WO2002094223A2

WO2002094223A2 - Formulation containing halofantrine hydrochloride

Info

Publication number: WO2002094223A2
Application number: PCT/EP2002/005404
Authority: WO
Inventors: David Robert Dumpleton; Simon Joseph Holland; Graham Stanley Leonard
Original assignee: Smithkline Beecham P.L.C.
Priority date: 2001-05-22
Filing date: 2002-05-16
Publication date: 2002-11-28
Also published as: AU2002313470A1; GB0112497D0; WO2002094223A3

Abstract

The invention relates to pharmaceutical formulation comprising the anti-malarial compound halofantrine, in finely divided particulate form, and a process for the preparation of the finely divided particles.

Description

Formulation

The present invention relates to a novel pharmaceutical formulation. More specifically, the present invention relates to a novel formulation of the compound halofantrine, which is useful in the treatment of malaria. Halofantrine is the compound of structure (I):

OH

The hydrochloride salt of the compound is currently marketed for the treatment of malaria (HALF AN TM, SmithKline Beecham pic), but the drug substance has low aqueous solubility, and suffers from poor and variable bio availability due to inconsistent levels of absorption into the bloodstream, particularly when dosed fasted. In view of this poor solubility, its use has been limited leading to a need for the development of a formulation having improved bio availability and so which is better and more consistently absorbed into the bloodstream following, in particular oral administration.

One way of addressing low aqueous solubility is the use of alternative, more powerful solvents such as DMSO. Such solvents, although suitable for pharmacology studies, are rarely suitable for general clinical use. It is well known that the rate of dissolution of a particulate drug can be inversely proportional to the particle size of the drag, i.e. the rate of solubility increases with increasing surface area. Consequently, an alternative strategy to increase the bioavailability of poorly soluble drugs is to prepare them as finely divided compositions. A number of methods for reducing drug particle size are known in the art.

Two such methods of fluid energy milling (micronising) are opposed jet (fluidised bed type) or spiral jet (pancake type). These methods are favoured because of the reduced risk of introducing unfavourable contamination into the drug from mill materials, size reduction being caused by particle-particle collisions. However, the smallest particle size achievable by either of these methods is in the range of 1 -5 microns in diameter. Dry milling methods (such as hammer milling) have also been used to reduce drug particle size and hence increase drug solubility. However, the smallest particle size obtainable is approximately 30 microns in diameter. Although these particle sizes are appropriate for tablet formation and other formulation types, the degree of division is not fine enough to significantly increase the rate of dissolution for poorly soluble drugs.

Another technique for finely dividing preparations is wet milling. Conventional wet milling techniques comprise subjecting a liquid suspension of coarse drag substance to mechanical means, such as a dispersion mill, for reducing the size of the drag substance. One example of a dispersion mill is a media mill, such as a bead mill. Wet bead milling involves preparing a suspension of unmilled coarse drug substance. This dispersion is then drawn through a mill chamber containing a motor driven paddle and a quantity of grinding beads, to produce a finely milled suspension. A screen is used to allow passage of milled product out of the chamber whilst retain the grinding media in the mill, and static In-line mixers may be used in the process line to break up milled/unmilled agglomerates.

Most wet bead milling is carried out using a re-circulation process through one mill chamber, with one bead size being used to achieve the necessary size reduction. This is an established process for paint, ink and ceramic processing where a fixed amount of energy [in Kw/hours per unit mass] is fed into the product during the wet milling process to meet a target particle size. The mills used for wet milling commonly employ toughened ceramic or stainless steel e.g. tungsten carbide to form the mill chambers and agitating paddles. Commonly used grinding media include the newly developed yttrium stabilised zirconium oxide beads, which have hardnesses approaching that of diamonds. U.S. Patent no. 5,145,684 discloses a wet milling procedure to produce particles of a crystalline drug substance having a surface modifier adsorbed on the surface in an amount sufficient to maintain an effective average particle size (D95 - D99) of less than about 400 nm. This particulate composition as a stable suspension is said to provide improved bioavailability for poorly water soluble compounds. However, the process itself is very long, often exceeding 24 hours, and can lead to grinding media contamination levels exceeding lOppm in the final drug product.

