U.S. patent application number 10/059759 was filed with the patent office on 2002-10-17 for method of making tablets and tablet compositions produced therefrom.
This patent application is currently assigned to Rexall Sundown, Inc.. Invention is credited to Chang, Kuei Tu, Holly, Gerald T., Mergens, William J..
Application Number | 20020150617 10/059759 |
Document ID | / |
Family ID | 24565509 |
Filed Date | 2002-10-17 |
United States Patent
Application |
20020150617 |
Kind Code |
A1 |
Mergens, William J. ; et
al. |
October 17, 2002 |
Method of making tablets and tablet compositions produced
therefrom
Abstract
The present invention provides a method of making tablet
compositions that are substantially free of excipients. The method
includes forming a compactable granular mixture containing at least
one compaction enhancing therapeutic compound, at least one other
therapeutic compound that is different form the compaction
enhancing therapeutic compound, and less than about 15 weight
percent of a non-aesthetic excipient. The compactable granular
mixture thus obtained is compressed to form a tablet composition.
The present invention also provides tablet compositions produced by
the methods of the present invention that are substantially free of
excipients.
Inventors: |
Mergens, William J.; (West
Palm Beach, FL) ; Chang, Kuei Tu; (Mountain Lakes,
NJ) ; Holly, Gerald T.; (Delray Beach, FL) |
Correspondence
Address: |
Woodcock Washburn LLP
One Liberty Place - 46th Floor
Philadelphia
PA
19103
US
|
Assignee: |
Rexall Sundown, Inc.
|
Family ID: |
24565509 |
Appl. No.: |
10/059759 |
Filed: |
January 29, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10059759 |
Jan 29, 2002 |
|
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|
09639780 |
Aug 16, 2000 |
|
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6358526 |
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Current U.S.
Class: |
424/465 ;
424/725; 424/728; 424/730; 424/752; 424/766; 424/769; 514/200;
514/54 |
Current CPC
Class: |
A61P 3/06 20180101; A61K
9/2095 20130101 |
Class at
Publication: |
424/465 ;
424/725; 514/54; 514/200; 424/730; 424/769; 424/728; 424/752;
424/766 |
International
Class: |
A61K 035/78; A61K
031/545; A61K 031/715; A61K 009/20 |
Claims
What is claimed is:
1. A tablet composition comprising, on a dry-weight basis: (a) from
about 3 weight percent to about 99.5 weight percent of a compaction
enhancing therapeutic compound; (b) from about 0.5 weight percent
to about 97 weight percent of at least one second therapeutic
compound that is different from the compaction enhancing
therapeutic compound, wherein the compaction enhancing therapeutic
compound enhances the compaction of the second therapeutic
compound; and (c) less than about 15 weight percent non-aesthetic
excipients.
2. The tablet composition of claim 1 wherein the compaction
enhancing therapeutic compound is in intimate admixture with the
second therapeutic compound.
3. The tablet composition of claim 1 wherein the tablet composition
has a friability of less than about 1 weight percent, and an
increased hardness of at least about 10% relative to a tablet of
the same weight, shape, and size, compressed under the same
conditions, and not containing the compaction enhancing therapeutic
compound.
4. The tablet composition of claim 1 wherein the compaction
enhancing therapeutic compound is selected from the group
consisting of glycosaminoglycans; herbal based extracts; botanical
based extracts; vitamins; salt forms of minerals; anti-inflammatory
agents; antibiotics; cholesterol lowering agents; and combinations
thereof.
5. The tablet composition of claim 4 wherein the glycosaminoglycan
is heparin, dermatan sulfate, chondroitin, sulodexide or a
pharmaceutically acceptable salt thereof; the herbal or botanical
based extract is St. John's Wort extract, horse chestnut, ginseng,
ginko biloba, grape seed extract or a pharmaceutically acceptable
salt thereof; the vitamin is niacinamide ascorbate or a
pharmaceutically acceptable salt thereof; the anti-inflammatory
agents is naproxen or a pharmaceutically acceptable salt thereof;
the antibiotic is cephalosporin or a pharmaceutically acceptable
salt thereof; the cholesterol lowering agent is cholestyramine or a
pharmaceutically acceptable salt thereof.
6. The tablet composition of claim 5 wherein the compaction
enhancing therapeutic compound comprises a glycosaminoglycan, grape
seed extract, or combinations thereof.
7. The tablet composition of claim 1 wherein the second therapeutic
compound is a non-compaction enhancing therapeutic compound.
8. The tablet composition of claim 7 wherein the compaction
enhancing therapeutic compound comprises a glycosaminoglycan and
the second therapeutic compound comprises an aminosugar.
9. The tablet composition of claim 8 wherein the glycosaminoglycan
is heparin, dermatan sulfate, chondroitin, sulodexide, or a
pharmaceutically acceptable salt thereof, and the aminosugar is
glucosamine, or a pharmaceutically acceptable salt thereof.
10. The tablet composition of claim 9 wherein the glycosaminoglycan
is chondroitin or a pharmaceutically acceptable salt thereof and
the glucosamine is N-acetyl glucosamine sulfate, glucosamine
hydrochloride, or glucosamine sulfate.
11. The tablet composition of claim 8 wherein the tablet
composition comprises from about 3 weight percent to about 99.5
weight percent glycosaminoglycan; and from about 0.5 weight percent
to about 97 weight percent aminosugar.
12. The tablet composition of claim 8 wherein the tablet
composition further comprises at least a third therapeutic compound
selected from the group consisting of kelp, manganese ascorbate,
sodium ascorbate, calcium ascorbate, Vitamin C, dried powder forms
of Vitamin A, Vitamin D, Vitamin E, Vitamin K, and beta carotene;
Vitamin B.sub.6, niacin, phosphorous containing salts, zinc
containing salts, copper containing salts, calcium containing
salts, calcium citrate, calcium carbonate, oyster shell, magnesium,
manganese sulfate, boron, estrogen, and combinations thereof.
13. The tablet composition of claim 8 wherein the amount of the
non-aesthetic excipient is less than about 5 weight percent.
14. The tablet composition of claim 13, wherein the non-aesthetic
excipient comprises a lubricant.
15. A tablet composition comprising, on a dry weight basis: (a)
from about 5 weight percent to about 50 weight percent of a
compaction enhancing therapeutic compound that is a
glycosaminoglycan; (b) from about 10 weight percent to about 95
weight percent of at least one second therapeutic compound that is
an aminosugar, wherein the compaction enhancing therapeutic
compound enhances the compaction of the second therapeutic compound
and is in intimate admixture with the second therapeutic compound;
and (c) less than about 10 weight percent non-aesthetic excipients.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 09/639,780, filed Aug. 16, 2000, now allowed.
FIELD OF THE INVENTION
[0002] The present invention relates to a method for making
tablets, and more particularly, relates to a method for making
tablets that are substantially free of excipients, where at least
one therapeutic compound in the tablet serves as a compaction
enhancing agent for the tablet. The present invention also relates
to tablet compositions produced by the methods of the present
invention.
BACKGROUND OF THE INVENTION
[0003] Tablet compositions are commonly used to deliver therapeutic
compounds to a patient such as a human or animal. By "tablet" as
used herein, it is meant solid particles, containing or including
therapeutic compounds, that are compressed under pressure into any
desirable shape, such as a pill or caplet.
[0004] Typically, tablets contain other ingredients, hereinafter
referred to as "excipients," that provide necessary physical or
aesthetic properties to a tablet for delivery of the therapeutic
compound. For example, with respect to physical properties, tablets
generally need to have acceptable hardness, disintegration,
dissolution rate for release of the therapeutic, friability,
stability, and size to effectively deliver a therapeutic compound.
With respect to aesthetics, it may be desirable for the tablet to
contain additives that appeal to the human senses such as
colorants, fragrances, texture modifiers, and/or flavorants.
Specific types of excipients commonly used in tablet compositions
include for example diluents, binders, lubricants, glidants,
disintegrants, gelling agents, flavoring agents, and coloring
agents. Many of these excipients are commonly added because the
therapeutic compound alone may have poor compactability, and thus
excipients are needed to achieve the desired tabletting
performance.
[0005] A problem, however, in using excipients, is that the tablet
may become too large to ingest due to the amount of excipients
needed to effectively formulate the tablet. A solution to this
problem would be to reduce the amount of therapeutic compound and
excipients to reduce the overall weight of the tablet, however,
multiple tablets would then be needed to deliver the appropriate
amount of therapeutic compound. Another problem in using excipients
is that, particularly in nutraceuticals, they do not adequately
compensate for low density of many herbal products and as such, are
in many cases unsatisfactory solutions to tabletting problems.
Additionally, excipients often add cost to the tablet, and also may
be objectionable to some consumers.
[0006] Tablet formulations in which it is especially desirable to
reduce the amount of excipients are those used for the treatment of
connective tissue to prevent, repair, or lessen ailments of the
joints and cartilage tissue, such as observed with arthritis. For
example, U.S. Pat. Nos. 5,364,845 and 5,587,363 both to Henderson
("Henderson") disclose therapeutic compositions for the treatment
and repair of connective tissue containing amino sugars such as
glucosamine, and glycosaminoglycans such as chondroitin. The
compositions disclosed in Henderson are used in the form of a
powder (for large animals) or capsule (for small animals).
Additionally, it is known that these same compositions can be
supplied in tablet form, if excipients are used. For example, the
commercially available product called "Osteo-Bi-flex" supplied by
Rexall Sundown, provides in tablet form a composition containing
glucosamine, chondroitin sulfate, and excipients, where the
excipients make up at least 23 wt % of the tablet formulation.
