U.S. patent application number 12/699129 was filed with the patent office on 2010-06-03 for simethicone solid oral dosage form.
Invention is credited to Christopher E. Szymczak, James T. Walter.
Application Number | 20100135982 12/699129 |
Document ID | / |
Family ID | 25511414 |
Filed Date | 2010-06-03 |
United States Patent
Application |
20100135982 |
Kind Code |
A1 |
Szymczak; Christopher E. ;
et al. |
June 3, 2010 |
SIMETHICONE SOLID ORAL DOSAGE FORM
Abstract
The present invention provides a composition for forming a
compressed solid dosage form that is a free-flowing compressible
admixture of simethicone, an adsorbant, and an optional active
agent, wherein the weight ratio of simethicone to adsorbent is at
least 1:2.22. Also included are solid dosage forms made from a
free-flowing compressible admixture of simethicone, an adsorbant,
and an optional active agent, wherein the weight ratio of
simethicone to adsorbent is at least 1:2.22.
Inventors: |
Szymczak; Christopher E.;
(Marlton, NJ) ; Walter; James T.; (Ambler,
PA) |
Correspondence
Address: |
PHILIP S. JOHNSON;JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
25511414 |
Appl. No.: |
12/699129 |
Filed: |
February 3, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11460741 |
Jul 28, 2006 |
7691409 |
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12699129 |
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09966441 |
Sep 28, 2001 |
7101573 |
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11460741 |
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Current U.S.
Class: |
424/94.61 ;
424/653; 514/63 |
Current CPC
Class: |
A61P 1/00 20180101; A61P
1/04 20180101; A61K 9/146 20130101; A61K 9/143 20130101; A61P 1/14
20180101 |
Class at
Publication: |
424/94.61 ;
514/63; 424/653 |
International
Class: |
A61K 38/47 20060101
A61K038/47; A61K 31/695 20060101 A61K031/695; A61K 33/24 20060101
A61K033/24; A61P 1/00 20060101 A61P001/00 |
Claims
1-28. (canceled)
29. A solid oral dosage form comprising a compressed admixture of
simethicone, silicified microcrystalline cellulose, and magnesium
aluminometasilicate, wherein the simethicone is adsorbed on the
silicified microcrystalline cellulose and magnesium
aluminometasilicate, and wherein the weight ratio of simethicone to
adsorbent is from about 1:1.68 to about 1:1.78.
30. The solid oral dosage form of claim 29, wherein the composition
has about 17 wt % to about 35 wt % simethicone.
31. The solid oral dosage form of claim 29, further comprising at
least one additional active agent.
32. The solid oral dosage form of claim 31, wherein the active
agent is selected from the group consisting of a bisacodyl, a
famotidine, a prucalopride, a diphenoxylate, a loperamide, a
lactase, a mesalamine, a bismuth, and pharmaceutically acceptable
salts and mixtures thereof
33. The solid oral dosage form of claim 32, wherein the active
agent is loperamide, or pharmaceutically acceptable salts
thereof.
34. The solid oral dosage form of claim 29, wherein the silicified
microcrystalline cellulose is about 19 wt % to about 27 wt % and
the magnesium aluminometasilicate is about 31 wt % to about 39 wt
%.
35. The solid oral dosage form of claim 34, wherein the silicified
microcrystalline cellulose is about 23 wt % to about 27 wt % and
the magnesium aluminometasilicate is about 33 wt % to about 37 wt
%.
36. The solid oral dosage form of claim 29, wherein the composition
is compressed into a tablet having a hardness value of at least
about 2 kp/cm.sup.2.
37. The solid oral dosage form of claim 36, wherein the composition
is compressed into a tablet having a hardness value of from about 5
to about 10 kp/cm.sup.2.
38. A composition for forming a compressed solid dosage form
comprising: a free-flowing compressible admixture of simethicone,
and an adsorbent comprising silicified microcrystalline cellulose
and magnesium aluminometasilicate, and wherein the weight ratio of
simethicone to adsorbent is from about 1:1.68 to about 1:1.78.
39. The composition of claim 38, wherein the simethicone is from
about 17 wt % to about 35 wt %.
40. The composition of claim 38, further comprising at least one
additional active agent.
41. The composition of claim 40, wherein the active agent is
selected from the group consisting of a bisacodyl, a famotidine, a
prucalopride, a diphenoxylate, a loperamide, a lactase, a
mesalamine, a bismuth, and pharmaceutically acceptable salts and
mixtures thereof.
42. The composition of claim 41, wherein the active agent is
loperamide, or pharmaceutically acceptable salts thereof
43. The composition of claim 38, wherein the silicified
microcrystalline cellulose is about 19 wt % to about 27 wt % and
the magnesium aluminometasilicate is about 31 wt % to about 39 wt
%.
44. The composition of claim 43, wherein the silicified
microcrystalline cellulose is about 23 wt % to about 27 wt % and
the magnesium aluminometasilicate is about 33 wt % to about 37 wt
%.
45. The composition of claim 38, wherein the composition is
compressed into a tablet having a hardness value of at least about
2 kp/cm.sup.2.
46. The composition of claim 45, wherein the composition is
compressed into a tablet having a hardness value of from about 5 to
about 10 kp/cm.sup.2.
47. The composition of claim 41, wherein the active agent is
bisacodyl, or pharmaceutically acceptable salts thereof.
48. The composition of claim 40, wherein the active agent is
selected from the group consisting of acetaminophen, ibuprofen,
naproxen, ketoprofen, cyclobenzaprine, meloxicam, rofecoxib,
celecoxib, and pharmaceutically acceptable salts and mixtures
thereof.
Description
[0001] FIELD OF THE INVENTION
[0002] The present invention is directed to a free-flowing
compressible composition containing simethicone and an adsorbent
for forming a solid dosage form, such solid oral dosage forms and
related processes.
BACKGROUND OF THE INVENTION
[0003] Active agents, e.g., pharmaceuticals, nutraceuticals, and
the like, intended for oral administration are often provided in
solid form as tablets, capsules, pills, lozenges, or granules. Oral
dosage forms are swallowed whole, chewed in the mouth,
disintegrated in the mouth and swallowed, or dissolved
sublingually.
[0004] When administered orally, simethicone is used as an adjunct
in the symptomatic treatment of flatulence, functional gastric
bloating, and postoperative gas pains. The clinical use of
simethicone is based on its antifoam properties. Silicone antifoams
spread on the surface of aqueous liquids, forming a film of low
surface tension and thus causing the collapse of foam bubbles.
