Surface modified nanoparticles based on nosteroidal inflammatory drugs, process for preparing them and pharmaceutical compns. contg. them

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used and pharmacologically effective drugs. However, gastric irritation problems can occur very often when NSAIDs are administered orally. This side effect is well known and is not a negligible problem in the clinical use of the drug.

Numerous studies have already been carried out to study the mechanism responsible for this effect. For example, Cioli et al., Tox. and Appl Pharm. 50, 283-289 (1979), states that oral administration of acidic NSAIDs to laboratory animals results in the following two mechanisms:

local effect due to contact with the gastric mucosa, and

- centrally mediated (systemic) effect following oral administration.

Prince et al., Drugs 40 (Suppl. 5): 1-11, 1990, report that NSAID-induced gastric injury is partly due to the adverse systemic effects of NSAID-mediated direct and indirect acid damage followed by almost simultaneous prostaglandin inhibition. consequences.

There are different approaches to eliminating NSAID-induced gastric injury. These are the following:

1) production of less toxic NSAIDs,

(2) reducing or eliminating the active ingredient that actually causes the injury; and

3) enhancement of the mucosal defense mechanism.

However, these efforts have not been completely successful.

The most effective means of eliminating gastric damage, for example, is the elimination of the primary pathogen. This is rarely the case with NSAIDs, because patients with severe inflammatory disease may rarely allow medication to be stopped. Although the use of less toxic NSAIDs is desirable, in the current practice only NSAID-induced gastric injury is treated. Misoprostl (methylated E, prostaglandin) was approved by the FDA to prevent stomach damage caused by NSAIDs. However, this drug is expensive, needs to be taken several times a day, and can cause unacceptable side effects.

For these reasons, it would be highly desirable to develop NSAIDs that produce less gastric injury. The preparation of accelerated NSAIDs would also be highly desirable.

In our work, it has been found that oral administration of surface modified NSAID nanoparticulate pharmaceutical formulations results in reduced gastric irritation and / or faster action.

The present invention relates to a pharmaceutical composition comprising nanoparticles consisting essentially of NSAIDs which adsorb on its surface a quantity of nanoparticles which is substantially less than about 400 nm, so as to form an effective average particle size.

A further object of the present invention is to provide a pharmaceutical composition comprising the nanoparticles described above and a pharmaceutically acceptable carrier.

Another object of the present invention is to provide a method of treating a mammal comprising administering the above pharmaceutical composition.

It is a further object of the present invention to provide a process for preparing the above-described nanoparticulate material comprising:

dispersing an NSAID in a liquid dispersion medium, and

- wet-grinding the NSAID dispersion thus obtained while maintaining the pH of the medium at 2-6 in the presence of a hard grinding material.

It is a further object of the present invention to provide a method of reducing and / or accelerating gastric irritation comprising treating a mammal using a pharmaceutical composition as described above.

An advantageous feature of the invention is that the oral administration of the NSAID-containing pharmaceutical compositions of the invention results in reduced gastric irritation.

Another advantageous feature of the invention is that the pharmaceutical compositions according to the invention produce an accelerated effect.

Further advantages of the invention will be apparent from the following detailed description of the preferred compositions of the invention.

The invention is based in part on the discovery that oral administration of surface modified NSAIDs such as neproxen nanoparticles results in reduced gastric irritation and accelerated action.

While the present invention is primarily directed to the preferred drug families, i.e., NSAIDs, the present invention is also effective in the preparation of other drug families, such as antibiotics, quinols, anti-lipid agents, and X-ray agents.

The particulate materials of the invention contain an NSAID. In these, the NSAID is present in a discrete crystalline phase. The crystal is not the same as that obtained by conventional solvent methods, such as those described in U.S. Patent 4,826,689, which is amorphous or non-crystalline. The NSAID may be present in one or more suitable crystalline phases.

The compositions of the present invention can be prepared with a wide variety of NSAIDs. However, the NSAID used requires that it be poorly soluble and dispersible in at least one liquid medium.

By "poorly soluble" is meant that the solubility of the NSAID at a processing temperature, such as room temperature, in a liquid dispersion medium, such as water, is less than 10 mg / ml, preferably less than 1 mg / ml. The preferred liquid dispersion medium is water. The invention

<img file="HUT70952A_D0001.tif" />

however, other liquid media, such as aqueous saline solutions, sunflower oil, or solvents such as ethanol, tert-butanol, hexane or glycol, may be used in practice. The pH of the aqueous dispersion medium can be adjusted by conventional methods.

