ENTERIC COATED PHARMACEUTICAL FORMULATION

Abstract: A method of making an oral pharmaceutical dosage form of an aqueous soluble drug including the steps of: forming a solution containing the drug, a soluble polymer and a binding or gelling agent into drops; contacting the drops with an acid precipitating medium allowing the polymer to precipitate to form particles containing the dissolved drug; drying the particles; wherein the gelling or binding agent retards or prevents migration of the drug towards the surface of the particles during drying.

Description: ENTERIC COATED PHARMACEUTICAL FORMULATION This invention relates to enteric coated pharmaceutical formulations and methods of production. Some drugs when given orally should not be released immediately into the stomach but should be formulated so that they are only available for absorption m the upper or lower intestine or colon. The reasons for a delay until they are passed out of the stomach vary, but include: instability in an acid medium, for example omeprazole; possible erosion and damage to the stomach wall by non- steroidal antl-mflammatory drugs for example diclofenac and gastric upset, for example some erythromycm salts. The normal means of preventing such problems is by coating a tablet containing the drug with an enteric layer. An enteric layer is a coating of a substance which is insoluble m the acid medium of the stomach but which is soluble at the higher pH encountered in the intestine. Such materials are used as film coatings on tablets. Suitable film coating materials include methyl methacrylate polymers (as sold under the trade mark Eudragit), cellulose acetate phthalate, polyvmyl acetate phthalate and hydroxypropyl methyl phthalate. However there is a problem with such tablets, particularly larger tablets because they may be retained m the stomach for a considerable time, for example 4 to 8 hours, before release into the intestine. Such retention is unsuitable for drugs where prompt action is desired or where the absorption and blood levels should be maintained at a constant value. It has been reported that some of these problems can be overcome with multiparticulate systems, wherein the dosage form breaks down m the stomach to form significantly smaller particles which pass through the stomach more quickly and reproducibly . Usually such dosage forms are capsules containing multiple particles, pellets or tablets. Such particles, pellets or tablets may consist of a core containing the drug with an overcoating of an enteric film. The core may be a conventional tablet, an extruded bead containing the drug or a non-pareil overcoated with a layer of drug. Capsules are widely used but have the drawback that the dosage cannot be varied easily as with a conventional tablet with a score- line which enables the tablet to be reasonably accurately divided into two or more parts containing known quantities of drug. Attempts have been made to produce tablets containing multiple particles but in many cases these have been unsatisfactory because the coated bead either does not deform enough to bind within a tablet or if it does deform, it causes failure of the enteric film due to cracking etc. An alternative approach has been disclosed by H C Zaniboni, J T Fell and J H Collett (International Journal of Pharmaceutics 125 (1995) 151-155). The authors disclosed manufacture of enteric particles by precipitation of the enteric polymer hydroxypropyl methyl cellulose phthalate m aqueous citric acid. However problems were found with water soluble compounds due to migration during the drying process. Deposition of significant quantities of drug on the outside of the particles facilitates rapid dissolution m acid conditions leading to very high dosage or burst effect . Accordmg to a first aspect of the present invention a method of making an oral pharmaceutical dosage form of an aqueous soluble drug includes the steps of: forming a solution containing the drug, a soluble polymer and a binding or gelling agent into drops, contacting the drops with an acid precipitating medium, allowing the polymer to precipitate to form particles containing the dissolved drug, drying the particles, wherein the gelling or binding agent retards or prevents migration of the drug towards the surface of the particles during drying. The particles may be incorporated into a tablet or filled into a gelatin capsule. According to a second aspect of the present invention an oral pharmaceutical dosage form comprises an aqueous soluble drug, a soluble polymer, a gelling or binding agent and one or more inert excipients, the gelling or binding agent being adapted to retard or prevent migration of the drug towards a surface of the dosage form. The dosage form preferably comprises a tablet or capsule containing particles of the formulation. The particles may be formed by sonicating or other pressure wave methods to break up the stream of drug/polymer solution as it enters the acid medium. A preferred soluble polymer is hydroxypropyl methyl cellulose phthalate. This polymer is suitable for enteric coating applications because it is insoluble in gastric fluid but dissolves rapidly at the higher pH values found m the small intestine. This polymer may be precipitated m accordance with the invention by contacting the drops with aqueous acid, for example 5 to 20% preferably 10 to 