MXPA97010413A - Controlled release formulations for poorly solub medications - Google Patents

Abstract

A controlled release formulation for oral administration comprises a solid dispersion of a poorly soluble active ingredient in a hydrophilic poloxamer, the solid dispersion being a component of a core and the core as such or followed by coating the core with a polymeric coating being effective to reach therapeutic levels of the active ingredient over extended periods of time (24 hours or more) followed by oral administration. The formulation can be in a multi-particulate form such as pellets or mini-tablets or in the form of tablets. Examples of active ingredients whose solubility and therapeutic effectiveness can be improved with the formulation are cisapride, cyclosporine, diclofenac, felodipine, ibuprofen, indomethacin, nicardipine, nifedipine, terfenadine and teofili

Description

Controlled release formulations for poorly soluble medications Technical Field This invention relates to controlled release formulations for poorly soluble drugs for oral administration.

BACKGROUND ART [0002] Various controlled release / absorption pharmaceutical formulations are available which have a particular dissolution pattern, resulting in controlled absorption of the ae substance and, consequently, a more effee medication. The use of many ae substances in therapy is complicated by solubility problems. In the case of some insoluble drugs, various methods have been used to enhance solubility such as micronization, formation of amorphous co-precipitates, or preparation of inclusion complexes using materials such as cyclodextrins. Several surfactants have also been used to enhance the solubility of various insoluble compounds using different formulation strategies. Some medications, such as nifedipine, are non-ionizable and show low solubility throughout all regions of the gastrointestinal tract. Other medications are either basic or acidic and show limited solubility dependent on pH in different regions of the gastrointestinal tract. One such example is cisapride, which is basic in nature and has only relatively low solubility in acid conditions in the upper part of the gastrointestinal tract and very little solubility as it passes lower in the gastrointestinal tract. Our EP 0 232 155 B1 and EP 0 274 176 describe adsorbates for use in drug delivery systems. EP 0 232 155 B1 discloses adsorbates consisting of a mixture of a pharmaceutically useful ae ingredient and an inae substance adsorbed on a cross-linked polymer which is granulated and then mixed with a polymer or mixture of polymers to form a matrix system of delivery of sustained-release medication. EP 0 274 176 discloses sustained release tablet and capsule formulations based on an adsorbate of a mixture of a pharmaceutically useful dihydropyridine and a polyvinylpyrrolidone having an average molecular weight greater than 55,000 adsorbed on a crosslinked polyvinylpyrrolidone, the adsorbate being mixed with at least one polymer which gels in the presence of water so that a sustained release effect can be obtained. EP-A-0 317 780 discloses 1, 4-dihydropyridine complexes with polyoxypropylene-polyoxyethylene complexes and their use to form sustained and rapid release dose formulations. The formulations are formed by combining the complexes with one or more water-soluble cellulose derivatives with molecular weights that provide a viscosity in water of 9 to 30 cps and 3 to 8 cps, respeely at 20 ° C as a 2% aqueous solution. p / p. The in vitro release data are given by the different types of formulations. When the hydroxypropylmethylcellulose (HP C) having a viscosity of 15 cps was used as the cellulose derivative, an in vitro release of nifedipine of -25% was observed in 6 hours. The in vitro release in six hours was greater than 80% for HPMC with a viscosity of 6 cps or a 50:50 mixture of HPMC with viscosities of 6 cps and 15 cps. Drug Development and Industrial Pharmacy (1992) 18, 16, 1719-1739 describes the investigation of potential bases including the polyoxypropylene-polyoxyethylene copolymer Lutrol-F68 for the preparation of solid dispersions formed from melt for molten filler in hard gelatin capsules. The investigations included dissolution studies in various drug / base formulations. When the in vitro release profile for ibuprofen from Lutrol-F68 was investigated a T50 value of about 30 min was observed. It is an object of the present invention to provide an improved drug delivery system wherein the bioavailability of a poorly bioavailable ae ingredient is otherwise intensified and controlled effeely. A further objee of the present invention is to provide controlled release dosage forms of poorly soluble ae ingredient, which provides therapeutic levels for a period of up to 24 hours or greater, dependent on the half-life of the ae ingredient.

