IE981008A1 - Microparticles Containing Water Insoluble Active Agents - Google Patents

Abstract

New dosage forms contain active agent/solubilizer compositions that have been thermoformed, along with optional processing aids, into microparticles.

Description

MICROPARTICLES CONTAINING WATER INSOLUBLE ACTIVE AGENTS Field of the Invention 5 The invention relates to microparticles, especially thermoformed microspheres, that are useful in dosage forms containing active agents that are insoluble or sparingly soluble in water. The dosage forms have immediate release properties.

Related Applications This application is related to U.S. SN. 08/946,065 and U.S. SN. 08/946,070, both filed October 7, 1998.

Background of the Invention The pain, swelling and other discomfort associated with some medicalconditions, e.g., inflammatory diseases, make it desirable to treat those conditions as quickly as possible. Immediate release dosage forms are often desirable when one is delivering anti-inflammatory agents to patients in need of such treatment. For oral dosage forms, fast action, involving rapid dissolution and release into the bloodstream, are key objectives.

Dosage forms that achieve these objectives can be difficult to prepare, especially when the anti-inflammatory agent does not dissolve readily in water.

Nimesulide and its metabolites are models for the group of active agents that are effective anti-inflammatories, but that are difficult to deliver because of the agents’ limited solubilities.

For oral dosage forms including these types of anti-inflammatory agents, the attainment of release profiles exhibiting high CNtAX (highest plasma concentration of drug); short Tmax (the time at which C^x is attained) and large A.U.C. (total amount of drug absorbed as measured by the area under the curve of a plot of plasma concentration vs. time) can be problematic. Thus, a need exists for immediate release products containing these types of agents. This invention addresses that need.

The art is aware of ways to use solubilizers with poorly soluble active agents to enhance their release, via oral dosage forms, into the bloodstream. The use of solubilizers in pharmaceutical systems is described in the following: U.S. 4,727,109 shows liquid preparations containing an active agent and a carrier system consisting of a hydrophilic component, a hydrophobic component and a solubilizer. The hydrophilic component may be a polyethylene glycol or a polyoxyethylene/polyoxypropylene copolymerjzate. See col. 2, lines 35-44.

U. S. 4,944,949 discloses micelles of NSAIDs with poloxamers (col. 5, line TO PURUC iNcPECTION Ο’· ΟΆΡ 23 π ™ iu JudejizJ •’•«’«liCISiw’.-v J 33C.2J3 JC i i”T qllb·· 31). Micelles are aggregates in which surfactant molecules take on a spheroidal structure, with the hydrophobic regions of the molecules at the core and the hydrophilic regions at the other surfaces. Drug:surfactant ratios of 1:5.7 to 1:50 are disclosed. The micelles are made by stirring the drugs into heated poloxamers.

U. S. 5,281,420 shows tebufelone, an anti-inflammatory agent, in solid dispersions containing 15% to 75% tebufelone and 25% to 65% of a poloxamer surfactant (col. 1, lines 35-51). The dispersions are made by melting the tebufelone and the surfactant together, with mixing, to form homogenous mixtures.

U.S. 5,292,461 shows controlled release pellets made by spraying active agents with wetting agents. Polyethylene glycols serve as lubricants and as agents that affect the release of the active ingredient (col. 7, line 62 and col. 8, line 1). Poloxamers are useful surface active agents (col. 7, line 65).

U.S. 5,456,923 describes solid dispersions of drugs in polymers made by extruding the two together and pulverizing the extrudate. Polyoxyethylene/polyoxypropylene copolymers are disclosed, at col. 3, lines 33-4, as plasticizers for use in such dispersions.

U. S. 5,525,355 deals with laxative compositions which contain poloxamer surfactants, as stool softeners, melt-blended with stimulants. The ratio of surfactant to stimulant is 2:1 to 20:1 (col. 2, line 22+).

