WO2005117834A1

WO2005117834A1 - Solid dispersions of a basic drug compound and a polymer containing acidic groups

Info

Publication number: WO2005117834A1
Application number: PCT/EP2004/050951
Authority: WO
Inventors: Guy René Jaak VAN DEN MOOTER; Geert Verreck; Marcus Eli Brewster; Jozef Peeters; Ilse Melanie Emiel Weuts; Annelies Marie Antonius Decorte; Koen Maria Leon Heymans; Dieter Marcel Mariette Kempen
Original assignee: Janssen Pharmaceutica N.V.
Priority date: 2004-05-27
Filing date: 2004-05-27
Publication date: 2005-12-15

Abstract

The present invention is concerned with pharmaceutical compositions of basic drug compounds which can be administered to a mammal, in particular a human. These compositions comprise solid dispersions comprising (a) at least one basic drug compounds; and (b) at least one pharmaceutically acceptable water-soluble polymer containing acidic groups.

Description

SOLTJD DISPERSIONS OF A BASIC DRUG COMPOUND AND A POLYMER CONTAINING ACIDIC GROUPS The present invention relates to a solid dispersion of (a) at least one basic drug compound and (b) at least one water-soluble polymer containing acidic groups. The invention further relates to a dosage form containing said solid dispersion.

Lee et al. describes in J.Pharm. Sci. 80:178-180 (1991) the formation of a propanolo methacrylic acid copolymer complex. It is disclosed that salt formation may occur in the complex. The complex is evaluated for its suitability as a prolonged release system.

Ozawa et al. describes in Chem.Pharm.Bull. 50(6): 802-807 (2002) a solid dispersion of ethenzamide and a crosslinked polymer of acrylic acid and a solid dispersion of theophylline and a crosslinked polymer of acrylic acid.

Broman et al. describes in IntJ.Pharm. 222:139-151 (2001) solid dispersions of probucol and polyacrylic acid. In said article it is stated that polyacrylic acid is not able to stabilize amorphous probucol against crystallization and the release from the polyacrylic acid system was poor.

WO 97/08950 describes solid dispersions of a bio-affecting agent in a water-soluble polymer in order to make the bio-affecting agent more bioavailable.

Solid dispersions are an approach to enhance the dissolution behaviour of drugs, especially sparingly water soluble drugs. By forming a solid dispersion the substance crystallinity may be decreased since the substance may be present in an amorphous state and this might be desirable since dissolution of an amorphous substance does not require energy to break up the crystalline lattice.

One major draw back is however the metastability of the amorphous state which might eventually lead to crystallization, hereby altering the dissolution characteristics of the solid dispersion preparation.

Unexpectedly, it has now been found that crystallization of a basic drug compound in a solid dispersion can be significantly suppressed when the basic drug compound is incorporated in a solid dispersion of a polymer wherein the polymer contains acidic groups. Thus, solid dispersions according to the present invention have an increased physical stability.

Furthermore, it was found that the dissolution properties of the basic drug compound from the solid dispersions of the present invention are improved compared to the ones from a solid dispersion with a non acidic polymer. Improved dissolution properties may have an advantageous effect on the bioavailability of the drug compound.

Without being bound by any theory, the improved stability and the improved dissolution properties of the solid dispersions of the present invention may be caused by salt formation between the basic drug and the acidic polymer.

By the formation of a salt between the basic group of the drug and the acidic functions of the polymer, strong electrostatic forces between both components exist and these forces may be responsible for suppressing crystallization even when a large amount of drug is present in the solid dispersion. It was observed that the solid dispersions exhibit high Tg 's in comparison to what one would expect from the Tg 's of the pure components. This may add to an increased physical stability of the drug compound in the solid dispersion.

The dissolution rate of the drug from the solid dispersion is not only enhanced by reduction of crystallinity and decrease of drug particle size, but also by improved dissolution characteristics inherent to a salt.

Thus, the present invention relates to a solid dispersion comprising

(a) at least one basic drug compound; and

(b) at least one pharmaceutically acceptable water-soluble polymer containing acidic groups.

