IE56151B1

IE56151B1 - Tablet formulation

Info

Publication number: IE56151B1
Application number: IE246883A
Authority: IE
Original assignee: Elan Corp Plc
Priority date: 1983-10-20
Filing date: 1983-10-20
Publication date: 1991-05-08
Also published as: BE900824A

Abstract

Comprimé à libération et absorption réglées du principe actif, contenu dans un noyau associé à un excipient, noyau enrobé d'une membrane à perméabilité variable et d'un enrobage externe contenant une éventuelle dose d'attaque du principe actif. La membrane comprend un consistuant perméable au principe actif et un constituant imperméable au principe actif. Le noyau a une vitesse de dissolution rapide et comporte un ou plusieurs ingrédients extremement solubles qui créent un écoulement de liquide dans un environnement aqueux.

Description

This invention relates to controlled release pharmaceutical formulations and, in particular, to n controlled release tablet formulation for the absorption <»f therapeutic substances through a differentially permeable membrane.

Many drugs are conventionally administered in the form of tablets by the oral route. Tablets have the advantages of convenience and ease of administration. Analgesics such as aspirin, paracetamol and indomethacin are normally administered in the form of tablets. It is desired that analgesics act quickly and for patient convenience it is desirable that they act for a significant period of time. Conventional preparations of these drugs do, in general, act within 30 minutes of ingestion but are usually required to be taken every 4 to 6 hours for continued pain relief.

A controlled release tablet formulation has already been proposed in Which a conventional tablet is encased in an impermeable membrane provided with a single aperture through which the active ingredient exits following administration to a patient. The release of active ingredient from such a tablet formulation is determined by the rate of release of active ingredient from the aperture.

Furthermore, controlled release tablet formulations exist Which are known as matrix tablets and Which consist of a polymeric material having an active ingredient dispersed therethrough. Such controlled release tablet formulations are the subject of British Patent Specification No. 1,113,660- In use, the active ingredient diffuses out of the polymer matrix and the formulation ultimately completely breaks up.

Other solid pharmaceutical oral dosage forms of the substained release type, in which a core of active ingredient is provided with a coating which controls the release of active ingredient, are known from British Patent Specification Nos. 1,510,573 and 1,568,837 and Patent Publication GB 2,025,227A.

It is an object of the present invention to provide nil improved controlled absorption and miens·' tablet lot initial lor* Iroin which Ihe rolnntw ol the.’ Accordingly, the invention provides a controlled absorption and release tablet formulation comprising a tablet core containing at least one active ingredient in association with a pharmaceutically acceptable excipient, a differentially permeable membrane surrounding said core and optionally an outer coating containing a priming dose of the or each active ingredient'*, said differentially permeable membrane including one component permeable to said active ingredient(s) and another component impermeable to said active ingredient(s) and said tablet core having: i) a rapid dissolution rate when tested by the method of U.S. Pharmacopoeia XX, namely a T90$ (time to 90S) dissolution of not more than 30 minutes; and ii) one or more highly soluble ingredients to create a flow of liquid therefrom in an aqueous environment.

The highly soluble ingredient may be the active ingredient. The highly soluble ingredient for the tablet core is also suitably selected from sodium bicarbonate, sodium citrate, sodium carbonate, citric acid, fumaric acid, malic acid, succinic acid and tartaric acid.

Preferably, the tablet core has sufficient hardness to withstand the coating process used to form the differentially permeable membrane as hereinafter described and a convex shape to avoid sticking during the coating process.

The tablet core is produced by conventional compression procedures.

The differentially permeable membrane Is preferably between 10 and 100 vm In thickness.

The drug impermeable component of the membrane is water insoluble, but optionally water permeable.

The drug permeable component of the membrane may be a w.ih'r Molublp material which Alternatively, the drug permeable component may be permeable to both water and active ingredient(s) and the associated excipient(s). The drug permeable component may also be porous.

Additionally, the drug permeable component may exhibit pH dependent solubility or porosity such that the drug permeability of the membrane varies with pH in an aqueous environment.

Preferred materials for the drug impermeable component of the membrane are: ethyl cellulose, polyvinyl chloride, methyl cellulose, polyurethane, cellulose acetate, polycarbonate, polyethylene, polypropylene, Eudragit RS (Eudragit RS is a Trade Mark) and She1 Jac.

Preferred materials for a drug permeable component of the membrane which is pH Independent ares polyvinyl alcohol, polyvinyl pyrrolidone, Eudragit RL(Eudragit RL is a Trade Mark), fumaric acid, citric acid, tartaric acid, sodium citrate, sodium bicarbonate, sodium fumarate, sodium carbonate, monosaccharides and disaccharides, hydroxypropylmethyl cellulose and Eudragit E (Eudragit E is a Trade Mark).