U.S. 5,646,131 discloses the use of cyclodextrins and carboxylic acids to enhance the solubility of sparingly soluble drugs in water. Col. 4 of the patent lists drugs which can be used in that invention. The formulations are made by combining the solubilizing ingredients with the drugs in the presence of water.

EPO Application 0 317 780, published May 31, 1989, shows quick-release and sustained-release formulations containing complexes formed from dihydropyridine calcium channel blockers and poloxamer surfactants. The complexes are made by combining the drugs and surfactants in the presence of warm ethanol.

WO 97/02017, published January 23, 1997, shows oral dosage forms containing a solid dispersion of active ingredients in a poloxamer polymers. The dosage forms are made using solvent dissolution or melt-blending.

None of these discuss the thermoformjng process of this invention.

Summary of the Invention The invention deals with the production of immediate release microparticles containing sparingly soluble active agents from compositions containing them along with polymeric solubilizers. It also includes dosage forms containing the microparticles and methods of making those dosage forms.

Specifically, the invention deals with oral dosage forms which use microparticles containing active agent(s) and solubilizing agent(s), with optional processing aid(s). The microparticles are dry, solid particles made by subjecting these ingredients to thermoforming conditions, preferably liquiflash conditions, to directly produce microparticles.

The microparticles, when ingested as is or used in more complex systems, give products which exhibit immediate release properties, as measured by CiV1AX, Tmax and A.U.C. values. Microparticles made using the invention release 80% or more of the active agent(s) in about 10 minutes, preferably about 5 minutes, or less.

The invention also includes a method of improving the taste of an active agent by thermoforming microparticles from a composition containing the active agent and a polymeric solubilizer. When nimesulide is used as the active agent, the microparticles are ture microspheres needing no milling or grinding step to give them uniform size, shape and appearance. Also, the nimesulide microspheres have a surprisingly good taste, when compared to unprocessed nimesulide particles.

Drawings Figures 1 and 2 show photographs of unmilled 100 micron microspheres containing nimesulide made in accordance with the invention at 250x and 300x magnification, respectively.

Figure 3 shows milled 100 micron microspheres containing ibuprofen made using a composition comparable to that used to make the nimesulide spheres. The magnification is 200x.

Detailed Description of the Invention Unless otherwise indicated, all percentages recited herein are weight percentages, based on total composition weight.

The invention deals with microsphere$ made by thermoforming compositions containing, as a minimum, at least one active agent and at least one solubilizer. “Thermoforming” is used herein to include various techniques which produce particles containing more than one material. Among these techniques are melt extrusion, controlled extrusion, and liquiflash processes.

The term “melt extrusion” refers to the process of mixing ingredients, in their molten states, in extrusion devices.

By “controlled extrusion” is meant extrusion under temperature and force conditions that facilitate one or more of eutectic formation, blending, coating, and encapsulation in an extruder. Irish application 980,115, filed February 16, 1998 describes the use of controlled extrusion to yield eutectics containing an active agent.

The phrase “liquiflash processes” includes liquiflash techniques for making microparticles, which techniques are known irj the art. One useful apparatus is disclosed in U. S. Serial No. 08/874,215, filed June 13, 1997. U. S. Patents 5,445,769 and 5,458,823 show devices which can be used to make liquiflash microparticles. The liquiflash process is also described in U. S. Patent 5,683,720.

In general, the compositions used in the invention contain: (a) active agent(s), (b) polymeric solubilizer(s), and (c) optional processing aids.

One or all of components (a) through (c) may contain one or several materials.

Prefened immediate release products will generally contain only (a) active agent(s) and (b) polymeric solubilizer(s).

By “immediate release” is meant dosage forms from which about 80% or more of the active agent(s) therein are released in vitro within about 10 minutes, preferably within about 5 minutes or less.

The active agents useful in the invention are those agents labeled “practically insoluble” in water. Their aqueous solubilities are 0.1 g/mL or less. These active agents are referred to as “sparingly soluble” throughout this description.