Suitable acidic and non-acidic NSAIDs may be used to practice the invention. Suitable acidic compounds include carboxylic and enolic acids, and suitable non-acidic compounds include, for example, nabumetone, tiaramide, procoazone, bufexamac, flumizole, epirazole, tinoridine, thymegadine and dapsone.

Suitable carboxylic NSAIDs include, for example, salicylic acid and its esters, such as aspirin, diflunisal, benorillate, and phosphosal; acetic acid derivatives, including phenylacetic acid derivatives such as diclofenac, alclofenac and fenclofenac; and heterocyclic acetic acid derivatives such as etodolac, indomethacin, sulindac, thymine, fentizac, and tilomisol; and phenamic acids such as flufenamine, mefenamine, meclofenamine and niflumin.

Examples of suitable NSAIDs for enolic acids are pyrazolone derivatives such as oxifenbutazone, phenylbutazone, apazone and feprazone, and oxicam derivatives such as piroxicam, sudoxicam, isoxicam and tenoxicam.

The NSAIDs mentioned above are known compounds which can be prepared by known methods.

Particularly preferred NSAIDs of the invention include naproxen, indomethacin and ibuprofen.

The NSAID-containing particles described above contain a surface-adsorbing agent adsorbed on their surface. Suitable surface modifiers are substances that physically adhere to the surface of the NSAID but do not form a chemical bond.

Well-known organic and inorganic drug binders are preferred as suitable surface modifiers. Examples of such binders are well known polymers, low molecular weight oligomers, natural materials and surfactants. Nonionic and ionic surfactants are preferred. Typical excipients are, for example, gelatin, casein, lecithin (phosphatides), acacia, cholesterol, tragancate gum, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifier, ethylene) alkyl ethers such as macrogol ethers such as cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters such as the commercially available agents Tween, polyethylene glycols, polyoxyethylene stearates, colloidal silicon oxide, phosphates, sodium dodecyl sulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxy ethyl ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, non-crystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA) and polyvinylpyrrolidone ) (PVP). Most of these are described in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain, Pharmaceutical Press, 1986.

Surface modifiers are commercially available and / or prepared by known methods. Two or more surface modifiers may be combined.

Particularly preferred surface modifiers are the following: polyvinylpyrrolidone, tyloxapol, polaxomers such as BASF Pluronic F68 and F108 ethylene oxide and propylene oxide block copolymers, BASF Tetronic 908 (T908) poloxamines, which are sequentially added to ethylene diamine. tetrafunctional block copolymers obtained by copolymerization of added ethylene oxide and propylene oxide, dextran, lecithin, sodium sulfonic acid dioctyl ester of Aerosol OT from American Cyanamid, Dupond P, sodium lauryl sulfate, Du Pont, Triton X, Rohm and Haas, alkyl aryl polyether sulfonate, ICI Specialty Chemicals, Tween 20, and Tween 80, polyoxyethylene sorbitan fatty acid ester, Carbowax 3550 and 934 polyethylene glycol from Union UniCarbide, Croda Inc. Mixture of sucrose stearate and sucrose distearate under the tradename Crodesta F-110 and Crodesta SL-40 under the tradename C and SA90HCO under the tradename C₁₈H₃7 CH₂ [CON (CH₃) CH₂(CHOH)₄CH₂OH] 2. Of these, polyvinylpyrrolidone, Pluronic F-68 and lecithin are particularly suitable.

The surface of the NSAID is adsorbed on a surface modifying agent that promotes the formation of an average particle size of less than about 400 nm. The surface modifier does not chemically react with the NSAID or itself. In addition, there is no intermolecular bond between the individually adsorbed surface modifying agent molecules.

As used herein, the term "particle size" refers to a number average particle size determined by standard particle size measurement techniques such as sedimentation field current fractionation, photon correlation spectroscopy, or plate centrifugation. By "promoting an effective average particle size of less than about 400 nm" is meant promoting a particulate material having a number average particle size of at least 90% by weight based on the above methods. In a preferred embodiment of the invention, this effective average particle size is less than about 300 nm. It is preferable that the effective average particle size of ♦ «• · · be at least 95% and more preferably at least 95% of the material, for example, below 400 nm. In a particularly preferred embodiment of the invention, substantially all of the particles have a size of less than 400 nm.

