IE58262B1 - Substained release tablets and method for preparation thereof - Google Patents

Description

Tht sustained release of a medicine or drug is important for several reasons. For example it serves to provide the body with medication over a long time and thereby eliminates the need for swallowing an ordinary tablet at frequent Intervals. Another advantage could be that a sudden release of a large amount of medicine which often occurs when conventional tablets are used can be avoided. Thereby the onset of toxic symptoms can be eliminated.

One type of commercially used slow release tablets comprises a firmly coherent skeleton structure composed of a non-toxic synthetic • a resin supstan*1 a 11v insoluble in the fluid of the human or animal body ι V with which tne tablet comes into contact. The structure includes porelike inter-connected canals or ducts open to the exterior of the structure and a material which comprises or contains a medical substance, which is soluble in the fluid contained in such canals or ducts. Slow release tablets of this type are disclose:' in the GF patent 808,014. i Another type of commercially used slow release preparation known as ' 'Osmetic device has been developed by A)?a Co. This device comprises a wal 1 .surrounding a reservoir containing an active age*'·; and having a passageway for releasing the agent from the device. Ins wall is comprised of a materiel permeable to external fluid. ίΛ A third type of slow release tablet is disclosed in e.g. the G3 patent 1,1B6,I?O and US patent 3,536,214. These patents disclose pharmaceutical preparations consisting of a tablet core comprising a medicament, which is soluble in the gastro-intestinal fluids, end a coating or, s?aid core. The coating consists of a polymer substance which remains -substantially intact and insoluble in the gastro-intestinal fluids.

Fine particles of a readily water-soluble substance are randomly distributed in the coating. Furthermore, it is disclosed in the patent that the preparation can se provided with an additional coating which i.a. may contain another pharm,ecologically active substance.

According to the 68 patent 1,188,950 the polymer substance is a polyamide and according to the US patent 3,536,314 the polymer substance is cellulose acetate, ethyl cellulose or low water soluble polyvinyl alcohol, However, to the best of our knowledge, none of the technical solutions disclosed in these two patents has led to a practically useful product.

As regards the US patent 3,538,214 the reason seems to be clear, as the tables of the dissolution rate disclose that the dissolution rate is neither pH-independent nor essentially constant over any longer period of time, two requirements that must be fulfilled in modern slow release preparations. The polymer substance used in the G8 patent 1,186,990 has rather poor film-forming properties, and it is difficult to get a proper adhesion to the tablet core surface. -, n Another slow release composition is disclosed in the US patent 4,244,941. This composition comprises a drug including a core of a soluble substance and a rigid porous coating completely surrounding the core. The coating is substantially free of substances soluble or swellable in the gastrointestinal liquids. Furthermore, the coating is selected from substances insoluble in the medium, in which they are intended to be used. The substances are compressed in powder form to form an inert non-disintegrating, noneroding porous coating on the core. The coating could e.g. consist of a copolymer of vinyl chloride and vinyl acetate However, this compression coating principle produces tablets, which O r consist up to about 50¾ of coating material. This in contrary to what is sought after in tne medical end pharmaceutical fields today.

An object of the present invention is to provide a slow-release preparation, in which the dissolution rate of the active substance is substantially constant over a long period of time. This means that the rate determining characteristics of the coating are substantially independ ent of any mechanical influence, enzymes, surface tension, pH and salt concentration.

Another object of the invention is to provide an inexpensive slow release preparation.

A third object is to provide a slow release preparation generally useful for different kinds of orally active drugs.

A fourth object is to provide a slow release preparation, which is small in size due to a favourable ratio between the amount of active substance and inactive ingredients.

A further object of the invention is to provide a slow release preparation, which can be manufactured in a simple process without problems with roughness of the tablet surface (orange peel) or other problems related to poor adhesion of the coating to the tablet core surface.

Accordingly, the invention provides a sustainedrelease coated pharmaceutical tablet exhibiting a substantially constant dissolution rate during a major portion of its dissolution time when exposed to gastrointestinal fluids, and comprising a drug-containing tablet and a coating surrounding the same, this coating essentially consisting of a polymer, which is insoluble in water and gastrointestinal fluids and a watersoluble pore-creating substance randomly distributed in the polymer, characterized in that the polymer is a terpolymer of vinylchloride, vinylacetate and vinylalcohol, that the ratio of pore-creating substance to terpolymer varies between 0.1 and 20, that the pore-creating sub20 stance consists of particles, which are essentially insoluble in the solvent used for coating the drug-containing tablet and that the pore-creating agent is substantially pharmacologically inactive in the amount used.

