WO1994010993A1

WO1994010993A1 - Pharmaceutical formulations of ibuprofen

Info

Publication number: WO1994010993A1
Application number: PCT/DK1993/000365
Authority: WO
Inventors: Hans Johansen
Original assignee: Nycomed Dak A/S
Priority date: 1992-11-17
Filing date: 1993-11-09
Publication date: 1994-05-26
Also published as: EP0668761A1; FI952377A0; FI952377A7; NO951933L; AU5560694A; DK138592D0; NO951933D0

Abstract

Pharmaceutical particulate formulations of the S-(+)- enantiomer of ibuprofen comprising i) 40-70 % w/w of S-(+)-ibuprofen, ii) a water-soluble pharmaceutically acceptable binder, iii) optionally, silica in an amount not exceeding 2 % w/w, with the proviso that the formulation does not contain water-soluble polyvinylpyrrolidone. The formulations have a relatively high load of S-(+)- ibuprofen and, accordingly, a relatively low content of excipients. The formulations exhibit good flowability, good compactability and possesses excellent tabletting properties. Thus, the formulations allow the preparation of, e.g., tablets which display minimal or greatly diminished adherence (sticking) to tablet punches and/or dies during compression, and which have excellent disintegration and dissolution properties and reduced tendency towards time-dependent reduction of dissolution rate. The water-soluble binder may be hydrophilic substances like, e.g., gelatin, starch or acacia. When silica is present in a formulation, colloidal silicas such as AerosilR 200, AerosilR 380, Cab-O-SilR M5, Cab-O-SilR EH5 or SyloidR have proved to be well suited. Furthermore, the invention relates to a process for the preparation of a formulation as mentioned above and to solid drug dosage forms comprising such a formulation.

Description

PHARMACEUTICAL FORMULATIONS OF IBUPROFEN

FIELD OF THE INVENTION

The present invention relates to pharmaceutical particulate formulations of the S-(+)-enantiomer of ibuprofen, and to a process for the preparation thereof.

The invention also relates to solid drug dosage forms comprising a pharmaceutical formulation according to the invention.

BACKGROUND OF THE INVENTION

Ibuprofen, which strictly speaking is the generic name for the racemic form of the drug [R,S-(±)-2-(4-isobutylphenyl)- propionic acid] , is a poorly water-soluble drug with a melting point of 75-77.5°C. Ibuprofen has well-established analgesic and antipyretic effect and is widely employed as a non-steroid anti-inflammatory drug. It is currently marketed on prescription in, e.g., the Nordic countries and in USA under the generic name, as well as under various trademarks (e.g. Brufen™) . The drug is generally available in the form of 200 mg, 400 mg and 600 mg tablets for oral administration.

As indicated above, the ibuprofen molecule has an asymmetric carbon atom and is present as the racemate in the above- mentioned tablet compositions. In the case of drugs having one or more asymmetric carbon atoms it has often been found that one optical isomeric form is more therapeutically active - sometimes dramatically more active - than the other optical isomeric form(s) . It has previously been found that of the two enantiomers present in racemic ibuprofen, the S-(+)₅₈ - enantiomer (i.e. the dextrorotatory isomer, which in the present specification and claims is denoted S-(+)-ibuprofen) is the therapeutically more active species. Although the R- (-)₅₈₉-enantiomer, denoted R-(-)-ibuprofen herein, is converted to S-(+)-ibuprofen within the human body, it is currently believed that S-(+)-ibuprofen administered as such has a greater therapeutic potency and a more rapid effect than the R-(-)-form.

Racemic ibuprofen has proved to be difficult to formulate in the form of tablets, and this is believed to be due in part to its poor "compressibility". In general, two properties of a formulation which is to be compressed into tablets, namely the flowability and compactibility of the formulation, are of particular importance. These two properties are together denoted "compressibility".

With respect to flowability, a particulate formulation should flow uniformly and readily from a delivery device (normally a delivery or feed hopper) to a table, e.g. a rotating table, that holds a certain number of dies. Some high-speed tablet compression machines require several feed hoppers and large number of dies. Each die is associated with a pair (upper and lower) of punches that fit tightly into the die. As a die passes under a feeding device, the lower punch is adjusted to the die so that it will hold a volume of particulate formulation equal in weight to the desired weight of the final tablet. Once the die is filled, the feed frame containing the die moves on. The upper punch is then lowered to deliver the force necessary for compression. Thereafter, the upper punch is withdrawn, and the bottom punch is moved upwards to eject the tablet. At this point, the empty die is ready for its next loading.

Thus, upon application of an appropriate pressure thereto, a particulate formulation must be able to establish the necessary binding or cohesive forces between the individual particles in the particulate formulation such that a tablet can be formed and such that the formed tablets are, e.g., sufficiently mechanically robust to withstand normal han¬ dling. In the case of ibuprofen, the poor compressibility is believed to be partly due to the fact that ibuprofen itself has a very low bulk density, and partly due to the rather low melting point for ibuprofen (75-77.5°C).

In the following is given a brief review of patent literature relating to tablets containing the racemic form of ibuprofen:

US 4,609,675 discloses the preparation of a dry granulate composition comprising racemic ibuprofen, and the composition is described as being suitable for the preparation of tablets and capsules. The dry granulate composition is prepared by compacting or slugging of a dry powder mixture comprising ibuprofen and various excipientε, e.g., croscarmellose sodium type A and/or B and colloidal silica.

In the latter patent it is stated that the well-known problems associated with the manufacture of ibuprofen- containing tablets can be overcome by compression of the dry granulate composition after addition of certain extragranular ingredients. From Examples 1 and 2 given therein, it can be calculated that tablets made from the dry granulate composition comprise about 75-89% w/w ibuprofen, about 6.3-8% w/w croscarmellose sodium type A, about 1.2-1.9% w/w colloidal silica and about 0.8-1.0% w/w magnesium stearate plus talc.

US 4,806,359 discloses a sustained-release matrix formulation of ibuprofen. The matrix comprises ethylcellulose and polyvinylpyrrolidone, and colloidal silica is used as a glidant. This patent further discloses a two-layered tablet having an immediate release layer comprising about 63.9% w/w ibuprofen, about 12.8% w/w microcrystalline cellulose, about 0.6% w/w hydroxypropyl-methylcellulose and about 0.3% w/w colloidal silica.

US 4,835,186 and US 4,835,187 disclose chewable tablets, each weighing approximately 3 g. The tablets comprise ibuprofen and a large amount of excipients (about 70-71% w/w) . In Example 3 of US 4,835,187, colloidal silica is added in an amount corresponding to about 2.7% w/w of the total tablet weight. The tablets are prepared by direct compression.

