Note: Descriptions are shown in the official language in which they were submitted.
1 33 60 70 ARC 1480
1 CONTROLLED RELEASE DOSAGE FORM
2 COMPRISING DIFFERENT CELLULOSE ETHERS
, . . . .
8 FIELD OF THE INVENTION
This invention concerns a controlled release dosage form.
11 More specifically, the invention relates to a dosage form comprising
12 at least two different cellulose ethers and at lease one beneficial
13 drug for administering the drug to a fluid environment of use. The
14 dosage form comprises at least thirty weight percent (wt %) of the
cellulose ethers.
16
17 BACKGROUND OF THE
18 INVENTION
19
Tablets comprising a cellulose ether are known to the pharmaceu-
21 tica1 drug delivery art. For example, tablets containing the cellu-
22 lose ether hydroxypropylmethylcellulose are known in United States
23 Patents Nos. 3,870,790; 4,140,755; 4,167,588; 4,226,849; 4,259,314;
24 4,357,469; 4,369,172; 4,389,3g3 and 4,540,566.
The tablets known to the prior art using the hydroxypropyl-
26 methylcellulose ether often have certain disadvantages associated with
27 their structure and with their use. For example, the mechanical
28 integrity of some prior art tablets frequently is insufficient to
~ 1 336070 ARC 1480
1 provide both a sustained and a rate controlled release of a drug over
2 a prolonged period of time in a moving fluid environment of use. The
3 prior art tablets often exhibit insufficient mechanical integrity,
4 that is the cohesive ability to stay together in a moving fluid envi-
ronment such as the gastrointestinal tract, without prematurely
6 breaking-up and without prematurely releasing all of its drug content.
7 The above-mentioned desirable properties are not readily apparent in
8 the prior art tablets, which appear to undergo substantial disintegra-
9 tion in a short time span, usually less than eight hours in a fluid environment of use.
11 Another disadvantage associated with the prior art tablets is
12 that they exhibit an unwanted, variable, and difficult to reproduce a
13 rate of release pattern. For example, prior art tablets comprising a
14 small amount of a cellulose ether exhibit this behavior, such as bytablets consisting of less than five weight percent of a hydroxy-
16 propylmethylcellulose having a number average molecular weight greater
17 than 50,000. The presence of the small amount of this high molecular
18 weight polymeric ether in the tablet masks the release characteristic
19 of other polymeric ethers in the tablets resulting in an erratic
release pattern which is difficult to reproduce from batch to batch
21 and from tablet to tablet.
22 Still other unacceptable disadvantages associated with the prior
23 art tablets are that the tablets during their shelf-life can exhibit
24 an unpredictable change in their release-rate characteristics; the
prior art tablet when tested in an in vitro test that substantially
26 reproduces the in vivo environment of the gastrointestinal tract often
27 releases the drug at a greater rate of release in vivo than in vitro,
28 which difference can be attributed to a premature disintegration of
1 3 3 6 0 7 0 67696-l45
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 be 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.
ASPECTS OF THE INVENTION
Accordingly, this invention seeks 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.
This invention also seeks to provide both a novel and a
useful dosage form that substantially overcomes the difficulties
associated with the tablets of the prior art.
1 336070
67696-145
The invention also seeks to provide a dosage form
comprising at least thirty weight percent of a nontoxic cellulosic
ether formulation.
The invention seeks to provide a dosage form comprising
at least two cellulose ethers that function together for enhancing
the pharmaco-release kinetics of the dosage form.
The invention also seeks 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 hydroxypropylmethyl~ellulose ether, which
cellulose ether formulation operate as a unit in a moving fluid
for ~ontrolling the rate of release of a benefi~ial drug from the
dosage form.
This invention also seeks 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 high shear
fluid environment of use at therapeutically useful rates over a
prolonged period of time.
The present invention also seeks 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.
A
1 3 3 6 0 7 ~ 67696-145
This invention also seeks 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.
The present invention also seeks to provide a dosage
form for 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.
The invention further seeks to provide a dosage form
~omprising 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.
The invention also seeks to provide a dosage form
comprising a low number molecular weight hydroxypropylmethyl-
cellulose ether, a high number molecular weight hydroxypropyl~methylcellulose ether and an optional hydroxypropylcellulose ether
for delivering a beneficial drug to the gastrointestinal tract of
an animal.
