WO2006041843A2

WO2006041843A2 - Pharmaceutical dosage form comprising meloxicam

Info

Publication number: WO2006041843A2
Application number: PCT/US2005/035686
Authority: WO
Inventors: Pratibha Kuldeep Bhat; Amit Mukharya; Praveen Reddy Billa; Mailatur Sivaraman Mohan
Original assignee: Dr. Reddy's Laboratories Ltd.; Dr. Reddy's Laboratories, Inc.
Priority date: 2004-10-04
Filing date: 2005-10-04
Publication date: 2006-04-20
Also published as: WO2006041843A3

Abstract

Meloxicam powder having a mean particle size of about 2 µm to about 25 µm, pharmaceutical compositions containing the powder, a process to prepare the compositions, and their use in the treatment of conditions such as inflammation, pain, fever and arthritis.

Description

PHARMACEUTICAL DOSAGE FORM COMPRISING MELOXICAM

INTRODUCTION TO THE INVENTION

The present invention relates to solid oral pharmaceutical compositions comprising meloxicam or pharmaceutically acceptable salts, solvates, enantiomers or mixtures thereof with improved solubility and desired dissolution characteristics.

Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and antipyretic activities. The mechanism of action of meloxicam is similar to other NSAIDs related to prostaglandin synthetase (cyclooxygenase) inhibition.

Meloxicam, an oxicam derivative, is a member of the enolic acid group of NSAIDs. It is chemically designated as 4-hydroxy-2-methyl-/V-(5-methyl-2- thiazolyl)-2H-1 ,2-benzothiazine-3-carboxamide-1 ,1 -dioxide with the structural Formula I.

Formula I

Meloxicam is the active ingredient in pharmaceutical products currently marketed using the trademark MOBIC, the tablet products containing 7.5 mg and 15 mg of meloxicam for oral administration. Pharmacokinetics of meloxicam have been shown to be dose proportional with single dosing within the dose range of 5 to 60 mg. Mean C_maχ (maximum plasma concentration) was achieved within 4-5 hours after administration of the 7.5 mg MOBIC tablet under fasted conditions.

U.S. Patent Nos. 6,184,220 and 6,682,747 to Tϋrck et al. describe an aqueous oral suspension formulation comprising particles of NSAID selected from the acid enolcarboxamides (oxicams), particularly meloxicam, having a suspendable particle size spectrum in which at least 90% of the particles are smaller than 50 μm. Preferably, at least 50% of the particles are smaller than 10 μm and most preferably about 90% of the particles are smaller than 10 μm. This can be achieved by grinding a coarser grade of the oxicam. An objective for making the suspension preparations was to get a rapid onset of action after single dose administration and also to lower the rate of sedimentation of active substance in the suspension, even during long-term storage, to ensure a high degree of accuracy in measuring the dose. The patents also compare the fine particle material suspension formulation and a capsule preparation. The t_max (time required for achieving a maximum plasma concentration of the drug) of 2 hours (range 1.5 to 5 hours) for the suspension formulation was statistically different from the t_max of 5 hours (range 2 to 6 hours) for the capsule.

U.S. Patent No. 6,284,269 to Struengmann et al. describes a pharmaceutical composition comprising meloxicam as an active ingredient, a cyclodextrin, a facultative oligosaccharide other than cyclodextrin, a facultative polysaccharide, one or more pharmaceutically acceptable additives, and facultative excipients, carriers and/or auxiliary agents, wherein the pharmaceutical composition is obtainable by co-milling, co-grinding or co-kneading meloxicam in the presence of cyclodextrin as a pharmaceutically acceptable additive. The composition after the grinding process in presence of cyclodextrin exhibited an improved dissolution profile compared to meloxicam ground alone under the same conditions.

PCT Publication No. WO 2005/002542 of Elan Pharma International Ltd. discloses a nanoparticulate composition comprising meloxicam particles having an effective average particle size of less than about 2000 nm and at least one surface stabilizer. The nanoparticulate compositions, either in the form of a colloidal dispersion or as a lyophilized wafer, have higher bioavailabilities as compared to the commercial MOB1C^® tablet.

The rate of dissolution of a poorly-soluble drug is a rate-limiting factor in its absorption by the body. A reduction in the particle size can increase the dissolution rate of such compounds through an increase in the surface area of the solid phase that is in contact with the liquid medium, thereby resulting in an enhanced bioavailability of the compositions containing such compounds. It is generally not possible to predict the exact particle size and distribution required for any particular drug substance to achieve a specific dissolution profile or a specific in vivo behavior, as different drugs show differing dissolution characteristics with a reduction in the particle size. The problem is further complicated by the fact that the same compound may exist in more than one crystalline form, each of which could have a different dissolution profile.

