CA1097220A

CA1097220A - Controlled release tablet

Info

Publication number: CA1097220A
Application number: CA262,583A
Authority: CA
Inventors: Aaron L. Weiss; Richard W. Walton; Albert E. De Lorimier
Original assignee: ER Squibb and Sons LLC
Current assignee: ER Squibb and Sons LLC
Priority date: 1975-10-10
Filing date: 1976-10-04
Publication date: 1981-03-10
Also published as: IE44540B1; SE7611241L; JPS5264420A; FR2326933A1; DE2645547A1; DK454876A; BE847095A; SE435569B; AU1844676A; AU516051B2; CH616843A5; NL7611148A; FR2326933B1; IE44540L; HU175540B; NO763450L; ZA765931B; PH14564A; GB1568837A

Abstract

TH7 Abstract The rate of release of medicament from a controlled release tablet having a polymeric vinylpyrrolidonecarboxy-vinyl hydrophilic core is improved by coating the medica-ment-containing core with a substantially water insoluble rupturable film which is water permeable and comprises a blend of hydrophobic polymer and hydrophilic polymer.

Description

~972zo TH7 This invention relates to a novel improved controlled release tablet for medicaments comprising an active ingredient which is dispersed in a water soluble permeable matrix~
A controlled release tablet or the administration of medicinal agents over a prolonged period of up to about eight hours is described in U. S. Patent ~o. 3,458,622, July 29, 1969 to John A. Hill. This patent discloses a compressed tablet for the prolonged release of a medicament containing that medicament in a core formed Erom a polymeric vinyl pyrrolidone, preferably polyvinyl pyrrolidone (Pve), and a carboxyvinyl hydrophilic polymer such as those marketed under the trademark Carbopol. The core material formed from the two polymeric substances provides the con-trolled release effect by forming a complex under the action of water or gas-tric fluid. This complex is gel-like in conslstency and re-tards the diffusion of active ingredient from the tablet.
It has been found, however, that there is a tendency for an initial surge of medicament to occur so -that the first amount of drug released may be larger than subsequently. This may be due to the short delay until water or gastric fluid acts on the polymeric blend and the gel which provides the delaying action forms.
It is therefore an object of thls invention to improve the characteristics of controlled release tablets formed from a blend of polymers such as those in the Hill patent re~erred to above by reducing the tendency for an initial surge in the release of medicament.
The present invention provides an lmproved controlled release tablet which comprises a compressed matrix com-prising an effective amount of medicament dispersed in a blend of poly-~ meric vinyl pyrro]idone and a carboxyvinyl hydrophilic polymer ` TH7

2;2(~

and a substantially water insoluble, water permeable, rup~turable film coating on the matrix oompris:ing a blend of hydrophobic polymer which is slightly soluble in water and hydrophilic polymer which is water solublel, The improvement comprises coating an insoluble swalling type delayed release matrix with a rupturable film which is water permeable and substantially insoluble in water comprising a combination of hydrophobic and hydrophilic poly-mers to modify the drug release rate.
In the water-insoluble matrix of tha type described in the Hill patent referred to above, the controlled release rate of the drug is dependent upon the interaction of the two principal ingredients, the polymer and the hydrocolloid, in the presence of water to form a gummy complex of low solu-bility. Since little of the gummy complex i~ present initially, the drug at or near the surface dissolves fairly rapidly and there is an initial surge wherein a relatively larga amount o drug is released in~the beginning or a period of about one hour. As the colloid complex is formad, once aqueous solution :
penetrates the surface of the tablet, the gel r~tards the dis-solution of the drug out of the tablet.

According to this inven~ion, the delayed release :
charactexistic of a water insoluble ma~rix of the type des-cri~ed in the Hill patent is improved by coating suah a matrix with a ~ilm o~ the kind describad below. Initially, while the film lS~ intact, the ralease of the drug contained in the matrix is pri~arily controlled by diffusion of solvent and soluta molecules through the film~ As watar or gastric fluid permeates through the film, the gummy complex forms and the slight swell-ing of -the complex causes the film to rupture or erode. The release rate is then controlled by the gummy complex. The appli-. . .