US 4,904,477 discloses a spray-dried ibuprofen composition suitable for the preparation of tablets by direct compres¬ sion, and examples of preparation of tablets in this manner are given in Examples 3-7 and 10 therein. In general, the resulting tablets comprise about 62-66% w/w ibuprofen, about 0.2-0.4% w/w colloidal silica, up to about 11% w/w croscarmellose sodium, type A, up to about 0.9% w/w poly¬ vinylpyrrolidone and about 0.6-0.8% w/w magnesium stearate plus talc.

In the case of S-(+)-ibuprofen, the above-mentioned problems associated with the preparation of tablets containing racemic ibuprofen are considerably more pronounced, owing to the fact that the melting point of S-(+)-ibuprofen (ca. 51-53°C) is significantly lower than for the racemate. Furthermore, S- (+)-ibuprofen has a very low bulk density, and its compressibility [i.e. compactability and flowability, (vide supra) ] is very poor.

Owing to the low melting point of S-(+)-ibuprofen, melting of some of the drug substance can occur during compression, leading to adhesion of the formulation [which initially typically will be in the form of particles (e.g. granules and/or powder, such as a so-called "powder blend" formula¬ tion) , such a formulation being referred to herein as a particulate formulation], e.g., to the tablet punch(es) or die(s) .

There are indications that the friction associated with feeding of a particulate formulation via a delivery hopper to the tablet press causes the temperature within the tabletting formulation to rise by approximately 10-15°C, leading to a temperature of the formulation of about 30-35°C. The

REPLACEMENTSHEET temperature further increases as a result of the external pressure applied during compression, so that the temperature of the formulation under compression, or the temperature of the resulting tablets, may be in the range of about 35-40°C. This increase in temperature during manufacture may give rise to localized melting of the low-melting S-(+)-ibuprofen, resulting in severe tabletting problems caused by adhesion of the compressed material to dies, punches and the like.

Cooling of the tablet press has been employed to overcome this latter manufacturing problem; cooling is, however, a highly inconvenient solution, and results in increased manufacturing costs.

It is well known that in the preparation of solid dosage forms in general, problems may arise owing to adhesion of the formulation or the solid dosage form itself to various parts of, or at various loci within, the preparation equipment, filling equipment, etc., employed.

In the case of tablets, adhesion may take place during the whole tablet compression process at points or loci where metal/metal and/or metal/formulation and/or metal/tablet friction is possible. Such adhesion may lead to "picking" or "sticking" during compression of the particulate formulation leading, at best, to lamination and friability problems with the tablets prepared from the formulation. Other problems associated with increased adhesion are, e.g., relatively long disintegration times or relatively low dissolution rates for tablets made from the formulation, and excessive variation in tablet weight (e.g. deviation from uniformity requirements in accordance with European Pharmacopoeia, Ph. Eur.).

In the following is given a brief review of patent literature relating to tablets containing S-(+)-ibuprofen:

US 4,851,444 relates to the use of S-(+)-ibuprofen in an attempt to achieve a fast and increased analgetic effect compared to racemic ibuprofen. No specific tablet or par¬ ticulate formulations or properties thereof are mentioned.

US 4,877,620 describes pharmaceutical tablet compositions comprising S-(+)-ibuprofen. Example 1 therein describes tablets having the following composition: 62.5% w/w S-(+)- ibuprofen, 4.2% w/w insoluble polyvinylpyrrolidone, 31.3% w/w microcrystalline cellulose and 2% w/w magnesium stearate.

US 4,980,375 relates to the use of S-(+)-ibuprofen. Phar¬ maceutical dosage forms are mentioned in the patent but no specific compositions or properties thereof are disclosed.

WO 92/05786 discloses a pharmaceutical combination composi¬ tion for use in the relief of pain, cramps, bloating and tension experienced during menstruation or premenstruation in a female. The composition comprises S-(+)-ibuprofen or a salt thereof, substantially free of R-(-)-ibuprofen, together with a diuretic. Example 3 therein describes a sustained-release composition comprising S-(+)-ibuprofen as an analgesic or anti-inflammatory drug substance, together with hydrochlorothiazide as a diuretic drug substance. The composition contains polyvinylpyrrolidone as a binder in a concentration of about 3.7% w/w, and two different types of methylcellulose in a total concentration of about 33% w/w.

WO 92/05783 relates to pharmaceutical compositions for use in the treatment of pain and inflammation and in the relief of allergy and cold symptoms in a mammalian organism. The composition comprises S-(+)-ibuprofen together with at least one antihistamine. Examples 2 and 5 therein describe sustained-release compositions comprising S-(+)-ibuprofen together with dexchlorpheniramine maleate (Example 2) and terfenadine (Example 5) , respectively. Two different types of methylcellulose are present in the composition in a total concentration of about 30-33% w/w. Polyvinylpyrrolidone is incorporated in a concentration of about 3-4% w/w. DESCRIPTION OF THE INVENTION

As will be apparent from the above, there is a need for the development of a pharmaceutical particulate formulation of ibuprofen, notably S- (+) -ibuprofen, which can be used for the preparation of solid dosage forms, especially for the preparation of tablets, and which allows such solid dosage forms to be prepared without the use of an undesirably large amount of pharmaceutically acceptable excipients while at the same time substantially eliminating problems relating to adhesion of the formulation to the manufacturing equipment. The present invention meets this need by providing S- (+) - ibuprofen formulations which have a relatively low content of excipients, and which exhibit good flowability, good compactibility and, e.g., excellent tabletting properties. Thus, these formulations allow the preparation of, e.g., tablets which display minimal or greatly diminished adherence (sticking) to tablet punches and/or dies during compression, and which have excellent disintegration and dissolution properties, excellent cosmetic and physical stability, and reduced tendency towards time-dependent reduction of dissolution rate.

When the novel formulations according to the invention are used for the preparation of tablets, it is not necessary to employ any cooling of the tablet press.

The present invention provides a pharmaceutical particulate formulation comprising

i) 40-70% w/w of S- (+) -ibuprofen,

ii) a water-soluble pharmaceutically acceptable binder,

iii) optionally, silica in an amount not exceeding 2% w/w (based on the total weight of the formulation) , with the proviso that the formulation does not contain water- soluble polyvinylpyrrolidone.