The invention also provides a method of producing a coated tablet exhibiting a substantially constant dissolution rate during a major portion of its dissolution time when exposed to gastrointestinal fluids, and comprising a drug-containing tablet and a coating surrounding the same, wherein the coating essentially consists of a polymer, which is insoluble in water and gastrointestinal fluids and a watersoluble, pore-creating substance randomly distributed in the polymer, characterized in that the polymer is a terpolymer of vinylchloride, vinylacetate and vinylalcohol, that the ratio of pore-creating substance, to terpolymer varies between 0.1 and 20, that the pore-creating substance consists of particles, which are essentially insoluble in the solvent used for coating and that the pore-creating substance is essentially inactive in the amount used, comprising the steps of dissolving the said terpolymer in a solvent, preparing a suspension of the pore-creating substance providing a pharmaceutical tablet, combining the suspension of pore-creating substance and solvent solution of the terpolymer to form a coating fluid, applying the coating fluid in the form of suspension to the tablet, and drying the coating fluid on the tablet to provide a terpolymer-coated tablet having watersoluble pore-creating substance randomly distributed within the coating or membrane.

Preferably the terpolymer contains 80-95* weight per weight of vinyl chloride, 1 to 19* weight per weight of vinyl acetate and 1 to 10% weight per weight of vinyl alcohol. In this context it can be mentioned that a coating comprising a copolymer consisting of only vinyl chloride and vinyl acetate can be used but the adhesion properties to different kinds of drug containing tablet cores are not sufficiently good to avoid roughness of the tablet surface (orange peel) and/or other problems related to poor adhesion. Furthermore, such a copolymer has not sufficient mechanical strength.

The pore-creating substance used according to the present invention should be highly water-soluble, pharmacologically acceptable and essential ly free from own pharmacological effects in the amounts used. Especially <Γ' C? Οι preferred as pore-creating substance is saccharose (sucrose). Other substances which may be used include polyvinyl pyrrolidone, polyethylene glycol 1500, 4000 or 6000 and sodium chloride.

The ratio of pore-creating agent to terpolymer depends on the desired dissolution rate and time and can be decided in each separate case from simple experiments in the laboratory. Generally it can be said that in order to get practically useful dissolution from tablets for oral use the ratio should vary between 1 and 5, preferably between 1.5 and 3.

The pore-creating substance is preferably but not necessarily in13 soluble in the solvent used for coating the tablets.

The particle size of the pore-creating substance may vary between 0.5 and 50 millimicrons.

Preferably a plasticizer is also present in the terpolymer. The amount of this plasticizer may vary between 0.1 and 47- weight by weight of the coating fluid. Examples of suitable plasticizers are a cetyltrifcutyl citrate, polyethylene glycol, blown castor oil and glyceryl triacetate. Furthermore, the coating may include sodium bicarbonate as stabilizing agent.

Depending on the size and area of the tablet the coat'rc weight may vary between 10 and 170 mg per tablet and the coating thickness may vary between 25 and 300 pm, preferably 50 and 200 pm.

According to the present invention the drug included in the core could be almost any drug that can be orally administered. In order to improve the solubility properties of the drugs the core may include conventionally used additives such as buffering agent, e.g. sodium bicarbonate or citric acid.

Examples of drugs that suitably are administered in the form of sustained and constant release preparations according to the present invention include, but are not limited to, e.g. phenylpropanolamine, cefalospcrin (Cefaclorum), bensodiazepine derivatives, potassium, chlo33 ride, sodium salicylate, choline theophyllinate, acetaminophen, acetylcystein, terbutaline, dextromethorphan, ascorbic acid, diltiazem, noscapine, oxybutynin, ibuprophen, urapidil, melperone, salbutamol, cimetidine, chlorpheniramine maleate, propranolol, L-dopa, piracetam, isosorbide dinitrate, indomethacin, zinc sulfate, diclofenac, litium sulfate, ferrous sulfate, pseudoephedrine, sodium cromoglycate, sodium PAS and meclomen.