Other features, aspects and advantages of the inven~ion
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.
1 336070
67696-145
The invention provides a dosage form for delivering a
beneficial drug to an environment of use, whi~h dosage form
comprisesS a matrix adapted for entrance into the environment of
use, said matrix comprising from 30% to 99.9% of a cellulosic
ether formulation, which formulation comprises from 10% to ~9% of
at least one hydroxypropylmethylcellulose comprising a high number
average molecular weight of from 30,000 to 350,000; from 5% to 80%
of at least one hydroxypropylmethylcellulose comprising a low
number average molecular weight of from 9,000 to 30,000; from 2%
to 30% of a hydroxypropylcellulose comprising a hydroxypropoxy
content of 7% to 16%, and a dosage amount of the beneficial drug.
In a preferred embodiment 5% to 90% of a hydroxypropyl-
methylcellulose comprising a different number average molecular
weight of from 30,000 to 350,000 replaces the hydroxypropyl-
cellulose in the dosage form.
The invention also relates to the use of such dosage
forms and commercial packages comprising such dosage forms
together with instru~tions for use thereof to deliver beneficial
drugs to the gastrointestinal tract of a warm-blooded mammal,
especially the stomach of a human.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings, which are not drawn to scale but are
set forth to illustrate various embodiments that can be provided
by the invention, the drawing figures are as follows:
Figure 1 is a side, elevational view of a dosage form
provided by the invention, designed and adapted for orally
5a
~ 1 336070
67696-145
administering a beneficial drug to the gastrointestinal tract of
an animal;
Figure 2 is a cross-section through 2-2 of Figure 1 for
illustrating the internal structure of the dosage form;
5b
A
1 336070 ARC 1480
1 Figures 3, 4, 5 and 6 are graphs that depict release rate
2 patterns for dosage forms provided by the invention.
3 In the drawings and in the specifications like parts in related
4 figures are identified by like numbers. The terms appearing earlier
in the specification and in the drawings, as well as embodiments
6 thereof, are further described elsewhere in this specification.
7 DETAILED DESCRIPTION OF
8 THE DRAWINGS
9 Turning now to the drawing figures in detail, which drawing
figures are an example of the dosage forms provided by the invention,
11 and which example is not to be construed as limiting, one example of
12 the dosage form is illustrated in Figure 1 and in Figure 2 designated
13 by the numeral 10. In Figure 1, dosage form 10 comprises a body or
14 matrix 11, which can be ~anufactured into various sizes and shapes
adapted for oral admittance into the gastrointestinal tract of a warm-
16 blooded animal. That is, dosage form 10 can be any convenient shape,
17 such as ellipsoid, bean-shaped, circular shaped, rectangular-shaped,
18 caplet-shaped, and the like.
19 In Figure 2, dosage form 10 is seen in cross-section through 2-2
of Figure 1. In Figure 2, dosage form 10 comprises a body 11 comprising
21 a cellulosic ether formulation. The cellulosic ether formulation
22 comprised in one presently preferred embodiment a low number average
23 molecular weight hydroxypropylmethylcellulose ether 12, represented by
24 dashes, and a high number average molecular weight hydroxypropyl-
methylcellulose ether 13, represented by wavy lines. In another
26 preferred embodiment, dosage form 10 comprises a low number average
27 molecular weight hydroxypropylmethylcellulose ether 12, a high number
28 average molecular weight hydroxypropylmethylcellulose ether 13, and a
~ 1 336070 ARC 1480
1 hydroxypropylcellulose 15, represented by vertical lines.
