AU743917B2 - Compositions comprising microparticles of water-insoluble substances - Google Patents

Description

P00011 Regulation 3.2 Revised 2/98

AUSTRALIA

Patents Act, 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT *r TO BE COMPLETED BY THE APPLICANT NAME OF APPLICANT: RESEARCH TRIANGLE PHARMACEUTICALS LTD INDU PARIKH and ULAGARAJ SELVARAJ ACTUAL INVENTORS: ADDRESS FOR SERVICE: 9* Peter Maxwell Associates Level 6 60 Pitt Street SYDNEY NSW 2000 COMPOSITIONS COMPRISING MICROPARTICLES OF WATER- INSOLUBLE SUBSTANCES INVENTION TITLE: DETAILS OF ASSOCIATED

APPLICATION(S):

Divisional of Australian Patent Application No. 719,085 (25,871/97) filed on 28 March 1997 The following statement is a full description of this invention including the best method of performing it known to me:fg -7 7, This invention relates to compositions of microparticles of waterinsoluble or poorly soluble drugs or other industrially useful insoluble compounds. The compositions of this invention include combinations of natural or synthetic phospholipids, and one or more non-ionic, anionic or cationic surfactants coated or adhered onto the surfaces of the water insolublecompound particles. The combination of phospholipids and surfactants allows the formation and stabilisation of the sub-micron and micron size compound particles via hydrophilic lipophilic and electrostatic interactions and therefore prevent these particles from aggregation or flocculation.

10 There is a critical need in the pharmaceutical and other biological based industries to formulate water-insoluble or poorly soluble substances into formulations for oral, injectable, inhalation and ophthalmic routes of delivery.

Water insoluble compounds are those having poor solubility in water, that is mg/ml at physiological pH Preferably their water solubility is <1 15 mg/ml, more preferably <0.1 mg/ml. It is desirable that the drug is stable in water as a dispersion; otherwise a lyophilised or spray-dried solid form may be desirable.

As used herein, "micro" refers to a particle having diameter of from nanometers to micrometers. Microparticles, as used herein, refer to solid particles of irregular, non-spherical or spherical shapes. Formulations containing these microparticles provide some specific advantages over the unformulated non-micronized drug particles, which include improved oral bioavalability of drugs that are poorly absorbed from GI tract, development of injectable formulations that are currently avaliable only in oral dosage form, less toxic injectable formulations that are currently prepared with organic solvents, sustained release of intramuscular injectable drugs that are currently I- III 1 I II 1 administered through daily injection or constant infusion, and preparation of inhaled, ophthalmic formulation of drugs that otherwise could not be formulated for nasal or ocular use.

Current technology for delivering insoluble drugs as described in US Patents 5,091,188; 5,091,187 and 4,725,442 focuses on either coating small drug particles with natural or synthetic phospholipids or dissolving the drug in a suitable lipophilic carrier and forming an emulsion stabilized with natural or semisynthetic phospholipids. One of the disadvantages of these .formulations is that certain drug particles in suspension tend to grow over time 10 because of the dissolution and reprecipitation phenomenon known as the S:""Oswald ripening".

According to one aspect of the invention there is provided a composition comprising solid microparticles of a water-insoluble or poorly soluble compound, a natural phospholipid and at least one non-phospholipid 15 non-ionic, anionic or cationic surfactant, said phospholipid and surfactant O adsorbed to the surfaces of said microparticles, in which the surfactant or surfactants provide volume-weighted mean particle size values of the S* water-insoluble compound at least 50% smaller than particles produced without the presence of the surfactant using the same energy input.

S 20 According to another aspect of the invention there is provided a pharmaceutical composition comprising solid microparticles of a waterinsoluble or poorly soluble compound, a natural phospholipid and at least one non-phospholipid non-ionic, anionic or cationic surfactant, as well as pharmaceutically acceptable excipient, said phospholipid and surfactant adsorbed to the surfaces of said microparticles, in which the surfactant or surfactants provide volume-weighted mean particle size values of the water-insoluble compound at least 50% smaller than particles produced without the presence of the surfactant using the same energy input.