[0007] U.S. Pat. No. 5,843,919 to Burger discloses a composition
and method for the treatment of arthritis where the composition
contains one or more glucosamines and one or more omega-3-fatty
acids. Although Burger discloses that a tablet can be prepared, it
is apparent that excipients would be needed as Burger discloses
that the glucosamine is preferably dissolved in an oil containing
the omega-3-fatty acid.
[0008] Other compositions, which may optionally be in the form of
tablets, for treating ailments of the joints and connective tissues
are disclosed in for example U.S. Pat. Nos. 5,605,891 to Prino et
al., 5,840,715 to Florio, and 5,849,336 to Aoyagi et al. These
patents however, provide no specific example of useful tablet
formulations.
[0009] Amino sugars and glycosaminoglycans have also been used in
compositions for treating skin. For example, U.S. Pat. No.
5,804,594 to Murad discloses a composition for the prevention and
treatment of skin conditions that contain a sugar compound, an
antioxidant, an amino acid, a transition metal component, a
catechin based preparation, a glucosamine and chondroitin. Although
tablet formulations are disclosed, it is taught that such
compositions need to be prepared in the presence of carriers.
[0010] With respect to other therapeutics, it is known that a
therapeutic alone may be compressible, without excipients. For
example, U.S. Pat. No. 5,079,007 to Putnam discloses an implant
containing a crystalline salt of cephalosporin, an amorphous salt
of cephalosporin and from 0 to 10 weight percent excipients. Putnam
teaches that the crystalline and amorphous cephalosporin forms are
compressible alone to form a tablet, and that the ratio of the two
components are adjusted to obtain the desired release
characteristics of the implant. Putnam thus does not describe a
method for making a tablet where one therapeutic compound serves as
a compaction enhancing agent for a different therapeutic
compound.
[0011] Thus, it would be desirable to develop a method of making
tablets and tablet compositions produced therefrom that are
substantially free of excipients, where at least one of the
therapeutic compounds is a compaction enhancing agent for the other
therapeutic compound.
SUMMARY OF THE INVENTION
[0012] The present invention provides a method of making tablets
that are substantially free of excipients. The method of the
present invention includes forming a compactable granular mixture
comprising (i) at least about 3 weight percent of a compaction
enhancing therapeutic compound, (ii) at least one other therapeutic
compound that is different from the compaction enhancing
therapeutic compound and (iii) less than about 15 weight percent of
non-aesthetic excipients. The compactable granular mixture is
compressed to form one or more tablets.
[0013] In a preferred embodiment of the present invention, the
compaction enhancing therapeutic compound includes a
glycosaminoglycan and the other therapeutic compound includes an
amino sugar.
[0014] The present invention also provides a tablet composition
containing from about 3 weight percent to about 99.5 weight percent
of a compaction enhancing therapeutic compound; from about 0.5
weight percent to about 97 weight percent of at least one second
therapeutic compound that is different from the compaction
enhancing therapeutic compound; and less than about 15 weight
percent excipients. The compaction enhancing therapeutic compound
enhances the compaction of the second therapeutic compound and is
preferably in intimate admixture with the second therapeutic
compound.
DETAILED DESCRIPTION OF THE INVENTION
[0015] The present invention provides a method of making tablets
that are substantially free of excipients. The tablets produced by
the method of the present invention contain at least two
therapeutic compounds, where at least one of the therapeutic
compounds serves as a compaction enhancing agent for the other
therapeutic compound. By being able to provide tablets that are
substantially free of excipients, smaller tablets and/or tablets
containing greater amounts of therapeutic compounds can be
produced. Thus, tablets can be provided that are more easily
ingested due to the smaller size, and/or eliminating the need for
taking multiple tablets to obtain a desired dosage of a therapeutic
compound.
[0016] By "substantially free" of excipients it is meant that the
tablet contains less than about 15 weight percent, more preferably
less than about 8 weight percent, and most preferably less than
about 2 weight percent excipients, based on the total weight of the
tablet on a dry basis (i.e., excluding moisture as hereinafter
defined). The term "excipient," as used herein refers to any
additive, liquid or solid, present in the tablet that provides some
non-therapeutic property to the tablet. For example, excipients are
usually added to enhance mechanical or aesthetic properties in a
tablet, or to dilute the therapeutic compound. As such, the term
excipient, as used herein, does not include therapeutic compounds,
or moisture, such as water or other solvent, that is used during
the manufacture of the tablet, or is inherently present in one of
the ingredients used to form the tablet. Common mechanical
excipients include for example binding agents, lubricants,
disintegrants, coating agents, gelling agents, glidants,
absorbents, surfactants, antiadherents, or combinations thereof.
Common aesthetic excipients include for example colorants,
flavorants, or combinations thereof. Common excipients used to
dilute the therapeutic compound include for example diluents,
fillers, or combinations thereof. Preferably, the tablet contains
less than about 15 wt %, more preferably less than 8 wt %, and most
preferably less than about 2 wt % mechanical or diluting excipients
(i.e., non-aesthetic excipients) based on the total weight of the
tablet on a dry basis.
[0017] By "therapeutic compound" it is meant any substance used to
treat (including prevent, diagnose, alleviate, or cure) a malady,
affliction, nutritional deficiency, disease or injury in a patient.
The term "therapeutic compound" is also meant to include substances
that are a supplement for improving the nutritional, physical, or
emotional well being of a patient such as vitamins, minerals, or
herbal based supplements. By "patient" it is meant a human and/or
animal such as a mammal or reptile.
[0018] In the method of the present invention, a compactable
granular mixture is formed containing (i) at least about 3 weight
percent of a compaction enhancing therapeutic compound, (ii) at
least one other therapeutic compound that is different from the
compaction enhancing therapeutic compound and (iii) less than about
15 weight percent of non-aesthetic excipients. The compactable
granular mixture is then compressed to form one or more
tablets.
[0019] The compaction enhancing therapeutic compound is any
therapeutic compound that enhances the compactability of the other
therapeutic compound. By "enhances the compactability" it is meant
that when the compaction enhancing therapeutic compound is mixed in
the amounts (i.e., at least 3 weight percent) and manner (such as
for example granulating, solvent dissolution and removal, or
blending) as described herein with the other therapeutic compound,
and optional lubricant, the granular mixture formed can be
compressed into a tablet having acceptable friability (i.e., about
1% or less), and an increased hardness of at least about 10%, more
preferably at least about 20%, and most preferably 50%, based on a
tablet of the same weight, shape, and size, compressed under the
same conditions, and not containing the compaction enhancing
therapeutic compound. Hardness and friability can be determined by
those techniques described hereinafter.
[0020] Preferably, the amount of compaction enhancing therapeutic
compound in the tablet is at least about 3 weight percent to about
99.5 weight percent, more preferably from about 5 weight percent to
about 50 weight percent and most preferably from about 5 weight
percent to about 15 weight percent, based on the total tablet
weight.
[0021] Examples of compaction enhancing therapeutic compounds
include for example glycosaminoglycans such as heparin, dermatan
sulfate, chondroitin, or sulodexide; herbal or botanical based
extracts such as St. John's Wort extract, horse chestnut, ginseng,
ginko biloba, kelp, grape seed extract; vitamins such as
niacinamide ascorbate, and derivatives thereof; salt forms of
minerals; anti-inflammatory agents such as naproxen; antibiotics
such as cephalosporin; cholesterol lowering agents such as
cholestyramine; pharmaceutically acceptable salts of any of the
foregoing; or any combination thereof.
[0022] In a preferred embodiment of the present invention, the
compaction enhancing therapeutic compound is a glycosaminoglycan
such as chondroitin, derivatives of chondroitin, including
pharmaceutically acceptable salts thereof; an herbal or botanical
extract such as St. John's Wort extract, or grape seed extract; or
combinations thereof.
[0023] The tablet also contains at least one other therapeutic
compound that is different from the compaction enhancing
therapeutic compound. This other therapeutic compound may be any
therapeutic compound known to those skilled in the art. For
example, the other therapeutic compound may be a compaction
enhancing therapeutic compound as previously described herein, or a
compound that does not enhance compaction (i.e., a non-compaction
enhancing therapeutic compound).
[0024] Examples of therapeutic compounds that may be used as the
other therapeutic compound include anti-inflammatory agents;
antibiotics; cholesterol lowering agents; antifungal agents;
antineoplastic agents; analgesics; hormones; peptides;
anticoagulation agents; circulatory drugs; antianginals;
antituberculars; antivirals; narcotics; sedatives; diet products;
nutritional supplements such as vitamins or minerals; herbal or
botanical extracts; anti-smoking libido agents; amino acids,
aminosugars; pharmaceutically acceptable salts or derivatives of
any of the foregoing; or any combination thereof. Specific examples
of vitamins and minerals useful as the other therapeutic compound
include Vitamin C, dried powder forms of Vitamin A, Vitamin D,
Vitamin E, Vitamin K, or beta carotene; B vitamins, such as
thiamin, riboflavin, niacin, Vitamin B.sub.6, Vitamin B.sub.12,
biotin, or folic acid; pantothenic acid, calcium, iron, zinc,
iodine, magnesium, zinc, selenium, copper, manganese, chromium,
molybdenum, potassium, boron, nickel, silicon, tin, vanadium;
derivatives or salts of the foregoing; or combinations thereof.
Examples of herbal or botanical extracts useful as the other
therapeutic compound in the present invention include St. John's
Wort extract, horse chestnut, ginseng, ginko biloba, kelp, grape
seed extract or combinations thereof.
