NO763450L - - Google Patents

Description

This invention relates to the production of a new and improved

tablet with regulated release of drugs, comprising an active ingredient ©om©r distributed in a water-soluble, permeable base mass.

A controlled-release tablet for the administration of medicinal substances over a longer period of up to approx. 8 hours,

is described in U.S. Patent 3,458,622. This patent describes a compressed tablet for prolonged release of a drug,

and it contains the drug in a core formed of polymeric vinylpyrrolidone, preferably polyvinylpyrrolidone (PVP), and a hydrophilic carboxyvinyl polymer such as those marketed under the trademark "Carbopol". The core material formed by the two polymeric substances provides the regulated release

effect by forming a complex under the influence of water or

stomach box. This complex has a gel-like consistency and delays the diffusion of active ingredient from the tablet.

However, it has been found that there is a tendency for one initial release wave of the active agent to occur, so that the initial amount of agent released may be greater than the

later quantity. This may be due to the short delay that occurs before water or stomach acid acts on the polymer mixture and the gel that provides the delaying effect is formed.

It is therefore an object of the present invention to improve the properties of controlled release tablets, which are formed from a mixture of polymers such as those described in the above patent, by reducing the tendency of a first release wave of the active agent* Present invention provides an improved

tablet with regulated release, which comprises a compressed base mass containing an effective amount of active agent distributed

in a mixture of polymeric vinylpyrrolidone and a hydrophilic carboxyvinyl polymer and a substantially water-insoluble, water-permeable, burstable film coating on the base material, comprising a mixture of a hydrophobic polymer that is slightly soluble in water, and a hydrophilic polymer that is water-soluble. The improvement comprises that an insoluble base mass for controlled release of the swelling type is coated with a breakable film which is water permeable and virtually insoluble in water

and comprising a combination of hydrophobic and hydrophilic polymers to modify the rate of release of the active agent.

In the water-insoluble base mass of the type described in the above-mentioned ps patent, the regulated release rate of the active agent depends on the action between two

main components, the polymer and the hydrocolloid, in the presence of water

to form a gummy complex with little solubility. Since little of the rubbery complex is present at the beginning, the agent on or near the surface will dissolve relatively quickly, and a first release wave takes place where a relatively large

amount of active agent is initially released for a period of approx.

1 hour. After the colloid complex is formed when the aqueous solution has penetrated the surface of the tablet, the gel delays the release of the agent from the tablet.

according to the present invention, the properties of controlled release from a water-insoluble base material of the type described in the above-mentioned US patent are improved by coating such a base material with a film of the type described below. Initially, when the film is intact, the release of the agent present in the matrix will be mainly regulated by diffusion of solvent and solute molecules through the film.

As water or gastric fluid penetrates the film, the gummy complex is formed, and the slight swelling of the complex causes

that the film breaks or breaks down. The release rate is then regulated by the gummy complex. Application of a relatively water-insoluble, water-permeable film primarily regulates the release rate of the active agent when the base gel is formed, and a smoother, gradual and more uniform release rate is achieved during the entire period of approx. 8 to 12 hours, with release approaching zero. The core release pattern

when using the film can be varied over a large area by varying the composition and amount of the film-forming mixture.

The tablets with regulated release are released according to the invention by forming a tablet-like base mass in which the active ingredient is distributed, and then this base mass is coated with a water-permeable film with low water solubility. The film is a combination of a hydrophobic polymer that is slightly soluble in water, and a hydrophilic polymer that is water-soluble. In combination, they form a relatively insoluble mixture.

