Controlled release dosage form comprising different cellulose ethers

A dosage form is disclosed comprising a low number average molecular weight hydroxypropylmethylcellulose, a high number average molecular weight hydroxypropylmethylcellulose, and a beneficial drug.

CROSS REFERENCE TO COPENDING APPLICATION 
The patent application is copending with a patent application identified by 
Ser. No. 034,971, filed 4-6-87, now U.S. Pat. No. 4,786,503. 
FIELD OF THE INVENTION 
This invention concerns a controlled release dosage form. More specifically 
the invention relates to a dosage form comprising at least two different 
cellulose ethers and at lease one beneficial drug for administering the 
drug to a fluid environment of use. The dosage form comprises at least 
thirty weight percent (wt %) of the cellulose ethers. 
BACKGROUND OF THE INVENTION 
Tablets comprising a cellulose ether are known to the pharmaceutical drug 
delivery art. For example, tablets containing the cellulose ether 
hydroxypropylmethycellulose are known in U.S. Pat. Nos. 3,870,790; 
4,140,755; 4,167,588; 4,226,849; 4,259,314; 4,357,469; 4,369,172; 
4,389,393 and 4,540,566. 
The tablets known to the prior art using the hydroxypropyl-methylcellulose 
ether often have certain disadvantages associated with their structure and 
with their use. For example, the mechanical integrity of some prior art 
tablets frequently is insufficient to provide both a sustained and a rate 
controlled release of a drug over a prolonged period of time in a moving 
fluid environment of use. The prior art tablets often exhibit insufficient 
mechanical integrity, that is the cohesive ability to stay together in a 
moving fluid environment such as the gastrointestinal tract, without 
prematurely breaking-up and without prematurely releasing all of its drug 
content. The above-mentioned desirable properties are not readily apparent 
in the prior art tablets, which appear to undergo substantial 
disintegration in a short time span, usually less than eight hours in a 
fluid environment of use. 
Another disadvantage associated with the prior art tablets is that they 
exhibit an unwanted, variable, and difficult to reproduce a rate of 
release pattern. For example, prior art tablets comprising a small amount 
of a cellulose ether exhibit this behavior, such as by tablets consisting 
of less than five weight percent of a hydroxypropylmethylcellulose having 
a number average molecular weight greater than 50,000. The presence of the 
small amount of this high molecular weight polymeric ether in the tablet 
masks the release characteristic of other polymeric ethers in the tablets 
resulting in an erratic release pattern which is difficult to reproduce 
from batch to batch and from tablet to tablet. 
Still other unacceptable disadvantages associated with the prior art 
tablets are that the tablets during their shelf-life can exhibit an 
unpredictable change in their release-rate characteristics; the prior art 
tablet when tested in an in vitro test that substantially reproduces the 
in vivo environment of the gastrointestinal tract often releases the drug 
at a greater rate of release in vivo than in vitro, which difference can 
be attributed to a premature disintegration of the prior art tablet; and 
the prior art tablet in a high fluid shear environment releases its drug 
too quickly, usually in less than six hours and these tablets therefore 
are not adapted to prolonged release. 
Thus, in the light of the above presentation it will be appreciated by 
those versed in the dispensing art, that if a novel dosage form is made 
available to the medical and the pharmaceutical arts for dispensing a 
difficult to deliver drug free of the tribulation known to the prior art, 
such a dosage form would have a definite use and would also be a valuable 
contribution to the dispensing art. It will be further appreciated by 
those versed in the dispensing art that if a dosage form can be provided 
that (a) possesses a desirable rate of release and mechanical properties 
for dispensing a drug over a prolonged period of time, and which dosage 
form (b) can be manufactured at an economical cost, such a dosage form 
would have a positive and a practical value and it would also represent an 
advancement in the dispensing arts. 
OBJECTS OF THE INVENTION 
Accordingly, it is an immediate object of this invention to provide a novel 
dosage form for the rate controlled delivery of a beneficial drug to a 
biological fluid environment of use, and which unique dosage form 
represents an improvement and an advancement in the drug delivery arts. 
Another object of this invention is to provide both a novel and a useful 
dosage form that substantially overcomes the difficulties associated with 
the tablets of the prior art. 
Another object of the invention is to provide a dosage form comprising at 
least thirty weight percent of a nontoxic cellulosic ether formulation. 