[0025] In a preferred embodiment of the present invention, the
other therapeutic compound is a therapeutic compound that does not
enhance the compactability of another therapeutic compound.
Examples of therapeutic compounds that do not enhance the
compactability of a therapeutic compound include for example
aminosugars such as glucosamine, including derivatives or
pharmaceutically acceptable salts thereof, such as N-acetyl
glucosamine sulfate, glucosamine hydrochloride, or glucosamine
sulfate; certain vitamins and derivatives or salts thereof such as
Vitamin C (e.g., ascorbic acid), Vitamin B (e.g., thiamin
hydrochloride, thiamin mononitrate, Vitamin B.sub.6, Vitamin
B.sub.12, niacin, biotin, folic acid, pantothenic acid), dried
powder forms of Vitamin A, Vitamin D, Vitamin E, Vitamin K, or beta
carotene; certain amino acids such as arginine and derivatives
thereof or salts thereof; or combinations thereof.
[0026] Preferably, the other therapeutic compound is present in the
tablet in an amount equal to or less than about 97 weight percent,
more preferably from about 0.5 weight percent to about 95 weight
percent and most preferably from about 10 weight percent to about
95 weight percent, based on the total tablet weight.
[0027] With respect to the compactability properties of a
therapeutic compound, one skilled in the art will recognize that a
therapeutic compound in one form may enhance the compactability of
another therapeutic compound and/or be compactable, but in another
form (such as crystalline) may not enhance compactability of a
therapeutic compound. As such it is possible that a therapeutic
compound in two different forms could be formulated in a single
tablet that is substantially free of excipients. However, the
tablet should contain at least one therapeutic compound that is
chemically different from the compaction enhancing therapeutic
compound. For example, the tablet may contain two different
compaction enhancing therapeutic compounds and no other therapeutic
compounds; one compaction enhancing therapeutic compound and one or
more non-compaction enhancing therapeutic compounds; or one or more
compaction enhancing therapeutic compound and one or more
non-compaction enhancing therapeutic compounds.
[0028] The compaction enhancing therapeutic compound and the other
therapeutic compound are formed into a compactable granular
mixture. By "compactable," it is meant that the granular mixture is
capable of forming a 500 mg sized round tablet having a diameter of
{fraction (7/16)}" (standard concave) at a compaction pressure of
greater than about 1000 lbs and having a hardness of at least about
5 Strong Cobb (SC) and a friability of less than about 1%.
Preferably, the compactable granular mixture will be freely
flowable for tabletting. Preferably, the compactable granular
mixture will have a particle size distribution of 95 percent by
weight of the particles passing through a 20 mesh screen and less
than 50% by weight of the particles passing through a 100 mesh
screen (standard US mesh size).
[0029] One skilled in the art will recognize that there are various
ways to form a compactable granular mixture. Any method may be used
for combining the therapeutic compounds and other desired additives
(e.g., excipients) that results in a compactable granular mixture.
For example, a compactable granular mixture may be formed by
blending the compaction enhancing therapeutic compound, the other
therapeutic compound, and any other additive as a dry blend. A
compactable granular mixture may also be formed by granulating a
mixture containing the compaction enhancing therapeutic compound
and other therapeutic compound. A compactable granular mixture may
also be formed by at least partially or completely dissolving the
compaction enhancing therapeutic compound and other therapeutic
compound in a suitable liquid, followed by removal of the liquid.
It may also be necessary, as hereinafter described, to subsequently
process the mixture formed (e.g. pulverize, agglomerate) after
combining the therapeutic compounds to form the compactable
granular mixture
[0030] One skilled in the art will recognize that the desired
method chosen for forming a compactable granular mixture will
depend upon, for example, the selection of the compaction enhancing
therapeutic compound, the other therapeutic compound, and any other
desired additive. For example, as explained in further detail
hereinafter, it may be necessary, based on the selected therapeutic
compounds, to form granules containing an intimate admixture of at
least a portion of the compaction enhancing therapeutic compound
and at least a portion of the other therapeutic compound to form a
compactable granular mixture. However, it may also be possible that
certain compaction enhancing therapeutic compounds may simply be
mixed with the other therapeutic compound to form a compactable
granular mixture.
[0031] By "intimate admixture," it is meant that the compaction
enhancing therapeutic compound is uniformly admixed at a molecular
level with the other therapeutic compound (e.g., in the case of at
least partially dissolving both therapeutic compounds in a fluid,
and removing the fluid), and/or admixed in a manner so that
discrete particles containing the compaction enhancing therapeutic
compound or a solid film containing the compaction enhancing
therapeutic compound are in at least partial contact with the
surfaces of the particles containing the other therapeutic
compound. In a preferred embodiment, the compaction enhancing
therapeutic compound is at least partially coated as a solid film
onto the surfaces of the other therapeutic compound.
[0032] There are various ways in which granules containing an
intimate admixture of the compaction enhancing therapeutic compound
and the other therapeutic compound may be formed. For example,
granules of an intimate admixture of the therapeutic compounds may
be prepared by wet granulating or solvent dissolution and removal
process methods. In some circumstances, dry granulating may be used
to form granules containing an intimate admixture of the
therapeutic compounds. "Granulating" as used herein refers to a
process where two or more smaller particles are combined to form
larger granule particles through such processes as extrusion,
compaction, fluid-bed granulation, or tumbling. "Solvent
dissolution and removal" as used herein refers to a process where
solids are at least partially dissolved in a liquid, and then the
liquid is removed to form a granular mixture (e.g., spray
drying).
[0033] One skilled in the art will recognize that there are various
ways to wet granulate the therapeutic compounds. Typically, the
therapeutic compounds will be mixed in the presence of a
granulating fluid, and wet granules containing an intimate
admixture of the therapeutic compounds will be formed
simultaneously with mixing, and/or subsequently through additional
means. The wet granules containing the therapeutic compounds are
then preferably dried and pulverized to a suitable particle size
for tabletting.
[0034] There are various ways in which the granulating fluid may be
added to the therapeutic compounds. For example, a dry blend may be
formed containing the therapeutic compounds, and the granulating
fluid may be added to the dry blend to form a wetted mixture of
therapeutic particles. Alternately, one or more compaction
enhancing therapeutic compounds may be dissolved or dispersed in
the granulating fluid that is then added (e.g., by spraying) to a
dry blend containing the other therapeutic compound to form a
wetted mixture of the therapeutic particles.
[0035] One skilled in the art will also recognize that there are
various ways in which to granulate the wetted mixture of
therapeutic particles. For example, granules may be simultaneously
formed while adding the granulating fluid to the therapeutic
compound(s) with mixing, such as tumbling, vibrating or shaking.
Also, granules may be formed by extruding the wetted mixture of
therapeutic granules and/or particles through a die or screen to
form larger granules in various shapes such as noodles, pellets,
briquettes, spheres, or combinations thereof.
[0036] Suitable equipment for wet granulating is disclosed in for
example Chemical Engineers' Handbook, by Perry and Chilton, fifth
edition, published by McGraw-Hill Inc., 1973, Chapters 8 and 19,
the disclosure of which is hereby incorporated by reference in its
entirety. In a preferred embodiment of the present invention,
continuous granulation equipment is used such as a single screw or
twin screw extruder. A preferred extruder is an extructor supplied
by Rietz Manufacturing Company. Alternatively, batch equipment
designed for the blending both solids and liquids may be used such
as for example cone and screw mixers, double arm kneaders, twin
blade conical mixers, planetary mixers, helical ribbon blade
mixers, conical blenders, or combinations thereof.
[0037] The granulating fluid used for wet granulating may be water
or any biocompatible solvent that is effective in forming granules
containing an intimate admixture of the therapeutic compounds. In a
preferred embodiment of the present invention, the granulating
fluid is chosen so that the compaction enhancing therapeutic
compound is at least partially soluble and more preferably
completely soluble in the granulating fluid. Preferably also, the
granulating fluid is selected so that the other therapeutic is at
least partially insoluble.
[0038] The amount of granulating fluid added during granulation to
form the wetted mixture of therapeutic particles will depend on
such factors as the processing equipment chosen, the types of
therapeutic compounds selected, the particle size of the
therapeutic compounds, and length of processing time. Typically
however the amount of fluid will be from about 5 weight percent to
about 30 weight percent, and more preferably from about 8 weight
percent to about 15 weight percent, based on the total weight of
solids being granulated.
[0039] Examples of fluids that may be used include water,
biocompatible organic solvents such as C.sub.1 to C.sub.4 alkyl
alcohols, such as methanol, ethanol, n-propanol, isopropanol, or
butanol; ethers such as alkoxylated ethers, alkyl ethers, diether,
triethers, oligo ethers, polyethers, or cyclic ethers; ketones such
as acetone or methyl ethyl ketone; alkyl acetates such as ethyl
acetate; alkanes, such as C.sub.5 to C.sub.8 aliphatic alkanes such
as hexane or heptane; cyclic hydrocarbons such as C5 to C.sub.6
cyclic hydrocarbons such as cyclopentane or cyclohexane; aromatic
hydrocarbons and derivatives thereof such as toluene; or
combinations thereof.
[0040] It is also possible to form the granulate mixture using a
supercritical fluid as the granulating fluid. A supercritical fluid
exists at conditions where its liquid and gaseous states are
indistinguishable from one another. The critical temperature of a
fluid is the temperature above which that fluid cannot be liquified
by an increase in pressure. The critical pressure of a fluid is the
pressure of the fluid at its critical temperature. Examples of
useful supercritical fluids include carbon dioxide, or mixtures of
carbon dioxide and aliphatic or cyclic alkanes.