As will be apparent from the following, the present inventors have found that when water-soluble polyvinylpyrrolidone is used alone as a binder (i.e. when no other substance(s) possessing binding properties apart from polyvinylpyrrolidone itself is/are included in the formulation) , particulate for¬ mulations exhibiting poor tabletting properties are obtained. Nevertheless, it is possible that the incorporation of relatively low levels of water-soluble polyvinylpyrrolidone

(e.g. in amounts not exceeding about 3% w/w, more probably in amounts not exceeding about 2% w/w or most probably in amounts not exceeding a level as low as about 1% w/w) may lead to acceptable particulate formulations (i.e. formulations possessing, for example, satisfactory tabletting properties) provided that one or more water-soluble pharmaceutically acceptable binders other than water-soluble polyvinylpyrrolidone itself are incorporated in the formula¬ tion.

The designation "S- (+) -ibuprofen" as used in the present specification and claims is intended to denote the substan¬ tially pure S- (+) -enantiomer of ibuprofen, i.e. S- (+) - ibuprofen which is substantially free of R- (-) -ibuprofen. In the working examples given herein, S- (+) -ibuprofen having an enantiomeric purity of ≥99% and an analytical purity corresponding to that specified in British Pharmacopoeia (BP) 1988 and British Pharmacopoeia Addendum (BP Add.) 1989 for racemic ibuprofen (≥98.5%) was employed. However, it would of course be possible, if so desired, to employ a less enan- tiomerically pure S- (+) -ibuprofen preparation, since the problems associated with the low melting point of pure S- (+) - ibuprofen will be expected to decrease in severity as the content of R- (-) -ibuprofen in the material increases. Furthermore, it is believed that particulate formulations and solid dosage forms analogous to those of the invention but containing R,S-ibuprofen instead of S- (+) -ibuprofen and having otherwise identical compositions may, if so desired, satisfactorily be prepared in the manner specified herein for S- (+) -ibuprofen.

Apart from the active drug substance, i.e. S- (+) -ibuprofen, the particulate formulation and the solid dosage form according to the present invention comprise pharmaceutically acceptable excipients. By proper selection of pharma¬ ceutically acceptable excipients, the inventors have found that it is possible to obtain a particulate formulation comprising S- (+) -ibupro en which can be further processed to form a solid dosage form, especially tablets, without the need for any special precautions during the preparation thereof.

It is a well-known principle in tablet formulation to add certain quantities of various pharmaceutically acceptable tablet excipients to the tabletting formulation in order to dilute or suppress an effect arising from a drug substance which in itself has very poor compressibility. In this connection, a particulate formulation according to the present invention comprises, apart from S- (+) -ibuprofen, at least a pharmaceutically acceptable binder, especially a water-soluble binder, as an excipient. A suitable binder in the context of the present invention will most frequently be a solid or semi-solid material which displays a reasonable degree of solubility in water, possesses good adhesive properties and imparts adequate cohesion between the par¬ ticles of, e.g., a tablet formed by compression of a for¬ mulation according to the invention. An important role of the binder in a formulation according to the present invention is thus to provide particulate formulations which may be processed to form solid dosage forms exhibiting the necessary cohesive strength.

The binder should preferably have no significant influence on the disintegration properties of the solid dosage form or the dissolution of the therapeutically active substance therefrom. The final effect of a binder, and the optimum concentration thereof, in a particular product cannot generally be predicted, and the required binder concentration must be determined on the basis of an experimental evaluation of the final product.

The binder is very suitably such that it can be introduced via a wet granulation procedure employing an aqueous solution containing the binder.

Water-soluble binders suitable for use in the context of the present invention will in general be hydrophilic substances, for example sugars such as sucrose, glucose and sorbitol, or certain polymers of natural or synthetic origin. Examples of polymeric binders of natural or synthetic origin include acacia (Gum Arabic) , alginic acid, sodium alginate, water- soluble proteins such as gelatin [notably hydrolyzed gelatin or gelatin which is soluble in water at room temperature (so- called "cold soluble gelatin")], polysaccharides or deriva¬ tives thereof, such as starch, hydrolyzed starch or pre- gelatinized starch, carboxymethylcellulose sodium, methylcel- lulose, hydroxypropyl-methylcellulose (also known as methyl hydroxypropylcellulose) , carboxypolymethylene and poly¬ ethylene glycols. Especially preferred binders for use in a formulation of the invention are binders exerting a strong binding or cohesive effect, in order to compensate for the poor compressibility properties of S- (+) -ibuprofen itself. Generally recognized examples of such binders include gelatin, starch and acacia. Gelatin is particularly preferred for use in the context of the present invention.

Polyvinylpyrrolidone is also recognized as a strong binder but the inventors have surprisingly found that water-soluble polyvinylpyrrolidone is generally unsuited for use in formulations according to the present invention (vide infra) . Polyvinylpyrrolidones can broadly be divided into two categories, viz. "soluble" and "insoluble" polyvinylpyrro¬ lidones. "Soluble" polyvinylpyrrolidones are normally sub¬ stantially non-cross-linked and exhibit solubility in water and a number of common organic solvents (such as a number of alcohols, glycols and lower carboxylic acids) to an extent of at least about 10% by weight at ambient temperature. In contrast, "insoluble" polyvinylpyrrolidones are generally cross-linked to a significant extent and exhibit, at best, only low solubility (≤1% by weight) in the above-mentioned solvents.

Thus, the term "water-soluble polyvinylpyrrolidone" as employed in the context of the present invention may broadly be understood to designate soluble polyvinylpyrrolidone as defined above, i.e. polyvinylpyrrolidone which is soluble, inter alia, in water at ambient temperature to an extent of at least about 10% by weight.

It appears that water-soluble polyvinylpyrrolidone forms an eutectic mixture with S- (+) -ibuprofen, i.e. the melting point of S- (+) -ibuprofen is depressed. As will be apparent from the disclosure in the introductory part of the present specif¬ ication, a depression of the melting point of S- (+) -ibuprofen is highly undesirable, since it will lead to an increased risk of problems associated with adhesion of the particulate formulation to the equipment used in preparing the formulation or a solid dosage form comprising the particulate formulation. Problems of this kind have been observed in experiments performed (vide infra) by the inventors using polyvinylpyrrolidone as water-soluble binder.

The concentration of the binder which is required, e.g., to produce acceptable tablets is dependent on the method of incorporating the binder. A formulation according to the present invention is preferably prepared by a method which involves a wet granulation procedure. In such cases the binder is suitably present in an amount in the range of 0.05- 8% w/w, preferably in the range of 0.25-5% w/w, and more preferably in the range of 0.5-2.0% w/w (based on the total weight of the formulation) .