The starting preparations are produced in the following manner: 1) A terpolymer containing (w/w*) 80-95% PVC (polyvinylchloride), 1-19¾ PVAC (polyvinylacetate), and 1-10% PVOH (polyvinylalcohol) is dissolved in a solvent, e.g. acetone, methylenechloride, methylethyl5 ketone, or mixtures of acetone and ethanol, acetone and methylenechloride, or the like. 2) A suspension or solution of the pore-creating substance is produced as follows: The pore-creating particles are ground either by dry milling in a 10 ball mill or by wet-milling in a glass bead milling device to a defined particle size, preferably between 0.5 pm and 50 ym . The particles are dispersed in solvents or mixtures of solvents, such as those previously mentioned, and mixed with the terpolymer solution.

The ratio between pore-creatir.q substance and terpolymer in the •J5 coating fluid is as previously described for the ratio in the coating.

The coating f.uid may, as previously stated, include a plasticizer and sodium bicarbonate.

The coating fluid, in the form of a solution or suspension, is then applied on drug-containing cores by conventional coating procedure. 2q Examples of such coating procedures are pan coating, manual or spraycoating, Wurster coating, and other fluid-bed coating procedures. Coloring matter can also be incorporated in the coating fluid, and insoluble coloring materials are preferred.

A second coating can be applied, and may contain one or more same or different drugs, for which a rapid release is desirable. This coat25 ing fluid is preferably a water-based sugar coating and, therefore, a seal coating between the latter and the terpolymer membrane coating is frequently necessary or desirable.

The invention is further illustrated by the following examples. Example 1 Coating on tablets containing potassium chloride 1 gram.

Composition of the coating fluid: grams Terpolymer (PVC)M (PVAC)N (PVOH)O, wherein PVC is polyvinylchloride, PVAC is polyvinylacetate, and PVOH is polyvinylalcohol, and wherein M=31, N=1, and 0=2 160 Micronized powdered saccharose (particle size 1-10 pm) 409 Acetyl tri butyl citrate 35.6 Blown castor oil 26.9 Sodium bicarbonate 15 Acetone ad 4400 The coating process is performed in a coating pan and the coating fluid is sprayed onto the tablets with an airless spray-coating device. Five thousand tablets are coated and the average membrane weight is 60 mg per tablet.

The following table discloses that the dissolution rate of the drug is essentially constant during 8 hours and essentially independent of pH.

Table 1 TEST FLUID Percent drug released time (hours) 1 2 3 4 5 6 7 8 Intestinal juice 18 32 50 64 77 69 97 100 Deionized water 12 30 45 62 73 66 95 95 Gastric juice 10 24 40 51 67 80 90 95 Example 2 Coating applied on tablets containing 500 mg of sodium salicylate Composition of the coating fluid: grams Terpolymer (PVC)M, (PVAC)N, (PVOH)O M=31, N=1, and 0*2 160 Micronized saccharose (particle size 1-10 urn) 4G9 Acetyl tributyl citrate 17.8 Sodium bicarbonate 15 Acetone ad 4400 The coating weight is 50 mg per tablet and the coating procedure is the same as in Example 1.

As diclosed in the following Table II this formulation is an example 13 of how the inherent pH dependency of the drug active substance can be used in order to obtain a desired dissolution rate at a certain pH.

Table II pH of test fluid 1 2 4 6 28 48 29 51 30 50 Percent drug released Time (hours) 3 4 5 6 24 16 22 30 36 98 65 77 88 94 99 69 79 87 92 99 68 80 90 93 99 2o The dissolution rate of the drug will be about four times slower in the stomach than in the intestine and the solid drug substance does not get into direct contact with the mucous membranes. Thus the local irritating effect of sodium salicylate on the gastric mucosa is minimized. Example 3 Noscapine HCI is a weak base and has low solubility in natural and basic media, while the solubility in acidic media is high. Below, two tablet compositions are listed, one buffered B, and one without buffer A. Both tablet batches are coated with the same coating and the dissolution rate is determined according to USP XX.