, .

~97;2~a~

cation of a relatively water lnsoluble, water permeable film primarily controls the drug release rate ~lile the matrix gel is being generated and a smoother, gradual, more uniform release rate is achieved during -the entire period of about eight to twelve hours, approaching a zero order release pat-texn. The release pattern of the core, upon application of the film, can be varied over a range by varying -the composi-tion and amount of film forming mixture.
The controlled release tablets are prepared, accord-ing to this invention, by forming a tablet-like matrix in which the active ingredient ls dispersed and then coatiny this matrix with a water permeable film of low wa-ter solubility.
The film is a combination of hydrophobic polymer which is slightly soluble in water and hydrophilic polymer which is water soluble. When combined, they constitutè a relatively insoluble blend.
The matrix comprises a polymer blend. One component of the polymer blend is a vinyl polymer, e.g., polyvinyl py-rrolidone ~Merck Index, 8th ed., 1968, page 849) having a molecular weight o~ about 5,000 to 80,000, preferably about 40,000, generally referred to as PVP. The second component of the polymer blend is a carboxypolymethylene hydrocolloid polymer of the type described in U. S~ Patent No. 2,909,462, October 10, 1959 ~see also Chem. Eng. News 36, No. 39, page ~;
64 (Sept. 29, 1958)], a carboxyvinyl hydrophilic polymer of ;~
acrylic acid cross-linked with polyalkenyl polyether and having active carboxyl groups, particularly acrylic acid cross-linked with polyallyl sucrose. Such carboxyvinyl hydro-philic polymers are marketed under -the trademark Car~opol with designations 934, 940 941 by B. ~. Goodrich Chemical Co.

972 % 0 TH7 Controlled release of the medicament ~rom tablet matrices formed from such polymer blends can be aahieved with relatively small proportions of the release controll-ing substances In general, the polymer blend comprises less than 50% by weight o~ the matrix and, indeed, weight of the complete tablet. The proportions by weight of the two polymeric substances in the blend which forms the matrix is about 1:10 to 10:1 (by weight) of vinyl polymer to car-boxypolymethylene polymer. The preferred ratio is about 1:1 to 1.5:1. The ratio tby weight) of carboxyvinyl poly-mer to active drug ingredient is less than 0~5:1, preferablyabout 0.1 to 0.45:1~ The combined weight of the two polymers in the blend may exceed half the weight of active medicament, ~-but is preferably below about 75% of the weight of active ~ ~
drug.~ These proportlons refer to the matrix. ;~ ~`
~ Finished tablets having a tot~l weight of up to about l gm can be prepared.~ Of this total weight,~the coat-ing described in detail below comprlses about 5 to 15 Thus the~controlled release tablet matrix preferably compri~es a blend of an effective amount of medicament which is preferably at least about 50% of the totaI matrix weight, vinyl polymer, preferably PVP, and a carboxyvinyl hydrophilic polymer of acrylic cross~linked with polyalkenyl polyether, preferably a polymer of acrylic acid cross-linked with poly-allyl sucrose and especially Carbopol. The release control substance is a gel formed by the interaction of the polymers in the presence of water.
~ The ratio by weight of vinyl polymer to carboxypoly-methylene polymer is about 1:10 to 10:1, preferably about 1:1.

The ration by weight of carboxyvinyl polymer to active drug ingredient is less than 0.5:1, preferably about 0.1 to 0.45:1.