As already mentioned, a particulate formulation according to the invention optionally comprises silica in an amount not exceeding 2% w/w (based on the total weight of the formulation). Silica is added as a lubricant or glidant, i.e. to reduce friction between particles in order to increase flowability and/or to reduce friction between the formulation and metal surfaces (dies and punches) , and particulate formulations according to the invention preferably comprise silica, in particular so-called "colloidal silica". In this connection it is noteworthy that satisfactory particulate formulations according to the invention may readily be prepared without the need for incorporation of the conventionally employed lubricant/glidant materials magnesium stearate and/or talc.

In the context of the present invention, silica (silicon dioxide) is suitably silica having CAS Registry Number [7631- 86-9] or [63231-67-4] ; such silica is also known as

"colloidal silica", "fumed silica", "light anhydrous silic-ic acid", "silicic anhydride", "silicon dioxide fumed", and is a low-density, loose, bluish-white, odorless, tasteless, non- gritty, amorphous powder. Commercially available silicas of this type include Aerosil^®, Cab-0-Sil^® and Syloid^®. It has been found, for example, that various grades of Cab-O-Sil^® and Aerosil^® may satisfactorily be employed in formulations according to the present invention. The various grades are obtained by varying the manufacturing process; they differ with respect to particle size, surface area and bulk density, although the silica content, microscopic specific gravity, refractive index and amorphous form are the same.

In particulate formulations according to the invention in which silica is present, colloidal silicas such as Aerosil^® 200, Aerosil^® 380, Cab-0-Sil^® M5, Cab-0-Sil^® EH5 or Syloid^® have proved to be well suited.

When silica is incorporated in a particulate formulation according to the present invention, it is suitably present in an amount in the range of 0.001-1.5 % w/w, preferably in the range of 0.005-1.0% w/w, more preferably in the range of 0.01-0.5% w/w, most preferably in the range of 0.05-0.15% w/w (based on the total weight of the formulation) .

A particulate formulation according to the invention may further comprise at least one pharmaceutically acceptable excipient selected from the group consisting of disint- egrants, fillers, wetting agents, lubricants and glidants. These excipients may be, for example: disintegrants such as cellulose derivatives, including microcrystalline cellulose; starches, including potato starch; croscarmellose sodium

(i.e. cross-linked carboxymethylcellulose sodium salt; e.g. Ac-Di-Sol^®) ; alginic acid or alginates; insoluble polyvinylpyrrolidone (e.g. Polyvidon^® CL, Polyvidon^® CL-M, Kollidon^® CL, Polyplasdone^® XL, Polyplasdone^® XL-10) ; sodium carboxymethylstarch (e.g. Primogel^® and Explotab^®) ; fillers or diluents, such as sucrose, sorbitol, mannitol, lactose (e.g., spray-dried lactose, α-lactose, β-lactose, Tablet- tose^®, various grades of Pharmatose^® or Fast-Floe^®) , micro¬ crystalline cellulose (e.g., various grades of Avicel^®, such as Avicel^® PH101, Avicel^® PH102 or Avicel^® PH105 , Emcocel^®, Vivacel^®, Ming Tai^® and Salka-Floc^®) , starches (including potato starch) , sodium chloride, sodium phosphate, calcium phosphate, calcium sulfate, calcium carbonate; wetting agents or humectants, such as glycerol, sorbitol or polyethylene glycols; and lubricants or glidants, including anti-ad- hesives, such as magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils or talc.

Other appropriate pharmaceutically acceptable excipients may include colourants, flavouring agents, plasticizers and buffering agents. A preferred embodiment of a particulate formulation according to the invention comprises microcrystalline cellulose, suitably in an amount of about 5-55% w/w, preferably about 15-55% w/w, more preferably about 20-50% w/w, most preferably about 30-40% w/w (based on the total weight of the formulation) .

Particulate formulations of the invention preferably comprise one or more constituents selected from lactose, potato starch and croscarmellose sodium.

Especially preferred particulate formulations of the inven¬ tion are formulations I) -III) , below, containing the fol¬ lowing ingredients:

Formulation I) :

i) 40-60% w/w of S- (+) -ibuprofen, ii) 0.5-2% w/w of gelatin, iii) 0.05-0.5% w/w of colloidal silica, iv) 30-35% w/w of microcrystalline cellulose, v) 4-7% w/w of potato starch, vi) 5-8% w/w of lactose, and vii) 0.25-3% w/w of croscarmellose sodium.

Formulation II) :

i) 50-53% w/w of S- (+) -ibuprofen, ii) 0.9-1.1% w/w of gelatin, iii) 0.08-0.09% w/w of colloidal silica, iv) 32-34% w/w of microcrystalline cellulose, v) 5.8-6.5% w/w of potato starch, vi) 6.5-7.0% w/w of lactose, and vii) 0.5-2.5% w/w of croscarmellose sodium.

Formulation III) :

i) about 51% w/w of S- (+) -ibuprofen, ii) about 1.0% w/w of gelatin, iii) about 0.085% w/w of colloidal silica, iv) about 32.8% w/w of microcrystalline cellulose, v) about 6.0% w/w of potato starch, vi) about 6.8% w/w of lactose, and vii) about 2.0% w/w of croscarmellose sodium.

The working examples provided herein illustrate the pre¬ paration of a particularly suitable form of a particulate formulation of the invention, namely a so-called "powder blend" formulation, i.e. a particulate formulation consisting of a blend of i) granulated material incorporating the active drug substance and ii) extragranular excipients in powder form.

As already mentioned, the present invention further provides solid dosage forms comprising a pharmaceutical particulate formulation according to the invention. The term "solid dosage form" as employed in the context of the present invention is intended to primarily encompass what are generally regarded as solid dosage forms (such as "hard" pills, tablets, capsules and sachets) . Although the particulate formulations of the invention are of primary importance in the context of the preparation of such solid dosage forms, it is envisaged that it may, in certain cases, be appropriate to incorporate them in semi-solid dosage forms. Examples of semi-solid dosage forms are dosage forms formulated as chewing gums, gels, jellies and gelatinous pastilles (e.g. pastilles having the consistency of "wine gums") and the like, and the term "solid dosage form" as employed herein is intended to also encompass such semi-solid dosage forms.

A solid dosage form according to the invention is suitably a unit dosage form, typically for oral use, and will preferably be in the form of, e.g., tablets, pills, sachets or. capsules, especially in the form of tablets. A unit dosage form in accordance with the invention, e.g. tablets, may be in uncoated form or may be provided with a coating. A suitable coating may be applied by techniques well known in the art, e.g. as described in the chapter entitled "Aqueous Film Coating" by James A. Seitz in "Encyclopedia of Pharmaceutical Technology", Vol. 1, pp. 337-349, edited by J. Swarbrick and J. C. Boylan, Marcel Dekker, Inc., New York, 1988.