DESCRIPTION OF THE INVENTION The invention provides a controlled release formulation for oral administration, comprising a dispersion of solids of an active ingredient, which has poor aqueous solubility, in a hydrophilic poloxamer polymer, said dispersion of solids being mixed with water-swellable hydroxypropylmethylcellulose. , a 2% solution of which has a viscosity in the range of 100-100,000 centipoise, to form a hydrogel matrix, and one or more tabletting ingredients to form a tablet core, said tablet core as such or followed of coating the core with a polymeric coating being effective to achieve therapeutic levels of said active ingredient over extended periods of time after oral administration. It was found that incorporation of a poorly soluble active ingredient into a solid dispersion in a formulation according to the invention reaches a significant level of solubility / wettability enhancement, as well as reaching therapeutic levels of said active ingredient over extended periods in vivo. . To adjust the variant solubility of the different active ingredients of the type referred to above, the dispersion of solids may need to include one or more ingredients to further enhance the solubility / wettability enhancement of the active ingredient. According to this, the dispersion of solids may include a surfactant component. The surfactant may be an anionic, cationic or non-ionic surfactant. The preferred surfactant components are selected from sodium lauryl sulfate, a sodium carboxylate, an alkyl sulfate, a polyethylene glycol ester, a polyethylene ether, a sorbitan ester, an ethoxylated sorbitan ester and an alkyltrimethyl ammonium halide and a mixture of the same.

Alternatively, the dispersion of solids may include an acid component. The preferred acid components are selected from adipic acid, ascorbic acid, citric acid, fumaric acid, malic acid, succinic acid and tartaric acid. In addition, alternatively, the dispersion of solids may include a base component. The preferred base components are selected from calcium carbonate, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, sodium carbonate, sodium citrate and sodium hydroxide. Preferably, the surfactant, acid or base component is present in a ratio of 0.01: 1.0 to 5.0: 1.0 by weight of the active ingredient. Any of such surfactant, acid or base components are collectively referred to hereafter as auxiliary agents. In addition, preferably, the active ingredient and the poloxamer are present in an amount of 0.1: 1.0 to 10.0: 1.0 by weight. By poloxamer is meant herein also a combination of two or more poloxamers. Poloxamer polyols are a series of block copolymers closely related to ethylene oxide and propylene oxide. More specifically, the poloxamer polyols are α-hydro-? -hydroxypoly (oxyethylene) poly (oxypropylene) poly (oxyethylene) block copolymers, more generally known as polyethylene-propylene glycol copolymer or polyoxyethylene-polyoxypropylene copolymer.

Preferred poloxamers are those containing between 60% and 90%, more especially between 70% and 80%, by weight of the polyoxyethylene portion. The polyoxyethylene segment is hydrophilic while the polyoxypropylene segment is hydrophobic. All poloxamers are chemically similar in composition, differing only in the relative amounts of propylene oxide and ethylene oxide added during production. The hydrophilic segment can comprise between 15 and 90% of the molecule. As indicated above, those recommended for use according to the invention have between 60% and 90%, more especially between 70% and 80%, by weight of the polyoxyethylene hydrophilic sequence or segment. Such poloxamer polyols, hereinafter referred to as poloxamers, are known by the trade names Lutrol, Monolan and Pluronic. Poloxamers are also defined by a number. The first two digits of the number, when multiplied by 100, correspond to the approximate average molecular weight of the polyoxypropylene (POP) portion of the molecule. The third digit, when multiplied by 10, corresponds to the percentage by weight of the polyoxyethylene portion (POE). When Pluronic is called by its name, the first two digits, when multiplied by 1000, indicate the total molecular weight, and the third digit, multiplied by 10, represents the approximate percentage of POE in the molecule. The associated capital letter indicates the physical state: L = liquid, P = paste, and F = solid. For further information, reference may be made to Pharmaceutical Technology Europe in May 1994. Preferred poloxamers for use according to the invention are the F series. The especially preferred poloxamers of the F series are F68, F108 and F127, especially those sold under the commercial brands Lutrol F68, Pluronic F108 and Lutrol F127 by BASF. Additional information on these poloxamers can be obtained from the technical information sheets provided by BASF (Ireland) Limited. The poloxamer is melted and then the active ingredient and any auxillary agent (s) are dispersed in the molox poloxamer. The poloxamer is suitably melted in a stainless steel container. The active ingredient and any auxiliary agent (s) and the inert filler, if used, are slowly added to the melt over time. The mixture is stirred while it is cooled and milled to a medium particle size in the range of 30-300 μm. Alternatively, the active ingredient, any auxiliary agent (s), and the poloxamer are dissolved in a solvent or organic solvents; the solvent is evaporated and the poloxamer melt is cooled and milled to a median particle size in the range of 30-300 μm. It has been found that several poorly soluble active ingredients are readily dispersible in the molten forms of the poloxamers used according to the invention. When the mixture of the active ingredient, auxiliary agent (s) is cooled, if present, and the poloxamer forms a dry and hard solid, which can be easily ground or ground. It is for this reason that poloxamers were selected herein as the polymer base for the dispersion of solids. The dispersion of solids according to the invention can include excipient agents, such as an inert filler. The inert filler is suitably an inert filler soluble in water. An example of an inert filler is lactose, more especially lactose monohydrate. The inclusion of an inert filler such as lactose may have the effect of lowering the melting point of the poloxamer. The incorporation of an inert filler is found to not have a detrimental impact on the solubility obtained. However, it significantly improves the overall processability and leads to a fine powder material, which is very suitable for tablet compression. The inert filler is suitably used in an amount of 3-35% by weight.