Thus, for self medication in over-the-counter preparations,
simethicone is used as an antiflatulent to relieve symptoms
commonly referred to as gas, including upper GI bloating, pressure,
fullness, or stuffed feeling. It is often combined with other
gastrointestinal medications, such as antacids, antispasmodics or
digestive enzymes and various simethicone formulations are
previously disclosed.
[0005] Simethicone can be administered orally as a liquid
preparation or as solid form for example capsules, chewable or
swallowable tablets. The advantage of tablets over liquids is the
ease of portability. The advantages of swallowable tablets over
chewable tablets include the ease of ingestion and lack of taste.
Coated tablets are preferred for swallowable tablets.
[0006] Historically, in preparing solid simethicone dosage forms,
difficulties have been encountered when attempting to incorporate
substantial quantities of the liquid simethicone in the solid final
blend for tableting. The difficulty has been to achieve sufficient
flowability for processing and sufficient cohesion for compaction,
particularly for direct compression tableting, so that the tablet
will withstand the rigors of further processing, e.g., film
coating, gelatin dipping, printing, packaging and the like.
Likewise, difficulties have been encountered in assuring that the
viscous liquid simethicone is uniformly distributed throughout the
solid formulation and expeditiously dispersed upon
administration.
[0007] Japanese Patent No. SHO 39[1961]-46451 to Kitsusho Yakuhin
Kogyo KK discloses a method for preparing simethicone tablets by
mixing and granulating simethicone with aluminium silicate,
magnesium aluminum metasilicate, and magnesium silicate. In
particular, the formulation disclosed by the above Japanese patent
requires at most 25% simethicone and 75% or greater silicate,
binder and dispersing agent. Binders were disclosed as being starch
and lactose. Dispersing agent was disclosed as being
carboxymethylcellulose. Further, the above Japanese patent
discloses that when the amount of simethicone exceeds 25%, a
portion of the simethicone can be carried away, therefore the
tablet workability is not desirable.
[0008] JP 5097681 to Horii Yakuhin Kogyo KK discloses a preparation
wherein simethicone is adsorbed to magnesium aluminate metasilicate
and dextrin. Excipient was then added and the preparation was
tableted. Following tableting a hydroxypropyl methylcellulose
phthalate coating was added, followed by applying additional
simethicone and gelatin. The amount of simethicone in the final
tablet was about 15%.
[0009] U.S. Pat. No. 4,906,478 discloses a simethicone preparation
including a powdered combinate of particulate calcium silicate and
simethicone. U.S. Pat. No. 5,073,384 discloses simethicone
preparations including combinates of water soluble agglomerated
maltodextrin and simethicone. U.S. Pat. No. 5,458,886 discloses a
free-flowing granular composition including titanium dioxide having
specific particle size and surface area in combination with
simethicone.
[0010] U.S. Pat. No. 6,103,260 describes the use of an admixture of
simethicone and either one or both of granular anhydrous tribasic
calcium phosphate or dibasic calcium, wherein the admixture in a
uniform granular composition of not more than 1000 micron particle
size, that is suitable for compression into a solid dosage form for
oral administration. While the amount of simethicone in the final
composition was disclosed as being 10% to 50%, the final tablet
weight was in excess of 1000 mg.
[0011] What is needed, therefore, is a free-flowing compressible
composition containing simethicone for forming a solid dosage,
wherein either larger quantities of simethicone can be incorporated
therein or smaller solid dosage forms containing the same amount of
simethicone.
[0012] Surprisingly, it has been discovered that using silicified
microcrystalline cellulose and magnesium aluminometasilicate as
substrates onto which simethicone or other oil or liquid active is
adsorbed provides such a composition. Thus, there is provided by
the present invention a free-flowing compressible composition
containing simethicone for forming a solid dosage form that
contains either larger weight percentages of simethicone while
maintaining substantially the same size than previously possible or
the same weight percentage of simethicone in a smaller size. In
addition, the present invention is directed to such solid oral
dosage forms and related processes.
SUMMARY OF THE INVENTION
[0013] The present invention provides a composition for forming a
compressed solid dosage form that is a free-flowing compressible
admixture of simethicone, an adsorbant, and an optional active
agent, wherein the weight ratio of simethicone to adsorbent is at
least 1:2.22. Also included are solid dosage forms made from a
free-flowing compressible admixture of simethicone, an adsorbant,
and an optional active agent, wherein the weight ratio of
simethicone to adsorbent is at least 1:2.22.
DETAILED DESCRIPTION OF THE INVENTION
[0014] The term, "active agent" is used herein in a broad sense and
encompasses any material that can be carried by or entrained in the
system. For example, the active agent can be a pharmaceutical,
nutraceutical, vitamin, dietary supplement, nutrient, or the like
and combinations thereof
[0015] The active agents useful herein can be selected from classes
from those in the following therapeutic categories: ace-inhibitors;
alkaloids; antacids; analgesics; anabolic agents; anti-anginal
drugs; anti-allergy agents; anti-arrhythmia agents; antiasthmatics;
antibiotics; anticholesterolemics; anticonvulsants; anticoagulants;
antidepressants; antidiarrheal preparations; anti-emetics;
antihistamines; antihypertensives; anti-infectives;
anti-inflammatories; antilipid agents; antimanics; anti-migraine
agents; antinauseants; antipsychotics; antistroke agents;
antithyroid preparations; anabolic drugs; antiobesity agents;
antiparasitics; antipsychotics; antipyretics; antispasmodics;
antithrombotics; antitumor agents; antitussives; antiulcer agents;
anti-uricemia agents; anxiolytic agents; appetite stimulants;
appetite suppressants; beta-blocking agents; bronchodilators;
cardiovascular agents; cerebral dilators; chelating agents;
cholecystokinin antagonists and agonists; chemotherapeutic agents;
cognition activators; contraceptives; coronary dilators; cough
suppressants; decongestants; deodorants; dermatological agents;
diabetes agents; diuretics; emollients; enzymes; erythropoietic
drugs; expectorants; fertility agents; fungicides; gastrointestinal
agents; growth regulators; hormone replacement agents;
hyperglycemic agents; hypoglycemic agents; ion-exchange resins;
laxatives; migraine treatments; mineral supplements; mucolytics,
narcotics; neuroleptics; neuromuscular drugs; non-steroidal
anti-inflammatories (NSAIDs); nutritional additives; peripheral
vasodilators; polypeptides; prostaglandins; psychotropics; renin
inhibitors; respiratory stimulants; sedatives; steroids;
stimulants; sympatholytics; thyroid preparations; tranquilizers;
uterine relaxants; vaginal preparations; vasoconstrictors;
vasodilators; vertigo agents; vitamins; wound healing agents; and
others.
