MXPA99011317A - Solid pharmaceutical dosage forms in form of a particulate dispersion - Google Patents

Abstract

Solid particulate dispersions of pharmaceutical agents in a matrix of a water-soluble polymer exhibiting good aqueous dissolution enhanced bioavailability. The method of the invention utilizes water-soluble polymers such as polyvinylpyrrolidone, hydroxypropyl cellulose or hydroxypropylmethyl cellulose as carriers. The invention provides for mixing or extracting the active ingredients in solid particulate form with the polymeric carrier at a temperature at which the polymer softens, or even melts, but the drug remains solid or crystalline. The drug particules thus become coated and produce a product that is matrix coated, i.e. a particulate dispersion.

Description

FORMS OF SOLID PHARMACEUTICAL DOSES IN THE FORM OF PARTICLE DISPERSION FIELD OF THE INVENTION This invention relates to orally bioavailable dosage forms of pharmaceutical agents of low water solubility.

BACKGROUND OF THE INVENTION Many pharmaceutical agents are chemical structures so complex that they are insoluble or only very poorly soluble in water. The foregoing results in null or sparse dissolution from conventional dosage forms designed for oral administration. The low dissolution rates result in no or low bioavailability of the active chemical substance, which makes the oral supply ineffective therapeutically, and parenteral administration is needed to achieve a beneficial therapeutic result. Drug products that are limited to parenteral delivery lead to higher health care costs, due to higher manufacturing costs, more expensive accessories required for delivery, and in many cases hospitalization of the patient to ensure proper dosing (eg, sterile intravenous delivery).

Poorly water soluble drugs that undergo gastrointestinal absorption limited to the type of solution usually show greater bioavailability when the type of solution is improved. To improve the dissolution property. and potentially the bioavailability of drugs that are poorly soluble in water, many strategies and methods have been proposed and used, including the reduction of particle size, selection of salts, formation of molecular complexes and solid dispersions, and the use of polymorphic forms metastable, cosolvent and surface active agents. Of these methods, the use of surface active agents is mainly to improve the wetting ability of drugs that are poorly soluble in water, which eventually results in the improvement of the type of solution.

We have now discovered a method for producing solid particulate dosage forms of poorly water-soluble pharmaceutical agents, which makes them ideally suited for oral administration, and which provides an improved type of water dissolution and thus an oral bioavailability. improved The method of this invention uses water-soluble polymers such as polyvinylpyrrolidone, hydroxypropyl cellulose or methylcellulose hydroxypropyl as carriers. The use of these water-soluble carriers improves the wetting ability of crystalline pharmaceutical agents which are poorly soluble in water, thus improving the type of solution after administration, which ultimately results in better bioavailability and therapeutic result. The invention provides the mixing or extrusion of the active ingredients in the form of solid particles with the polymeric carrier at a temperature at which the polymer softens, or even melts, but in which the drug remains solid or crystalline. The particles of the drug are thus covered and produce a product that is covered by the matrix, that is, a dispersion of particles.

SUMMARY OF THE INVENTION This invention provides solid dosage forms of pharmaceutical agents with poor water solubility. More particularly, the invention is a pharmaceutical composition in the form of a solid particle dispersion of a pharmaceutical ingredient in dispersed particles in a matrix of a water-soluble polymer such as polyvinylpyrrolidone, hydroxypropyl cellulose or methylcellulose hydroxypropyl.

In a preferred example, the particulate pharmaceutical ingredient is dispersed in a water soluble polymer in a weight ratio of from about 10% to about 90% active ingredient for about 90% to about 10% of the polymer. A preferred formulation comprises about 20% to about 80% of the active ingredient and about 80% to about 20% of the polymer. The most preferred composition comprises about 50% to about 80% of the active ingredient and about 20% to 50% of the polymer or other excipients.

In another preferred specimen, the pharmaceutical ingredient is dispersed in hydroxypropyl cellulose or methylcellulose hydroxypropyl. Especially preferred compositions comprise from 40% to 80% by weight of the active ingredient. The precise ratio of the polymer to the drug in the matrix is dictated by the size of the particle, and thus the surface area of the crystalline drug substance. Other conventional excipients such as glycerin, propylene glycol, Tween, salts of stearic acids, polyvinyl pyrrolidones and the like can be added.