A suitable coating may, for example, be:

a sugar coating;

a film coating, e.g. a coating based on one or more materials selected from the following: hydroxypropyl-methylcellulose, methylcellulose, hydroxyethyl-methylcellulose, hydroxypropylcellulose, carboxymethylcellulose sodium, acrylate polymers (e.g. Eudragit^® E) , polyethylene glycols and polyvinylpyrrolidone;

an enteric coating, e.g. a coating based on one or more materials selected from the following: methacrylic acid copolymers (e.g. Eudragit^® L or S) , cellulose acetate phthalate, ethylcellulose, hydroxypropyl-methylcellulose acetate succinate, polyvinyl acetate phthalate and shellac; or

a controlled-release coating, e.g. a coating based on one or more materials selected from the following: shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resin, dl-polylactic acid, cellulose acetate butyrate, polyvinyl acetate, vinylpyrrolidone, polyethylene, poly(methyl methacrylate) , methacrylate hydrogels, 1,3-butylene glycol, ethylene glycol methacrylate and a polyethylene glycols. If appropriate, the coating in question may suitably comprise a plasticizer, such as a plasticizer among those mentioned in provisional leaflet No. 060208 published by Rδhm Pharma GmbH, Darmstadt, Germany. Suitable examples of plasticizers may be selected from propylene glycol, polyethylene glycols, glyceryl triacetate, triethyl citrate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, diethyl phthalate, dibutyl phthalate and mixtures thereof.

Tablets according to the invention may suitably be film- coated with hydroxypropyl-methylcellulose, optionally in combination with hydroxyethylcellulose or other suitable film coating material (s). By way of example, the straightforward preparation of a solid dosage form in the form of film-coated tablets (provided with a coating based on hydroxypropyl- methylcellulose) intended for immediate release of S- (+) - ibuprofen is illustrated herein (vide infra) .

Preferred compositions of tablets according to the invention include those specified above (in relation to particulate formulations of the invention) for Formulations I) -III) .

As mentioned previously, a further aspect of the present invention relates to a process for preparing a pharmaceutical particulate formulation according to the invention, the process in question comprising: i) adding an aqueous solution of the binder to S- (+) -ibuprofen, the S- (+) -ibuprofen optionally being in admixture with one or more pharmaceuti¬ cally acceptable excipients, ii) forcibly sieving the resulting moist mixture, iii) drying the sieved moist mixture to obtain a granulate, iv) sieving the dried granulate, and, optionally, v) mixing the sieved granulate with silica and/or one or more pharmaceutically acceptable excipients.

The invention is further illustrated by the working examples described in the following: Materials

Materials employed in the formulations which were in¬ vestigated in the course of development of the present invention (see Table 1, below) were as follows:

S- (+) -ibuprofen: in accordance with BP 1988 and BP Add. 1989.

Potato starch (amylum solani) : in accordance with Ph. Eur., 2nd Ed.

Lactose: in accordance with Ph. Eur., 2nd Ed.

Microcrystalline cellulose: in accordance with Ph. Eur., 2nd Ed. Avicel^® PH101 (from FMC Corporation) was used in component I (Table 1; vide infra) , and Avicel^® PH102 (from FMC Corporation) was used in component III (Table 1; vide infra) .

Croscarmellose sodium (i.e. cross-linked carboxymethyl- cellulose, sodium salt) : Ac-Di-Sol^® (from FMC Corporation) in accordance with National Formulary XVII (NF XVII) .

Magnesium stearate: in accordance with Ph. Eur., 2nd Ed.

Talc: in accordance with Ph. Eur., 2nd Ed.

Silica: in accordance with Ph. Eur., 2nd Ed. Aerosil^® 200 (from Degussa) was employed throughout, although in the case of formulation No. 18 in Table 1 (vide infra) , Aerosil^® 380 (from Degussa) , Cab-O-Sil^® M5 and Cab-O-Sil^® EH5 (both from Cabot Corp.) and Syloid^® (Davidson; from W.R. Grace & Co.) were also tested and were found to give satisfactory results.

Polyvinylpyrrolidone: Kollidon^® 30 (BASF) in accordance with Ph. Eur. , 2nd Ed.

Gelatin: in accordance with Ph. Eur., 2nd Ed. Equipment and apparatus employed

The equipment/apparatus employed in the procedures and measurements involved in the preparation and assessment of the various formulations examined in connection with the invention was as follows:

Weighing: Mettler PC4400 or Sauter Multirange EB60 (for weighing on laboratory scale) ; Mettler KB60 or Sauter EC240 (production scale) .

Mixing/granulation: Erweka PRS or Fielder PMA.T.25-2G (laboratory scale) ; Diosma-Pharma- Mischer P250 (production scale) .

Sieving: Frewitt MGIF312 (laboratory scale) ; Frewitt MG 1/628 (production scale)

Drying: Aeromatic MP-1 (laboratory scale) ; Aeromatic 60 (production scale) .

Tabletting: Korsch PH100 (laboratory scale) ; Manesty Betapress (production scale)

Coating: AccelaCota 24" (laboratory scale) ; AccelaCota 48" (production scale) .

Hardness testing of (uncoated) tablets: Schleuniger 2E/205,

Disintegration testing: Erweka ZT3.

Dissolution testing: Pharmatest PTWS

Spectrophotometry: Hitachi 150-20, pH measurement: Radiometer PHM83.

S- (+) -Ibuprofen tablet formulations

Table 1, below, summarizes the composition of various S- (+) - ibuprofen tablet formulations prepared in connection with the present invention. The final tablet formulations were prepared as follows:

a) the constituents listed under "Component I" in the table were thoroughly mixed; b) an aqueous solution of "Component II" (binder) was added to the mixture, and the resulting product was then granulated and sieved (sieve aperture size 1.6 mm) ; c) the sieved granulate was dried; d) the dried, sieved granulate was thoroughly mixed with the constituents listed under "Component III" in the table; e) the resulting mixture was sieved (sieve aperture size 1.0 mm) .

The formulations were pressed into tablet cores (i.e. uncoated tablets; referred to generally in the following simply as "tablets") using a conventional tablet press (vide supra) .

The various formulations were assessed with respect to their tabletting characteristics on the basis of the following tests:

Tablet punch adherence and flake formation: This was assessed visually by inspection of the punches and dies. No material should adhere to the punches, and the tablet surface should be smooth; furthermore, no material should adhere to the die table or the open feed frame, and no flakes should be visible in the granulate in the open feed frame.

