful of such
21 ~9 73~
WO95/05l73 PCT~Sg4/09204
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~. :
product forms is the chewable or frangible tablet, lozenge
or troche. Examples of the preparation of chewable
products are found in U.S. Patent No. 4,711,774 which is
cited in the Background section above.
As stated above, the pharmaceutical art has long
recognized that the natural or processed magnesium
aluminum silicates adsorb a wide variety of medicaments to
some degree. Natural clays such as attapulgite and
montmorillonite have been used, but, in our hands, these
are not as satisfactory for use with H2-antagonists as are
the processed silicates known by the trade name "Veegum".
The latter are also described in detail in the above cited
prior art and are widely accepted for pharmaceutical use.
The literature describes the nature of silicate-drug
binding and the uncertain release of various active
ingredients from the adsorbate complex. Mechanical and
chemical methods of increasing the reliability of release
are many but, more often than not, unsuccessful. Ionic
additives such as the halide salts have not been
successful due to the side effects due to large ingestions
of such salts.
This i~nvention is based on several discoveries which
are unique with the u~e of H2-antagonists. Firstly, the
H2-antagonist compounds form tasteless adsorbates with
magnesium aluminum silicate readily and substantially
completely. Secondly, the addition of a selected quantity
of calcium carbonate dramatically improves the release of
active ingredient from the silicate adsorbate, but does
not cause overt side effects such as substantial release
of carbon dioxide by effervescence. This is so especially
when the formulations are prepared with acid addition
salts of the biologically active ingredients or with added
solid acid formulation aids such as the fruit acids, for
example citric acid, within the granules in the
formulation process. The complex between the active
biological ingredient and the magnesium aluminum silicate
WO95/05173 2 ~ ~ 9 ~ 35 PCT~S94/09204 -
is usually formed in situ, that is, during the formulation
of the dosage unit composition.
The composition of this invention, therefore, is in
its preferred form a chewable tablet comprised essentially
of a therapeutically effective but non-toxic dosage unit
quantity of an H2-antagonist complex formed with a
magnesium aluminum silicate, which complex is usually
prepared during formulation, and a quantity of calcium
carbonate.
The magnesium aluminum silicate which is the support
component of this combination is preferably the commercial
product known as "Veegum" supplied by R.T. Vanderbilt
Company, Inc. Analysis of the commercial product is
carried out as oxide contents. No control of the particle
size of the commercial grade of product has been found
necessary. Comprehensive descriptions of the product are
in the Zentner-Denick patents noted above.
The exact quantity of the silicate support is not
critical to the invention as long as enough is present to
completely adsorb the drug component in situ. An excess
is most convenient and preferred with ranges of from lO -
30% by weight of the dosage unit. Magnesium aluminum
silicates have been used in the literature to delay the
release of other active ingredients in time release
products when used in excess. This is in contrast to the
present invention which affords good quick release of
drug.
The H2-antagonist, in either the base or its acid
addition salt form as appropriate, is preferably selected
from those approved for use in either the prescription or
over-the-counter pharmaceutical markets. The dosage units
will contain either a full therapeutic dose or a partial
dose for a subject in need of relief so that from 1-5
units may be administered per day to obtain satisfactory
treatment of symptoms. The non-prescription products
usually contain a lower dose, often about half the
quantity. Examples of active H2-antagonists and suggested
WO95/05173 21~69 735 PCT~Sg4/09204
doses are cimetidine (300 mg), nizatidine (150 mg),
roxatidine (acetate), famotidine (20 mg), ranitidine (150
mg), tiotidine, lamtidine, mifentidine, zaltidine, KV-1257
or loxtidine (Handbook Exp. Pharmacol. 97 573-748 (1991),
"Histamine and Histamine Antagonists").
The daily dose range of active ingredient is a
nontoxic but H2-antagonist effective quantity and may be
chosen from 40 to 1600 mg. The dosage units may range
from 10 - 800 mg of active ingredient depending on the
known individual activity and market of the H2-antagonist
drug. The units are administered from 1-5 times daily
orally to a patient in need of H2-antagonist treatment.