15% citric acid. Other suitable polymers which may be used include methyl methacrylate polymers (as sold under the trade mark Eudragit), cellulose acetate phthalate, polyvmyl acetate phthalate and hydroxypropyl methyl phthalate. A variety of binding or gelling agents may be employed, including polymers, cellulosic materials, sugars, coacervatmg and complexmg agents. Polyvmyl pyrrolidone, methacrylate acid esters and gelatin may be used. Cellulosic polymers including hydroxypropyl methyl cellulose, methyl cellulose and cellulose suspensions are preferred. Other compounds include cyclodextrms , polydextroses and modified starches. In preferred formulations the amount of the gelling agent may lie m the range 20 to 200% w/w of the weight of active ingredient. An amount of 1 to 10%, preferably 2 to 6% by weight may be employed. Materials which may be cross-linked by photolysis may also be employed, for example 2-hydroxyethyl methacrylate. In this case the method of production of the dosage form includes the step of exposing the particles to photolytic radiation prior to drying m order to cause the gelling and binding agent to cross-link. Alternative formulations incorporate one or more water absorbing agents, for example a partially hydrated hydrogel adapted to absorb the drug containing aqueous solution within the core of the bead during drying. A partially hydrated hydrogel may be added to the concentrated drug/polymer solution immediately prior to precipitation of the particles. The drying technique is preferably selected to minimise migration of the drug during evaporation. Water or alkali soluble drugs suitable for formulation in accordance with this invention include omeprazole, diclofenac, sodium valproate, steroids, antibiotics etc. The method m accordance with this invention may be selected so that the rate of formation of the particles is accelerated to reduce diffusion of the drug during the formation of the particles. Precipitation of the polymer may be enhanced using an acid, for example hydrochloric acid which is stronger than the previously employed citric acid. This results m more rapid bead formation, reducing the liability to drug diffusion during the precipitation step. Once the particles are dry they may be filled into capsules or mixed with inert excipients and compressed into tablets. The inert excipients may also include another active substance or substances if a product is required with two or more drugs where only one needs enteric coating. For example diclofenac with misoprostol. The inert excipients will include fillers, binders, lubricants, colours and will preferably include microcrystalline cellulose which has good carrying capacity for the particles. The tablets may be provided with one or more break lines to facilitate division into smaller doses. They may also be over coated with a standard film or sugar coating m case of taste problems, light instability or discolouration of the tablets. If a varied release profile in the intestine is required, a mixture of particles from different batches with different amounts of polymer may be used. Methacrylate polymers are preferred for this aspect. In this aspect, uncoated drug fine powder may be added to the tablet mixture to give some immediate release of drug. The invention is described by means of example, but not n any limitative sense. EXAMPLE 1 - Preparation of HPMCP Macroparticles A polymer solution was prepared by dissolving HPMCP (2- 10 %w/v) and polyvmyl pyrrolidone (PVP) in an alkaline solution of sodium bicarbonate (2 %w/v) . Particles were formed by adding -10 ml of the HPMCP dropwise, into -100 ml of citric acid solution (,5-25 %w/v) at a temperature of ca 0-5°C with constant stirring. After the HPMCP was added the emulsion was left to continue stirring for a further 2 hr, after which the particles were filtered off and washed 3 times with distilled water. The particles were dried m a freeze-drier for at least 12 hr . In the first instance, no drug was used m the preparation order to compare particles made on a low speed laboratory stirrer with a Silversun high speed stirrer. The most effective recipes were used m the preparation for drug loaded particles. The drug used for these preparations was diclofenac. EXAMPLE 1 A LOW SPEED STIRRER: Tables 1-3 show the formulations used in the preparation of particles on a low speed stirrer. Table 1. Recipes for low speed stirrer. Particles made from 2% w/v HPMCP did not form as the solution was viscous enough for the particles to maintain their form in the emulsion medium. 5% w/v HPMCP particles were elongated in the shape but the 10% w/v particles were rounded. Table 2. Particles were all rounded shape but the case of the highest concentration of citric acid (25% w/v) the dried particles appeared glassy in colour and sticky rather than opaque and dry as for the others. They also appeared slightly shrunken in size by comparison. 