2 The expression low number average molecular weight as used for
3 the purposes of this invention comprise a cellulosic polymer compri-
4 sing a low number average molecular weight of from about 9,000 to
30,000. Representative of hydroxypropylmethylcellulose polymers ex-
6 hibiting a low number average molecular weight of about 9,000 to
7 30,000 are as follows: (a) a hydroxypropylmethylcellulose having a
8 viscosity of 3, a degree of polymerization (DP) of 48 and a low number
9 average molecular weight (MWn) of 9,200; (b) a hydroxypropylmethyl-
cellulose having a viscosity of 3, a degree of polymerization of 48
11 and a low number average molecular weight of 9,600; (c) a hydroxy-
12 propylmethylcellulose having a viscosity of 5, a degree of polymeriza-
13 tion of 56, and a low number average molecular weight of 11,300; (d)
14 a hydroxypropylmethylcellulose having a viscosity of 15, a degree of
polymérization of 79, and a number average molecular weight of 15,900;
16 (e) a hydroxypropylmethylcellulose having a viscosity of 35, a degree
17 of polymerization of 102, and a number average molecular weight of
18 19,600; (f) a hydroxypropylmethylcellulose having a viscosity of 50,
19 a degree of polymerization of 116, and a number average molecular
weight of 22,600; (9) a hydroxypropylmethylcellulose having a visco-
21 sity of 50, a degree of polymerization of 116, and a number average
22 molecular weight of 23,300; (h) a hydroxypropylmethylcellulose having
23 a viscosity of 100, a degree of polymerization of 145, and a number
24 average molecular weight of 27,800; (i) a hydroxypropylmethylcellulose
having a viscosity of 106, a degree of polymerization of 156 and a low
26 number average molecular weight of about 30,000.
27 The expression "high numbér average molecular weight" as used for
28 the purpose of this invention comprises a high number average molecular
~ 1 336~7~ ARC 1480
1 weight of greater than 30,000 to 350,000. Representation of hydroxy-
2 propylmethylcellulose ethers exhibiting a high number average molecular
3 weight of from 30,000 to 350,000 are as follows: (a) a hydroxypropyl-
4 methylcellulose comprising a viscosity of 1,500, a degree of polymeri-
zation of 335 and a number average molecular weight of 65,300; (b) a
6 hydroxypropylmethylcellulose ether comprising a viscosity of 4,000, a
7 degree of polymerization of 460 and a high number average molecular
8 weight of 88,300; (c) a hydroxypropylmethylcellulose comprising a
9 viscosity of 4,000, a degree of polymerization of 460 and a number
average molecular weight of 92,500; (d) a hydroxypropylmethylcellulose
11 ether comprising a viscosity of 15,000, a degree of polymerization of
12 690 and a number average molecular weight of 132,500; (e) a hydroxy-
13 propylmethylcellulose ether comprising a viscosity of 30,000, a degree
14 of polymerization of 860 and a number average molecular weight of
165,100; (f) a hydroxypropylmethylcellulose comprising a viscosity of
16 100,000, a degree of polymerization of 1,260 and a number average
17 molecular weight of 241,900; (9) a hydroxypropylmethylcellulose
18 comprising a viscosity of 220,000, a degree of polymerization of 1,600
19 and a number average molecular weight of 307,200. Viscosity is
related to number average molecular weight and is determined from
21 measurements on aqueous solutions of the cellulosic polymer.
22 The expression "hydroxypropylcellulose" as used for the purpose
23 of this invention comprises a low substituted hydroxypropylcellulose
24 15 having a hydroxypropyl content of 7 to 16%. More specific hydroxy-
propylcellulose ethers comprise a hydroxypropyl content of 7 to 10%, a
26 hydroxypropyl content of 10 to 13%, and a hydroxypropyl content of 13
27 to 16%.
28 In one presently preferred embodiment dosage form 10 provided by
~ ~ 33607~ ARC 1480
1 this invention comprises from 30% to 99.9% of a cellulose ether compo-
2 sition. This cellulose ether composition comprises from 5 to 80% of a
3 low number average molecular weight cellulose ether and from 15 to 90%
4 of a high number average molecular weight hydroxypropylmethylcellulose
ether. Dosage form 10 in another embodiment comprises from 30 to
6 99.9% of a cellulosic ether composition which composition comprises
7 from 5 to 80% of a low number average molecular weight hydroxypropyl-
8 methylcellulose, from 10 to 90% of a high number average molecular
9 weight hydroxypropylmethylcellulose ether and 2 to 30% of a low sub-
stituted hydroxypropylcellulose. Dosage form 10 comprises from 0.1 to
11 70% of drug 14, and other optional dosage form 10 forming ingredients,
12 with all the ingredients in dosage form 10 equal to 100%.