The term "solid dispersion" defines a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, wherein one component is dispersed more or less evenly throughout the other component or components. When said dispersion of the components is such that the system is chemically and physically uniform or homogenous throughout or consists of one phase as defined in thermodynamics, such a solid dispersion will be called "a solid solution" hereinafter. Solid solutions are preferred physical systems because the components therein are usually readily bioavailable to the organisms to which they are administered. This advantage can probably be explained by the ease with which said solid solutions can form liquid solutions when contacted with a liquid medium such as gastric juice. The ease of dissolution may be attributed at least in part to the fact that the energy required for dissolution of the components from a solid solution is less than that required for the dissolution of components from a crystalline or microcrystalline solid phase.

The term "a solid dispersion" also comprises dispersions which are less homogenous throughout than solid solutions. Such dispersions are not chemically and physically uniform throughout or comprise more than one phase. For example, the term "a solid dispersion" also relates to particles having domains or small regions wherein amorphous, microcrystalline or crystalline (a), or amorphous, microcrystalline or crystalline (b), or both, are dispersed more or less evenly in another phase comprising (b), or (a), or a solid solution comprising (a) and (b). Said domains are regions within the particles distinctively marked by some physical feature, small in size compared to the size of the particle as a whole, and evenly and randomly distributed throughout the particle.

In the present invention, the term basic drug compound defines a drug compound with a pKa value which is at least 1.5 units higher than the pKa of the polymer containing acidic groups. The pKa values are values determined in aqueous solution.

Preferably, the basic drug compound is a compound with a relative inability to be dissolved into aqueous media. Thus preferably, the basic drug compound is a sparingly water soluble drug compound. A compound may be said to be sparingly water soluble if it has a solubility of less than lOmg ml in water. The solubility of a compound in an aqueous medium is a property which can easily be determined by a person skilled in the art. Most preferably, the basic drug compound is a compound which is defined as a "practically insoluble" or "insoluble" compound according to the United States

Pharmacopeia. According to the USP, a "very slightly soluble" compound requires from 1000 to 10,000 parts of solvent for 1 part of solute (drug compound); a "practically insoluble" or "insoluble" compound requires more than 10,000 parts of solvent for 1 part of solute (drug compound). The solvent referred to herein is water. The term basic drug compound includes drug compounds belonging to BCS

(Biopharmaceutical Classification System) class II and IV. For the definition of BCS, reference can be made to • Amidon GL, Lennernas H, Shah VP, Crison TR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo unavailability. Pharm. Res. 1995;12:413-420. • Lobenberg R, Amidon GL. Modem bioavailability, bioequivalence and biopharmaceutics classification system. New scientific approaches to international regulatory standards. Eur. J. Pharm. Biopharm. 2000;50:3-13.

• Dressman J, Butler J, Hempenstall J, Reppas C. The BCS: where do we go from here? Pharm. Tech. North Am. 2001;25(7):68-76.

• van de Waterbeemd H. The fundamental variables of the biopharmaceutics classification system (BCS): a commentary. Eur. J. Pharm. Sci. 1998;7:1-3.

• Hόrter D, Dressman JB. Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract. Adv. Drug Deliv. Rev. 2001;46:75-87.

As described hereinabove, the solid dispersion of the present invention comprises at least one water-soluble polymer containing acidic groups.

The term "water-soluble" as used hereinbefore or hereinafter applies to polymers which readily dissolve or disperse in water or other aqueous media at any or all pH values without the assistance of a dissolution-promoting substance, such as for example a surfactant or an emulsifier. Since the polymers of the present invention contain acidic groups implies that their solubility may be pH dependent. The fact that the polymer does not require a dissolution-promoting substance to mediate its dissolution in an aqueous medium does not mean that the compositions of the present invention may not include such substances.

The term "acidic groups" is meant to indicate that the polymer contains groups which are able to react with an appropriate base, which are able to perform an acid-base reaction with an appropriate base, which are able to form a salt with an appropriate base. Preferably, the acidic groups are COOH groups.

Preferably, the water-soluble acidic polymer in the solid dispersion according to the present invention is a polymer that has an apparent viscosity, when dissolved at 20°C in an aqueous solution at 2 % (w/v), of 1 to 5000 mPa.s or of 1 to 700 mPa.s or of 1 to 100 mPa.s.