[0041] The temperature and pressure at which wet granulation is
carried out will depend on the therapeutic compounds and
granulating fluid chosen. Preferably, when using water, wet
granulation will be carried out at a temperature of from about
22.degree. C. to about 37.degree. C., and more preferably from
about 22.degree. C. to about 30.degree. C. Typical granulation
pressures through the die range from about atmospheric pressure to
several thousand pounds per square inch (psi). In the case of using
a supercritical fluid, wet granulation would be carried out at a
temperature and pressure at which the fluid exists in a
supercritical state.
[0042] Following wet granulation, at least a portion of the
granulating fluid is removed from the wet granulate mixture to form
a dry granulate mixture. The amount of fluid removed will depend on
such factors as the total amount of granulating fluid added,
selection of the therapeutic compounds, particle sizes of the
therapeutic compounds, and the solubilities of the therapeutic
compounds in the granulating fluid. Preferably, at least about 50
weight percent, and more preferably from about 80 weight percent to
about 98 weight percent of the added granulating fluid in the wet
granulate mixture is removed to form a dry granulate mixture. The
drying temperature is preferably chosen to efficiently remove the
granulating fluid without degrading the therapeutic compounds in
the granulate mixture.
[0043] A granulate mixture may also be formed by at least partially
dissolving, and more preferably completely dissolving the
compaction enhancing therapeutic compound and the other therapeutic
compound in a liquid, and removing the liquid by any suitable
technique to form granules containing the therapeutic compounds in
intimate admixture. The selection and amount of liquid used will
depend on the solubilities of the therapeutic compounds.
[0044] Examples of suitable liquids include water, biocompatible
organic solvents such as C.sub.1 to C.sub.4 alkyl alcohols, such as
methanol, ethanol, n-propanol, isopropanol, or butanol; ethers such
as alkoxylated ethers, alkyl ethers, diether, triethers, oligo
ethers, polyethers, or cyclic ethers; ketones such as acetone or
methyl ethyl ketone; alkyl acetates such as ethyl acetate; alkanes,
such as C.sub.5 to C.sub.8 aliphatic alkanes such as hexane or
heptane; cyclic hydrocarbons such as C.sub.5 to C.sub.6 cyclic
hydrocarbons such as cyclopentane or cyclohexane; aromatic
hydrocarbons and derivatives thereof such as toluene; or
combinations thereof.
[0045] Any technique known to those skilled in the art for removing
the liquid from the therapeutic compound may be used such as
continuous dryers (e.g., spray, fluid bed, tube, Witte or tunnel
dryers), or batch dryers (e.g., rotary, pan, vacuum, or microwave
dryers). In a preferred embodiment, the liquid is removed by a
spray dryer. The drying conditions (e.g., temperature and pressure)
will depend on the selection of liquid and therapeutic compounds,
and should be chosen so as to not degrade the therapeutic
compounds.
[0046] It is also possible, depending on the compaction enhancing
therapeutic compound chosen, and possibly the level of moisture
present in the mixture being granulated, that dry granulation can
be used to form granules containing an intimate admixture of the
compaction enhancing therapeutic compound and other therapeutic
compound. "Dry granulation" refers to a granulation process where
no external fluid is added during processing. In such an
embodiment, preferably the therapeutic compounds being granulated
contain a total of at least about 4 wt % moisture, more preferably
from about 5 wt % to about 15 wt % moisture, and most preferably
from about 6 wt % to about 10 wt % moisture, based on the total
weight of the therapeutic compounds. Such moisture is preferably
inherently present in the therapeutic compounds as supplied.
Preferably, the moisture present is water. It is believed that
having some moisture in the therapeutic compounds aids in achieving
an intimate admixture during dry granulation.
[0047] Any technique known to those skilled in the art may be used
for dry granulating that promotes the formation of an intimate
admixture of the therapeutic compounds. For example, dry
granulation may be accomplished by admixing the compaction
enhancing therapeutic compound and other therapeutic compound in a
suitable piece of mixing equipment, and/or using compaction
equipment, such as a roll press, to compact the dry blend into a
desired shape to form an intimate admixture. In a preferred
embodiment, dry granulation is carried out using a Chilsonator.TM.
press.
[0048] The temperature and pressure at which dry granulation is
carried out will depend on the therapeutic compounds chosen.
Preferably, dry granulation will be carried out at a temperature of
from about ambient to about 45.degree. C., and more preferably from
about 20.degree. C. to about 30.degree. C.
[0049] Although it is preferred to form granules containing an
intimate admixture of the compaction enhancing therapeutic compound
and other therapeutic compound, it may be possible to simply blend
the therapeutic compounds to form a compactable granular mixture.
Any suitable equipment may be used to blend the therapeutic
compounds including continuous or batch mixers suitable for mixing
solids such as cone and screw mixers, twin blade conical mixers,
planetary mixers, helical ribbon blade mixers, conical
blenders.
[0050] To obtain a freely flowable compactable granular mixture, it
may be desirable to further process the mixture containing the
compaction enhancing therapeutic compound and other therapeutic
compound prior to compressing into tablets. For example, when the
therapeutic compounds are combined using wet or dry granulating
methods, it may be desirable to further reduce the particle size of
the coarse granules (e.g., noodles, pellets) obtained from such
methods. Any suitable particle size reduction technique may be used
that will provide the desired granulate particle size. Examples of
suitable particle size reduction equipment is disclosed in for
example Chemical Engineers' Handbook, by Perry and Chilton, fifth
edition, published by McGraw-Hill Inc., 1973, Chapter 8, the
disclosure of which is incorporated by reference in its entirety.
Preferred particle size reduction equipment includes a comil; a
Fitz mill manufactured by the Fitzpatrick Company; delumpers;
hammer mills or combinations thereof.
[0051] In the case of using solvent dissolution and removal
techniques as previously described herein (e.g., spray drying), it
may be desired to further increase the particle size of the
granulate mixture. Any method known to those skilled in the art may
be used to further agglomerate the granulate mixture, such as the
wet granulation and dry granulation techniques previously described
herein. Also, fluid beds, spheronization equipment, or rotating
pans may be used to agglomerate.
[0052] The compactable granular mixture that is compressed may
contain low levels of excipients (i.e., additivies) as hereinafter
described, or other therapeutic compounds, that are added after
combining the at least one compaction enhancing therapeutic
compound and other therapeutic compound by such techniques as
granulation. In a preferred embodiment of the present invention, at
least a portion of the compaction enhancing therapeutic compound is
wet granulated with at least a portion of the other therapeutic
compound. Preferably, at least 5 weight percent, and more
preferably at least 10 weight percent of the compaction enhancing
therapeutic compound is granulated with at least 15 weight percent,
and more preferably at least 30 weight percent of the other
therapeutic compound. The remaining therapeutic compounds may be,
for example, simply admixed after granulation.
[0053] In a preferred embodiment, the compactable granular mixture
is prepared by wet granulating all the compaction enhancing
therapeutic compound and all the other therapeutic compound by
adding water in a high shear granulator or extructor, and drying
the granules formed in a fluid-bed dryer, tunnel dryer, or tray
dryer to obtain granules containing from about 0.5 weight percent
to about 10 weight percent moisture, based on the total weight of
the granules. The granules are then preferably milled through a
Fitz mill equipped with a 20 U.S. standard mesh screen.
[0054] The compactable granular mixture formed is preferably in a
freely flowable form for feeding into compression equipment to form
tablets. Preferably, the flow of the compactable granular mixture
is from about 5 to about 30 seconds through a funnel having an
upper opening diameter of about 8.89 cm, a lower opening of about
1.11 cm, and a height from upper opening to lower opening of about
20.32 cm. Also preferably, the particle size distribution is such
that 95 percent by weight of the particles pass through a 20 mesh
screen and less than 50% by weight of the particles pass through a
100 mesh screen (standard US mesh size). Also, preferably, any
fluids used in forming the compactable granular mixture are removed
so that the mixture contains less than about 15 weight percent,
more preferably less than about 10 weight percent, and most
preferably less than about 8 weight percent moisture based on the
total weight of the therapeutic compound.
[0055] In addition to the therapeutic compounds, the compactable
granular mixture that is compressed to form a tablet may contain
additives (i.e., excipients) in an amount of less than about 15
weight percent, based on the total weight of the compactable
granular mixture (dry basis). Examples of additives that may be
included in the compactable granular mixture are non-therapeutic
binding agents, lubricants, diluents, disintegrants, glidants,
absorbents, antiadherents, surfactants, coating agents, gelling
agents, colorants, flavorants, or combinations thereof. One skilled
in the art will recognize that some additives may serve a dual
purpose in the tablet composition. For example, many cellulose
containing compounds can serve as a binding agent, and diluent or
disintegrant at high levels.
[0056] The additives may be added in any manner that provides a
uniform dispersion of the additives in the compactable granular
mixture that is compressed into tablets. For example, the additives
may be added to one or more of the therapeutic compounds prior to,
or during combining of the therapeutic compounds. For example, the
additive may be mixed with the therapeutic compounds to form a dry
blend prior to wet granulation or dry granulation. The additive may
also be dissolved or dispersed in a liquid containing the
therapeutic compounds prior to a solvent dissolution and removal
process, or in a granulating fluid, optionally containing the
compaction enhancing therapeutic compound prior to wet granulating.
In such procedures, the additive is preferably part of the granule
particles making up the granulate mixture. The additives may also
be added subsequent to forming granules of therapeutic particles
provided that the additive is uniformly dispersed in the
compactable granular mixture prior to forming the tablet
composition. For example, the additive may be blended as is with
the granules of therapeutic compounds or may be dissolved or
dispersed in a biocompatible liquid and applied to the granules of
therapeutic compounds.