Uniformity of mass (uniformity of tablet weight) : 20 tablets prepared from a given formulation were weighed individually. Their average weight should be equal to the theoretical value ± 1%. S_rel for the tablets should be 2.5% at most [S_rel being defined as: {coefficient of variation(20 tablets)} x 100/{average tablet weight}] .

Flow properties: These were assessed partly on the basis of uniformity of tablet weight (vide supra) and partly visually; thus, the granulate should not flow discontinuously from the hopper, and the granulate should not be so voluminous that the open feed frame becomes overfilled.

Tablet hardness: The hardness of each of 10 tablets prepared from a given formulation was measured. The hardness for all tablets should lie between 4.5 and 8.0 kg.

Disintegration time: This was measured according to Ph. Eur., 2nd Ed., V.5.1.1, using the apparatus described in Ph. Eur., 2nd Ed., V.5.1.1 without discs. The disintegration time, i.e. the time elapsing between introduction of a tablet into the disintegration medium (water) and passage of all material through the sieve, is noted for each of 6 tablets prepared from a given formulation. The disintegration time for each tablet should not exceed 5 min, although a disintegration time of between 20 seconds and 2 minutes was preferred in the present case.

Dissolution time: This was measured in accordance with the method specified for R,S-ibuprofen in US Pharmacopoiea, using the paddle apparatus according to Ph. Eur., 2nd Ed., V.5.4. One tablet is introduced into 900 ml of phosphate buffer (pH 6.0) containing 0.05% Tween™ 20 as surfactant, with a measurement temperature of 37 + 0.5°C and a rotation rate of 50 revolutions per minute. Aliquots (2.5 ml) are withdrawn 5, 10, 20, 30 and 60 minutes from start and are filtered through a 0.45 μm Millipore™ filter. The concentration of liberated S- (+) -ibuprofen in each filtrate is determined spectrophotometrically by comparing the measured absorbance at 265.5 nm with that of a standard solution of S- (+) - ibuprofen. The tabulated results are the mean of six such determinations.

The overall assessments on the basis of the above tests (indicated in Table 1, below) are given according to the following scale:

unacceptable (-) poor (+) acceptable + good ++ very good

Table 1

Constituents mg of constituent in formulation

Formulation No.

1 2 3 4

Component I

S- (+) -Ibuprofen 150 150 150 150

Potato starch 40 40 17.5 17.5

Lactose 0 20 20 20

Microcrystalline cellulose 0 0 20 20

Croscarmellose sodium 0 0 0 0

Component II

Polyvinylpyrrolidone

Component III

Microcrystalline cellulose 76 76 0 0

Magnesium stearate 4 4 4 2

Talc 5 5 5 5

Silica 4 4 2 2

Croscarmellose sodium 4 2 1 1.7

Total tablet weight: 283 301 220.2 224.2 Assessment of tabletting properties: Table 1 (continued)

Constituents mg of constituent in formulation

Formulation No.

5 6 7 8

Component I

S- (+) -Ibuprofen 150 150 150 150 Potato starch 17.5 17.5 17.5 17.5

Lactose 0 20 20 20

Microcrystalline cellulose 20 20 20 20

Croscarmellose sodium 0

Component II

Polyvinylpyrrolidone 6

Component III

Microcrystalline cellulose 26 51 26 50

Magnesium stearate 2 2 2 2

Talc 5 5 5 5

Silica 2 2 2 2

Croscarmellose sodium 1.7 1.7 1.7 1.7

Total tablet weight: 230.2 275.2 253.2 277.2

Assessment of tabletting properties: - - (-) (-) Table 1 (continued)

Constituents mg of constituent in formulation

Formulation No. 9 10 11 12

Component I

S- (+) -Ibuprofen 150 150 150 150

Potato starch 17.5 17.5 17.5 17.5

Lactose 20 20 20 20

Microcrystalline cellulose 20 20 20 20

Croscarmellose sodium 0 0 0 0

Component II

Polyvinylpyrrolidone 12 18 24

Component III

Microcrystalline cellulose 76 26 26 26

Magnesium stearate 2 2 2 2

Talc 5 5 5 5

Silica 4 2 2 2

Croscarmellose sodium 1.7 1.7 1.7 1.7

Total tablet weight: 305.2 256 . 2 262 . 2 268 . 2

Assessment of tabletting properties: (-) ( - ) Table 1 (continued)

Constituents mg of constituent in formulation

Formulation No. 13 14 15 16

Component I

S- (+) -Ibuprofen 150 150 150 150

Potato starch 17.5 17.5 17.5 17.5

Lactose 20 20 20 20

Microcrystalline cellulose 20 20 20 20

Croscarmellose sodium 0 0 0 0

Component II

Gelatin 3 3 3 3

Component III

Microcrystalline cellulose 0 76 76 76

Magnesium stearate 4 0 0 3

Talc 5 0 3 0

Silica 2 0 0 0

Croscarmellose sodium 1.7 1.7 1.7 1.7

Total tablet weight: 223.2 288 . 2 291 . 2 291 . 2 Assessment of tabletting properties: (+) ( + ) Table 1 (continued)

Constituents mg of constituent in formulation

Formulation No. 17 18 19 20

Component I

S- (+) -Ibuprofen 150 150 150 150

Potato starch 17.5 17.5 17.5 17.5

Lactose 20 20 20 20

Microcrystalline cellulose 20 20 20 20

Croscarmellose sodium 0 0 1.5 3

Component II

Gelatin 3 3 3 3

Component III

Microcrystalline cellulose 76 76 76 76

Magnesium stearate 0 0 0 0

Talc 0 0 0 0

Silica 1 0.25 0.25 0.25

Croscarmellose sodium 1.7 1.7 1.7 3

Total tablet weight: 289.2 288.45 289.95 292.75 Assessment of tabletting properties: (+) ++ Table 1 (continued)

Constituents mg of constituent in formulation

Formulation No. 21 22

Component I

S- (+) -Ibuprofen 150 150

Potato starch 21 26

Lactose 25 30

Microcrystalline cellulose 25 30

Croscarmellose sodium 0

Component II

Gelatin 4

Component III

Microcrystalline cellulose 90 100

Magnesium stearate 0 0

Talc 0 0

Silica 0.30 0.38

Croscarmellose sodium 2.0 2.5

Total tablet weight: 317.3 343.88 Assessment of tabletting properties: (+) ++ As is apparent from the results shown in Table 1, all of the formulations containing polyvinylpyrrolidone (water-soluble) exhibited "unacceptable" or "poor" tabletting properties. It is believed that this is a result of the binding capacity being too low to give technically acceptable tablets and/or - as mentioned earlier, and notably in the case of higher levels of polyvinylpyrrolidone - a result of depression of the melting point of S- (+) -ibuprofen (which, as discussed in the introductory part of the present specification, in itself is rather low) owing to the formation of a eutectic mixture of polyvinylpyrrolidone and S- (+) -ibuprofen.