13 Dosage form 10 comprises beneficial drug 14. In the present
14 specificatio~ the term "drug" includes any physiologically or pharma-
cologically active substance that produces a local or systemic effect
16 in animals, including warm-blooded mammals, humans and primates;
17 avians; household, sport and farm animals; laboratory animals;
18 fishes, reptiles and zoo animals. The term "physiologically", as used
19 herein, denotes the administration of a drug to produce generallynormal levels and functions in a warm-blooded animal. The term
21 "pharmacologically" generally denotes variations in response to the
22 amount of drug administered to the host. See Stedman's Medical
23 Dictionary, 1966, published by Williams and Wilkins, Baltimore, MD.
24 The active drug that can be delivered includes inorganic and
organic compounds without limitation, including drugs that act on the
26 peripheral nerves, adrenergic receptors, cholinergic receptors,
27 nervous system, skeletal muscles, cardiovascular system, smooth muscles,
28 blood circulatory system, synaptic sites, neuroeffector junctional
l ~ ~ 6 0 7 0 ARC 1480
1 sites, endocrine system, hormone systems, immunological system, organ
2 systems, reproductive system, skeletal system, autacoid systems,
3 alimentary and excretory systems, inhibitory or autocoids and
4 histamine systems. The active drug that can be delivered for acting
on these recipients include anticonvulsants, analgesics, anti-parkinsons,
6 anti-inflammatories, anesthetics, antimicrobials, antimalarials, anti-
7 parasitic, anti-hypertensives, angiotensin converting enzyme inhibitor, 8 antihistamines, antipyretics, alpha-adrenergic agnoist, alpha-blockers,9 biocides, bactericides, bronchial dilators, beta-adrenergic stimulators,
beta-adrenergic blocking drugs, contraceptives, cardiovascular drugs,
11 calcium channel inhibitors, depressants, diagnostics, diuretics, elec-
12 trolytes, hypnotics, hormonals, hyperglycemics, muscle contractants,
13 muscle relaxants, opthalmics, psychic energizers, parasympathomimetics,14 sedatives, sympathomimetics, tranquilizers, urinary tract drugs, vaginal
drugs, vitamins, and the like.
16 Exemplary drugs that are very soluble in water can be delivered
17 by dosage form 10 of this invention include prochlorperazine edisylate,18 ferrous sulfate, aminocaproic acid, potassium chloride, mecamylamine
19 hydrochloride, procainamide hydrochloride, amphetamine sulfate,
benzphetamine hydrochloride, isoproteronol sulfate, methamphetamine
21 hydrochloride, phenmetrazine hydrochloride, bethanechol chloride,
22 methacholine chloride, pilocarpine hydrochloride, atropine sulfate,
23 scopolamine bromide, isopropamide iodide, tridihexethyl chloride,
24 phenformin hydrochloride, methylphenidate hydrochloride, cimetidine
hydrochloride, theophylline cholinate, cephalexin hydrochloride, and
26 the like.
27 Exemplary drugs that are poorly soluble in water and that can be
28 delivered by dosage form 10 of this invention include diphenidol,
~ 1 336070 ARC 1480
1 meclizine hydrochloride, prochlorperazine maleate, phenoxybenzamine,
2 thiethylperazine maleate, anisindone, diphenadione erythrityl tetra-
3 nitrate, digoxin, isoflurophate, acetazolamide, methazolamide,
4 bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone
acetate, phenaglycodol, allopurinol, aluminum aspirin, methotrexate,
6 acetyl sulfisoxazole, erythromycin, progestins, esterogenic, progesta-
7 tional, corticosteroids, hydrocortisone, hydrocorticosterone acetate,
8 cortisone acetate, triamcinolone, methyltesterone, 17-beta-estradiol,
9 ethinyl estradiol, prazosin hydrochloride, ethinyl estradiol 3-methyl
ether, pednisolone, 17-alpha-hydroxyprogesterone acetate, 19-nor-
11 progesterone, norgestrel, norethindrone, norethindrone, norethindrone,
12 progesterone, norgesterone, norethynodrel, and the like.