[0016] Active agents that may be used in the invention include, but
are not limited to: acetaminophen; acetic acid; acetylsalicylic
acid, including its buffered forms; acrivastine; albuterol and its
sulfate; alcohol; alkaline phosphatase; allantoin; aloe; aluminum
acetate, carbonate, chloral hydrate; alprazolam; amino acids;
aminobenzoic acid; amoxicillin; ampicillin; amsacrine; amsalog;
anethole; ascorbic acid; aspartame; astemizole; atenolol; azatadine
and its maleate; bacitracin; balsam peru;; beclomethasone
dipropionate; benzocaine; benzoic acid; benzophenones; benzoyl
peroxide; benzquinamide and its hydrochloride; bethanechol; biotin;
bisacodyl; bismuth subsalicylate; bornyl acetate; brompheniramine
and its maleate; buspirone; caffeine; calamine; calcium carbonate,
caseinate and hydroxide; camphor; captopril; carmustine; cascara
sagrada; castor oil; cefaclor; cefadroxil; cephalexin; centrizine
and its hydrochloride; cetirizine; cetyl alcohol; cetylpyridinium
chloride; chelated minerals; chloramphenicol; chlorcyclizine
hydrochloride; chiorhexidine gluconate; chloroxylenol;
chloropentostatin; chlorpheniramine and its maleate and tannate
salts; chlorpromazine; cholestyramine resin; choline bitartrate;
chondrogenic stimulating protein; cimetidine; cinnamedrine
hydrochloride; citalopram; citric acid; clarithromycin; clemastine
and its fumarate; clonidine; clofibrate; cocoa butter; cod liver
oil; codeine and its fumarate and phosphate; cortisone acetate;
ciprofloxacin HCI; cyanocobalamin; cyclizine hydrochloride;
cyproheptadine; danthron; dexbrompheniramine maleate;
dextromethorphan and its hydrohalides; diazepam; dibucaine;
dichloralphenazone; diclofenac sodium; digoxin; dihydroergotamine
and its hydrogenates/mesylates; diltiazem; dimethicone;
dioxybenzone; diphenhydramine and its citrate salt; diphenhydramine
and its hydrochloride; divalproex and its alkali metal salts;
docusate calcium, potassium, and sodium; doxycycline hydrate;
doxylamine succinate; dronabinol; efaroxan; enalapril; enoxacin;
ergotamine and its tartrate; erythromycin; estropipate; ethinyl
estradiol; ephedrine; epinephrine bitartrate; erythropoietin;
eucalyptol; famotidine; fenoprofen and its metal salts; ferrous
fumarate, gluconate and sulfate; fexofenadine; fluoxetine; folic
acid; fosphenytoin; 5-fluorouracil (5-FU); fluoxetine;
flurbiprofen; furosemide; gabapentin; gentamicin; gemfibrozil;
glipizide; glycerin; glyceryl stearate; granisetron; griseofulvin;
growth hormone; guaifenesin; hexylresorcinol; hydrochlorothiazide;
hydrocodone and its tartrates; hydrocortisone and its acetate;
8-hydroxyquinoline sulfate; hydroxyzine and its pamoate and
hydrochloride salts; ibuprofen; indomethacin; inositol; insulin;
iodine; ipecac; iron; isosorbide and its mono- and di- nitrates;
isoxicam; ketamine; kaolin; ketoprofen; lactic acid; lactase,
lanolin; lecithin; leuprolide acetate; lidocaine and its
hydrochloride salt; lisinopril; liotrix; loperamide, loratadine;
lovastatin; luteinizing hormone; LHRH (luteinizing hormone
replacement hormone); magnesium carbonate, hydroxide, salicylate,
and trisilicate; meclizine; mefenamic acid; meclofenamic acid;
meclofenamate sodium; medroxyprogesterone acetate; methenamine
mandelate; menthol; meperidine hydrochloride; metaproterenol
sulfate; methscopolamine and its nitrates; methysergide and its
maleate; methyl nicotinate; methyl salicylate; methyl cellulose;
methsuximide; metoclopramide and its halides/hydrates;
metronidazole; metoprol tartrate; miconazole nitrate; mineral oil;
minoxidil; morphine; naproxen and its alkali metal sodium salts;
nifedipine; neomycin sulfate; niacin; niacinamide; nicotine;
nicotinamide; nimesulide; nitroglycerin; nonoxynol-9; norethindrone
and its acetate; nystatin; octoxynol; octoxynol-9; octyl dimethyl
PABA; octyl methoxycinnamate; olsalazine; omega-3 polyunsaturated
fatty acids; omeprazole; ondansetron and its hydrochloride;
oxolinic acid; oxybenzone; oxtriphylline; para-aminobenzoic acid
(PABA); padimate-O; paramethadione; pentostatin; peppermint oil;
pentaerythritol tetranitrate; pentobarbital sodium; perphenazine;
phenelzine sulfate; phenindamine and its tartrate; pheniramine
maleate; phenobarbital; phenol; phenolphthalein; phenylephrine and
its tannates and hydrochlorides; phenylpropanolamine; phenytoin;
pirmenol; piroxicam and its salts; polydimethylsiloxanes; polymixin
B sulfate; potassium chloride and nitrate; prazepam; procainamide
hydrochloride; procaterol; promethazine and its hydrochloride;
propoxyphene and its hydrochloride and napsylate; pramiracetam;
pramoxine and its hydrochloride salt; prochlorperazine and its
maleate; propranolol and its hydrochloride; promethazine and its
hydrochloride; propranolol; pseudoephedrine and its sulfates and
hydrochlorides; pyridoxine; pyrilamine and its hydrochlorides and
tannates; quinapril; quinidine gluconate and sulfate; quinestrol;
ranitidine; resorcinol; riboflavin; salicylic acid; scopolamine;
sesame oil; shark liver oil; simethicone; sodium bicarbonate,
citrate, and fluoride;; sucralfate; sulfamethoxazole;
sulfasalazine; sulfur; sumatriptan and its succinate; tacrine and
its hydrochloride; theophylline; terfenadine; thiethylperazine and
its maleate; timolol and its maleate; tioperidone; tramadol;
trimetrexate; triazolam; tretinoin; tetracycline hydrochloride;
tolmetin; tolnaftate; triclosan; trimethobenzamide and its
hydrochloride; tripelennamine and its hydrochloride; triprolidine
hydrochloride; undecylenic acid; vancomycin; verapamil
hydrochloride; vidarabine phosphate; vitamins and minerals; witch
hazel; xylometazoline hydrochloride; zinc; zinc sulfate; zinc
undecylenate. Active agents may further include, but are not
limited to food acids; insoluble metal and mineral hydroxides,
carbonates, oxides, polycarbophils, and salts thereof; adsorbates
of active drugs on a magnesium trisilicate base and on a magnesium
aluminum silicate base, and mixtures thereof. Mixtures and
pharmaceutically acceptable salts of these and other actives can be
used.