The present invention focuses on preparing submicron size particles using a combination of surface modifier(s) with a phospholipid, and how the growth of particle size, and hence storage stability, is 1 3 controlled by adding a combination of surface modifier(s) with a phospholipid to the formulation.

The use of a surface modifier or combination of surface modifiers in addition to a phospholipid is characterized by its ability to result in volume weighted mean particle size values that are at least 50% and preferably about 50-90% smaller than what can be achieved using phospholipid alone without the use of a surfactant with the same energy input, and (ii) provide compositions resistant to io particle size growth on storage. While resistance to particle size growth on storage was an objective of this invention we were surprised to observe a significant reduction in particle size with the addition of the surfactant. In order to achieve the advantages of the present invention it is necessary that the phospholipid and the 15 surfactant both be present at the time of particle size reduction or precipitation.

Although we do not wish to be bound by any particular theory, it appears that these surface modifiers generally, that is phospholipids and one or more surfactants, adsorb to the surfaces of drug particles.

and convert lipophilic to hydrophilic surfaces with increased steric hindrance/stability, and possibly modify zeta potential of surfaces with more charge repulsion stabilization. The concentrations of surface modifiers used in the process described here are normally above their critical micelle concentrations (CMC) and hence facilitate the formation of sub-micron particles by stabilizing the particles.

Phospholipid and surface modifier(s) are adsorbed on to the surfaces of drug particles in sufficient quantity to retard drug particle growth, reduce drug average particle size from 5 to 100 A±m to submicron and micron size particles by one or combination of methods known in the art, such as sonication, homogenization, milling, microfluidization, precipitation or recrystallization or precipitation from supercritical fluid, and maintain sub-micron and micron size particles on subsequent storage as suspension or solid dosage form.

10o The concentration of phospholipid or surface modifier in the suspension or solid dosage form can be present in the range of 0.1 to preferably 0.2 to 20%, and more preferably 0.5 to The formulations prepared by this invention may be lyophilized into powders, which can be resuspended or filled into capsules or converted into granules or tablets with the addition of binders and other excipients known in the art of tablet makina.

By industrially useful insoluble or poorly soluble compounds we include biologically useful compounds, imaging agents, pharmaceutically useful compounds and in particular drugs for human and veterinary medicine. Water insoluble compounds are those having a poor solubility in water, that is less than 5 mg/ml at a physiological pH of 6.5 to 7.4, although the water solubility may be less than 1 mg/ml and even less than 0.1 mg/ml.

Examples of some preferred water-insoluble drugs include immunosuppressive and immunoactive agents, antiviral and t "Ef-I n .fl',LiZ antifungal agents, antineoplastic agents, analgesic and antiinflammatory agents, antibiotics, anti-epileptics, anesthetics.

hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, anticonvulsant agents, antagonists, neuron blocing agents, anticholinergic and cholinom ei agens antimuscarlflic and muscariijc agents, antiadrenergic and antarrhythmics, antihypertensive agents, antineoplastic agents, hormlones, and nutrients. A detailed description of these and other suitable drugs may be found in Rernington's Pharmaceutical Sciences.

I18th edition, 1990, Mack Publishing Co. Philadelphia,

PA.

The phospholipid may be any natural or synthetic phospholipid, for example phosphatidylcholine, phosphatidylethanolamime, phosphatidylseie, phosphatidylinositol, phosphatddvlglycerol.

.15 phosphatidic acid, lysophospholipids. egg, or soybean phospholipid or a combination thereof. The phospholipid may be salted or desalted.

hydrogenated or partially hydrogenated or natural semnisynthetic or synthetic.