The granular material of the present invention is prepared by a process wherein:

dispersing the NSAID in a liquid dispersion medium, and

grinding the dispersion thus obtained in the presence of a hard grinding material such that the effective average particle size is less than about 400 nm.

The reduction of the particle size is carried out in the presence of a surface modifying agent. Contact with the surface modifying agent may occur after abrasion.

The preparation of the particulate material according to the invention will now be described in detail. The NSAID used is a coarse-grained product obtained from a commercial source and / or produced by a known method. It is preferred, but not limited, that if the particle size of the applied coarse-grained NSAID is less than about

100 pm. If the coarse-grained NSAID has a particle size greater than about 100 µm, it is preferably milled to less than 100 µm by a conventional milling process such as air jet or fragmentation milling.

The NSAID used is then added to form a premix which is substantially insoluble in a liquid medium. The concentration of NSAID in the liquid medium is 0.1 to 60% by weight, preferably 5 to 30% by weight. Advantageously, but not exclusively, the surfactant is present in the premix.

The concentration of the surfactant is about 0.1-90% by weight, preferably 1-75% and more preferably 20-60% by weight, based on the combined weight of the drug and surfactant. The premix suspension preferably has an apparent viscosity of less than 1 Pa.

• ·

<img file="HUT70952A_D0002.tif" />

The premix can be applied directly by mechanical means to reduce the average particle size of the dispersion to less than 400 nm. Direct application of the premix is ​​advantageous when using a ball mill for grinding. Dispersion of the NSAID and optionally the surface modifier in a liquid medium is accomplished by appropriate mixing, such as a roller mill or a Cowles mixer, to form a homogeneous dispersion without large visible agglomerates. Preferably, the premix is ​​subjected to a pre-grinding dispersion step in which the mill is carried out in a mill with a recirculating medium.

A conventional means of reducing NSAID particle size is a dispersion mill. Suitable dispersion mills are, for example, ball mills, rock mills, vibration mills, planetary mills, grinding mills such as sand or pearl mills. Preferably, the grinding medium mill requires relatively less time to achieve the desired result, i.e., to reduce the appropriate particle size. When using a milling mill, the apparent viscosity of the premix is ​​preferably from about 0.1 to about 1 Pa. For a ball mill, the apparent viscosity of the premix is ​​preferably from about 0.001 to about 0.1 Pa · s. Within these ranges, an optimal equilibrium is reached between the effective particle size fraction and the media erosion.

Preferably, the grinding medium used in the particle size reduction step is a spherical or particulate hard medium having an average particle size of less than 3 mm, more preferably less than 1 mm. Such a medium allows processing of the particulate material according to the invention in a shorter processing time and is less costly for the retention apparatus. The choice of media is presumably not critical. However, zirconium oxide such as 95% ZrO stabilized with magnesium oxide, zirconium silicate and ··· glass grinding media are preferred because of acceptable levels of contaminants in pharmaceutical formulations. Other media expected to be useful include acid-proof steel, titanium oxide, alumina and 95% ZrO stabilized with yttrium. The preferred grinding medium has a density greater than about 2.5 g / cm³.

The grinding time can vary within wide limits and depends primarily on the particular mechanical device and the processing parameters used. In the case of a ball mill, processing time can be up to 5 days or longer. In the case of high shear mills, the processing time is less than 1 day (residence time varies from 1 minute to several hours).

The particle size reduction should be performed at a temperature where the NSAID does not undergo significant degradation. This processing temperature is generally preferably 30-40 ° C. If necessary, the processing equipment can be cooled with some conventional refrigeration equipment. The process is conveniently carried out at room temperature and at a pressure suitable for conducting the grinding process safely and efficiently. Ball mills and friction mills, for example, typically operate at atmospheric pressure. Processing pressures for grinding media mills typically range up to 1.4 bar.

The milling is carried out under acidic conditions with a pH of 2-6, preferably 3-5. The preferred pH depends on, for example, the acidity and solubility of the particular NSAID. Acid-resistant grinding equipment, such as those made from high-grade stainless steels, such as 316SS steel, or with an acid-resistant coating, are highly preferred.

The surface modifier, if not present in the premix, is added to the dispersion after grinding in the amounts described above for the premix. The dispersion can then be mixed with, for example, vigorous shaking. The dispersion may also be subjected to a sonication step, such as sonication with an ultrasound device. The energy used for sonication, for example, can be released over a period of about 1 to 120 seconds at a vibration rate of 20 to 80 kHz.