For example, the polymer of the present invention can be selected from the group comprising - carboxyalkylcelluloses such as carboxymethylcellulose,

- carboxyalkylalkylcelluloses such as carboxymethylethylcellulose,

- carboxyalkylcellulose esters,

- alginic acid, carrageenans, galactomannans, tragacanth, agar-agar, gummi arabicum, guar gummi and xanthan gummi,

- polyacrylic acids,

- polymethacrylic acids, methacrylate copolymers,

Preferred water soluble acidic polymers are polymers of formula

wherein i represents hydrogen or CH₃, and R₂ represents hydrogen or CH₃.

Most preferred is polyacrylic acid, methacrylic acid or methacrylic acid:methacrylic acid methyl ester copolymer, in particular polyacrylic acid.

Preferably, the water-soluble polymer of the present invention is not cross-linked.

The weight-by- weight ratio of (a) (i.e. the basic drug compound(s)) : (b) (i.e. the acidic polymer(s)) is in the range of about 5 : 1 to about 1 : 899, preferably about 5: 1 to about 1:100, more preferably about 2:1 to about 1:100, even more preferably about 1 : 1 to about 1 : 100, still more preferably about 1 : 1 to about 1 : 5 or about 2:1 to about 1:5, or about 1 : 1 to about 1 : 3.

The most appropriate weight by weight ratio of the at least one basic drug compound to the at least one water-soluble polymer containing acidic groups may be determined by a person skilled in the art by straightforward experimentation. The lower limit is determined by practical considerations. Indeed, given the therapeutically effective amount of a drug, the lower limit of the ratio is determined by the maximum amount of mixture that can be processed into one dosage form of practical size. When the relative amount of too high, the absolute amount of mixture needed to reach the therapeutic level will be too high to be processed into one capsule or tablet. Tablets, for example, have a maximum weight of about 1 g, and the solid dispersion can account for maximally about 90 % (w/w) thereof. Consequently, the lower limit of the amount of the basic drug over polymer will be about 1 : 899 (1 mg of the basic drug compoundπ- 899 mg of the water-soluble polymer).

On the other hand, if the ratio is too high, this means the amount of the basic drug is relatively high compared to the amount of water-soluble polymer, then there is the risk that the drug will not dissolve sufficiently in the water-soluble polymer, and thus the required bioavailability will not be obtained. The degree to which a compound has dissolved into a water-soluble polymer can often be checked visually : if the solid dispersion is clear then it is very likely that the compound will have dissolved completely in the water-soluble polymer. It will be appreciated that the upper limit of 5: 1 may be underestimated for particular basic drugs and particular water-soluble polymers. This can be established easily but for the experimentation time involved, solid dispersions wherein the ratio (a) : (b) is larger than 5 : 1 are also meant to be comprised within the scope of the present invention.

The solid dispersions of the present invention may be ground or milled to particles. Thus, the present invention also relates to a particle consisting of a solid dispersion comprising (a) at least one basic drug compounds; and

(b) at least one pharmaceutically acceptable water-soluble polymers containing acidic groups.

Various techniques exist for preparing solid dispersions including melt-extrusion, spray-drying and solution-evaporation, melt-extrusion or spray-drying being preferred.

The melt-extrusion process comprises the following steps : a) mixing the components (a) and (b), b) optionally blending additives with the thus obtained mixture, c) heating the thus obtained blend until one obtains a homogenous melt, d) forcing the thus obtained melt through one or more nozzles; and e) cooling the melt till it solidifies.

The terms "melt" and "melting" should be interpreted broadly. For our purposes, these terms not only mean the alteration from a solid state to a liquid state, but can also refer to a transition to a glassy state or a rubbery state, and in which it is possible for one component of the mixture to get embedded more or less homogeneously into the other. In particular cases, one component will melt and the other component(s) will dissolve in the melt thus forming a solution, which upon cooling may form a solid solution having advantageous dissolution properties.

One of the most important parameters of melt extrusion is the temperature at which the melt-extruder is operating. It was found that the operating temperature can easily range between about 20°C and about 300°C, more preferably about 70°C and 250°C. The lower temperature limit depends on the solubility of the basic drug in the water-soluble polymer and on the viscosity of the mixture. When the basic drug is not completely dissolved in the water-soluble polymer, the extrudate will not have the required bioavailability; when the viscosity of the mixture is too high, the process of melt extrusion will be difficult. At temperatures of more than 300°C the water-soluble polymer may decompose to an unacceptable level. A person skilled in the art will easily recognize the most appropriate temperature range to be used.