Examples of some suitable second surface- modifiers include: natural surfactants such as casein, gelatin, tragacanth. waxes.

enteric resins, paraffin, acacia, gelatin, cholesterol esters and triglycerides, nonionic surfactants such as polyoxyethylene fatty alcohol ethers, sorbitan fatty acid esters, polyoxyethylene fatty acid esters, sorbitan esters, glycerol monostearate, polyethylene glycols.

cetyl alcohol, cetostearyl alcohol, stearyl alcohol, poloxamers.

polaxamines, methylcellutose, hydroxycellIu lose, hdroxy propvlcellulose. hydroxy propylmethylcellulose. noncrystalline 6 cellulose, Polyvinyl alcohol, PolYvinylpyroldofle, and synthetic phosphohics, anionic surfactanits such as Potassium laurate, triethanolmine stearate, sodium laurvi sulfate, aill polvoxyethylenle sulfates, sodium alginate, dioctyl sodium sulfosuccinate, negatively phospholipids (phosphatidyl glycerol, phosphatidvi inosite.

phosphatidylserine, phosphatidic acid and their salts), and negativel .y charged glycervi esters, sodium carboxvmethvicellulose, and calcium carboxvmethylcellulose, cationic surfactants such as quaternary~ ammonium compounds, benzalkonium chloride, cetltrimethylamoniur bromide, chitosans and laurldimethyeunyl~~amnoniu chloride, colloidal clays such as bentomite and veeguin. A detailed description of these surfactants may be found in Remingtqon's Pharmaceutical Sciences, and TheorY and Practice of Industrial P harmacy, Lachmnan et al. 1986.

More specifically, examples of suitable second Surface modifiers include 'one or combination of the following: polaxomers, such as Pluronjcm F68, F108 and F127, which are block copolymers of ethylene oxide and propylene oxide available from BASF, and poloxamines, such as TetronicrM 908 (T908), which is a tetrafunctional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethvlene-diaje valal from BASF, TnitonTm!v X-200, which is an alkyl aryl polvether sulfonate, available from Rohm and H-aas. Tween 20, 40, 60 and which are polyoxyethylene sorbitan fatty acid esters,.viabefo ICI Speciality Chemicals, CarbowaXTI- 3550 and 934, which are polyethylene glycols available from Union Carbide, hvdroxy propvlmethyvlcellulose, dimyristoyl phosphatidyltxlycerol sodium salt, sodium dodecylsulfate, sodium deoxycholate, and cetyltrimethylammonium bromide.

It is thought that some of the functions of the second surface 6 modifier(s) as it relates to this invention are suppressing the process of Oswald Ripening and therefore maintaining the particle size.

increasing the storage stability, minimizing sedimentation, and :decreasing the particle growth during lyophilization and reconstitution: adhere or coat firmly onto the surfaces of 10 water-insoluble drug particles and therefore modify the interfaces between the particles and the liquid in the resulting formulations: increase the interface compatibility between water-insoluble drug particles and the liquid; and possibly to orient preferentially themselves with the hydrophilic portion sticking into the aqueous 15 solution and the lipophilic portion strongly adsorbed at the water-insoluble drug particle surfaces Considerable variations as to the identities and types of phospholipid and especially the surface active agent or agents should be expected depending upon the drug or active agent selected as the surface properties of these small particles are different. The most advantageous surface active agent for the insoluble drug will be apparent following empirical tests to identify the surfactant or surfactant system/combination resulting in the requisite particle size and particle size stability on storage over time.

Various procedures can be used to produce these stable sub-micron and micron size particles including mixing the insoluble 8 substance with phospholipid and precipitating from a dissolved mixture of the substance, phospholipid and surfactant using other surfactants followed by sonication, milling, homogenization, microfluidization, and antisolvent and solvent precipitation. Mannitol and other agents may be added to adjust the final formulation to isotonicity as well as a stabilizing aid during drying.

Unless otherwise specified, all parts and percentages reported erein are weight per unit volume in which the volume in the 1o denominator represents the total volume of the system. Diameters of dimensions are given in millimeters (mm 10- 3 meters), micrometers (,um 10 meters), nanometers (nm 10- 9 meters) or Angstrom units 0.1 nm). Volumes are given in liters milliliters (mL 10- 3

L)

and microliters (gL 10 Dilutions are by volume. All 15 temperatures are reported in degrees Celsius. The compositions of the invention can comprise, consist essentially of or consist of the materials set forth and the process or method can comprise. consist essentially of or consist of the steps set forth with such materials.