[0057] The preferred method of adding the additive will depend upon
the additive. For example, binding agents,such as
polyvinylpyrolidone (PVP) or hydroxypropylmethylcellulose are
preferably added prior to, or during the forming of the granules
containing the therapeutic compounds, so that the additive is part
of the granule formed. Dry binding agents, such as microcrystalline
cellulose, are preferably added subsequent to forming granules of
the therapeutic compound. Also, for example, non-compaction
enhancing therapeutic compounds, such as glucosamine, can be
granulated with 5 wt % polyvinylpyrolidone, and mixed with a
compaction enhancing therapeutic compound such as chondroitin that
has a moisture content above 7 wt %. Some specific examples of
additives useful in the method of the present invention are
described below.
[0058] In a preferred embodiment of the present invention, the
compactable granular mixture may contain less than about 10 weight
percent, more preferably less than about 5 weight percent and most
preferably from 0 to about 3 weight percent non-therapeutic binding
agents based on the total weight of the compactable granular
mixture (dry basis). Any binding agent that imparts cohesive
strength to granules containing the therapeutic compounds or the
compactable granular mixture may be used. Examples of
non-therapeutic binding agents useful in the present invention
include for example polyvinyl pyrrolidone; modified or unmodified
starch; cellulose containing compounds such as hydroxypropyl
methylcellulose (HPMC), hydroxypropylcellulose (HPC),
carboxymethylcellulose (CMC), methylcellulose or ethylcellulose;
polyalkyleneglycols such as polyethyleneglycol or
polypropyleneglycol; gelatin; acacia gum; guar gum; sodium
alginate; amylopectin, sorbitol; glucose; dextrin or combinations
thereof. Preferred binding agents are polyvinyl pyrrolidone, HPMC,
lower substituted HPC or combinations thereof.
[0059] The compactable granular mixture may also contain one or
more lubricants to inhibit sticking of the granules or compactable
granular mixture during processing. Preferably, the lubricant is
present in the compactable granular mixture in an amount of from 0
weight percent to about 5.0 weight percent, and more preferably
from about 0 to about 2.0 weight percent based on the total weight
of the compactable granular mixture (dry basis). Examples of
suitable lubricants include stearates such as stearic acid,
palmitostearate, magnesium stearate, zinc stearate or calcium
stearate; talc; hydrogenated vegetable oil; hydrogenated castor
oil; liquid paraffin; surfactant; or combinations thereof.
[0060] The compactable granular mixture may also contain diluents
that increase the bulk of the tablet. Examples of diluents useful
in the present invention include for example sugars such as
mannitol, sorbitol, or xylitol, lactose, dextrose, fructose,
amylose, or sucrose; microcrystalline cellulose; ethyl cellulose;
modified or unmodified starch; clays such as kaolin, alkaline earth
metal carbonates, phosphates or sulfates such as calcium carbonate,
magnesium carbonate, calcium phosphate, (e.g. di and tri basic
calcium phosphate), calcium sulfate, or barium sulfate; magnesium
trisilicate; aluminum hydroxide; or combinations thereof. The
diluents preferably make up from 0 to about 15 weight percent, and
more preferably 0 to about 10 weight percent of the compactable
granular mixture (dry basis).
[0061] Disintegrants are used to facilitate the break-up of the
tablet, after the tablet is administered to the patient.
Preferably, the compactable granular mixture will contain from 0 to
about 5 weight percent and more preferably from about 0.5 weight
percent to about 2.0 weight percent disintegrants based on the
total weight of the compactable granular mixture (dry basis).
Examples of disintegrants useful in the present invention include
modified or unmodified starches such as corn starch, potato starch,
or wheat starch; croscarmellose, clays; cross-linked polyvinyl
pyrrolidone; cellulose containing compounds, gums, algins,
surfactant, HPC, or combinations thereof.
[0062] Coating agents are applied to the surfaces of the formed
tablet and provide, for example, reduced future friability and ease
of swallowability. Preferably, the amount coating agent is from
about 0.5 wt % to about 6.0 wt % and more preferably from about 1.0
wt % to about 5.0 wt % based on the total weight of the compactable
granular mixture (dry basis). Examples of suitable coating agents
include cellulose containing compounds such as
hydroxypropylmethylcellulose, hydroxypropylcellulose,
carboxymethylcellulose, methylcellulose or ethylcellulose;
polyalkyleneglycols such as polyethyleneglycol or
polypropyleneglycol; or combinations thereof.
[0063] The compactable granular mixture may also contain wetting
agents, colorants, flavorants or combinations thereof. These
additives preferably make-up from about 0.1 weight percent to about
10 weight percent, and more preferably from about 0.3 weight
percent to about 5 weight percent of the compactable granular
mixture (dry basis). Examples of suitable wetting agents include
sodium dodecyl sulphate, sodium lauryl sulphate, polyoxyethylene
sorbitan fatty acid esters (e.g., Tween.TM. compounds),
polyoxyethylene stearates, sorbitan fatty acid esters or
combinations thereof. Suitable colorants include for example red
beet powder, ferric oxides, FD & C dyes or combinations
thereof. Flavoring agents useful in the present invention include
for example fruit flavors, or sweeteners such as sodium saccharin,
aspartame, confectionary sugar, sorbitol, sucrose, xylitol, or
combinations thereof
[0064] The compactable granular mixture thus prepared in accordance
with the method of the present invention is compressed into a
tablet according to any technique known to those skilled in the
art. For example, in compacting the compactable granular mixture,
the compactable granular mixture can be added to a die, and
compressed into a tablet having the desired shape and weight. Prior
to adding the compactable granular mixture to the die, it may be
desirable to apply an external lubricant to the wall of the die.
Examples of external lubricants useful in the method of the present
invention include talc; starch; stearates such as magnesium
stearate; hydrogenated vegetable oil; surfactant or combinations
thereof.
[0065] Preferably the compactable granular mixture is compressed at
any suitable pressure and temperature to form a tablet having the
desired properties such as strength, hardness, disintegration and
release of the therapeutic compounds upon administration.
Preferably, the compaction conditions are such that there is no
degradation of the therapeutic compounds. Also, preferably, the
compaction conditions are below the melting points of the
therapeutic compounds to prevent lower tablet hardness or other
tabletting process problems (e.g. glazing). Typical compaction
pressures range from about 1000 lbs to about 10,000 lbs, and more
preferably from about 4,000 lbs to about 8,000 lbs, where lbs is
pounds force. Typical compaction temperatures range from about
15.degree. C. to about 6020 C. and more preferably from about
20.degree. C. to about 40.degree. C.
[0066] The tablets thus produced may be further processed as
desired. For example, the tablet may be coated according to any
technique known to those skilled in the art. Suitable coatings
include those compounds previously described as being useful as
coating agents for the compactable granular mixture. The tablets
may also be enteric or regularly polished with such compounds as
Carnuba wax.
[0067] The tablet compositions useful in the present invention
contain preferably from about 3 weight percent to about 99.5 weight
percent, more preferably from about 5 weight percent to about 50
weight percent, and most preferably from about 5 weight percent to
about 15 weight percent of at least one compaction enhancing
therapeutic compound, based on the total weight of the tablet
composition. The tablets also preferably contain from about 0.5
weight percent to about 97 weight percent, more preferably from
about 10 weight percent to about 95 weight percent, and most
preferably from about 40 weight percent to about 95 weight percent
of at least one second therapeutic compound that is different from
the compaction enhancing therapeutic compound, based on the total
weight of the tablet composition. The compaction enhancing
therapeutic compound is preferably in intimate admixture with the
second therapeutic compound. More preferably, the compaction
enhancing therapeutic compound at least partially coats particles
of the second therapeutic compound.
[0068] The tablet composition thus produced also preferably
contains less than about 15 weight percent, more preferably less
than about 8 weight percent, and most preferably less than about 2
weight percent excipients, based on the total weight of the tablet
composition (dry basis). The excipients may be any of the additives
previously described herein that are present in the compactable
granular mixture and in the amounts previously described for the
compactable granular mixture. Preferably, excipients that serve as
a lubricant are present in the tablet composition in an amount of
no more than 0.5 weight percent based on the total weight of the
tablet composition.
[0069] The overall weight of the tablet ranges from about 100 mg to
about 2000 mg, and more preferably from about 450 mg to about 1600
mg.
[0070] One skilled in the art will recognize that the tablet
compositions made in accordance with the methods of the present
invention can be used for a variety of purposes. For example, the
tablets may be formulated to provide treatment of connective
tissue, such as to prevent, repair, or lessen ailments of the
joints and cartilage tissue, such as observed with arthritis. The
tablet compositions may also be prepared to treat ailments of the
skin such as hardening, roughening, aging, or wrinkling of the
skin. The tablet compositions may also be prepared to provide to a
patient nutritional supplements of vitamins, minerals,
antioxidants, or to function as an appetite suppressant, analgesic,
anti-smoking libido, or combinations thereof. The tablet
compositions may also be prepared to enhance the emotional well
being of a patient through for example herbal based extracts. The
tablet compositions of the present invention may also be prepared
to treat ailments such as viral, fungal, or bacterial infections,
diseases, or injuries to the body.
[0071] There are many advantages to the tablet compositions
prepared in accordance with the methods of the present invention.