Another object of the invention is to provide a dosage form comprising at 
least two cellulose ethers that function together for enhancing the 
pharmaco-release kinetics of the dosage form. 
Another object of the invention is to provide a novel dosage form that 
comprises a cellulose ether formulation, which cellulose ether formulation 
comprises a low number average molecular weight 
hydroxypropylmethylcellulose ether and a high number average molecular 
weight hydroxypropylmethylcellulose ether, which cellulose ether 
formulation operate as a unit in a moving fluid for controlling the rate 
of release of a beneficial drug from the dosage form. 
Another object of this invention is to provide a dosage form comprising 
means for delivering a beneficial drug formulation that is difficult to 
deliver at meaningful rates and now can be delivered by the dosage form of 
this invention in a higher shear fluid environment of use at 
therapeutically useful rates over a prolonged period of time. 
Another object of the present invention is to provide a dosage form 
comprising a beneficial drug formulation that can be from insoluble to 
very soluble in an aqueous fluid, and which drug formulation can be 
delivered by the dosage form of this invention comprising two different 
cellulose ethers at an in vitro rate of release that is substantially 
paralleled by the in vivo rate of drug release. 
Another object of this invention is to provide a dosage form that can 
administer to a warm-blooded host a complete pharmaceutical regimen 
comprising very soluble or poorly soluble drugs, at a rate controlled by 
the dosage form and at a continuous rate for a particular time period, the 
use of which dosage form requires intervention only for initiation of the 
drug delivery regimen. 
Another object of the present invention is to provide a dosage form of 
delivering a drug in the gastrointestinal tract that substantially avoids 
a premature disintegration and delivers a drug at a rate of dosage form 
release that corresponds to the rate of change of the integrity of the 
dosage form over a prolonged period of at least eight hours. 
Another object of the invention is to provide a dosage form comprising a 
high loading up to 70 wt % of an aqueous soluble drug, which can be 
delivered at a controlled rate by the dosage form and which high loading 
of the insoluble drug could not be delivered by prior art and osmotic 
tablets. 
Another object of the invention is to provide a dosage form comprising a 
low number molecular weight hydroxypropylmethylcellulose ether, a high 
number molecular weight hydroxypropylmethylcellulose ether and an optional 
hydroxypropylcellulose ether for delivering a beneficial drug to the 
gastrointestinal tract of an animal. 
Other objects, features, aspects and advantages of the invention will be 
more apparent to those versed in the dispensing art from the following 
detailed specification taken in conjunction with the drawing figures and 
the accompanying claims.

DETAILED DESCRIPTION OF THE DRAWINGS 
Turning now to the drawing figures in detail, which drawing figures are an 
example of the dosage forms provided by the invention, and which example 
is not to be construed as limiting, one example of the dosage form is 
illustrated in FIG. 1 and in FIG. 2 designated by the numeral 10. In FIG. 
1, dosage form 10 comprises a body or matrix 11, which can be manufactured 
into various sizes and shapes adapted for oral admittance into the 
gastrointestinal tract of a warm-blooded animal. That is, dosage form 10 
can be any convenient shape, such as ellipsoid, bean-shaped, circular 
shaped, rectangular-shaped, caplet-shaped, and the like. 
In FIG. 2, dosage form 10 is seen in cross-section through 2--2 of FIG. 1. 
In FIG. 2, dosage form 10 comprises a body 11 comprising a cellulosic 
ether formulation. The cellulosic ether formulation comprised in one 
presently preferred embodiment a low number average molecular weight 
hydroxypropylmethylcellulose ether 12, represented by dashes, and a high 
number average molecular weight hydroxypropylmethylcellulose ether 13, 
represented by wavy lines. In another preferred embodiment, dosage form 10 
comprises a low number average molecular weight 
hydroxypropylmethylcellulose ether 12, a high number average molecular 
weight hydroxypropylmethylcellulose ether 13, and a hydroxypropylcellulose 
15, represented by vertica lines. 