Such contamination of the product by the grinding media and mill chambers is a problem commonly encountered with wet milling. In large scale batches (>10Kg), to achieve a particle size of less than 1 micron, grinding media contamination levels (zirconium and yttrium, plus the elements that form stainless steel e.g. iron, vanadium, etc.) can increase beyond 250ppm. Such levels of contamination are clearly unacceptable in the preparation of pharmaceuticals. One way of avoiding this problem is to use polystyrene based grinding beads. However, this has the disadvantage that process times for large batches (i.e. >20Kg) can be several days. An alternative approach has been to coat milling surfaces of the wet bead mill with polyurethane (Netzsch Feimnahltechnik GmbH). However, mill components coated with polyurethane have been found in practice to have a short life span, being easily damaged by the grinding media used in the wet milling process.

It is therefore an object of the present invention to provide a wet milling process suitable for preparing finely divided pharmaceutical compositions, in which contamination of the product is avoided without compromising process speed.

It has surprisingly been found that the above objective can be achieved by a wet milling procedure using a mill in which at least some of the milling surfaces are made of polyamide (nylon).

Accordingly, in first aspect the present invention provides a process for preparing a finely divided preparation of halofantrine comprising wet milling a liquid suspension of the drug substance in a dispersion mill; said mill having at least one mill chamber and said mill chamber comprising a chamber, agitation means and a quantity of grinding media; wherein said chamber(s) and/or said agitation means comprise nylon.

The process of the present invention uses a wet milling step carried out in a dispersion mill in order to produce a finely divided particulate suspension of halofantrine. The present invention may be put into practice using a conventional wet milling technique, such as those described in Lachman et al., The Theory and Practice of

Industrial Pharmacy, Chapter 2, "Milling" p.45 (1986). The liquid suspension of the drug substance for use in the wet milling is typically a suspension of the coarse drug substance in a liquid medium. By "suspension" is meant that the drug substance is essentially insoluble in the liquid medium. Suitably an aqueous medium can be used. The coarse drag substance may be obtained commercially or prepared by techniques known in the art. Using the process of the present invention the average particle size of the coarse drug preparation may be up to 1mm in diameter. This advantageously avoids the need to pre-process the drug substance. To assist in further processing, that is preparation of pharmaceutical formulations for therapeutic use, such as tablets, injectable dispersions, etc., the wet milling of halofantrine preferably takes place in an aqueous medium including one or more excipients such as a soluble carrier suitable for spray drying, a surfactant to maintain the particles in suspension, and an anti-agglomeration agent effective after administration of a pharmaceutical formulation to a patient. Suitable excipients for spray-drying include freely water soluble carriers such as sorbitol and polyvinylpyrrolidone. Preferably, hydroxypropyl methyl cellulose (HPMC) is used as a stabilising agent

In the aqueous medium to be subjected to the milling, the halofantrine may be present from about 10 to about 40% w/w. At 40% w/w and above there may be difficulties in mamtaining a suspension of the halofantrine during milling. In practice, 30% w/w provides an effective compromise between the desire for a high throughput and short milling times.

The amount of the soluble carrier may vary from about 4 to about 15% w/w of the composition to be milled. Preferably the amount of the soluble carrier does not exceed 50% by weight of the amount of halofantrine to be processed. For a compound loading of about 30% w/w, an amount of soluble carrier from about 5 to 10% has been found to be effective and an amount of about 10% w/w is preferred.

