CA1331739C - Dosage form comprising parallel laminae - Google Patents
Dosage form comprising parallel laminaeInfo
- Publication number
- CA1331739C CA1331739C CA000563233A CA563233A CA1331739C CA 1331739 C CA1331739 C CA 1331739C CA 000563233 A CA000563233 A CA 000563233A CA 563233 A CA563233 A CA 563233A CA 1331739 C CA1331739 C CA 1331739C
- Authority
- CA
- Canada
- Prior art keywords
- lamina
- bilaminated
- environment
- delivering
- drug
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
Abstract
ABSTRACT OF THE INVENTION
A bilaminated dosage form is disclosed comprising at least 30 weight percent cellulose ether, a first lamina and a second lamina with each lamina comprising a different cellulose ether formulation, and a drug in at least one of the lamina.
A bilaminated dosage form is disclosed comprising at least 30 weight percent cellulose ether, a first lamina and a second lamina with each lamina comprising a different cellulose ether formulation, and a drug in at least one of the lamina.
Description
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This invention pertains to a sustatned release dosage form. More 11 parttcularly, the invent~on concerns a dosage form comprising a ftrst12 lamina and a second lamina ~n laminated arrangement. The f1rst lamina13 comprises a cellulose ether composttion and the second lamtna com~
14 prises a different cellulose ether compostt~on wtth the amount of cellulose ether composttton ln the dosage form exceedlng thirty weight 16 percent. A dosage amount of drug ts present in at least one of the 17 lam~na.
21 Dosage forms, often manufactured tn the shape of a compressed 22 stngle layered tablet, compristng a cellulose ether are known to the 23 pharmaceutkal drug dispenstng art. For example, dosage forms com-24 pr1sing the cellulose ether hydroxypropylmethylcellulose are disclosed ~n United States Nos. 3,870~790; 4,140,755; 4,167,588; 4,226,849;
26 4,259,314; 4,357,469; 4,369,172; 4,389,393 and 4,540,566.
27 While the dosage forms known to the prior art use the cellulose 28 ether hydroxypropylmethylcellulose for the manufacture of the dosage .... .. ... ..... . . .. ...... .. . . . .. . . .. .. . . . .
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; ~ 3 3 ~ 7 ^J ~ ARC 1397 1 form, there are major disadvantages associated with the prior art 2 dosage forms. For instance, the mechanical integrity of some prior 3 art dosage forms often is insufficient to provide both a sustained and 4 a controlled release of drug over a prolonged period of time. The ~ prior art dosage forms often exhibit insufficient mechanical integrity, 6 that is, the ability to stay together in a moving fluid environment, 7 such as the gastrointestinal tract, without prematurely breaking-up 8 and prematurely releasing all of its drug. The above-mentioned 9 desirable properties are not apparent in the prior art dosage forms that undergo substantial disintegration in less then eight hours in a 11 fluid environment of use. -12 Another disadvantage associated with the prior art dosage forms 13 is that the dosage forms frequently exhibit an unwanted, variable and 14 difficult to reproduce release rate pattern. For example, prior art dosage forms comprising a small amount of a cellulose ether frequently 16 exhibit this behavior, such as those having less than five weight 17 percent hydroxypropylmethylcellulose having a molecular weight greater 18 than 50,000 and blended with a hydroxypropylmethylcellulose having a 19 molecular weight much less than 50,000 grams per mole. The presence of the high molecular weight polymer in the dosage form masks the 21 release characteristics of the low molecular weight polymer in the 22 dosage form resulting in an erratic release rate pattern which is 23 difficult to reproduce from losage form to dosage form and from batch 24 to batch of dosage forms.
Still other disadvantages associated with the prior art dosage 26 forms are that the dosage form over its shelf-life can exhibit an 27 unpredictable change in its release rate characteristics; the prior 28 art dosage form when tested in an in vitro test that substantially 1~31 739 reproduces the in vivo environment of the gastrointestinal tract often release the drug at a great rate of release in vivo rather than in vitro, which difference can be attributed to a premature disintegration of the prior art dosage form; and, the prior art dosage form in a high shear environment releases its drug too quickly, usually in less than six hours and it is therefore not adapted to prolonged release.
Thus, in the light of the above presentation it will -r.'~.
be appreciated by those versed in the dispensing art that if a novel dosage form is made available to the medical and phar-maceutical arts for dispensing difficult to deliver drugs free of the tribulation known to the prior art, such a dosage form would have a definite use and would also be a valuable contribut-ion 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 desirable release rate 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 also represent an advancement in the pharmaceutical arts.
OBJECTS OF THE INVENTION
Accordingly, this invention seeks to provide a novel dosage form for the controlled delivery of a beneficial drug to ., , ... ,. ,-.. ... .
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1 3 3 3 7 ^3 9 67696-119 a biological environment of use, and which dosage form represents an improvement and an advancement in the delivery arts.
Another aspectof-:the invention is to seek to provide both a novel and a useful dosage form that overcomes the difficult-ies associated with the prior art.
Another aspect of the invention is to seek to provide a dosage form comprising a first lamina and a second lamina com-prising a cellulose ether composition with at least one of the laminae comprising a beneficial drug.
Another aspect of this invention is to seek to provide a dosage form that is useful for delivering a beneficial drug formulation that is difficult to deliver and now can be delivered by the dosage form of this invention at a meaningful therapeutic rate over a prolonged period of time.
Another aspect of the present invention is to seek to provide a dosage form comprising a beneficial drug that can be from insoluble to very soluble in an aqueous fluid, and which drug can be delivered by the dosage form at an in vitro rate of release that is parallel by the in vivo rate of release.
Another aspect of this invention is to seek 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 controlled and continuous rate for a part-icular time period, the use of which requires intervention only for initiation and possible termination of the regimen.
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Another aspect of the present invention i~ to seek to provide a dosage form for delivering a drug in the gastro-lntestinal tract that substantially avoids a premature break-up and undergoes a change ln its integrity at a rate corresponding to the rate of release of drug over a prolonged period of time at least eight hours.
Other aspectsr features and advantages of the invention will be more apparent to those versed in the dispensing art from the following detailed specificatlon taken in con~unction with the drawings and the claims.
The invention therefore provides a bilaminated system for delivering a beneficial drug to an environment of use, the bilaminated system comprising~ 30 to 90 weight percent of a cellulose ether composition; said composition comprising a first lamina comprislng 30 to 80 weight percent of a cellulose ether ~elected from the groups of hydroxypropylmethylcellulose ethers having a number average molecular weight of 9,000 to 250,000 and a dosage amount of from about 0.05 ng to 5 g of a beneficial drug;
and, a second lamina in contacting arrangement with the first lamina, the second lamina compriæing 2 to 50 weight percent of a different cellulose ether composition comprising a hydroxypropyl-cellulose comprising a hydroxypropoxyl content of 7~ to 16%.
In a preferred embodiment the second lamina comprises a hydroxypropylmethylcellulose ether having a number average molecular weight of from about 9,000 to 250,000.
The invention also provides a bilaminated system for delivering a beneficial drug to an environment of use, the 4a .:
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bllaminated system comprising~ (a) 30 to 90 weight percent of a cellulose ether composition; (b) a first lamlna comprising 30 to 80 weight percent of a cellulose ether selected from the group of hydroxypropylmethylcellulose ethers havin~ a number average molecular weight of 9,000 to 250,000; and (c) a second lamlna ln parallel mated relation with the first lamina, the second lamina comprising 2 to 50 weight percent of a cellulose ether composltion comprising a hydroxypropylcellulose comprising a hydroxypropoxyl content of 7% to 16% and a dosage unit amount of from about 0.05 ng to 5 g of a beneficial drug.
The invention also provldes a bilaminated system for delivering a beneficial drug to an environment of use, wherein the bilaminated system comprlses~ (a) 30 to 90 weight percent of a cellulose ether composltion preæent in a first lamina and a second lamina; wherein the first lamina comprises 30 to 80 weight percent of a cellulose ether hydroxypropylmethylcellulose having a number average molecular weight of from 9,000 to 250,000; and wherein the second lamina comprises 2 to 50 welght percent of a cellulose ether hydroxypropylmethylcellulose havlng a dlfferent number average molecular ~elght of from 9,000 to 250,000, a dosage amount of from about 0.05 ng to 5 g of a beneficial drug, and 18 thlcker than the flrst lamina.
The invention further provides a bilaminated system for delivering a beneficial drug to an environment of use, wherein the bilaminated system comprises. (a) 30 to 90 weight percent of a cellulose ether composition comprislng a first lamina and a second lamlna; said firæt lamlna comprisin~ 30 to 80 welght percent of a 4b p-:
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~ellulose ether hydroxypropylmethylcellulose ether havlng a number average molecular weight of from 9,000 to 2S0,000 and a dosage unit amount of from about 0.05 ng to 5 g of a beneficlal drug; and wherein the second lamlna comprises 2 to 50 weight percent of a cellulose ether hydroxypropylmethylcellulose having a dlfferent number average molecular weight of from 9,000 to 250,000.
The invention additionally provides a bllaminated system for delivering a beneficial drug to an environment of use, the bllaminated system comprlsing. ~a) a cellulose ether composltion comprising. (b) a first lamina comprising up to 80 weight percent of a cellulose ether ~elected from the group consistlng of hydroxypropylmethylcellulose ethers comprising a degree of polymerlzatlon of 40 to 1600, a vlsco~lty of 2 to 225,000 and a number average molecular welght of 9,000 to 307,200; and Ic) a second lamlna ln parallel mated relation wlth the flrst lamlna, the second lamlna comprlsing up to S0 weight percent of a cellulose ether compositlon comprislng a hydroxypropylcellulose compri~ing a hydroxypropoxyl content of 7 percent to 16 percent, and a do~age unlt amount of 25 ng to 1.5 g of a beneflclal drug.
The lnvention also provldes a bllaminated system for deliverlng a beneficial drug to an environment of use, wherein the bilaminated ~ystem comprises: (a) at least 30 weight percent of a cellulose ether compositlon present ln a first lamlna and a second lamlnaS wherein the fir~t lamlna comprl~es up to 85 welght percent of at least one hydroxypropylmethylcellulose compri~ing a number average molecular weight of from 9,000 to 250,000; and whereln the second lamlna comprlses up to 85 welght percent of hydroxypropyl-4c ~ 1~3~ 739 methylcellulose comprlsing a dlfferent number average molecular welght of from 9,000 to 250,000 and a dosage amount of from 25 ng to 1.5 g of a beneflcial drug.
The lnventlon further provldes a bllaminated system for deliverlng a beneficlal drug to an environment of use, wherein the bllaminated system comprises~ ~a) 30 weight percent to 90 weight percent of a cellulo~e ether compositlon comprlslng a fir~t lamina and a second lamina; said first lamina comprising a cellulose ether ~elected from a hydroxypropylmethylcellulo~e ether comprising a number average molecular weight of from 9,000 to 250,000 and a dosage unlt amount of 25 ng to 1.5 g of a beneficial drug; and wherein the second lamina comprises a cellulose ether selected from a hydroxypropylmethylcellulose ether comprlsing a different number average molecular weight of from 9,000 to 250,000.
The invention additlonally provldes a bilaminated system for delivering the beneficial drug lbuprofen to an environment of use, wherein the bilaminated system comprise3~ a first lamlna . ;~
comprising up to 80 weight percent of a hydroxypropylmethyl-cellulose comprtslng a degree of polymerization of about 50 to 1260, a viscosity of about 3 to 100,000 centipoises and a number average molecular weight of 9,000 to 250,000, and a dosage amount of from 25 ng to 1.5 g of lbuprofen; and a second lamina comprising up to 50 welght percent of a hydroxypropylcellulose comprising from 7 percent to 16 percent hydroxypropoxyl, and a dosage amount of from 25 ng to 1.5 g of ibuprofen. ~.
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133~ 739 The inventlon also provides a bilaminated system for dellverlng a beneficial drug to an environment of use whereln the bllamlnated system comprlses- a flrst lamlna comprlslng up to 80 weight percent of a hydroxy-propylmethylcellulose comprlslng a degree of polymerization of about 50 to 1260~ a viscosity of about 3 to 100,000 centipolses and a number average molecular weight of 9,000 to 250,000; a second lamina comprlsing a hydroxypropyl-cellulose comprlslng a hydroxypropoxyl content of 7% to 16%; and whereln the bllamlnated system comprlses from 25 ng to 1.5 g of a beneficlal drug selected from the group conslstlng of clmentldlne, umetldlna, ranltldlne, naproxen, estrogenic, progestlatlonal, captopril, diltlazom, and isosorbide dinitrate.