The throughput rate is also of importance because even at relatively low temperatures the water-soluble polymer may start to decompose when it remains too long in contact with the heating element.

It will be appreciated that the person skilled in the art will be able to optimize the parameters of the melt extrusion process within the above given ranges. The working temperatures will also be determined by the kind of extruder or the kind of configuration within the extruder that is used. Most of the energy needed to melt, mix and dissolve the components in the extruder can be provided by the heating elements. However, the friction of the material within the extruder may also provide a substantial amount of energy to the mixture and aid in the formation of a homogenous melt of the components.

A person skilled in the art will easily recognize the most appropriate extruder, such as, for example, a single screw, a twin screw extruder or a multi-screw extruder, for the preparation of the subject-matter of the present invention.

Spray-drying of a solution of the components also yields a solid dispersion of said components and may be a useful alternative to the melt-extrusion process, particularly in those cases where the water-soluble polymer is not sufficiently stable to withstand the extrusion conditions and where residual solvent can effectively be removed from the solid dispersion. Yet another possible preparation consists of preparing a solution of the components, pouring said solution onto a large surface so as to form a thin film, and evaporating the solvent therefrom.

As already stated hereinabove. the solid dispersion product may be milled or ground to particles having a particle size of less than 1500 μm, preferably less than 400 μm, more preferably less than 250 μm, and most preferably less than 125 μm. The particle size proves to be an important factor determining the speed with which a particular dosage form can be manufactured on a large scale. For instance, for capsules, the particle size may range preferably from 100 to 1500 μm; for tablets the particle size is preferably less than 250 μm. The smaller the particles, the faster the tabletting speed can be without detrimental effects on their quality. The particle size distribution is such that more than 70% of the particles (measured by weight) have a diameter ranging from about 50 μm to about 1400 μm, in particular from about 50 μm to about 200 μm, more in particular from about 50 μm to about 150, and most in particular from about 50 μm to about 125 μm. Particles of the dimensions mentioned herein can be obtained by sieving them through nominal standard test sieves as described in the CRC Handbook, 64^th ed., page F-114. Nominal standard sieves are characterized by the mesh/hole width (μm), DIN 4188 (mm), ASTME 11-70 (No), Tyler® (mesh) or BS 410 (mesh) values. Throughout this description, and in the claims hereinafter, particle sizes are designated by reference to the mesh/hole width in μm and to the corresponding Sieve No. in the ASTM El 1-70 standard.

Preferred solid dispersions are those dispersions wherein the basic drug compound is in a non-crystalline phase as these have an intrinsically faster dissolution rate than those wherein part or all of the drug is in a microcrystalline or crystalline form.

Preferably, the solid dispersion is in the form of a solid solution comprising (a) and (b). Alternatively, it may be in the form of a dispersion wherein amorphous or microcrystalline (a) or amorphous or microcrystalline (b) is dispersed more or less evenly in a solid solution comprising (a) and (b).

The solid dispersions of the present invention may further comprise one or more pharmaceutically acceptable excipients such as, for example, plasticizers, flavors, colorants, preservatives and the like. Said excipients should preferably not be heat- sensitive, in other words, they should not show any appreciable degradation or decomposition at the working temperature of the melt-extruder. Plasticizers as mentioned hereinbelow lower the temperature at which a melt of (a), (b) and plasticizer is formed, and this lowering of the melting point is advantagous where the polymer has limited thermal stability. Suitable plasticizers are pharmaceutically acceptable and include low molecular weight polyalcohols such as ethylene glycol, propylene glycol, 1,2 butylene glycol, 2,3-butylene glycol, styrene glycol; polyethylene glycols such as diethylene glycol, triethylene glycol, tetraethylene glycol; other polyethylene glycols having a molecular weight lower than 1,000 g/mol; polypropylene glycols having a molecular weight lower than 200 g/mol; glycol ethers such as monopropylene glycol monoisopropyl ether; propylene glycol monoethyl ether; diethylene glycol monoethyl ether; ester type plasticizers such as sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, allyl glycollate; and amines such as monoethanolamine, diethanolamine, triethanolamine, monoisopropanolamine; triethylenetetramine, 2-amino-2-methyl-l,3-propanediol and the like. Of these, the low molecular weight polyethylene glycols, ethylene glycol, low molecular weight polypropylene glycols and especially propylene glycol are preferred.