The amount of the anti-agglomeration agent is typically from about 1% w/w to about 2% w/w of the aqueous medium. An effective concentration of agglomeration agent such as HPMC within a milled suspension containing 30% of halofantrine was found to be 1.05%. The particles of the halofantrine are preferably present as a monomodal distribution, typically with no more than 50% of the particles having a volume diameter of 500 nm or below, and no less than 90% of the particles having a volume diameter of 2000 nm or below as determined by refractive index corrected laser diffraction size analysis

In a preferred embodiment of the invention, the median volume diameter is in the range of 400 to 2000 nm, especially 400 to 600 nm. In this median range, effective compositions are obtained when 10% of particles have a volume diameter of 300 nm or below and 90% of particles have a volume diameter of 1400 nm or below. Using the milling beads and aqueous carrier system described above, a composition having the preferred particle size distribution may be obtained surprisingly quickly, for example after milling for about 30 minutes on a small scale mill using product recirculation. Increasing the milling time, for example to about 1 hour, enables the largest particles to be reduced so that at least 90% of particles have a volume diameter of less than 2000 nm. However, the effect on the median value is marginal so longer milling times are not cost effective. Similarly, for large scale processing, batch sizes of up to 200Kg for a compound loading of about 30% w/w, can be processed surprisingly quickly, with the preferred particle size distribution obtained after one pass of product through a series of bead mills where the total residence time of the product is less than 15 minutes and the whole batch is milled "within a 70 minute period.

The aqueous dispersion obtained from the milling process may be used directly as a therapeutic agent if prepared under conditions of appropriate hygiene using water and other components which meet Ph Eur standards, compositions can be obtained. However, for the preparation of formulations for use in human therapy, it is preferred that the aqueous dispersion is converted to a dried powder. This is carried out most suitably by spray drying, typically collecting the product from the dryer using a cyclone separator. By including the excipients mentioned above in the aqueous medium for milling, a powder composition containing the particulate compounds of Formula I and Formula II is obtainable as a composition which has good flowability and is suitable for incorporation into a tablet formulation or a powder formulation for capsules.

Dispersion mills suitable for use in the present invention include ball mills, attritor mills, vibratory mills and media mills such as sand mills and bead mills. Dispersion mills such as these are well known in the art. A dispersion mill suitable for use in the present invention would comprise at least one mill chamber unit, defining an internal chamber and having within the internal chamber means for agitating the substance to be milled and the grinding media. The dispersion mill may comprise a single mill chamber unit, or alternatively a plurality of mill chamber units. In the latter case the mill chambers could be arranged in sequence such that during milling the liquid suspension of drug substance is passed via fluid connections through one, some or all of the chambers in a sequential manner. In either case the drug substance may be processed through the dispersion mill in a single pass or by re-circulating the drag substance through the mill a desired number of times i.e. a multipass process. A single pass process is preferred. In the case of media mills the agitation may be achieved by paddles, pins, discs etc. moveably mounted within the mill chamber, for example on a rotating shaft driven by an external motor. The grinding media may be a medium such as sand or beads, but for the preparation of a finely milled drug substance beads are recommended. To achieve the advantages of the present invention it is envisaged that at least the surfaces of the chamber and/or the surfaces of the agitation means which make contact with the drug substance and the grinding media during the milling process are made of nylon. Thus, the chamber and/or agitation means may be moulded entirely of nylon, or they may be made of conventional materials with a nylon insert or coated with a complete or partial layer of nylon.

In a preferred embodiment of this aspect of the invention the chamber(s) and agitation means of the dispersion mill comprise nylon. Thus, at least the surfaces of the chambers and the surfaces of the agitation means which make contact with the drug substance and the grinding media during the milling process are made of nylon.

Preferably, a high molecular weight nylon is used in this aspect of the invention. Suitable high molecular weight nylons for use in the present invention include nylons having a weight average molecular weight of greater than about 30,000Da. Favourably, the high molecular weight nylon has a weight average molecular weight of greater than about 100,O00Da. Preferably the high molecular weight nylon will have at least one of the following characteristics:

• Coefficient of friction of 0.08 to 0.4

• Tensile strength at 23°C of 710-920 kg/cm²

• Tensile impact of 650-1100 joule/cm² _• Wear loss of 0.1 to 0.3 mg / Km under test conditions of 30 to 80 m(min).MPa Particular commercial products which have these characteristics include the high molecular weight cast nylons containing internal plasticisers such as Nylube™, Oilon™ and Natural 6™, all available from Nylacast Ltd. supra. For example, Nylube™ has the following characteristics: _♦ Wear loss of less than 0.1 mg / Km under test conditions of 30 to 80 m(rnin).MPa

• Coefficient of friction of 0.08 to 0.1

• Tensile strength at 23 °C of 710-890 kg/cm²

• Tensile impact of 650-1050 joule/cm²

The use of Nylacast's Nylube CF016™ is particularly preferred in the process of the present invention.