1(;~9722~ TH7 The combined weight oE the polymers is below about 75% of the weight oE the active drug ingredient.
To form the tablet matrix or core~ a dry granula-tion technique ls preferred. All of the ingredlents are blended in dry form, made more dense by s].ugginy or com-paction and reducing to a granulation by grinding. The ground particles are then compressed into tablet foxm which can take any of the conventional shapes, e.g., round, elon-gated, oval, etc. A tablet press fitted with 5Ui tably sized punches and dies are used to form a tabIet core o any de-sired weight, shape and composition.
In carrying out the dry granulation procedure various ;~
other conventional ingredients can be included as required~
For example, a diluent or filler may be included for welght adjustment~ Such diluents includej for example, lactose, mannitol, ~orn starch, particularly, various cellulose deri-vatives such as wood cellulose (Solkafloc) and especially microcrystalline cellulose~marketed under the trademark - Avicel (see U. S. Patents 2,978,446 and 3,141,875). Other additives may include lubricants like stearic acid, pa]mitic .:
acid, magnesium stearater calcium stearate, ta}c, carnauba wax or the like. Silica flow conditioners or glidants may .
also be included. Colors acceptable in drugs such as the various F.D. & C. colors can be added at various stages, in-cluding spray coatings o the finished core.
As an alternative, though not preerred, the wet granulation technique can also be used. ~ccording to this procedure, the dry active ingredient, vinyl polymer and poly-methylene polymer and other diluents are blended, for example, in a planetary mixer. The powders are wetted with a granulating 3Q liquid like methylene chloride, chloroorm, methyl chloroform, ~97Z2~ TH7 pure or denatured ethyl alcohol, isopropyl alcohol, 1,1-dichloroethane, 1,2-dichloroethane, l,l,l-trichloroethana or the like. Binders such as zein, ethyl cellulose, beta-pinene polymers, gelatin, shellac or the like may be inclu-ded in the granulating liquid. The moist mass is granulated, e.g., by ~orcing thxough a screen of suitable mesh size, driedt and if desired, the particles further reduced in size~ The granulate is then compressed in conventional manner, using lubricants, glidants, etc., as required.
When the tablet matrix has been ~ormed and, optionally the color has been applied, a film is applied according to this invention. The film comprises a combination of hydro-phobic and hydrophilic polymers which permits the entry of water and hydration of the matrix so that there is not a large initial surge in the release of medlcament.
The hydrophllic polymers are water soluble~polymers (lmder pH 5.5). They include cellulose methyl ethers like me~hyl cellulose, hydroxypropylmethyl cel~lulose, hydroxy-methyl celluIose phthalate, also hydroxypropyl cellulose, cellulose acetate phthalate or polyvinyl alcohol.
The hydrophobic poLymers are slightly soluble in water, ` (By slightly soluble is meant the definitlon in USP XIX,~page 6, ;~ although polymers up to 3% solubLe ln water can be used.~ They include cellulose ethyl~esters like ethyl cellulose, also cellu-lose acetate, polyvinyl alcohol-maleic anhydride copolymers, .
pinene polymers (Picolyte), glycerol esters of wood resins like glycerol ester of partially dimerized rosin, ~lycero}
ester of partially hydrogenated wood rosin, glycerol ester of polymeriæed rosin, hydroxypropyl methyl cellulose phthalate, etc.

.

~097ZZo TH7 Preferred are combinations of methyl cellulose and ethyl cellulosa ox hydroxypropylmethyl cellulose and ethyl cellulose.
One or more members of each class of polymer can be used. The proportion of hydrophilic polymer or polymers to hydrophobic polymer or polymers is within the range of about 4:1 to about 1:4 (by weight) preferably about 1.5:1 to 1 1.
These polymers are best combined in a proportion which re-sults in rupture in about one hour. ~ film of about 1 to 15 mil (.001 to 0.015 inches) preferably 3 to 7 mil, in thickness is sufficient to achieve the purpose.
1~ The film formers are applied by spraying a system containing them on the core by conventional ~llm coating tech-niques. The film formers are dissolved in a solv~nt or mixture of solvents in which both types are solubl~ or form a solvent.
Such solvents include alcohols like methyl alcohol, ethyl alco~
hol or isopropyl alcohol, ketones like acetone,~ methyl~thyl , .
ketone, chlorina-ted hydrocarbons like methylene chloride, di~
chloroethane, l,lgl-trichloroethane, atc. Preferred are methyl-ene chloride plus isoprcpyl alcohol or methylene chloride plus methyl alcohol (preferably 70~:30%).
~he ilm forming composition may optionally inclu~e plasticizers such as triethyl citrate, diethyl phthalate, propylene glycol, glycerin, butyl phthalate, castor oil or the like to provide the desired balanced characteristics.
Preferably, the ~olor! if used, is applied in this fil~ coat-ing composition. ~hese colors include F.D. & C. approved colors or lakes. Opacifiers such as titanium dioxide can also be included.
A wide variety of medicaments which are orally ad-ministered in tablet form can be used in the form of tab-lets pxepared according to this invention. These include, 2Z~