Particularly useful active agents are sparingly soluble solid anti-inflammatory agents whose release properties are enhanced by processing them in accordance with the invention. Those sparingly soluble active agents whose melting points are above those of the polymeric solubilizers used are preferred. Most preferred active agents are sparingly soluble in water and have melting points above about 90°C.

Particularly useful active agents are: nimesulide and the pharmaceutically acceptable salts, esters, and derivatives thereof- Nimesulide (m.p. 143-144.5 °C) and metabolites, such as its hydroxyalkyl-substitiited metabolites, e.g., (420. hydroxymethyl)-nimesulide, are most preferred. Mixtures of these are contemplated.

U.S. 3,840,597 discusses the preparation of nimesulide and refers to tablets containing it. It does not show the microparticles or the processes of this invention.

While anti-inflammatories are preferred, various active agents which have the solubilities and/or melting points described herein may be used. Included are: baclofen, bromazepam, butalbital, butasbarbital, carbamazepine, chlordiazepoxide, chlorpromazine, cinnarizine, clobazam, diazepam, dimethyl diazepam, etomidate, fludiazepam, flunitraze-pam, ketoprofen, ketorolac, lovastatin, medazepam, methaqualone, naproxen, nimesulide, nimetazepam, nitrazepam, olanzapine, orazepam, oxazepam, pentazocine, pentobarbital, phenobarbital, phenytoin, piroxicam, prostaglandin E2, prostaglandin El, prostaglandin F2, salbutamol, secobarbital, sulpride, tenoxicam, terfenadine and their pharmaceutically acceptable derivatives and the like. Mixtures are operable.

Preferred active agents for use in the invention include sparingly soluble antiinflammatories having meltung points above about 90 °C, that is: ketoprofen (m.p. 94 °C), ketorolac (m.p. 160-161 °C), lovastatin (m.p. 174.5 °C ), naproxen (m.p. 152-154 °C), nimesulide (m.p. 143-144.5 °C), piroxicam (m.p. 198-200 °C), tenoxicam (m.p. 209-213 °C), and derivatives thereof.

The polymeric solubilizers are polymeric hydrophilic surfactants.

One group of useful solubilizers are diblock copolymers containing only polyoxyethylene units and polyoxypropylene units. Poloxamers containing polyoxyethylene and polyoxypropylene block segments are very useful, with those having about 60% to about 90%, and particularly those having about 70% to about 80%, polyoxyethylene units being notable. Suitable polymers are sold using “Lutrol,” “Monolan” and “Pluronic” trade names (manufactured by BASF).

Poloxamer 188 (also called “Lutrol F68 and “Pluronic F68) is effective.

This solubilizer contains blocks having 80 and 27 polyoxyethylene units and has an average molecular weight of about 7680 to 9510. See Handbook of Pharmaceutical Excipients (2nd Edition), 1994, pages 352-354.

Useful polymers include “Pluronics” F87, FI08, FI27 and Poloxamer 237.

While processing aids can be used, some embodiments, e.g., microspheres made using nimesulide, are preferably made from compositions containing only the active agent and a polymeric solubilizer.

The phrase “processing aids” means agents which assist in the formation of uniformly sized particles during the thermoforming process. When spheres are made, these agents are called “spheronization aids’1. While processing aids are optional, the processing of some active agent/solubilizer combinations into microparticles may be enhanced by their use. Processing aids may be included in tablet formulations, serving as lubricants/glidants or providing other assistance in the preparation of tablets.

A wide variety of such aids can be used, with preferred processing aids including one or more of: polyalkylene glycol glyceryl fatty esters and glyceryl fatty esters.

Preferred polyalkylene glycol glyceryl esters used in the invention are sold as “Gelucires”, products of Gattefosse S.A. (France). “Gelucire 50/13, a polyethylene glycol 32 glyceryl palmitostearate (HLB 13), is particularly effective.