Preferably, the dispersion mill used in the process of the present invention is a bead mill. A suitable bead mill is the APOOlO mill from Nylacast Ltd., Leicester, UK. Bead mills manufactured by others such as Dena Systems BK Ltd., Barnsley, UK; Drais, GmbH, Mannheim, Germany or Netzsch, Selb, Germany could also be used for wet milling drug substances.

In this embodiment the agitation means suitably comprise paddles, pins or discs or any combination of these. A favoured agitation means is one or more rotating paddles. The beads may be made from polystyrene, glass, zirconium oxide stabilised with magnesia, zirconium oxide stabilised with yttrium, zirconium oxide stabilised with cerium, zirconium silicate, zirconia-alumina, stainless steel, titanium or aluminium. Particularly suitable for use in the present invention are beads made of zirconium oxide stabilised with yttrium. Beads suitable for use in this embodiment of the invention such as those listed above are available in a variety of sizes. Generally, spherical beads having mean diameter of up to about 5mm may be employed, but good results are achieved when the beads have a mean diameter of less than 2mm, preferably about 0.1 to about 1.25mm. In this aspect of the invention, preferably a mill comprising a plurality of mill chambers is used. These chambers should be in fluid connection with each other as described above. For example, a bead mill may comprise 2-10 mill chambers, the precise number of mill chambers being selected to optimise process time and depending on the size of the drug particles both in the coarse suspension of the drag substance and desired in the resulting milled preparation. Variable bead loadings and/or motor speeds are selected to optimise the milling process.

In embodiments of the invention in which the dispersion mill is a bead mill with a plurality of mill chambers, additional advantages are achieved if the average diameter of the grinding beads in a first mill chamber is less than the average diameter of the grinding beads in a second mill chamber, wherein the second mill chamber is upstream of the first mill chamber. For example, the average diameter of the grinding beads in the first mill chamber may be larger than the average diameter of the beads in the following mill chamber. In a particularly preferred embodiment, the average diameter of the beads is reduced in successive mill chambers, i.e. each mill chamber contains on average similar sized or smaller beads than the preceding mill chamber. This enables smaller particle sizes of drug substance to be achieved without an increase in the level of contamination from the grinding media or chamber.

In embodiments of the invention in which the dispersion mill is a bead mill with a plurality of mill chambers the drug substance may be circulated through all of the chambers. Alternatively, by isolating one or more of the mill chambers the number of mill chambers through which the drug substance is circulated may be reduced to one or some of the total number of mill chambers in the bead mill. Regardless of the number of mill chambers through which the drug substance is circulated, the drug substance may be passed through the bead mill just once before being further processed, or a number of times. In other words, the drug substance may be wet milled in a single pass or a multipass process. In multi-pass processes the number and/or order of mill chambers through which the drag substance is circulated may vary from cycle to cycle. Preferably, the drug substance is circulated through all of the chambers in sequence only once. This one-pass process offers the advantages of decreased processing time and minimised contact of the drug substance with the grinding beads and the chamber surfaces, thereby reducing contamination.

The process of the present invention may comprise the further step of drying the drag substance. By "drying" is meant the removal of any water or other liquid vehicle used during the process to keep the halofantrine in liquid suspension or solution. This drying step may be any process for drying known in the art, including freeze drying, spray granulation or spray drying. Of these methods spray drying is particularly preferred. All of these techniques are well known in the art. Spray drying/fluid bed granulation of milled compositions is carried out most suitably using a spray dryer such as a Mobile Minor Spray Dryer [Niro, Denmark], or a fluid bed drier, such as those manufactured by Glatt, Germany.