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,.. ,. . -.. , . - - - - .. - ~ . . , . . ... , -1~3~ ~39 3 In the draw~ngs, wh1ch are not drawn to scale but are set forth 4 to 111ustrate var10us embod1ments of the lnvent10n, the draw1ng f1gures are as follow:
6 F1gure I ls a slde, elevated vlew of a dosage form prov1ded by 7 th1s lnventlon, des19ned and shaped for orally adm1n1ster1ng a bene-8 flclal drug to the gastro1ntest1nal tract of a rec1p1ent;
9 F1gure 2 1s an opened v1ew of the dosage form of F19ure I through 2-2 of the dosage form for 111ustrat1ng the 1nternal structure of the II dosage form; and, I2 F1gures 3, 4, 5 and 6 dep1ct release patterns over t1me for 13 dosage forms prov1ded by th1s 1nvent10n.
14 In the draw1ngs and 1n the speclf1cat10n 11ke parts 1n related f1gures are 1dent1f1ed by 11ke numbers. The terms appearlng earl1er 16 1n the speclf1cat10n and 1n the draw1ngs, as weil as embodlments 17 thereof, are further descr1bed elsewhere 1n th1s spec1f1cat10n.
Turn1ng now to the drawlng f1gures 1n detall, whlch drawlng 21 f1gures are an example of the dosage forms provlded by the 1nvent10n, 22 and whlch example ~s not to be construed as llmltlng, one example of 23 thls dosage form ls lllustrated ln Flgure I and ln Flgure 2 and 24 deslgnated by the nùmeral IO. In Flgure I, dosage form IO comprlses body 11. Dosage form IO can be manufactured 1nto var10us s1zes and 26 shapes adapted for oral adm1ttance 1nto the gastro1ntest1nal tract of 2~ a warm-blooded an1mal. For example, dosage form IO can be of any 28 convenlent geometrlc shape, such as elllpsoid, bean-shaped, clrcular-` i,~
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1 shaped, rectangular-shaped, caplet-shaped; and the like.
2 In Figure 2, dosage.form 10 is seen in opened section through 2-2 3 of Figure 1. In Figure 2 dosage form 10 comprises body 11, which body 4 11 comprises a first lamina 12 and a second lamina 13. First lamina 12 and second lamina 13 are laminated together and they function in 6 concert as a single dosage form 10. Dosage form 10 comprises at least 7 one beneficial drug 14 present in at least one of first lamina 12, or 8 present in second lamina 13 or, optionally, present in both first 9 lamina 12 and second lamina 13. Dosage form 10 comprising lamina 12 and lamina 13 comprises a non-toxic cellulose ether composition and, 11 optionally, ot.her pharmaceutically acceptable laminae forming ingre-12 dients. .
13 Dosage form 10 comprises from about 30 weight percent to 90 14 weight percent (wt X) of a cellulose ether composition based on the total weight of the dosage form. In a presently preferred embodiment 16 the cellulose ether composition of dosage form 10 comprises at least 17 one hydroxypropylmethylcellulose and at least one hydroxypropylcellulose.
18 The hydroxypropylcellulose operable for the purpose of this invention 19 comprises a hydroxypropoxyl content of 4X to 12X and a methyloxy content 19% to 24X, and the hydroxypropylcellulose comprises a hydropropxyl . .
21 content of from 7X to 16X. Exemplary hydroxypropylmethylcellulose 22 that can be used for forming dosage form 10 comprises at least one of 23 a member selected from the group consisting of (a) a hydroxypropyl- ~ :
24 methylcellulose having a degree of polymerization (DP) of about 50, a : -. .
viscosity of about 3 centipoises of a 2X solution in water, a number 26 average molecular weight of about 9,200; (b) a hydroxypropylmethyl-27 cellulose having a DP of 100, a viscosity of 35 centipoises (cps), a :~
28 number averaye molecular weight (MWn) of 19,600; (c) a hydroxypropyl-'': ' ' : ' i.
~33~ 739 1 methylcellulose comprising a DP of 145, a viscosity of 100 cps, a MWn 2 of 27,800; (d) a hydroxypropylmethylcellulose comprising a DP of 460, 3 a viscosity of 4,000 cps, a MWn of 88,300; (e) a hydroxypropylmethyl-4 cellulose comprising a DP of 690, a viscosity of 15,000 cps, a MWn of 132,500; and (f) a hydroxypropylmethylcellulose having a DP of 1260, a 6 viscosity of 100,000 cps, a MWn of 242,000.
7 The hydroxypropyTcellulose used for the purpose of this invention 8 is a nonionic ether with neutral pH range and a hydroxypropyl content 9 of 7% to 16X, with more specific hydroxypropylcelluloses comprising a hydroxypropyl content of 7% to 10X; a hydroxypropyl content 10X to 11 13X, and a hydroxypropyl content 13% to 16%. In the above specifica-12 tion DP is the degree of polymerization indicating the number of 13 monomers polymerized.in the final polymer and MWn is the number 14 average molecular weight of the polymer.
G~her hydroxypropylmethylcellulose ethers that can be for the 16 purpose of providing dosage form 10 are (9) a hydroxypropylmethyl-17 cellulose comprising a DP of 59, a viscosity of 6 and a MWn of 11,900;
18 and (h) a hydroxypropylmethylcellulose possessing a DP of 860, a 19 viscosity of 30,000 and a MWn of 165,000. The examples as set forth above generally comprise a hydroxypropylmethylcellulose comprising a 21 DP of 40 to 1600, a viscosity of 2 to 225,000 and a MWn of from 9,000 ~.
22 to 307,200, and mixtures thereof.
23 Lamina 12 of dosage form 10 comprises at least one hydroxypropyl-24 methylcellulose in an amount of at least 30 wt X to 80 wt X based on the total weight of dosage form 10, or at least 40 wt X to 80 wt X
26 based on the total weight of lamina 12. Lamina 13 of dosage form 10 27 comprises at least one hydroxypropylcellulose in an amount of at least 28 2 wt X to 20 wt X based on the total weight of dosage form 10, or ~ .
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1 about 10 wt g to S0 wt % based on the total weight of lamina 13.
2 Lamina 12 and lamina 13 can comprise each a single cellulose ether, a 3 blend of two cellulose ethers, a tertiary blend comprising three 4 cellulose ethers, and the like.
Representative of cellulose ether compositions comprising lamina 6 12 are (a) a composition comprising a hydroxypropylmethylcellulose 7 having a MWn of about 242,000; (b) a hydroxypropylmethylcellulose 8 having a MWn of about 132,500; (c) a composition comprising both a g hydroxypropylmethylcellulose-having a MWn of 9,200 and a hydroxy-~ ~'f2, 000 propylmethylcellulose having a MWn of 212,00; (d) a composition 11 comprising a hydroxypropylmethylcellulose having a MWn of 19,600 and a 12 hydroxypropylmethylcellulose having a MWn of about 242,000; (e) a 13 composition comprising a hydroxypropylmethy1cellulose having a MWn of 14 about 27,800 and a hydroxypropylmethylcellu1Ose having a MWn of about 242,000; (f) a composition comprising a hydroxypropylmethylcellulose 16 having a MWn of 88,300 and a hydroxypropylmethylcellulose having a MWn 17 of about 242,000; (9) a composition comprising a hydroxypropylmethyl-18 cellulose having a MWn of 132,500 and a hydroxypropylmethylcellulose 19 hav~ng a MWn of about 242,000; (h) a composition comprlsing a hydroxypropylmethylcellulose having a MWn of 9,200, a hydroxypropyl- -:~
21 methylcellulose having MWn of 19,600 and a hydroxypropylmethylcellulose .. . ~. , ...................................... -- 22 having a MWn of about 242,000; (i) a composition comprising a . .. : ~-23 hydroxypropylmethylcellulose having a MWn of g,200, a hydroxypropyl-24 methylcellulose comprising MWn of 88,300 and a hydroxypropylmethyl-cellulose having a MWn of about 242,00; (j) a composition comprising 26 a hydroxypropylmethylcellulose cellulose having a MWn of 19,600, :~
27 hydroxypropylmethylcellu;ose having a MWn of about 27,800 and a Z8 hydroxypropylmethylcellulose haviny a MWn of about 242,000; and the ;: ;
1~3~ ~9 1 like. A binary composition comprising two cellulose ethers in a 2 presently preferred embodiment comprises from 1 wt % to 99 wt % of one 3 cellulose ether and from 99 wt % to 1 wt % of the other cellulose 4 ether. A tertiary composition comprises from 1 wt % to 99 wt % of each cellulose ether with a total cellulose ether content of up to 6 80 wt % based on the total weigh of lamina 12.
7 . Lamina 13, in one presently preferred embodiment, comprises from 8 2 wt g to 30 wt % of a single low substituted hydroxypropylcellulose 9 ether having a hydroxypropyl content of 7~ to 16%. Lamina 13 in other preferred embodiments comprises (a) a binary blend of a hydroxypropyl-11 cellulose having a hydroxypropyl content of 7 to 10 wt X blended with 12 a hydroxypropylcellulose having a hydroxypropyl content of 13 to 16 wt %;
13 (b) a composition comprising a hydroxypropylcellulose having a 14 hydroxypropyl content of 7 to 10 wt g blended with a hydroxypropyl-cellulose having a hydroxypropyl content of about 10 to 13 wt %; (c) 16 a composition comprising a hydroxypropylcellulose and a hydroxypropyl-17 methylcellulose having a MWn of 9,200; (d) a composition comprising a 18 hydroxypropylcellulose and a hydroxypropylmethylcellulose having a MWn 19 of about 19,600; (e) a hydroxypropylcellulose and a hydroxypropyl-methylcellulose having a MWn of 27,800; (f) a composition comprising 21 a hydroxypropylcellulose and a hydroxypropylmethylcellulose having a 22 MWn of about 88,300; (9) a composition comprising a hydroxypropyl-23 cellulose and a hydroxypropylmethylcellulose having a MWn of about 24 132,500; (h) a composition comprising a hydroxypropylcellulose and a hydroxypropylmethylcellulose having a MWn of about 242,000; and the 26 like.
27 Dosage form 10 comprises a beneficial drug 14. Drug 14 can be 28 presented in lamina 12; drug 14 can be presented in lamina 13, and .
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1 drug 14 can be presented in both lamina 12 and lamina 13. In this 2 specification the term "drug" includes any physiologically or pharma-3 cologically active substance that produces a local or systemic effect 4 in animals, including warm-blooded mammals, humans and primates;
avians; household, sport and farm animals; laboratory animals;
6 fishes, reptiles and zoo animals. The term "physiologically", as used 7 herein, denotes the administration of a drug to produce generally 8 normal levels and functions in a warm-blooded animal. The term 9 "pharmacologically" generally denotes variations in response to the amount of drug administered to the host. See Stedman's Medical 11 Dictionary, 1966, published by Williams and Wilkins, Baltimore, MD.
12 The active drug that can be delivered includes inorganic and 13 organic compounds without limitation, including drugs that act on the 14 peripheral nerve, adrenergic receptors, cholinergic receptors, nervous system, skeletal muscles, cardiovascular system, smooth muscles, blood 16 circulatory system, synaptic sites, neuroeffector junctional sites, ;~
17 endocrine system, hormone systems, immunological system, organ systems, 18 reproductive system, skeletal system, autocoid systems, alimentary and 19 excretory systems, inhibitors of autocofds and histamine systems. The active drug that can be delivered for acting on these recipients -21 include anticonvulsants, analgesics, anti-parkinsons, anti-inflammatories, 22 anesthetics, antimicrobials, antimalarials, antiparasitic, antihyper-23 tensives, angiotensin converting enzyme inhibitor, antihistamines, ~ -~
24 antipyretics, alpha-adrenergic agnoist, alpha-blockers, biocides, bactericides, bronchial dilators, beta-adrenergic stimulators, beta-26 a,drenergic blocking drugs, contraceptives, cardiovascular drugs, 27 calcium channel inhibitors, depressants, diagnostics, diuretics, 28 electrolytes, hypnotics, hormonals, hyperglycemics, muscle contrac-~ 3 ~
1 tants, muscle relaxants, opthalmics, psychic energizers, parasym-2 pathomimetics, sedatives, sympathomimetics, tranquilizers, urinary 3 tract drugs, vaginal drugs, vitamins, and the like.
4 Exemplary drugs that are very soluble in water can be delivered by dosage form 10 of this invention include prochlorperazine edisylate, 6 ferrous sulfate, aminocaproic acid, potassium chloride, mecamylamine 7 hydrochloride, procainamide hydrochloride, amphetamine sulfate, 8 benzphetamine hydrochloride, isoproteronol sulfate, methamphetamine g hydrochloride, phenmetrazine hydrochloride, bethanechol chloride, methacholine chloride, pilocarpine hydrochloride, atropine sulfate, 11 scopolamine bromide, isopropamide iodine, tridihexethyl chloride, 12 phenformin hydrochloride, methylphenidate hydrochloride, cimetidine 13 hydrochloride, theophylline cholinate, cephalexin hydrochloride, and -- ;
14 the like.