Eudragit polymers are polymeric lacquer substances based on acrylate or methacrylate.

An especially suitable monosaccharide is glucose.

Preferred materials for a drug permeable component of the membrane which is pH dependent are: cellulose acetate phthalate, polyvinylacetate phthalate, Eudragit (Eudragit L in a Trade Mark), Eudragit S (Eudragit S is a Trade Mark), methyl ('»*1 lulose phthalate, hydroxyethyl cellulone phthalate, and hydroxypropy 1 ntt-t.hyt cellulose phthalate.

The differentially permeable membrane is preferably formed by dissolving at least one drug permeable component and at least drug impermeable component in a respectively suitable solvent at a concentration which allows spraying with an air spray or airless spray system in conventional manner. Preferably, the concentration of each component used varies between 2% and 25% depending on the material involved and the viscosity of the resulting solution.

Each solution of membrane component may include one or more additives which facilitate spraying such as plasticisers or other additives such as colouring agents and opacifiers. However, these additives do not substantially affect the nature of the membrane formed.

The final solution used in coating the tablet cores is made by mixing the solutions of soluble/permeahle component(s) and insoluble/Impermeable component(s) so that the proportion of soluble to insoluble component (s) is between 1:9 and 9:1. Pigments, plasticisers, colouring agents and other conventional additives may also be added to the final solution.

Preferably, the membrane is formed around the tablet core by spraying using an air spray or an air-less spray system and standard tablet coating equipment. As stated above, the differentially permeable membrane preferably has a thickness of 10-100 pm which corresponds to a weight gain per tablet of 1-20%. After spraying the coated tablets are oven dried at 40-50°C to evaporate all residual solvents.

The membrane coated tablets have a dissolution rate which is determined by the solubility properties of the active ingredient(s) and excipient(s) in the core tablet and by the composition of the membrane. In some cades, it may be desirable to have some drug available for immediate release in order to achieve rapid on-set of action of the drug. Accordingly, the membrane coated tablet according to the invention may be provided with an outer coating which contains a priming dose of the or each active ingredient. Suitably, the outer coating comprises a sugar coating containing the active ingredient(») and one or more excipient(s)· The outer coating of active ingredient/sugar/excipient is applied to the membrane coated tablets using a modified sugar coating procedure which results in the tablets having the appearance of conventional sugar-coated tablets· Preferably, the membrane coated tablets are placed in a coating pan and warmed to 30-35°C using heated air. A sub-coating solution, typically consisting of gelatin (6%) acacia (8.1%) sugar (45%) and water (41%), pre-heated to 60-70°C, is poured over the tumbling tablets (6-10 ml solution per kg tablets). A measured quantity (20-30g/kg tablets) of dusting powder consisting of a mixture of: a) Calcium Carbonate 40% Titanium Dioxide 5% Talc 25% Powdered Sugar 28% Acacia (powdered) 2% and b) Finely powdered active ingredient(a) 75% Talc 25% is then applied.

The relative proportions of a) and b) used are dependent on the amount of active ingredient(s) required in the outer coating. The tablets are allowed to dry in the coating pan and two further coats of 10-12 ml subcoating solution and 30-50 g of dusting powder per kg of tablets are similarly applied. Up to 10 further coats of 13-18 ml of sub-coating solution and 60-80 g of dusting powder per kg of tablets may be applied. The tablets are - 7 then suitably dried at 40-50°C.

The semi-coated tablets are smoothed by coating them with a standard glossing suspension (for example 70% sugar solution) and a final colour coating. The coloured coated tablets may be polished with Carnuba Wax or Beeswax after drying.

Drugs which are degraded by low pH such as that* found in the human stomach or drugs which give rise to gastric irritation may be successfully formulated in a tablet formulation according to the invention by using a soluble/porous component, the solubility/porosity of which varies with pH, such that the solubility is low at low pH and high at high pH. Examples of acid labile drugs which can be suitably formulated in a tablet formulation according to the invention are Erythromycin and Penicillin and examples of gastric irritant drugs which can be so formulated include aspirin, potassium chloride and indomethacin. An example of such a formulation is illustrated in Example 2.