In second aspect the present invention provides a finely divided preparation halofantrine obtainable by the process according to the first aspect of the invention. In this aspect of the invention the effective average particle size (D95 - D99) of the preparation typically is in the range of 1000 nm to about 2300 nm. Frequently the effective average particle size of the preparation is in the range of 1000 to 1600 nm. The particle size distributions of the suspension formulations may be determined by a number of analytical techniques such as laser diffraction or photon correlation spectroscopy. For example, a Malvem laser diffraction unit, Master Sizer S Model S4700, from Malvern Instruments Ltd., Malvem, England may be employed to characterise finely divided suspensions. Any other particle size technique with sufficient sensitivity and resolution for nanoparticulates can be used. In this aspect of the invention the level of grinding media contamination in the drag preparation is typically <20 ppm, preferably <10ppm, more preferably <5ppm. In third aspect the present invention provides a pharmaceutical composition comprising a finely divided preparation of halofantrine prepared according to the process of the invention. Compositions are prepared by admixture and, thus, they are suitably adapted for oral or parenteral administration. The compositions may be in the form of tablets, capsules, reconstitutable powders or suppositories. Orally administerable compositions are preferred.

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, flavourings, and wetting agents. The tablets may be coated according to techniques well known in the art.

The solid oral compositions may be prepared by conventional methods of blending, filling, tableting, or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, well known in the art.

The compositions of the invention are preferably adapted for oral administration. The compositions are preferably presented as a unit dose. Such a composition is taken preferably from 1 to 2 times daily. The preferred unit dosage forms include tablets or capsules. The compositions of this invention may be formulated by conventional methods of admixture such as blending, filling and compressing. Suitable pharmaceutically acceptable carriers for use in this invention include diluents, fillers, binders and disintegrants. It is of particular note that the conventional marketed formulations of halofantrine comprise 250mg per unit dose to be taken six times-a day. It is anticipated that the formulation of the present invention will allow the preparation of unit dosages of 100-150mg per dose, which will have the same therapeutic effect as the current 250mg dose.

For a better understanding of the present invention and to illustrate how the same may be put into effect, reference will now be made, by way of example, to the accompanying drawings, in which:

Figure 1 is a dispersion mill which may be used in accordance with a preferred embodiment of the present invention.

Figure 2 is an alternative mill arrangement. With reference to Figure 1, a mill in accordance with the present invention comprises two mill chambers (1, 2) each having a paddle (3) driven by a motor (5). The chambers (1, 2) and paddles (3, 4) are moulded from Nylube CF016. The first chamber is in fluid connection with a reservoir (7) and the second chamber (2) via pipes (9, 11). Each pipe (9, 11) is fitted with an-in line mixer (13, 15). The pipe connecting the reservoir and the first chamber (9) is also fitted with suitable pump such as an air pump (16) which is powerful enough to pump liquid medium around the whole mill. The reservoir contains a mixing device (17), which in use maintains a liquid suspension of the coarse drug substance (18). Each mill chamber (1, 2) contains a quantity of yttrium stabilised zirconium oxide beads (not shown) which are retained by screens (19, 21). An exit pipe (23) links the second mill chamber (2) to a recirculation pipe (24) connected to the reservoir (7). The recirculation pipe (24) contains a tap (25). A collection reservoir (27) is provided to collect the nano-milled drug suspension (29).

In use, the reservoir (7) is charged with coarse drug substance in a liquid medium (18) and maintained in suspension by the mixing device (17). The suspension of the coarse drag substance is pumped by the air pump (16) along the pipe (9) through the first in-line mixer (13), which removes agglomerates from the suspension. The superfine dispersion then enters the first mill chamber (1). In the first mill chamber the combined action of the paddle (3) as it is driven by the motor (5) and the beads (not shown) grinds the coarse drag suspension for a pre-set duration which is controlled by the operation of the pump (16). This partly milled dispersion is then pumped through a further in-line mixer (15) and the second mill chamber (2) before exiting the second mill chamber through exit pipe (23). This nano-milled suspension of drug substance (29) may then be either recirculated back into the first reservoir (7) via the recirculation pipe (24) or, if the tap (25) is opened, drained into the collection reservoir (27).