TABLET COMPOSITION A B Noscapine HCL 50 mg 50 mg Acidic Sodiumcitrate - 50 mg Citric Acid - 50 mg Powdered Sucrose 242.5 mg 142.5 mg PVP 25 15 mg 15 mg Coating composition Film-forming polymer 6.96 mg Micronized sucrose 22.26 mg Acetyltributylcitrate 0.30 mg Blown Castor Oil 0.24 mg Example 4 Meclomen, Mefenanic acid, is a weak acid with a pKa of 10 which means that the drug is practically insoluble in physiological fluids having ph' bet-een 1 and 8. The tablet was buffered with sodium bicarbonate and the internal pH rises to about 10.5 where Mef?namic acid is freely soluble. As in the earlier experiments two formulations were manufactured, one containing buffer and one without.

TABLET COMPOSITION A B Mefenamic acid Sodium salt 164 164 mg Sodium carbonate - 13 mg Stearic acid/Talc 50? 20 mg 20 mg Polyethylene glycol 6000 50 mg 50 me Powdered Sucrose 126 mg 113 mg Coating composition Micronized sucrose 17.9 mg Film-forming polymer 6.0 mg Acetyltributylcitrate 0.25 mg Blown Castor oil 0.2 mg Example 5 Melperone, a weak base, has a ρΚθ of 8.8 and shows pH-dependent release rate. Two formulations, one containing citric acid as buffering agent, and one without, were manufactured.

TABLET FORMULATION A B Melperone HCl 50 mg 50 mg Acetylglyci namide 95 mg 95 mg PVP 25 Koilidon 5 mg 5 mg Glycerol 1 mg 1 mg Citric acid - 25 mg Lactose 97.5 mg 97.5 mg Stearic acid / Talc, 50% 10 mg 1C mg Avicel PH 62.5 mg 37.5 mg Coating formulation Micronized sucrose 21.3 mg Film-forming polymer 6.85 mg Acetyl tri butyl citrate 0.32 mg Blown Castor oil 0.24 mg The following Table III discloses the differences in dissolution rate for the preparations with and without buffer according to the examples 3-5.

Table III Dissolved amount after four hours: Meclomen Melperone Noscapine pH 10 pH 7.4 pH 7.4 pH 8.0 pH 1 pH 7.4 Buffered 91% 84% 74% 78% 73% 69% Wi thout Buffer 91% 24% 34% 78% 75% 1.2% Example 6 Coated Choline Theophyllinate Tablets Coating applied on tablets containing 270 mg of choline theo1 2 phyllinate.

Composition of the coating fluid: grams Terpolymer (PVC)M, (PVAC)N, (PVOH)O 5 M=31, N=1, and 0=2 130 Micronized saccharose (particle size 1-10 ym) 409 Acetyl tributyl citrate 14.3 Blown castor oil 10.9 Sodium bicarbonate 15 Acetone ad 4400 The weight of the membrane is 40 mg per tablet and the coating procedure is the same as in Example 1.

Example 7 Coated benzodiazepine tablets Coating applied on tablets containing 6 mg nitrazepame (benzodiazepi nderivotive) Tablet: Nitrazepame 4 mg Powdered sucrose 120 mg Polyethylen oxide 6000 110 mg Polyvinylpyrrolidone 5 mg Magnesium stearate 2 mg The ingredients except for Mg-stearate were mixed and moistened with ethanol. After drying Mg-stearate was added and the powder was compressed to tablets.

Coati ng: Terpolymer according to Example 1 9.8 mg Acetyltributyl citrate 1.87 mg Blown castor oil 1.40 mg Micronized sucrose 23 mg Acetone 530 mg Example 8 Coated Paracetamol Tablets Coating applied on tablets containing 500 mg of paracetaminophenol 3 Composition of the coating fluid: grams Terpolymer (PVC)M, (PVAC)N, (PVOH)O M=31, N=1, and 0=2 120 Polyethyleneglycol 6000 (pore-creating substance) 410 Acetyl tributyl citrate 12 Acetone ad. 4400 The coating procedure is the same as in Example 1.

Example 9 Terpolymer Variation Coating applied on tablets containing 1 g of potassium chloride Composition of the coating fluid: grams Terpolymer (PVC)M, (PVAC)N, (PVOH)O 15 M=1OO, N=l, and 0=8 160 Micronized powdered saccharose (particle size 1-10 um) 409 Acetyltri butyl citrate 35.6 own castor oil 25.4 Sodium bicarbonate 15 Acetone ad 4400 The weight of the dried memnrane was 69 mg per tablet and the coating procedure was the same as in Example 1.