In a particularly preferred example, the poorly soluble pharmaceutical agent used is chosen from the class known as gliotazones. Glitazones are antidiabetic agents of thiazolidinedione such as troglitazone, cyclotazone, pioglitazone, englitazone and BRL 49653.

The most preferred composition of the invention is a solid dispersion of troglitazone in hydroxypropyl cellulose.

DETAILED DESCRIPTION OF THE INVENTION The compositions provided by this invention are dispersions of pharmaceutical agent particles barely soluble in a water soluble polymer such as hydroxypropyl cellulose or methylcellulose hydroxypropyl.

Hydroxypropyl cellulose is also known as cellulose 2-hydroxypropyl ester, oxypropylated cellulose and HPC. It is a non-ionic water soluble cellulose ether that exists as an almost white powder. While hydroxypropyl cellulose is soluble in many polar organic solvents, it readily precipitates from water at about 40 ° C. It is a thermoplastic material that has been used in the pharmaceutical field as an emulsifier, stabilizer, shake aid, protective colloid, as well as a film former or thickener in foods.

The methylcellulose hydroxymethyl is 2-hydroxypropyl methyl ether cellulose or HPMC. It is a nonionic water soluble ether of methylcellulose, which is insoluble in hot water but dissolves slowly in cold water. It is more soluble than methylcellulose, and has been used extensively as an emulsifier, stabilizer, suspending agent, tablet excipient, and most notably as an ophthalmic lubricant. It is sold commercially as Ultra Tears, Tearisol and Goniosol.

The compositions of this invention utilize barely soluble pharmaceutical agents. The term "barely soluble pharmaceutical agent" means any solid or crystalline drug substance that will dissolve in from 30 to 100 grams of water at 25 ° C. Numerous drug substances are "barely soluble pharmaceutical agents" as used herein, and can be used to make the particle dispersions of this invention. As noted above, a preferred group of such agents are glitazones, especially troglitazone, also known as "Cl-991". Glitazones are described in more detail in U.S. Patent No. 5,478,852, which is incorporated herein by reference. Other agents that may be employed include antibiotics, such as cephalosporins and penicillins, fluoroquinolinones such as clinafloxacin, naphthyridinones such as Cl-990 and compounds of the arithromycin amine type. Antidepressant agents such as chlorothiazide and ACE inhibitors (quinapril, vasotec) can be formulated according to this invention. Anticarcinogenic agents such as methotrexate, suramin and vinca alkaloids can be used.

Other pharmaceuticals that can be formulated as particle dispersions include, but are not limited to acetohexamide, ajamaline, amylobarbitone, bendrofluazide, benzbromarone, benzonatate, benzibenzoate, betamethasone, chloramphenicol, chlorpropamide, chlorthalidone, clofibrate, corticosteroids, diazepam, dicumerol, digitoxin , dihydroxypropylteophylline, ergot alkaloids, etotine, frusemide, glutethimide, griseofulvin, hydrochlorothiazide, hydrocortisone, hydroflumethiazide, hydroquinone, hydroxyalkyloxanthines, indomethacin, isoxuprin hydrochloride, ketoprofen, quelin, meprobamate, nabilone, nicotainamide, nifedipine, nitrofurantoin, novalgin, nystatin, papaverine, paracetamol, phenylbutazone, phenobarbitone, prednisolone, prednisone, primadone, reserpine, romglizone, pill acid, spiranolactone, sulfabenzamide, sulfadiamadine, sulfamethoxydiazine, sulfamerzain, succinylsulfatiazole, sulfametiazole, sulfamethoxazole, sulfathiazole, sulfisoxazole, testosterone, tolazoline, tolbutamide, trifluoperazine, trimethoprim and other water soluble drugs.