13 Examples of other drugs that can be delivered by dosage form 10
14 inciude aspirin, indomethacin, naproxen, fenoprofen, sulindac,
indoprofen, nitroglycerin, propranolol, timolol, atenolol, alprenolol,
16 cimetidine, clonidine, imipramine, levodopa, chloropromazine, methyl-
17 dopa, dihydroxyphenylalanine, pivaloyloxyethyl ester of alpha-methyldopa,
18 theophylline, calcium gluconate, ketoprofen, ibuprofen, cephalexin,19 erythromycin, haloperidol, zomepirac, ferrous lactate, vincamine,
diazepam, captopril, phenoxybenzamine, nifedipine, diltiazem,
21 milrinone, madol, quanbenz, hydrochlorothiazide, and the like. The
22 beneficial drugs are know to the art in Pharmaceutical Sciences, 14th
23 Ed., edited by Remington, (1979) published by Mack Publishing Co.,
24 Easton, PA; The Drug, The Nurse, The Patient, Including Current Drug
Handbook, by Falconer et al., (1974-1976) published by Sunder Co.,
26 Philadelphia, PA; Medicinal Chemistry, 3rd Ed., Vol. 1 and 2, by
27 Burger, published by Wiley-Interscience, New York and in Physicians'
28 Desk Reference, 38 Ed., (1984) published by Medical Economics Co.,
11
1 336070 ARC 1480
1 Oradell, NJ.
2 The drug in dosage form 10 can be in various forms, such as
3 uncharged molecules, molecular complexes, pharmacologically acceptable
4 salts such as hydrochloride, hydrobromide, sulfate, laurate, palmitate,
phosphate, nitrite, borate, acetate, maleate, tartrate, oleate and
6 salicylate. For acidic drugs, salts of metals, amines or organic
7 cations, for example, quaternary ammonium can be used. Derivatives of
8 drugs such as ester, ethers and amides can be used. Also, a drug that
9 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
11 device is converted by enzymes, hydrolyzed by body pH or other
12 metabolic processes to the original biologically active form.
13 Drug 14 can be present in dosage form 10 neat or, as in a
14 presently preferred optional embodiment, with a binder, dispersant,
wetting agent, lubricant, or dye. Representative of these include
16 acacia, agar, calcium carrageenan, alginic acid, algin, agarose powder,
17 colloidal magnesium silicate, pectin, gelatin, and the like; binders
18 like polyvinyl pyrrolidone; lubricants such as magnesium stearate;
19 wetting agent such as fatty amines, fatty quaternary ammonium salts;
esters of sorbitol, and the like. The phrase drug formulation
21 indicates the drug is present in dosage form 10 neat or accompanied by
22 a binder, and the like. The amount of beneficial drug in dosage form
23 10 generally is from about 0.05 ng to 5 g or more, with individual
24 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
26 form can be administered once, twice or three times a day.
27 Dosage form 10 is manufactured from a well-mixed composition of
28 dosage-forming members. For example, a particular dosage form is made
-
~ 1 336070 ARC 1480
1 as follows: first, each of the ingredients comprising a dosage form2 are independently screened and then blended together, except for the
3 lubricant. Then, the homogeneous blend is wet granulated by adding a
4 solvent such as anhydrous ethanol, and the wet ingredients mixed until
a uniform blend is obtained by said process. Next, the wet blend is
6 passed through a screen and dried to evaporate the solvent. The
7 resulting granules are passed again through a sieve. Next, a small
8 amount of a finely divided lubricant is added to the dry granules and
9 the lubricant and granules blended to provide a uniform blend. Then,
the dosage forming composition is fed to the hopper of a compression
11 machine, and the composition pressed into a dosage form. Typically,12 about two tons of pressure are applied to yield the final dosage form.
13 The dosage form can be made also by a dry granulation process of
14 manufacture. The dry process co~prises first mixing all the dosage
forming ingredients, except for the lubricant, passing the mixed
16 ingredients through a grinding mill to a small mesh size, and then
17 transferring the sized powder to a dry compactor. The compactor
18 densifies the powder, which dense powder is then passed through a
19 sizing mill to regrind the composition. The composition is ground to
a small size, typically 20 mesh or smaller. Finally, a dry lubricant
21 is added and the ingredients blended to produce the final dosage
22 forming composition. Then, the composition is fed to a compaction
23 press and compressed into the dosage form 10.
24 Other standard manufacturing procedures can be used to form the
dosage form. For example, the various ingredients can be mixed with a
26 solvent by ballmilling, calendering, stirring or rollmilling, and then
27 pressed into a preselected sized and shaped dosage form 10.