Once the extrudate is obtained, it can be milled and sieved, and it can be used as ingredient to make pharmaceutical dosage forms.

The solid dispersion or the particles consisting of the solid dispersion of the present invention can be formulated into pharmaceutical dosage forms comprising a therapeutically effective amount of the solid dispersion. Although, at first instance, pharmaceutical dosage forms for oral administration such as tablets and capsules are envisaged, the solid dispersion/particles of the present invention can also be used to prepare pharmaceutical dosage forms e.g. for rectal administration. Preferred dosage forms are those adapted for oral administration shaped as a tablet. They can be produced by conventional tabletting techniques with conventional ingredients or excipients and with conventional tabletting machines.

In order to facilitate the swallowing of such a dosage form by a mammal, it is advantageous to give the dosage form, in particular tablets, an appropriate shape. Tablets that can be swallowed comfortably are therefore preferably elongated rather than round in shape. Especially preferred are biconvex oblate tablets. As discussed hereunder in more detail, a film coat on the tablet further contributes to the ease with which it can be swallowed. Tablets that give an immediate release of the basic drug upon oral ingestion and that have good bioavailability are designed in such a manner that the tablets disintegrate rapidly in the stomach (immediate release) and that the particles which are liberated thereby are kept away from one another so that they do not coalesce, give local high concentrations of the drug and that the chance that the drug precipitates

(bioavailability) is decreased. The desired effect can be obtained by distributing said particles homogeneously throughout a mixture of a disintegrant and a diluent.

Suitable disintegrants are those that have a large coefficient of expansion. Examples thereof are hydrophilic, insoluble or poorly water-soluble crosslinked polymers such as crospovidone (crosslinked polyvinylpyrrolidone) and croscarmellose (crosslinked sodium carboxymethylcellulose). The amount of disintegrant in immediate release tablets according to the present invention may conveniently range from about 3 to about 15 % (w/w) and preferably is about 7 to 9 %, in particular about 8.5 % (w/w). This amount tends to be larger than usual in tablets in order to ensure that the particles are spread over a large volume of the stomach contents upon ingestion. Because disintegrants by their nature yield sustained release formulations when employed in bulk, it is advantageous to dilute them with an inert substance called a diluent or filler.

A variety of materials may be used as diluents or fillers. Examples are spray-dried or anhydrous lactose, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (e.g. micro- crystalline cellulose Avicel™), dihydrated or anhydrous dibasic calcium phosphate, and others known in the art, and mixtures thereof. Preferred is a commercial spray- dried mixture of lactose monohydrate (75 %) with microcrystalline cellulose (25 %) which is commercially availble as Microcelac™. The amount of diluent or filler in the tablets may conveniently range from about 20 % to about 40 % (w/w) and preferably ranges from about 25 % to about 32 % (w/w).

The tablet may include a variety of one or more other conventional excipients such as binders, buffering agents, lubricants, glidants, thickening agents, sweetening agents, flavors, and colors. Some excipients can serve multiple purposes.

Lubricants and glidants can be employed in the manufacture of certain dosage forms, and will usually be employed when producing tablets. Examples of lubricants and glidants are hydrogenated vegetable oils, e.g hydrogenated Cottonseed oil, magnesium stearate, stearic acid, sodium lauryl sulfate, magnesium lauryl sulfate, colloidal silica, talc, mixtures thereof, and others known in the art. Interesting lubricants and glidants are magnesium stearate, and mixtures of magnesium stearate with colloidal silica. A preferred lubricant is hydrogenated vegetable oil type I, most preferably hydrogenated, deodorized Cottonseed oil (commercially available from Karlshamns as Akofine NF ™ (formerly called Sterotex™)). Lubricants and glidants generally comprise 0.2 to 7.0 % of the total tablet weight.

Other excipients such as coloring agents and pigments may also be added to the tablets of the present invention. Coloring agents and pigments include titanium dioxide and dyes suitable for food. A coloring agent is an optional ingredient in the tablet of the present invention, but when used the coloring agent can be present in an amount up to 3.5 % based on the total tablet weight.