Any number of water-soluble polymers can be used as a carrier for the dispersion of particles. All that is required is that the polymer be able to soften or melt at a temperature that does not melt the solid drug substance, so that the matrix covering the particulate drug substance can be formed. The polymer must also be sufficiently soluble in water to allow the dispersion of the dispersion of particles at a rate that provides the desired oral bioavailability and the resulting therapeutic benefit. Typical polymers to be employed include polyvinylpyrrolidone (PVP), polyethylene oxides, pregelatinized starch, methylcellulose, hydroxymethylcellulose, polyvinyl alcohol, sodium alginate, sodium carboxymethylcellulose, lecithin, tweens, maltodextrin, poloxamer, sodium lauryl sulfate, polyethylene glycol (PEG). , acetate vinyl copolymer, Eudragit® acrylic polymers, E-100 and mixtures thereof. The carrier chosen obviously depends on the drug to be dispersed but usually, the carrier chosen must be pharmaically inert and chemically compatible with the drug in the solid state. They should not form highly bound complexes with a strong constant association and more importantly they should be freely soluble in water with rapid intrinsic dissolution properties.

Another polymer chosen in most dispersions is PVP, which is a free-flowing amorphous powder that is soluble at the same time in water and in organic solvents. It is hygroscopic in nature and compatible with a wide range of hydrophilic and hydrophobic resins. Another preferred carrier is a high molecular weight polyethylene glycol such as PEG 6000, which is a condensation polymer of ethylene glycol. The polyethylene glycols are generally from a liquid to a clear, colorless, odorless, viscous waxy solid that is soluble or miscible in water.

The surprising and unexpected results of the present invention is the creation of a pharmaical dispersion of solid particles composed of the aforementioned water-insoluble drugs and carriers without the need to use aqueous or organic solvents. In another example, the addition of a plasticizer / solubilizer during the mixing of the particulate drug and the water soluble polymer results in a chemical environment that readily lends itself to the formation of particle dispersion.

Suitable plasticizers / solubilizers useful in the practice of the present invention include polyethylene glycols of low molecular weight such as PEG 200, PEG 300, PEG 400, and PEG 600. Other suitable plasticizers include propylene glycol, glycerin, triacetin and triethyl citrate. Optionally, an active tense agent such as Tween 80 can be added to facilitate wetting within the formulation.

The water-insoluble drug of interest can be ground first to the desired particle size, usually from about 1 miera to 20 micras. It is then mixed with the polymeric carrier using any suitable mixer or mixer in a drug / carrier ratio of from about 1: 9 to about 5: 1, respectively, based on a percentage basis by weight. Preferably, the drug / carrier ratio will be from about 3: 1 to about 1: 3, respectively. The mixture is then transferred to a mixer, for example a low or high power mixer or a fluid bed granulator, and additional excipients can be added, for example a plasticizer such as PEG 400, which can be dissolved in water with an agent surfactant as is tween 80, if desired. Other surfactants include Tween 20 and 60, Span 20, Span 40, pluronics, polyoxyethylene sorbitol esters, monoglycerides, polyoxyethylene acids, polyoxyethylene alcohols and mixtures thereof. Once all the ingredients are sufficiently dissolved or suspended, the solution is sprayed onto the powder mix in the fluid bed granulator under specific conditions. The mix can also be granulated in a low or high power mixer, dry and mold to produce the granulated product. The resulting granulation is transferred to a container and fed into a high intensity mixer such as a twin screw extruder with at least one, and preferably more than one heating zone. The mixture is then extruded at appropriate temperatures depending on the heat stability of the drug, until a dispersion of particles is collected as an extract, which is then transferred to a barrel to be milled. The pharmaceutical dispersion of ground particles can then be ground into a powdery mass, and can be further mixed with other excipients before their encapsulation or being pressed into tablets. The final dosage form can optionally be covered with a film such as methylcellulose hydroxypropyl, if desired.

In a preferred example, the particle dispersions of the invention are prepared by melt extrusion of a pharmaceutical agent and about 10 to 90 percent by weight of a polymer such as HPC. The molten extrusion is carried out by mixing the ingredients until uniformity is reached at a temperature of about 50 ° C to about 200 ° C, the temperature that is high enough to melt or soften the polymer, but not high enough to melt the particles of the drug. The melted or softened mixture is passed through a commercial twin screw extruder. The resulting extract can be used directly, or can be further processed, by example by grinding or pulverizing to the desired consistency, and further mixed with conventional carriers such as starch, sucrose, talc and the like, and can be pressed into tablets or encapsulated. The final dosage forms will usually contain about 1 mg to about 1000 mg of the active ingredient, and more typically about 300 mg to about 800 mg.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 is the X-ray powder diffraction of crude troglitazone (Cl-991), where: A) Diffraction intensity - counts per second (cps); and B) Diffraction angle (° 2 (H)).