[0017] Examples of suitable active agents include stirnulent
laxatives, such as bisacodyl, cascara sagrada, danthron, senna,
phenolphthalein, aloe, castor oil, ricinoleic acid, and
dehydrocholic acid, and mixtures thereof; antisecretory; H2
receptor antagonists, such as famotadine, which is commercially
available from McNeil-PPC, Inc. under the PEPCID brand; proton pump
inhibitors; gastrointestinal cytoprotectives, such as sucraflate
and misoprostol; gastrointestinal prokinetics, such as
Prucalopride, antibiotics for H. pylori, such as clarithromycin,
amoxicillin, tetracycline, and metronidazole; antidiarrheals, such
as diphenoxylate and loperamide, which is commercially available
from McNeil-PPC, Inc. under the IMMODIUM brand; glycopyrrolate,
such as Robinul; antiemetics, such as Ondansetron, analgesics, such
as mesalamine, commerically available under the ASACOL brand,
aspirin, and salicylic acid; and mixtures thereof.
[0018] In one embodiment, the additional active agent may be
selected from bisacodyl, famotadine, prucalopride, diphenoxylate,
loperamide, lactase, mesalamine, bismuth, and pharmaceutically
acceptable salts, esters, isomers, and mixtures thereof.
[0019] In another embodiment, the additional active agent may be
selected from acetaminophen, ibuprofen, naproxen, ketoprofen,
cyclobenzaprine, meloxicam, rofecoxib, celecoxib, and
pharmaceutically acceptable salts, esters, isomers, and mixtures
thereof.
[0020] Examples of suitable polydimethylsiloxanes, which include,
but are not limited to dimethicone and simethicone, are those
disclosed in U.S. Pat. No. 4,906,478, U.S. Pat. No. 5,275,822, and
U.S. Pat. No. 6,103,260, the contents of each is expressly
incorporated herein by reference. As used herein, the term
simethicone refers to the broader class of polydimethylsiloxanes,
including simethicone and dimethicone.
[0021] Suitable lactase for use herein include, a lactase isolated
from Saccharomyces lactis, by Gist-Brocade in Delft, Holland, and
sold by Enzyme Development Corporation, New York, N.Y.; a lactase
from Aspergillus oryzae, Lactase Y-400, produced by K. K. Yakult
Honsha; a lactase from Aspergillus oryzae, Plexazym LA 1, produced
by Roehm GmbH; a lactase from Aspergillus oryzae, produced by
Shinnihon Kagaku Kogyo Co.; a lactase from Kluyveroinyces fragilis,
produced by Sturges Enzymes, Selby, North Yorkshire, England; a
lactase from Aspergillus oryzae, Takamine lactase, produced by
Miles Laboratories, Inc., Elkhart, Ind.; a lactase from
Kluyveromyces fragilis produced by Novo Enzymes, Bagsvaerd,
Denmark, and a lactase from Aspergillus oryzae, e.g., Lactase F
"Amano" 100, produced by Amano Pharmaceutical Co., Ltd. Naka-ku,
Nagoya, Japan. These suppliers and others offer, generally, lactase
composition, including a diluent, having a potency of between
14,000 and 100,000 FCC lactase units/gram.
[0022] The active agent can be in the form of a fine powder,
granule, or large crystal, and has an average particle size from
about 1 .mu.m to about 1000 .mu.m, also from about 150 .mu.m to
about 500 .mu.m. Typically, the active agent used in the present
invention has an average size of greater than 50 .mu.m.
[0023] If the active agent has an objectionable taste, it may be
coated with a taste masking coating, as known in the art. Examples
of suitable taste masking coatings are described in U.S. Pat. No.
4,851,226, U.S. Pat. No. 5,075,114, and U.S. Pat. No. 5,489,436.
Commercially available taste masked active agents may also be
employed. For example, acetaminophen particles that are
encapsulated with ethylcellulose or other polymers by a
coaccervation process may be used in the present invention.
Coaccervation-encapsulated acetaminophen may be purchased
commercially from Eurand America, Inc. Vandalia, Ohio, or from
Circa Inc., Dayton, Ohio.
[0024] As used herein, all ranges provided are intended to
expressly include at least all numbers that fall between the
endpoints of ranges.
[0025] As used herein, simethicone conforms to the United States
Pharmacopoeia (USP XXII) definition, that is a mixture of fully
methylated linear siloxane polymers containing repeating units of
polydimethylsiloxane stabilized with trimethylsiloxy end-blocking
units, and silicon dioxide. Also, as used herein, dimethicone can
be substituted for simethcone. Simethicone contains about 90.5-99%
of polydimethylsiloxane and about 4-7% silicon dioxide. The
polydimethylsiloxanes present in simethicone are practically inert
polymers having a molecular weight of 14,000-21,000. The mixture is
a gray, translucent, viscous fluid that is insoluble in water.