Exemplary drugs that are poorly soluble in water and that can be 16 dellvered by dosage form 10 of this invention include diphenidol, 17 meclizlne hydrochloride, prochlorperazine maleate, phenoxybenzamine, 18 thiethylperazine maleate, anisindone, diphenadione, erythrityl 19 tetranitrate, digoxin, isoflurophate, acetazolamide, methazolamide, bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone acetate, 21 phenaglycodol, allopurinol, aluminum aspirln, methotrexate, acetyl 22 sulfisoxazole, erythromycin, progestins, esterogenic, progestational, 23 corticosteroids, hydrocortisone, hydrocorticosterone acetate, cortisone 24 acetate, triamcinolone, methyltesterone, 17-beta-estradiol, ethinyl estradiol, prazosin hydrochloride, ethinyl estradiol 3-methyl ether, 26 pednisolone, 17alpha-hydrocyprogesterone acetate, l9-nor-progesterone, 27 norgestrel, norethindrone, progesterone, norgesterone, norethynodrel, 28 and the like.
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1 Examples of other drugs that can be delivered by dosage form 10 2 include aspirin, indomethacin, naproxen, fenoprofen, sulindac, 3 indoprofen, nitroglycerin, propranolol, timolol, atenolol, alprenolol, 4- cimetidine, clonidine, imipramine, levodopa, chloropromazine, methyl-dopa, dihydroxyphenylalnine, pivaloyloxyethyl ester of alpha-methyldopa, 6 theophylline, calcium gluconate, ketoprofen, ibuprofen, cephalexin, 7 erythromycin, haloperidol, zomepirac, ferrous lactate, vincamine, 8 diazepam, captopril, phenoxybenzamine, nifedipine, diltiazem, verapamil, 9 milrinone, madol, quanbenz, hydrochlorothiazide, and the like. The beneficial drugs are known to the art in Pharmaceutical Sciences, 14th 11 Ed., edited by Remington, (1979) published by Mack Publishing Co., 12 Easton, PA; The Drug, The Nurse, The Patient, ~ncluding Current Drug ;~
13 Handbook, by Falconer et al., (1974-1976) published by Sunder Co., 14 Philadelphia, PA; Medicinal Chemistry, 3rd Ed., Vol. 1 and 2, by Burger, published by Wiley-Interscience, New York and in Physicians' 16 Desk Reference, 38 Ed., (1984) published by Medical Economics Co., 17 Oradell, NJ.
18 The drug in dosage form 10 can be in various forms, such as 19 uncharged molecules, molecular complexes, pharmacologically acceptable salts such as hydrochloride, hydrobromide sulfate, laurate, palmitate, -~
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21 phosphate, nitrite, borate, acetate, mal,eate, tartrate, oleate and 22 salicylate. For acidic drugs, salts of metals, amines or organic ~-~
23 cations; for example, quaternary ammonium can be used. Derivatives of 24 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 26 derivative thereof to serve as a solute, and on its release from the 27 device is converted by enzymes, hydrolyzed by body pH or other 28 metabolic processes to the original biologically active form.
f' i~3~ 739 1 Drug 14 can be present in dosage form 10 neat or, as in a 2 presently preferred optional embodiment, w~th a binder, dispersant, 3 wetting agent, lubricant or dye. Representative of these include 4 acacia, agar, calcium carrageenan, alginic acid, algin, agarose powder, collagen, colloidal magnesium silicate, pectin, gelatin, and 6 the like; binders like polyvinyl pyrrolidone; lubricants such as 7 magnesium stearate; wetting agent such as fatty amines, fatty 8 quaternary ammonium salts, ester of sorbitol, and the like. The 9 phrase drug formulation indicates the drug is present in dosage form 10 neat or accompanied by a binder, and the like. The amount of 11 beneficial drug in dosage form 10 generally is from about 0.05 ng to 12 5 9 or more, with individual dosage form 10 comprising for example, 13 25 ng, 1 mg, 5 mg, 10 mg, 25 mg, 250 mg, 750 mg, 1.0 9, 1.2 9, 1.5 9, 14 and the like. In a presently preferred embodiment lamina 12 comprises more drug 14 than does lamina 13; however, the amount of drug 14 can 16 be the same. G~nerally, the amount of drug will be in a ratio in 17 lamina 12 to lamina 13 in a ritio of 1:1 to 15:1. The dosage form can 18 be administered once, twice or three times daily.
19 Dosage form 10 is manufactured by first making independently lamina 12, or lamina 13, which laminae are made from a well-mixed 21 composition of laminae forming member.s. For example, a particular 22 lamina is made as follows: first, each of the lngredients comprising Z3 a lamina are independently screened and then blended together, except 24 for the lubricant. Then the homogeneous blend is wet granulated by adding a solvent such a anhydrous ethanol, and the wet ingredients 26 mixed until a uniform blend is obtained by said process. Next, the 27 wet blend is passed through a screen and dried to evaporate the solvent.
28 The resulting granules are passed again through a sieve. Next, a .~. .. ;~. . : :
3~ 7~9 l small amount of a fine~y divided lubricant is added to the dry granules 2 and the lubricant and granules blended to provide a uniform blend.
3 Next, the above described procedure is repeated for the other lamina.
4 Next, the two lamina forming compositions are fed independently into separate hoppers of a compression machine. The machine lightly 6 compresses one lamina and then adds the second lamina forming granula-7 tion in laminating arrangement to the first lamina and then compresses 8 the two laminae together. Typically, about two tons of pressure are 9 applied to laminate the laminae and yield the final dosage form.
The dosage form can be made also by a dry granulation process of ll manufacture. The dry process comprises first mixing, for a particular 12 lamina, all the lamina forming ingredients, except for the lubricant, 13 passing the mixed ingredients through a grinding mill to a small mesh 14 size, and then transferring the sized powder to a dry compactor. The compactor densifies the powder, which dense powder is then passed 16 through a sizing mill to regrind the composition. The composition is 17 - ground to a small size, typically 20 mesh or smaller. Finally, a dry 18 lubricant is added and the ingredients blended to produce the final 19 lamina forming composition. The second lamina is made in a similar manner. Then, each composition is fed independently to the compaction 21 press and compressed into the dosage form comprising parallel laminae.
h 22 Other standard manufacturing procedures can be used to form the 23 laminae and the laminated dosage form. For example, the various 24 ingredients can be mixed with a solvent by ballmilling, calendering, stirring or rollmilling, and then pressed into a preselected sized and 26 shaped lamina. A second lamina made in a like process comprising a 27 shape and size corresponding to the first lamina is then laminated 28 with pressure to the first lamina to yield the dosage form.
i;: ':: - - :, -~ 13~ 73~
1 Exemplary solvents suitable for manufacturing the lamina include 2 inorganic and organic solvents that do not adversely harm the lamina, 3 the lamina forming ingredients and the final dosage form. The sol-4 vents broadly include a member selected from the group consisting of alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated 6 solvents, cycloaliphatic solvents, aromatic, heterocyclic solvents, 7 and mixtures thereof. Typical solvents include acetone, diacetone, 8 methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, 9 ethyl acetate, isopropyl acetate, n-butylacetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, h-heptane, methylene 11 dichloride, ethylene dichloride, propylene dichloride, ethyl ether, 12 mixtures such as acetone and ethanol, acetone and methanol, methylene 13 dichloride and methanol, ethylene dichloride and methanol, and the 14 like.
The following examples illustrate means and methods for carrying 16 out the present invention. The examples are merely illustrative and 17 they should not be considered as limiting the scope of the invention, 18 as these examples and other equivalents thereof will become more 19 apparent to those versed in the pharmaceutical dispensing art in the light of the present disclosure, the drawings and the accompanying 21 claims.
h ' ';
23 A lamina forming composition comprising 29.5 wt % isosorbide 24 dinitrate, 29.5 wt X lactose, 40.0 wt X hydroxypropylmethylcellulose, having an average molecular weight of 27,800 and 1.0 wt X magnesium 26 stearate is compressed into a first lamina. Next, a second lamina 27 forming composition comprising 97.0 wt X hydroxypropylmethylcellulose 28 having a molecular weight of 242,000, 1.0 wt g ferric oxide and 2.0 wt g - 1~33 739 1 magnesium stearate is deposited over the first lamina and the second 2 lamina laminated to the first lamina with a compression of 2 tons.
3 The first lamina weighed 271 mg and the second lamina weighed 100 m~.
4 The laminae are compressed in a 13/32 inch round dye. The dosage form released pattern measured in a shaking flask containing water and a 6 few marbles for producing mechanical abuse, exhibited a cumulative 7 release of 98X over a 24 hour period of time. Lamina 1 comprising the 8 lower molecular weight cellulose either erodes in the aqueous environ-9 ment and administers the drug over time. Lamina 2 comprising the higher molecular weight ether maintains its mechanical integrity 11 longer because of its composition. Lamina 2 serves as a support 12 member for lamina 1.
14 The procedures described above are followed in this example.
First a lamina forming composition comprising 58.0 wt % acetaminophen, 16 25.0 wt X hydroxypropylmethylcellulose having a number average molecular 17 weight of 242,000, a number average degree of polymerization of about 18 1260 and a viscosity of lO0,000 centipoises, 15.0 wt % hydroxypropyl-19 methylcellulose having a number average molecular weight of 9,200 a number average degree of polymerization of 50 and a viscosity of 3 21 centipoises, and 2.0 wt X magnesium stearate is compressed into a 22 first lamina. The lamina weighed 604 mg. Then, a second lamina 23 forming composition weighing 170.5 mg and comprising 88.0 wt %
24 acetaminophen, 10.0 wt X hydroxypropylcellulose with 10-13 wt X
hydroxypropxy content, and 2.0 wt % magnesium stearate is laminated to 26 the first lamina to yield the dosage form. The release rate measured 27 in mg/hr for this bilaminated dosage form is depicted in Figure 3.
28 The cumulative amount of acetaminophen released over a percent basis 133~ 739 1 over a a 12 hour period of time is depicted in Figure 4. The dosage 2 form exhibited in initial release of 200 mg drug within the first 3 hour, followed by a mean release rate of 24 mg per hour for the next 4 eleven hours.
6 The procedure described above is followed in this example. A
7 first lamina forming composition weighing 690 mg and comprising 58.0 8 wt % ibuprofen, 25.0 wt ~ hydroxypropylcellulose having a number g average molecular weight of 242,000, 15.0 wt % hydroxypropylmethyl-cellulose having a number average molecular weight of 9,200, and 2.0 11 wt % stearic acid is compressed into a first lamina. Then a second 12 lamina weighing 230 mg comprising 87.0 wt % ibuprofen, 10.0 wt X
13 hydroxypropylcellulose with 10-13 wt X hydroxypropxy content, 2.0 wt X
14 hydroxypropylmethylcellulose having an average number molecular weight of 9,200, and 2.0 wt % stearic acid is deposited over a surface of the 16 first lamina and the second lamina compressed thereto. The dosage 17 form exhibited an initial burst of 200 mg drug within the first hour 18 followed by a mean release rate of 28 mg/hr for the following eleven 19 hours. The release rate in mg/hr is illustrated in Figure 5. The cumulative amount of ibuprofen released over time is illustrated in 21 F~gure 6.
23 The procedures described above are followed for manufacturing 24 dosage forms comprising the following drugs: (a) 150 mg of ibuprofen in the first lamina and 50 mg of ibuprofen in the second lamina; (b) 26 400 mg of ibuprofen in the first lamina and 200 mg of ibuprofen in the 27 second lamina; (c) 300 mg of aspirin in the first lamina and 200 mg 28 of aspirin in the second lamina; (d) 400 mg of cimetidine in the 1.~3~ 739 l first lamina and 200 mg of cimetidine in the second lamina; (e) 200 2 mg of umetidine in the first lamina and 100 mg of umetidine in the .
3 second lamina; (f) 100 mg of ranitidine in the first lamina and 50 mg 4 of ranitidine in the second lamina; (9) 250 mg of acetaminophen in the first lamina and 250 mg of acetaminophen in the second lamina;
6 (h) 250 mg of aspirin in the first lamina and 20 mg of caffeine in the 7 second lamina; (i) 150 mg of aspirin in the first lamina and 12 mg of 8 caffeine in the second lamina; (j) 350 mg of naproxen in the first 9 lamina and 175 mg of naproxen in the second lamina; (k~ 50 mg of phenylpropanolamine in the first lamina and 25 mg phenylpropanolamine ll in the second lamina; (1) 80 mg of pseudoephedrine in the first :-~
12 lamina and 40 mg of pseudoephedrine in the second lamina; (m) 40 mg 13 of pseudoephedrine hydrochloride in the first lamina and 20 mg of 14 pseudoephedrine hydrochloride in the second lamina; (n) 20 mg of pseudoephedrine in the first lamina and 1 mg of chlorpheniramine 16 maleate in the second lamina; (o) 40 mg of pseudoephedrine in the 17 first lamina and 3 mg of chlorpheniramine maleate in the second lamina;
18 (p) acetaminophen in the first lamina and codeine in the second lamina;
19 and (q) ibuprofen in the first lamina and codeine in the second lamina.
