GB1568837A

GB1568837A - Controlled release tablet

Info

Publication number: GB1568837A
Application number: GB41121/76A
Authority: GB
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: 1980-06-04
Also published as: BE847095A; FR2326933B1; DK454876A; IE44540L; HU175540B; DE2645547A1; AU1844676A; SE435569B; CA1097220A; IE44540B1; FR2326933A1; JPS5264420A; SE7611241L; CH616843A5; PH14564A; NO763450L; ZA765931B; AU516051B2; NL7611148A

Description

(54) CONTROLLED RELEASE TABLET (71) We, E. R. SQUIBB & SONS, INC., a Corporation organised under the laws of Delaware, United States of America, of Lawrenceville-Princeton Road, Princeton, New Jersey 08540, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to a novel improved controlled release tablet for medicaments comprising an active ingredient which is dispersed in a water insoluble permeable matrix.

A controlled release tablet for the administration of medicinal agents over a prolonged period of up to about eight hours is described in U.S. Patent No. 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 from a polymeric vinyl pyrrolidone, preferably polyvinyl pyrrolidone (PVP), and a carboxyvinyl hydrophilic polymer such as those marketed under the trademark Carbopol. The core material formed from the two polymeric substances provides the controlled release effect by forming a complex under the action of water or gastric fluid. This complex is gel-like in consistency and retards 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 this invention to improve the characteristics of controlled release tablets formed from a blend of polymers such as those in the Hill patent referred to above by reducing the tendency for an initial surge in the release of medicament.

The present invention provides a controlled release tablet which comprises water-insoluble matrix comprising a dosage amount of medicament dispersed in a blend of polymeric vinyl pyrrolidone and a carboxyvinyl hydrophilic polymer and a water-permeable, rupturable film coating of low water solubility on the matrix comprising a blend of hydrophobic polymer which is - slightly soluble (as hereinafter defined) in water and hydrophilic polymer which is water soluble under pH 5.5.

The improvement on the prior compositions comprises coating an insoluble water-swellable delayed release matrix with a rupturable film which is water permeable and of low water solubility comprising a blend of hydrophobic and hydrophilic polymers to modify the drug release rate.

In the water-insoluble matrix of the 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 vinyl pyrrolidone polymer and the hydrophilic polymer colloid, in the presence of water to form a gummy water-insoluble complex.

Since little of the gummy complex is present initially, the drug at or near the surface dissolves fairly rapidly and there is an initial surge wherein a relatively large amount of drug is released in the beginning for a period of about one hour. As the colloid complex is formed, once aqueous solution penetrates the surface of the tablet, the gel retards the dissolution of the drug out of the tablet.

According to this invention, the delayed release characteristic of a water-insoluble matrix of the type described in the Hill patent is improved by coating such a matrix with a film of the kind described below.

Initially, while the film is intact, the release of the drug contained in the matrix is primarily controlled by diffusion of solvent and solute molecules through the film. As water or gastric fluid permeates through the film, the gummy complex forms and the slight swelling of the complex causes the film to rupture or erode. The release rate is then controlled by the gummy complex. The application of a water-permeable film of low water solubility primarily controls the drug release rate while 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 pattern.

The release pattern of the core, upon application of the film, can be varied over a range by varying the composition and amount of film-forming mixture.

The controlled release tablets are prepared, according to this invention, by forming a tablet-like water-insoluble matrix in which the active ingredient is dispersed and then coating this matrix with a water permeable film of low water solubility. The film is a blend of hydrophobic polymer which is slightly soluble in water and hydrophilic polymer which is water soluble.

Together they constitute a blend which is of low water solubility.

The matrix comprises a polymer blend.

One component of the polymer blend is a vinyl polymer, e.g., polyvinyl pyrrolidone (Merck Index, 8th ed., 1968, page 849) having a molecular weight of 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)1, 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 hydrophilic polymers are marketed under the trademark Carbopol with designations 934, 940 and 941 by B. F.

Goodrich Chemical Co.

Controlled release of the medicament from tablet matrices formed from such polymer blends can be achieved with relatively small proportions of the release controlling substances. In general, the polymer blend comprises less than 50 Nn by weight of 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 preferably 1:10 to 10:1 (by weight) of vinyl polymer to carboxypolymethylene polymer.

The preferred ratio is about 1:1 to 1.5:1. The ratio (by weight) of carboxyvinyl polymer to active drug ingredient is preferably less than 0.5:1, more preferably about 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 proportions refer to the matrix.