15% w/v citric *as considered to give the best particles. Table 3. The particles produced on the lower 2 speed settings were relatively evenly shaped (especially the 15% w/v citric prepared on the lowest speed; 300 rpm) as the speed is increased to >650 rpm the shapes are irregular and elongated. EXAMPLE 1B Silversun Stirrer Particles were prepared in the same way on the Silversun mixer as for the low speed mixer described above except a larger vessel for the preparation was used and a larger volume of citric acid due to the requirements for high speed mixing. Formulations for the preparation were as shown m Table Table 4 * 3 < 2 < 1 5% HPMCP formulation did not form particles due to the low viscosity of the polymer solution and the droplets not holding their shape under the high shear of the mixing process . Of the particles prepared on the highest speed setting (3) , although some were well formed and spherical in shape, there were also some misshapen, oval shaped particles and a proportion of the polymer did not form any particles. The third speed setting was not preferred due to the large volume of citric acid and the size of the container required to produce a reasonable emulsion medium. The particles obtained indicated that an increase in the concentration of the polymer solution improved the shape of the particles but could result in some glassy particles and slight stickiness. Increasing the citric acid content did not appear to have a significant affect on the particles except when the HPMCP concentration is also high as this resulted sticky particles. Increasing the speed appeared to have a negligible effect on the size and shape of the particles . EXAMPLE 2 - Diclofenac Sodium Particles Preparation of Particles Particles using PVP as a gelling agent may be prepared the same way as described previously. Diclofenac sodium may be introduced into the bead formulation in the following ways : 1 ) Suspended the HPMCP solution 2) Dissolved m NaHC0 3 solution prior to preparation the HPMCP solution, (max solubility of diclofenac in NAHCO = 2.6 mg/ml [0.26% w/v] ) 3) Dissolved m ethanol and added to NaHCO j solution (approx max solubility of diclofenac ethanol = 0.1 g/ml [10% w/v] ) . Concentrations of NaHC0 3 and citric acid solutions used were 2% and 5% w/v respectively. Bead Formulations * In total volume of polymer solution F = particles were formed 1/2F = not all polymer formed particles, some polymer debris remained amongst particles collected N/F = particles were not formed EXAMPLE 3 - Encapsulation of Diclofenac m HPMCP particles: 0.2 g of particles were redissolved 10 cm' of the 2- w/v NaHCO solution (0.02% w/v). The samples that did not dissolve to produce a clear solution were filtered. The solution was diluted 1 m 100 and the absorption 275.7 was measured and compared to a previously constructed calibration of diclofenac sodium m NaHC0 3 solution. Equivalent blank particles prepared from 10 and 15% w/v HPMCP were also analysed in this way and the results subtracted from values for the drug loaded particles. The results are shown the following table. * No particles were formed + Sample did not dissolve and had to be filtered. Bead formation and highest entrapment efficiency was achieved when first dissolving the diclofenac sodium in ethanol and then mixing with the NaHC0 solution the ratio 10/90 ethanol/NaHC0 3 solution, prior to dissolving the HPMCP. As the volume of ethanol increases the viscosity of the polymer solution decreases and particles are not formed.

Claims: :LAIMS 1. A method of making an oral pharmaceutical dosage form of an aqueous soluble drug including the steps of: forming a solution containing the drug, a soluble polymer and a binding or gelling agent into drops; contacting the drops with an acid precipitating medium allowing the polymer to precipitate to form particles containing the dissolved drug; drying the particles; wherein the gelling or binding agent retards or prevents migration of the drug towards the surface of the particles during drying. 2. A method as claimed m claim 1 wherein the particles are incorporated into a tablet or filled into a gelatin capsule. 3. A method as claimed in claim 1 or 2 wherein the soluble polymer is hydroxypropyl methylcellulose phthalate. 4. A method as claimed claim 3 wherein the acid precipitating medium is citric acid. 5. A method as claimed m claim 4 wherein the acid precipitating medium is 5 to 20% citric acid. 6. A method as claimed in claim 5 wherein the acid precipitating medium is 10 to 15% citric acid. 7. A method as claimed m claim 1 wherein the soluble polymer is selected from: methylmethacrylate polymers, cellulose acetate phthalate, polyvmyl acetate phthalate and hydroxypropyl methyl phthalate. 8. A method as claimed m any preceding claim wherein the binding or gelling agent is selected from: polyv ylpyrolidone, methacrylate acid esters, gelatin, cellulosic polymers, cyclodextrms , polydextroses and modified starches. 9. A method as claimed in claim 8 wherein the amount of binding or gelling agent is 20 to 200% of the weight of the soluble drug. 10. A method as claimed m any preceding claim wherein the formulation includes a partially hydrated hydrogel . 11. An oral pharmaceutical dosage form comprising particles formed from an aqueous soluble drug, a soluble polymer, a gelling or binding agent and one or more inert excipients, the gelling or binding agent being adapted to retard or prevent migration of the drug towards a surface of the dosage form. 12. A tablet or capsule containing or incorporating a dosage form as claimed in claim 11.

Inventors: WOOLFE AUSTEN JOHN, WOOLFE, AUSTEN, JOHN
Applicants: NORTON HEALTHCARE LTD, WOOLFE AUSTEN JOHN, NORTON HEALTHCARE LTD., WOOLFE, AUSTEN, JOHN
Application year: 1999
Main classification: A61K9
IPC codes: A61K9