21 A dosage form for the controlled and the continuous adminis- .
22 tration of the drug 6-methoxy-alpha-methyl-2-naphthaleneacetic acid is 23 prepared by following the above described process of manufacture. The 24 dosage form is manufactured by making a first lamina comprising 59 wt of the drug, with 39 wt X low molecular weight hydroxypropylmethyl-26 cellulose having an average number molecular weight of 19,600; a 27 number average degree of polymerization of 100; and a viscosity of 35 28 centipoises; a second lamina comprising 1 wt ~ hydroxypropylcellulose ~ ~33~ ~9 1 with a 10-13 wt % hydroxypropxy content and 1 wt ~ magnesium stearate 2 and a different hydroxypropylmethylcellulose having an average number 3 molecular weight of 242,000; a number average degree of polymeriza-4 tion of 1260 and a viscosity of 100,000 centipoises measured as a 2%
S aqueous solution at 20C, was laminated to the first lamina. The two 6 lamina operated as a unit dosage form for the release of the drug at a 7 controlled rate over time.
9 A dosage form for the controlled and the continuous adminis-tration of isosorbide dinitrate is prepared by following the above 11 described process of manufacture. The dosage form is manufactured by 12 making a first lamina comprising 59 wt % isosorbide/lactose, 50/50, 13 with 39 wt % low molecular weight hydroxypropylmethylcellulose having 14 an average number molecular weight of 27,000; a number average degree of polymerization of 145 and a viscosity of 100 centipoises; and a 16 second lamina comprising 1 wt % hydroxypropylcellulose having a 10-13 17 wt X hydroxypropxy content; 97 wt % of a different hydroxypropyl-18 methylcellulose having an average number molecular weight of about 19 242,000; a number average degree of polymerization of 1260; a viscosity of 100,000 centipoises measured as a 2% aqueous solution as 21 20% C; 1% ferric oxide~and 1 wt % magnesium stearate.
23 Dosage form 10 of this invention provides many advantages to the 24 dispensing art. For example, the bilaminated structure of dosage for 10 comprises a fast drug releasing lamina 12 and a slower drug releasing `~
26 lamina 13. The fast drug releasing lamina 12 begins to dispense drug 27 14 immediately for producing an initial plasma concentration of drug 28 14 in a warm-blooded animal, which expression includes humans. The ~ 33~ 739 1 slower drug releasing lamina 13 releases drug 14 continuously and over 2 time for producing a steady-state drug 14 concentration. The expression 3 "fast drug 14 releasing lamina 12 and slower drug 14 releasing lamina 4 13" as used for the purpose of this invention, denotes that lamina 12 S releases drug 14 at a faster rate per unit time than does lamina 13.
6 Also, lamina 13 because of its physical properties provides mechanical 7 support for lamina 12 thereby extending its drug releasing period over 8 time. Another advantage provided by dosage form 10 is that it exhibits 9 stomach retention during part of its drug releasing life. This stomach retention provides release of drug 14 in the stomach for drug absorption 11 in the upper gastrointestinal tract. This retention in the upper 12 gastrointestinal tract and delivery of drug from the stomach allows 13 the drug to be absorbed throughout the gastrointestinal tract. This 14 delivery system is particularly useful for drugs with known absorption windows in the upper tract.
16 Additional advantages of dosage form 10 are its release of drug 14 17 at a rate independent of the pH of the environment of use, dosage form 18 10 releases drug 14 at about the same rate per unit time in artificial 19 stomach fluld and in art~ficial intestinal fluid, dosage form 10 releases drug 14 substantially free of irritating laboratory mucosal 21 tissue, and eventually dosage form 10 fully erodes and dissolves in 22 the gastrointestinal tract substantially free of residual particles.
, - ~:,. ~. . : :
,~ -. . . .. , .. ., .. ~ . i 1~3~ 73~
1 The novel dosage form of this invention comprises means for the 2 obtainment of precise release rate in the environment of use while 3 simultaneously providing beneficial therapy to a recipient. While 4 there has been described and pointed out features of the invention as applied to presently preferred embodiments, those skilled in the 6 dispensing art will appreciate that various modification, changes, 7 additions and omissions in the dosage form illustrated and described 8 can be made without departing from the spirit of this invention.
9 ' 21 ~-. ~ ........ ,.. .. ... .... ,~ ~, .. .
'~`'t'~
r
This invention pertains to a sustatned release dosage form. More 11 parttcularly, the invent~on concerns a dosage form comprising a ftrst12 lamina and a second lamina ~n laminated arrangement. The f1rst lamina13 comprises a cellulose ether composttion and the second lamtna com~
14 prises a different cellulose ether compostt~on wtth the amount of cellulose ether composttton ln the dosage form exceedlng thirty weight 16 percent. A dosage amount of drug ts present in at least one of the 17 lam~na.
21 Dosage forms, often manufactured tn the shape of a compressed 22 stngle layered tablet, compristng a cellulose ether are known to the 23 pharmaceutkal drug dispenstng art. For example, dosage forms com-24 pr1sing the cellulose ether hydroxypropylmethylcellulose are disclosed ~n United States Nos. 3,870~790; 4,140,755; 4,167,588; 4,226,849;
26 4,259,314; 4,357,469; 4,369,172; 4,389,393 and 4,540,566.
27 While the dosage forms known to the prior art use the cellulose 28 ether hydroxypropylmethylcellulose for the manufacture of the dosage .... .. ... ..... . . .. ...... .. . . . .. . . .. .. . . . .
~?
., . . - . - . . -i,.,,. .: , . . ~ . . .
~ ':
; ~ 3 3 ~ 7 ^J ~ ARC 1397 1 form, there are major disadvantages associated with the prior art 2 dosage forms. For instance, the mechanical integrity of some prior 3 art dosage forms often is insufficient to provide both a sustained and 4 a controlled release of drug over a prolonged period of time. The ~ prior art dosage forms often exhibit insufficient mechanical integrity, 6 that is, the ability to stay together in a moving fluid environment, 7 such as the gastrointestinal tract, without prematurely breaking-up 8 and prematurely releasing all of its drug. The above-mentioned 9 desirable properties are not apparent in the prior art dosage forms that undergo substantial disintegration in less then eight hours in a 11 fluid environment of use. -12 Another disadvantage associated with the prior art dosage forms 13 is that the dosage forms frequently exhibit an unwanted, variable and 14 difficult to reproduce release rate pattern. For example, prior art dosage forms comprising a small amount of a cellulose ether frequently 16 exhibit this behavior, such as those having less than five weight 17 percent hydroxypropylmethylcellulose having a molecular weight greater 18 than 50,000 and blended with a hydroxypropylmethylcellulose having a 19 molecular weight much less than 50,000 grams per mole. The presence of the high molecular weight polymer in the dosage form masks the 21 release characteristics of the low molecular weight polymer in the 22 dosage form resulting in an erratic release rate pattern which is 23 difficult to reproduce from losage form to dosage form and from batch 24 to batch of dosage forms.
Still other disadvantages associated with the prior art dosage 26 forms are that the dosage form over its shelf-life can exhibit an 27 unpredictable change in its release rate characteristics; the prior 28 art dosage form when tested in an in vitro test that substantially 1~31 739 reproduces the in vivo environment of the gastrointestinal tract often release the drug at a great rate of release in vivo rather than in vitro, which difference can be attributed to a premature disintegration of the prior art dosage form; and, the prior art dosage form in a high shear environment releases its drug too quickly, usually in less than six hours and it is therefore not adapted to prolonged release.
Thus, in the light of the above presentation it will -r.'~.
be appreciated by those versed in the dispensing art that if a novel dosage form is made available to the medical and phar-maceutical arts for dispensing difficult to deliver drugs free of the tribulation known to the prior art, such a dosage form would have a definite use and would also be a valuable contribut-ion 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 desirable release rate 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 also represent an advancement in the pharmaceutical arts.
OBJECTS OF THE INVENTION
Accordingly, this invention seeks to provide a novel dosage form for the controlled delivery of a beneficial drug to ., , ... ,. ,-.. ... .
. ".,: : i . : :
1 3 3 3 7 ^3 9 67696-119 a biological environment of use, and which dosage form represents an improvement and an advancement in the delivery arts.
Another aspectof-:the invention is to seek to provide both a novel and a useful dosage form that overcomes the difficult-ies associated with the prior art.
Another aspect of the invention is to seek to provide a dosage form comprising a first lamina and a second lamina com-prising a cellulose ether composition with at least one of the laminae comprising a beneficial drug.
Another aspect of this invention is to seek to provide a dosage form that is useful for delivering a beneficial drug formulation that is difficult to deliver and now can be delivered by the dosage form of this invention at a meaningful therapeutic rate over a prolonged period of time.
Another aspect of the present invention is to seek to provide a dosage form comprising a beneficial drug that can be from insoluble to very soluble in an aqueous fluid, and which drug can be delivered by the dosage form at an in vitro rate of release that is parallel by the in vivo rate of release.
Another aspect of this invention is to seek 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 controlled and continuous rate for a part-icular time period, the use of which requires intervention only for initiation and possible termination of the regimen.
~,A, 5.;~
133~ 7~
Another aspect of the present invention i~ to seek to provide a dosage form for delivering a drug in the gastro-lntestinal tract that substantially avoids a premature break-up and undergoes a change ln its integrity at a rate corresponding to the rate of release of drug over a prolonged period of time at least eight hours.
Other aspectsr features and advantages of the invention will be more apparent to those versed in the dispensing art from the following detailed specificatlon taken in con~unction with the drawings and the claims.
The invention therefore provides a bilaminated system for delivering a beneficial drug to an environment of use, the bilaminated system comprising~ 30 to 90 weight percent of a cellulose ether composition; said composition comprising a first lamina comprislng 30 to 80 weight percent of a cellulose ether ~elected from the groups of hydroxypropylmethylcellulose ethers having a number average molecular weight of 9,000 to 250,000 and a dosage amount of from about 0.05 ng to 5 g of a beneficial drug;
and, a second lamina in contacting arrangement with the first lamina, the second lamina compriæing 2 to 50 weight percent of a different cellulose ether composition comprising a hydroxypropyl-cellulose comprising a hydroxypropoxyl content of 7~ to 16%.
In a preferred embodiment the second lamina comprises a hydroxypropylmethylcellulose ether having a number average molecular weight of from about 9,000 to 250,000.
The invention also provides a bilaminated system for delivering a beneficial drug to an environment of use, the 4a .:
~ 33~
bllaminated system comprising~ (a) 30 to 90 weight percent of a cellulose ether composition; (b) a first lamlna comprising 30 to 80 weight percent of a cellulose ether selected from the group of hydroxypropylmethylcellulose ethers havin~ a number average molecular weight of 9,000 to 250,000; and (c) a second lamlna ln parallel mated relation with the first lamina, the second lamina comprising 2 to 50 weight percent of a cellulose ether composltion comprising a hydroxypropylcellulose comprising a hydroxypropoxyl content of 7% to 16% and a dosage unit amount of from about 0.05 ng to 5 g of a beneficial drug.
The invention also provldes a bilaminated system for delivering a beneficial drug to an environment of use, wherein the bilaminated system comprlses~ (a) 30 to 90 weight percent of a cellulose ether composltion preæent in a first lamina and a second lamina; wherein the first lamina comprises 30 to 80 weight percent of a cellulose ether hydroxypropylmethylcellulose having a number average molecular weight of from 9,000 to 250,000; and wherein the second lamina comprises 2 to 50 welght percent of a cellulose ether hydroxypropylmethylcellulose havlng a dlfferent number average molecular ~elght of from 9,000 to 250,000, a dosage amount of from about 0.05 ng to 5 g of a beneficial drug, and 18 thlcker than the flrst lamina.
The invention further provides a bilaminated system for delivering a beneficial drug to an environment of use, wherein the bilaminated system comprises. (a) 30 to 90 weight percent of a cellulose ether composition comprislng a first lamina and a second lamlna; said firæt lamlna comprisin~ 30 to 80 welght percent of a 4b p-:
13~ 7~
~ellulose ether hydroxypropylmethylcellulose ether havlng a number average molecular weight of from 9,000 to 2S0,000 and a dosage unit amount of from about 0.05 ng to 5 g of a beneficlal drug; and wherein the second lamlna comprises 2 to 50 weight percent of a cellulose ether hydroxypropylmethylcellulose having a dlfferent number average molecular weight of from 9,000 to 250,000.