The active ingredient can be any poorly soluble medicament of the aforementioned type. Examples of such drugs are cisapride, cyclosporine, diclofena, felodipine, ibuprofen, indomethacin, nicardipine, nifedipine, terfenadine and theophylline. One purpose of the present invention is to provide poorly soluble active ingredients such as cisapride in an easily solubilized form and absorbable at distal sites in the gastrointestinal tract so that extended and continuous absorption is achieved. The aqueous solubility of cisapride, which is inherently low and significantly dependent on pH, becomes limiting as cisapride is normally presented to more distal sites in the gastrointestinal tract where the water content and pH adversely impact solubility of cisapride. Although it is not desired to be bound by any theoretical explanation of the invention, it is postulated that the increased solubility of the cisapride obtained through the use of a solid dispersion as described hereinbefore results in an optimal microenvironment, which promotes the availability of absorbable and solubilized cisapride. Additionally, the presence of a hydroxy acid in the solid dispersion, combined with the controlled release system employed, results in a gradual availability of the hydroxy acid to promote the solubilization of cisapride over the volume of the release rate curve. Similar results were obtained with other poorly soluble active ingredients as described hereinafter. The solid oral dosage form according to the invention may be in the form of capsules. In this way, the capsules according to the invention can contain the formulation according to the invention in a multi-particulate form such as mini-tablets. Suitably, the capsules will include a number of mini-tablets for the immediate release of the active ingredient comprising a dispersion of solids as defined hereinbefore. Several multi-particulate forms or a small number of discrete units can be presented in the capsule form. The capsules can be soft or hard gelatin capsules. The tablets consist of a tablet core defined by a dispersion of solids as described above dispersed in a hydrogel matrix. In this tablet form, the solids dispersion is compressed into a dosage form containing a polymer or mixture of polymers, which upon wetting will swell to form a hydrogel. The rate of release of the active ingredient from this dosage form is controlled both by diffusion of the mass of the swollen tablet and by erosion of the surface of the tablet over time. The release rate of the active ingredient can be controlled both by the amount of polymer per tablet and by the inherent viscosities of the polymers used. The water-swellable hydroxypropylmethylcellulose (HPMC) polymer is suitably present in an amount of 5-75% by weight. By hydroxypropylmethylcellulose is meant here a combination of hydroxypropylmethylcelluloses. As indicated above, HPMC polymer will suitably be present in an amount from 5% to 75% by weight, more especially from 10% to 60% by weight. A particularly preferred type of HPMC to be used according to the invention is HPMC sold under the trademark Methocel. The amount of HPMC polymer used will be dependent on the viscosity thereof. In general, the higher the viscosity of the polymer, the smaller the amount of polymer required to give the desired release properties. Methocels are Methocel K15M, a 2% solution which has a viscosity of 15,000 centipoise. Other suitable Methocels include Methocel K4M, K100M, K100LV or E, F, and J grades, depending on the desired release characteristics. As indicated above, the use of hydrogel matrices causes the tablet to swell and release the medicament in a controlled manner by erosion of the tablet surface and diffusion of the tablet mass.

Cellulose polymers with different inherent viscosities are preferably used to control the rate of dissolution. HPMC hydrogels are linear macromolecules which swell in water or biological fluids. The release of the drug in such systems can be basically modified by varying the following parameters: Type and degree of viscosity of polymers; and Current concentrations. The type of polymer chosen according to the invention is determined mainly by the solubility characteristics of the solid dispersion to be compressed. The degree of viscosity is dictated by the desired release rate of the active ingredient from the mass of the tablet. The hardness of the tablet is also a parameter to be considered in the case of hydrogel tablets. Suitably, the average hardness of the tablets is in the range of 60-260 N. For tableting purposes, it will also be normal to use a diluent or compactor such as microcrystalline cellulose, more especially microcrystalline cellulose sold under the trademark Avicel, for example, Avicel pH 101.