Flavors are optional in the composition and may be chosen from synthetic flavor oils and flavoring aromatics or natural oils, extracts from plants leaves, flowers, fruits and so forth and combinations thereof. These may include cinnamon oil, oil of wintergreen, peppermint oils, bay oil, anise oil, eucalyptus, thyme oil. Also useful as flavors are vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth, The amount of flavor may depend on a number of factors including the organoleptic effect desired. Generally the flavor will be present in an amount from about 0 % to about 3 % (w/w).

As known in the art, tablet blends may be dry-granulated or wet-granulated before tabletting. The tabletting process itself is otherwise standard and readily practised by forming a tablet from desired blend or mixture of ingredients into the appropriate shape using a conventional tablet press.

Tablets of the present invention may further be film-coated to improve taste, to provide ease of swallowing and an elegant appearance. Many suitable polymeric film-coating materials are known in the art. A preferred film-coating material is hydroxypropyl methylcellulose HPMC, especially HPMC 29105 mPa.s. Other suitable film-forming polymers also may be used herein, including, hydroxypropylcellulose, and acrylate- methacrylate copolymers. Besides a film-forming polymer, the film coat may further comprise a plasticizer (e.g. propylene glycol) and optionally a pigment (e.g. titanium dioxide). The film-coating suspension also may contain talc as an anti-adhesive. In immediate release tablets according to the invention, the film coat is small and in terms of weight accounts for less than about 3 % (w/w) of the total tablet weight. Preferred dosage forms are those wherein the weight of the solid dispersion is at least 40 % of the total weight of the total dosage form, that of the diluent ranges from 20 to 40 %, and that of the disintegrant ranges from 3 to 10 %, the remainder being accounted for by one or more of the excipients described hereinabove.

The exact dosage of the drug compound that has to be administered and the frequency of administration depends on the particular drug compound used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.

The present invention further concerns a process of preparing the solid dispersions of the present invention as described hereinbefore, characterized by blending the components, extruding said blend at a temperature in the range of 20 - 300 °C. The invention also concerns of a process of preparing particles of the present solid dispersions, characterized by blending the components, extruding said blend at a temperature in the range of 20 - 300 °C, grinding the extrudate, and optionally sieving the particles.

The present invention also relates to another process of preparing the present solid dispersions characterized by dissolving the components in a suitable solvent followed by evaporating the solvent, preferably by spray-drying.

It is another object of the invention to provide a process of preparing a pharmaceutical dosage form as described hereinbefore, characterized by blending a therapeutically effective amount of solid dispersion/particles as described hereinbefore, with pharmaceutically acceptable excipients and compressing said blend into tablets or filling said blend in capsules.

Further, this invention concerns solid dispersion/particles as described hereinbefore, for use in preparing a pharmaceutical dosage form for oral administration to a mammal suffering from a disease, wherein preferably a single such dosage form can be administered once daily to said mammal. The present invention also concerns the use of solid dispersion/particles according to the present invention as described hereinbefore, for the preparation of a pharmaceutical dosage form for oral administration to a mammal suffering from a disease, wherein preferably a single such dosage form can be administered once daily to said mammal.

The invention also relates to a method of treating a disease in a mammal which comprises administering to said mammal an effective therapeutic amount of one or more basic drug compounds, preferably in a single oral dosage form which can be administered once daily.

The invention also relates to a pharmaceutical package suitable for commercial sale comprising a container, an oral dosage form of one or more basic drug compounds as described hereinbefore, and associated with said package written matter.