The invention additionally provides a bllaminated system for delivering a beneficial drug to an environment of use, the bllaminated system comprlsing. ~a) a cellulose ether composltion comprising. (b) a first lamina comprising up to 80 weight percent of a cellulose ether ~elected from the group consistlng of hydroxypropylmethylcellulose ethers comprising a degree of polymerlzatlon of 40 to 1600, a vlsco~lty of 2 to 225,000 and a number average molecular welght of 9,000 to 307,200; and Ic) a second lamlna ln parallel mated relation wlth the flrst lamlna, the second lamlna comprlsing up to S0 weight percent of a cellulose ether compositlon comprislng a hydroxypropylcellulose compri~ing a hydroxypropoxyl content of 7 percent to 16 percent, and a do~age unlt amount of 25 ng to 1.5 g of a beneflclal drug.
The lnvention also provldes a bllaminated system for deliverlng a beneficial drug to an environment of use, wherein the bilaminated ~ystem comprises: (a) at least 30 weight percent of a cellulose ether compositlon present ln a first lamlna and a second lamlnaS wherein the fir~t lamlna comprl~es up to 85 welght percent of at least one hydroxypropylmethylcellulose compri~ing a number average molecular weight of from 9,000 to 250,000; and whereln the second lamlna comprlses up to 85 welght percent of hydroxypropyl-4c ~ 1~3~ 739 methylcellulose comprlsing a dlfferent number average molecular welght of from 9,000 to 250,000 and a dosage amount of from 25 ng to 1.5 g of a beneflcial drug.
The lnventlon further provldes a bllaminated system for deliverlng a beneficlal drug to an environment of use, wherein the bllaminated system comprises~ ~a) 30 weight percent to 90 weight percent of a cellulo~e ether compositlon comprlslng a fir~t lamina and a second lamina; said first lamina comprising a cellulose ether ~elected from a hydroxypropylmethylcellulo~e ether comprising a number average molecular weight of from 9,000 to 250,000 and a dosage unlt amount of 25 ng to 1.5 g of a beneficial drug; and wherein the second lamina comprises a cellulose ether selected from a hydroxypropylmethylcellulose ether comprlsing a different number average molecular weight of from 9,000 to 250,000.
The invention additlonally provldes a bilaminated system for delivering the beneficial drug lbuprofen to an environment of use, wherein the bilaminated system comprise3~ a first lamlna . ;~
comprising up to 80 weight percent of a hydroxypropylmethyl-cellulose comprtslng a degree of polymerization of about 50 to 1260, a viscosity of about 3 to 100,000 centipoises and a number average molecular weight of 9,000 to 250,000, and a dosage amount of from 25 ng to 1.5 g of lbuprofen; and a second lamina comprising up to 50 welght percent of a hydroxypropylcellulose comprising from 7 percent to 16 percent hydroxypropoxyl, and a dosage amount of from 25 ng to 1.5 g of ibuprofen. ~.
4d .:
.. ~,._ _ .. . . .
133~ 739 The inventlon also provides a bilaminated system for dellverlng a beneficial drug to an environment of use whereln the bllamlnated system comprlses- a flrst lamlna comprlslng up to 80 weight percent of a hydroxy-propylmethylcellulose comprlslng a degree of polymerization of about 50 to 1260~ a viscosity of about 3 to 100,000 centipolses and a number average molecular weight of 9,000 to 250,000; a second lamina comprlsing a hydroxypropyl-cellulose comprlslng a hydroxypropoxyl content of 7% to 16%; and whereln the bllamlnated system comprlses from 25 ng to 1.5 g of a beneficlal drug selected from the group conslstlng of clmentldlne, umetldlna, ranltldlne, naproxen, estrogenic, progestlatlonal, captopril, diltlazom, and isosorbide dinitrate.
4e -.-:.
~ .. - ~
,.. ,. . -.. , . - - - - .. - ~ . . , . . ... , -1~3~ ~39 3 In the draw~ngs, wh1ch are not drawn to scale but are set forth 4 to 111ustrate var10us embod1ments of the lnvent10n, the draw1ng f1gures are as follow:
6 F1gure I ls a slde, elevated vlew of a dosage form prov1ded by 7 th1s lnventlon, des19ned and shaped for orally adm1n1ster1ng a bene-8 flclal drug to the gastro1ntest1nal tract of a rec1p1ent;
9 F1gure 2 1s an opened v1ew of the dosage form of F19ure I through 2-2 of the dosage form for 111ustrat1ng the 1nternal structure of the II dosage form; and, I2 F1gures 3, 4, 5 and 6 dep1ct release patterns over t1me for 13 dosage forms prov1ded by th1s 1nvent10n.
14 In the draw1ngs and 1n the speclf1cat10n 11ke parts 1n related f1gures are 1dent1f1ed by 11ke numbers. The terms appearlng earl1er 16 1n the speclf1cat10n and 1n the draw1ngs, as weil as embodlments 17 thereof, are further descr1bed elsewhere 1n th1s spec1f1cat10n.
Turn1ng now to the drawlng f1gures 1n detall, whlch drawlng 21 f1gures are an example of the dosage forms provlded by the 1nvent10n, 22 and whlch example ~s not to be construed as llmltlng, one example of 23 thls dosage form ls lllustrated ln Flgure I and ln Flgure 2 and 24 deslgnated by the nùmeral IO. In Flgure I, dosage form IO comprlses body 11. Dosage form IO can be manufactured 1nto var10us s1zes and 26 shapes adapted for oral adm1ttance 1nto the gastro1ntest1nal tract of 2~ a warm-blooded an1mal. For example, dosage form IO can be of any 28 convenlent geometrlc shape, such as elllpsoid, bean-shaped, clrcular-` i,~
_",~,... ..... . .... . . . .
- ` 13~ 7~
1 shaped, rectangular-shaped, caplet-shaped; and the like.
2 In Figure 2, dosage.form 10 is seen in opened section through 2-2 3 of Figure 1. In Figure 2 dosage form 10 comprises body 11, which body 4 11 comprises a first lamina 12 and a second lamina 13. First lamina 12 and second lamina 13 are laminated together and they function in 6 concert as a single dosage form 10. Dosage form 10 comprises at least 7 one beneficial drug 14 present in at least one of first lamina 12, or 8 present in second lamina 13 or, optionally, present in both first 9 lamina 12 and second lamina 13. Dosage form 10 comprising lamina 12 and lamina 13 comprises a non-toxic cellulose ether composition and, 11 optionally, ot.her pharmaceutically acceptable laminae forming ingre-12 dients. .
13 Dosage form 10 comprises from about 30 weight percent to 90 14 weight percent (wt X) of a cellulose ether composition based on the total weight of the dosage form. In a presently preferred embodiment 16 the cellulose ether composition of dosage form 10 comprises at least 17 one hydroxypropylmethylcellulose and at least one hydroxypropylcellulose.
18 The hydroxypropylcellulose operable for the purpose of this invention 19 comprises a hydroxypropoxyl content of 4X to 12X and a methyloxy content 19% to 24X, and the hydroxypropylcellulose comprises a hydropropxyl . .
21 content of from 7X to 16X. Exemplary hydroxypropylmethylcellulose 22 that can be used for forming dosage form 10 comprises at least one of 23 a member selected from the group consisting of (a) a hydroxypropyl- ~ :
24 methylcellulose having a degree of polymerization (DP) of about 50, a : -. .
viscosity of about 3 centipoises of a 2X solution in water, a number 26 average molecular weight of about 9,200; (b) a hydroxypropylmethyl-27 cellulose having a DP of 100, a viscosity of 35 centipoises (cps), a :~
28 number averaye molecular weight (MWn) of 19,600; (c) a hydroxypropyl-'': ' ' : ' i.
~33~ 739 1 methylcellulose comprising a DP of 145, a viscosity of 100 cps, a MWn 2 of 27,800; (d) a hydroxypropylmethylcellulose comprising a DP of 460, 3 a viscosity of 4,000 cps, a MWn of 88,300; (e) a hydroxypropylmethyl-4 cellulose comprising a DP of 690, a viscosity of 15,000 cps, a MWn of 132,500; and (f) a hydroxypropylmethylcellulose having a DP of 1260, a 6 viscosity of 100,000 cps, a MWn of 242,000.
7 The hydroxypropyTcellulose used for the purpose of this invention 8 is a nonionic ether with neutral pH range and a hydroxypropyl content 9 of 7% to 16X, with more specific hydroxypropylcelluloses comprising a hydroxypropyl content of 7% to 10X; a hydroxypropyl content 10X to 11 13X, and a hydroxypropyl content 13% to 16%. In the above specifica-12 tion DP is the degree of polymerization indicating the number of 13 monomers polymerized.in the final polymer and MWn is the number 14 average molecular weight of the polymer.
G~her hydroxypropylmethylcellulose ethers that can be for the 16 purpose of providing dosage form 10 are (9) a hydroxypropylmethyl-17 cellulose comprising a DP of 59, a viscosity of 6 and a MWn of 11,900;
18 and (h) a hydroxypropylmethylcellulose possessing a DP of 860, a 19 viscosity of 30,000 and a MWn of 165,000. The examples as set forth above generally comprise a hydroxypropylmethylcellulose comprising a 21 DP of 40 to 1600, a viscosity of 2 to 225,000 and a MWn of from 9,000 ~.
22 to 307,200, and mixtures thereof.
23 Lamina 12 of dosage form 10 comprises at least one hydroxypropyl-24 methylcellulose in an amount of at least 30 wt X to 80 wt X based on the total weight of dosage form 10, or at least 40 wt X to 80 wt X
26 based on the total weight of lamina 12. Lamina 13 of dosage form 10 27 comprises at least one hydroxypropylcellulose in an amount of at least 28 2 wt X to 20 wt X based on the total weight of dosage form 10, or ~ .
t .
h :~., 3 ~
1 about 10 wt g to S0 wt % based on the total weight of lamina 13.
2 Lamina 12 and lamina 13 can comprise each a single cellulose ether, a 3 blend of two cellulose ethers, a tertiary blend comprising three 4 cellulose ethers, and the like.
Representative of cellulose ether compositions comprising lamina 6 12 are (a) a composition comprising a hydroxypropylmethylcellulose 7 having a MWn of about 242,000; (b) a hydroxypropylmethylcellulose 8 having a MWn of about 132,500; (c) a composition comprising both a g hydroxypropylmethylcellulose-having a MWn of 9,200 and a hydroxy-~ ~'f2, 000 propylmethylcellulose having a MWn of 212,00; (d) a composition 11 comprising a hydroxypropylmethylcellulose having a MWn of 19,600 and a 12 hydroxypropylmethylcellulose having a MWn of about 242,000; (e) a 13 composition comprising a hydroxypropylmethy1cellulose having a MWn of 14 about 27,800 and a hydroxypropylmethylcellu1Ose having a MWn of about 242,000; (f) a composition comprising a hydroxypropylmethylcellulose 16 having a MWn of 88,300 and a hydroxypropylmethylcellulose having a MWn 17 of about 242,000; (9) a composition comprising a hydroxypropylmethyl-18 cellulose having a MWn of 132,500 and a hydroxypropylmethylcellulose 19 hav~ng a MWn of about 242,000; (h) a composition comprlsing a hydroxypropylmethylcellulose having a MWn of 9,200, a hydroxypropyl- -:~
21 methylcellulose having MWn of 19,600 and a hydroxypropylmethylcellulose .. . ~. , ...................................... -- 22 having a MWn of about 242,000; (i) a composition comprising a . .. : ~-23 hydroxypropylmethylcellulose having a MWn of g,200, a hydroxypropyl-24 methylcellulose comprising MWn of 88,300 and a hydroxypropylmethyl-cellulose having a MWn of about 242,00; (j) a composition comprising 26 a hydroxypropylmethylcellulose cellulose having a MWn of 19,600, :~
27 hydroxypropylmethylcellu;ose having a MWn of about 27,800 and a Z8 hydroxypropylmethylcellulose haviny a MWn of about 242,000; and the ;: ;
1~3~ ~9 1 like. A binary composition comprising two cellulose ethers in a 2 presently preferred embodiment comprises from 1 wt % to 99 wt % of one 3 cellulose ether and from 99 wt % to 1 wt % of the other cellulose 4 ether. A tertiary composition comprises from 1 wt % to 99 wt % of each cellulose ether with a total cellulose ether content of up to 6 80 wt % based on the total weigh of lamina 12.