Other excipients may include lubricants such as magnesium stearate and a glidant such as colloidal silicon dioxide sold under the trademark Aerosil. The solid oral dosage form according to the invention may also be in the form of tablets comprising a core containing a dispersion of solids as described above, surrounded by a multi-porous membrane, which controls the speed. Suitably, the solids dispersion is in the form of an instant release tablet core that is adapted for direct compression followed by coating with the speed controlling membrane. A major consideration with such formulations is the selection of suitable tablet ingredients to impart the desired effect while being easily compressed. In order to achieve an instant release tablet core, the solid dispersion is suitably mixed with standard tablet excipients such as a standard compression base, a compressible sugar, a solubilizing agent and a lubricating agent. In this type of dosage form, the release of the active ingredient is controlled via a diffusion mechanism. The hardness of the tablet and the friability play an important role in the characterization of the membrane-covered tablet. It is essential that the core tablets are strong enough to withstand the coating process. In order to obtain the desired release profile suitable for once-a-day administration, the velocity-controlling membrane will suitably contain a higher proportion of a water insoluble polymer, pharmaceutically acceptable film former and optionally a smaller proportion of a water soluble polymer, pharmaceutically acceptable film former. The term "water-soluble polymer" as used herein includes polymers which are freely permeable to water, while the term "water-insoluble polymer" as used herein includes polymers which are slightly permeable to water, as indicated by here on. Preferably, the water-soluble polymer in the membrane, if present, is selected from polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, agar, carrageenan, xanthan or polyethylene glycol or a mixture thereof. The incorporation of various hydrophilic agents in the coating of the polymer so as to form channels in said coating can be used and in general leads to a more linear release rate. Such hydrophilic agents include fumaric acid, citric acid, tartaric acid, sodium citrate, sodium bicarbonate, sodium fumarate, sodium carbonate, monosaccharides and disaccharides. A particularly suitable monosaccharide is glucose. Alternatively, the water soluble polymer in the membrane can be replaced by a polymeric material, which is freely permeable to the active ingredient and water, and comprises a copolymer of methacrylic acid esters and acrylic.

A suitable polymer, which is freely permeable to several poorly soluble active ingredients and water is a polymer sold under the trademark EUDRAGIT RL. Preferably, the water-insoluble polymer in the membrane is selected from ethyl cellulose, cellulose acetate, cellulose propionate (low molecular weight, medium or high molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutylmethacrylate) ), poly (hexylmethacrylate), poly (isodecylmethacrylate), poly (allylmethacrylate), poly (phenylmethacrylate), poly (methylacrylate), poly (isopropyl acrylate), poly (isobutylacrylate), poly (octadecylacrylate), poly (ethylene), poly (ethylene) ) of low density, high density poly (ethylene), poly (propylene), polyethylene oxide, poly (ethylene terephthalate), poly (vinyl isobutyl ether), poly (vinyl acetate), polyvinyl chloride or polyurethane or a mixture of they. The water insoluble polymer of the membrane may also comprise resins or polymers that occur naturally. In this manner, other preferred water-insoluble polymers are selected from naturally occurring polymers selected from lacquer, "chitosan", juniper gum or a mixture thereof. Alternatively, the water-insoluble polymer in the membrane can be replaced by a polymeric material which is slightly permeable to the active ingredient and water, and comprises a copolymer of methacrylic acid esters and acrylic.

A suitable polymer which is slightly permeable to several poorly soluble active ingredients and water is a polymer sold under the trademark EUDRAGIT RS or a polymer whose permeability is pH dependent and is sold under the trademark EUDRAGIT L, EUDRAGIT S or EUDRAGIT E The polymers especially preferred in this category are EUDRAGIT S. EUDRAGIT polymers are polymeric varnish substances based on acrylates and / or methacrylates. The polymeric materials sold under the trademark EUDRAGIT RL and EUDRAGIT RS are acrylic resins comprising copolymers of methacrylic acid esters and acrylic with a low content of quaternary ammonium groups and are described in the brochure "EUDRAGIT" by Messrs, Rohm Pharma GmbH ( 1984) where detailed physical-chemical data of these products are given. The ammonium groups are present as salts and provide increase in the permeability of the varnish films. EUDRAGIT R L and RS are freely permeable (RL) or slightly permeable (RS) respectively, regardless of pH. EUDRAGIT S is an anionic polymer synthesized from methacrylic acid ester and methacrylic acid methyl ester. It is insoluble in acids and pure water. It becomes soluble in a weakly alkaline medium by forming salts with alkalis. The permeability of EUDRAGIT S is pH dependent. Above pH 6.0 the polymer becomes increasingly permeable. The EU DRAGIT S is described in the brochure "EU DRAGIT S" by Messrs. Rohm Pharma GmbH (1986) where the detailed physicochemical data of the product are given.