Figure 2 is the X-ray powder diffraction of the dispersion of Cl-991 particles in PEG-8000 and PVP in a weight ratio of 80: 10:10:10, wherein: A) Diffraction intensity - counts per second (cps); and B) Diffraction angle (° 2 (H)).

Figure 3 is the powder X-ray diffraction of the dispersion of Cl-991 particles in PEG-8000 and HPC in a weight ratio of 80:10: 10, where: A) Diffraction intensity - counts per second (cps); and B) Diffraction angle (° 2 (H)).

Figure 4 is the X-ray powder diffraction of the dispersion of Cl-991 particles in PEG-8000 and PVP in a weight ratio of 75:10:15, where: A) Diffraction intensity - counts per second (cps); and B) Diffraction angle (° 2 H).

Figure 5 is the powder X-ray diffraction of the dispersion of Cl-991 particles in PEG-8000 and HPC in the weight ratio of 75:10:15, where: A) Diffraction intensity - counts per second (cps); and B) Diffraction angle (° 2 H).

Figure 6 is the X-ray powder diffraction of the dispersion of Cl-991 particles in PEG-8000 and HPC in the weight ratio of 75: 5: 20, where: A) Diffraction intensity - counts per second (cps); and B) Diffraction angle (° 2 (H :)).

Figure 7 is the X-ray powder diffraction of the dispersion of Cl-991 particles in PEG-8000 and HPC in the weight ratio of 75:25, where: A) Diffraction intensity - counts per second (cps) ); and B) Diffraction angle (° 2 (H)).

Figure 8 is a comparison of dissolution profiles at pH 8 for various dispersion formulations of Cl-991 particles, wherein: A) percentage of drug dissolved; B) Cl-991 PD [drug / HPC (75/25)]; C) Cl-991 PD [drug / PEG / HPC (75/5/20)]; D) Cl-991 PD [drug / PEG / HPC (75/10/15)]; E) Cl-991 PD [drug / PEG / HPC (80/10/10)]; F) Mixture [drug / HPC (75/25)]; G) Cl-991 pure; and H) time (minutes).

Figure 9 is a comparison of dissolution profiles at pH 9 for various dispersion formulations of Cl-991 particles, wherein: A) percentage of drug dissolved; B) Cl-991 PD [drug / HPC (75/25)]; C) Cl-991 PD [drug / PEG / HPC (75/5/20)]; D) Cl-991 PD [drug / PEG / HPC (75/10/15)]; E) Cl-991 PD [drug / PEG / HPC (80/10/10)]; F) Mixture [drug / HPC (75/25)]; G) Cl-991 pure; and H) time (minutes).

Figure 10 is a comparison of dissolution profiles at pH 8 for various dispersion formulations of Cl-991 particles in PVP, wherein: A) percentage of drug dissolved; B) Cl-991 PD [drug / PEG / PVP (75/10/15)]; C) Cl-991 PD [drug / PEG / PVP (80/10/10)]; D) Cl-991 pure; and E) time (minutes).

Figure 11 is a comparison of dissolution profiles at pH 9 for various dispersion formulations of Cl-991 particles in PVP, wherein: A) percentage of drug dissolved; B) Cl-991 PD [drug / PEG / PVP (75/10/15)]; C) Cl-991 PD [drug / PEG / PVP (80/10/10)]; D) Cl-991 pure; and E) time (minutes).

Figure 12 is a comparison of dissolution profiles at pH 8 for various dispersion formulations of Cl-991 particles in PVP, wherein: A) percentage of drug dissolved; B) Cl-991 PD [drug / PEG / HPC (75/10/15)]; C) Cl-991 PD [drug / PEG / HPC (80/10/10)]; D) Cl-991 PD [drug / PEG / PVP (75/10/15)]; E) Cl - 991 PD [drug / PEG / PVP (80/10/10)]; and F) time (minutes).