Drugs v/hich exhibit a pH dependent solubility may also be formulated in a tablet formulation according to the invention by incorporating a pH controlling sub-stance in the tablet core. Drugs which exhibit high acid solubility and low alkaline solubility, for example dipyridamole, methyldopa, quinidine sulphate, tetracycline hydrochloride, propranolol hydrochloride, verapamil hydrochloride and theophylline benefit from the addition of organic acids such as tartaric acid, citric acid, malic acid, succinic acid and fumaric acid. An example of such a formulation is illustrated in Example 3. Drugs with low acid solubility and high alkaline solubility, for example indomethacin, ibuprofen, naldixic acid, naproxen, ketoprofen, piroxicam, phenylbutazone, oxyphenylbutazone, fenoprofen, fenclofenac, flurbiprofen and phenytoin sodium benefit from the inclusion of bases such as sodium bicarbonate, sodium citrate and sodium carbonate. An example of such a formulation is illustrated in Example 4.

It The invention will be further illustrated by the following Examples· EXAMPLE 1 Rapid-acting paracetamol (Acetaminophen) formulation having extended release of drug for prolonged action -0 kg of paracetamol were blended with 0-9 kg of lactose and the resulting mixture was granulated with sufficient 10¾ polyvinyl pyrrolidone in isopropanol to thoroughly wet the mixture. The mixture was then dried at 40-50eC and sized through a 20 mesh screen. The following ingredients were then blended ins Explotnb (starch dinintegrator) 0.10 kg (Explotab is a Trade Mark) Stearic acid 0.10 kg Talc 0.25 kg Sodium bicarbonate 0.25 kg The resulting mixture was compressed into tablets of 715 mg weight (corresponding to 550 mg active ingredient) using capsule shaped punches.

The membrane solution was prepared by mixing the following ingredients in the proportions stated: ¾ Cellulose acetate solution in methylene chloride/methanol - 60/40 1 litre ¾ High purity polyvinyl chloride in acetone 1 litre 5S Polyvinyl alcohol in isopropanol Diethylphthalate (plasticiser) 20 g The proportion of polyvinyl alcohol (soluble component) is high due to the low solubility of paracetamol The membrane colution was applied to the tablet cores in an Accela-Cota coating machine (Manesty Machines Limited) using an airless spray system until a 5§weight gain was achieved. The membrane coated tablet were then dried at 40-50°C for 12 hours.

When tested by the paddle method of the U-S. Pharmacopoeia XX using water as the medium, the dissolution rate of the tablets formed was as follows: Time (h) % Dissolution 6 8 0-10 -20 -30 -40 45-60 70-90 85-100 A sugar coating containing a priming dose of paracetamol was applied as follows. Firstly, a dusting powder was prepared using the following ingredients; Calcium carbonate 0.87 kg Titanium dioxide 0*11 kg Powdered sugar 0.54 kg Powdered acacia 0.05 kg Paracetamol (100 mesh) 0.91 kg TaLc 0.68 kg A sub-coating solution was prepared by dissolving gelatin, acacia and sugar in water in the following amounts: Gelatin 0.06 kg Acacia 0.08 kg Sugar 0.45 kg Water (70°C) 0.41 kg Using an Accela-Cota coating machine coats of sub-coating solution and dusting powder were applied to the membranecoated tablets according to the following schedule: ΙΟ Coal No. Soliition (ml) Powder (q) 1 52 160 2 72 260 3 72 260 4-9 92 413 The tablets where then dried for 8 hours at 40-50°CThe tablets where then smoothed in the Accela-Cota machine by applying successive layers of 70% sugar in water containing 12.5% by volume Opalux colour dispersion, according to the following schedule; Coat No. Coloured Syrup (ml) 37 2-4 31 -6 22 7-8 15 9-10 12 11-12 9 3-15 Coat No. 16-17 Clear Syrup (70%) The tablets were then dried overnight at 40-50°C, following which the tablets were polished by applying a coat of 20 ml of a 10% solution of Carnuba Wax in chloroform/acetone 50/50 and allowed to dry.

When tested by the paddle method of the U.S.

Pharmacopoeia XX using water as dissolution rate of the tablets follows: the medium, the was found to be as Time (h) % Dissolution 6 8 -25 -35 -45 40-55 55-70 75-90 85-100 ln addition the percentage dissolution at 5 minutes was not less than 15%.

EXAMPLE 2 Potassium chloride tablet formulation 5 A potassium chloride tablet formulation substantially free of gastric irritant properties was prepared in the following manner. Firstly tablet cores were prepared by blending the following ingredients in the amounts stated: Potassium chloride (granular) 5.00 kg Dipac (direct compression agent) 1.00 kg Avicel (direct compression agent) 1.00 kg Magnesium stearate 0.10 kg The mixture was then compressed info oval tablets having a weight of 710 mg (equivalent to 500 mg potassium chloride per tablet).