Globally, regulatory authorities require that, for a drug product to be used as a generic substitute for a marketed formulation of a compound, it is essential that the generic formulation be equivalent to the marketed formulation in terms of both in vitro behavior as well as in vivo behavior.

SUMMARY OF THE INVENTION

The present invention relates to solid oral pharmaceutical compositions of meloxicam or pharmaceutically acceptable salts, solvates, enantiomers or mixtures thereof of a defined particle size and distribution and processes for preparing the same.

The invention also relates to solid oral pharmaceutical compositions comprising meloxicam having a defined particle size wherein a plurality of meloxicam particles have a mean particle size of about 2 μm to about 25 μm, or about 2 μm to about 10 μm, or about 2 μm to about 5 μm. In an embodiment, the particles have a size distribution of Di₀ about 2 μm or less, D₅₀ about 5 μm or less, and D₉₀ about 15 μm or less.

In one embodiment of the invention, the solid oral pharmaceutical composition is a dosage form such as a tablet or capsule.

The invention further relates to processes for preparing the pharmaceutical compositions using meloxicam of defined particle size and distribution as defined above. An embodiment of the process comprises: a. forming a mixture of the meloxicam particles and at least one pharmaceutically acceptable excipient; b. optionally granulating the mixture, optionally using an aqueous or organic solvent, with or without a binder, and removing solvent to form a granulate; and -A-

c. compressing the mixture of a. or the granulate of b. into a tablet, or filling the mixture or granulate into a capsule.

The invention also includes therapeutic uses and methods of treatment employing the composition comprising meloxicam of defined particle size and distribution or such pharmaceutical dosage forms, medicaments or products.

DETAILED DESCRIPTION

The present invention relates to solid oral pharmaceutical compositions of meloxicam of defined particle sizes and distribution and processes for preparing the same.

A particle size distribution of D₅₀ as used herein is defined as the distribution where 50 volume-% of the particles are smaller than that size given, A particle size distribution of Dio as used herein is defined as the distribution where 10 volume-% of the particles are smaller than that size given, A particle size distribution of Dgo as used herein is defined as the distribution where 90 volume-% of the particles are smaller than that size given. The D₅₀ value is considered to be a "mean particle size."

The drug meloxicam as used herein includes without any limitation pharmaceutically acceptable salts, solvates, enantiomers, other polymorphic or crystalline forms or mixtures thereof.

In one embodiment of the invention, meloxicam with a defined particle size and distribution is provided which enables the preparation of pharmaceutical dosage forms with a better control on the in vitro and in vivo behavior. The meloxicam of the invention comprises a plurality of meloxicam particles having a mean particle size (D₅₀) of about 2 μm to about 25 μm, or about 2 μm to about 10 μm, or about 2 μm to about 5 μm.

It will be appreciated by those skilled in the art of particle size reduction that there are numerous known methods which can be applied to the production of meloxicam of defined particle size, such as fluid energy milling or micronizing, ball milling, colloid milling, roller milling, hammer milling, and the like. The principal operations of conventional size reduction known in the art are milling of the feed stock material and sorting of the milled material by size. In an embodiment, feedstock used comprises but is not limited to crystals, powder aggregates, and coarse powders of either crystalline or amorphous meloxicam, and the like.

The most widely practiced methods of sorting by particle size involve passing the milled material through a stack of sieves, each having openings of different sizes. The sieves are arranged so that the material encounters the sieve having the largest openings first, and those particles that pass through the first sieve encounter a second sieve with smaller openings. Particles that pass through the second sieve may encounter a third sieve, and so forth. Meloxicam particles can also be separated by particle size using various techniques such as cyclonic techniques, centrifugation techniques, and the like.

In one embodiment, a fluid energy mill or "micronizer" is found to be useful for its ability to produce particles of small sizes in a narrow size distribution. Micronizers use the kinetic energy of collisions between particles suspended in a rapidly moving fluid (typically air or an inert gas) stream to cleave the particles.

In an embodiment, an air jet mill is found to be useful as an example of a fluid energy mill. The suspended particles are injected under pressure into a recirculating particle stream, typically in a manner to intersect with the recirculating stream at an oblique angle. Smaller particles are carried aloft inside the mill and swept into a vent connected to a particle size classifier such as a cyclone separator. The feedstock used will usually first be milled to have a mean particle size about 150 to 850 μm, or smaller.

The size distribution of meloxicam particles of the present invention can be determined by techniques such as, for example, laser diffraction, Coulter counter measurement, or microscopy. Other techniques for the measurement of particle size are also acceptable.