The following detailed examples further illustrate the present invention. The examples are illustrative only and should not be construed as limiting the invention in any respect.

EXAMPLE 1 Dispersion of Chlorotiazide Particles A mixture of 54 g of chlorothiazide and 6 g of hydroxypropyl cellulose were mixed until unm at 24 ° C using a mortar and pedestal. The mixture was transferred to a rotary mixing vessel and heated to 150 ° C, and stirred at 50 rpm. The moment remained at 2000 meter - grams. The mixture was frozen and after cooling to 24 ° C, it was solid and unm. The product pulverized and ground, and pressed into tablets. Each tablet was a solid particulate formulation of chlorothiazide.

EXAMPLE 2 A mixture of 54 g of chlorothiazide and 6 g of hydroxypropyl cellulose were mixed until unm at 24 ° C in a mortar and pedestal. The mixture was added to a rotary mixing vessel and stirred for 1 hour at 70 ° C at 50 rpm. The mixture was cooled, ground and pressed into tablets which were dispersions of solid chlorothiazide particles.

EXAMPLE 3 Troglitazone (Cl-991), a new drug developed for the treatment of non-insulin dependent diabetes, is a drug practically insoluble in water of the gastrointestinal range pH 1.0 to 7.5. To date, Cl-991 has been prepared as a solid dispersion, in which the crystalline drug substance is converted to the amorphous form by hot melt extrusion methods, to improve its rate of dissolution and its oral biodiposibility. In this study, Cl-991 was used as a model drug to test whether the type of dissolution of poorly water-soluble drugs could be improved by the approach of forming a dispersion of particles in a matrix of a water-soluble polymer.

Troglitazone (Cl-991) Materials The crude drug Cl-991 (batch XX020195) and the water-soluble excipients chosen HPC, PVP K28-32 and PEG-8000, were all obtained from Centralized Raw Materials (Morris Plains, New Jersey) . The chemicals used to prepare the dissolution medium, including hydrogen disodium phosphate (Na2HPO), dipotassium hydrogen phosphate (K2HPO4) and 85% phosphoric acid (H3PO4), were obtained from J.T. Baker Co. (Phillisburg, New Jersey) while sodium lauryl sulfate (SLS) was obtained from Centralized raw Materials.

Preparation of Cl-991 Particle Dispersions (PD) Cl-991 particle dispersions were prepared by the mixing vessel method. The appropriate weights of Cl-991 and the excipients were placed in a screw capped bottle and mixed by a turbula mixer (Glenn Mills Co. Maywood, New Jersey) for 15 minutes to give powder mixtures (or physical mixtures). About 65 g of the powder mixtures were then mixed in a Brabender double screw mixing vessel (C. W. Brabender Instruments, South Hackensac, New Jersey) at 110 ° C or 130 ° C for 5 minutes. The resulting products (Cl-991 PD) were collected, ground and divided. The samples that had particle size between 80- and 100-mesh were used for the dissolution study and other tests.

HPLC Assay of Cl-991 Particle Dispersions The HPLC method used for the Cl-991 assay was adopted from RTD-0991 -TAC-5 (pages 5-12). HPLC analysis was carried out on Hewlett-Packard 1090 HPLC system with a Hewlett-Packard 1050 absorbance detector and a Cte Alltech Hypersil column (4.5 x 100 mm, 3 μm). The mobile phase consisted of a 50:50 mixture (% v / v) of pH 3 (0.05 M) of regulator triethylamine and acetonitrile. The flow rate was 1-5 ml / minute, the wavelength of the UV detection was 225 nm, the injection volume was 20 μl and the execution time was 15 minutes. The retention time for the maximum of Cl-991 was found to be approximately 5.6 minutes. The acquisition and integration of data was carried out with a computer program Hewlett-Packard ChemStation (Rev. A.02.00).