for example, adrenergic agents such as ephedrine, desoxy-ephedrine, phenylephrine, epinephrine and the like, cholinergic agents such as physostigmine, neostigmine and the like, antispasmodic agents such as a-tropine, methanetheline, papaverine and the like, curariform agents such as chlorisondamine and the like, tranquilizers and muscle relaxants such as fluphenazine, chlorpromaæine, triflupromazine, mephenesin, meprobamate and the like, antidepressants like amitrip-tyline, nortriptyline, and the like, antihistamines such as diphenylhydramine, dimenhydrinate, tripelennamine, perphenazine, chlorprophenazine, chlorprophenpyridamine and the like, hypotensive agents such as rauwolfia, reserpine and the like, cardioactive agents such as benzydroflumethiazide, flumethiazide, chlorothiazide, aminotrate, propranolol, procainamide and the like, steroids~such as testosterone, prednlsolone, and the like, antibacterial agents, e.g., sulfonamides such as sulfadiazine, sulfamerazine, sulfametha-zine, sulfisoxazole and the like, antimalarials such as chloroquine and the like, antlbiotics such as the tetra-cyclines, nystatin, streptomycin, cephradine and other cephalosporlns, penlcillin, semi-synthetic penicillins, griseofulvin and the like, sedatives such as chloral hydrate, phenobarbital and other barbiturates, glutethimide, antitubercular agents such as isoniazid and the like, analgesics such as aspirin, propoxyphene, meperidine and the like, etc. These substances are frequently employed either as the free compound or in a salt form, e.g~, acid addition salts, basic salts like alkali metal salts, etc. Other therapeutic agents having the same or di.fferent physiological activity can also bc em~loycd in pharrllaccutical preparatioJls 7;~
rrll7 within the scope of the present .invention.
The invention is particularly ada,pted for controlled release tablets eontai.n.ing the an~iarrhythmic agent procai.namide (usually formulated in the Eorm of its hydrochlorideJ.
The following examples are il.lust:rative of the invention and constitute preferred embodiments. They also serve as models for additional compositions within the ~:
scope of the invention.

Example 1 ~ :~
~ , The following ingredients are used to make 1000 tablets each containing 500 mg. of procainamide hydrochloride:
A. Compressed Tablet ;~
Procainamide HCl S00 gm.

Polyvinylpyrrolidone (pharmaceutical grade)144 gm.

Carbopol 934 -(carboxypolymethylene polymer) 96 gm.

Avicel (microcrystalline cellulose) 23.4 gm.

Carnauba wax (~.S.P.No. 1 yellaw powdered, 100 mesh) 15.6 gm.
Stearic acid (food gradeJ 7.8 gm. ~ ~ -*Syloid 244 Grade 68 ~silica glidantJ3.95 gm.

B Coating Solution :
Per ~iter -Methocel 60 HG 15 cps.
(hydroxypropylmethyl cellulose) 30 gm.
Ethyl cellulose 20 gm>
T.riethyl Citrate 2 gm.
Isopropyl Alcohol 99%
~30% v/v of solventJ2~4.4 ml.