[0026] Conventional excipients useful in the present include
fillers or dry binders, such as water soluble simple and complex
carbohydrate (e.g., sucrose, glucose, fructose, maltose, lactose,
maltodextrins, starch, modified starches, mannitol, sorbitol,
maltitol, xylitol, and erthritol), cellulose, and cellulosic
derivatives (e.g., microcrystalline cellulose, carboxymethyl
cellulose, and hydroxyethyl cellulose); wet binders , such as
polyvinyl pyrrolidone, methycellulose, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, carboxymethylcellulose, xanthan gum,
carrageenan gum, locust bean gum, alginates, and acacia;
disintegrants, such as sodium starch glycolate, crosspovidone,
crosscarmellose, microcrystalline cellulose, starch, and the like,
lubricants, such as magnesium stearate, stearic acid and its
pharmaceutically acceptable salts, talc, vegetable oils, and waxes;
glidants, such as colloidal silicon dioxide; sweeteners, including
aspartame, acesulfame potassium, sucralose and saccharin; flavors,
acidulants, antioxidants, preservatives, surfactants, wetting
agents, and coloring agents, and mixtures thereof
[0027] As used herein, the term "adsorbant" means a solid material
or combination of solid materials that is capable of adsorbing and
carrying an oily or fluid material, such as simethicone, while
retaining sufficient flowability to assure content uniformity and
sufficient compactability to be processed into tablets using direct
compression methods.
[0028] As used in the present invention, silicified
microcrystalline cellulose may be the PROSOLV brand (PenWest
Pharmaceuticals, Patterson, N.Y.).
[0029] As used herein magnesium aluminometasilicate may be the
NEUSILIN brand, e.g., S1, FH2, US2, and UFL2 (Fuji Chemical
Industries (USA) Inc., Robbinsville, N.J.).
[0030] In accordance with one embodiment of the present invention,
simethicone is admixed with the magnesium aluminometasilicate to
form a uniform free flowing granular admixture. The silicified
microcrystalline cellulose is then added, as well as any optional
additional active agent, and any additional excipients. The
composition is then mixed until uniform. The resulting granular
composition is then compressed.
[0031] In embodiments wherein one or more additional active agents
are included, the additional active agent may optionally be admixed
with the simethicone prior to adsorbing onto the magnesium
aluminometasilicate and silicified microcrystalline cellulose. The
resulting blend is then further blended with any additional active
agents and any additional excipients, and compressed into
tablets.
[0032] Generally, it is desired that the composition contains a
proportionate amount of simethicone, magnesium aluminometasilicate,
and silicified microcrystalline cellulose, which is consistent with
forming a free-flowing granular composition. For example, the
proportionate amounts, by weight, of the ingredients of the
granular admixture composition is about 1: about 0.5 to about 0.85:
about 0.9 to about 1.30 per solid dosage unit (simethicone:
magnesium aluminometasilicate:silicified microcrystalline
cellulose).
[0033] The weight ratio of simethicone to total adsorbant (e.g.
magnesium aluminometasilicate and silicified microcrystalline
cellulose) is at least about 1:2.22, for example at least about
1:2.00, or at least about 1:1.80. In one embodiment, the weight
ratio of simethicone to total adsorbant is at least about 1 part
simethicone to 1.75 parts adsorbant.
[0034] The solid dosage forms of the present invention may be
shaped, in other words, formed, by a variety of methods known in
the art. Optionally, the dosage form of the present invention,
either with or without active agent, can be molded, deposited or
compacted under methods commonly known in the art.
[0035] Solid dosage forms of the present invention may be formed by
direct compression. Using this technique, the solid dosage forms
are produced by directly compacting a blend of the active agent and
any other appropriate inactive ingredients, i.e., excipients (e.g.
flavoring, binders, lubricants, etc.). Any conventional compacting
methods for forming a chewable dosage form may be used to make the
soft core of the present invention. These methods include, but are
not limited to, dry granulation followed by compression, and wet
granulation followed by drying and compression. Compression methods
include rotary compression, compacting roller technology, such as a
chilsonator or drop roller, or by molding, casting, or extrusion
technologies. These methods are well known in the art, and are
described in detail in, for example, Lachman, et al., The Theory
and Practice of Industrial Pharmacy, Chapter 11, (3.sup.rd Ed.
1986).
[0036] One such method utilizes placing a pre-determined volume of
particles or components into a die cavity of a rotary tablet press,
which continuously rotates as part of a die table from the filling
position to a compaction position. At the compaction position, the
particles are compacted between an upper punch and a lower punch.
The die table then rotates to an ejection position, at which the
resulting tablet is pushed from the die cavity by the lower punch
and guided to an ejection chute by a stationary take-off bar.
[0037] On aspect of the present invention is a compressed solid
dosage form, e.g., a tablet or a caplet. The hardness of the solid
dosage form is up to about 20 kiloponds per square centimeter
(kp/cm.sup.2), e.g., about 2 to 15 kp/cm.sup.2 or about 4 to 10
kp/cm.sup.2. As used herein, the term hardness is used to describe
the diametral breaking strength as measured by conventional
pharmaceutical hardness testing equipment, such as a Schleuniger
Hardness Tester. In order to compare values across different size
tablets, the breaking strength is normalized for the area of the
break (which may be approximated as tablet diameter times
thickness). This normalized value, expressed in kp/cm.sup.2, is
sometimes referred in the art as tablet tensile strength. A general
discussion of tablet hardness testing is found in Leiberman et al.,
Pharmaceutical Dosage Forms--Tablets, Volume 2, 2.sup.nd ed.,
Marcel Dekker Inc., 1990, pp. 213-217, 327 329,
[0038] The solid oral dosage forms of the present invention may be
prepared in the form of tablets, caplets, gelcaps, capsules,
chewable tablets, lozenges, fast dissolving wafers, and other known
and effective solid oral delivery modes.
[0039] A typical solid dosage form of the present invention may
contain a formulation containing various components in accordance
with the following:
TABLE-US-00001 Simethicone about 1 to about 75% Silicified
microcrystalline cellulose about 5 to about 40% Magnesium
aluminometasilicate about 5 to about 30% Additional Active agent
about 0 to about 89% Lubricant about 0 to about 5% Filler/dry
binder about 0 to about 35% Wet Binder about 0 to about 10%
Flavorants/Colorants/Sweeteners about 0 to about 5% All % are w/w
%.
[0040] Specific embodiments of the present invention are
illustrated by way of the following examples. This invention is not
confined to the specific limitations set forth in these examples,
but rather to the scope of the appended claims. Unless otherwise
stated, the percentages and ratios given below are by weight.