For example, by the tablet compositions being substantially free of
excipients, smaller (in weight and volume) tablets can be prepared
containing the same amount of therapeutic compound. By decreasing
the excipients present in the tablet, the tablets prepared
according to the method of the present invention can be more easily
ingested, and/or formulated to contain more therapeutic compound(s)
in a single tablet. By being able to increase the amount of
therapeutic compounds in a single tablet, one reduces the need to
ingest multiple tablets at a single time and/or multiple doses of
the same product. Additionally, the reduction of excipients in
tablets is beneficial to hyper-allergenic patients and also has a
very positive effect on diurnal consumer compliance.
[0072] In a preferred embodiment of the present invention, the
tablet composition made in accordance with the methods of the
present invention contains from about weight percent 3 to about 80
weight percent, and more preferably from about 30 to about 60
weight percent of at least one glycosaminoglycan; from about 3
weight percent to about 95 weight percent, and more preferably from
about 5 weight percent to about 70 weight percent of at least one
amino sugar; and less than about 2 weight percent, and more
preferably less than about 0.5 weight percent of excipients based
on the total weight of the tablet (dry basis). Preferably, the
amino sugar is glucosamine, or a derivative or pharmaceutically
acceptable salt thereof and the glycosaminoglycan is chondroitin or
a derivative or pharmaceutically acceptable salt thereof. In this
preferred embodiment, other therapeutic compounds may be present in
the tablet composition such as manganese ascorbate, sodium
ascorbate, calcium ascorbate, Vitamin C (i.e., ascorbic acid),
dried powder forms of Vitamin A, Vitamin D, Vitamin E, Vitamin K,
or beta carotene; vitamin B.sub.6, niacin, phosphorous containing
salts, zinc containing salts, copper containing salts, calcium
containing salts such as calcium citrate, calcium carbonate, oyster
shell, magnesium, manganese sulfate, boron, estrogen(s), or
combinations thereof. Preferably calcium is present in an amount of
from about 7 weight percent to about 15 weight percent; and the
vitamin C is preferably present in an amount of from about 1 weight
percent to about 10 weight percent, based on the total weight of
the tablet composition (dry basis).
[0073] Also preferably in this embodiment, the overall weight of
the tablet ranges from about 100 mg to about 2000 mg, and more
preferably from about 500 mg to about 2000 mg. The aminosugar is
preferably present in an amount of from about 250 mg to about 1000
mg, and the glycosaminoglycan is preferably present in an amount of
from about 200 mg to about 1000 mg. Any excipients are preferably
present in an amount of less than about 50 mg.
[0074] The above preferred tablet composition containing an
aminosugar and glycosaminoglycan is particularly useful for the
treatment of connective tissues. Other preferred compositions that
can be formed into a tablet in accordance with the method of the
present invention are those compositions disclosed in for example
U.S. Pat. Nos. 5,364,845 and 5,587,363 both to Henderson, the
disclosures of which are hereby incorporated by reference in their
entireties.
EXAMPLES
[0075] Some embodiments of the present invention will now be
described in detail in the following Examples. Tablet compositions
were prepared in accordance with the method of the present
invention and evaluated for various properties. The following test
procedures were used in the Examples for evaluating tablet
properties.
1TABLE 1 Test Methods for Properties Measured and Abbreviations
Used in Examples Property Units Method Equipment Hardness
Strong-Cobb -- Key International Hardness Tester Disintegration
Minutes USP.sup.1 2040 VanderCamp-disintegration Time (min)
Apparatus (DT) Ejection Pounds -- B.sub.3B 16 station Instrumented
Force (lbs) Tablet Press (EJ Force) Weight % USP 2091 Mettler 3
place balance variation (Wt. Var.) Friability % USP 1216 Tablet
Friability Apparatus (Friab.) .sup.1USP refers to the United States
Pharmacopea, Vol. USP XXIV/NF XIX, published by US Pharmacopea
Convention Incorporated located in Rockville, MD, 1999, The number
following "USP" refers to the section in which the test method is
found.
[0076] In Table 1 above, weight variation is expressed as the
percent standard deviation in tablet weight for 20 tablets based on
the average tablet weight. Friability is expressed as the percent
of the tablet weight loss that was friable in the friabilitator
after 100 rotations (20 tablets).
[0077] Unless otherwise indicated in the Examples, the chondroitin
used was chondroitin sulfate sodium salt obtained from Tomen
America located in New York, N.Y. The chondroitin had an active
ingredient content of 85 weight percent, and loss on drying (LOD)
of 9.25 weight percent based on the total weight. Unless otherwise
indicated in the Examples, the glucosamine used was glucosamine HCl
obtained from Nutratech Corp., located in Fairfield, N.J. The
glucosamine had an active ingredient content of 99 weight percent
and was milled prior to use in a Fitz mill having a 60 mesh screen.
Magnesium stearate was obtained from Mallinkrodt located in St.
Louis, Mo. Any reference in the examples to mesh screen size refers
to U.S. standard mesh size.
Comparative Example 1
[0078] Tablets containing 470.59 mg of chondroitin, 505.05 mg
glucosamine and 4.90 mg of magnesium stearate were prepared using
either milled glucosamine as previously described or unmilled
glucosamine. The unmilled glucosamine had a particle size
distribution of 95 wt % of the particles being smaller than a 20
mesh screen size, and 50 wt % of the particles being greater than a
60 mesh screen size.
[0079] The tablets were prepared by mixing the proper amounts of
chondroitin and glucosamine in a blender for 15 minutes to form a
dry blend. The magnesium stearate was separately mixed with an
equal amount of the dry blend and passed through a 30 mesh screen
to form a magnesium stearate mixture. This magnesium stearate
mixture was then added to the dry blend and mixed for an additional
5 minutes. Tablets were then prepared using a Manesty 16 station
B.sub.3B instrument equipped with an instrumentation package,
supplied by SMI Corp., capable of continuously recording
compression speed, compression force, and ejection force.
[0080] The tabletting conditions were as follows:
2 Tabletting speed 40 revolutions per minute (RPM) Compression
force varied Tablet punches 5/16" .times. 3/4" caplet, B tooling
Tablet weight 989.24 mg
[0081] For tablets prepared using milled glucosamine, a tablet
hardness of 10 Strong-Cobb was achieved at a compaction pressure of
5500 lbs. For tablets prepared using unmilled glucosamine a
hardness of 1.5 Strong-Cobb was obtained at a compaction pressure
of 3000 lbs. For both tablets, at a compaction pressure of 4000 lbs
and greater, capping was observed.
Comparative Example 2
[0082] To a blender was added 470.59 parts by weight chondroitin,
505.05 parts by weight glucosamine, and 35.35 parts by weight red
beet powder to form a dry blend. This dry blend was mixed for 15
minutes and then dry granulated in a chilsonator supplied by
Fitzpatrick located in South Hackensack, N.J. to form large
granules. The resulting granules were then fed into a Fitz mill
having a 60 mesh screen size to form chondroitin/glucosamine
granules. The chondroitin/glucosamine granules were then passed
though a Sweco supplied by Sweco Inc. located in Florence, Ky. to
collect particles between 20 mesh and 100 mesh particle size for
tabletting. Oversized particles were recycled back to the Fitz mill
and undersized particles were recycled back to the chilsonator.
[0083] The chondroitin/glucosamine granules thus obtained were
tabletted by preparing a magnesium stearate mixture containing 3.81
parts magnesium stearate and 3.81 parts chondroitin/glucosamine
granules and passing this mixture through a 30 mesh screen. The
magnesium stearate mixture and the remaining
chondroitin/glucosamine granules were then blended for five
minutes. The resulting mixture was then tabletted in accordance
with the procedure described in Comparative Example 1 (target
tablet weight 975.64 mg). It was found that capping was observed at
a compaction pressure of 3000 lbs and tablets could not be
formed.
Example 3
[0084] Tablets containing 470.59 mg of chondroitin, 526.35 mg of
polyvinylpyrolidone (PVP) granulated glucosamine, and 3.75 mg of
magnesium stearate were prepared. The PVP granulated glucosamine
contained 93 weight percent glucosamine and 5 wt % PVP and was
obtained from Nutratech Corp., located in Fairfield, N.J. Tablets
were prepared according to the procedure described for Comparative
Example 1. The tablets were evaluated for disintegration time,
hardness, and friability. The results are shown below in Table
2:
3TABLE 2 Tablet Performance Using PVP Granulated Glucosamine
Property Measured Value Disintegration Time, minutes 18.5
(compressed at 7000 lbs) Hardness, Strong-Cobb (SC) Compressed at
4000 pound 7.6 Compressed at 7000 pound 17.2 Compressed at 9000
pound 22.8 Friability, wt % loss 0.01% (compressed at 7000 lbs)
Weight Variation, % standard 2.82% (compressed at 7000 lbs)
deviation
[0085] In a separate experiment, the PVP granulated glucosamine was
compressed at various pressures with no chondroitin. The PVP
granulated glucosamine did not compress into a tablet indicating
that the chondroitin was acting to enhance the compactability of
the PVP granulated glucosamine.
Examples 4 to 17
[0086] In Examples 4 to 17 tablets were prepared as described below
where the following parameters were varied:
[0087] (a) particle size of a compaction enhancing therapeutic
compound (chondroitin, particles ranging in size ranges between (i)
20 and 80 mesh, (ii) between 80 and 200 mesh, and (iii) through 200
mesh, (where the greater the mesh size, the smaller the particle
size);
[0088] (b) moisture level of granulate mixture (10 wt %, 7 wt %,
and less than 4 wt % moisture, based on the total weight of the
granulate mixture); and
[0089] (c) amount of lubricant in tablet (0.1 wt %, 0.55 wt %, and
1.0 wt %, based on the total weight of the granulate mixture).