The solution / suspension of the coating of the polymeric material comprises one or more polymers dissolved / suspended in a suitable solvent or mixture of solvents. The concentration of the polymeric material in the solution / suspension of the coating is determined by the viscosity of the final solution / suspension. The addition of a plasticizer to the polymer solution / suspension may be necessary depending on the formulation to improve the elasticity and also the stability of the polymer film and to avoid changes in polymer permeability over extended storage. Such changes could affect the release rate of the medication. Suitable plasticizing agents include polyethylene glycol, propylene glycol, glycerol, triacetin, dimethyl phthalate, diethyl phthalate, dibutylphthalate, dibutylsebacate, triethyl citrate, tributyl citrate, tyrettylacetyl citrate, castor oil and various percentages of acetylated monoglycerides. The coating of the active tablet core with a differentially permeable membrane allows active dissolution and diffusion of the active core micro-environment. Especially, suitable polymers are celluloses and poly (meta-plate) -based polymers for use as coating agents. The polymer coating is most suitably made in a D.Fix 360 granulator. Preferred solvents for use in the application / coating of the polymer include acetone, isopropyl alcohol and industrial methylated alcohol.

Based on the information provided on other ways of incorporating the solids dispersion described above to achieve improved solubilization / wettability and improved controlled absorption / release will be apparent to one skilled in the art.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph of plasma levels of nifedipine (ng / ml) versus time (hours) after administration for the formulations of Examples 1 and 2; Figure 2 is a graph of plasma levels of nifedipine (ng / ml) versus time (hours) after administration for the formulations of Examples 3 and 4; Figure 3 is a graph of plasma levels of nifedipine (ng / ml) versus time (hours) after administration for the formulations of Example 5 and the reference product; Figure 4 is a graph of plasma levels of cisapride (ng / ml) versus time (hours) after administration for the tablet formulations of Examples 6 and 7; wherein: curve a) corresponds to the tablet formulation of Example 6; and curve b) corresponds to the tablet formulation of Example 7; and Figure 5 is a graph of plasma levels of cisapride (ng / ml) versus time (hours) after administration for the formulations of Examples 8-1 and the reference product.

MODES FOR CARRYING OUT THE INVENTION This invention will be further illustrated by the following Examples.

Example 1 (comparative example) Preparation of the tablet A tablet formulation was prepared by mixing the following tablet ingredients in the indicated proportions. Ingredient% by weight Nifedipine 12.82 Methocel K15M 64. 10 Avicel PH 101 22.22 Magnesium Stearate 0.86 The tablet mixture was tabletted at an average hardness of 55N in a Killian RTS tablet press. In vitro dissolution for the tablets was determined in a USP II Apparatus (paddles) at 100 r.p.m. in 1.25% SLS aqueous solution in a medium of pH 6.8, in a volume of 900 ml and a temperature of 37 ° C + 0.5. The following results were obtained.

Ti me (hours)% of release 1.0 2.5 2.0 8.7 4.0 21.7 6.0 30.3 8.0 43.3 10.0 52.4 24.0 101 .0 Example 2 Preparation of solids dispersion The Lutrol F127 (500g) was melted by heating at 80 ° C.

Nifedipine (500 g) was gradually added to, and dispersed in, the Molten Lutrol Mixing was continued for 2 h before allowing the solids dispersion to cool to room temperature, followed by grinding.

Preparation of the tablet A tablet formulation was prepared by mixing the solid dispersion with the following tablet ingredients in the indicated proportions: Ingredient% by weight Dispersion of solids 23.43 Methocel K15M 56.30 Avicel PH 101 19.52 Magnesium stearate 0.75 The tablet mixture was tabletted at an average hardness of 52N in a Killian RTS tablet press. The in vitro dissolution for the tablets was determined under the conditions as specified in Example 1. The following results were obtained: Time (hours)% of release 1 .0 5.3 2.0 8.2 4.0 20.3 6.0 31 .6 8.0 42.3 10.0 53.6 24.0 1 10.8 A comparison of pharmacokinetic data for the formulations prepared in Examples 1 and 2 are shown in Table 1 and accompanying Figure 1.

Table 1 * Area under the curve of the plasma drug level against time ** Maximum plasma concentration of the drug reached *** The time in which C max is reached The effect of including the solids dispersion (Example 2) with the assistant increase in bioavailability is clear from a comparison of Example 1 (raw material alone) and Example 2.

Example 3 Preparation of the solids dispersion The Lutrol F127 (1500g) was melted by heating at 80 ° C. Nifedipine (500 g) was gradually added to, and dispersed in, the molten Lutrol. Mixing was continued for 2 h before allowing the solids dispersion to cool to room temperature, followed by grinding.

Preparation of the tablet A tablet formulation was prepared by mixing the solids dispersion with the following tablet ingredients in the indicated proportions: Ingredient% by weight Solids dispersion 35.29 Methocel K15M 30.00 Methocel K100LV 0.1 Avicel PH 101 33.35 Magnesium stearate 0.86 Aerosil 200 0.4 The tablet mixture was tabletted at an average hardness of 73 N in a tablet press Fette E 1. The in vitro dissolution for the tablets was determined under the conditions as specified in Example 1. The following results were obtained: Time ( hours)% release 1 .0 9.8 2.0 19.3 4.0 41 .7 6.0 55.8 8.0 67.5 10.0 77.3 12.0 88.6 24.0 103.9 Example 4 Preparation of the dispersion of solids The dispersion of solids corresponded to that prepared in Example 3.