The expression low number average molecular weight as used for the purposes 
of this invention comprise a cellulosic polymer comprising a low number 
average molecular weight of from about 9,000 to 30,000. Representative of 
hydroxypropylmethylcellulose polymers exhibiting a low number average 
molecular weight of about 9,000 to 30,000 are as follows: (a) a 
hydroxypropylmethylcellulose having aexhibiting a low number average 
weight of about 9,000 to viscosity of 3, a degree of polymerization (DP) 
of 48 and a low number average molecular weight (MW.sub.n) of 9,200; (b) a 
hydroxypropylmethylcellulose having a viscosity of 3, a degree of 
polymerization of 48 and a low number average molecular weight of 9,600; 
(c) a hydroxypropylmethylcellulose having a viscosity of 5, a degree of 
polymerization of 56, and a low number molecular weight of 11,300; (d) a 
hydroxypropylmethylcellulose having a viscosity of 15, a degree of 
polymerization of 79, and a number average molecular weight of 15,900; (e) 
a hydroxypropylmethylcellulose having a viscosity of 35, a degree of 
polymerization of 102, and a number average molecular weight of 19,600; 
(f) a hydroxypropylmethylcellulose having a viscosity of 50, a degree of 
polymerization of 116, and a number average molecular weight of 22,600; 
(g) a hydroxypropylmethylcellulose having a viscosity of 50, a degree of 
polymerization of 116, and a number average molecular weight of 23,300; 
(h) a hydroxypropylmethylcellulose having a viscosity of 100, a degree of 
polymerization of 145, and a number average molecular weight of 27,800; 
(i) a hydroxypropylmethylcellulose having a viscosity of 106, a degree of 
polymerization of 156 and a low number average molecular weight of about 
30,000. 
The expression "high number average molecular weight" as used for the 
purpose of this invention comprises a high number average molecular weight 
of greater than 30,000 to 350,000. Representation of 
hydroxypropylmethylcellulose ethers exhibiting a high number average 
molecular weight of from 30,000 to 350,000 are as follows: (a) a 
hydroxypropylmethylcellulose comprising a viscosity of 1,500, a degree of 
polymerization of 335 and a number average molecular weight of 65,300; (b) 
a hydroxypropylmethylcellulose ether comprising a viscosity of 4,000, a 
degree of polymerization of 460 and a high number average molecular weight 
of 88,300; (c) a hydroxypropylmethylcellulose comprising a viscosity of 
4,000, a degree of polymerization of 460 and a number average molecular 
weight of 92,500; (d) a hydroxypropylmethylcellulose ether comprising a 
viscosity of 15,000, a degree of polymerization of 690 and a number 
average molecular weight of 132,500; (e) a hydroxypropylmethylcellulose 
ether comprising a viscosity of 30,000, a degree of polymerization of 860 
and a number average molecular weight of 165,100; (f) a 
hydroxypropylmethylcellulose comprising a viscosity of 100,000, a degree 
of polymerization of 1,260 and a number average molecular weight of 
241,900; (g) a hydroxypropylmethylcellulose comprising a viscosity of 
220,000, a degree of polymerization of 1,600 and a number average 
molecular weight of 307,200. Viscosity is related to number average 
molecular weight and is determined from measurements on aqueous solutions 
of the cellulosic polymer. 
The expression "hydroxypropylcellulose" as used for the purpose of this 
invention comprises a low substituted hydroxypropylcellulose 15 having a 
hydroxypropyl content of 7 to 16%. More specific hydroxypropylcellulose 
ethers comprise a hydroxypropyl content of 7 to 10%, a hydroxypropyl 
content of 10 to 13%, and a hydroxypropyl content of 13 to 16%. 
In one presently preferred embodiment dosage form 10 provided by this 
invention comprises from 30% to 99.9% of a cellulose ether composition. 
This cellulose ether composition comprises from 5 to 80% of a low number 
average molecular weight cellulose ether and from 15 to 90% of a high 
number average molecular weight hydroxypropylmethylcellulose ether. Dosage 
form 10 in another embodiment comprises from 30 to 99.9% of a cellulosic 
ether composition which composition comprises from 5 to 80% of a low 
number average molecular weight hydroxypropylmethylcellulose, from 10 to 
90% of a high number average molecular weight hydroxypropylmethylcellulose 
ether and 2 to 30% of a low substituted hydroxypropylcellulose. Dosage 
form 10 comprises from 0.1 to 70% of drug 14, and other optional dosage 
form 10 forming ingredients, with all the ingredients in dosage form 10 
equal to 100%. 