The following examples are intended to illustrate the present invention. As model basic drug loperamide was used and two of its fragments (fragment 1 and fragment 2). This should not be construed to limit the ambit of the invention.

polyacrylic acid

Experimental part

Polymer

Polyacrylic acid (PAA) (not crosslinked, M_w = 100000), was isolated by freeze drying a 35 wt. % solution of polyacrylic acid in water; PVPK30

Preparation of the solid dispersions by spray drying

The solid dispersions were prepared by spray drying of solutions with an overall solid concentration (drug compound (loperamide) + polymer) of 5 % w/v using a Biichi Mini

Spray Dryer B191 (Biichi Labortechnik AG, Flawil, Switserland). The compound and polymer were dissolved in a 1/1 (v/v) ratio of methanol and dichloromethane and the evaporation temperature was set at 80 °C. However, dispersions containing a high amount of fragment 2 of loperamide were poorly soluble in this mixture and the methanol/dichloromethane ratio was adjusted. All adjustable parameters of the equipment were kept constant (feeding rate : 7.5 ml/min, air flow : 700, power of the aspirator : maximum). Solutions containing 5, 10, 20, 30, 40, 50, 60 and 80 % w/w of drug relative to the total amount of solids (drug compound + polymer) were spray dried.

After spray drying, the dispersions were dried at 40 °C under vacuum until constant weight, after which they were stored in a dessicator over P₂Os in a freezer at -40 °C to reduce aging of the sample between preparation and measurement.

Dissolution measurements

Solid dispersions containing loperamide as model basic drug were prepared as described hereinabove. The dissolution properties of these solid dispersions were measured by directly adding the solid dispersion (equivalent dose of 200 mg) to 600 ml of water (37°C). Dissolution was assessed using a paddle, rotating at 50 rpm (USP XXIV). The release was followed for 2 hours. The concentration of loperamide was quantified at pre-determined time intervals. 2 ml of sample was removed from the dissolution vessel and replaced by fresh water. The amount of loperamide was determined by the use of the HPLC-method described hereinafter.

High performance liquid chromatography (HPLC)

All measurements were performed using a Merck Hitachi pump L7100, a Merck

Hitachi autosampler L7200 and a Merck Hitachi UV-detector L7400. A Hypersil BDS-C18 (3μm, 4.0 x 100mm) column (Agilent, USA) was used. All measurements were performed at room temperature, the flow rate was set at 1 ml/min, the injection volume was 10 μl and the detection wavelength was 220 nm.

For the determination of the content of loperamide an isocratic method was used, using a 70/30 (v/v) mixture of lmM tetrabutylammonium hydrogen sulfate in water and acetonitrile.

Results of the dissolution measurements

Table 1 gathers the % release of loperamide from solid dispersions of 20% loperamide in PAA (Lo-PAA), of 20% of loperamide in PVPK30 (Lo-PVPK30) and the dissolution profile of pure and crystalline loperamide (Lo). The results are the average of 3 measurements. Table 1

From the above results it can be concluded that the dissolution rate is improved by formulating loperamide in a solid dispersion. When PAA is used as a carrier, the dissolution properties are clearly improved when compared to PVPK30.

Infra-red spectroscopy IR-measurements were performed to investigate salt formation. FTIR-measurements were performed on a Perkin-Elmer 2000 at room temperature using KBr-tablets containing approximately 0.35 % (w/w) of dispersion. Analysis of the spectra was performed using the Spectrum v2.00 software. Dispersions containing 10, 20, 30 and 80% of the compounds were examined and compared with spectra obtained from the pure substances and physical mixtures (20 and 80% of the compounds). The physical mixtures were prepared by weighing the appropriate amounts of the compound and polymer and mixing them in a mortar during 3 minutes.

The formation of a carboxylate group leads to two new and specific absorption bands compared to the protonated form (carboxylic acid) : around 1550 cm^"1 (asymmetric stretch vibration) and 1400 cm^"' (symmetric stretch vibration). The IR-spectra of the dispersions of fragment 2 molecules with PAA clearly showed the appearance of a peak at 1545 cm^"1 that increased as the amount of fragment 2 increased. Around 1400 cm^"1, absorption peaks of the compound were observed, thus masking the peak originating from the symmetric stretch of the COO^" group. Similar observations were made for the fragment 1 molecules. The spectra of the dispersions of PAA with loperamide were less clear since the drug exhibits absorption peaks in both spectral ranges of interest. As conclusion from the IR-measurements it can be stated that the salt formation theory seems to be confirmed.

Stability of the solid dispersions

Solid dispersions were prepared and stored for 1 month, 6 months and 12 months under different conditions of temperature and humidity.

The dissolution properties were determined in order to evaluate the stability of the solid dispersions. Different polymers were used : HPMC 2910, PVP-VA64, PVP K30 and

PAA.