Characterization of Crystallinity The Crystallinity of the dispersions of Cl - 991 particles was characterized using X - ray powder diffractometry. Diffractometry patterns of X - ray powder were recorded by using a Rigaku Geiger - Flex X - ray diffractometer with radiation of Cu-Ka filtered in Ni (? = 1.5418 Á) during the interval 4 - 40 2T. In some cases, optical polarization microscopy was used to confirm the results obtained with X-ray powder diffraction. Microscopic investigation was carried out in a Leitz Labolux 12 polarization optical microscope equipped with a Polaroid camera.

Dissolution Studies Preparation of Dissolution Medium pH 8 (0.1 M. Phosphate Regulator with 0.5% Content (g / mL) SLS Phosphate solution (0.1 M) was prepared by dissolving a calculated amount of Na2HPO4 in USP water. The pH value of the phosphate solution (0.1 M) was then adjusted to 8.0 ± 0.02 by 85% phosphoric acid to give a phosphate buffer (0.1 M) with pH 8 .. An appropriate amount of SLS is added and dissolved in the phosphate buffer (0.1 M) of pH 8 to give the phosphate buffer (0.1 M) pH 8 containing 0. 5% / g / mL) of SLS.

Phosphate Regulator (0.05 M) pH 9 Phosphate solution (0.05 M) was prepared by mixing 1: 1 of the aqueous solutions of (0.025 M) Na2HPO and (0.025 M) K2HPO4. The pH value of the phosphate solution (0.05 m) was then adjusted to 9.0 ± 0.02 by 85% phosphoric acid to give the phosphate buffer with pH 9 (0.05 M).

Dissolution tests The dissolution studies were carried out in 900 ml of dissolution medium maintained at 37 ° C, using USP II devices (Dissolution System Distek 2100 and North Brunswick, New Jersey) at 75 rpm of blade speed. After dispersing a sample containing 100 Cl-991 in the dissolution medium, about 10 ml of solutions were sampled periodically and filtered with 0.45 μm Gelman Nylon Acrodisc filters to give clear filtrations (discard the first 2 ml of filtered out). The amount of the drug dissolved in the dissolution medium was determined by UV spectrometry a? = 284 nm. The interference of the excipients was not observed during the analysis. The experiments were run in duplicate, and the results were averaged.

RESULTS AND DISCUSSION Preparation and HPLC Assay of Cl-991 Particle Dispersions Depending on the sizes of the samples, the particle dispersion could be prepared by the method of the mixing or extrusion vessel. To minimize the amount of crude Cl - 991 drug used, dispersions of Cl - 991 particles were used using the mixing vessel method in this exploratory study. Since the melting range of Cl - 991 has been reported from 165 ° C to 175 ° C, the temperature applied to the mixing processes should be lower than the melting temperature of CI - 991 to prevent the drug from melting but it must be high enough to soften or melt the water-soluble excipients used. By using this method of mixing vessel, six dispersions of Cl-991 particles, namely Cl-991 / PEG -8000 / PVP (80:10:10), Cl-991 / PEG-8000 HPC (80: 10:10), Cl-991 / PEG-8000 / PVP (75: 0: 25), Cl-991 / PEG-8000 / HPC (75:10:15), Cl-991 / PEG-8000 / HPC (75 : 5: 20) and Cl-991 / HPC (75:25) PD, were prepared at 110 ° C or 130 ° C [Table 1].

To investigate the chemical stability of Cl-991 during the mixing process, the six dispersions of Cl-991 particles were tested using HPLC methods. As presented in Table 1, the contents of the drug as measured in the six dispersions of Cl-991 particles agreed well with those of the theoretical values, suggesting that Cl-991 did not decompose significantly as that the drug was mixed with PEG, HPC and / or PVP at 110 ° C or 130 ° C.