The base material comprises a polymer mixture. One component of the polymer mixture is a vinyl polymer, e.g. polyvinylpyrrolidone (Merck Index, 8th. ed., 1968, page 849) with a molecular weight of

about. 5,000 to 80,000, preferably approx. 40,000, commonly referred to as PVP. The second component 1 polymer composition is a hydro-colloidal carboxypolymethyl polymer of the type described in US-*patent 2,909,462 (see also Chem. Eng. News 36, no. 39, page 64 (Sept. 29, 1958)), a hydrophilic carboxyvinyl polymer of acrylic acid preheated with polyalkenyl polyether and with active carboxyl groups, in particular acrylic acid crosslinked with polyallyl sucrose. Such hydrophilic carboxyvinyl polymers are on the market under the trademark "Carbopol" with the designations 934, 940, 941 from B.F. Goodrich Chemical Co. Regulated release of the drug from tablet bases formed from such polymer mixtures can be achieved with relatively small amounts of release-regulating substances. In general, the polymer mixture comprises less than 50% by weight of the base mass and then also of

the entire tablet. The weight ratios between the two polymeric substances in the mixture that make up the base mass are approx. 1:10 to 10:1 between viriyl polymer and carboxypolymethylene polymer. The preferred ratio is approx. lii to 1.5:1. The weight ratio between carboxyvinyl polymer and active ingredient is less than 0.5:1, preferably approx. 0.1 to 0.45:1. The combined weight of the two polymers in the mixture may exceed half the weight of the active ingredient, but is preferably below approx. 75% by weight of the active ingredient. These quantities refer to the base mass.

Finished tablets with a total weight of up to approx. lg can be produced. Of this total weight, the coating, which is described in detail below, accounts for approx. 5 to 15%.

The base mass in the tablet with regulated release thus preferably contains a mixture of an effective amount of a medical agent which is preferably at least approx. 50% of the total weight of the base mass, vinyl polymer, preferably PVP, and a hydrophilic carboxyvinyl polymer of acrylic acid saturated with polyalkenyl polyether, preferably a polymer of acrylic acid saturated with polyallyl sucrose, especially "Carbopol". The release-regulating substance is a gel that is formed by reaction between the polymers in the presence of water.

The weight ratio between vinyl polymer and carboxypolymethylene polymer is approx. 1:10 to 10:1, preferably approx. 1:1. The weight ratio between carboxyvinyl polymer and active ingredient is less than 0.5:1, preferably approx. 0.1 to 0.45:1. The total weight of the polymers is below approx. 75% of the weight of the active agent. For the preparation of the tablet matrix or core, a dry granulation technique is preferred. All the ingredients are mixed in dry form, densified by being beaten or compressed, and then reduced to a granule by being ground. The

milled particles are then compressed into tablet form which may be of any common shape, e.g. round, oblong, oval, etc. A tablet press equipped with suitable embossing equipment is used

to form a tablet core of any desired weight, shape and composition.

When carrying out the dry granulation, various other common ingredients can be introduced to the extent necessary. E.g. a diluent or filler may be introduced to adjust the weight. Such diluents include e.g. lactose, mannitol, corn starch, various cellulose derivatives such as wood cellulose ("Splkafloc") and especially microcrystalline cellulose which is on the market under the trademark "Aviae!" (see US patents 2,978,446 and 3,141,875). Other additives may include lubricants such as stearic acid, palmitic acid, magnesium stearate, calcium stearate, talc, carnauba wax etc. Flow-regulating silicic acid raiders or lubricants can also be introduced. Colorants accepted in pharmaceuticals, such as the various F.D.&C colorants can be added at various stages, including spray coating of the finished core. As an alternative, although not preferred*, wet granulation can also be used. According to this method, the dry active ingredient, vinyl polymer and polymethylene polymer and other diluents, e.g. in a planetary mixer. The powders are moistened with a granulation liquid such as methylene chloride, chloroform, methylchloroform, pure or denatured ethyl alcohol, isopropyl alcohol, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,1-trichloroethane, etc. Binders such as zein, ethyl cellulose, p-pinene polymers,

gelatin*shellac or similar can be introduced into the granulation liquid. The moist mass is granulated, e.g. by being pressed through a sieve with a suitable mesh size, dried, and possibly further reducing the size of the particles. The granulate is then compressed in the usual way using lubricants, lubricants etc. to the necessary extent.