Finished tablets having a total weight of up to about I gm can be prepared. Of this total weight, the coating described in detail below comprises about 5 to 15%.

Thus the controlled release tablet matrix preferably comprises a blend of a dosage amount of medicament which is preferably at least 50% of the total matrix weight, vinyl polymer, preferably PVP, and a carboxyvinyl hydrophilic polymer of acrylic acid cross-linked with polyalkenyl polyether, preferably a polymer of acrylic acid cross-linked with polyallyl 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 carboxypolymethylene polymer is preferably 1:10 to 10:1, more preferably about 1:1. The ratio by weight of carboxyvinyl polymer to active drug ingredient is preferably less than 0.5:1, more preferably about 0.1 to 0.45:1. The combined weight of the polymers is preferably below about 75% of the weight of the active drug ingredient.

To form the tablet matrix or core, a dry granulation technique is preferred. All of the ingredients are blended in dry form, made more dense by slugging or compaction and reducing to a granulation by grinding. The ground particles are then compressed into tablet form which can take any of the conventional shapes, e.g., round, elongated, or oval. A tablet press fitted with suitably sized punches and dies is used to form a tablet core of any desired 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 weight adjustment. Such diluents include, for example, lactose, mannitol, corn starch, particularly, various cellulose derivatives such as wood cellulose (Solkafloc*) and especially microcrystalline cellulose marketed under the trademark Avicel (see U.S. Patents Nos. 2,978,446 and 3,141,875). Other additives may include tabletting lubricants such as stearic acid, palmitic acid, magnesium stearate, calcium stearate, talc or carnauba wax. 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, including spray coatings of the finished core.

As an alternative, though not preferred, the wet granulation technique can also be used. According to this procedure, the dry active ingredient, vinyl polymer and *"Solkafloc" is a Registered Trade Mark.

polymethylene polymer and other diluents are blended, for example, in a planetary mixer. The powders are wetted with a granulating liquid such as methylene chloride, chloroform, methyl chloroform, pure or denatured ethyl alcohol, isopropyl alcohol, l,l-dichloroethane, 1,2dichloroethane or 1,1,1 -trichloroethane.

Binders such as zein, ethyl cellulose, betapinene polymers, gelatin or shellac may be dissolved in the granulated liquid. The moist mass is granulated, e.g., by forcing through a screen of suitable mesh size, dried, 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 formed and, optionally the color has been applied, a film is applied according to this invention.

The film comprises a blend of hydrophobic 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 medicament.

The hydrophilic polymers are watersoluble polymers (soluble under pH 5.5).

They include cellulose methyl ethers such as methyl cellulose, hydroxypropylmethyl cellulose, hydroxymethyl cellulose phthalate, also hydroxypropyl cellulose, cellulose acetate phthalate or polyvinyl alcohol.

The hydrophobic polymers are slightly soluble in water. (By slightly soluble is meant the definition in USP XIX, page 6, although polymers up to 3% soluble in water can be used). They include cellulose ethyl esters such as ethyl cellulose, also cellulose acetate, polyvinyl alcoholmaleic anhydride copolymers, p-pinene polymers (Picolyte*), glycerol esters of wood resins (e.g. glycerol ester of partially dimerized rosin, glycerol ester of partially hydrogenated wood rosin and glycerol ester of polymerized rosin), and hydroxypropyl methyl cellulose phthalate.

Preferred are mixtures of methyl cellulose and ethyl cellulose or 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 preferably within the range of 4:1 to 1:4 (by weight) preferably about 1.5:1 to 1:1. These polymers are best blended in a proportion which gives a film which results in rupture in about one hour. A 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.

*"Picolyte" is a Registered Trade Mark.

The film formers are applied by spraying a system containing them on the core by conventional film coating techniques. The film formers are dissolved in a solvent or mixture of solvents in which both types are soluble. Such solvents include alcohols such as methyl alcohol, ethyl alcohol or isopropyl alcohol, ketones such as acetone and methyl ethyl ketone, and chlorinated hydrocarbons such as methylene chloride, dichloroethane, and 1,1,1 -trichloroethane.

Preferred are methylene chloride plus isopropyl alcohol or methylene chloride plus methyl alcohol (preferably 70%:30% by volume).