The sizes of meloxicam particles and the distributions reported herein were determined using a Malvern Mastersizer™ laser diffraction instrument (Malvern Instruments Ltd., Worcestershire, UK). Samples of the meloxicam were suspended in hexane containing the surfactant, 1% polyoxyethylene sorbitan monooleate. The suspensions were mixed and then sonicated for 1-5 minutes to thoroughly disperse the meloxicam particles. The dispersion was then circulated in the flow cell of the Malvern Mastersizer™ for about two minutes before particle size measurements were taken.

The invention also relates to solid oral pharmaceutical compositions comprising meloxicam having a defined particle size wherein a plurality of meloxicam particles have a mean particle size (D₅o) about 2 μm to about 25 μm, or about 2 μm to about 10 μm, or about 2 μm to about 5 μm, with a desired in vitro and in vivo behavior.

Meloxicam with a defined particle size and distribution as described herein is useful for preparing pharmaceutical compositions and encapsulated free flowing and compressed solid dosage forms such as tablets, caplets, capsules, troches, lozenges and the like. The meloxicam is also useful for preparing solid dosage forms such as powders, including granulated powders. In one of the embodiments, the meloxicam with a particle size and distribution as defined herein is useful in the preparation of tablet formulations which have in vitro and in vivo behavior comparable to that of a commercially available product, MOBIC.

As used herein, "pharmaceutical composition" means a solid dosage form (medicament) for use in treating a mammal that includes meloxicam of a defined particle size distribution and is prepared in a manner that is appropriate for administration to a mammal, preferably a human. A pharmaceutical composition contains one or more pharmaceutically acceptable excipients that are non-toxic to the mammal intended to be treated when the composition is administered in an amount effective to treat the mammal.

Pharmaceutically acceptable excipients are well known in the art and perform various functions. They add bulk or act as diluents, improve bulk-handling properties or aid in dissolution or disintegration of the final oral solid dosage form. A person skilled in the art of development and manufacture of pharmaceutical solid oral dosage forms is aware of the factors involved in making a choice of different excipients. A given pharmaceutically acceptable excipient may have more than one of the foregoing characteristics or properties and classification of excipients according to function is therefore somewhat arbitrary.

The pharmaceutical compositions of the present invention can contain one or more diluents added to make the tablet or capsule mass and hence easier for the formulator, patient and caregiver to handle. Common diluents are, but are not limited to, microcrystalline cellulose, powdered cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, and the like.

Binders can also be included in the pharmaceutical compositions of the present invention to help hold granules or tablets together. Some typical binders are: gums like acacia, alginic acid, sodium alginate, gelatin, guar gum; starch; pregelatinized starch; carbomer (e.g. carbopol); povidone (e.g. Kollidon®, Plasdone®); celluloses like carboxy methylcellulose sodium, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®); liquid glucose; magnesium aluminum silicate (Veegum™); dextrin; maltodextrin; polymethacrylates; and the like. Useful organic alkalizers or inorganic salts for pH adjustment include but are not limited to sodium or potassium carbonate; sodium or potassium citrate; sodium or potassium acetate, and basic amines such as arginine, tromethamine and meglumine.

The pharmaceutical compositions to be made into tablets or capsules can further include a disintegrant to accelerate disintegration of the tablet or capsule in the patient's digestive system. Useful disintegrants include alginic acid, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium (e.g. Ac-Di- Sol®, Primellose®), colloidal silicon dioxide, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab®), starch, and the like.

Pharmaceutical compositions for tableting and encapsulation may further include glidants, lubricants, flavoring agents, colorants and other commonly used excipients, as will be readily appreciated by a person skilled in the art. Pharmaceutical compositions are prepared using process known to those skilled in the art, such as direct compression, dry granulation, compaction granulation, or wet granulation. Powder blends or granules are further mixed with other excipients and either filled into capsules or compressed as tablet. These and other excipients may all be used without limitation to provide a pharmaceutical composition containing meloxicam with the above described particle size characteristics of the invention.

The meloxicam compositions of the present invention can be administered to a mammal via the oral route. As used herein the term "mammal" is used to define a human or a non-human. The term patient and mammal may be used interchangeably. The present invention provides a method of rapidly increasing the plasma levels of meloxicam in a patient. Such a method comprises administering to a mammal an effective amount of a composition comprising meloxicam particles having a mean particle sizes (D₅o) of about 2 μm to about 25 μm, or about 2 μm to about 10 μm, or about 2 μm to about 5 μm.

The compositions of the invention are useful in treating or preventing disorders or conditions such as arthritic disorders, gastrointestinal conditions, inflammatory conditions, pulmonary inflammation, ophthalmic diseases, central nervous system disorders, pain, fever, inflammation related cardiovascular disorders, disorders of female reproductive system such as endometriosis, osteoporosis, dysmenorrhea, and fibromyalgia syndrome, infectious arthritis, psoriatic arthritis, osteoarthritis, rheumatoid arthritis, and the like.