_ g _ * Trade Mark ~'^" i " ~, :

~97~:ZC~
1`~17 Methylene Chloride q.s. 1 liter (ca. G64 ml.) All of the ingredients under A above, except the stearic acid and Syloid are h:lendecl in t:he dry form. The dry blend is compacted on a tablet press then reduced by grinding to about 20 mesh. The stearic acid lubricant and glidant are added to the dry granu].a-te and blended -thoroughly. The mixture is then compressed on a tablet press to form biconvex oval tablet matrices with slightly flattened ends weighing 790 mg. each.

The coating solution B is then applied to the tablet matrices by airless spray in a back outlet rotary coating pan. The coating is applied until a 3.5 to 4 mil.
coating is obtained.
Example 2 Tablet matrices are prepared as described in Example l.
A~color coat solution is prepared by adding 400 ml.
of Opaspray Yellow (a dispersion of F.D. & C. yellow ~5 & 6 ~;~

lakes, titanium oxide and hydroxypropylmethyl cellulose in SD3A Alcohol) to the coating solution B in Example l and mixing. The compressed tablet matrices are then sprayed as in Example l to obtain yellow coated tablets each weighlng a total of 840 mg. and containing 500 mg. of procainamide HCl (core = 791 mg.).

Example_3_ The following ingredients are used to make l000 tablets each containing 570 mg. of cephradine:

~ * Trade Mark ,, .

. - , .

T~7 A. Compressed Tablet Cephradine 570.6 gm.
Lactose anhydrous274.4 gm.
Plasclone (PVP) ~-3060.0 g~.
Carbopol 934 40.0 gm.
Ethyl cellulose 6.0 gm.
Talc 39.7 grn.
*Emersol 9.3 gm.
Methylene chloride qs~
lQ B. Coatin~ Solution Per Liter Hydroxypropylmethylcellulose 50 ym.
phthalate (XD-55) Methocel 60 HG
- premium 15 cps. 25 gm.
Methanol ca 12.5~ q.s.
Isopropyl Alcohol 15% q.s Methylene chloride ca 65% q.s.
* *
The cephradine, lactose, Plasdone and Carbopol are ~-mixed. The mixture is granulated with the ethyl cellulose and methylene chloride. The granulation is dried and reduced to 20 mesh size. The talc and Emersol are added and the mixture is compressed into tablets (1000). The coating solution is well mixed and sprayed onto the compressed cores to a thickness of 3 - 4.5 mil.
Example 4 The release rate of active drug determined for the uncoated cores and the film coated tablets prepared according to Example 1 by the U.S.P. XIX dissolution method (p.651) using l liter of water at 37 C. with the basket rotated at 50 rpm. is as follows:
:, ., Trade Mark i ~ ~

~lg7Z~ TH7 TABLE I
P6 Procainamide ReLeased Per HQur_ _ HourYi].m Coated Tablet Uncoated Core 1 14.6 ~ ~0.0 %
2 20.1 ~1.8

3 13~3 14.4

4 20.0 9.8 S 1.5 ~ 3.6 6 6.3 3.2 7 5.7 3.0 :
8 2.1 0 ~ :;
3-10 9.9 6.1 Example 5 The release rate of cephradlne de-termined for the ~ :
coated tablets of Example 3 is as follows-;~ TABLE II
: % Cephradine Released .
Per Hour HourPer~ent : : 1 26 2 ~ 15 4 : 10 6 ~ 8 ~ -12--; - i

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:-

1. A controlled release medicinal tablet which comprises a compressed matrix comprising an effective amount of medica-ment dispersed in a blend of polymeric vinyl pyrrolidone and a carboxyvinyl hydrophilic polymer and a substantially water in-soluble, water permeable, rupturable film coating on the matrix comprising a blend of hydrophobic polymer which is slightly soluble in water and hydrophilic polymer which is water soluble, release of the medicament through said film beginning within about one hour after the tablet has been ingested.

2. A tablet as in claim 1 wherein the hydrophobic poly-mer is ethyl cellulose, cellulose acetate, polyvinyl alcohol-maleic anhydride copolymer, .beta.-pinene polymer or glycerol ester of wood resin, and the hydrophilic polymer is a cellulose methyl ether, hydroxypropyl cellulose, cellulose acetate phthalate or polyvinyl alcohol.