Tablet preparation A tablet formulation was prepared by mixing the solids dispersion with the following tablet ingredients in the indicated proportions: Ingredient% by weight Solids dispersion 35.29 Methocel K15M 0.10 Methocel K100LV 40.00 Avicel PH 101 23.35 Magnesium stearate 0.86 Aerosil 200 0.40 The tablet mixture was tabletted at an average hardness of 73N in a Fette E1 tablet press. The in vitro dissolution for the tablets was determined under the conditions as specified in Example 1. The following results were obtained: Time (hours)% of release 1 .0 22.2 2.0 35.8 4.0 67.9 6.0 92.1 8.0 103.1 10.0 105.6 12.0 105.5 24.0 106.2 A comparison of the pharmacokinetic data for the formulations prepared in Examples 3 and 4 is shown in Table 2 and accompanying Figure 2. Table 2 Example 3, which uses a high percentage of a high viscosity Methocel (relative to Example 4) shows a slower dissolution profile and consequently shows a favorable in vivo plasma profile, demonstrating in this way that changes in the profile can be achieved with different degrees of Methocel.

Example 5 Preparation of solid dispersion The Lutrol F127 (4500g) was melted by heating at 80 ° C. Nifedipine (1500g) was gradually added to, and dispersed in, the Molten Lutrol Mixing was continued for 2 h before the dispersion of solids was allowed to cool to room temperature, followed by grinding.

Preparation of the tablet A tablet formulation was prepared by mixing a dispersion of solids with the following tablet ingredients in the indicated proportions: Ingredient% by weight Solids dispersion 35.29 Methocel K15M 15.00 Methocel K100LV 0.1 Avicel PH 101 47.95 Magnesium stearate 0.86 Aerosil 200 0.8 The tablet mixture was tabletted at an average hardness of 90N in a Fette E1 tablet press. The in vitro dissolution for the tablets was determined under the conditions as specified in Example 1. The following results were obtained: Time (hours)% of release 1 .0 15.7 2.0 40.0 4.0 63.9 6.0 81.7 8.0 103.8 10.0 109.9 A comparison of the pharmacokinetic data for the formulation prepared in Example 5 with a commercially available once-daily nifedipine tablet (hereinafter referred to as reference) is shown in Table 3 and accompanying Figure 3.

Table 3 Example 6 Preparation of solids dispersion The Lutrol F127 (463g) obtained from BASF (Ireland) Limited was melted by heating to 80 ° C. Cisapride (237 g) obtained from Janssen Pharmaceutica N.V., tartaric acid (150 g), obtained from R. B. Chemicals, and lactose (150 g) obtained from Forum Chemicals, were gradually added to, and dispersed in, the molten Lutrol. The mixing was continued for 0.5 hours until the last of the lactose was added. The resulting solids dispersion was allowed to cool to room temperature, followed by milling thereof.

Preparation of the tablet A tablet formulation was prepared by mixing the solids dispersion with the following ingredients for tabletting in the indicated proportions: Ingredient% by weight Dispersion of solids 24.2 Methocel K15M 20.0 Avicel pH 101 55.3 Magnesium stearate 0.5 The tablet mixture was tabletted at an average hardness of 129N in a Killian RTS tablet press. The in vitro dissolution for the tablets thus prepared was determined using the apparatus U.S. P I I standard (pallets) operating at 50 r. p. m. using a solution medium of 0.01 M HCl, volume 900ml and temperature of 37 ° C + 0.5 ° C. At the indicated sampling times an aliquot of 6.0 ml was removed and filtered through a 0.45 μm filter. A 4/10 dilution with 0.01 M HCl was performed and the absorbance at 270 nm measured against 0.01 M HCl. The following results were obtained: Time (hours)% of release 0.5 13.8 1 .0 16.7 2.0 22.2 4.0 33.0 6.0 41 .5 8.0 49.9 10.0 57.0 12.0 61 .3 16.0 67.3 24.0 81 .2 The plasma levels of cisapride achievable with the tablet preparation prepared before was evaluated in 10 healthy male volunteers subjects. The results are shown in the accompanying Figure 4, where curve a) corresponds to the present Example.

Example 7 Preparation of solids dispersion The Lutrol F127 (463 g) was melted by heating to 80 ° C. Cisapride (237 g), tartaric acid (150 g) and lactose (150 g), were gradually added to, and dispersed in, the molten Lutrol. The mixing was continued for 0.5 hours until the last lactose had been added. The resulting solids dispersion was allowed to cool to room temperature, followed by milling thereof.