Dosage form 10 comprises beneficial drug 14. In the present specification 
the term "drug" includes any physiologically or pharmacologically active 
substance that produces a local or systemic effect in animals, including 
warm-blooded mammals, humans and primates; avians; household, sport and 
farm animals; laboratory animals; fishes, reptiles and zoo animals. The 
term "physiologically", as used herein, denotes the administration of a 
drug to produce generally normal levels and functions in a warm-blooded 
animal. The term "pharmacologically" generally denotes variations in 
response to the amount of drug administered to the host. See Stedman's 
Medical Dictionary, 1966, published by Williams and Wilkins, Baltimore, 
MD. 
The active drug that can be delivered includes inorganic and organic 
compounds without limitation, including drugs that act on the peripheral 
nerves, adrenergic receptors, cholinergic receptors, nervous system, 
skeletal muscles,, cardiovascular system, smooth muscles, blood 
circulatory system, synaptic sites, neuroeffector junctional sites, 
endocrine system, hormone systems, immunological system, organ systems, 
reproductive system, skeletal system, autacoid systems, alimentary and 
excretory systems, inhibitory or autocoids and histamine systems. The 
active drug that can be delivered for acting on these recipients include 
anticonvulsants, analgesics, anti-parkinsons, anti-inflammatories, 
anesthetics, antimicrobials, antimalarials, anti-parasitic, 
anti-hypertensives, angiotensin converting enzyme inhibitor, 
antihistamines, antipyretics, alpha-adrenergic agnoist, alpha-blockers, 
biocides, bactericides, bronchial dilators, beta-adrenergic stimulators, 
beta-adrenergic blocking drugs, contraceptives, cardiovascular drugs, 
calcium channel inhibitors, depressants, diagnostics, diuretics, 
electrolytes, hypnotics, hormonals, hyperglycemics, muscle contractants, 
muscle relaxants, opthalmics, psychic energizers, parasympathomimetics, 
sedatives, sympathomimetics, tranquilizers, urinary tract drugs, vaginal 
drugs, vitamins, and the like. 
Exemplary drugs that are very soluble in water can be delivered by dosage 
form 10 of this invention include prochlorperazine edisylate, ferrous 
sulfate, aminocaproic acid, potassium chloride, mecamylamine 
hydrochloride, procainamide hydrochloride, amphetamine sulfate, 
benzphetamine hydrochloride, isoproteronol sulfate, methamphetamine 
hydrochloride, phenmetrazine hydrochloride, bethanechol chloride, 
methacholine chloride, pilocarpine hydrochloride, atropine sulfate, 
scopolamine bromide, isopropamide iodide, tridihexethyl chloride, 
phenformin hydrochloride, methylphenidate hydrochloride, cimetidine 
hydrochloride, theophylline cholinate, cephalexin hydrochloride, and the 
like. 
Exemplary drugs that are poorly soluble in water and that can be delivered 
by dosage form 10 of this invention include diphenidol, meclizine 
hydrochloride, prochlorperazine maleate, phenoxybenzamine, 
thiethylperazine maleate, anisindone, diphenadione erythrityl 
tetranitrate, digoxin, isoflurophate, acetazolamide, methazolamide, 
bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone acetate, 
phenaglycodol, allopurinol, aluminum aspirin, methotrexate, acetyl 
sulfisoxazole, erythromycin, progestins, esterogenic, progestational, 
corticosteroids, hydrocortisone, hydrocorticosterone acetate, cortisone 
acetate, triamcinolone, methyltesterone, 17-beta-estradiol, ethinyl 
estradiol, prazosin hydrochloride, ethinyl estradiol 3- methyl ether, 
pednisolone, 17-alpha-hydroxyprogesterone acetate, 19-norprogesterone, 
norgestrel, norethindrone, norethindrone, norethindrone, progesterone, 
norgesterone, norethynodrel, and the like. 