The membrane solution was prepared by mixing the following ingredients in the amounts stated: % Ethyl cellulose solution in methanol/methylene chloride 60/40 4 litres % Polyvinylacetate phthalate solution in methanol 3 litres Diethylphthalate (plasticiser) 40 g Opaspray Colour (Opaspray is a 0.4 litres Trade Mark) Stearic acid 70 g The membrane solution was sprayed onto the tablet cores using a conventional coating pan in the manner indicated in Example 1 until an 8% weight increase was achieved. The tablets were then dried at 40-50°C for 8 hours.

When tested by the U.S. Pharmacopoeia XX paddle method at four pH values, the dissolution rates of the tablets were found to be as follows: Time (h) pH 1.5 pll 3.0 pll 6.0 pll 7.5 1 0% Oft IS 2ft 2 Oft Oft 18ft 2 OS 3 Oft OS 34ft 37ft 4 Oft 2ft 47ft 51ft 6 IS 4ft 69ft 72ft 8 4ft 8ft 81ft 84ft 12 5ft 10ft 94ft 97ft Accordingly, it will be appreciated that the tablets only exhibit drug release in an environment where the pH is relatively high. The result is a controlled release form of potassium chloride which does not irritate the gastric mucosa.

EXAMPLE 3 Methyldopa tablet formulation A methyldopa tablet formulation which exhibits pH dependent solubility was formed in the following manner· The following Ingredients were blended In the amounts stated: Methyldopa 5.00 kg Citric acid 2.50 kg Malic acid 2.50 kg Explotab (Explotab is a 0.20 kg Trade Mark) The resulting mixture was wetted with sufficient 10% polyvinyl pyrrolidone to uniformily dampen the powder mass which was then dried and milled through a 20 mesh screen. Magnesium stearate (0.10 kg) and talc (0-20 kg) were blended into the mixture which was then compressed into tablets weighing 850 mg (equivalent to 350 mg methyldopa per tablet). The tablets so formed were found to have a dissolution rate of greater than 85% in 15 minutes in water at pH 1.5 buffer and pH 7.5 buffer when tested by the paddle method of U.S. Pharmacopoeia XX. kg of the tablets were then placed in an AccelaCota coating machine and film coated to a weight increase of 5% with a membrane solution formed from the following ingredients in the amounts stated: % Eudragit RS in isopropanol/ acetone 60/40 3 litres Fumaric acid (100 mesh) 0.225 kg Polyethylene glycol 200 Q.02 kg Talc 0.02 kg As the fumaric acid does not completely dissolve the suspenaion must be kept constantly agitated. After drying the tablets at 40-50°C for 12 hours, the membrane-coated tablets were colour coated using a solution comprising the following ingredients in the proportions stated: Hydroxypropylmethyl cellulose 3.2% by weight Ethyl cellulose 0.8% by weight Diethylphthalate 0-5% by weight Methylene chloride 56.75% by weight Methanol 33-75% by weight Opaspray Colour (40% solids) 5.00% by weight As the coloured coating dissolves rapidly it does not affect the dissolution rate of the coated tablets. The dissolution rates of the coated tablets when tested by the paddle method of the U.S. Pharmacopoeia XX at four pH values using water as the medium were found to be as follows: Time (h) PH 1.5 pH 3.0 pH 6.0 pH 7.5 1 35% 37% 39% 39% 2 59% 58% 59% 55% 3 72% 70% 68% 66% 4 82% 80% 76% 75% 6 92% 91% 84% 82% 8 98% 99% 94% 92% - 14 EXAMPLE 4 Phenytoin sodium tablet formulation A controlled release phenytoin sodium tablet formulation having pH dependent solubility was formed in the following manner. Tablet cores were formed by mixing phenytoin sodium (2.5 kg) sodium bicarbonate (2-3 kg) and Explotab (0.10 kg). The resulting mixture was granulated with 5% hydroxypropylmethyl cellulose solution in methanol. The granulated mixture was sized through a 20 mesh screen. After the sizing step, Explotab (0.10 kg) stearic acid (0-10 kg) and talc (0.20 kg) were added and tin* resulting mixture was compressed into tablets weighing7O5 mg (equivalent to 300 mg of phenytoin sodium)The membrane solution was prepared by mixing the following ingredients in the amounts stated: % Eudragit RL in isopropanol acetone, 60/40 3 litres % Eudragit RS in isopropanol acetone, 60/40 2 litres Polyethylene Glycol 400 0.025 kg Opaspray (Colour Dispersion) 0.625 kg The tablet cores were coated with the membrane solution to a weight increase of 5% using an Accela-Cota coating machine. The resulting membrane-coated tablets when tested by the U-S- Pharmacopoeia XX paddle method at four different pH values were found to have the following dissolution rates: Time (h) PIL3.0 pH 6.0 pH 7.5 1 8.1% 10.6% 13.1% 12.7% 2 15.C% 20.9% 23.6% 22-9% 3 25.1% 30.8% 34.2% 33-7% 4 33.2% 41.2% 44.0% 42.1% 6 49.6% 61.1% 63.9% 62.3% 8 62.1% 75.4% 79.1% 79.7% 12 70.6% 85.2% 91.1% 91.2% ta