[0090] To an appropriately sized Hobart type blender was added 1882
parts by weight of chondroitin having one of the particle size
ranges described above, 2020 parts by weight of glucosamine, and
magnesium stearate, as a lubricant, at one of the levels described
above to form a dry blend. This dry blend was granulated by
gradually adding 500 parts by weight water at ambient temperature
while mixing until granules were formed. This wet granulate mixture
was then dried in an oven at 70.degree. C. until the target
moisture level (indicated in Table 2) in the granulate mixture was
achieved. After drying, the granulate mixture was milled in an
oscillator, supplied by Erweka, located in Heusenstamm, Germany
using a 20 mesh screen.
[0091] The granulate mixtures produced were tabletted on a Manesty
16 station B.sub.3B instrument equipped with an instrumentation
package, supplied by SMI Corp., capable of continuously recording
compression speed, compression force, and ejection force.
4 Tabletting speed 40 revolutions per minute (RPM) Compression
force 7000 lbs. Tablet punches 5/16" .times. 3/4" caplet, B tooling
Tablet weight 1.085 gms.
[0092] The tablet compositions produced were measured for hardness,
friability, disintegration time, ejection force, and weight
variation according to the aforementioned test procedures.
[0093] A summary of the properties measured for each tablet
composition prepared is shown below in Table 3. The values for
ejection forces are based on the average of four punches, which
were based on 5 revolutions.
5TABLE 3 Measured Properties of Tablet Compositions Prepared Hard-
ness EJ Wt. H.sub.2O Lub. Part. Size (Strong- DT Force Var. Friab.
Ex. (wt %) (wt %) (mesh) Cobb) (min) (lbs) (%) (%) 4 7.0 0.55
80-200 25.7 22.5 70 1.986 .06 5 7.0 1.0 20-80 15.6 25.5 57 2.106
.19 6 7.0 0.55 80-200 24 25 68 2.196 .08 7 7.0 0.1 through 36.5
20.5 181 1.785 .05 200 8 4.0 0.1 80-200 16.1 23.5 98 0.685 .1 9
10.0 0.1 80-200 41.1 21.5 123 0.81 .06 10 7.0 0.1 20-80 24.3 25 129
2.027 .08 11 7.0 0.55 80-200 23.7 23.5 66 2.252 .07 12 4.0 1.0
80-200 14.8 20.5 97 2.377 .3 13 4.0 0.55 through 16.5 21.5 106 2.27
.1 200 14 7.0 1.0 through 28.2 24.5 54 1.391 .07 200 15 10.0 0.55
through 35.1 23 20.4 1.626 .07 200 16 10.0 1.0 80-200 0 26 17.7
1.94 .14 17 10.0 0.55 20-80 24.8 20.5 26 2.165 .15
[0094] The results in Table 3 show that the method of the present
invention produces tablets that are substantially free of
excipients having superior properties. The results show that
tablets can be formed from compaction enhancing therapeutic
compounds having various particle sizes (column labeled "Part.
Size"), lubricant content (column labeled "Lub."), and tablet
moisture content (column labeled H.sub.2O). A preferred tablet
moisture is around 6.0 to 9.0 weight percent based on an analysis
of the above data.
Examples 18 to 23
[0095] Tablets containing double dosage strength (label claim of
400 mg chondroitin, 500 mg glucosamine) or triple dosage strength
(label claim of 600 mg chondroitin, 750 mg glucosamine) of
chondroitin and glucosamine were prepared according to the
following procedure. A granulate mixture was prepared by mixing for
15 minutes in a planetary blender, a dry blend of 1882.36 grams of
chondroitin and 2020.20 grams of glucosamine. Following mixing, 400
grams of purified water was gradually added to the blender with
mixing. Following addition of the water, the wet mixture was mixed
for an additional time to produce wet granules. The wet granules
were then dried in an oven at a temperature of 70.degree. C. until
a moisture level of 8.4 wt % was achieved, based on the total
weight of the chondroitin/glucosamine granules. The
chondroitin/glucosamine dry granules obtained were passed through
an oscillator as described in the procedure for Examples 4 to
17.
[0096] Tabletting mixtures were prepared, as described below, to
achieve upon compaction, (a) a double strength caplet (label claim
400 mg chondroitin and 500 mg glucosamine) containing 975.64 mg of
the chondroitin/glucosamine dry granules and 3.81 mg of the
magnesium stearate, and (b) a triple strength caplet (label claim
600 mg chondroitin and 750 mg glucosamine) containing 1463.46 mg of
the chondroitin/glucosamine dry granules and 5.72 mg of the
magnesium stearate. The tabletting mixtures were prepared by mixing
the desired amount of magnesium stearate (lubricant) with an
approximately equal amount by weight of the dried
chondroitin/glucosamine granules having a particle size of less
than 30 mesh in a blender. This mixture was then passed through a
30 mesh screen. This screened mixture was added to the dried
chondroitin/glucosamine granules in the blender, and mixed for an
additional 5 minutes to produce the desired tabletting mixture. The
tabletting mixture was then formed into caplets in accordance with
the procedure used in Examples 4 to 17 except that the compaction
pressure was varied as shown in Table 4 below. The resulting
caplets were measured for hardness, disintegration time, weight
variation, and friability. The results are reported below in Table
4.
6TABLE 4 Properties of Caplets for Examples 4 to 23 Compaction
Hardness Wt. Dosage Pressure (Strong- DT Var. Friab. Ex. Strength
(lbs) Cobb) (min) (%) (%) 18 Double 4000 13.7 -- -- -- 19 Double
7000 25.6 19 1.05 0.09 20 Double 9000 30.4 -- -- -- 21 Triple 4000
37.7 -- -- -- 22 Triple 7000 >45 28.5 0.96 0.10 23 Triple 9000
>45 -- -- --
[0097] The data in Table 4 shows that the method of the present
invention produces tablets that are substantially free of
excipients having suitable properties such as compressibility,
tablet weight variability, disintegration, and friability. Another
advantage of using the present invention under the above conditions
was that no capping was observed, even at compression forces up to
9000 pounds.
Examples 24 to 29
[0098] Tablet compositions were prepared according to the methods
of the present invention using low amounts of a disintegrating
agent. The tablets prepared contained 98.62 wt %
chondroitin/glucosamine granules prepared in accordance with
Examples 18 to 23, 1 wt % Croscarmellose Sodium, supplied by
Blanver Farmoquimica Ltda., located in Brazil, and 0.38 wt %
magnesium stearate. Also, double strength tablets containing 99.62
wt % chondroitin/glucosamine and 0.38 wt % magnesium stearate were
prepared according to the procedure described in Examples 18 to
23.
[0099] The tablets containing the disintegrant were prepared by
mixing in a blender for 10 minutes, the proper amounts of
croscarmellose sodium and chondroitin/glucosamine granules to form
a tabletting mixture. The proper amount of magnesium stearate was
separately mixed with an equal amount, by weight, of the tabletting
mixture that had been passed through a 30 mesh screen. The
magnesium stearate mixture was then passed though a 30 mesh screen.
The magnesium stearate mixture was then added to the blender
containing the tabletting mixture and mixed for 5 minutes. This
mixture was then compressed into tablets at various compaction
pressures according to the procedure described in Examples 4 to
17.
[0100] The resulting tablets were then evaluated for hardness,
disintegration time, friability, and weight variation.
[0101] The results are shown in Table 5 below:
7TABLE 5 Properties of Tablets of Examples 24 to 29 Compaction
Hardness Disintegrant Pressure (Strong- DT Wt. Var. Friab. Ex. (wt
%) (lbs) Cobb) (min) (%) (%) 24 0 4000 13.7 19 0.93 0.19 25 0 7000
25.6 18.5 1.09 0.091 26 0 9000 30.4 19.5 0.89 0.083 27 1 4000 14.0
17.5 0.79 0.21 28 1 7000 25.3 19 0.95 0.10 29 1 9000 30.1 18.5 0.73
0.082
[0102] The results in Table 5 show that the method of the present
invention produces tablets having acceptable disintegration
properties with and without the use of a disintegrant. The tablets
also had acceptable hardness, friability and weight
variability.
Examples 30 to 32
[0103] To a planetary blender was added 106.33 grams of chondroitin
and 2020 grams of glucosamine. This mixture was mixed for 15
minutes in the blender to form a dry blend. This dry blend was
granulated by gradually adding 200 grams of purified water at
ambient temperature while mixing until granules were formed. This
wet granulate mixture was then dried in an oven at 700.degree. C.
until a moisture level 1.50 wt % in the granulate mixture was
achieved. After drying, the granulate mixture was passed through an
oscillator according to Examples 4 to 17. To produce granules
containing 5 wt % chondroitin and 95 wt % glucosamine.
[0104] Tablets were prepared by mixing in a blender for 15 minutes,
2126.53 grams of the chondroitin/glucosamine granules (containing 5
wt % chondroitin), and 1776.03 grams of chondroitin to form a
tabletting mixture. The proper amount of magnesium stearate was
separately mixed with an equal amount, by weight, of the tabletting
mixture that had been passed through a 30 mesh screen. The
magnesium stearate mixture was then passed though a 30 mesh screen.
The magnesium stearate mixture was then added to the blender
containing the tabletting mixture and mixed for 5 minutes. This
mixture was then compressed into tablets at various compaction
pressures according to the procedure described in Examples 4 to
17.
[0105] The resulting tablets were then evaluated for hardness,
disintegration time, and weight variation. A summary of the
properties measured for each tablet prepared is shown below in
Table 6
8TABLE 6 Properties of Tablets Formed from 5 wt % Chondroitin
Granules Compaction Hardness Pressure (Strong- DT Wt. Var. Ex.