The following examples further explain and illustrate the invention: Example 1 Microparticle-cyclosporine, of an immunosuppressive drug, was prepared as follows. The composition and concentration of excipients of the microparticle cyclosporine formulation are listed below: Cyclosporine 50 mg/ml Egg Phosphatidylcholine 100 mg/ml Mannitol 55 mg/ml Tween 80 10 mg/ml Distilled Water qs to 100% Total Volume 20 ml Cyclosporine with an average particle size from 5-100 um. and mannitol were purchased from Sigma, egg phosphatidylcholine was 10o produced by Pfanstiehl, Tween 80 was purchased from ICI The above components were placed in a 30 ml beaker and pre-mixed with a hand-held biohomogenizer (Honeywell DR 4200 model GP) for 1-5 min. During homogenization, dilute NaOH was 15 added to the pre-mix to adjust the pH from 3.1 to 7 0.5. The pre-mix was placed in a water jacketed vessel (50 ml capacity) through which thermostated water at 4°C was circulated to control the temperature of the formulation. The pre-mix was subjected to high shear energy of a probe sonicator (Fisher, model 550 Sonic Dismembrator) with a 0.5 inch diameter probe. Sonic pulses of seconds at 10-seconds intervals at a power setting of 5 were utilized.

During sonication the temperature of the formulation was 18 2 C.

The pH during sonication was adjusted to 7 0.5 with dilute NaOH.

Total sonication time employed to prepare the microparticle cyclosporine was usually 10.5 hours or less. The microparticlecyclosporine formulation was placed in 20 ml vials and stored at 4 and 25 C for further stability studies.

Particle size distribution of the suspension was analyzed with a NICOMP model 370 Particle Size Analyzer. This instrument utilizes photon correlation spectroscopy for particle sizing in the submicron region. A small volume of the suspension was diluted with water and placed in the cell of the particle size analyzer. Particle size determination based on volume weighted and number weighted particle size determination of the suspension, represented as a Gaussian distribution by the NICOMP 370 software, yielded the mean particle size values, which are listed below in Table I.

Table I: Volume-and Number-weighted Particle Size Stability of Microparticle-Cyclosporine a Storage Storage at 4 C Time Mean Particle Size (am) Days Volume- Number- Weighted Weighted 0 361 63 7 337 69 51 358 76 Storage at

J

Mean Particle Size (nm) Volume- Number- Weighted Weighted 361 63 423 67 455 66 Approximately 20 ul of the freshly prepared suspension was placed on a clean slide, with a clean cover glass, and examined under an Olympus BH2 microscope with 1000X magnification. An eye-piece equipped with a graticule was used to estimate the particle size. Most of the particles in the suspension were 0.3-0.5 um.

Furthermore, microscopic examination of the suspension confirmed non-agglomerated or flocculated micron and sub-micron size drug particles exhibiting Brownian motion.

Example 2 For purpose of comparison (not according to the invention) using only a phospholipid, microparticle-cyclosporine with lecithin alone (without the second surface modifier. Tween 80) was also lo prepared using the same procedure as Example 1. The suspension was stored in 20 ml glass vials for storage stability studies. The volume and number weighted mean particle size values of the suspension stored at 4 and 25 C are listed below. The results in Table II illustrate that the presence of lecithin alone (without the presence of Tween 80) does not provide the particle size reduction and enhancement in storage stability as described in Example 1.