7 . Lamina 13, in one presently preferred embodiment, comprises from 8 2 wt g to 30 wt % of a single low substituted hydroxypropylcellulose 9 ether having a hydroxypropyl content of 7~ to 16%. Lamina 13 in other preferred embodiments comprises (a) a binary blend of a hydroxypropyl-11 cellulose having a hydroxypropyl content of 7 to 10 wt X blended with 12 a hydroxypropylcellulose having a hydroxypropyl content of 13 to 16 wt %;
13 (b) a composition comprising a hydroxypropylcellulose having a 14 hydroxypropyl content of 7 to 10 wt g blended with a hydroxypropyl-cellulose having a hydroxypropyl content of about 10 to 13 wt %; (c) 16 a composition comprising a hydroxypropylcellulose and a hydroxypropyl-17 methylcellulose having a MWn of 9,200; (d) a composition comprising a 18 hydroxypropylcellulose and a hydroxypropylmethylcellulose having a MWn 19 of about 19,600; (e) a hydroxypropylcellulose and a hydroxypropyl-methylcellulose having a MWn of 27,800; (f) a composition comprising 21 a hydroxypropylcellulose and a hydroxypropylmethylcellulose having a 22 MWn of about 88,300; (9) a composition comprising a hydroxypropyl-23 cellulose and a hydroxypropylmethylcellulose having a MWn of about 24 132,500; (h) a composition comprising a hydroxypropylcellulose and a hydroxypropylmethylcellulose having a MWn of about 242,000; and the 26 like.
27 Dosage form 10 comprises a beneficial drug 14. Drug 14 can be 28 presented in lamina 12; drug 14 can be presented in lamina 13, and .
, ~ .
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1 drug 14 can be presented in both lamina 12 and lamina 13. In this 2 specification the term "drug" includes any physiologically or pharma-3 cologically active substance that produces a local or systemic effect 4 in animals, including warm-blooded mammals, humans and primates;
avians; household, sport and farm animals; laboratory animals;
6 fishes, reptiles and zoo animals. The term "physiologically", as used 7 herein, denotes the administration of a drug to produce generally 8 normal levels and functions in a warm-blooded animal. The term 9 "pharmacologically" generally denotes variations in response to the amount of drug administered to the host. See Stedman's Medical 11 Dictionary, 1966, published by Williams and Wilkins, Baltimore, MD.
12 The active drug that can be delivered includes inorganic and 13 organic compounds without limitation, including drugs that act on the 14 peripheral nerve, adrenergic receptors, cholinergic receptors, nervous system, skeletal muscles, cardiovascular system, smooth muscles, blood 16 circulatory system, synaptic sites, neuroeffector junctional sites, ;~
17 endocrine system, hormone systems, immunological system, organ systems, 18 reproductive system, skeletal system, autocoid systems, alimentary and 19 excretory systems, inhibitors of autocofds and histamine systems. The active drug that can be delivered for acting on these recipients -21 include anticonvulsants, analgesics, anti-parkinsons, anti-inflammatories, 22 anesthetics, antimicrobials, antimalarials, antiparasitic, antihyper-23 tensives, angiotensin converting enzyme inhibitor, antihistamines, ~ -~
24 antipyretics, alpha-adrenergic agnoist, alpha-blockers, biocides, bactericides, bronchial dilators, beta-adrenergic stimulators, beta-26 a,drenergic blocking drugs, contraceptives, cardiovascular drugs, 27 calcium channel inhibitors, depressants, diagnostics, diuretics, 28 electrolytes, hypnotics, hormonals, hyperglycemics, muscle contrac-~ 3 ~
1 tants, muscle relaxants, opthalmics, psychic energizers, parasym-2 pathomimetics, sedatives, sympathomimetics, tranquilizers, urinary 3 tract drugs, vaginal drugs, vitamins, and the like.
4 Exemplary drugs that are very soluble in water can be delivered by dosage form 10 of this invention include prochlorperazine edisylate, 6 ferrous sulfate, aminocaproic acid, potassium chloride, mecamylamine 7 hydrochloride, procainamide hydrochloride, amphetamine sulfate, 8 benzphetamine hydrochloride, isoproteronol sulfate, methamphetamine g hydrochloride, phenmetrazine hydrochloride, bethanechol chloride, methacholine chloride, pilocarpine hydrochloride, atropine sulfate, 11 scopolamine bromide, isopropamide iodine, tridihexethyl chloride, 12 phenformin hydrochloride, methylphenidate hydrochloride, cimetidine 13 hydrochloride, theophylline cholinate, cephalexin hydrochloride, and -- ;
14 the like.
Exemplary drugs that are poorly soluble in water and that can be 16 dellvered by dosage form 10 of this invention include diphenidol, 17 meclizlne hydrochloride, prochlorperazine maleate, phenoxybenzamine, 18 thiethylperazine maleate, anisindone, diphenadione, erythrityl 19 tetranitrate, digoxin, isoflurophate, acetazolamide, methazolamide, bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone acetate, 21 phenaglycodol, allopurinol, aluminum aspirln, methotrexate, acetyl 22 sulfisoxazole, erythromycin, progestins, esterogenic, progestational, 23 corticosteroids, hydrocortisone, hydrocorticosterone acetate, cortisone 24 acetate, triamcinolone, methyltesterone, 17-beta-estradiol, ethinyl estradiol, prazosin hydrochloride, ethinyl estradiol 3-methyl ether, 26 pednisolone, 17alpha-hydrocyprogesterone acetate, l9-nor-progesterone, 27 norgestrel, norethindrone, progesterone, norgesterone, norethynodrel, 28 and the like.
.~.. . .. . :
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1 Examples of other drugs that can be delivered by dosage form 10 2 include aspirin, indomethacin, naproxen, fenoprofen, sulindac, 3 indoprofen, nitroglycerin, propranolol, timolol, atenolol, alprenolol, 4- cimetidine, clonidine, imipramine, levodopa, chloropromazine, methyl-dopa, dihydroxyphenylalnine, pivaloyloxyethyl ester of alpha-methyldopa, 6 theophylline, calcium gluconate, ketoprofen, ibuprofen, cephalexin, 7 erythromycin, haloperidol, zomepirac, ferrous lactate, vincamine, 8 diazepam, captopril, phenoxybenzamine, nifedipine, diltiazem, verapamil, 9 milrinone, madol, quanbenz, hydrochlorothiazide, and the like. The beneficial drugs are known to the art in Pharmaceutical Sciences, 14th 11 Ed., edited by Remington, (1979) published by Mack Publishing Co., 12 Easton, PA; The Drug, The Nurse, The Patient, ~ncluding Current Drug ;~
13 Handbook, by Falconer et al., (1974-1976) published by Sunder Co., 14 Philadelphia, PA; Medicinal Chemistry, 3rd Ed., Vol. 1 and 2, by Burger, published by Wiley-Interscience, New York and in Physicians' 16 Desk Reference, 38 Ed., (1984) published by Medical Economics Co., 17 Oradell, NJ.
18 The drug in dosage form 10 can be in various forms, such as 19 uncharged molecules, molecular complexes, pharmacologically acceptable salts such as hydrochloride, hydrobromide sulfate, laurate, palmitate, -~
-:, :. :
21 phosphate, nitrite, borate, acetate, mal,eate, tartrate, oleate and 22 salicylate. For acidic drugs, salts of metals, amines or organic ~-~
23 cations; for example, quaternary ammonium can be used. Derivatives of 24 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 26 derivative thereof to serve as a solute, and on its release from the 27 device is converted by enzymes, hydrolyzed by body pH or other 28 metabolic processes to the original biologically active form.
f' i~3~ 739 1 Drug 14 can be present in dosage form 10 neat or, as in a 2 presently preferred optional embodiment, w~th a binder, dispersant, 3 wetting agent, lubricant or dye. Representative of these include 4 acacia, agar, calcium carrageenan, alginic acid, algin, agarose powder, collagen, colloidal magnesium silicate, pectin, gelatin, and 6 the like; binders like polyvinyl pyrrolidone; lubricants such as 7 magnesium stearate; wetting agent such as fatty amines, fatty 8 quaternary ammonium salts, ester of sorbitol, and the like. The 9 phrase drug formulation indicates the drug is present in dosage form 10 neat or accompanied by a binder, and the like. The amount of 11 beneficial drug in dosage form 10 generally is from about 0.05 ng to 12 5 9 or more, with individual dosage form 10 comprising for example, 13 25 ng, 1 mg, 5 mg, 10 mg, 25 mg, 250 mg, 750 mg, 1.0 9, 1.2 9, 1.5 9, 14 and the like. In a presently preferred embodiment lamina 12 comprises more drug 14 than does lamina 13; however, the amount of drug 14 can 16 be the same. G~nerally, the amount of drug will be in a ratio in 17 lamina 12 to lamina 13 in a ritio of 1:1 to 15:1. The dosage form can 18 be administered once, twice or three times daily.
19 Dosage form 10 is manufactured by first making independently lamina 12, or lamina 13, which laminae are made from a well-mixed 21 composition of laminae forming member.s. For example, a particular 22 lamina is made as follows: first, each of the lngredients comprising Z3 a lamina are independently screened and then blended together, except 24 for the lubricant. Then the homogeneous blend is wet granulated by adding a solvent such a anhydrous ethanol, and the wet ingredients 26 mixed until a uniform blend is obtained by said process. Next, the 27 wet blend is passed through a screen and dried to evaporate the solvent.
28 The resulting granules are passed again through a sieve. Next, a .~. .. ;~. . : :
3~ 7~9 l small amount of a fine~y divided lubricant is added to the dry granules 2 and the lubricant and granules blended to provide a uniform blend.
3 Next, the above described procedure is repeated for the other lamina.
4 Next, the two lamina forming compositions are fed independently into separate hoppers of a compression machine. The machine lightly 6 compresses one lamina and then adds the second lamina forming granula-7 tion in laminating arrangement to the first lamina and then compresses 8 the two laminae together. Typically, about two tons of pressure are 9 applied to laminate the laminae and yield the final dosage form.
The dosage form can be made also by a dry granulation process of ll manufacture. The dry process comprises first mixing, for a particular 12 lamina, all the lamina forming ingredients, except for the lubricant, 13 passing the mixed ingredients through a grinding mill to a small mesh 14 size, and then transferring the sized powder to a dry compactor. The compactor densifies the powder, which dense powder is then passed 16 through a sizing mill to regrind the composition. The composition is 17 - ground to a small size, typically 20 mesh or smaller. Finally, a dry 18 lubricant is added and the ingredients blended to produce the final 19 lamina forming composition. The second lamina is made in a similar manner. Then, each composition is fed independently to the compaction 21 press and compressed into the dosage form comprising parallel laminae.
h 22 Other standard manufacturing procedures can be used to form the 23 laminae and the laminated dosage form. For example, the various 24 ingredients can be mixed with a solvent by ballmilling, calendering, stirring or rollmilling, and then pressed into a preselected sized and 26 shaped lamina. A second lamina made in a like process comprising a 27 shape and size corresponding to the first lamina is then laminated 28 with pressure to the first lamina to yield the dosage form.
i;: ':: - - :, -~ 13~ 73~
1 Exemplary solvents suitable for manufacturing the lamina include 2 inorganic and organic solvents that do not adversely harm the lamina, 3 the lamina forming ingredients and the final dosage form. The sol-4 vents broadly include a member selected from the group consisting of alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated 6 solvents, cycloaliphatic solvents, aromatic, heterocyclic solvents, 7 and mixtures thereof. Typical solvents include acetone, diacetone, 8 methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, 9 ethyl acetate, isopropyl acetate, n-butylacetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, h-heptane, methylene 11 dichloride, ethylene dichloride, propylene dichloride, ethyl ether, 12 mixtures such as acetone and ethanol, acetone and methanol, methylene 13 dichloride and methanol, ethylene dichloride and methanol, and the 14 like.
The following examples illustrate means and methods for carrying 16 out the present invention. The examples are merely illustrative and 17 they should not be considered as limiting the scope of the invention, 18 as these examples and other equivalents thereof will become more 19 apparent to those versed in the pharmaceutical dispensing art in the light of the present disclosure, the drawings and the accompanying 21 claims.
h ' ';
23 A lamina forming composition comprising 29.5 wt % isosorbide 24 dinitrate, 29.5 wt X lactose, 40.0 wt X hydroxypropylmethylcellulose, having an average molecular weight of 27,800 and 1.0 wt X magnesium 26 stearate is compressed into a first lamina. Next, a second lamina 27 forming composition comprising 97.0 wt X hydroxypropylmethylcellulose 28 having a molecular weight of 242,000, 1.0 wt g ferric oxide and 2.0 wt g - 1~33 739 1 magnesium stearate is deposited over the first lamina and the second 2 lamina laminated to the first lamina with a compression of 2 tons.
3 The first lamina weighed 271 mg and the second lamina weighed 100 m~.
4 The laminae are compressed in a 13/32 inch round dye. The dosage form released pattern measured in a shaking flask containing water and a 6 few marbles for producing mechanical abuse, exhibited a cumulative 7 release of 98X over a 24 hour period of time. Lamina 1 comprising the 8 lower molecular weight cellulose either erodes in the aqueous environ-9 ment and administers the drug over time. Lamina 2 comprising the higher molecular weight ether maintains its mechanical integrity 11 longer because of its composition. Lamina 2 serves as a support 12 member for lamina 1.