Preparation of the tablet A tablet formulation was prepared by mixing the solids dispersion with the following tabletting ingredients in the indicated proportions: Ingredient% by weight Dispersion of solids 24.2 Methocel K15M 40.0 Avicel pH 101 35.3 Magnesium stearate 0.5 The tablet mixture was tabletted at an average hardness of 139 N in a Killian RTS tablet press. The in vitro dissolution for the tablets thus prepared was determined under the conditions specified in Example 6. The following results were obtained.

Time (hours)% of release 0.5 8.4 1 .0 12.0 2.0 21 .3 4.0 43.4 6.0 54.1 8.0 70.5 10.0 87.6 12.0 98.7 16.0 108.3 24.0 1 12.5 The plasma levels of cisapride achievable with the tablet formulation prepared according to the present Example were evaluated in 10 healthy male volunteers subjects as before. The results are shown in Figure 4, where curve b) corresponds to the present Example. ******* In in vivo studies based on the tablet formulations of Examples 6 and 7 each of the 10 subjects received a 40 mg tablet once a day. It will be clear from the accompanying Figure 4 that the tablet formulations of Examples 6 and 7 have an extended plasma level and absorption profile. Each product seems to show an absorption phase with a faster initial absorption rate (over the first 4 hours) and a slower absorption rate over the remaining 12-16 hours. The main difference between the plasma level profile of the product of Example 6 in relation to the product of Example 7 is that the last product has a more dominant peak concentration (C max) while the previous product has the plasma level profile and more widespread absorption. The respective products, while sharing a common solids dispersion formulation, differ in the rate of release characteristics and the viscosity grade of the cellulose-based polymer used to achieve the speed control.

Table 4 The elimination rate constant '* * The half-life of the drug in the plasma.

Example 8 Preparation of the solids dispersion The Lutrol F68 (2087.4 g) was melted by heating to 80 ° C. Cisapride (522.4 g) and tartaric acid (391.4 g) were gradually added to, and dispersed in, the molten Lutrol. Mixing was continued for one hour before allowing the solids dispersion to cool to room temperature, followed by grinding it.

Preparation of the tablet A tablet formulation was prepared by mixing the solids dispersion with the following tabletting ingredients in the indicated proportions: Ingredient% by weight Solids dispersion 32.8 Methocel K100LV 40.0 Methocel K15M 0.1 Avicel pH101 26.1 Aerosil 200 0.5 Magnesium stearate 0.5 The tablet mixture was tabletted at an average hardness of 125 N in a Killian RTS tablet press. The in vitro dissolution for the tablets was determined under the conditions specified in Example 6. The following results were obtained: Time (hours)% of release 0.5 6.3 1 .0 8.5 2.0 14.4 4.0 28.6 6.0 37.9 8.0 51 .1 10.0 60.7 24.0 104.6 Example 9 Preparation of the solids dispersion Tartaric acid (156.4 g) was dissolved in ethanol (833 g). In a separate vessel Cisapride (500 g) was dissolved in acetone (5000 g) followed by Lutrol F68 (2001 .7 g). The two solutions were mixed at 50 ° C and the solvent was evaporated under vacuum at elevated temperatures. The resulting molten solids dispersion was allowed to cool to room temperature, followed by milling thereof.

Preparation of the tablet A tablet formulation was prepared by mixing the solids dispersion with the following tabletting ingredients in the indicated proportions: Ingredient% by weight Dispersion of solids 30.35 Methocel K100LV 5.0 Methocel K15M 10.0 Avicel pH 101 53.65 Aerosil 200 0.5 Magnesium stearate 0.5 The tablet mixture was tabletted at an average hardness of 108N in a Killian RTS tablet press. The in vitro dissolution for the tablets was determined under the conditions specified in Example 6. The following results were obtained: Time (hours)% of release 0.5 6.6 1 .0 10.2 2.0 16.7 4.0 26.1 6.0 32.8 8.0 40.0 10.0 44.3 24.0 84 1 Example 10 Preparation of solids dispersion The solids dispersion used was the solids dispersion of Example 9.

Tablet preparation A tablet formulation was prepared by mixing the dispersion with the following tabletting ingredients in the indicated proportions: Ingredient% by weight Dispersion of solids 30.35 Methocel K100LV 40.0 Methocel K15M 0. 1 Avicel pH 101 28.55 Aerosil 200 0.5 Magnesium stearate 0.5 The tablet mixture was tabletted at an average hardness of 15N in a Killian RTS tablet press. The in vitro dissolution for the tablets was determined under the conditions specified in Example 6. The following results were obtained: Time (hours)% of release 0.5 5.0 1 .0 9.5 2.0 16.0 4.0 28.4 6.0 40.1 8.0 49.5 10.0 65.7 24.0 103.9 Example 1 1 (Comparative example) Preparation of the solids dispersion The solids dispersion used was the solids dispersion of Example 9.