28 Exemplary solvents suitable for manufacturing the dosage form
1 33607~
ARC 1480
1 include inorganic and organic solvents that do not adversely harm the
2 dosage form. The solvents broadly include a member selected from the
3 group consisting of alcohols, ketones, esters, ethers, aliphatic
4 hydrocarbons, halogenated solvents, cycloaliphatic solvents, aromatic,
heterocyclic solvents, and mixtures thereof. Typical solvents include
6 acetone, diacetone, methanol, ethanol, isopropyl alcohol, butyl
7 alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-
8 butylacetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane,
9 n-heptane, methylene dichloride, ethylene dichloride, propylene
dichloride, ethyl ether, mixtures such as acetone and ethanol, acetone
11 and methanol, methylene dichloride and methanol, ethylene dichloride
12 and methanol, and the like.
13 The following examples illustrate means and methods for carrying
14 out the present invention. The examples are merely illustrative and
they should not be considered as limiting the scope of the invention,
16 as these examples and other equivalents thereof will become more
17 apparent to those versed in the pharmaceutical dispensing art in the
18 light of the present disclosure, the drawings and the accompanying
19 claims.
EXAMPLE 1
21 A dosage form 10 comprising 29.5% isosorbide dinitrate (5,900 9);
22 29.5% lactose (5,900 9); 20% hydroxypropylmethylcellulose ether
23 (4,000 9) exhibiting a low 27,800 number average molecular weight and
24 20% hydroxypropylmethylcellulose ether (4,000 9) exhibiting a high
88,300 number average molecular weight, were presieved through a
26 40 mesh screen. The presieved ingredients were mixed in a twin shell
27 blender for 15 minutes and then transferred to a Hobart~ mixer. Next,
28 anhydrous methyl alcohol was added slowly with mixing to form a
14
1 336070 ARC 1480
1 uniform dough. The dough was passed through a 20 mesh screen and then
2 air dried for 2 hours at room temperature. The resulting granules
3 were repassed through the 20 mesh screen and dried at ambient
4 conditions overnight. Then, magnesium stearate, 1~, (200 9), was
passed through an 80 mesh per inch screen and then was blended into
6 the mixture in a twin shell mixer for 3 minutes. The resulting
7 granulation was compressed on a D3B Manesty~ Press at 2 tons pressure
8 using a 13/32 inch, (1.0 mm) round standard concave punch. The dosage
9 form 10 provided by the manufacture weight 271 mg, comprising 54.2 mg
of the hydroxypropylmethylcellulose ether having the low number
11 average molecular weight of 27,800; 54.2 mg of the hydroxypropyl-
12 methylcellulose having the high molecular number average molecular
13 weight of 88,300; and 80 mg of isosorbide dinitrate. The dosage forms
14 were placed in artificial gastric fluid and the release of drug
measured from the dosage form. The results of the test indicated 78%
16 of the drug was delivered in a 24 hour period at an average delivery
17 rate of isosorbide dinitrate of 2.5 mg per hour. Accompanying Figure
18 3 depicts the release rate pattern for the dosage form and
19 accompanying Figure 4 depicts the cumulative amount released over a
prolonged period of 24 hours.
21 EXAMPLE 2
22 A dosage form 10 comprising 15% of the enzyme inhibitor captopril,23 5% of a low 9,200 number average molecular weight hydroxypropylmethyl-
24 cellulose, 78% of a high 88,300 molecular weight hydroxypropylmethyl-
cellulose and 2% of stearic acid was prepared as follows: first,
26 1,500 9 of the enzyme inhibitor, 500 9 of the low number average
27 molecular weight hydroxypropylmethylcellulose, and 7,800 9 of the high
28 molecular weight hydroxypropylmethylcellulose are presieved through a
1 336070
ARC 1480
1 40 mesh screen and mixed for 15 minutes in a twin shell blender, and
2 the resulting mixture transferred to a Hobart~ blender. Then, anhydrous
3 ethanol was added slowly with mixing to form a damp mass. The ethanol
4 alcohol damp mass was passed through a 20 mesh screen and air dried
overnight. The dry product was repassed through a 20 mesh screen.