In contrast, ten of the eleven gelatin-containing formula¬ tions (formulations Nos. 13-22 in Table 1) exhibited tab¬ letting properties ranging from "acceptable" to "very good". Thus, gelatin - a naturally occurring, common substance whose safety, physiological compatibility and general pharmaceutical suitability are very well established, and which is, a priori, generally to be preferred to polyvinylpyrrolidone - is clearly a very suitable substance for use in formulations according to the present invention.

On the basis of the results with respect to tabletting properties, two of the formulations, viz. Nos. 20 and 22

[both of which exhibited very good overall tabletting pro¬ perties (cf. Table 1) ] , were selected for further study: Tablets prepared from these two formulations were examined with respect to dissolution properties after storage at 49°C

(i.e. ca. 2-3°C below the melting point for S- (+) -ibuprofen) for 24 hours, and at 40°C for 1 month, respectively.

The results are summarized in Table 2, below, in which the percentage of the original content of S- (+) -ibuprofen in the tablets which is released (dissolved) within a period of 10 minutes (mean of six determinations as described above for determination of dissolution time) is shown as a function of the conditions of storage of the tablets in question. The decrease in the released amount (as a relative percentage) relative to the amount released for freshly prepared tablets is also shown.

Table 2

Tabletted % ibuprofen released within 10 minutes formulation

Fresh Stored 49°C/24 h Stored 40°C/1 month tablet (rel. % decrease) (rel. % decrease)

20 96 70 (27) 92 (4) 22 87 71 (12) 84 (3)

It is apparent from a consideration of the data presented in Tables 1 and 2 that tablets prepared from formulation No. 20 constitute a very good compromise with regard to tablet size (tablet weight), release of the active agent [i.e. S- (+) - ibuprofen] , minimal content of tabletting substances other than the active agent itself, and stability/robustness during storage (including storage at relatively high temperatures) .

In the following Tables 3-7 preliminary results are reported with regard to the behaviour of coated tablets of formulation Nos. 18 and 20, respectively; these preliminary results indicate that formulation No. 18 as well as formulation No. 20 will be a formulation of choice for the preparation of satisfactorily coated tablets.

Tablets prepared from formulation No. 18 [which has a low content of silica and croscarmellose sodium but which exhibits good overall tabletting properties (cf. Table 1)] were coated with a pharmaceutically acceptable, non-enteric film coating of hydroxypropyl-methylcellulose/propylene glycol prepared by a standard procedure using a film coating composition consisting of hydroxypropylmethyl-cellulose E15 (2.5 g) , propylene glycol (0.5 g) and purified water (47 g) . Table 3 summarizes results obtained for the thus-coated tablets tested in the same manner as the (uncoated) tablets prepared from formulations Nos. 20 and 22 (cf. Table 2) .

Table 3

Tabletted % ibuprofen released within 10 minutes formulation

18, coated 78 45 (42; 72 (8!

Table 4 summarizes dissolution test data for thus-coated tablets which had been stored for 3 months at various temperatures. Data for freshly prepared coated tablets are included for comparison.

Table 4

Tabletted % ibuprofen released within 10 minutes formulation

Fresh After storage for 3 months at tablet

25°C 30°C 35°C 40°C

18, coated 78 78 68 63 48

Table 5 summarizes dissolution test data for thus-coated tablets which had been stored in glass containers or PVC blister packages, respectively, at 25°C for up to 24 months. Data for freshly prepared coated tablets are included for comparison. Table 5

Formulation No. 18 (coated)

Storage time ibuprofen released within at 25°C (months)

10 minutes 20 minutes

A^a B^b A B

0 76 76 93 93

6 78 78 94 94

12 78 76 96 93

24 77 76 95 94

^a storage in glass containers ^b storage in PVC blister packages

Tablets prepared from formulation No. 20 were coated with a pharmaceutically acceptable, non-enteric film coating of hydroxypropyl-methylcellulose prepared by a standard procedure using a film coating composition consisting of hydroxypropylmethyl-cellulose E5 (2.5 g) and purified water (47.5 g) . Tables 6 and 7 summarize results obtained for the thus-coated tablets which had been stored at 25°C for up to 6 months and at 40°C and 75 % relative humidity (RH) for up to 3 months, respectively. The tablets were tested in the same manner as the (uncoated) tablets prepared from formulations Nos. 20 and 22 (cf. Table 2). Data for freshly prepared coated tablets are included for comparison.

Table 6

Formulation No. 20 (coated)

Storage time ibuprofen released within at 25°C (months)

10 minutes 20 minutes

A^a B^b A B

0 88 90 99 101 3 83 90 95 100 6 85 85 96 96

storage in glass containers storage in PVC blister packages

Table 7

Formulation No. 20 (coated)

Storage % ibuprofen released within

time condition 10 minutes 20 minutes

(months) A^a B^b A B

0 25°C 91 92 102 102

3 25°C 87 90 97 99

3 40°C 85 82 98 94

3 40°C/75% RH 83 68 96 90

6 25°C 86 86 99 97

storage in glass containers storage in PVC blister packages

It is thus apparent from the results summarized in Tables 3, 4, 5, 6 and 7, above, that coated tablets prepared from for¬ mulation No. 18 as well as from formulation No. 20 are among realistic candidates for pharmaceutically satisfactory coated tablets prepared from a formulation according to the inven¬ tion. Tablets prepared from formulation Nos. 18 and 20 and stored at 25°C and 40°C, respectively, under normal humidity conditions are very stable (cf. Table 7) both when the tablets are stored in glass containers and in PVC blister packages. However, in those cases where the tablets prepared from formulation No. 20 are stored at 40°C and a relatively high relative humidity (i.e. 75%), the stability with respect to dissolution tends to decline in the case of the tablets stored in blister packages. In contrast, no such tendency has been observed when the tablets were stored in glass containers.

