WO2001013889A1

WO2001013889A1 - Pharmaceutical composition comprising nabumetone

Info

Publication number: WO2001013889A1
Application number: PCT/GB2000/003312
Authority: WO
Inventors: Paul John Cummings
Original assignee: Smithkline Beecham P.L.C.
Priority date: 1999-08-25
Filing date: 2000-08-25
Publication date: 2001-03-01
Also published as: EP1207855A1; JP2003507409A; AU6854200A; GB9920148D0

Abstract

This invention relates to a novel composition of comprising nabumetone in particulate form and methods of using the composition to treat pain, osteoarthritis and rheumatoid arthritis.

Description

PHARMACEU ICAL COMPOSITION COMPRISING NABUMETONE

Field of the Invention This invention relates to a novel composition of nabumetone and to the use of this composition in the treatment of pain, osteoanhπtis and rheumatoid aπhritis.

Background of the Invention The compound 4-(6^"-methoxy-2^*-naphthyl)butan-2-one is known by the name "nabumetone" and is the subject of U.S. Patent No. 4,420.639 issued December 13. 1983. Nabumetone has the following structure:

This compound is useful as an anti-inflammatory and has been approved for treating osteoaπhritis and rheumatoid aπhritis.

It is known that pharmaceutically active compounds may be subjected to milling procedures to obtain a panicle size appropriate for tablet formation and for other formulation types. Air jet milling and fluid energy milling have been favoured because of the reduced risk from introducing contamination from mill materials. However, wet milling processes have been proposed for preparation of finely divided paπicies for pharmaceutical use. for example see U.S. Patent No. 5.145.684. This patent discloses a wet milling procedure to produce panicles of a crystalline drug substance having a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average panicle size of less than about 400 nm. This paniculate composition as a stable suspension is said to provide improved bioavailability for poorly water soluble compounds.

According to the instant invention, it has been found that nabumetone can be formulated in a novel composition that has enhanced bioavailability and faster absorption. Also, this novel formulation can be used not only in the treatment of osteoaπhritis and rheumatoid aπhritis. but also in the treatment of pain.

Summary of the Invention The present invention is based on the finding that nabumetone has enhanced bioavailability in ceπain compositions of controlled particle size. The present invention provides a novel composition comprising nabumetone in paniculate form, said composition having a particle size distribution or nabumetone such that the median particle size is in the range of about 10 micrometers to about 0 55 micrometers

The present invention also provides a pharmaceutical composition comprising nabumetone wherein the active metabolite 6-MNA appears in plasma at about 20% of Cmax within 0 5 hours after administration, at about 50% of Cmax within 1 hour after administration, at about 80% of Cmax within 2 hours after administration and at about 90% of Cmax within 3 hours after administration.

Additionally, the present invention provides a pharmaceutical composition comprising nabumetone wherein the dissolution rate for nabumetone is at about 100% ten minutes after administration

Furthermore, the present invention provides a pharmaceutical composition comprising nabumetone wherein the active metabolite 6-MNA provides a single dose Tmax which is significantly shorter, preferably by at least 2 hours and more preferably by at least 4 hours, and a Cmax which is significantly higher, preferably by at least 40% and more preferably by at least 70%. than tnat for α comparable dosage strength of commercial nabumetone

This invention also prov ides for the use of this novel composition in the treatment of pain, osteoarthπtis and rheumatoid arthritis

Descπption of the Invention

According to the present invention, compositions compnsing nabumetone are provided with nabumetone in particulate form The compositions are prepared using a process that involves a wet milling step in order to produce a particle size distribution of nabumetone wherein the median particle size is in the range of about 10 micrometers to about 0 55 micrometers The paniculate suspension, thus produced, is spray απed using a spray dryer or granulated using a fluid bed granulator The paniculate composition may then be formulated in the form of tablets, capsules, reconstitutable powders, semiso d products or suppositoπes, or used directly in liquid form as an oral suspension or spray for local or buccal administration Orally administrate formulations are preferred. To assist in further processing, that is the preparation of pharmaceutical formulations for therapeutic use, such as capsules and tablets, the wet milling of nabumetone takes place in an aqueous medium containing one or more pharmaceutically acceptable water-soluble earners suitable for spray drying The aqueous suspension contains a wetting agent to maintain the particles in suspension duπng milling and to ensure their recovery following administration of the pharmaceutical formulation to a patient Pharmaceutically acceptable excipients most suitable for spray-drying are water soluble hydroxypropylmethyl cellulose, a binder, and mannitol. but other binders, such as polyvinylpynohdone (PVP), hydroxypropyl cellulose ( HPC , and methyl cellulose or other carbohydrates, such as sucrose, sorbitol, lactose, lactitol and xylitol and starch may also be used as a earner