14 The procedures described above are followed in this example.
First a lamina forming composition comprising 58.0 wt % acetaminophen, 16 25.0 wt X hydroxypropylmethylcellulose having a number average molecular 17 weight of 242,000, a number average degree of polymerization of about 18 1260 and a viscosity of lO0,000 centipoises, 15.0 wt % hydroxypropyl-19 methylcellulose having a number average molecular weight of 9,200 a number average degree of polymerization of 50 and a viscosity of 3 21 centipoises, and 2.0 wt X magnesium stearate is compressed into a 22 first lamina. The lamina weighed 604 mg. Then, a second lamina 23 forming composition weighing 170.5 mg and comprising 88.0 wt %
24 acetaminophen, 10.0 wt X hydroxypropylcellulose with 10-13 wt X
hydroxypropxy content, and 2.0 wt % magnesium stearate is laminated to 26 the first lamina to yield the dosage form. The release rate measured 27 in mg/hr for this bilaminated dosage form is depicted in Figure 3.
28 The cumulative amount of acetaminophen released over a percent basis 133~ 739 1 over a a 12 hour period of time is depicted in Figure 4. The dosage 2 form exhibited in initial release of 200 mg drug within the first 3 hour, followed by a mean release rate of 24 mg per hour for the next 4 eleven hours.
6 The procedure described above is followed in this example. A
7 first lamina forming composition weighing 690 mg and comprising 58.0 8 wt % ibuprofen, 25.0 wt ~ hydroxypropylcellulose having a number g average molecular weight of 242,000, 15.0 wt % hydroxypropylmethyl-cellulose having a number average molecular weight of 9,200, and 2.0 11 wt % stearic acid is compressed into a first lamina. Then a second 12 lamina weighing 230 mg comprising 87.0 wt % ibuprofen, 10.0 wt X
13 hydroxypropylcellulose with 10-13 wt X hydroxypropxy content, 2.0 wt X
14 hydroxypropylmethylcellulose having an average number molecular weight of 9,200, and 2.0 wt % stearic acid is deposited over a surface of the 16 first lamina and the second lamina compressed thereto. The dosage 17 form exhibited an initial burst of 200 mg drug within the first hour 18 followed by a mean release rate of 28 mg/hr for the following eleven 19 hours. The release rate in mg/hr is illustrated in Figure 5. The cumulative amount of ibuprofen released over time is illustrated in 21 F~gure 6.
23 The procedures described above are followed for manufacturing 24 dosage forms comprising the following drugs: (a) 150 mg of ibuprofen in the first lamina and 50 mg of ibuprofen in the second lamina; (b) 26 400 mg of ibuprofen in the first lamina and 200 mg of ibuprofen in the 27 second lamina; (c) 300 mg of aspirin in the first lamina and 200 mg 28 of aspirin in the second lamina; (d) 400 mg of cimetidine in the 1.~3~ 739 l first lamina and 200 mg of cimetidine in the second lamina; (e) 200 2 mg of umetidine in the first lamina and 100 mg of umetidine in the .
3 second lamina; (f) 100 mg of ranitidine in the first lamina and 50 mg 4 of ranitidine in the second lamina; (9) 250 mg of acetaminophen in the first lamina and 250 mg of acetaminophen in the second lamina;
6 (h) 250 mg of aspirin in the first lamina and 20 mg of caffeine in the 7 second lamina; (i) 150 mg of aspirin in the first lamina and 12 mg of 8 caffeine in the second lamina; (j) 350 mg of naproxen in the first 9 lamina and 175 mg of naproxen in the second lamina; (k~ 50 mg of phenylpropanolamine in the first lamina and 25 mg phenylpropanolamine ll in the second lamina; (1) 80 mg of pseudoephedrine in the first :-~
12 lamina and 40 mg of pseudoephedrine in the second lamina; (m) 40 mg 13 of pseudoephedrine hydrochloride in the first lamina and 20 mg of 14 pseudoephedrine hydrochloride in the second lamina; (n) 20 mg of pseudoephedrine in the first lamina and 1 mg of chlorpheniramine 16 maleate in the second lamina; (o) 40 mg of pseudoephedrine in the 17 first lamina and 3 mg of chlorpheniramine maleate in the second lamina;
18 (p) acetaminophen in the first lamina and codeine in the second lamina;
19 and (q) ibuprofen in the first lamina and codeine in the second lamina.
21 A dosage form for the controlled and the continuous adminis- .
22 tration of the drug 6-methoxy-alpha-methyl-2-naphthaleneacetic acid is 23 prepared by following the above described process of manufacture. The 24 dosage form is manufactured by making a first lamina comprising 59 wt of the drug, with 39 wt X low molecular weight hydroxypropylmethyl-26 cellulose having an average number molecular weight of 19,600; a 27 number average degree of polymerization of 100; and a viscosity of 35 28 centipoises; a second lamina comprising 1 wt ~ hydroxypropylcellulose ~ ~33~ ~9 1 with a 10-13 wt % hydroxypropxy content and 1 wt ~ magnesium stearate 2 and a different hydroxypropylmethylcellulose having an average number 3 molecular weight of 242,000; a number average degree of polymeriza-4 tion of 1260 and a viscosity of 100,000 centipoises measured as a 2%
S aqueous solution at 20C, was laminated to the first lamina. The two 6 lamina operated as a unit dosage form for the release of the drug at a 7 controlled rate over time.
9 A dosage form for the controlled and the continuous adminis-tration of isosorbide dinitrate is prepared by following the above 11 described process of manufacture. The dosage form is manufactured by 12 making a first lamina comprising 59 wt % isosorbide/lactose, 50/50, 13 with 39 wt % low molecular weight hydroxypropylmethylcellulose having 14 an average number molecular weight of 27,000; a number average degree of polymerization of 145 and a viscosity of 100 centipoises; and a 16 second lamina comprising 1 wt % hydroxypropylcellulose having a 10-13 17 wt X hydroxypropxy content; 97 wt % of a different hydroxypropyl-18 methylcellulose having an average number molecular weight of about 19 242,000; a number average degree of polymerization of 1260; a viscosity of 100,000 centipoises measured as a 2% aqueous solution as 21 20% C; 1% ferric oxide~and 1 wt % magnesium stearate.
23 Dosage form 10 of this invention provides many advantages to the 24 dispensing art. For example, the bilaminated structure of dosage for 10 comprises a fast drug releasing lamina 12 and a slower drug releasing `~
26 lamina 13. The fast drug releasing lamina 12 begins to dispense drug 27 14 immediately for producing an initial plasma concentration of drug 28 14 in a warm-blooded animal, which expression includes humans. The ~ 33~ 739 1 slower drug releasing lamina 13 releases drug 14 continuously and over 2 time for producing a steady-state drug 14 concentration. The expression 3 "fast drug 14 releasing lamina 12 and slower drug 14 releasing lamina 4 13" as used for the purpose of this invention, denotes that lamina 12 S releases drug 14 at a faster rate per unit time than does lamina 13.
6 Also, lamina 13 because of its physical properties provides mechanical 7 support for lamina 12 thereby extending its drug releasing period over 8 time. Another advantage provided by dosage form 10 is that it exhibits 9 stomach retention during part of its drug releasing life. This stomach retention provides release of drug 14 in the stomach for drug absorption 11 in the upper gastrointestinal tract. This retention in the upper 12 gastrointestinal tract and delivery of drug from the stomach allows 13 the drug to be absorbed throughout the gastrointestinal tract. This 14 delivery system is particularly useful for drugs with known absorption windows in the upper tract.
16 Additional advantages of dosage form 10 are its release of drug 14 17 at a rate independent of the pH of the environment of use, dosage form 18 10 releases drug 14 at about the same rate per unit time in artificial 19 stomach fluld and in art~ficial intestinal fluid, dosage form 10 releases drug 14 substantially free of irritating laboratory mucosal 21 tissue, and eventually dosage form 10 fully erodes and dissolves in 22 the gastrointestinal tract substantially free of residual particles.
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1 The novel dosage form of this invention comprises means for the 2 obtainment of precise release rate in the environment of use while 3 simultaneously providing beneficial therapy to a recipient. While 4 there has been described and pointed out features of the invention as applied to presently preferred embodiments, those skilled in the 6 dispensing art will appreciate that various modification, changes, 7 additions and omissions in the dosage form illustrated and described 8 can be made without departing from the spirit of this invention.
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Claims (41)
1. A bilaminated system for delivering a beneficial drug to an environment of use, the bilaminated system comprising: 30 to 90 weight percent of a cellulose ether composition; said composition comprising a first lamina comprising 30 to 80 weight percent of a cellulose ether selected from the groups of hydroxy-propylmethylcellulose ethers having a number average molecular weight of 9,000 to 250,000 and a dosage amount of from about 0.05 ng to 5 g of a beneficial drug; and, a second lamina in contacting arrangement with the first lamina, the second lamina comprising 2 to 50 weight percent of a different cellulose ether composition comprising a hydroxypropylcellulose comprising a hydroxypropoxyl content of 7% to 16%.
2. The bilaminated system for delivering a beneficial drug to an environment of use according to claim 1, wherein the second lamina comprises a hydroxypropylmethylcellulose ether having a number average molecular weight of from about 9,000 to 250,000.
3. The bilaminated system for delivering a beneficial drug to an environment of use according to claim 1, wherein the second lamina comprises a dosage amount of from about 0.05 ng to 5 g of a beneficial drug.
4. The bilaminated system for delivering a beneficial drug to an environment of use according to claim 1, wherein the second lamina comprises a hydroxypropylmethylcellulose ether having a number average molecular weight of from about 9,000 to 250,000 and a dosage amount of from about 0.05 ng to 5 g of a beneficial drug.
5. The bilaminated system for delivering the beneficial drug to the environment of use according to claim 1, wherein the second lamina comprises a hydroxypropylmethylcellulose ether having a number average molecular weight of from about 9,000 to 250,000, a dosage amount of from 0.05 ng to 5 g of a beneficial drug, and wherein the second lamina releases more drug per unit time than the first lamina releases drug per unit time and erodes at a faster rate of erosion than the first lamina when the bilaminated system is in an environment of use comprising an aqueous fluid.
6. The bilaminated system for delivering the drug to an environment of use according to claim 1, wherein the drug in the first lamina is a member selected from the group consisting of ibuprofen, acetaminophen and codeine; and wherein the second lamina comprises a dosage amount of a drug selected from the group consisting of ibuprofen, acetaminophen and codeine.
7. The bilaminated system for delivering a beneficial drug to an environment of use according to claim 1, wherein the drug in the first lamina is ibuprofen, and wherein the second lamina comprises a dosage amount of the drug ibuprofen.
8. The bilaminated system for delivering a beneficial drug to an environment of use according to claim 1, wherein the drug in the first layer is acetaminophen, and wherein the second lamina comprises a dosage amount of the drug acetaminophen.
9. The bilaminated system for delivering a beneficial drug to an environment of use according to claim 1, wherein the first lamina comprises acetaminophen and the second lamina comprises the drug codeine.
10. The bilaminated system for delivering a beneficial drug to an environment of use according to claim 1, wherein the first lamina comprises ibuprofen and the second lamina comprises codeine.
11. The bilaminated system for delivering a beneficial drug to an environment of use according to claim 1, wherein the first lamina comprises more than one hydroxypropylmethylcellulose ether.
12. A bilaminated system for delivering a beneficial drug to an environment of use, the bilaminated system comprising: (a) 30 to 90 weight percent of a cellulose ether composition; (b) a first lamina comprising 30 to 80 weight percent of a cellulose ether selected from the group of hydroxypropylmethylcellulose ethers having a number average molecular weight of 9,000 to 250,000; and (c) a second lamina in parallel mated relation with the first lamina, the second lamina comprising 2 to 50 weight percent of a cellulose ether composition comprising a hydroxypropylcellulose comprising a hydroxypropoxyl content of 7% to 16% and a dosage unit amount of from about 0.05 ng to 5 g of a beneficial drug.
13. A bilaminated system for delivering a beneficial drug to an environment of use according to claim 12, wherein the second lamina comprises a hydroxypropylmethylcellulose ether having a number average molecular weight of from 9,000 to 250,000.
14. A bilaminated system for delivering a beneficial drug to an environment of use according to claim 12, wherein the beneficial drug in the second lamina is codeine.
15. A bilaminated system for delivering a beneficial drug to an environment of use according to claim 12, wherein the second lamina comprises a hydroxypropylmethylcellulose ether having a number average molecular weight of from 9,000 to 250,000 and the beneficial drug is ibuprofen.
16. A bilaminated system for delivering a beneficial drug to an environment of use according to claim 12, wherein the second lamina comprises a hydroxypropylmethylcellulose ether having a number average molecular weight of from about 9,000 to 250,000 and the drug is acetaminophen.