The relative amounts of NSAIDs and surfactants can be varied within wide limits, and the optimal amount of surfactant is determined, for example, as a function of the particular NSAID and surfactant, the critical micelle concentration of the micelle-prone surfactant, and the surface of the NSAID. The preferred amount of surface modifier is 0.1 to 10 mg per square meter of NSAID. The amount of surface modifier is from 0.1% to 90%, preferably from 0.5% to 80% and more preferably from 1% to 60%, based on the total weight of the dry particulate material.

The following simple screening assays have been developed to select the compatible surface modifying agent and NSAID required to form a stable dispersion of the desired particulate material. The coarse NSAID particles are first dispersed in a liquid in which the NSAID is substantially insoluble. An example of such a solvent is water in which a 5% w / v dispersion is prepared and the resulting dispersion is ground in a rolling mill for 120 hours under the following milling conditions.

Grinding vessel: 250 ml glass jar, useful volume of grinding vessel: 250 ml, grinding medium: 120 ml milling medium: 1.0 mm pre-purified zirconia bead (manufactured by Zircoa Inc.), grinding time: 120 hours, sludge volume: 60 ml, rpm: 92 rpm, pH at room temperature: 4.0 (with hydrochloric acid or sodium hydroxide, if necessary).

• * » «

·« ·♦

Separation of the sludge from the grinding medium is accomplished by a conventional method such as pouring sludge from a vessel or pipetting. The separated slurry is then divided into two equal portions and then added to the surfactant in an amount of 2 to 50% by weight based on the combined weight of the NSAID and the surface modifier. The dispersions are sonicated for 1 minute at 20 kHz ultrasound to disperse agglomerates or vortexed for 1 minute in a multi-tube vortex apparatus. The particle size is then determined by analysis of particle size, for example by photon correlation spectroscopy and / or 1000x magnification optical microscopy. When a stable dispersion is observed, optimization of the NSAID and surfactant association process is performed as described above. By "stable" is meant that the dispersion does not exhibit flocculation or visible particle agglomeration, and a 1000x magnification by optical microscopy shows a stable dispersion for at least 15 minutes, preferably at least two days or more after preparation. In addition, the preferred sized particles do not exhibit flocculation or agglomeration when dispersed in 0.1 N hydrochloric acid or in stimulated Gl fluid (USP).

The dispersion thus obtained is stable and contains, in the liquid dispersion medium, the granules described above. The surface modified NSAID nanoparticle dispersion can then be sprayed onto sugar spheres or drug binders. The spraying is carried out by the well-known fluidized bed spray coating process.

The pharmaceutical compositions of the present invention comprise a particulate material as described above and a pharmaceutically acceptable carrier. Such carriers are well known in the art. These include, for example, non-toxic physiologically acceptable carriers, parenteral injection adjuvants or solvents, solids or liquids suitable for oral use, and rectal administration.

The method of treating mammals of the present invention comprises treating the mammal with an effective amount of a pharmaceutical composition as described above. The amount of effective NSAID required for treatment will depend upon the desired therapeutic response to the particular formulation and the method of treatment. Thus, the amount of NSAID used will depend upon the particular NSAID, the desired therapeutic effect, the treatment process, the desired duration of treatment, and other factors.

One particularly advantageous feature of the pharmaceutical compositions of the present invention is that, as can be seen in the following examples, they exhibit reduced gastric irritation and faster action.

The following examples illustrate the invention in more detail.

First example

A nanoparticulate naproxen dispersion (formulation 1) was prepared in a roll mill as follows:

In a 250 ml glass jar, 120 ml of 1.0 mm pre-purified zirconia (product of Zirceads XR, Zirbeads XR, 1.0 mm in diameter) containing 60 g of 3 g of naproxen in aqueous suspension (Sigma, St. Louis, MO) Pluronic F-68 (3% w / w). The beads are subjected to a pre-purification with 1 N sulfuric acid solution and some rinsing with water. The material thus obtained was ground at a rolling speed of 92 rpm for 120 hours. The resulting dispersion is stable when poured into 0.1 N hydrochloric acid. The average particle size measured by photon correlation spectroscopy is 240-300 nm.

The preparation of the control naproxen formulation is accomplished by adding 5% w / v of unground milled naproxen to 3% Pluronic F-68. The resulting suspension is vortexed and the particle size is measured. The particle size range is 20-30 µm.