Examples of other drugs that can be delivered by dosage form 10 include 
aspirin, indomethacin, naproxen, fenoprofen, sulindac, indoprofen, 
nitroglycerin, propranolol, timolol, atenolol, alprenolol, cimetidine, 
clonidine, imipramine, levodopa, chloropromazine, methyldopa, 
dihydroxyphenylalanine, pivaloyloxyethyl ester of alpha-methyldopa, 
theophylline, calcium gluconate, ketoprofen, ibuprofen, cephalexin, 
erythromycin, haloperidol, zomepirac, ferrous lactate, vincamine, 
diazepam, catopril, phenoxybenzamine, nifedipine, diltiazem, milrinone, 
madol, quanbenz, hydrochlorothiazide, and the like. The beneficial drugs 
are know to the art in Pharmaceutical Sciences, 14th Ed., edited by 
Remington, (1979) published by Mack Publishing Co., Easton, PA; The Drug, 
The Nurse, The Patient, Including Current Drug Handbook, by Falconer et 
al., (1974-1976) published by Sunder Co., Philadelphia, PA; Medicinal 
Chemistry, 3rd Ed., Vol. 1 and 2, by Burger, published by 
Wiley-Interscience, New York and in Physicians' Desk Reference, 38 Ed., 
(1984) published by Medical Economics Co., Oradell, NJ. 
The drug in dosage form 10 can be in various forms, such as uncharged 
molecules, molecular complexes, pharmacologically acceptable salts such as 
hydrochloride, hydrobromide, sulfate, laurate, palmitate, phosphate, 
nitrate, borate, acetate, maleate, tartrate, oleate and salicylate. For 
acidic drugs, salts of metals, amines or organic cations, for example, 
quaternary ammonium can be used. Derivatives of drugs such as ester, 
ethers and amides can be used. Also, a drug that is water insoluble can be 
used in a form that is a water soluble derivative thereof to serve as a 
solute, and on its release from the device is converted by enzymes, 
hydrolyzed by body pH or other metabolic processes to the original 
biologically active form. 
Drug 14 can be present in dosage form 10 neat or, as in a presently 
preferred optional embodiment, with a binder, dispersant, wetting agent, 
lubricant, or dye. Representative of these include acacia, agar, calcium 
carrageenan, alginic acid, algin, agarose powder, colloidal magnesium 
silicate, pectin, gelatin, and the like; binders like polyvinyl 
pyrrolidone; lubricants such as magnesium stearate; wetting agent such as 
fatty amines, fatty quaternary ammonium salts; esters of sorbitol, and the 
like. The phrase drug formulation indicates the drug is present in dosage 
form 10 neat or accompanied by a binder, and the like. The amount of 
beneficial drug in dosage form 10 generally is from about 0.05 ng to 5 g 
or more, with individual dosage form 10 comprising for example, 25 ng, 1 
mg, 5 mg, 10 mg, 25 mg, 250 mg, 750 mg, 1.0 g, 1.2 g, 1.5 g, and the like. 
The dosage form can be administered once, twice or three times a day. 
Dosage form 10 is manufactured from a well-mixed composition of 
dosage-forming members. For example, a particular dosage form is made as 
follows: first, each of the ingredients comprising a dosage form are 
independently screened and then blended together, except for the 
lubricant. Then the homogeneous blend is wet granulated by adding a 
solvent such as anhydrous ethanol, and the wet ingredients mixed until a 
uniform blend is obtained by said process. Next, the wet blend is passed 
through a screen and dried to evaporate the solvent. The resulting 
granules are passed again through a sieve. Next, a small amount of a 
finely divided lubricant is added to the dry granules and the lubricant 
and granules blended to provide a uniform blend. Then, the dosage forming 
composition is fed to the hopper of a compression machine, and the 
composition pressed into a dosage form. Typically, about two tons of 
pressure are applied to yield the final dosage form. 
The dosage form can be made also by a dry granulation process of 
manufacture. The dry process comprises first mixing all the dosage forming 
ingredients, except for the lubricant, passing the mixed ingredients 
through a grinding mill to a small mesh size, and then transferring the 
sized powder to a dry compactor. The compactor densifies the powder, which 
dense powder is then passed through a sizing mill to regrind the 
composition. The composition is ground to a small size, typically 20 mesh 
or smaller. Finally, a dry lubricant is added and the ingredients blended 
to produce the final dosage forming composition. Then, the composition is 
fed to a compaction press and compressed into the dosage form 10. 
Other standard manufacturing procedures can be used to form the dosage 
form. For example, the various ingredients can be mixed with a solvent by 
ballmilling, calendering, stirring or rollmilling, and then pressed into a 
preselected sized and shaped dosage form 10. 
Exemplary solvents suitable for manufacturing the dosage form include 
inorganic and organic solvents that do not adversely harm the dosage form. 