Glyceryl stearate, sold as “Myvaplex 600P” (HLB 3.8) by Eastman Chemical Co., is one useful glyceryl fatty ester.

Mixtures of Gelucire 50/13 and Myvaplex 600P are highly effective.

When microspheres are produced, they have uniform sphericity and smooth surfaces. See Figures 1 and 2. These characteristics make them suitable for coating, encapsulation, and other processes used in the pharmaceutical art.

Taste-masking or other types of coatings, e.g., protective coatings, may be applied to the microparticles of the invention. However, it has been surprisingly found that when nimesulide is processed using the invention, the resultant microparticles are microspheres that have an acceptable taste in the absence of taste-masking coatings.

Microspheres made using the invention can be used ingested as is, e.g., in sachet or powder products. Also, they may be used in liquid or (semi)solid suspensions; placed into capsules (e.g., gelatin capsules); or used to make tablets.

Tablets made using the microparticles of the invention may contain a variety of pharmaceutical ingredients, such as those tjiscussed below.

Disintegrants to be used in tablet formulations are materials which tend to render the thermoformed particles physically unstable in the presence of the moisture found in the mouth and/or the gastrointestinal tract. Typically, disintegrants dissolve or swell to some extent in water, so that microparticles containing them are broken up into multiple pieces, so that the release of the active agent(s) is facilitated.

Useful tablet disintegrants include polyvinylpyrcolidone (PVP), croscarmellose sodium, sugars, and the like. PVP products sold under the tradename, “Kollidon” and croscarmellose sodium sold a$ “Ac-Di-Sol” are useful.

Typical tablet excipients include microcrystalline cellulose (e.g., “Avicel” solid diluents from FMC Corp.), colloidal silicon dioxide (e.g., “Cab-O-Sil” suspending and/or thickening agent from Cabot Corp.), and stearic acid (a tablet lubricant).

Pharmaceutical excipients, e.g., flavorants, perfumes, colorants, diluents (liquid or solid), fillers, lubricants, suspending agents, thickening agents, sweeteners, etc., can be used in suitable amounts in tablet formulations. They can be mixed with the microparticles. Also, they can be included in one or more of the optional coatings.

Typical quantity ranges for microparticle and tablet ingredients, in percentages by weight, are given in the following table.

Table I.

Quantities of Ingredients in Microparticles and Tablets % bv Weight Microparticles Tablets Ingredient Broad Preferred Broad Preferred a. Active agent(s) 1.0-80 40-60 1.0-40 25- 40 b. Solubilizer(s) 20-80 40-60 10-50 25-40 c. Processing aid(s) 0-20 0-10 10-50 25 -35 d. Disintegrant(s) N.A. N.A. 10-50 25-35 e. Total Excipient(s) N.A. N.A. 0-99 10-75 N.A.= not applicable Particle Shape and Size The microparticles of the invention are preferably microspheres of uniform shape, i.e., having high levels of sphericity. As Figures 1 and 2 show, they have smooth surfaces and few non-spherical particles. Compare the microparticles shown in Figure 3, wherein ibuprofen, which has a melting point of only about 75°C, was employed in a similar thermoforming process.

The microparticles of the invention will have average particle diameters of about 100 to about 350 microns, with about 150 to about 250 microns preferred.

After forming, the microparticles are screened to collect those having the desired particle sizes.

In preferred embodiments, the microparticles are true spheres, requiring little or no milling to make them suitable for use in subsequent operations, such as encapsulation, formulation and/or tabletting operations. For example nimesulide microspheres made in accordance with the invention can be placed directly into gelatin capsules. They may also be compressed, with suitable excipients, into tablets. Intermediate milling or other attrition to modify the shape or size of the microspheres is not necessary.

Coatings Optionally, microparticles made in accordance with the invention can be coated with one or more layers of coating materials which enhance such properties as stability (e.g., protective coatings) and consumer acceptability (e.g., taste masking coatings). The nature of the property desired will dictate the types and amounts of any coatings used.