The H2-antagonist may be present either as the base if
appropriate or as a salt thereof with a nontoxic,
pharmaceutically acceptable acid. Usually, the dose and
the form which is commercially available is conveniently
used. Surprisingly, the H2-antagonist-silicate adsorbate
is formed substantially completely during formulation
despite which base or salt form of the active H2-antagonist
is selected.
Preferably, the calcium carbonate is selected from
the range of 75-500 mg per dosage unit.
The calcium carbonate supplemented product is
preferably used in non-toxic quantities in up to 5 units
per day. A general range of calcium carbonate content of
the oral product is from about 1-35% by weight of the
chewable tablet products. For example, for a 1500 mg.
tablet as much as 500 mg. of calcium carbonate may be
present. Overt evolution of carbon dioxide has not been
observed when the compositions contact water. One skilled
in the art will recognize that the size of chewable
tablets may be larger than that of normal compressed
tablets.
A variety of other pharmaceutical additives may be
optionally used in the composition of this invention in
addition to the essential ingredients described above.
Among these are bulking agents, flavoring agents,
WO95/05173 2~9~ 3~ PCT~Sg4/09204 -
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granulating agents, buffering agents, coloring agents,
preservatives, confectioneries and the like. Reference
may be made to U.S. Patent No. 4,711,774 for more specific
formulation information.
Especially useful optional ingredients are the solid
fruit acids such as citric, malic or tartaric acids in up
to 3% by weight for good stability and palatability of the
chewable tablet as well as xylitol or mannitol as a
sweetening-bulking agent in up to 70~ by weight. Citric
acid as well as xylitol are particularly advantageous
since each contributes unexpectedly well to the
palatability of the chewable tablets. When such acids are
used for this purpose, quantity of calcium carbonate and
acid should be selected to insure good release, but not to
cause overt carbon dioxide evolution. The absence of the
acid component gives acceptable products as well.
The chewable tablets of this invention are prepared
by mixing the H2-antagonist compound with magnesium
aluminum silicate in a weight ratio chosen from the range
of 1 to 1 down to 1 to 10 with an optional sweetening
agent in a mixer, adding water to form the complex and
granulate. The dried and milled granules are mixed with
the calcium carbonate, bulking-sweetening agents and
tabletting aids then compressed into tablets.
The chewable pharmaceutical products are taken by the
subject in need of H2-antagonist treatment orally from 1 to
5 times daily as required to satisfy the acceptable daily
dosage regimen of active ingredients. It should be
particularly noted that the antacid component of the
chewable tablet may also contribute to lowering the acid
content of the gastrointestinal tract. The dosage units
should be prepared and used with this in mind.
The method of analysis used and detailed hereafter is
the ultraviolet dissolution method as reported in the USP
XXII (p. 3074). Usually times for pulling samples were
15, 30, 45, 60 minutes. The ultraviolet wave lengths
vary, of course, with the active ingredient. Cimetidine
WO95/05173 21 ~9 73$ PCT~Sg4/09204
is at 218 nm. Nizatidine and ranitidine are at 314 nm.
Famotidine is at 265 nm.
The following embodiments of this invention are
designed to illustrate and teach the specific use of the
invention but not to limit its scope.
W 095/05173 2 1~ 9 7 -8- PCTrUS94109204 -
Example 1
% By Weight
A B C D
Ingredient~ r
Nizatidine USP 5 - - -
Cimetidine USP - 5
Ranitidine USP - - 5
Famotidine USP - - - 2
Magnesium Aluminum Silicate NF 25 25 25 lO
Sodium Sac~-hA r; n NF .25.25 .25 .125
Mannitol NF Q.S. Q.S.Q.S Q.S.
Xylitol NF Q.S. Q.S. Q.S. Q.S.
Colloidal Solicon Dioxide NF
Magne~ium Stearate NF l.5 l.5 l.5 l.5
Flavor~ Q.S. Q.S. Q.S. Q.S.
Purified water*
100 100 100 100
* Remove during proce~ing
Method of Manufacturing
l. Mix drug with magne~ium al~ 'nnm ~ilicate and ~odium ~aCChAr; n
in a planetary mixer for five minute~.