EXAMPLES
Example 1
TABLE-US-00002 [0041] Unit Wt Batch Wt Ingredients (mg) % (w/w) (g)
Simethicone** 135 33.75 337.5 Magnesium aluminometasilicate 77
19.25 192.5 (NEUSILIN, US-2 from Fuji Chemical Ltd.) Silicified
microcrystalline cellulose 150 37.5 375.0 (PROSOLV HD-90, from
PenWest Co.) Loperamide, USP 2 0.5 5 Sodium starch glycolate, NF 32
8 80 Stearic acid, NF 4 1 10 TOTAL 1000 **Note: 10% overage
added
[0042] In a 4 quart Hobart mixer, the magnesium aluminometasilicate
and one-half of the batch quantity of the silicified
microcrystalline cellulose were combined with the simethicone by
initially sandwiching the simethicone between the magnesium
aluminometasilicate (bottom) and the silicified microcrystalline
cellulose (top) and mixed at speed setting "1" for about 5
minutes.
[0043] The loperamide was screened using a No. 40 mesh screen.
After screening, the loperamine, sodium starch glycolate and
remaining silicified microcrystalline cellulose were added to
Hobart mixer and mixed at speed setting "1" for about 5
minutes.
[0044] The stearic acid was screened using a No. 30 mesh screen.
After screening, the stearic acid was added to the Hobart mixer and
mixed for about five minutes to form a free-flowing compressible
powder.
[0045] The powder was then compressed into individual units, e.g.,
tablets, on a Manesty Beta Press with caplet shape standard concave
tooling (diameter=6.092 mm, length=19.995 mm) through
pre-compression at 5 kN followed by main compression. The target
weight per unit was 400 mg. Each unit was measure for total weight,
thickness (mm) and hardness (Kp) at various compression forces.
Such data is presented below.
TABLE-US-00003 Average Average Main Compression Thickness Hardness
Force (kN) Weight of 10 Units (g) (mm) (kp/cm.sup.2) 5 4.037 5.135
5.75 10 3.990 4.943 6.64 12.5 3.947 4.814 7.5 15 3.906* 4.743 5.88
20 3.912* 4.687 5.95 *some picking upon compression.
Example 2
Simethicone (120 mg) Loperamide (2 mg) Caplets
TABLE-US-00004 [0046] Unit Batch Wt Wt Ingredients (mg) % (w/w) (g)
Simethicone 135 33.75 33.75 Magnesium 85 21.25 21.25
aluminometasilicatealuminometasilicate (NEUSILIN, US-2 from Fuji
Chemical Ltd.) Silicified microcrystalline cellulose 150 37.5 37.5
(PROSOLV HD-90, from PenWest Co.) Loperamide, USP 2 0.5 0.5 Sodium
starch glycolate, NF 26 6.5 6.5 Stearic acid, NF 2 0.5 0.5 TOTAL
100
[0047] In a glass mortar and pestle, the simethicone was levigated
into the magnesium aluminometasilicate. The silicified
microcrystalline cellulose was added to the dry
simethicone/magnesium aluminometasilicate mixture and mixed
thoroughly. The loperamide and sodium starch glycolate were added
while mixing until uniform. The stearic acid was added and mixing
was continued for about five minutes.
[0048] The powder was then compressed into individual units, e.g.,
tablets, on a Manesty Beta Press with caplet shape standard concave
tooling (diameter=6.092 mm, length=19.995 mm) through
pre-compression at 5 kN followed by main compression. Each unit was
measured for total weight, thickness (mm) and hardness (kp) at
various compression forces. Such data is presented below.
TABLE-US-00005 Average Average Average Main Weight of Thickness of
Hardness of Compression Three Units Three Units Three Units Force
(kN) (mg) (mm) (kp/cm.sup.2) 3.5 421 5.602 10.16 5 424 5.29 9.62 7
410 4.601 5.71 10 418.3 5.129 7.68 18 402.7 4.89 5.37
Example 3
Simethicone (120 me) Loperamide (2 mg) Caplets
TABLE-US-00006 [0049] Batch Unit Wt Wt Ingredients (mg) % (w/w) (g)
Simethicone 135 31.034 62.1 Magnesium aluminometasilicate 105
24.138 48.3 (NEUSILIN, US-2 from Fuji Chemical Ltd) Silicified
microcrystalline cellulose 170 39.08 78.2 (PROSOLV HD-90, from
PenWest Co.) Loperamide, USP 2 0.4598 0.9 Sodium starch glycolate,
NF 20 4.5977 9.2 Stearic acid, NF 3 0.6897 1.4 TOTAL 200
[0050] In a 4 quart Hobart mixer, the magnesium aluminometasilicate
and one-half of the batch quantity of the silicified
microcrystalline cellulose were combined with the simethicone by
initially sandwiching the simethicone between the magnesium
aluminometasilicate (bottom) and the silicified microcrystalline
cellulose (top) and mixed at speed setting No. 1 for about 5
minutes.
[0051] The loperamide was screened using a No. 40 mesh screen.
After screening, loperamide, sodium starch glycolate and remaining
silicified microcrystalline cellulose were added to Hobart mixer
and mixed at speed setting "1" for about 5 minutes.
[0052] The stearic acid was screened using a No. 30 mesh screen.
After screening, the stearic acid was added to the Hobart mixer and
mixed for about five minutes to form a free-flowing compressible
powder.
[0053] The powder was then compressed into individual units, e.g.,
tablets, on a Manesty Beta Press with caplet shape standard concave
tooling (diameter=6.092 mm, length=19.995 mm) through
pre-compression at 3 kN followed by main compression. Each unit was
measure for total weight, thickness (mm) and hardness (kp) at
various compression forces. Such data is presented below.
TABLE-US-00007 Average Average Average Main Weight of Thickness of
Hardness of Compression Five Units Five Units Five Units Force (kN)
(mg) (mm) (kp/cm.sup.2) 1 405 5.994 11.50 3.4 404.4 5.7522 15.24
5.0 371.6 5.129 15.87 6.0 390.2 5.145 17.23 7.5 394 5.164 15.26 10
390.6 4.874 13.13 13 386.4 4.763 10.30 20 397.8 4.795 8.18
[0054] While the target weight per unit was 435 mg, with tooling
(604.times.224.times.052 BB caplet), i.e., volume of die at
maximum, only about 400 mg weight was possible.
Example 4
[0055] A disintegration test comparing a unit from Example 1,
(pre-compression 5 KN and main compression 5 kN) and a unit from
Example 3 (pre-compression 3 kN and main compression 5 kN) in water
was carried out. The results showed that the Example 1 unit
disintegrated in less than about 2 minutes after the unit was
placed in water, while the Example 3 unit remained intact and was
floating in the water after about 2 and one-half minutes.