TABLE 1. Preparation and HPLC Assay of Various Particle Dispersions of Cl-991 / Polymer (PD) X-ray Powder Diffraction Study Since the mixing temperature (110 or 130 ° C) is well below the melting range of Cl-991 (165 - 175 ° C), the drug is not expected to melt or convert amorphous during the formation of the Cl-991 particle dispersion. The X-ray powder diffraction patterns of the crude Cl-991 drug and the six particulates of Cl-991 are illustrated in Figure 1 and in the Figures from 2 to 7, respectively. The crystalline properties of the crude drug are characterized by several major diffraction maxima near 5.5, 11.8, 17.6, 19.6 and 23.7 ° (2T), in the diffractome [Figure 1]. For Cl-991 / PEG / PVP and Cl-991 / PEG / HPC (80:10:10) PD that were prepared at 110 ° C, their X-ray diffraction patterns (Figures 2 - 3) are almost identical to those of the crude drug Cl-991. Except for a few slight diffraction maxima in the region of 8.5 - 0.2 2T (, most of the identifiable diffraction maxima of Cl - 991 were observed in the diffractograms of Cl - 991 / PEG / PVP (75:10:15) , Cl-991 / PEG / HPC (75:10:15), Cl-991 / PEG / HPC (75: 5: 20) and Cl-991 / HPC (75:25) PD [Figures 4 to 7], which were prepared at 130 ° C. Figures 1 to 7 also revealed that the dispersions of Cl-991 particles, especially those prepared at 130 ° C, exhibited higher diffraction maxima than the crude Cl-991 drug. These data may indicate that the crude crystalline drug has been partially converted to the amorphous form and / or interacts with the polymers used during the mixing process at elevated temperatures for the preparation of the dispersions of Cl-991 particles.

Dissolution Studies The dissolution behaviors of the dispersions of Cl - 991 / polymer particles were studied in two different dissolution media, namely phosphate buffer pH 8 (0.1 M) with 0.5% SLS content and phosphate buffer pH 9 (0.05 M). The dissolution profiles of several dispersions of particles Cl-991 / PEG-8000 / HPC in phosphate buffer pH 8 (0.1 M) with content of 5% of SLS and in phosphate buffer pH 9 (0.05 M) are illustrated in the Figures 8 and 9, respectively. The dissolution profiles of the crude drug Cl-991 (or pure Cl-991) and the physical mixture of Cl-991 / HPC (75:25) are also illustrated in Figures 8 and 9 for comparison.

It is clearly indicated that the four dispersions of Cl-991 particles exhibit a type and a larger amount of Cl-991 solution than the pure drug and the physical mixture in these two dissolution media. The improvement in the Cl - 991 dissolution types would be mainly due to the increase in wettability of Cl - 991, since the drug has been covered with HPC and / or PEG - 8000 (water - soluble polymers) during the formation of the dispersion. of Cl-991 particles. In addition to the coverage of water-soluble polymers, the type of Cl-991 solution could be improved by reducing the size of the particles since the drug can be finely dispersed in the matrix of the particles. polymers during the mixing process.

Of the four particle dispersions studied, Cl-991 / HPC (75:25) PD exhibited the highest type of solution. The above is understandable because this dispersion of particles has the highest concentration of HPC, in which the resulting particles could have the best wettability of the four dispersions of Cl-991 / HPC particles. Cl - 991 / HPC (75:25) PD produced a 12-fold higher initial dissolution type (computed during the first five minutes of dissolution) in phosphate buffer pH (0.1 M) with 0.5% SLS content than Cl - 991 pure (Table 2 and Figure 8). In phosphate buffer 9 (0.05 M), Cl-991 / HPC (75:25) PD also produced a much higher type of solution than pure Cl-991 (Table 2 and Figure 9). After 15 minutes, this dispersion of particles produced a 7-fold type of solution in phosphate buffer pH 8 (0.1 M) with a content of 5% SLS and a type of solution 20 many times higher in phosphate buffer pH 9 (0.05) M) than the pure drug.