2. Add water until a uniform granulation occur~.
3. Dry the granule~.
4. Size the granule~ into fine powder.
5. Add mannitol, xylitol and colloidal ~ilicon dioxide and mix for
ten minutes.
6. Add magne~ium ~tearate and mix for five minute~.
7. Com~re~ into chewable tablet~.
W 095/OSl73 16~ ~35 PCTrUS94/09204
Example 2
% By Weight
A B C D
Ingredient~
Nizatidine USP 5 - - -
Cimetidine USP - 5
Ranitidine USP - - 5
Famotidine USP - - - 2
Magne~ium Aluminum Silicate NF 25 25 25 10
Calcium Carbonate 5 5 5 5
Sodium Saccharin NF .25 .25 .25 .125
Mannitol NF Q.S. Q.S. Q.S. Q.S.
Xylitol NF Q.S. Q.S. Q.S. Q.S.
Colloidal Solicon Dioxide NF
Magne~ium Stearate NF 1.5 1.5 1.5 1.5
Flavorq Q.S. Q.S. Q.S. Q.S.
Purified water~
100 100 100 100
* Remove during proce-~ing
Method of Manufacturing
1. Mix drug with magneqium all nllm ~ilicate and qodium qaccharin
in a planetary mixer for five minute~.
2. Add water until a uniform granulation occur~.
3. Dry the granule~.
4. Size the granule~ into fine powder.
5. Add mannitol,.xylitol, calcium carbonate, colloidal ~olicon
dioxide to and mix for ten minutes.
6. Add magne~ium -qtearate and mix for five minute~.
7. Compre~ into chewable tablet~.
W 095/05173 ~69 PCTrUS~ 204 ~
--10--
If the operator wi~he~ an acid agent ~uch a~ a fruit acid, for
example, citric, malic or tartaric acid in the formulation, thi~ i~
added to the -n~f~cturing proce~ at Step 1 before the granulation
procesR, u~ually at about 1.5%.
The following comparative examples were ~elected to illu~trate
the enhanced relea~e of active ingredient from the granule-~/tablet~ of
this invention uYing the preparative and te~ting procedure-Q de~cribed
above.
Example 3
The percentage of cimetidine di~301ved in water using the U.S.P.
method II at 50 RPM to 60 minute~ from granule~ with added citric acid
(3~), calcium carbonate (75 mg) and without calcium carbonate.
Time Without CaCO3 With CaCO3
39.967.5
44.674.4
46.978.8
48.382.8
51.6104.3
Example 4
Ranitidine Hydrochloride (75 mg ba~e) with Calcium Carbonate (75 mg)
Time Without CaCo3With CaCo3
30.3% 44.0~
36.6% 51.4%
36.9% 53.7%
37.6% 56.8%
40.4% 63.6%
Example 5
Nizatidine with and without calcium carbonate compared at 0 time
and l month ~tability (40O; 75%RH), citric acid (1.5%) added to all
sample~.
Time Without CaCO3 StabilityWith CaCO3 Stability
30.3 30.0 77.6 45.7
34.8 34.5 82.3 60.3
36.6 37.42 84.2 67.2
38.8 39.4 85.3 70.0
42.9 44.1 94.4 90.3
~ W 095/05~73 2 PCTrUS94/09204
169 73~
Example 6
Nizatidine granule~ compared in water with tablet with 1.5% citric
acid and tablet with 1.5~ of citric acid and 37.5 mg of calcium
carbonate.
Time Gran Tab (1.5% C.A.) Tab (C.A. plus CaCO3)
O O O O
88.8 39.1 97
Example 7
The proces~ of Example 1 is used with 25% by weight of magnesium
al, nllm -~ilicate, 5% of nizatidine, 0.25% of ~od-um ~ac~hAr;n and 1.2%
of citric acid. The granules, before tabletting, were compared with the
tabletted product and with the Ch~ --hl e tablet with 5% of calcium
carbonate.
Time Gran (Without CaCO,) (With CaCO7)
O O O O
37 45 92.2
39.2 47 93
47.4 47.4 95.7