In the aqueous medium to be subjected to the milling process, nabumetone may be present from about 20 to about 40% w/v The amount of the pπmarv earner (suspending agent), such as hydroxypropylmethyl cellulose (HPMC). mav vary from about 2 to about 4% w/v of the composition to be milled The amount of wetting agent mav be vaπed from about 0 1 to about 0 4% w/\ Preferably, it is present at about 0 3% w/v A suitable wetting agent is sodium lauryl sulphate

The compositions of this invention are most suitably prepared by wet milling nabumetone preferably using a bead mill, such as Nylacast Mill by Nylacast Ltd , Leicester, England Alternate milling equipment is available from Dena Systems BK and Netzsch The milling medium consists of zirconium oxide beads Specifically, the mill chambers were loaded with YZT® ceramic beads manufactured from ttπa-stabιlιzed, high puπty zircoma powder (manufactured bv Ni kato Corporation Japan) The panicle size distributions of the suspension lormuiations were determined using a Malvern laser diffraction unit. Mastersizer S Model S4700. from Malvern Instruments Ltd , Malvem. England Any other laser diffraction particle sizer with sufficient sensitivity and resolution for nanoparticulates can be used In a preferred embodiment of the invention, the median panicle size is in the range of about 10 micrometers to about 0 55 micometers Preferably, the median panicle size is about 1 8 to 0 8 micrometers

Sprav drying/fluid bed granulation of milled compositions is earned out most suitably using a spray dr er, such as a NIRO SD 63R Spray Dryer or a Yamato GA-32 Spray Dryer [Yamato Scientific Ameπca Inc . Orangeburg, NY], or a fluid bed granulator, such as Glatt fluid bed granulator According to the instant invention, a wet milling process is used to improve the bioa ailabihtv and the therapeutic efficacy of the poorly water soluble drug nabumetone A DENA Bead Mill was used to reduce the panicle size distribution of the commercially available nabumetone drug substance

Nabumetone is preferably wet milled as an aqueous dispersion However, if required, the compound may be milled in any suitable non-aqueous or organic solvent, e g an oil The wet milling of nabumetone in an aqueous medium could include one or more excipients. such as a soluble earner suitable for freeze or spray drying, a surfactant to maintain the particles in suspension, and one or more anti-agglomeration/suspending agents An especially suitable excipient for spray-drying is mannitol. but other carbohydrates, such as sorbitol and starch, may be used as soluble earner Preferably sodium lauryl sulphate is used as the wetting agent or surfactant, and cellulosic thickening agents, such as hydroxypropyl methyl cellulose or hydroxyethyl cellulose, may be used as anti-agglomeration/suspending agents After milling the formulations, the panicle size distπbution was measured using a Malvern Mastersizer S laser diffraction unit. The prefened method of reporting the particle size distπbution is to quote parameters such as D(0 I ). D(0 5 ), and D(0 9). D(0.1 ) represents the size ⁽ as equivalent volume diameter) below w hich 10% of the panicles lie. D(0 5) is the size below which 50% of the panicles he. also known as the median D(0.9) is the value below which 90% of the particles lie.

The aqueous paniculate suspension could be further formulated for use as a paediatπc/adult strength suspension However, for the preparation of formulations for use in human therapy^, it is prefened that the aqueous dispersion is converted to a dry powder. This is earned out most suitably by freeze or spray drying, collecting the product from the dryer using standard techniques. The suspensions containing mannitol are ideal for pouπng into a pre-formed blister and freeze-drymg to make a tablet. However, the prefened method of production for nabumetone is to dry the suspension to a powder by spray drying. Since nabumetone has a melting point of 80 degrees C. the spray dπed powder is produced using relatively low temperatures The spray dryer was pre-heated until the inlet temperature was at 100 degrees C. and the outlet temperature reached 35-40 degrees C. By including excipients in the aqueous medium for milling, a powder composition containing the paniculate nabumetone is obtainable as a composition which has good flowabi ty and is suitable for incorporation into capsules or tablet formulations. This result is surpπsmg since one skilled in the art would not expect that a satisfactory spray dπed product would be produced at such low temperatures from an aqueous system.