The concentration of naproxen in both formulations is 50 mg / ml (w / v). For oral administration, the two formulations are diluted with 3% Pluronic F-68 to a dosage of 10 mg / ml.

Evaluation of the effects of preparations:

Male Sprague-Dawley rats were housed under the conditions described in "Guide for Care and Use of Laboratory Animals", NIH Publication 86-23. The temperature is 22 ± 1 ° C, the relative humidity is 50 ± 10% and the light / dark cycle is 12 hours. The rats were fed with laboratory food and water. Rats (200-300 g) were anesthetized with 55 mg / kg intraperitoneal injection of Nembutal (sodium pentobarbital). The external cervical veins were cannulated continuously to facilitate blood sampling.

Prior to the administration of naproxen, the rats were allowed to recover for 24 hours with water as desired.

The rats were then anesthetized with Metofane, fed by gavage with the above formulations, and tethered. 100 μΙ blood samples were taken from the cervical vein heparinized tubes after 0 (before injection), 5, 10, 15, 30, 34, 60, 75, 90, 120, 180 and 240 after the administration of naproxen. minutes. Plasma samples of 50 μΙ were immediately mixed with 130 μΙ of acetonitrile and 20 μΙ of standard solution (20 µg / ml indomethacin) and vortexed to precipitate the protein. The samples were centrifuged, the supernatant was removed and placed in vials and subjected to HPLC analysis. Naproxen was resolved on an analytical column (Waters Novapack C18, 15 cm x 4 mm, 5 μπι).

At the end of the ghost (240 minutes), the rats were given a single cervical artery

euthanized by iv bolus injection of Nembutal. They had their stomachs removed and cut along the greater curvature from the duodeum to the stomach end muscle. The stomachs were then spread out and stretched in dissection trays and washed with 0.9% sodium chloride solution.

Evaluation and enumeration of gastric irritation (erosion / injury / ulcer) using a modified version of the accepted procedure (Cioli et al., Tox. And Appln., Pharm., 1979, 50: 283-289 and Beck et al., Arch. Toxicol., 1990). , 64: 210217), the severity was altered to the extent described below. Differences in severity rates are a consequence of varying degrees of gastric pathology following oral administration of NSAIDs (Balaa, Am. Joum., Med. Sci., 1991, 301: 272-276 and Lanza et al., Dig. Dis. and Sci., 1990, 35:12).

Each gastric irritation was determined by measuring the length or diameter of the lesion using a 10 mm surgical ruler. The length of the irritations varied from 0.25 to 10.0 mm. Irritations of less than 0.25 mm are designated as "needle point". The severity of the irritations was also determined by color. Red irritation received a "mild" mark and a severity rating of 1. Brown irritation is marked as moderate and has a value of 2. Black irritation is most severe and has a value of 3. To measure the degree of irritation, the individually measured lengths were multiplied by the severity value. The sum of the total irritations of a given stomach is the index of all the irritations.

The mean values ​​of irritations caused by the control formulation and formulation 1 according to the invention are summarized in Table 1. From the data it can be seen that the use of the composition according to the invention results in a reduced irritation number (p = 0.099) compared to the control.

From this it can be concluded that the oral administration of the composition of the invention produces less gastric irritation than the control.

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<td colspan="3">Table 1</td>

<td>Rat number</td><td>Control (n = 6)</td><td>Preparation 1 (n = 8)</td>

<td> 1</td><td> 293</td><td> 43</td>

<td> 2</td><td> 200</td><td> 139</td>

<td> 3</td><td> 133</td><td> 149</td>

<td> 4</td><td> 140</td><td> 80</td>

<td> 5</td><td> 110</td><td> 129</td>

<td> 6</td><td> 101</td><td> 163</td>

<td> 7</td><td></td><td> 54</td>

<td> 8</td><td></td><td> 98</td>

<td>Average</td><td> 163</td><td> 107</td>

<td>SEM</td><td> 30</td><td> 16</td>

Surprisingly, it has been found that oral administration of the composition of the invention produces a similar degree of gastric irritation as parenteral administration, i. This means that direct irritation of the stomach of rats is practically avoided.