When the tablet base has been formed and, if necessary, the color has been added, one film is applied according to the invention. The film comprises a combination of hydrophobic and hydrophilic polymers which allow water to penetrate and hydrate the base mass so that there is no first strong release wave of the active agent.

The hydrophilic polymers are water-soluble polymers

(below pH 5.5). They include cellulose methyl ethers such as methyl cellulose, hydroxypropyl methyl cellulose, hydroxy methyl cellulose phthalate, and also hydroxypropyl cellulose, cellulose acetate phthalate or polyvinyl alcohol.

The hydrophobic polymers are slightly soluble in water (slightly soluble is to be understood as the definition given in USP XIX,

page 6, although polymers that are up to 3% soluble in water can

used). They include cellulose ethyl esters such as ethyl cellulose,

also cellulose acetate, polyvinyl alcohol-maleic anhydride copolymers, Ø-pinene polymers ("Picolyte"), glycerol esters of wood resins such as glycerol ester of partially dimerized rosin, glycerol ester of partially hydrogenated rosin, glycerol ester of polymerized rosin, hydroxypropyl methyl cellulose phthalate, etc. .

Combinations of methyl cellulose and ethyl cellulose or hydroxypropyl methyl cellulose and ethyl cellulose are preferred.

One or more representatives from each class of polymer can be used. The proportion of hydrophilic polymer or hydrophilic polymers to hydrophobic polymer or hydrophobic polymers is in the range of a few approx. 4:1 to approx. 1:4 (by weight), preferably approx. 1.5:1 to 1:1.

These polymers are best mixed in a quantity ratio that results in 1 break during a<y>approx. 1 hour. A film with a thickness of approx.

0.025 to 6.375 mm, preferably 0.075 to 0.175 mm, is sufficient to achieve the desired result.

The film-forming components are applied by spraying a system containing them onto the core using a conventional film coating technique. The film-forming components are dissolved in a

solvent or a mixture of solvents where both types are soluble or form a solvent. Such solvent agents include alcohols such as methyl alcohol/ethyl alcohol or isopropyl alcohol, ketones such as acetone, methyl ethyl ketone, chlorinated hydrocarbons such as methylene chloride, dichloroethane,

1,1,1-trichloroethane, etc. Particularly preferred is methylene chloride plus isopropyl alcohol or methylene chloride plus methyl alcohol (preferably 70%:30%).

The film-forming mixture may optionally contain plasticizers such as ethyl citrate, diethyl phthalate, propylene glycol, glycerol, butyl phthalic castor oil or the like in order to achieve the desired balanced properties. If color is used, it is preferably added to this film-forming mixture. The coloring agents used include the coloring agents or lacquer colors approved by F.D. s C. Clearing agents such as titanium dioxide can also be introduced.

A number of different drugs that are administered orally in tablet form can be used in the form of tablets prepared according to

the invention. These include, for example, adrenergic agents such as ephedrine, desoxyephedrine, phenylephrine, epinephrine and the like,

cholinergic agents such as physostigmine, neostigmine etc., anti-spasmodic agents such as atropine, methanetheline, papaverine and similar, carariform agents such as chlorisondamine bg similar,

sedatives and muscle relaxants such as fluphenazine, chlorpromazine, triflupromazine, mefenesine, meprobamate and the like, anti-depressants such as amitriptyline, nortriptyline and the like, antihistamines such as diphenylhy&ramine, dimenhydrinate,

tripelennamine, perphenazln, chlorprofenazine, chlorprofenpyridamine and

similar, hypotensive agents such as rauwolfia, reserpine dg similar, cardioactive agents such as benzhydroflumethiazidy fiumethiazide, chlorothiazide, aminotrate, propranolol, procainamide and the like, steroids

such as testosterone, prednisolone and the like, antibacterial agents,

e.g. sulfonamides such as sulfadiazine, suifamerazine, sulfamethazine,

sulfisoxazole and the like, antimalarials such as lloroquin and the like, antibiotics such as tetracyclines, nystatin, streptomycin, cephradine and other cephalosporins, penicillin, hal<y->synthetic

■ penicillins, griseofulvin and the like, sedatives such as chloral hydrate, phenobarbital and other barbiturates, glutethimide, anti-tuberculosis agents such as isoniazld and the like, analgesics such as aspirin, propoxyphene, meperidine and the like, etc.