Tablets and capsules for oral administration are usually presented in a unit dose. and contain conventional excipients such as binding agents, fillers and diluents (tableting or compression aids ^), lubricants, disintegrants. colorants, flavouπngs. and wetting agents The tablets may be coated according to techniques well known in the art

The solid oral formulations may be prepared by conventional methods of blending, filling^, tableting^, and the like. Repeated blending operations may be used to distπbute the active agent throughout those compositions employing large quantities of fillers Such operations are, of course, well known in the art. Oral formulations also include conventional controlled release formulations, such as tablets or pellets, beads or granules, having a sustained release or an enteπc coating_, or otherwise modified to control the release of the active compound, for example by the inclusion of gel forming polymers or matrix forming waxes.

Advantageously, a wetting agent is included in the composition to facilitate uniform distπbution of the compound of the invention.

Thus, the present invention provides a novel composition which comprises nabumetone. The composition is adapted for oral administration. The composition is presented as a unit dose. Such a composition is taken preferably from 1 to 4 times daily. The prefened unit dosage forms include tablets or capsules. Typically, the oral dose is about 450-2250 mg. Preferably, the oral dose is 1350 mg given once daily.

Nabumetone is a pro-drug that is metabolised by the liver to form the active compound 6-methoxy-2-naphthyiacetic acid (6-MNA). To establish the effect of the dissolution rate of nabumetone in-vitro on the bioavailability of 6-MNA. non-disintegrating disks were prepared by compressing the nabumetone spray dried powder. Dissolution testing was conducted on these disks in 2% sodium lauryl sulphate maintained at 37 degrees C. Unmilled nabumetone and a blend of unmilled nabumetone containing equivalent quantities of the excipients required for the milling process were compressed and used as controls. A significant increase in the dissolution profile of the spray dried DENA milled nabumetone was observed.

A clinical trial was conducted to establish the effect of the increased dissolution rate of nabumetone observed in-vitro on the bioavailability of 6-MNA in-vivo. The trial evaluated the bioavailability of 6-MNA from a single dose of nabumetone administered in capsules containing paniculate nabumetone relative to capsules containing regular commercial material.

Comparison of PK parameters for 6-MNA for formulations containing the paniculate nabumetone material relative to the commercial nabumetone material showed an average 75% greater Cmax value and an approximately 9 hour earlier Tmax for 6-MNA for the particulate material relative to the commercial material. These data suggested that the particulate material provides a considerably faster rate of appearance of 6-MNA in plasma than the commercial material. These results most likely reflect a faster rate of absorption of nabumetone from the particulate material. However, the effect of the particulate material on the extent of appearance of 6-MNA in plasma (as assessed by AUC) was less marked.

An average 16% greater AUC for 6-MNA for the paniculate material when compared to the commercial material suggests a slightly greater extent of absorption of nabumetone from the paniculate material relative to the commercial material.

Thus, the present invention provides a pharmaceutical composition comprising nabumetone wherein the active metabolite 6-MNA appears in plasma at about 20% of

Cmax within 0.5 hours after administration, at about 50% of Cmax within 1 hour after administration, at about 80% of Cmax within 2 hours after administration and at about 90% of Cmax within 3 hours after administration.

Additionally, the present invention provides a pharmaceutical composition comprising nabumetone wherein the dissolution rate for nabumetone is at about 100% ten minutes after administration. Furthermore, the present invention provides a pharmaceutical composition compnsing nabumetone wherein the active metabolite 6-MNA provides a single dose Tmax which is significantly shorter, preferably by at least 2 hours and more preferably by at least 4 hours, and a Cmax which is significantly higher, preferably by at least 40% and more 5 preferably by at least 70%. than that for a comparable dosage strength of commercial nabumetone

No unacceptable toxicological effects are expected when nabumetone is administered in accordance with the present invention

Nabumetone is useful in the treatment of pain, osteoarthπtis and rheumatoid 10 arthπtis Also, nabumetone is useful in controlling fever, in the prevention and treatment of colon cancer and in the prevention and treatment of Alzheimer s disease In particular, the instant composition containing nabumetone in particulate form is useful in the treatment of pain

I D The following examples are illustrative of the instant inv ention These examples are not intended to limit the scope of this invention as defined hereinabove and as claimed hereinbelovv

Examples

To investigate the influence of drug loading and level of suspending agent the following formulations were prepared where the level of nabumetone loading was increased from 20- 40%w/v and the level of suspending agent (hydroxypropyimethylcellulose. (HPMO) was increase from 2-4%w/v The level of wetting agent ( sodium lauryl sulphate. (SLS)) remained constant.