The solvents broadly include a member selected from the group consisting 
of alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated 
solvents, cycloaliphatic solvents, aromatic, heterocyclic solvents, and 
mixtures thereof. Typical solvents include acetone, diacetone, methanol, 
ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, 
isopropyl acetate, n-butylacetate methyl isobutyl ketone, methyl propyl 
ketone, n-hexane, n-heptane, methylene dichloride, ethylene dichloride, 
propylene dichloride, ethyl ether, mixtures such as acetone and ethanol, 
acetone and methanol, methylene dichloride and methanol, ethylene 
dichloride and methanol, and the like. 
The following examples illustrate means and methods for carrying out the 
present invention. The examples are merely illustrative and they should 
not be considered as limiting the scope of the invention, as these 
examples and other equivalents thereof will become more apparent to those 
versed in the pharmaceutical dispensing art in the light of the present 
disclosure, the drawings and the accompanying claims. 
EXAMPLE 1 
A dosage form 10 comprising 29.5% isosorbide dinitrate (5,900 g); 29.5% 
lactose (5,900 g); 20% hydroxypropylmethylcellulose ether (4,000 g) 
exhibiting a low 27,800 number average molecular weight and 20% 
hydroxypropylmethylcellulose ether (4,000 g) exhibiting a high 88,300 
number average molecular weight, were presieved through a 40 mesh screen. 
The presieved ingredients were mixed in a twin shell blender for 15 
minutes and then transferred to a Hobart.RTM. mixer. Next, anhydrous 
methyl alcohol was added slowly with mixing to form a uniform dough. The 
dough was passed through a 20 mesh screen and then air dried for 2 hours 
at room temperature. The resulting granules were repassed through the 20 
mesh screen and dried at ambient conditions overnight. Then, magnesium 
stearate, 1%, (200 g), was passed through an 80 mesh per inch screen and 
then was blended into the mixture in a twin shell mixer for 3 minutes. The 
resulting granulation was compressed on a D3B Manesty.RTM. Press at 2 tons 
pressure using a 13/32 inch, (1.0 mm) round standard concave punch. The 
dosage form 10 provided by the manufactured weight 271 mg, comprising 54.2 
mg of the hydroxypropylmethylcellulose ether having the low number average 
molecular weight of 27,800; 54.2 mg of the hydroxypropylmethylcellulose 
having the high molecular number average molecular weight of 88,300; and 
80 mg of isosorbide dinitrate. The dosage forms were placed in artificial 
gastric fluid and the release of drug measured from the dosage form. The 
results of the test indicated 78 % of the drug was delivered in a 24 hour 
period at an average delivery rate of isosorbide dinitrate of 2.5 mg per 
hour. Accompanying FIG. 3 depicts the release rate pattern for the dosage 
form and accompanying FIG. 4 depicts the cumulative amount released over a 
prolonged period of 24 hours. 
EXAMPLE 2 
A dosage form 10 comprising 15% of the enzyme inhibitor captopril, 5% of a 
low 9,200 number average molecular weight hydroxypropylmethylcellulose, 
78% of a high 88,300 molecular weight hydroxypropylmethylcellulose and 2% 
of stearic acid was prepared as follows: first, 1,500 g of the enzyme 
inhibitor, 500 g of the low number average molecular weight 
hydroxypropylmethylcellulose, and 7,800 g of the high molecular weight 
hydroxypropylmethylcellulose are presieved through a 40 mesh screen and 
mixed for 15 minutes in a twin shell blender, and the resulting mixture 
transferred to a Hobart.RTM. blender. Then, anhydrous ethanol was added 
slowly with mixing to form a damp mass. The ethanol alcohol damp mass was 
passed through a 20 mesh acreen and air dried overnight. The dry product 
was repassed through a 20 mesh screen. The resulting granules were 
lubricated with 200 g of stearic acid by passing the stearic acid through 
an 80 mesh screen over the granules and mixing the granules in a twin 
shell blender for 3 minutes. Next, the resulting granulation was 
compressed into dosage form using a Manesty press fitted with a standard 
concave round die of 3/8 inch (0.95 mm) diameter under a compression head 
of 2 tons. The dosage forms weighed 334 mg and contained 50 mg of 
captopril. 