(lbs) Cobb) (min) (%) 30 4000 13.7 18.5 1.09 31 7000 23.5 19 0.71
32 9000 33.6 19.5 0.71
[0106] The data in Table 6 shows that suitable tablets can be
formed from granules containing 5 wt % of chondroitin and 95 wt %
glucosamine, ungranulated chondroitin, and magnesium stearate.
Based on the results of Example 3, using 5 wt % PVP/glucosamine
granules, chondroitin appears to be a more effective compacting
agent for glucosamine. This is a surprising result considering that
PVP is commonly used as a binder for chondroitin and glucosamine
tablets.
Examples 33 to 44
[0107] Tablets containing 500 mg glucosamine, 400 mg chondroitin,
20 mg Vitamin C, 133 IU Vitamin D and 167 mg calcium were prepared
by using (a) ungranulated glucosamine and chondroitin, (b)
glucosamine granulated with 5 wt % chondroitin, and (c) fully
granulated glucosamine and chondroitin. Three different tablet
compositions were prepared as shown in Table 7 below:
9TABLE 7 Tablet Compositions for Examples 33 to 44 B C A (5 wt %
(Fully (Ungranulated, Granulated, Granulated, Ingredients mg) mg)
mg) Chondroitin, 85% 470.59 444.01 0.0 Glucosamine, 99 wt % 505.05
0.0 0.0 5 wt % granulated 0.0 531.63 0.0 chondroitin/glucosamine
fully granulated 0.0 0.0 975.64 chondroitin/glucosamine Vitamin
C-90 25.82 25.82 25.82 Vitamin D 1.84 1.84 1.84 Calcium Carbonate
DC 473.13 473.13 473.13 Magnesium Stearate 7.50 7.50 7.50 Total
1483.93 1483.93 1483.93
[0108] The chondroitin/glucosamine granules containing 5 weight
percent chondroitin, were prepared according to the procedure used
in Examples 30 to 32, except that the wet granules were dried to a
LOD content of 1.5 weight percent. The fully granulated
chondroitin/glucosamine granules were prepared according to the
procedure used in Examples 18 to 23, except that the wet granules
were dried to a LOD content of 6.5 weight percent.
[0109] Tablets were prepared by mixing Vitamins C-90 and D in a
blender for 10 minutes to form a vitamin mixture. Also, magnesium
stearate and an equal amount, by weight, of the calcium carbonate
were mixed separately and passed through a 30-mesh screen. To an
appropriately sized blender was added the vitamin mixture, the
remaining calcium carbonate, and the glucosamine and chondroitin
(granulated or ungranulated as specified in Table 7 above). This
mixture was blended for I 0 minutes after which the magnesium
stearate mixture was added and blended for 5 more minutes. The
resulting tabletting mixtures were tabletted according to the
procedure in Examples 4 to 17 at various pressures. The results are
shown below in Table 8.
10TABLE 8 Performance of Tablet Compositions A through C Compaction
Hardness Wt. Tablet Pressure (Strong- DT Var. Friab. Ex.
Composition (lbs) Cobb) (min) (%) (%) 33 A 4000 10.2 15 2.61 6.34
34 A 6000 17.1 19 2.14 1.10 35 A 8000 26.7 21 1.78 capped 36 A 9000
27.2 21.5 2.32 capped 37 B 4000 19.0 18.5 0.90 0.23 38 B 6000 30.8
21.5 0.56 0.06 39 B 8000 40.2 24 0.61 0.02 40 B 9000 >45 24.5
0.92 0.01 41 C 4000 20.7 23 1.05 0.22 42 C 6000 33.5 27.5 0.76 0.08
43 C 8000 42.2 29.5 0.66 0.07 44 C 9000 >45 29 0.69 0.06
[0110] For compositions containing the ungranulated glucosamine and
chondroitin (i.e., composition A), the tablets could be compressed
up to 6000 pounds without capping. For compositions containing
glucosamine granulated with chondroitin (i.e., compositions B and
C), the addition of other therapeutic compounds in the tablet did
not hinder the performance properties of the tablet.
Example 45 to 48
[0111] Tablets containing Vitamin C (i.e., ascorbic acid) and
chondroitin were prepared using Vitamin C as is (ungranulated) and
Vitamin C granulated with 5 wt % chondroitin (as a compaction
enhancing therapeutic compound). Two different tablet compositions
were prepared as shown in Table 9 below:
11TABLE 9 Tablet Compositions for Examples 45 to 48 (500 mg Vitamin
C label claim) E (5 wt % D Granulated, Ingredients (Ungranulated,
mg) mg) Chondroitin, 85% 27.63 0.0 Ascorbic acid fine powder 525
0.0 5 wt % granulated chondroitin/ 0.0 552.63 ascorbic acid
Microcrystalline cellulose 22.76 22.76 Stearic acid 5.74 5.74
Magnesium stearate 7.50 7.50 Total 582.02 582.02
[0112] The chondroitin/ascorbic acid granules were prepared by
mixing in a blender for 10 minutes, the appropriate amounts of
chondroitin and ascorbic acid to form granules containing 5 wt %
chondroitin and 95 wt % ascorbic acid. Following mixing, water was
gradually added with mixing until uniform granules were formed and
the mixture was free of loose powder. The granules produced were
dried at 75.degree. C. until the moisture content of the granules
was less than 0.2 wt %. The dried granules were passed through an
oscillator equipped with a 20 mesh screen according to the
procedure in Examples 4 to 17.
[0113] To form the tabletting mixtures, ascorbic acid (granulated
or ungranulated) and chondroitin (if ungranulated)were mixed in a
blender for 10 minutes. A mixture of stearic acid, magnesium
stearate, and an equal amount by weight of microcrystalline
cellulose (based on the combined weight of the stearic acid and
magnesium stearate) was mixed separately in a blender for 2 minutes
and passed through a 20 mesh screen. The magnesium stearate mixture
was then added to the blender containing the ascorbic acid and
chondroitin, and mixed for an additional 5 minutes. The tabletting
mixtures were then compressed according to the procedure described
in Examples 4 to 17 at various pressures. The results are shown
below in Table 10.
12TABLE 10 Tablet Performance for Examples 45 to 48 Compaction
Hardness DT Wt. Tablet Pressure (Strong- Time Var. Friab. Ex.
Composition (lbs) Cobb) (min) (%) (%) 45 D 2000 -- -- -- capping 46
E 4000 8.6 5.5 0.68 0.66 47 E 5000 8.9 6 0.66 capped 48 E 6000 8.0
6.5 0.32 capped
[0114] The results in Table 10 show that when chondroitin is
granulated with ascorbic acid, the compactability of the ascorbic
acid can be significantly improved in comparison to simply admixing
the ascorbic acid with the chondroitin.
Examples 49 to 50
[0115] Grape seed extract was evaluated for its ability to act as a
compaction enhancing therapeutic compound for L-arginine HCl. The
following procedure was used for preparing granules of grape seed
extract and L-arginine.
[0116] To a Hobart blender was added 900 grams of L-Arginine HCl. A
granulating fluid was prepared by dispersing 100 grams of grape
seed extract (90 wt % polyphenols) in 150 grams of isopropanol. To
the isopropanol/grape seed extract mixture was added with stirring
100 grams of water in three equal additions (i.e.,about 33.3 grams
each). The granulating fluid was then added to the L-arginine with
mixing to form granules. The granules were then dried in an oven at
50.degree. C. until the moisture in the granules was 1.2 wt %. The
dried granules were then passed through an oscillator according to
the procedure used in Examples 4 to 17.
[0117] Tabletting mixtures were prepared using (a) ungranulated
grape seed extract and arginine and (b) granulated grape seed
extract and arginine prepared as described above. The compositions
of the tabletting mixtures (in weight per tablet) are shown in
Table 11.
13TABLE 11 Tablet Compositions Containing Grape Seed Extract and
L-Arginine HCl F G (Ungranulated, (Granulated, Ingredients mg) mg)
Grape Seed/Arginine granules 0.0 267 L-Arginine HCl 240 0.0 Grape
seed extract (90 wt % polyphenols) 27 0.0 Magnesium stearate 3.0
3.0 Total 270 270
[0118] To form the tabletting mixtures, the magnesium stearate was
separately mixed with an equal amount by weight of either the grape
seed extract/arginine granules (composition G) or a blend of the
grape seed extract and L-arginine (composition F) that had been
passed through a 30 mesh screen. To this magnesium stearate mixture
was added the remaining amount of the grape seed extract and
arginine HCl in the appropriate granulated or ungranulated form.
These ingredients were then mixed for 2 minutes. The tabletting
mixtures were then compressed according to the procedure described
in Examples 4 to 17 at various pressures, except that 3/8" SC
punches were used. The results are shown below in Table 12.
14TABLE 12 Tablet Performance of Tablets Containing Grape Seed
Extract and L-Arginine HCl Hardness DT Tablet (Strong- Time Friab.
Ex. Composition Cobb) (min) (%) 49 F -- -- -- 50 G 7.2 4 0.90
[0119] The results in Table 12 show that when grape seed extract is
granulated with L-arginine a tabletting mixture is formed that can
be tabletted. The ungranulated grape seed extract and L-Arginine
could not be formed into a tablet under the same conditions used to
form a tablet from the grape seed extract/arginine granules.
[0120] There have thus been described certain preferred embodiments
of the present invention. While preferred embodiments have been
disclosed and described, it will be recognized by those with skill
in the art that variations and modifications are within the true
spirit and scope of the invention. The appended claims are intended
to cover all such variations and modifications.
* * * * *