Table II: Volume-weighted Particle Size Stability of Microparticle-Cyclosporine Storage Storage at 4 0 C Storage at Time Mean Particle Size (nm) Mean Particle Size (nm) Days Volume- Number- Volume- Number- Weighted Weighted Weighted Weighted 0 704 91 704 91 1 1472 503 2230 755 6 1740 416 2290 874 ii~i- Example 3 For purpose of comparison (not according to the invention) using only a surface modifier, microparticle-cyclosporine with Tween alone (without a phospholipid, egg phosphatidylcholine) was also prepared using the same procedure as Example 1. The suspension was stored in 20 ml glass vials. The results in Table Il illustrate that the presence of Tween 80 alone (without the presence of phospholipid does not provide particle size reduction as in Example

I.

i 10 Table III: Volume- and Number-weighted Particle Size Stability of Microparticle-Cyclosporine Mean Particle Size (nm) Day Volume-Weighted Number-Weighted 0 521 67 Example 4 The following microparticle-Docosanol formulations were prepared by the process of the invention with Tween 80, Tween egg phosphatidylcholine, and/or Phospholipon 90H as surface modifiers. Docosanol is available from Sigma. The formulations were prepared according to the procedures of Example 1. The compositions and concentration of excipients of the microparticle formulations are listed below: 13 iNficroparticle..Docosanof (Example 4.1, comparative) Docosariol Egg Phosphatidylchoffe Mannitol Distilled Water Total Volume mg/mI mg/mi mg/mI qs to 100% 20 ml 0000 00 0* 0 0

OSOS

S

0000 0 @0 @0 0 S 0 0050 0

OS*S

0 0@ 6 0 @00 0 *000 0 *000 0 0.O@ 0 605000 0 Microparticle.Docosanol (Example 4.2) Docosanol Egg Phosphatjdylcholine Mannitol Tween Distilled Water Total Volume mg/mI 50 mg/mi 55 malmi 10 memi qs to 100% ml Microparicle-.Docosanol (Example 4.3) Docosapol Egg Phosphatidvlcholine Manitoi Tween 20 Distilled Water Total Volume )0 mg/mi mz/mi mg/mi 10 mg/mi qs to 100% mI Microparticle-Docosanol (Example 4.4) Docosanol Phospholipon 90H Mannitol Tween 80 Distilled Water Total Volume 20 mg/mI 30 mg/mI 55 mg/mI 10 mg/mi qs to 100% 20 ml 10 MNTicroparticle.Docosanol (Example 4.5, Comparative) Docosanol Mannitol Tween 80 Distilled Water Total Volume 20 malml 55 mei'ml 10 mg/mi qs to 100%'O 20 ml The mean volume-and numiber-wejghted particle size values of the suspension were 286 am, and 98 nm, respectively.

The volume weighted mean particle size values of the above suspension stored at 4*C are listed below in Table IV.

Table IV: Volume-.weighted and Number Weighted Particle Size Stability of M'vicroparticle-.Docosanol Stored at 4"C.

(Example 4. 1) (Example 4.2) Mean Particle Size (nm) Mean Particle ie(m Volume- Number- Volume- Number- Weighted Weighted Weighted Weliffted ND___ND 156 [81 Weigted ei hted Wei hte Weih8e 12 619=3 184 mpl 993 127 ml 44 rStjorage Time Days 0 ND Not Determined The above data illustrate the much smaller particles produced by the present invention with the presence of a surfactant in additi on to the phospholipid and that these particles retain their partie size over time without significant increase in size.

Example The following seven microparticle-RTP.4oss an antiviral drug) formulations were prepared with combinations of.Tween Tetronic 908, Pluronic F-68, egg phosphatidvicholine. and/or phospholipon 90H as surface modifiers. The details of the sonication method are similar to those discussed in Example 1. The compositions and concentration of excipients of the microparticle formulations are listed below: Micro particle-RTP-4055 (Exa mple 5.1, Cominparative) RTP-4055 Eggo Phosphatidylcholine Distilled Water Total Volume 50 m21I 50 m-a/ml qs to 100% 2)5 ml The mean volume weighted particle size of the suspension was 319 nIm.