3. A tablet as in claim 1 wherein the hydrophobic poly-mer is ethyl cellulose and the hydrophilic polymer is methyl cellulose.

4. A tablet as in claim 1 wherein the hydrophobic poly mer is ethyl cellulose and the hydrophilic polymer is hydroxy-propylmethyl cellulose.

5. A tablet as in claim 1 wherein the matrix comprises an effective amount of medicament, polymeric vinyl pyrrolidone and a carboxyvinyl hydrophilic polymer of acrylic acid cross-linked with polyalkenyl polyether and the film coating com-prises a blend of hydrophobic polymer which is slightly solu-ble in water and hydrophilic polymer which is water soluble.

6. A tablet as in claim 5 wherein the film coating com-prises ethyl cellulose and hydroxypropylmethyl cellulose.

7. A tablet as in Claim 5 wherein the film coating comprises ethyl cellulose and methyl cellulose.

8. A tablet as in Claim 5 wherein the medicament is procainamide or salt thereof.

9. A tablet as in Claim 5 wherein the medicament is cephradine.

10. A tablet as in Claim 5 wherein the matrix com-prises medicament, polyvinyl pyrrolidone and polymer of acry-lic acid cross-linked with polyallyl sucrose and the film coat-ing comprises ethyl cellulose and hydroxypropylmethyl cellulose.

11. A tablet as in Claim 5 wherein the matrix comprises medicament, polyvinyl pyrrolidone and polymer of acrylic acid cross-linked with polylallyl sucrose and the film coating com-prises ethyl cellulose and methyl cellulose.

12. A tablet as in Claim 11 wherein the medicament is procainamide or salt thereof.

13. A tablet as in Claim 1 which comprises a matrix comprising an effective amount of medicament which is at least about 50% of the total tablet weight and polymer blend compris-ing 1:10 to 10:1 parts by weight of polyvinyl pyrrolidone and polymer of acrylic acid cross-linked with polylallyl sucrose, said matrix having a substantially water insoluble, water per-meable film comprising a blend of about 4:1 to 1:4 parts by weight of water soluble hydrophilic polymer and slightly water soluble hydrophobic polymer.

14. A tablet as in Claim 13 wherein the medicament is procainamide or salt thereof.

15. A tablet as in Claim 13 wherein the hydrophobic polymer is ethyl cellulose and the hydrophilic polymer is methyl cellulose.

16. A tablet as in claim 13 wherein the hydrophobic polymer is ethyl cellulose and the hydrophilic polymer is hy-droxypropylmethyl cellulose.

17. A tablet as in claim 13 wherein the medicament is procainamide hydrochloride, the hydrophobic polymer is ethyl cellulose and the hydrophilic polymer is hydroxypropylmethyl cellulose.

18. Process for preparing a controlled release medici-nal tablet which comprises coating a compressed matrix com-prising an effective amount of medicament dispersed in a blend of polymeric vinyl pyrrolidone and a carboxyvinyl hydrophilic polymer with a substantially water insoluble, water permeable, rupturable film comprising a blend of hydrophobic polymer which is slightly soluble in water and hydrophilic polymer which is water soluble, release of the medicament through said film be-ginning within about one hour after the tablet has been inges-ted.

19. The process as in claim 18 wherein the coating com-prises ethyl cellulose and methyl cellulose.

20. The process as in claim 18 wherein the coating com-prises ethyl cellulose and hydroxypropylmethyl cellulose.

21. The process as in any of claims 18 to 20 wherein the matrix comprises an effective amount of medicament disper-sed in a blend of polymeric vinyl pyrrolidone and a carboxy vinyl hydrophilic polymer of acrylic acid cross-linked with polyalkenyl polyether.

22. The process as in claim 18 wherein the medicament is procainamide or salt thereof.

23. The process as in claim 18 wherein the medicament is cephradine.