Example 5
Simethicone (120 mg) Loperamide (2 mg) Caplets
TABLE-US-00008 [0056] Batch Unit Wt Wt Ingredients (mg) % (w/w) (g)
Simethicone* 135 33.75 67.5 Magnesium aluminometasilicate 90 22.5
45 (NEUSILIN, US-2 from Fuji Chemical Ltd.) Silicified
microcrystalline cellulose 150 37.5 75 (PROSOLV HD-90, from PenWest
Co.) Loperamide, USP 2 0.5 1 Sodium starch glycolate, NF 20 5 10
Stearic acid, NF 3 0.75 10 TOTAL 200 *Note: 10% overage added
[0057] In a 4 quart Hobart mixer bowl, simethicone was slowly added
to about one-half of the batch quantity of the magnesium
aluminometasilicate and mixed with a spatula for about 5
minutes.
[0058] The remaining magnesium aluminometasilicate was added to the
mixture and mixing continued until the uniform, scraping the sides
of the bowl.
[0059] The loperamide was screened using a No. 40 mesh screen.
After screening, loperamide, sodium starch glycolate and the
silicified microcrystalline cellulose were added. The resulting
mixture was mixed at speed setting "1" for about five minutes.
[0060] The stearic acid was screened using a No. 30 mesh screen.
After screening, the stearic acid was added and mixed for about
five minutes to form a free-flowing compressible powder.
[0061] The powder was then compressed into individual units, e.g.,
tablets, on a Manesty Beta Press with caplet shape standard concave
tooling (diameter=6.092 mm, length=19.995 mm) through
pre-compression at 3 kN followed by main compression. Target weight
was 400 mg per unit. Each unit was measure for total weight,
thickness (mm) and hardness (kp) at various compression forces.
Such data is presented below.
TABLE-US-00009 Average Average Average Main Weight of Thickness of
Hardness of Compression Five Units Five Units Five Units Force (kN)
(mg) (mm) (kp/cm.sup.2) 1 397.4 5.920 6.60 3.0 396.6 5.572 9.66 5.0
396.6 5.263 9.67 6.0 399.6 5.156 9.30 7.0 395.6 5.018 8.37 90 396.2
4.974 8.45 12.5 389.4 4.806 7.24 20.0 372.4 4.655 <4.94
Example 6
Simethicone (120 mg) Loperamide (2 mg) Caplets
TABLE-US-00010 [0062] Batch Unit wt Wt Ingredients (mg) % (w/w) (g)
Simethicone 135 33.75 67.5 Magnesium aluminometasilicate 100 25 50
(NEUSILIN, US-2 from Fuji Chemical Ltd) Silicified microcrystalline
cellulose 140 35 70 (PROSOLV HD-90, from PenWest Co.) Loperamide,
USP 2 0.5 1 Sodium starch glycolate, NF 20 5 10 Stearic acid, NF 3
0.75 10 TOTAL 200
[0063] In a 4 quart Hobart mixer bowl, simethicone was slowly added
to about one-half of the batch quantity of the magnesium
aluminometasilicate and mixed with a spatula for about 5
minutes.
[0064] The remaining magnesium aluminometasilicate was added to the
mixture and mixing continued until the uniform, scraping the sides
of the bowl.
[0065] The loperamide was screened using a No. 40 mesh screen.
After screening, loperamide, sodium starch glycolate and the
silicified microcrystalline cellulose were added. The resulting
mixture was mixed at speed setting "1" for about five minutes.
[0066] The stearic acid was screened using a No. 30 mesh screen.
After screening, the stearic acid was added and mixed for about
five minutes to form a free-flowing compressible powder.
[0067] The powder was then compressed into individual units, e.g.,
tablets, on a Manesty Beta Press with caplet shape standard concave
tooling (diameter=6.092 mm, length=19.995 mm) through
pre-compression at 3 kN followed by main compression. Target weight
was 400 mg per unit. Each unit was measure for total weight,
thickness (mm) and hardness (kp) at various compression forces.
Such data is presented below.
TABLE-US-00011 Average Average Main Weight of Thickness of Hardness
of Compression Five Units Five Units Five Units Force (kN) (mg)
(mm) (kp/cm.sup.2) 1 395.6 5.773 6.94 2.0 398.2 5.672 8.57 3.0 400
5.263 10.23 4.0 395.8 5.296 7.81 5.0 390.8 5.1128 8.48 10 397.6
4.975 <7.26 20 374.8 4.671 7.10
Example 7
Simethicone (120 mg) Loperamide (2 mg) Caplets
TABLE-US-00012 [0068] Batch Unit Wt Wt Ingredients (mg) % (w/w) (g)
Simethicone 135 33.75 67.5 Magnesium aluminometasilicate 110 27.5
55 (NEUSILIN, US-2 from Fuji Chemical Ltd) Silicified
microcrystalline cellulose 125 31.25 62.5 (PROSOLV HD- 90, from
PenWest Co.) Loperamide, USP 2 0.5 1 Sodium starch glycolate, NF 25
6.25 12.5 Stearic acid, NF 3 0.75 1.5 TOTAL 200
[0069] In a 4 quart Hobart mixer bowl, simethicone was slowly added
to about one-half of the batch quantity of the magnesium
aluminometasilicate and mixed with a spatula for about 5
minutes.
[0070] The remaining magnesium aluminometasilicate was added to the
mixture and mixing continued until the uniform, scraping the sides
of the bowl.
[0071] The loperamide was screened using a No. 40 mesh screen.
After screening, the loperamine, sodium starch glycolate and the
silicified microcrystalline cellulose were added. The resulting
mixture was mixed at speed setting "1" for about five minutes.
[0072] The stearic acid was screened using a No. 30 mesh screen.
After screening, the stearic acid was added and mixed for about
five minutes to form a free-flowing compressible powder.
[0073] The powder was then compressed into individual units, e.g.,
tablets, on a Manesty Beta Press with caplet shape standard concave
tooling (diameter=6.092 mm, length=19.995 mm) through
pre-compression at 3 kN followed by main compression. Each unit was
measure for total weight, thickness (mm) and hardness (kp) at
various compression forces. Such data is presented below.