Microparticle-RTP-4055 (Example 5.2) RTP-4055 Egg, Phosphatidyicholine Mannitol Pluronic F-68 Distilled Water Total Volume 50 mz/ml 50 mg-/mI 55 m~Irnl 5 mc-Iml qs to 100% 2 5 mlI .The mean volume- and number-weighted particle size values of the suspension were 672 amn and 76 um respectively.

Nlicroparticle-RTP40'~55 (Example 5.3) RTP-4055 Egga Phosphatidyicholine Mannitol Tetronic 908 Distilled Water Total Volume 50 mg/mI 50 m-cImL 55 aiml qs to 100% 2)5 ml The mean volume- and number- weighted particle size values of the suspension were 436 amn and 59 rum respectively.

MVicropa rticle-RTP-40:55 (Example 5.4, Cornpa rative) RTP-4055 Phospholipon 90H Distilled Water Total Volume 50 m-aJml 30 ma-ml qs to 100%/o 2 5m1I The mean volume- number- weighted particle size values of the suspension were 1117 am. and 108 rum respectively.

18 Microparticle-RTP4OSS (Example RTP-4055 Phospholipon 90H Mannitol Dimiyristoylphosphatidyl choline (DMPG) Tween 80 Distilled Water Total Volume 50 mg/mI 30 mg/ml 55 mg/mI 3 mg/mi 10 meIml qs to 100% 2)5 ml The mean volume weighted particle size of the suspension was 236 nm. The particle size of the suspension stored at 4'C for I week and I month are 328 and 397 arn, respectivelY, which indicates the stability of the suspension.

Mlicro pa rticle-RTP-4055 (Example 5.6) RTP-4055 Phospholipon 90H Mannitol Tween 80 Distilled Water Total Volume 50 mg/mI 30 mo-IMl 55 mZiMl 10 mC-IMI qs to 100% 25 ml The mean volume- anid number- weighlted particle size values of the suspension were 382 nm and 59 nm respectively. Within the 19 error limits, there was no variation in the mean particle size after one week of storage at 4 C.

Microparticle-RTP-4055 (Example 5.7, Comparative) RTP-4055 50 mg/ml Mannitol 55 mg/ml Tween 80 10 ma!ml Distilled Water qs to 100% Total Volume 25 ml The volume- and number-weighted mean particle size values of the suspension were 545 nm, and 75 nm. respectively within the error :limits, there was no variation in the mean particle size after one week of storage at 4 °C.

Example 6 The following six microparticle-Piroxicam formulations were prepared with combination of Tween 80, Tetronic 908, Pluronic F-68, and/or egg phosphatidylcholine as surface modifiers. Piroxicam was received from Cipla. The details of the sonication method are similar to those discussed in example 1. The compositions and concentration of excipients of the microparticle formulations are listed below: NficroparticePiroxcam (Example 6.1)' Piroxicam Egg Phosphatidyicholine Mannitol Tween 80 Tetronic 908 Distilled Water Total Volume a a a 67 mg/mi 67 mg/mi 67 mg/mi 5 mg/mi 5 mg/mi qs to 100% (w/v) 15 ml The mean volume- and number- weighted particle size values of the suspension were 674 amn and 72 nim respectively.

Nlicroparticle-Pironcam (Example 6.2) Piroxicam Eggo Phosphatidyicholie Mannaitol Tetronic 908 Distilled Water Total Volume 67 mag/ml 67 ma/ml 67 mg/mi 5 mg/mi qs to 100%( w/v) 15 ml The mean volume- and number- weighted particle size values of the suspension were 455 n~m and 58 nm respectively.

Nlicroparticle..Piroxicm (Example 6.3) Piroxicam Egg Phosphatidyicholine Mannitol Pluronic: F-68 Distilled Water Tot al Volume 6 7 mg/ml 67 mg/mI 6 7 mgm 5 mg/mI qs to 100% (w/v) 15 ml The mean volume- and number- weighted particle size values of the suspension were 564 nim and 68 nmn respectively.