6 The resulting granules were lubricated with 200 9 of stearic acid by
7 passing the stearic acid through an 80 mesh screen over the granules
8 and mixing the granules in a twin shell blender for 3 minutes. Next,
9 the resulting granulation was compressed into dosage forms using a
Manesty press fitted with a standard concave round die of 3/8 inch
ll (0.95 mm) diameter under a compression head of 2 tons. The dosage
12 forms weighed 334 mg and contained 50 mg of captopril.
13 EXAMPLE 3
14 A dosage form 10 was prepared by following the procedure of
Example 2. The dosage form of this example comprises 53% ibuprofen;
16 20% of a hydroxypropylmethylcellulose having a number average molecular
17 weight of 9,200; 20% of a hydroxypropylmethylcellulose having a
18 number average molecular weight of 241,900; 5% hydroxypropylmethyl-
19 cellulose, and 2% magnesium stearate. The drug release rate pattern
for this dosage form is seen in Figure 5 and the cumulative amount
21 released over a prolonged period of time is seen in Figure 6.
22 EXAMPLES 4 T0 9
23 The procedures described above are followed for manufacturing
24 dosage forms comprising the following drugs and the cellulosic ethers:
(a) 120 mg of propanolol hydrochloride and 40 wt % of a cellulosic
26 ether formulation comprising 20 wt % hydroxypropylmethylcellulose
27 having a number average molecular weight of 241,900 and 20 wt % of a
28 hydroxypropylmethylcellulose having a number average molecular weight
16
1 336070 ARC 1480
1 of 9,200; (b) a dosage form comprising 50 mg of hydrochlorothiazide
2 and 60 wt % of a cellulosic ether formulation comprising 20 wt %
3 hydroxypropylmethylcellulose having a molecular weight of 132,500 and
4 40 wt % of a hydroxypropylmethylcellulose having a molecular weight of
9,200; (c) a dosage form comprising 75 mg of dipyridamole and 60 wt %
6 of a cellulosic ether composition comprising 20 wt % of a hydroxy-
7 propylmethylcellulose having a number average molecular weight of
8 88,300 and 40 wt % of a hydroxypropylmethylcellulose having a number
9 average molecular weight of 27,800; (d) a dosage form comprising 100
mg of verapamil hydrochloride and 50 wt % of a hydroxypropylmethyl-
11 cellulose having a number average molecular weight of 307,200 and 15
12 wt % of a hydroxypropylmethylcellulose having a number average molecular
13 weight of 19,600; (e) a dosage form comprising 50 mg of codeine
14 phosphate, 60 wt % of a hydroxypropy~methylcellulose having a number
average molecular weight of 241,900 and 15 wt % of a hydroxypropyl-
16 methylcellulose having a number average molecular weight of 9,200;
17 (f) a dosage form comprising 200 mg of nitrofurantoin, 15 wt % of a
18 hydroxypropylmethylcellulose having a number average molecular weight
19 of 241,900 and 45 wt % of a hydroxypropylmethylcellulose having a
2~ number average molecular weight of 19,600.
21 EXAMPLES 10 T0 15
22 The procedures described above are followed for manufacturing
23 dosage forms comprising the following drugs and cellulosic ether
24 formulation: (g) 250 mg of tetracycline; 5 wt % of hydroxypropyl-
methylcellulose having a number average molecular weight of 132,500,
26 and, 10 wt % of hydroxypropylmethylcellulose comprising a number
27 average molecular weight of 241,900; and 40 wt % of a hydroxypropyl-
28 methylcellulose comprising a number average molecular weight of 9,200;
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(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 % of hydroxypropylmethyl-
cellulose 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;
11 20 wt % of hydroxypropylmethylcellulose having a number average
12 molecular weight of 241,900; 20 wt % of hydroxypropylmethylcellulose
13 comprising a number average molecular weight of 307,200; and, 20 wt %
14 of a hydroxypropylmethylcellulose comprising a number average molecular
weight of 9,200, (k) 30 mg of morphine suifate; 60 wt % of hydroxy-
16 propylmethylcellulose having a number average molecular weight of17 132,500; 20 wt % of hydroxypropylmethylcellulose comprising a number
18 average molecular weight of 307,200; and, 10 wt % of a hydroxypropyl-
methylcellulose comprising a number average molecular weight of 9,200;
and, (1) 20 mg of nifedipine; 5 wt % of hydroxypropylmethylcellulose
21 having a number average molecular weight of 132,500; 10 wt ~ of
22 hydroxypropylmethylcellulose comprising a number average molecular
23 weight of 241,900; and, 75 wt % of a hydroxypropylmethylcellulose24 comprising a number average molecular weight of 9,200.