Table 1 Summary of susDension formulations investigated

Suspension preparation

The HPMC and SLS were blended and the nabumetone drug substance added in equal volumes to ensure a homogeneous blend Water was added gradually to the powder bed and mixed to from a paste The gradual addition of water was continued until the mixture was pourable. The suspension was transfened to a calibrated container and made up to the appropriate volume ( 1 -2 litres).

Dena Wet Milling Milling Parameters. Chamber 1 - 360ml ! 25mm YZT® Ceramic Beads Chamber 2 - 860ml 0.4mm YZT® Ceramic Beads Pre-chamber 1 reactor: D3, Post-chamber 2 reactor: S 1 & SS Mechanical seal - 3 bar Processing regulator - 2-2.5 bar

The suspension was poured gradually into the mill reservoir. The suspension was then pumped through the D3 reactor into milling chamber 1. through a heat exchanger, into milling chamber 2. through a second heat exchanger and into the S 1 &. SS reactors before returning to the reservoir where the milling cycle was continued for 60 minutes. A sample of the milled suspension was taken from the reservoir every 10 minutes for panicle size analysis. After milling the resulting suspensions were stored at 5 degrees C Sprav drving

Mannitol (Grade fine 60) was blended with the milled suspension in a ratio of 2 parts drug to 1 part mannitol using a Heidolph mixer

The spray dryer was pre-heated (inlet temperature 100 degrees C. outlet temperature 35 degrees C. exhaust fan setting 2) The milled drug slurry was then slowly pumped througn the atomiser under -6 bar pressure and the resulting dried spheres were collected in an appropriate vessel

Particle Sizing Particle sizing of the initial nabumetone sample, the unmilled suspensions, the milled suspensions and the spray dried milled particles was earned out using a Malvern Mastersizer S (using the standard Mie theory without nabumetone refractive index conection to calculate the panicle size) where tne sample was dispersed in water

Dissolution Testing

Dissolution testing on Formula A was earned out in 900 ml, 2% SLS at 37 degrees C using USP paddle apparatus at 100 rpm The dissolution of lg powder samples and lg non- disintegrating disks was investigated Non-disintegrating disks were prepared by compressing l g powder in an IR press under 7 ton pressure for 1 minute Unmilled nabumetone and a blend of unmilled nabumetone containing equivalent quantities of the excipients required for the milling process were used as controls

In Vivo Testing

A clinical tπal was conducted on 18 healthv volunteers The trial evaluated the bioavailability of 6-MNA from a single 501mg dose of nabumetone administered as 3 x

167 mg capsules containing paniculate nabumetone relative to 3 x 167 mg capsule containing commercial material The formulations administered during the tπal are shown in Table 2 The spray dried paniculate nabumetone was filled in to a dark green hard gelatin capsule shell without further processing The components of the commercial comparator formulation of nabumetone were blended in a Matcon Buls blender rotating at

12 rpm for 15 minutes The resulting nabumetone blend was filled into dark green hard gelatin capsules

The D(0 1). D(0 50) and D(0 9) values for the clinical particulate nabumetone after a two hour milling time were 0 28*, 0 61 * and 2 02* microns, respectively (* standard Mie theory not coπected for nabumetone refractive index) The median particle size D(0 5) value quoted on the Certificate of Analysis of the commercial nabumetone used in the comparator formulation was 29* microns (* standard Mie theory not coπected for nabumetone refractive index)

Table 2 Formulations of nabumetone administered in the relative bioavailability studv

Paniculate Nabumetone capsule 1 % w/w | Nabumetone capsule ( 167 mg) % w/w ( 167 mg ) !