Claims (17)

1. CLAIMS;
1. I. A sustained-release coated pharmaceutical tablet exhibiting a substantially constant dissolution rate during a major portion of its dissolution time when exposed to gastrointestinal fluids, and comprising a drug-containing tablet and a coating surrounding the same, this coating essentially consisting of a polymer, which is insoluble in water and gastrointestinal fluids and a watersoluble pore-creating substance randomly distributed in the polymer, characterized in that the polymer is a terpolymer of vinylchloride, vinylacetate and vinylalcohol, that the ratio of pore-creating substance to terpolymer varies between 0.1 and 20, that the pore-creating substance consists of particles, which are essentially insoluble in the solvent used for coating the drug-containing tablet and that the pore-creating agent is substantially pharmacologically inactive in the amount used.
2. 2. A coated tablet according to claim 1, wherein the terpolymer contains 80 to 95 weight by weight of vinylchloride, 1 to 15% weight by weight of vinylacetate, and 1 to 10¾ weight by weight o.f vinylalcohol.
3. 3. A coated tablet according to claim 2, wherein the pore-creating substance is a water-soluble substance selected from saccharose, sodium chloride, polyvinylpyrrolidone and a polyethylene glycol .
4. 4. A coated tablet according to any of the claims 1-3, wherein the ratio of pore-creating substance to terpolymer varies between 1 ar.d 5. And preferably between 1.5 and 3.
5. 5. A coated tablet according to any of the preceding claims, wherein the tablet also includes a buffering agent.
6. 6. A coated tablet according to any of the preceding claims, wherein the coating also includes a plasticizer selected from acetyltributylcitrate, polyethylene glycol, blown castor oil and glyceryl triacetate.
7. 7. A coated tablet according to claim 6, wherein the plasticizer is present in a concentration of 0.1 to 4% weight by weight of coating fluid. 1 5
8. 8. Method of producing a coated tablet exhibiting a substantially constant dissolution rate during a major portion of its dissolution time when exposed to gastrointestinal fluids, and comprising a 5 drug-containing tablet and a coating surrounding the same, wherein the coating essentially consists of a polymer, which is insoluble in water and gastrointestinal fluids and a watersoluble, porecreating substance randomly distributed in the 1 θ polymer, characterized in that the polymer is a terpolymer of vinylchloride, vinylacetate and vinylalcohol, that the ratio of pore-creating substance to terpolymer varies between 0.1 and 20, that the pore-creating substance consists of 15 particles, which are essentially insoluble in the solvent used for coating and that the pore-creating substance is essentially inactive in the amount used, comprising the steps of dissolving the said terpolymer in a solvent, preparing a suspension of 20 the pore-creating substance, providing a pharmaceutical tablet, combining the suspension of pore-creating substance and solvent solution of the terpolymer to form a coating fluid, applying the coating fluid in the form of suspension to the 25 tablet, and drying the coating fluid on the tablet to provide a terpolymer-coated tablet having watersoluble pore-creating substance randomly distributed within the coating or membrane.
9. 9. A method according to claim 8, wherein the terpolymer contains 80 30 to 95« weight by weight of vinylchloride, 1 to 19« weight weight of vinylacetate, and 1 to 10« weight by weight of vinylalcohol.
10. 10. A method according to claim 8 or 9, wherein the pore-creating substance is a water-soluble substance selected 35 -from saccharose, sodium chloride, polyvinylpyrrolidone and a polyethylene glycol.
11. 11. A method according to any of the claims 8-10, wherein the ratio of pore-creating substance to terpolymer varies between 1 and 5 and preferably between 1.5 and 3. lo
12. 12. A method according to any of the claims 8-11, wherein the tablet also includes a buffering agent.
13. 13. A method according to any of the claims 8-12, wherein a plasticizer is also present in the terpolymer. .
14. 14. A method according to claim 13, wherein the plasticizer is present in a concentration of 0.1 to 4% weight by weight of coating fluid, preferably selected from acetyltributylcitrate, polyethylene glycol, blown castor oil, and glyceryl triacetate. 5
15. 15. A sustained-release coated pharmaceutical tablet according to claim 1, substantially as hereinbefore described with particular reference to the accompanying Examples.
16. 16. A method according to claim 8 of producing a coated 10 tablet, substantially as hereinbefore described with particular reference to the accompanying Examples.
17. 17. A coated tablet whenever produced by a method claimed in a preceding claim.