In an alternative mill arrangement, an equal number of mill chambers (31) and air pumps (16) are arranged in series (see Figure 2).

The following examples are illustrative of the present invention. These examples are not intended to limit the scope of this invention as defined hereinabove and as claimed hereinbelow. Example 1: Preparation of Nanoparticles

A lKg batch of an aqueous suspension containing 30% w/w of 3-dibutylamino-l-(l,3- dichloro-6-triflouromethyl-9-phenanthryl)-propan-l-ol hydrochloride was passed through a Dena DM- 100 bead mill. The single 100ml chamber fabricated from Nylacast Nylube was used in a recirculation configuration, with the chamber containing 85% by volume of 0.4mm diameter yttrium stabilised zirconium oxide beads (from Tosoh, Japan). The batch was processed in ten 10ml sublots for 15 minutes. The yield exceeded 85% and the finely milled suspension was subsequently spray dried.

Grinding media contamination levels in the spray dried powder were < 3ppm Zirconium (Zr) and < lppm Yttrium (Y).

The unprocessed particle size of the drug was approximately 1mm, and the product had a median particle size of 0.42 microns as measured by refractive index corrected laser diffraction size analysis

Example 2: Biological data

Two oral absorption studies comparing the nanoparticulate formulation of halofantrine and the commercial Halfan tablet have been carried out in beagle dogs.

Study 1

The first study was conducted as a four-way crossover in four fasted male beagle dogs. The four treatments were (i) IV administration of halofantrine free base (2 mg/kg) administered as a lipid emulsion, (ii) oral actaiinistration of nanoparticulate halofantrine hydrochloride administered as 2 x 50 mg tablets, (iii) oral administration of nanoparticulate halofantrine hydrochloride administered as 2 x 50 mg capsules, and (iv) oral administration of a soft gel capsule containing an aqueous suspension of 100 mg nanoparticulate halofantrine hydrochloride. All three formulations employed the composition described in Example 1

The pharmacokinetic data are summarised in Table 1 Table 1: Pharmacokinetic data from Absolute Bioavailability Assessment of Three Nanoparticle Formulations of Halofantrine Hydrochloride (HfHCl) in Fasted Male Beagle Dogs beagle study

AUC = area under the cruve

* Previous study: Humberstone, A.J., Porter, C.J.H. and Charman, W.N., J. Pharm. Sci, 85, 525-529, 1996.

The data in table 1 clearly demonstrate the improved oral absorption of the new nanoparticulate tablet, with an approximately 2 1/2 fold increase over the existing commercial formulation. In addition the in vivo variability is reduced as demonstrated by the reported error bars in the absolute bioavailability data

Study 2

The second study was conducted as a four-way crossover in four male beagle dogs, with the treatments consisting of (i) 1 x 250 mg Hf.HCl (Halfan^®) tablet to fasted dogs; (ii) 1 x 250 mg HfHCl (Halfan^®) tablet to fed dogs; (iii) 100 mg nanoparticulate Hf.HCl (2 x 50 mg tablets) to fasted dogs, and (iv) 100 mg nanoparticulate HfHCl (2 x 50 mg tablets) to fed dogs. The pharmacokinetic data are summarised in Table 2 Table 2 bioavailability Assessment of a Novel Nanoparticle Tablet Formulation of Halofantrine Hydrochloride (Hf.HCl) and Halfan^® in Fed and Fasted Beagles

The data in table 2 clearly demonstrate a reduced inter-subject variability and a diminished food effect for the nanoparticle tablet formulation compared to Halfan^®. They also show that in the fasted state the nanoparticle formulation has a greater than 2 fold absorption than the conventional Halfan^® tablet

Claims

1. A pharmaceutical composition halofantrine hydrochloride in particulate form, said composition having a particle size distribution such that the median value of the volume mean diameter is within the range of from 400 to 2000 nm:

2. A composition according to claim 1 in which the particles are present as a monomodal distribution.

3. A composition according to claim 2 in which no more than 10% of the particles having a volume diameter of 500 nm or below, and no less than 90% of the particles having a volume diameter of 2000 nm or below.