The following method was used for the dissolution test.

An amount of the solid dispersion equal to 200 mg of loperamide was added to 600 ml of dissolution medium (0.01N HC1 for PAA and buffer pH 4.5 for the other polymers) (37°C). Dissolution was assessed using a paddle, rotating at 50 rpm (USP XXTV). The amount of released loperamide was determined by UV absorption.

The following Tables list the results obtained for the different solid dispersions.

% release of loperamide from solid dispersion of 60wt% of loperamide in PVP K30 after preparation

% release of loperamide from solid dispersion of 60wt% of loperamide in PVP K30 after 1 month storage

% release of loperamide from solid dispersion of 60wt% of loperamide in PVP K30 after 6 month storage

% release of loperamide from solid dispersion of 60wt% of loperamide in PVP K30 after 12 month storage

% release of loperamide from solid dispersion of 60wt% of loperamide in PVP-VA 64 after preparation

% release of loperamide from solid dispersion of 60wt% of loperamide in PVP-VA 64 after 1 month storage

% release of loperamide from solid dispersion of 60wt% of loperamide in PVP-VA 64 after 6 month storage

% release of loperamide from solid dispersion of 60wt% of loperamide in PVP-VA 64 after 12 month storage

% release of loperamide from solid dispersion of 60wt% of loperamide in PAA after preparation

% release of loperamide from solid dispersion of 60wt% of loperamide in PAA after 1 month storage

% release of loperamide from solid dispersion of 60wt% of loperamide in PAA after 6 month storage

% release of loperamide from solid dispersion of 60wt% of loperamide in PAA after 12 month storage

Preparation of particles of the present invention

8 g of a basic drug and 12 g of a water-soluble polymer containing acidic groups is mixed until the mixture is homogenous. The mixture is fed into a Gimac single screw extruder IJD 24:1 having the following operating parameters : screw rate is 30 revolutions per minute, the temperature ranges from 70°C to 235°C. The melt extrudate is milled and fractions with particle size below 150 μm (condition I in point 6) and between 500 and 850 μm (condition H in point 6) are collected.

Claims

Claims 1. A solid dispersion comprising

(a) at least one basic drug compound; and

2. A solid dispersion according to claim 1 wherein the basic drug compound is a compound having a pKa value which is at least 1.5 units higher than the pKa of at least one pharmaceutically acceptable water-soluble polymers containing acidic groups.

3. A solid dispersion according to claim 1 or 2 wherein the polymer is a polymer of formula

wherein Ri represents hydrogen or CH₃, and R₂ represents hydrogen or CH₃.

4. A solid dispersion according to any one of claims 1 to 3 wherein the polymer is poly acrylic acid.

5. A solid dispersion according to any one of the preceding claims wherein the solid dispersion is in the form of particles.

6. A solid dispersion according to claim 5 wherein the particles have a particle size of less than 1500 μm.

7. A solid dispersion according to any one of the preceding claims wherein the active ingredient is in a non-crystalline phase.

8. A solid dispersion according to any one of claims 1 to 7 wherein the solid dispersion is in the form of a solid solution comprising (a) and (b), or in the form of a dispersion wherein amorphous or microcrystalline (a) or amorphous or microcrystalline (b) is dispersed more or less evenly in a solid solution comprising (a) and (b).

9. A solid dispersion according to any one of claims 1 to 8 obtainable by solvent evaporation.

10. A solid dispersion according to any one of claims 1 to 8 obtainable by melt- extrusion of the components and grinding, and optionally sieving.

11. A solid dispersion according to any one of claims 1 to 10 wherein the basic drug is loperamide.

12. A pharmaceutical dosage form comprising a therapeutically effective amount of a solid dispersion as claimed in any one of the preceding claims.

13. A process of preparing solid dispersions as claimed in any one of claims 1 to 8 characterized by blending the components, extruding said blend at a temperature in the range of 20 - 300 °C, grinding the extrudate, and optionally sieving the particles.

14. A process of preparing solid dispersions as claimed in any one of claims 1 to 8 characterized by dissolving the components in a suitable solvent followed by evaporating the solvent.

15. Use of a solid dispersion according to any one of claims 1 to 11 for the preparation of a pharmaceutical dosage form for oral administration to a mammal.