The film forming composition may optionally include plasticizers such as triethyl citrate, diethyl phthalate, propylene glycol, glycerin, butyl phthalate or castor oil to provide the desired balanced characteristics. Preferably, the color, if used, is applied in this film coating composition. These colours 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 administered in tablet form can be used in the form of tablets prepared according to this invention. These include, for example, adrenergic agents such as ephedrine, desoxyephedrine, phenylephrine and epinephrine, cholinergic agents such as physostigmine and neostigmine, antispasmodic agents such as atropine, methanetheline, and papaverine, curariform agents such as chlorisondamine, tranquillizers and muscle relaxants such as fluphenazine, chlorpromazine, triflupromazine, mephenesin and meprobamate, antidepressants such as amitriptyline and nortriptyline, antihistamines such as diphenylhydramine, dimenhydrinate, tripelennamine, perphenazine, chlorprophenazine and chlorprophenpyridamine, hypotensive agents such as rauwolfia and, reserpine, cardioactive agents such as benzydroflumethiazide, flumethiazide, chlorothiazide, aminotrate, propanolol and procainamide, steroids such as testosterone and prednisolone, antibacterial agents, e.g.

sulfonamides such as sulfadiazine, sulfamerazine, sulfamethazine and sulfisoxazole, antimalarials such as chloroquine, antibiotics such as the tetracyclines, nystatin, streptomycin, cephradine and other cephalosporins, penicillin, semi-synthetic penicillins and griseofulvin, sedatives such as chloral hydrate, phenobarbital and other barbiturates, and glutethimide, antitubercular agents such as isoniazid and analgesics such as aspirin, propoxyphene and meperidine. These substances are frequently employed either as the free compound or in a salt form, e.g., acid addition salts or base salts (e.g. alkali metal salts). Other therapeutic agents having the same or different physiological activity can also be employed in pharmaceutical preparations with the scope of the present invention.

The invention is particularly adapted for controlled release tablets containing the antiarrhythmic agent procainamide (usually formulated in the form of its hydrochloride).

The following examples are illustrative of the invention and constitute preferred embodiments. They also serve as models for other 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 HC1 500 gm.

Polyvinylpyrrolidone (pharmaceutical grade) 144 gm.

Carbopol 934 (carboxypolymethylene polymer) 96 gm.

Avicel (microcrystalline cellulose) 23.4 gm.

Carnauba wax (U.S.P. No. 1 yellow powdered, 100 mesh) 15.6 gm.

Stearic acid (food grade) 7.8 gm.

Syloid* 244 Grade 68 (silica glidant) 3.95 gm.

B. Coating Solution Per Liter Methocel* 60 HG 15 cps.

(hydroxypropylmethyl cellulose) 30 gm.

Ethyl cellulose 20 gm.

Triethyl Citrate 2 gm.

Isopropyl Alcohol 99% (30% v/v of solvent) 284.4 ml.

Methylene Chloride q.s. 1 liter (ca. 664 ml.) *"Syloid" and "Methocel" are Registered Trade Marks.

All of the ingredients under A above, except the stearic acid and Syloid are blended in the 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 granulate 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 1.

A color coat solution is prepared by adding 400 ml. of Opaspray Yellow (a dispersion of F.D. & C. yellow &num;5 & 6 lakes, titanium oxide and hydroxypropylmethyl cellulose in SD3A Alcohol) to the coating solution B in Example 1 and mixing. The compressed tablet matrices are then sprayed as in Example 1 to obtain yellow coated tablets each weighing a total of 840 mg. and containing 500 mg. of procainamide HCI (core =791 mg.).

Example 3 The following ingredients are used to make 1000 tablets each containing 570 mg.

of cephradine: A. Compressed Tablet Cephradine 570.6 gm.

Lactose anhydrous 274.4 gm.

Plasdone* (PVP) K-30 60.0 gm.

Carbopol 934 40.0 gm.

Ethyl cellulose 6.0 gm.

Talc 39.7 gm.

Emersol* 9.3 gm.

Methylene chloride qs.

B. Coating Solution Per Liter Hydroxypropylmethylcellulose phthalate (XD-55) 50 gm.

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.

*"Plasdone" and "Emersol" are Registered Trade Marks.