The dissolution profiles of Cl-991 / PEG-8000 / PVP (80:10:10) and (75:10:25) in phosphate buffer pH 8 (0.1 M) with content of 5% SLS and in regulator of phosphate pH 8 (0.05 M) are illustrated in Figures 10 and 11, respectively. As with the Cl-991 / PEG-8000 / HPC particle dispersions, these two Cl-991 / PEG / PVP PD exhibited faster drug release profiles than pure Cl-991. Again, Cl-991 / PEG / PVP PD with higher concentration of PVP resulted in faster release of the drug from the particle dispersions (Figures 10 and 11). These dissolution studies show that Cl - 991 / PEG / HPC (80:10:10) and (75:10:15) PD have higher dissolution rates than the corresponding Cl - 991 / PEG / PVP PD, especially in the regulator phosphate pH 8 (0.1 M) with 5% SLS content (Figure 12). These obtained data may indicate that HPC is a better water-soluble polymer than PVP to improve the type of dissolution of the drug for the dispersion of Cl-991 particles. The reason for these differences is not clear yet; however, it may be due to the different physical and chemical properties between HPC and PVP, such as glass transition temperature (Tg), rheological behavior at elevated temperatures, and / or drug / polymer interactions. However, this study clearly showed that the type of dissolution of a drug poorly soluble in water, Cl-991, can be improved by the formation of a particle dispersion, in which the drug was covered with (or finely dispersed in ) the water-soluble excipients, such as HPC and PVP, with high drug loads.

TABLE 2. Dissolution of several particle dispersions of Cl-991 / polymer (PD), pure Cl-991, and physical mixture of Cl-991 / HPC (75:25) in Two Different Dissolution Means CONCLUSION Six dispersions of Cl-991 / polymer particles (PD), namely Cl-991 / PEG-8000 / PVP (80:10:10), Cl-991 / PEG-8000 / HPC (80:10:10) , Cl-991 / PEG-8000 / PVP (75: 0: 25), Cl-991 / PEG-8000 / HPC (75:10:15), Cl-991 / PEG-8000 / HPC (75: 5: 20 ) and Cl-991 / HPC (75:25) PD were prepared by the mixing vessel method at 110 ° C or 130 ° C. The HPLC assay revealed that the drug contents of these particle dispersions are almost identical to those of the theoretical values, suggesting that Cl-991 did not undergo any significant decomposition during the mixing process at 110 ° C or 130 ° C. X-ray powder diffraction studies suggested that the drug substance in dispersions of Cl-991 particles is almost as it existed in the crystalline state. The six dispersions of Cl-991 particles exhibited all drug release profiles faster than pure Cl-991 and the physical mixture Cl-991 / HPC / (75:25) in phosphate buffer pH 8 (0.1 M) with content of 0.5% SLS and phosphate buffer pH 9 (0.05) M) The improvement in the type of dissolution of the drug can be mainly due to the increase in wettability and / or the reduction of the size of the Cl-991 particles as the drug was covered with highly water soluble polymers such as HPC and PVP during the extrusion process. It was found that HPC appears to be a better water-soluble polymer than PVP to improve the type of Cl-991 dissolution of the particle dispersion. This study showed that the type of dissolution of large doses of poorly water soluble drugs such as Cl - 991 could be improved by improving the wettability of the drugs due to the formation of particle dispersions.

Claims (7)

1. CLAIMS: 1. A solid form of pharmaceutical particle dosage suitable for oral delivery comprising a particulate pharmaceutical agent barely soluble in dispersed water through a matrix composed of a water soluble polymer.
2. 2. A dosage form of Claim 1 wherein the pharmaceutical agent is glitazone.
3. 3. A dosage form of Claim 2 wherein the glitazone is troglitazone.
4. 4. A dosage form of Claim 2 wherein the glitazone is BRL 49653.
5. 5. A dosage form of Claim 1 wherein the polymer is hydroxypropyl cellulose.
6. 6. A dosage form of Claim 1 wherein the polymer is methylcellulose hydroxypropyl.
7. 7. A dosage form of Claim 1 wherein the polymer is polyvinyl pyrrolidone. EXTRACT OF THE INVENTION Solid particle dispersions of pharmaceutical agents in a matrix of a water soluble polymer exhibiting good bioavailability enhanced by aqueous solution. The method of the invention uses water soluble polymers such as polyvinyl pyrrolidone, hydroxypropyl cellulose or hydroxypropylmethyl cellulose as carriers. The invention provides for the mixing or extraction of the active ingredients in the form of solid particles with the polymeric carrier at a temperature at which the polymer softens, or even melts, but the drug remains solid or crystalline. The particles of the drug are thus covered and produce a product that is covered by the matrix, that is, a dispersion of particles.