These substances are often used either as a free compound or in the form of a salt, e.g. acid addition salts or basic salts such as alkali metal salts. Other therapeutic agents with the same or different physiological effect can also be used in pharmaceutical preparations prepared according to the invention.

The invention is particularly suitable for the production of tablets

with controlled release containing the antiarrhythmic agent procainamide (which is usually used in the form of its hydrochloride).

The following examples shall serve to further illustrate the invention and represent preferred embodiments.

Example 1

The following ingredients are used for the production of

1000 live tablets contain 500 mg procainamide hydrochloride.

A. Compressed tablet

All the ingredients under A above, except the stearin-lilac and "Syloid" are mixed in dry form. The dry mixture is compressed in a tabiet press and then reduced by grinding to approx.

20 mesh. The stearic acid surfactant and lubricant are added to the dry granules and carefully mixed in. The mixture is then compressed in a tablet press to form biconvex, oval tablet cores with slightly flattened ends and weighing 790 mg each.

Coating solution B is then applied to the tablet core by airless spraying in a rotating coating pan with a rear outlet. The coating is applied until a coating with a thickness of 0.09 to 0.1 mm has been obtained.

Example 2

Tablet cores are prepared as described in example 1. A colored coating solution is prepared by setting

400 ml "Opaspray1* yellow (a dispersion of F.D. a C. yellow no. 5 and 6 varnish colors, titanium oxide and hydroxypropylmethyl cellulose in SD3A

alcohol) to the coating solution B 1 example 1, and mixing together. : The compressed tablet cores are then sprayed as in Example 1 to give yellow, coated tablets each weighing 840 mg and containing 500 mg procainamide-HCl (core* 791 mg).

Example 3

The following ingredients are used for the production of

1000 tablets each containing 570 mg cephradine:

A. Compressed tablet

Cefradin, lactose, "Plasdone" and "Carbopol" are mixed.

The mixture is granulated with the ethyl cellulose and the methylene chloride.

The granulate is dried and reduced to 20 rceah size* Talc and "Entersol" are added, and the mixture compressed into tablets (lOOO). The coating solution is mixed well and sprayed onto the compressed cores to a thickness of 0.075 to 0.12 mm.

■ Example 4 r The release rate of active ingredient was determined

for the uncoated cores and for the film-coated tablets prepared

pursuant to Example 1 of U.S.F. XIX release method (page 651) using 1 liter of water at 37°C while the basket rotated at 50 rpm and the results were as follows:

Example 5

The release rate of cephradine determined for the coated

tablets According to example 3 are as follows:

Claims (6)

1* Method for producing a medicinal tablet with controlled release, characterized in that a compressed base mass containing an effective amount of drug distributed in a mixture of polymeric vinylpyrrolidone and a hydrophilic carboxyvinyl polymer is coated with an almost water-insoluble, water-permeable, breakable film comprising a mixture of hydrophobic polymer which is slightly soluble in water, and hydrophilic polymer which is water soluble. 2. Procedure as stated in claim 1, characterized by the use of a coating material containing ethyl cellulose and methyl cellulose. 3» Method as stated in claim 1, characterized in that a coating material containing ethyl cellulose and hydroxypropyl raethyl cellulose is used, 4. Method© as stated in one of claims 1 to 3, characterized in that a base mass is used containing an effective amount of drug distributed in a mixture of polymeric vinyl pyrrolidone and a hydrophilic arbox <y> vin <y>l<p> ol< y> more of acrylic acid crosslinked with polyalkenyl polyether. 5. Method as stated in claim 1, characterized in that procainamide or a salt thereof is used as a drug. 6. Method as stated in claim 1, characterized in that it uses 3 cephradine as a drug.