The following section describes the results of tests to examine whether various tabletting formulations described in the patent literature relating to R,S-ibuprofen - viz. in US 4,609,675, US 4,806,359 and US 4,904,477, all of which are discussed earlier (vide supra) - are applicable for use in the preparation of tablets containing S- (+) -ibuprofen:

US 4.609.675:

Tablets formulated in accordance with those described in column 6, lines 18-45 in this patent, but containing S- (+) - ibuprofen instead of R,S-ibuprofen, were prepared by "slug¬ ging". The tablets exhibited satisfactory hardness and disin¬ tegration behaviour, but they exhibited poor weight unifor- mity and were very prone to undergo so-called "capping".

US 4.806.359:

Tablets formulated and prepared in accordance with those described in column 6, lines 36-54 in this patent, but containing S- (+) -ibuprofen instead of R,S-ibuprofen, ex- hibited satisfactory hardness, disintegration behaviour and weight uniformity; however, the tablets were extremely prone to undergo "capping". US 4 . 904 . 477 :

Tablets formulated in accordance with those described in column 3, lines 15-25 and in column 4, lines 35-46 in this patent, but containing S- (+) -ibuprofen instead of R,S- ibuprofen, were prepared by wet granulation. These tablets exhibited poor hardness (maximum hardness attained ca. 2-3 kg) , poor weight uniformity and marked tendency to undergo "capping" .

Claims

1. A pharmaceutical particulate formulation comprising

i) 40-70% w/w of S- (+) -ibuprofen,

ii) a water-soluble pharmaceutically acceptable binder,

iii) optionally, silica in an amount not exceeding 2% w/w,

with the proviso that said formulation does not contain water-soluble polyvinylpyrrolidone.

2. A formulation according to claim 1 comprising silica, preferably colloidal silica.

3. A formulation according to claim 2, in which said silica is present in an amount in the range of 0.001-1.5 % w/w, preferably in the range of 0.005-1.0% w/w, more preferably in the range of 0.01-0.5% w/w, most preferably in the range of 0.05-0.15% w/w.

4. A formulation according to any one of the preceding claims prepared by a method involving a wet granulation procedure.

5. A formulation according to any one of the preceding claims, in which said binder is a protein, preferably a gelatin.

6. A formulation according to any one of the preceding claims, in which said binder is present in an amount in the range of 0.05-8% w/w, preferably in the range of 0.25-5% w/w, more preferably in the range of 0.5-2.0% w/w.

7. A formulation according to any one of the preceding claims further comprising at least one pharmaceutically acceptable excipient selected from the group consisting of disintegrants, fillers, wetting agents, lubricants and glidants.

8. A formulation according to any one of the preceding claims further comprising microcrystalline cellulose.

9. A formulation according to claim 8, in which said micro¬ crystalline cellulose is present in an amount of about 5-55% w/w, preferably about 15-55% w/w, more preferably about 20- 50% w/w, most preferably about 30-40% w/w.

10. A formulation according to any one of the preceding claims further comprising lactose.

11. A formulation according to any one of the preceding claims further comprising potato starch.

12. A formulation according to any one of the preceding claims further comprising croscarmellose sodium.

13. A formulation according to any one of the preceding claims comprising

i) 40-60% w/w of S- (+) -ibuprofen,

ii) 0.5-2% w/w of gelatin,

iii) 0.05-0.5% w/w of colloidal silica,

iv) 30-35% w/w of microcrystalline cellulose,

v) 4-7% w/w of potato starch,

vi) 5-8% w/w of lactose, and

vii) 0.25-3% w/w of croscarmellose sodium.

14. A formulation according to any one of the preceding claims comprising

i) 50-53% w/w of S- (+) -ibuprofen,

ii) 0.9-1.1% w/w of gelatin,

iii) 0.08-0.09% w/w of colloidal silica,

iv) 32-34% w/w of microcrystalline cellulose,

v) 5.8-6.5% w/w of potato starch,

vi) 6.5-7.0% w/w of lactose, and

vii) 0.5-2.5% w/w of croscarmellose sodium.

15. A formulation according to any one of the preceding claims comprising

i) about 51% w/w of S- (+) -ibuprofen,

ii) about 1.0% w/w of gelatin,

iii) about 0.085% w/w of colloidal silica,

iv) about 32.8% w/w of microcrystalline cellulose,

v) about 6.0% w/w of potato starch,

vi) about 6.8% w/w of lactose, and

vii) about 2.0% w/w of croscarmellose sodium.

16. A solid dosage form comprising a formulation according to any one of the preceding claims.

17. A solid dosage form according to claim 16 in unit dosage form.

18. A unit dosage form according to claim 17 in the form of tablets .

19. A unit dosage form according to claim 17 or 18 which is coated with a film coating, a sugar coating, an enteric coating or a controlled release coating.

20. A unit dosage form according to claim 18 comprising

i) 40-60% w/w of S- (+) -ibuprofen,

ii) 0.5-2% w/w of gelatin,

iii) 0.05-0.5% w/w of colloidal silica,

iv) 30-35% w/w of microcrystalline cellulose,

v) 4-7% w/w of potato starch,

vi) 5-8% w/w of lactose, and

vii) 0.25-3% w/w of croscarmellose sodium.

21. A unit dosage form according to claim 18 comprising

i) 50-53% w/w of S- (+) -ibuprofen,

ii) 0.9-1.1% w/w of gelatin,

iii) 0.08-0.09% w/w of colloidal silica,

iv) 32-34% w/w of microcrystalline cellulose,

v) 5.8-6.5% w/w of potato starch, vi) 6.5-7.0% w/w of lactose, and

vii) 0.5-2.5% w/w of croscarmellose sodium.

22. A unit dosage form according to claim 18 comprising

i) about 51% w/w of S- (+) -ibuprofen,

ii) about 1.0% w/w of gelatin,

iii) about 0.085% w/w of colloidal silica,

iv) about 32.8% w/w of microcrystalline cellulose,

v) about 6.0% w/w of potato starch,

vi) about 6.8% w/w of lactose, and

vii) about 2.0% w/w of croscarmellose sodium.

23. A unit dosage form according to any one of claims 20-22, further coated with a film coating, a sugar coating, an enteric coating or a controlled release coating.

24. A process for preparing a pharmaceutical particulate formulation according to claim 1, the process comprising the steps of

i) adding an aqueous solution of said binder to S- (+) - ibuprofen, said S- (+) -ibuprofen optionally being in admixture with one or more pharmaceutically acceptable excipients,

ii) forcibly sieving the resulting moist mixture,

iii) drying the sieved moist mixture to obtain a . granulate, iv) sieving the dried granulate, and, optionally,

v) mixing the sieved granulate with silica and/or one or more pharmaceutically acceptable excipients.

25. A process according to claim 24 comprising step v) and further comprising the step of

vi) forming the resulting mixture from step v) into a pharmaceutical unit dosage form.