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 3h.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 1 liter of water at 370C. with the basket rotated at 50 rpm. is as follows: TABLE I /n Procainamide Released Per Hour Film Coated Hour Tablet Uncoated Core 1 14.6% 40hun 2 20.1 11.8 3 13.3 14.4 4 20.0 9.8 5 1.5 3.6 6 6.3 3.2 7 5.7 3.0 8 2.1 0 9-10 9.9 6.1 Example 5 The release rate of cephradine determined for the coated tablets of Example 3 is as follows: TABLE II % Cephradine Released Per Hour Hour Percent 1 26 2 15 3 12 4 10 5 9 6 8 WHAT WE CLAIM IS: 1. A controlled release medicinal tablet which comprises a compressed waterinsoluble matrix comprising a dosage amount of medicament dispersed in a blend of polymeric vinyl pyrrolidone and a carboxyvinyl hydrophilic polymer and a substantially water-insoluble, water permeable, rupturable film coating on the matrix comprising a blend of hydrophobic polymer which is slightly soluble (as hereinbefore defined) in water and hydrophilic polymer which is water soluble under pH 5.5.

2. A tablet as in Claim 1, wherein the hydrophobic polymer is ethyl cellulose, cellulose acetate, polyvinyl alcohol-maleic anhydride copolymer, A-pinene polymer or glycerol ester of wood resin, and the water soluble 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 polymer is ethyl cellulose and the water-soluble hydrophilic polymer is methyl cellulose.

4. A tablet as in Claim 1, wherein the hydrophobic polymer is ethyl cellulose and the water-soluble hydrophilic polymer is hydroxypropylmethyl cellulose.

5. A tablet as in Claim 1, wherein the carboxyvinyl hydrophilic polymer is acrylic acid cross-linked with polyalkenyl polyether.

6. A tablet as in Claim 5, wherein the film coating comprises 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 polymeric vinyl pyrrolidone is polyvinyl pyrrolidone, the polymer of acrylic acid is cross-linked with polyallyl sucrose, and the film coating comprises ethyl cellulose and hydroxypropylmethyl cellulose.

11. A tablet as in Claim 5, wherein the polymeric pyrrolidone is polyvinyl pyrrolidone, the polymer of acrylic acid is cross-linked with polyallyl sucrose, and the film coating comprises 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, wherein the medicament constitutes at least 50% of the total tablet weight, the polymer blend of the matrix comprises 1:10 to 10:1 parts by weight of polyvinyl pyrrolidone and polymer of acrylic acid cross-linked with polyallyl sucrose, and the substantially water-insoluble water-permeable film comprises 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 hydroxypropylmethyl 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 medicinal tablet which comprises coating a compressed water-insoluble matrix comprising dosage amounts of medicament dispersed in a blend of polymeric vinyl pyrrolidone and a carboxyvinyl hydrophilic polymer with a water-permeable, rupturable film of low water-solubility comprising a blend of hydrophobic polymer which is slightly

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. Example 1 by the U.S.P. XIX dissolution method (p. 651) using 1 liter of water at 370C. with the basket rotated at 50 rpm. is as follows: TABLE I /n Procainamide Released Per Hour Film Coated Hour Tablet Uncoated Core 1 14.6% 40hun 2 20.1 11.8 3 13.3 14.4 4 20.0 9.8 5 1.5 3.6 6 6.3 3.2 7 5.7 3.0 8 2.1 0 9-10 9.9 6.1 Example 5 The release rate of cephradine determined for the coated tablets of Example 3 is as follows: TABLE II % Cephradine Released Per Hour Hour Percent

1 26

2 15

3 12

4 10 5 9 6 8 WHAT WE CLAIM IS: 1. A controlled release medicinal tablet which comprises a compressed waterinsoluble matrix comprising a dosage amount of medicament dispersed in a blend of polymeric vinyl pyrrolidone and a carboxyvinyl hydrophilic polymer and a substantially water-insoluble, water permeable, rupturable film coating on the matrix comprising a blend of hydrophobic polymer which is slightly soluble (as hereinbefore defined) in water and hydrophilic polymer which is water soluble under pH 5.5.

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

soluble (as hereinbefore defined) in water and hydrophilic polymer which is water soluble under pH 5.5.

19. The process as in Claim 18, wherein the coating comprises ethyl cellulose and methyl cellulose.

20. The process as in Claim 18, wherein the coating comprises ethyl cellulose and hydroxypropylmethyl cellulose.

21. The process as in any of Claims 18 to 20, wherein the carboxyvinyl hydrophilic polymer is a polymer of acrylic acid crosslinked 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.

24. A tablet as claimed in Claim 1, substantially as herein described.

25. A process as claimed in Claim 18, substantially as herein described.

26. A tablet as claimed in any of Claims I to 17 and 24, which has been prepared using a process as claimed in any of Claims 18 to 23 and 25.