The composition of the invention and the control composition are C_uppharmacokinetic plasma parameters (peak plasma concentration), (time to peak plasma concentration), and AUC (0-240 min); Arca Under the Curve (values ​​from 0 to 240 minutes) obtained by statistical comparison of relative bioavailability are as follows:

Average + SEM

<td></td><td>control</td><td>Preparation 1</td>

<td>Cmax</td><td> 126 + 4</td><td> 187 + 19</td>

<td>(Pg / ml)</td><td>(N = 5)</td><td>(N = 6)</td>

<td>Tmax</td><td> 24 + 3</td><td> 24 + 5</td>

<td>(minute)</td><td>(N = 5)</td><td>(N = 6)</td>

• · · · · · · · • · ···· · ·*· • · · · · · ···· · · · · ·· · ·

AUCq.240 min 15228 + 994 19062 + 573 (µg x min / ml) (n = 5) (n = 3)

The data show that the time to peak plasma concentration in the formulation of the invention is less than that of the control (p = 0.15) and that both bioavailability and peak plasma concentration of the formulation of the invention are significantly higher (p = 0.03). , and (p = 0.02). The apparent increase in absorption rate clearly indicates a faster onset of action.

Second example

The composition was prepared according to the procedure of Example 1 except that 5% by weight of polyvinylpyrrolidone was used instead of Pluronic F-68. The average particle size is 250 nm.

3-8. Examples 1 to 4 produce nanoparticulate ibuprofen.

Third example

The nanoparticulate ibuprofen is prepared in 2 planetary mills (Pulverisette-7 from Fritsch GmbH) containing 2 25 ml bowls.

12.5 ml of 1 mm pre-purified zirconia beads, 6.25 ml of an aqueous suspension containing 100 mmol / l hydrochloric acid and 3% (w / v) ibuprofen and 2% (w / v) Pluronic F were added to the first spigot. -68 surface modifiers. The ibuprofen formulation is ground at 325 rpm for 24 hours.

The resulting dispersion was added to a stimulated gastric fluid, i.e., a solution of 2 g sodium chloride, 3.2 pepsin, 7 ml hydrochloric acid and 1 liter of water, pH 1.2; the formulation remains stable. The average particle size determined by photon correlation spectroscopy was 253 nm.

4th example

The composition was prepared according to the procedure of Example 3, except that 1% Tween 20 was added to the first strip and the grinding time was 17 hours. The average particle size is 263 nm.

5th example

The formulation was prepared according to the procedure of Example 3, except that a grinding time of 4 hours was used. The average particle size is 314 nm.

6th example

The composition was prepared according to the procedure of Example 3, except that in this case, the surface modifier added to the first pillar had a Tween 20: Span 20 weight ratio of 1: 2 and a grinding time of 175 rpm for 20 hours.

7th example

The formulation was prepared according to the procedure of Example 3, except that 0.25% w / v tyloxapol and 10 mM hydrochloric acid were added to the first strand as a surface modifier. The mandrel was ground at 175 rpm, cooled to 5 ° C, for 20 hours. The average particle size is 344 nm.

8th example

The composition was prepared according to the procedure of Example 7 except that Tween 20 was used in place of tyloxapol. The average particle size is 351 nm.

9-12. Examples 1 to 5 are nanoparticulate indomethacin formulations.

9th example

The nanoparticulate indomethacin formulations are prepared in a rolling mill as follows:

In a 250 ml bottle 125 ml 1.0 mm pre-purified zirconia beads, 200 g (5 wt%) 10 g indomethacin and 2 g (1 wt%) Vinol 2IO5 polyvinyl alcohol containing an aqueous suspension. The batch size of 200 g in the bottle is justified by the reduction of air space and thus the minimization of foam formation. The batch was milled at 88.5 rpm for a total of 240 hours. The dispersion is in 0.1 N hydrochloric acid solution and 3. is stable in the stimulated gastric fluid as described in Example 1. The average particle size measured by photon correlation spectroscopy is 331 nm.

10th example

The composition was prepared by the method of Example 9 except that polyvinylpyrrolidone was used instead of polyvinyl alcohol. The average particle size is 216 nm.

11th example

The composition was prepared according to the procedure of Example 9 except that Pluronic F-68 was used instead of polyvinyl alcohol. The average particle size is 228 nm.

12th example

The formulation was prepared according to the procedure of Example 9 except that Pluronic F-108 was used in place of polyvinyl alcohol. The average particle size is 235 nm.

Although the invention has been described only in certain preferred embodiments, any modified version thereof is within the scope of the invention.