Nabumetone 61 9 i Nabumetone 82 0

Sodium Laurvl Sulphate 1 0 9 Sodium Starch Glvcollate i 8 7

HPMC ¹ 6 2 ¹ Sodium Laurvl Sulphate 1 0 3 Mannitol 60 i 31 0 1 Hvdroxvpropvlmethy l cellulose l 4 1

1 1 Microcrv stalline cellulose 1 4 9

Results

Summary: Figure 1 shows a significant reduction in the panicle size distribution of nabumetone w as achieved within 10 minutes of processing The coπesponding increase in the specific suπace area of the panicles is shown in Figure 2 After 10 minutes a polydisperse distπbution of particle sizes was observed (Figure 3) Further milling continued to decrease the particle size distribution of nabumetone After 60 minutes of processing througn the Dena mill, a monodisperse distribution of particle sizes was obtained At this point the median particle size was 0 45 microns (Figure 3) The level of drug loading or suspending agent present in the initial suspension did not affect the size distπbution of the nabumetone particles produced, and the milling process was very reproducible

Figure 4 shows the percentage of nabumetone released as a function or time for v arious milled/unmilled nabumetone powder blends The sprav dried Dena milled blend demonstrated the most rapid dissolution An improvement in the dissolution oi nabumetone in the presence of the hvdrophilic excipients used in the milling/drv ing process was also observed A significant increase in the dissolution profile of the spray dπed Dena milled nabumetone was observed when the powder blends were compressed into non- disintegrating disks (Figure 5) Figure 6 shows the mean plasma concentration time profiles for 6-MNA following a single oral administration of 501 mg of nabumetone as a formulation containing commercial or paniculate nabumetone to healthv volunteers These results reflect a faster rate of absorption of nabumetone and a greater bioavailability of 6- MNA from the paniculate material Data

Reduction in Volume Median Diameter D(v.0 5 ) ( microns )

• Nabumetone starting mateπai = 24.23 microns

• Table 3: Effect of milling time on the mean particle size of milled suspensions

Time (min ) D(v.0 5) microns

Formula A Formula B Formula C Formula D

0 34.42 27.21 27.92 23.67

10 0.85 0.88 0.91 0.66

20 0.61 0.65 0.63 0.53

30 0.53 0.55 0.55 0.50

40 0 49 0.5 1 0.51 0.47

50 0.46 0.47 0.48 0.45

60 0.45 0.45 0.46 0.45

• Spray dπed spheres = 5- 15 microns (estimated from ESEM micrographs )

• Spray Dried Milled Nabumetone (regenerated nabumetone particles)

Formula A = 0.48* microns Formula D = 0.50* microns ( * standard Mie theory not coπected for nabumetone refractive index )

Increase in Specific Surface Area of the Particles i sq.m/g)

• Nabumetone starting material = 1 .38 sq.m/g

• Table 4 Effect of milling time in the specific surface area of milled suspensions

• Spray Dried Milled Nabumetone ( regenerated nabumetone particles )

Formula A = 1 3 18 sq.m/g

• Formula D = 1 1 84 sq.m/g

Manufacturing Process

Four 250 kg batches of 30% w/w nabumetone suspension were wet bead milled and then spray dried in order to qualify the manufacturing process of nabumetone spray dried powder 80.1 % w/w Table 5" Nabumetone wet bead milled suspension 30.0% w/w

Suspension Preparation

The required v olume of Sterile Water for Irngation was charged to the 300 L mixing vessel. The hydroxypropyl methylcellulose was carefully added and dissolved using both the mixing vessel agitator and in-line mixer. The mannitol w as then added, followed by the sodium laury 1 sulphate, care being taken to avoid foaming Unmilled nabumetone was finally added and the batch mixed to obtain a homogenous suspension.

Table 6: Nabumetone spray dried powder 80.17c

Wet Bead Milling Process

The suspension was pumped from the mixing vessel through the single pass five chambered DENA DS 15P wet bead mill. Each chamber was filled with the required volume and size of wear resistant yttria stabilised zirconia beads. The milled suspension was collected in 50L blue plastic Bowater Mauser kegs and held overnight for spray drying.

The DENA DS 1P5 wet bead mill process parameters are listed in Table 7 below:

Table 7: Wet bead mill processing parameters

Mechanical Seal Pressure , 65 psi Cooling water flow rate 40-50 L/min The bead charge of 20 kg fills 67 % of the available chamber volume. The chamber pump pressures were set to achieve an end line product flow rate of l. l- 1.5L/mιn.

Sprav Drving Process

The milled suspension was charged to the feed vessel and pumped to the NIRO SD 6.3R spray drier. The spray dried powder was collected in stainless steel bins, transfened individually into liners and packed in Bowater Mauser kegs containing desiccant (225g 3 A molecular sieve).