EXAMPLE 3 
A dosage form 10 was prepared by following the procedure of Example 2. The 
dosage form of this example comprises 53% ibuprofen; 20% of a 
hydroxypropylmethylcellulose having a number average molecular weight of 
9,200; 20% of a hydroxypropylmethylcellulose having a number average 
molecular weight of 241,900; 5% hydroxypropylmethylcellulose, and 2% 
magnesium stearate. The drug release rate pattern for this dosage form is 
seen in FIG. 5 and the cumulative amount released over a prolonged period 
of time is seen in FIG. 6. 
EXAMPLES 4 to 9 
The procedures described above are followed for manufacturing dosage forms 
comprising the following drugs and the cellulosic ethers: (a) 120 mg of 
propanol hydrochloride and 40 wt % of a cellulosic ether formulation 
comprising 20 wt % hydroxypropylmethylcellulose having a nunber average 
molecular weight of 241,900 and 20 wt % of a hydroxypropylmethylcellulose 
having a number average molecular weight of 9,200; (b) a dosage form 
comprising 50 mg of hydrochlorothiazide and 60 wt % of a cellulosic ether 
formulation comprising 20 wt % hydroxypropylmethylcellulose having a 
molecular weight of 132,500 and 40 wt % of a hydroxypropylmethylcellulose 
having a molecular weight of 9,200 ; (c) a dosage form comprising 75 mg of 
dipyridamole and 60 wt % of a cellulosic ether composition comprising 20 
wt % of a hydroxypropylmethylcellulose having a number average molecular 
weight of 88,300 and 40 wt % of a hydroxypropylmethylcellulose having a 
number average molecular weight of 27,800; (d) a dosage form comprising 
100 mg of verapamil hydrochloride and 50 wt % of a 
hydroxypropylmethylcellulose having a number average molecular weight of 
307,200 and 15 wt % of a hydroxypropylmethylcellulose having a number 
average molecular weight of 19,600; (e) a dosage form comprising 50 mg of 
codeine phosphate, 60 wt % of a hydroxypropylmethylcellulose having 
anumber average molecular weight of 241,900 and 15 wt % of a 
hydroxypropylmethylcellulose having a number average molecular weight of 
9,200; (f) a dosage form comprising 200 mg of mitrofurantoin, 15 wt % of a 
hydroxypropylmethylcellulose having a number average molecular weight of 
241,900 and 45 wt % of a hydroxypropylmethylcellulose having a number 
average molecular weight of 19,600. 
EXAMPLES 10 to 15 
The procedures described above are followed for manufacturing dosage forms 
comprising the following drugs and cellulosic ether formulation: (g) 250 
mg of tetracycline; 5 wt % of hydroxypropylmethylcellulose having a number 
average molecular weight of 132,500; and, 10 wt % of 
hydroxypropylmethylcellulose comprising a number average molecular weight 
of 241,900; and 40 wt % of a hydroxypropylmethylcellulose comprising a 
number average molecular weight of 9,200; (h) 300 mg of cimetidine; 5 wt % 
of hydroxypropylmethylcellulose having a number average molecular weight 
of 88,300; 25 wt % of hydroxypropylmethylcellulose comprising a number 
average molecular weight of 241,900; and, 10 wt % of a 
hydroxypropylmethylcellulose comprising a number average molecular weight 
of 9,200; (i) 160 mg of nadolol; 20 wt % of hydroxypropylmethylcellulose 
having a number average molecular weight of 88,300; 5 wt % 
hydroxypropylmethylcellulose comprising a number average molecular weight 
of 307,200; and, 40 wt % of a hydroxypropylmethylcellulose comprising a 
number average molecular weight of 9,200; (j) 300 mg of quinidine 
gluconate; 20 wt % of hydroxypropylmethylcellulose having a number average 
molecular weight of 241,900; 20 wt % of hydroxypropylmethylcellulose 
comprising a number average molecular weight of 307,200; and, 20 wt % of a 
hydroxypropylmethylcellulose comprising a number average molecular weight 
of 9,200; (k) 30 mg of morphine sulfate; 60 wt % of 
hydroxypropylmethylcellulose having a number average molecular average 
weight of 132,500 ; 20 wt % of hydroxypropylmethylcellulose comprising a 
number average molecular weight of 307,200; and, 10 wt % of a 
hydroxypropylmethylcellulose comprising a number average molecular weight 
of 9,200; and, (l) 20 mg of nifedipine; 5 wt % of 
hydroxypropylmethylcellulose having a number average molecular weight of 
132,500; 10 wt % of hydroxypropylmethylcellulose comprising a number 
average molecular weight of 241,900; and, 75 wt % of a 
hydroxypropylmethylcellulose comprising a number average molecular weight 
of 9,200. 