For immediate release products, it is preferred that no coating be used. Alternatively, a thin coating, ie., no more than 20% by weight, based upon the weight of the coated particle, can be applied to particles for use in immediate release dosage forms.

Coatings to be used to give protective/taste-masking properties include (meth)acrylic polymers, such as the “Eudragits” or cellulosics, e.g. “Klucels”, and the like, and mixtures thereof.

Useful (meth)acrylics include (meth)acrylic acid polymers, and (meth)acrylate polymers, optionally bearing aminoalkyl and/or ammonioalkyl substituents. “Eudragits” NE30D, RS, RI and S are useful.

Useful cellulosic polymers include ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, and the like. Mixtures are operable. Blends of ethylcellulose with hydroxypropylcellulose are useful.

If used, coatings are generally applied in weight percentages, based upon the weight of the coated particle, of about 5% to about 50%, with about 5% to about 20% preferred.

When used, coatings are applied from solutions containing one or more solvents. Useful solvents include ketones, e.g., acetone, alcohols and glycols, e.g., isopropyl alcohol, water, and the like.

Devices/Procedures The particles of the invention are preferably made using spinning techniques and devices disclosed in U.S. SN. 08/874,215, filed June 13, 1997 (corresponding to PCT/US98/10805, filed May 28, 1998, to be published in early 1999). When these devices are used, they are usually operated at about 10 to about 20% power at speeds of about Hz 40 to about 80 Hz.

The use of other thermoforming devices, for example extruders, at suitable temperatures, is contemplated.

When coatings are used, they are applied from a fluid bed or conventional spray device. One preferred device is a Glatt GPC-G1 coating machine.

When tablets are made, they are produced on conventional tabletting presses, such as the Kilian rotary tablet press. The tablets usually have final hardness values of about 20N (Newtons) to about 40 N.

Dosage Forms The microparticles of the invention are preferably microspheres having uniform shape and size. Due to their uniformity and size, such particles are suitable for use in oral dosage forms.

The microparticles can be used as is, for example in dry powders or sachets. Alternatively, they can be used to make capsules; solid, liquid, or semisolid suspensions; tablets; or other dosage forms. In these forms, they may be compressed along with other ingredients, contained in an enclosure (e.g., a capsule) and/or associated with one or more vehicles (e.g., a suspending media).

The microparticles may be used in dosage forms which do not involve oral administration. Thus, nasal, buccal, anal, and transdermal routes of administration are contemplated.

Examples The following examples illustrate the invention.

Example I: Nimesulide Microspheres A blend of 50% milled Pluronic F68 and 50% nimesulide was made. The blend was thermoformed into microspheres using the 5-inch V-groove head in the device described in U.S. SN. 08/874,215, filed June 13, 1997, at 10% power and 60 Hz speed.

The spinning device was operated at 10% power at 60Hz speed. Microspheres were screened and collected using 125 micron mesh and 425 micron mesh screens.

The microspheres were very spherical, having uniform shapes and sizes without milling.

The uncoated microspheres taste better than nimesulide alone. The microspheres were put into gelatin capsules, each capsule containing 100 mg of the active agent.

Example II: Other Microparticles An attempt was made to produce spherical microparticles using the same procedure shown in Example I, but substituting a composition containing 60% ibuprofen (m.p. 75-77°C.) and 40% Pluronic F68. The particles produced were of irregular shape and size. They lacked uniform sphericity. They had to be milled in order to reduce their particle size. ’ A comparison of Figure 3 (milled ibuprofen particles) with Figures 1 and 2 (unmilled nimesulide spheres) shows that microparticles made using ibuprofen, an active agent having a melting point below 90°C., were inferior to the microspheres of the invention, in terms of uniformity of shape and size.

Example III: Bioavailability Study The bioavailability of nimesulide from products containing microparticles (i.e., microspheres) made in accordance with Example I was assessed using the following procedure: In a cross over study, volunteers were each given either (i) 2 x lOOmg nimesulide microspheres poured out of capsules or (ii) 2 x 100 mg AULIN tablets.