4. A composition according to any one of claims 1 to 3 in which the median volume diameter is in the range of 400 to 600 nm.

5. A composition according to claim 4 in which 10% of particles have a volume diameter of 300 nm or below and 90% of particles have a volume diameter of 1400 nm or below.

6. A composition according to any one of claims 1 to 5 including an anti-agglomeration agent effective after administration of a pharmaceutical formulation to a patient.

7. A composition according to claim 6 in which the anti-agglomeration agent is hydroxypropyl methyl cellulose.

8. A process for preparing a finely divided preparation of a halofantrine comprising wet milling a liquid suspension of the drag substance in a dispersion mill; said mill having at least one mill chamber and said mill chamber comprising a chamber, agitation means and a quantity of grinding media; wherein said chamber(s) and/or said agitation means comprise polyamide (nylon).

9. The process as claimed in claim 2 wherein the high molecular weight nylon is Nylube™, Oilon™ or Natural 6™ or Nyloil-FG (Cast Nylons, USA) or any suitable source of nylon 6, having a wear properties such that the loss is less than 0.1 mg / Km under test conditions of 30 to 80 m(min).MPa

10. The process as claimed in claim 8 or claim 9 wherein the nylon is high molecular weight nylon.

11. The process according to claim 10 wherein the high molecular weight nylon has a weight average molecular weight of at least around 30,000Da.

12. The process according to claim 10 or claim 11 wherein the high molecular weight nylon has a weight average molecular weight of at least around 100,000Da

13. The process according to any one of claims 10 to 12 wherein the high molecular weight nylon is Nylube™, Oilon™ or Natural 6™.

14. The process according to any one of claims 10 to 13 wherein the high molecular weight nylon is Nylube CF016™.

15. The process according to any one of claims 8 to 14 wherein the dispersion mill is a bead mill and the grinding media comprise grinding beads.

16. The process according to claim 15 wherein the grinding beads are made of polystyrene, glass, zirconium oxide stabilised with magnesia, zirconium oxide stabilised with yttrium, zirconium oxide stabilised with cerium, zirconium silicate, zirconia- alumina, stainless steel, titanium or aluminium.

17. The process according to claim 15 or claim 16 wherein the bead mill comprises a plurality of mill chambers.

18. The process according to claim 17 wherein the bead mill comprises 2-10 chambers.

19. The process according to claim 17 or claim 18, wherein the average diameter of the grinding beads in a first mill chamber is less than the average diameter of the grinding beads in a second mill chamber, wherein the second mill chamber is upstream of the first mill chamber.

20. The process according to any one of claims 17 to 19 wherein the halofantrine is circulated once through the bead mill.

21. The process according to any one of claims 8-20 which further comprises the step of drying the halofantrine.

22. A finely divided preparation of a halofantrine obtainable by the process of any one of claims 8 to 21.

23. The finely divided preparation of claim 22 wherein the level of grinding media contamination is <20 ppm.

24. The finely divided preparation of claim 22 wherein the level of grinding media contamination is <10ppm.

25. The finely divided preparation of claim 22 wherein the level of grinding media contamination is <5ppm.

26. A pharmaceutical composition comprising a finely divided preparation of halofantrine as claimed in any one of claims 22 to 25.

27. A pharmaceutical composition according to any one of claims 1 to 7 or 26 in unit dosage form.

28. A method of treatment and or prophylaxis of malaria anxiety comprising administering to the sufferer in need thereof an effective or prophylactic amount of a composition according to any one of claims 1 to 7.

29. The use of a composition according to any one of claims 1 to 7 for the manufacture of a medicament for the treatment and/or prophylaxis of malaria .