The NIRO SD 6.3R spray drying parameters are listed below:

Table 8: Nabumetone spray drying parameters

Vessel Agitator Speed ! 150-200 rpm*

Rotary Atomiser Speed 21.500 rpm

Inlet Temperature 100.0 °C

Outlet Temperature . 40.0 °C . i

Gas Flow i 550-650 kg/h

* Switched OFF after approximately 3 hrs to prevent foaming.

Suspension Particle Sizing Data

Table 9 The mean (± sd) Malvern Mastersizer S particle sizing data of Nabumetone 30 % suspension taken from the end product line. ( Mean of sizing data from samples taken start, middle and end of batch)

D10 = 10% of particles with Mean particle diameter = or < size indicated D50 = 50% of particles with Mean particle diameter = or < size indicated D90 = 90% of particles with Mean particle diameter = or < size indicated End Product Line

Size Batch 1 Batch 2 1 Batch 3 Batch 4

D10 ! 0.46 (±0.05) 0.54 (±0.03) I 0.35 (±0.03) 0.39 (±0.03)

D50 1 1.18 (±0.05) 1.28 (±0.04) 1 1.09 (±0.07) Ll - 10 (±0.05)

D90 i 2.88 (±0.07) 2.98 (±0.08) ! 3.67 (±0.82) 2.87 (±0.13) When the product flow rate is maintained within the set limits of 1. 1 - 1 5 1/mιn during milling, the particle size reduction of nabumetone drug substance is consistent and reproducible. The suspension was milled consistently to produce a product where 50% of the particles have a diameter of less than 1.16 (±0.09) micrometer, and 90% of the particles have a diameter of less than 3.1 (±0.38) micrometer.

Preparation of Tablets

Composition mg/tab Nabumetone Spray Dried Powder 561.8*

Sodium Starch Glycolate 68 0

Magnesium stearate 3.0

632.8mg total

*equιvalent to 450mg nabumetone drug substance

Nabumetone spray dπed powder is screened using a 1 mm screen The sodium starch glycolate and magnesium stearate are screened through 0 5 micron screen The dry mateπals are blended in a bin blender and then compressed on a rotary tablet press

( Compπma 300)

All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth

It is to be understood that the inv ention is not limited to the embodiments illustrated hereinabove and the right is reserved to the illustrated embodiments and all modifications coming within the scope of the following claims

Claims

What is claimed is:

1. A pharmaceutical composition comprising nabumetone wherein the active metabolite 6-MNA appears in plasma at about 20% of Cmax within 0 5 hours after administration, at about 50% of Cmax within 1 hour after administration, at about 80% of Cmax w ithin 2 hours after administration and at about 90% of Cmax within 3 hours after administration

2. A pharmaceutical composition comprising nabumetone wherein the dissolution rate for nabumetone is at about 100% ten minutes after administration.

3 A pharmaceutical composition comprising nabumetone wherein the active metabolite 6-MNA provides a single dose Tmax which is shorter by at least 2 hours and a Cmax w hich is higher by at least 40% than that for a comparable αosage strength of commercial nabumetone.

4 A pharmaceutical composition according to claim 3 wherein the active metabolite 6-MNA provides a single dose Tmax which is shorter by at least 4 hours and a Cmax which is higher by at least 70% than that for a comparable dosage strength of commercial nabumetone

5. A pharmaceutical composition compnsing nabumetone in paniculate form, said composition having a panicle size distπbution such that the median value of the volume mean diameter is within the range from about 10 micrometers to about 0.55 micrometers

6. The composition according to claim 5 wherein the particle size distπbution is such that the median value of the volume diameter is within the range from 1.8 to 0 8 micrometers.

7. A method of treating pain which compπses administering to a subject in need thereof an effective amount of the composition according to any one of claims 1-6

8. A method of treating osteoarthπtis which comprises administering to a subject in need thereof an effective amount of the composition according to any one of claims 1-6.

9 A method of treating rheumatoid arthritis which comprises administeπng _to a subject in need thereof an effective amount of the composition according to any one of claims 1 -6.

10 The use of a composition according to any one of claims 1 -6 for the treatment of pain

1 1. The use of a composition according to any one of claims 1-6 for the treatment of osteoarthπtis.

12. The use of a composition according to any one of claims 1 -6 for the treatment of rheumatoid arthπtis.

13 A process for preparing nabumetone in paniculate form which compπses spray drying a suspension containing nabumetone using a spray dryer with an inlet temperature at about 100 degrees C and an outlet tempeπaure at about 40 degrees C.