17. A bilaminated system for delivering a beneficial drug to an environment of use, wherein the bilaminated system comprises:
(a) 30 to 90 weight percent of a cellulose ether composition present in a first lamina and a second lamina; wherein the first lamina comprises 30 to 80 weight percent of a cellulose ether hydroxypropylmethylcellulose having a number average molecular weight of from 9,000 to 250,000; and wherein the second lamina comprises 2 to 50 weight percent of a cellulose ether hydroxy-propylmethylcellulose having a different number average molecular weight of from 9,000 to 250,000, a dosage amount of from about 0.05 ng to 5 g of a beneficial drug, and is thicker than the first lamina.
(a) 30 to 90 weight percent of a cellulose ether composition present in a first lamina and a second lamina; wherein the first lamina comprises 30 to 80 weight percent of a cellulose ether hydroxypropylmethylcellulose having a number average molecular weight of from 9,000 to 250,000; and wherein the second lamina comprises 2 to 50 weight percent of a cellulose ether hydroxy-propylmethylcellulose having a different number average molecular weight of from 9,000 to 250,000, a dosage amount of from about 0.05 ng to 5 g of a beneficial drug, and is thicker than the first lamina.
18. The bilaminated system for delivering the beneficial drug to the environment of use according to claim 17, wherein the first lamina comprises more than one hydroxypropylmethylcellulose ether.
19. The bilaminated system for delivering the beneficial drug to the environment of use according to claim 17, wherein the second lamina comprises more than one hydroxypropylmethylcellulose ether.
20. A bilaminated system for delivering a beneficial drug to an environment of use, wherein the bilaminated system comprises:
(a) 30 to 90 weight percent of a cellulose ether composition comprising a first lamina and a second lamina; said first lamina comprising 30 to 80 weight percent of a cellulose ether hydroxy-propylmethylcellulose ether having a number average molecular weight of from 9,000 to 250,000 and a dosage unit amount of from about 0.05 ng to 5 g of a beneficial drug and wherein the second lamina comprises 2 to 50 weight percent of a cellulose ether hydroxypropylmethylcellulose having a different number average molecular weight of from 9,000 to 250,000.
(a) 30 to 90 weight percent of a cellulose ether composition comprising a first lamina and a second lamina; said first lamina comprising 30 to 80 weight percent of a cellulose ether hydroxy-propylmethylcellulose ether having a number average molecular weight of from 9,000 to 250,000 and a dosage unit amount of from about 0.05 ng to 5 g of a beneficial drug and wherein the second lamina comprises 2 to 50 weight percent of a cellulose ether hydroxypropylmethylcellulose having a different number average molecular weight of from 9,000 to 250,000.
21. The bilaminated system for delivering the beneficial drug to the environment of use according to claim 20, wherein the first lamina comprises more than one cellulose ether and the second lamina comprises more than one cellulose ether.
22. A bilaminated system for delivering a beneficial drug to an environment of use, the bilaminated system comprising: (a) a cellulose ether composition comprising: (b) a first lamina comprising up to 80 weight percent of a cellulose ether selected from the group consisting of hydroxypropylmethylcellulose ethers comprising a degree of polymerization of 40 to 1600, a viscosity of 2 to 225,000 and a number average molecular weight of 9,000 to 307,200; and (c) a second lamina in parallel mated relation with the first lamina, the second lamina comprising up to 50 weight percent of a cellulose ether composition comprising a hydroxy-propylcellulose comprising a hydroxypropoxyl content of 7 percent to 16 percent, and a dosage unit amount of 25 ng to 1.5 g of a beneficial drug.
23. The bilaminated system for delivering a beneficial drug to an environment of use according to claim 22, wherein the second lamina comprises a hydroxypropylmethylcellulose ether comprising a degree of polymerization of 40 to 1600, a viscosity of 2 to 225,000, and a number average molecular weight of from 9,000 to 307,200.
24. The bilaminated system for delivering a beneficial drug to an environment of use according to claim 22 wherein the first lamina comprises more than one hydroxypropylmethylcellulose ether.
25. The bilaminated system for delivering a beneficial drug to an environment of use according to claim 22, wherein the bilaminated system is sized and shaped for oral administration into the gastrointestinal tract of an animal and the first lamina comprises more than one hydroxypropylmethylcellulose and a dosage unit amount of a beneficial drug.
26. A bilaminated system for delivering a beneficial drug to an environment of use, wherein the bilaminated system comprises, (a) at least 30 weight percent of a cellulose ether composition present in a first lamina and a second lamina; wherein the first lamina comprises up to 85 weight percent of at least one hydroxy-propylmethylcellulose comprising a number average molecular weight of from 9,000 to 250,000; and wherein the second lamina comprises up to 85 weight percent of hydroxypropylmethylcellulose comprising a different number average molecular weight of from 9,000 to 250,000 and a dosage amount of from 25 ng to 1.5 g of a beneficial drug.
27. The bilaminated system for delivering the beneficial drug to the environment of use according to claim 26, wherein the first lamina comprises more than one hydroxypropylmethylcellulose.
28. The bilaminated system for delivering the beneficial drug to the environment of use according to claim 26, wherein the second lamina comprises more than one hydroxypropylmethylcellulose ether.
29. A bilaminated system for delivering a beneficial drug to an environment of use, wherein the bilaminated system comprises:
(a) 30 weight percent to 90 weight percent of a cellulose ether composition comprising a first lamina and a second lamina said first lamina comprising a cellulose ether selected from a hydroxy-propylmethylcellulose ether comprising a number average molecular weight of from 9,000 to 250,000 and a dosage unit amount of 25 ng to 1.5 g of a beneficial drug; and wherein the second lamina comprises a cellulose ether selected from a hydroxypropylmethyl-cellulose ether comprising a different number average molecular weight of from 9,000 to 250,000.
(a) 30 weight percent to 90 weight percent of a cellulose ether composition comprising a first lamina and a second lamina said first lamina comprising a cellulose ether selected from a hydroxy-propylmethylcellulose ether comprising a number average molecular weight of from 9,000 to 250,000 and a dosage unit amount of 25 ng to 1.5 g of a beneficial drug; and wherein the second lamina comprises a cellulose ether selected from a hydroxypropylmethyl-cellulose ether comprising a different number average molecular weight of from 9,000 to 250,000.
30. The bilaminated system for delivering the beneficial drug to the environment of use according to claim 29, wherein the first lamina comprises more than one cellulose ether and the second lamina comprises more than one cellulose ether.
31. A bilaminated system for delivering the beneficial drug ibuprofen to an environment of use, wherein the bilaminated system comprises, a first lamina comprising up to 80 weight percent of a hydroxypropylmethylcellulose comprising a degree of polymerization of about 50 to 1260, a viscosity of about 3 to 100,000 centipoises and a number average molecular weight of 9,000 to 250,000, and a dosage amount of from 25 ng to 1.5 g of ibuprofen; and a second lamina comprising up to 50 weight percent of a hydroxypropyl-cellulose comprising from 7 percent to 16 percent hydroxypropoxyl, and a dosage amount of from 25 ng to 1.5 g of ibuprofen.
32. The bilaminated system for delivering the beneficial drug ibuprofen to an environment of use according to claim 31, wherein the first lamina comprises up to 80 weight percent of a different hydroxypropylmethylcellulose comprising a degree of polymerization of about 50 to 1260, a viscosity of about 3 to 100,000 centipoises, and a number average molecular weight of from 9,000 to 250,000.
33. The bilaminated system for delivering the beneficial drug ibuprofen to an environment of use according to claim 31, wherein the second lamina comprises up to 50 weight percent of a different hydroxypropylmethylcellulose comprising a degree of polymerization of about 50 to 1260, a viscosity of about 3 to 100,000 centipoises and a number average molecular weight of from 9,000 to 250,000.
34. The bilaminated system for delivering the beneficial drug ibuprofen to an environment of use according to claim 31, wherein the first lamina comprises 58 weight percent ibuprofen, and the second lamina comprises 87 weight percent ibuprofen.
35. The bilaminated system for delivering the beneficial drug ibuprofen to an environment of use according to claim 31, wherein the bilaminated system comprises 200 mg of ibuprofen.
36. The bilaminated system for delivering the beneficial drug ibuprofen to an environment of use according to claim 31, wherein the bilaminated system comprises 400 mg of ibuprofen.
37. The bilaminated system for delivering the beneficial drug ibuprofen to an environment of use according to claim 31, wherein the bilaminated system comprises 600 mg of ibuprofen.
38. The bilaminated system for delivering the beneficial drug ibuprofen to an environment of use according to claim 31, wherein the first lamina comprises 400 mg of ibuprofen and the second lamina comprises 200 mg of ibuprofen.
39. The bilaminated system for delivering the beneficial drug ibuprofen to an environment of use according to claim 31, wherein the first lamina comprises a hydroxypropylmethylcellulose comprising a molecular weight about 9,200 and a hydroxypropyl-methylcellulose comprising a molecular weight about 241,900, and the second lamina comprises a hydroxypropylmethylcellulose comprising a molecular weight about 9,200.
40. A bilaminated system for delivering a beneficial drug to an environment of use wherein the bilaminated system comprises: a first lamina comprising up to 80 weight percent of a hydroxy-propylmethylcellulose comprising a degree of polymerization of about 50 to 1260, a viscosity of about 3 to 100,000 centipoises and a number average molecular weight of 9,000 to 250,000; a second lamina comprising a hydroxypropylcellulose comprising a hydroxypropoxyl content of 7% to 16%; and wherein the bilaminated system comprises from 25 ng to 1.5 g of a beneficial drug selected from the group consisting of cimentidine, umetidine, ranitidine, naproxen, estrogenic, progestiational, captopril, diltiazom, and isosorbide dinitrate.
41. Use of a bilaminated system according to any one of claims 1 to 40 to deliver a beneficial drug to an environment of use.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/034,971 | 1987-04-06 | ||
| US07/034,971 US4786503A (en) | 1987-04-06 | 1987-04-06 | Dosage form comprising parallel lamine |
| US07/039,405 US4871548A (en) | 1987-04-06 | 1987-04-17 | Controlled release dosage form comprising different cellulose ethers |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1331739C true CA1331739C (en) | 1994-08-30 |
Family
ID=39967167
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000563233A Expired - Lifetime CA1331739C (en) | 1987-04-06 | 1988-04-05 | Dosage form comprising parallel laminae |
Country Status (21)
| Country | Link |
|---|---|
| US (3) | US4786503A (en) |
| EP (1) | EP0413061B1 (en) |
| JP (2) | JP2916147B2 (en) |
| KR (1) | KR950003918B1 (en) |
| AT (1) | ATE116844T1 (en) |
| AU (1) | AU601033B2 (en) |
| BE (1) | BE1001699A3 (en) |
| CA (1) | CA1331739C (en) |
| CH (1) | CH677447A5 (en) |
| DE (2) | DE3811114C2 (en) |
| ES (2) | ES2006394A6 (en) |
| FR (1) | FR2613224B1 (en) |
| GB (1) | GB2203338B (en) |
| GR (1) | GR1000053B (en) |
| IE (1) | IE67156B1 (en) |
| IT (1) | IT1219750B (en) |
| LU (1) | LU87189A1 (en) |
| NL (1) | NL8800867A (en) |
| PT (1) | PT91442B (en) |
| SE (1) | SE503611C2 (en) |
| ZA (1) | ZA882034B (en) |
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1988
- 1988-03-22 ZA ZA882034A patent/ZA882034B/en unknown
- 1988-03-25 ES ES8800932A patent/ES2006394A6/en not_active Expired
- 1988-03-29 GB GB8807493A patent/GB2203338B/en not_active Expired - Lifetime
- 1988-03-30 CH CH1241/88A patent/CH677447A5/de not_active IP Right Cessation
- 1988-03-31 AU AU14065/88A patent/AU601033B2/en not_active Expired
- 1988-03-31 DE DE3811114A patent/DE3811114C2/en not_active Expired - Lifetime
- 1988-04-01 GR GR880100214A patent/GR1000053B/en unknown
- 1988-04-05 LU LU87189A patent/LU87189A1/en unknown
- 1988-04-05 SE SE8801240A patent/SE503611C2/en not_active IP Right Cessation
- 1988-04-05 JP JP63083965A patent/JP2916147B2/en not_active Expired - Lifetime
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- 1988-04-05 IT IT67302/88A patent/IT1219750B/en active
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- 1988-04-06 FR FR888804509A patent/FR2613224B1/en not_active Expired - Lifetime
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- 1988-09-01 US US07/239,231 patent/US4946685A/en not_active Expired - Lifetime
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1989
- 1989-08-11 PT PT91442A patent/PT91442B/en not_active IP Right Cessation
- 1989-08-14 ES ES89308220T patent/ES2069588T3/en not_active Expired - Lifetime
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