Claims

CLAIMS:

1. A 5 pharmaceutically acceptable excipient, a differentially permeable membrane surrounding said core and optionally an outer coating containing a priming dose of the or each active ingredient, said differentially permeable membrane including one component permeable to said active 10 ingredient(s) and another component impermeable to said active ingredient(s) and said tablet core having: i) a rapid dissolution rate when tested by the method of U.S. Pharmacopoeia XX, namely a T90S (time to 90%) dissolution of not more 15 than 30 minutes; and ii) one or more highly soluble ingredients to create a flow of liquid therefrom in an aqueous envi ronment.

2. A tablet; formulation according to claim I, v/heroln 20 the highly soluble ingredient of the tablet core is selected from: sodium bicarbonate, sodium carbonate, sodium citrate, citric acid, fumaric acid, malic acid, succinic acid and tartaric acid.

3. A tablet according to claim 1 or 2, wherein the 25 tablet core has sufficient hardness to withstand the coating process used to form the differentially permeable membrane and a convex shape to avoid sticking during the coating process.

4. A tablet formulation according to any one of claims 30 1 to 3, wherein the differentially permeable membrane is between 10 and 100 pm in thickness.

5. A tablet formulation according to any one of Claims 1 to 4, wherein the drug permeable component of the membrane is a water soluble material which dissolves in 35 water resulting in the generation of pores which permit the egress of the active ingredient(s) and excipient(e) li. from the core in an aqueous environment.

6. - A tablet formulation according to any one Claims I to 4, wherein the drug permeable component is permeable to both water and active Ingredient(s) and the associated excipient(s).

7. A tablet formulation according to any one of Claims 1 to 4, wherein the drug permeable component is porous.

8. A tablet formulation according to any one of Claims 1 to 7, wherein the drug permeable component exhibits pH dependent solubility or porosity such that the drug permeability of the membrane varies with pH in an aqueous environment.

9. A tablet formulation according to any preceding Claim, wherein the material for the drug impermeable component of the membrane is selected from: ethyl cel 1 til os»·, polyvinyl chloride, methyl cellulose, polyurethane, cellulose acetate, polycarbonate, polyethylene, polypropylene,’ Eudragit RS and Shellac.

10. A tablet formulation according to Claim 8 or 9, wherein the drug permeable component of the membrane which is pH independent is selected from: polyvinyl alcohol, polyvinyl pyrrolidone, Eudragit RL, fumaric acid, citric acid, tartaric acid, sodium citrate, sodium bicarbonate, sodium fumarate, sodium carbonate, a monosaccharide, a disaccharide, hydroxypropylmethyl cellulose and Eudragit E.

11. - A tablet formulation according to Claim 8 or 9, Wherein the material for the drug permeable component of the membrane which is pH dependent is selected from: cellulose acetate phthalate, polyvinylacetate phthalate, Eudragit L, Eudragit S, methyl cellulose phthalate, hydroxyethyl cellulose phthalate and hydroxypropylmethyl cellulose phthalate.

12. A tablet formula*.ion according to any precedi ng Claim, which is provided with an outer coating which contains a priming dose of the or each active ingredient.

13. A tablet formulation according to Claim 12, wherein the outer coating comprises a sugar coating containing the active ingredient(s) and one or more excipient(s)·

14. A tablet formulation according to any preceding Claim wherein the active ingredient is acetaminophen. 5

15. A tablet formulation according to any one of Claims 1 tO 13, wherein the active ingredient is potassium chloride.

16. - A tablet formulation according to any one of Claims 1 to 13, wherein the active ingredient is methyldopa.

17. A tablet formulation according to any one of Claims 1 10 to 13, wherein the active ingredient is phenytoin or the sodium salt thereof. IR. A tablet formulation according to Claim 1, substantialLy as hereinbefore described with particular reference to the accompanying Examples. Dated this the 8th day of October, 1984. F. R KELLY & CO.