Mlicroparticle-Piroxicam (Example 6.4) Piroxicam Egg, Phosphati dy Icho line IMannitol Tween 80 Cetyltrimethylammonium bromide Distilled Water Total Volume 67 m~Jml 67 meg/mI 6 7 ma/ml 5 mo-/ml 10 MSirnl qs to 100% (w/v) 15 ml The mean volume- and number- weighted particle size values of the suspension were 479 n~m and 80 am respectively.

Nlicroparticle-Piroxicam (Example

C

C

Piroxicaxn Egg Phosphatidyicholine Mannitol Cetyltrimethylammonium bromide Distilled Water Total Volume 67 mg/mI 67 mg/mi 67 mg/mi 10 mg/mI qs to 100% 15 Ml The mean volume- and number- weighted particle size values of the suspension were 670 nm and 128 am respectively.

15 Mticroparticle-Piroxicam (Example 6.6, Comparative) Piroxiucam Mannitol Tween 80 Tetronic 908 Distilled Water Total Volume 67 ma."Ml 67 maIml 5 mg/mI 5 mg/mI qs to 1 00% O 25 ml The volume- and number- weighted particle size values of the suspension were 1184 am and 38-5 amn, respectivelv.

7--7

Claims (8)

1. A composition comprising solid microparticles of a water-insoluble or poorly soluble compound, a natural phospholipid and at least one non- phospholipid non-ionic, anionic or cationic surfactant, said phospholipid and surfactant adsorbed to the surfaces of said microparticles, in which the surfactant or surfactants provide volume-weighted mean particle size values of the water-insoluble compound at least 50% smaller than particles produced without the presence of the surfactant using the same energy input.

2. A pharmaceutical composition comprising solid microparticles of a water-insoluble or poorly soluble compound, a natural phospholipid and at least one non-phospholipid non-ionic, anionic or cationic surfactant, as well as pharmaceutically acceptable excipient, said phospholipid and surfactant adsorbed to the surfaces of said microparticles, in which the surfactant or surfactants provide volume-weighted mean particle size values of the water-insoluble compound at least 50% smaller than particles produced without the presence of the surfactant using the same energy input.

3. A pharmaceutical composition according to claim 2 formulated for oral, inhalation, ocular, nasal or injectable administration.

4. A pharmaceutical composition according to claim 2 or claim 3 formulated in injectable form for intravenous, intra-arterial, intra-muscular, intradermal, subcutaneous, intra-articular, cerebrospinal, epidural, intracostal, intraperitoneal, intratumor, intrabadder, intra-lesion or subconjunctival administration. i i: I:1 I- i 14/11/2001 24 A composition formulated according to any one of claims 1 to 4, in the form of a dried suspension which can be resuspended in aqueous or non-aqueous media.

6. A composition formulated according to any one of claims 1 to 4 which is formulated as a suspension, spray-dried powder, lyophilized powder granules or tablets.

7. A composition according to any one of claims 1 to 6 in which the water-insoluble compound is a biologically useful compound or an imaging agent.

8. A composition according to any one of claims 1 to 7 wherein the surfactant is a polyoxyethylene sorbitan fatty acid ester, a block copolymer of ethylene oxide and propylene oxide, a tetrafunctional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethylenediamine, an alkyl aryl polyether sulfonate, polyethylene glycol, hydroxypropylmethylcellulose, sodium dodecylsulfate, sodium S. deoxycholate, cetyltrimethylammonium bromide or a combination thereof.

9. A composition according to any one of claims 1 to 8 wherein the phospholipid is of egg or plant origin or semisynthetic or synthetic in partly or fully hydrogenated form or in a desalted or salt form such as phosphatidylcholine, phospholipon 90H or dimyristoyl phosphatidylglycerol sodium salt, phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, lysophospholipids or a combination thereof. I- 14/11/2001 A pharmaceutical composition of microparticles substantially as hereinbefore described with reference to the examples. Dated this 14th day of November 2001 Research Triangle Pharmaceuticals Ltd Patent Attorneys for the Applicant PETER MAXWELL ASSOCIATES *S 77, 1-