All administra-tions were made with 240 mL water. After administration, blood samples were drawn for up to 36 hours.

Plasma concentrations of nimesulide were determined for each sample. Cmax, or maximum plasma concentration, was determined for each subject. A mean Cmax value was calculated. Tmax, or the time point' at which Cmax occurred in each subject, was determined and a mean was calculated. Plots were made of plasma concentrations vs. time and area under the curve (AUC) calculations were made.

The values of Cmax and Tmax for lOOmg microspheres is set out in the following table, along with the values based on similar tests run using a single dosing of 2 x 100 mg AULIN™. AULIN™ is a commercial nimesulide tablet sold by Helsinn Birex Pharmaceuticals, Ltd.. Based on the package insert for AULIN™, each 100 mg tablet contains nimesulide and the following inactive ingredients: docusate sodium, hydroxypropylcellulose, lactose, sodium starch glycolate, microcrystalline cellulose, hydrogenated vegetable oil and magnesium stearate.

Table 2· Bioavailability Data for Microparticles of the Invention and Commercial Product c '-'max fmcg./L) Tmax AUC o., ImcgJiZL) AUC0,nf (mca.h/Lj Microparticles of Invention 12,353 2.10 104,102 106,406 Commercial Product 12,569 2.03 101,386 101,250 Table 2 shows that the microparticles are comparable to the commercial tablet where Cmax and Tmax are concerned. In addition, AUC values indicate that the microspheres’ overall bioavailability is equivalent to that of the AULIN™ product. Example III: Nimesulide Tablets Rapid acting tablets are made using the microspheres of Example I, with no intermediate processing, in a formulation as follows: 67% uncoated microspheres, 26% Avicel PH 101, 3% Ac-Di-Sol, 2% Cab-0-Sil and 2% stearic acid. The ingredients are blended in a V-blender and compressed on a Kilian rotary tablet press using 8x16 mm caplet tooling to yield 300 mg tablets, having 30N hardness.

In standard dissolution studies made using a USP Apparatus II and pH 8.0 phosphate buffer solution, the tablets were 96% dissolved in 45 minutes.

Reasonable variations, such as those which would occur to a skilled artisan, can be made herein without departing from the scope of the invention.

Claims (10)

What is claimed is:

1. Microparticles suitable for delivering active agents from immediate release dosage forms, which microparticles are made by thermoforming a composition comprising: (a) about 1.0 % to about 80 % sparingly soluble active agent(s), (b) about 20 % to about 80 % polymeric solubilizer(s), and (c) about 0 % to about 20 % processing aid(s).

2. A dosage form comprising the microparticles of claim 1.

3. The microparticles of claim 1 having mean particle diameters, without milling, of about 100 to about 350 microns.

4. The microparticles of claim 3 wherein (a) is nimesulide or a derivative thereof and (b) is a polyoxyethylene/polyoxypropylene block copolymer solubilizer.

5. A dosage form comprising the microparticles of claim 4.

6. A process for making an oral dosage form comprising the steps: (1) subjecting a composition containing active agent(s), polymeric solubilizer(s) and processing aid(s) to thermoforming, and (2) recovering particles having mean particle diameters of about 100 to about 350 microns from the product of step (1).

7. The process of claim 6 further including the step of placing a plurality of the particles in a capsule.

8. The process of claim 7 further including the step of compressing a composition containing a plurality of the particles into a tablet.

9. A method of improving the taste of an active agent comprising the steps of: (1) thermoforming a composition containing: (a) about 1.0 % to about 80 % sparingly soluble active agent(s), (b) about 20 % to about 80 % polymeric solubilizer(s), and (c) about 0 % to about 20 % processing aid(s); and (2) recovering particles having mean particles diameters of about 100 to about 350 microns.

10. The method of claim 9 wherein the active agent is nimesulide or a derivative thereof.