TABLE-US-00013 Average Average Average Main Weight of Thickness of
Hardness of Compression Five Units Five Units Five Units Force (kN)
(mg) (mm) (kp/cm.sup.2) 1 399 5.935 7.47 2 398.8 5.898 7.68 3.0
404.2 5.709 8.74 4.0 408 5.438 9.60 5.0 408.8 5.344 9.46 10.0 408.6
5.090 5.80 15.0 405.8 4.944 <4.45 20.0 400.8 4.8716 <4.04
Example 8
Simethicone (120 mg) Loperamide (2 mg) Caplets
TABLE-US-00014 [0074] Batch Unit Wt Wt Ingredients (mg) % (w/w) (g)
Simethicone** 135 35.065 140.3 Magnesium aluminometasilicate 90
23.377 93.5 (NEUSILIN, US-2 from Fuji Chemical Ltd) Silicified
microcrystalline cellulose 146 37.922 151.7 (PROSOLV HD-90 from
PenWest Co.) Loperamide, USP 2 0.520 2.1 Sodium starch glycolate,
NF 10 2.597 10.4 Stearic acid, NF 2 0.520 2.1 TOTAL 400 **Note: 10%
overage added
[0075] In a 4 quart Hobart mixer bowl, simethicone was slowly added
to about one-half of the batch quantity of the magnesium
aluminometasilicate and mixed with a spatula for about 5
minutes.
[0076] The remaining magnesium aluminometasilicate was added to the
mixture and mixing continued until the uniform, scraping the sides
of the bowl.
[0077] The loperamide was screened using a No. 40 mesh screen.
After screening, the loperamine, sodium starch glycolate, NF and
the silicified microcrystalline cellulose were added. The resulting
mixture was mixed at speed setting "1" for about five minutes.
[0078] The stearic acid was screened using a No. 30 mesh screen.
After screening, the stearic acid was added and mixed for about
five minutes to form a free-flowing compressible powder.
[0079] The powder was then compressed into individual units, e.g.,
tablets, on a Manesty Beta Press with caplet shape standard concave
tooling (diameter=6.092 mm, length=19.995 mm) through
pre-compression at 3 kN followed by main compression (* these units
were not pre-compressed). Target weight was 385 mg per unit. Each
unit was measure for total weight, thickness (mm) and hardness (kp)
at various compression forces. Such data is presented below.
TABLE-US-00015 Average Average Average Main Weight of Thickness of
Hardness of Compression Five Units Five Units Five Units Force (kN)
(mg) (mm) (kp/cm2) 1 382.8 5.460 9.56 2 383.4 5.395 9.31 3.0 382
5.356 7.60 4.0 379.8 5.123 8.78 5.0 382.8 4.993 <6.58 10.0 383.6
4.841 <4.07 1.5* 384.8 5.439 7.12 3.0* 382.4 5.306 7.61
Example 9
Simethicone (120 mg)/Acetaminophen (250 mg) Caplets
TABLE-US-00016 [0080] Unit Wt Ingredients (mg) Simethicone** 135
Magnesium aluminometasilicate 90 (NEUSILIN, US-2 from Fuji Chemical
Ltd) Silicified microcrystalline cellulose 150 (PROSOLV HD-90 from
PenWest Co.) Acetaminophen, USP 250 Sodium starch glycolate, NF 20
Stearic acid, NF 5 TOTAL 650 **Note: 10% overage added
[0081] In a 4 quart Hobart mixer bowl, simethicone is slowly added
to about one-half of the batch quantity of the magnesium
aluminometasilicate with mixing using a spatula for about 5
minutes.
[0082] The remaining magnesium aluminometasilicate is added to the
mixture and mixing continued until the uniform, scraping the sides
of the bowl.
[0083] The acetaminophen is screened using a No. 40 mesh screen.
After screening, the acetaminophen, sodium starch glycolate, NF and
the silicified microcrystalline cellulose are added. The resulting
mixture is mixed at speed setting "1" for about five minutes.
[0084] The stearic acid is screened using a No. 30 mesh screen.
After screening, the stearic acid is added and mixed for about five
minutes to form a free-flowing compressible powder.
Example 10
Simethicone (120 mg) I Ibuprofen (200 mg) Caplets
TABLE-US-00017 [0085] Unit Wt Ingredients (mg) Simethicone** 135
Magnesium aluminometasilicate 90 (NEUSILIN, US-2 from Fuji Chemical
Ltd) Silicified microcrystalline cellulose 150 (PROSOLV HD-90 from
PenWest Co.) Ibuprofen, USP 200 Sodium starch glycolate, NF 20
Stearic acid, NF 5 TOTAL 600 **Note: 10% overage added
[0086] In a 4 quart Hobart mixer bowl, simethicone is slowly added
to about one-half of the batch quantity of the magnesium
aluminometasilicate with mixing using a spatula for about 5
minutes.
[0087] The remaining magnesium aluminometasilicate is added to the
mixture and mixing continued until the uniform, scraping the sides
of the bowl.
[0088] The ibuprofen is screened using a No. 40 mesh screen. After
screening, the ibuprofen, sodium starch glycolate, NF and the
silicified microcrystalline cellulose are added. The resulting
mixture is mixed at speed setting "1" for about five minutes.
[0089] The stearic acid is screened using a No. 30 mesh screen.
After screening, the stearic acid is added and mixed for about five
minutes to form a free-flowing compressible powder.
Example 11
Simethicone (120 mg)/Mesalamine (400 mg) Caplets
TABLE-US-00018 [0090] Unit Wt Ingredients (mg) Simethicone** 135
Magnesium aluminometasilicate 110 (NEUSILIN, US-2 from Fuji
Chemical Ltd) Silicified microcrystalline cellulose 125 (PROSOLV
HD-90 from PenWest Co.) Mesalamine (5-aminosalicylic acid, 5-ASA) 2
Stearic acid, NF 10 TOTAL 781 **Note: 10% overage added
[0091] In a 4 quart Hobart mixer bowl, simethicone was slowly added
to about one-half of the batch quantity of the magnesium
aluminometasilicate and mixed with a spatula for about 5
minutes.
[0092] The remaining magnesium aluminometasilicate was added to the
mixture and mixing continued until the uniform, scraping the sides
of the bowl.
[0093] The mesalamine is screened using a No. 40 mesh screen. After
screening, the mesalamine and the silicified microcrystalline
cellulose are added. The resulting mixture was mixed at speed
setting "1" for about five minutes.
[0094] The stearic acid is screened using a No. 30 mesh screen.
After screening, the stearic acid is added and mixed for about five
minutes to form a free-flowing compressible powder.
* * * * *