Preparation of mini-tablets A formulation of mini-tablets was prepared by mixing the dispersion of solids with the following tableting ingredients in the indicated proportions: Ingredient% by weight Dispersion of solids 29.57 Avicel pH 101 58.93 Aerosil 200 2.0 Magnesium stearate 0.5 The tablet mixture was tabletted at an average hardness of 75N in a Killian RTS tablet press.

Coating of mini-tablets An amount of 500g of the above mini-tablets was coated with the following coating solution in a Hi-Coater (registered trademark) at a weight gain of 10.7%. Ingredient% by weight Eudragit L12.5 50.0 Diethylphthalate 1 .25 Talc .1 .50 Isopropanol 44.4 Purified water 2.85 Another 500 g of mini-tablets were coated with the following solution in a Hi-Coater at a weight gain of 8.6%.

Ingredient% by weight Eudragit S12.5 50.0 Diethylphthalate 1.25 Talc 1.55 Jsopropanol 44.35 Purified water 2.85 Final dosage form The final dosage form was a double zero capsule filled with three uncoated mini-tablets, three mini-tablets coated with Eudragit L and three mini-tablets coated with Eudragit S. This formulation provides a smooth plasma profile over an extended period as shown in Figure 5. The uncoated mini-tablets showed rapid disintegration in acid (<7 minutes) and 95% release in solution in 0.01 N HCl. The enteric coated tablets did not show acid disintegration ( until 60 minutes) and 100% release in the solution in pH buffer 6. 8 with SLS.

A summary of the pharmacokinetic data for the formulations prepared in Examples 8-11 and the product sold under the trademark Prepulsid (hereinafter referred to as a reference) is presented in Table 5 and accompanying Figure 5.

Table 5

Claims (17)

1. Claims 1 . A controlled release formulation for oral administration, comprising a dispersion of solids of an active ingredient, which has a poor aqueous solubility, in a hydrophilic poloxamer polymer, said solid dispersion being mixed with a water swellable hydroxypropylmethylcellulose, a 2% of which has a viscosity in the range 100-100,000 centipoise, to form a hydrogel matrix and one or more tabletting ingredients to form a tablet core, said tablet core as such or followed by a coating of the tablet. core with a polymeric coating being effective to achieve therapeutic levels of said active ingredient over extended periods of time following oral administration.
2. 2. A formulation according to claim 1, wherein the dispersion of solids includes a surfactant component.
3. 3. A formulation according to claim 2, wherein the surfactant component is selected from sodium lauryl sulfate, sodium carboxylate, an alkyl sulfate, a polyethylene glycol ester, a polyethylene ether, a sorbitan ester, and sorbitan ester. ethoxylated and an alkyltrimethylammonium halide and a mixture thereof.
4. 4. A formulation according to any of the preceding claims, wherein the dispersion of solids includes an acid component.
5. 5. A formulation according to claim 4, wherein the acid component is selected from adipic acid, ascorbic acid, citric acid, fumaric acid, malic acid, succinic acid and tartaric acid.
6. 6. A formulation according to any of claims 1-3, wherein the dispersion of solids includes a base component.
7. 7. A formulation according to claim 6, wherein the base component is selected from calcium carbonate, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, sodium carbonate, sodium citrate and sodium hydroxide.
8. 8. A formulation according to any of claims 2-7 wherein the surfactant, acid or base component is present in a ratio of 0.01: 1.0 to 5.0: 1.0 by weight of the active ingredient.
9. 9. A formulation according to any of the preceding claims, wherein the active ingredient and the poloxamer are present in an amount of 0.1: 1.0 to 10.0: 1.0 by weight. 1 0.
10. A formulation according to any of the preceding claims, wherein the poloxamer contains between 60% and 90% by weight of polyoxyethylene. eleven .
11. A formulation according to any of the preceding claims, which is in a multi-particulate form.
12. 12. A formulation according to claim 1 which is in the form of mini-tablets.
13. 13. A formulation according to claim 11 or 12, which includes an amount of said dispersion of solids for immediate release.
14. 14. A formulation according to any of the preceding claims, wherein the hydroxypropylmethylcellulose is present in an amount of 5-75% by weight.
15. 15. A formulation according to any of the preceding claims, wherein the core is surrounded by a multi-porous speed controlling membrane.
16. 16. A formulation according to any of the preceding claims, wherein the active ingredient is selected from cisapride, cyclosporine, diclofenac, felodipine, iboprofen, indomethacin, nicardipine, nifedipine, terfenadine and theophylline.
17. 17. A controlled release formulation for oral administration, substantially as described and exemplified in the foregoing.