EXAMPLES 16 to 21 
The procedures described above are followed for manufacturing dosage forms 
comprising the following drugs and cellulosic ether formulation: (m) 250 
mg of erthromycin stearate; 15 wt % of hydroxypropylmethylcellulose having 
a number average molecular weight of 241,900; 15 wt % of 
hydroxypropylmethylcellulose comprising a number average molecular weight 
of 9,200; and, 5 wt % of a hydroxypropylmethylcellulose comprising a 
hydroxypropoxy content of 7 to 10%; (n) 12 mg of chlorpheniramine maleate; 
70 wt % of hydroxypropylmethylcellulose having a number average molecular 
weight of 241,900; 20 wt % of hydroxypropylmethylcellulose comprising a 
number average molecular weight of 9,600; and, 5 wt % of a 
hydroxypropylmethylcellulose comprising a hydroxypropoxy content of 10 to 
16%; (o) 8 mg of brompheniramine maleate; 70 wt % of 
hydroxypropylmethylcellulose having a number average molecular weight of 
241,900; 20 wt % of hydroxypropylmethylcellulose comprising a number 
average molecular weight of 19,600; and, 5 wt % of a 
hydroxypropylcellulose consisting of a hydroxypropoxy content of 13 to 
16%; (p) a dosage form comprising 8 mg of chlorpheniramine maleate; 120 mg 
of pseudoephedrine sulfate; 25 wt % of hydroxypropylmethylcellulose 
consisting of a number average molecular weight of 241,900; 25 wt % of 
hydroxypropylmethylcellulose consisting of a number average molecular 
weight of 27,800; and, 10 wt % hydroxypropylcellulose consisting of 10 to 
13% hydroxypropoxy; and (q) 150 mg of ranitidine hydrochloride; 35 Wt % of 
hydroxypropoxymethycellulose having a number average molecular weight of 
241,900; 15 wt % of hydroxypropoxymethylcellulose consisting essentially 
of a low number average molecular weight of 19,600; and, 15 wt % 
hydroxypropylcellulose consisting of 13 to 16 hydroxypropoxy content. 
Dosage form 10 provided by the invention makes available a drug delivery 
matrix suitable for retention in the stomach for gastric retention over 
the drug releasing life time of the dosage system. Also, when all the drug 
is released, the system bioerodes into innocuous particles and dissolved 
polymers that pass from the gastrointestinal tract. The dosage form of the 
invention comprising higher concentrations of cellulosic ether 
formulations exhibit better mechanical integrity and they better withstand 
the abrasive fluidic action of the gastrointestinal tract. The dosage form 
of the invention provides a broader range of erosion rates including 
decreased and increased erosion rates in its use of low and high number 
average molecular weight blends of cellulosic ethers. Another advantage 
provided by dosage form 10 resulting from its use of high number average 
molecular weight cellulose ethers is that it provides more physical 
stability, improved resistance to thermal shock and it helps lessen the 
incidence of matrix cracking over storage time, when stored in fluctuating 
ambient temperature conditions. Also, the dosage forms use of the high 
number average molecular weight cellulosic ethers exhibit decreased 
tackiness in high humidity thereby preventing sticking of one to another. 
The use of high number average molecular weight cellulose ethers provides 
more rate control of the drug administration over time. The use of the 
cellulose ethers, especially the high number average molecular wt 
cellulose ethers which swell extensively when hydrated, lessens direct 
drug contact with mucosal tissues and thereby lessens the incidence of 
tissue irritation for irritating drugs. 
The novel dosage form of this invention comprises means for the obtainment 
of precise release rates in the environment of use while simultaneously 
providing beneficial therapy to a recipient. While there has been 
described and pointed out features of the invention as applied to 
presently preferred embodiments, those skilled in the dispensing art will 
appreciate that various modifications, changes, additions and omissions in 
the dosage form ilustrated and described can be made without departing 
from the spirit of this invention.