EXAMPLES 16 T0 21
26 The procedures described above are followed for manufacturing
dosage forms comprising the following drugs and cellulosic ether
28 formulation: (m) 250 mg of erthromycin stearate; 15 wt % of
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1 hydroxypropylmethylcellulose having a number average molecular weight
2 Of 241,900; 15 wt % of hydroxypropylmethylcellulose comprising a
3 number average molecular weight of 9,200; and, S wt % of a hydroxy-
4 propylcellulose comprising a hydroxypropoxy content of 7 to 10%; (n)
12 mg of chlorpheniramine maleate; 70 wt % of hydroxypropyl-
6 methylcellulose having a number average molecular weight of 241,900;
7 20 wt % of hydroxypropylmethylcellulose comprising a number average
8 molecular weight of 9,600; and, 5 wt % of a hydroxypropylcellulose
9 comprising a hydroxypropoxy content of 10 to 16%; (o) 8 mg of
brompheniramine maleate; 70 wt % of hydroxypropylmethylcellulose
11 having a number average molecular weight of 241,900; 20 wt % of
12 hydroxypropylmethylcellulose comprising a number average molecular
13 weight of 19,600; and, 5 wt % of a hydroxypropylcellulose consisting
14 of a hydroxypropoxy content of 13 to 16%; (p) a dosage form
comprising 8 mg of chlorpheniramine maleate; 120 mg of pseudoephedrine
16 sulfate; 25 wt % of hydroxypropylmethylcellulose consisting of a
17 number average molecular weight of 241,900; 25 wt % of hydroxypropyl-
18 methylcellulose consisting of a number average molecular weight of
19 27,800; and, 10 wt % hydroxypropylcellulose consisting of 10 to 13%
hydroxypropoxy; and (q) 150 mg of ranitidine hydrochloride; 35 Wt %
21 of hydroxypropoxymethylcellulose having a number average molecular
22 weight of 241,900; 15 wt % of hydroxypropoxymethylcellulose consisting
23 essentially of a low number average molecular weight of 19,600; and,
24 15 wt % hydroxypropylcellulose consisting of 13 to 16 hydroxypropoxy
content.
26 Dosage form 10 provided by the invention makes available a drug
27 delivery matrix suitable for retention in the stomach for gastric
28 retention over the drug releasing life time of the dosage system.
19
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1 Also, when all the drug is released, the system bfoerodes into
2 innocuous particles and dissolved polymers that pass from the
3 gastrointestinal tract. The dosage form of the invention comprising
4 higher concentrations of cellulosic ether formulations exhibit better
mechanical integrity and they better withstand the abrasive fluidic
6 action of the gastrointestinal tract. The dosage form of the
7 invention provides a broader range of erosion rates including
8 decreased and increased erosion rates in its use of low and high
9 numbe~ average molecular weight blends of cellulosic ethers. Another
advantage provided by dosage form 10 resulting from its use of high
11 number average molecular weight cellulose ethers is that it provides
12 more physical stability, improved resistance to thermal shock and it
13 helps lessen the incidence of matrix cracking over storage time, when
14 stored in fluctuating ambient temperature conditions. Also, the
dosage forms use of the high number average molecular weight cellulosic
16 ethers exhibit decreased tackiness in high humidity thereby preventing
17 sticking of one to another. The use of high number average molecular
18 weight cellulose ethers provides more rate control of the drug admini-
19 stration over time. The use of the cellulose ethers, especially the
high number average molecular wt cellulose ethers which swell
21 extensively when hydrated, lessens direct drug contact with mucosal
22 tissues and thereby lessens the incidence of tissue irritation for
23 irritating drugs.
24 The novel dosage form of this invention comprises means for the
obtainment of precise release rates in the environment of use while
26 simultaneously providing beneficial therapy to a recipient. While
27 there has been described and pointed out features of the invention as
28 applied to presently preferred embodiments, those skilled in the
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1 dispensing art will appreciate that various modifications, changes,
2 additions and omissions in the dosage form illustrated and described
3 can be made without departing from the spirit of this invention.
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