An orally administered tablet or capsule according to the invention can contain one or more NSAIDs as a pharmaceutically active substance in addition to meloxicam particles having a mean particle size (D₅₀) of about 2 μm to about 25 μm. The classic active substance acetylsalicylic acid and the following active substances of the following categories are examples of these NSAIDs: propionic acid derivatives such as but not limited to ibuprofen, naproxen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, and the pharmaceutically acceptable salts and derivatives thereof; acetic acid derivatives such as but not limited to indomethacin, sulindac, tolmetin, zomepirac, nabumetone, diclofenac, fenclofenac, alclofenac, bromfenac, ibufenac, aceclofenac, acemetacin, fentiazac, clidanac, etodolac. oxpinac, and the pharmaceutically acceptable salts and other derivatives thereof; fenamic acid derivatives, such as but not limited to, mefenamic acid, meclofenamic acid, flufenamic acid, nifluminic acid, tolfenamic acid and the pharmaceutically acceptable salts thereof; biphenylcarboxylic acid derivatives, such as but not limited to, diflunisal, flufenisal, and the pharmaceutically acceptable salts thereof; acid enolcarboxamides (oxicams), such as but not limited to, piroxicam, tenoxicam, lomoxicam, and the pharmaceutically acceptable salts thereof; diaryl heterocycles with methylsulphonyl or aminosulphonyl substitutes, acid sulphonamides such as but not limited to nimesulide; and the like.

The dose of meloxicam in a pharmaceutical composition according to the instant invention can range from about 1 to about 20 milligrams, or from about 5 to about 15 milligrams.

In one embodiment, meloxicam with a mean particle size in the range of about 2 to about 25 μm, or about 2 to about 10 μm, or about 2 to about 5 μm, is suitable for purposes of the invention. Useful meloxicam average particle sizes for compositions of the invention include about 2 μm, or about 3 μm, or about 4 μm, and the particles will typically have bulk densities about 0.2 to about 0.3 g/ml, with tapped bulk densities about 0.4 to about 0.6 g/ml, as determined using the standard method of Test 611 (Bulk Density and Tapped Density) of United States Pharmacopeia 24, The United States Pharmacopeial Convention, Inc., Rockville, Maryland, 1999. In an embodiment, meloxicam particles have a particle size distribution of Di₀ about 2 μm or less, D₅₀ about 5 μm or less, and Dg₀ about 15 μm or less. In one of the embodiments of the invention, a process for the manufacture of the meloxicam composition of the invention is provided, comprising:

1. forming a mixture of meloxicam having the desired particle size with a desired excipient or excipients;

2. optionally granulating the dry mixture, optionally using an aqueous or organic solvent, with or without a binder, and removing solvent to form a granulate; and

3. filling the mixture or granulate into a capsule, or compressing into a tablet.

Useful solvents for granulating the dry mixture containing meloxicam of desired particle sizes include, without limitation thereto, water, isopropyl alcohol, acetone, dichloromethane, methanol, ethanol, chloroform and the like. Combinations of one or more solvents for use in granulation also falls within the scope of invention. The following examples will further illustrate certain aspects of the invention in greater detail and are not intended to limit the scope of the invention.

EXAMPLE 1

A coarse meloxicam powder was subjected to size reduction by jet milling, using air as the fluid at pressures about 4-6 bar, in an Alpine jet micronizer manufactured by Hosokawa Alpine AG, of Augsburg, Germany. Particle size distributions of the feed material and two batches of micronized products were determined using a Malvern Mastersizer instrument. The feed material and micronized products were also characterized according to Test 611 (Bulk Density and Tapped Density) of United States Pharmacopeia 24, The United States Pharmacopeial Convention, Inc., Rockville, Maryland, 1999, using tapping Method II, and the following results were obtained:

EXAMPLE 2

Samples of meloxicam having different particle size distribution profiles were filled into gelatin capsules, for dissolution testing. The samples were characterized, as follows:

Capsules containing 15 mg of drug were tested according to Test 711 (Dissolution) of United States Pharmacopeia 24, The United States Pharmacopeial Convention, Inc., Rockville, Maryland, 1999, using Apparatus 2, a stirring rate of 75 rpm, and 900 ml of a pH 7.5 phosphate buffer.

The above data show that the Sample B comprising meloxicam having a mean particle size about 4 μm exhibits a higher rate and extent of drug dissolution, when compared to the Sample A with a mean particle size of about 79 μm. The above results demonstrate the impact of a particle size reduction on enhancing the dissolution of meloxicam.

EXAMPLE 3

The following ingredients were used to prepare tablets:

Manufacturing process:

1. The first four ingredients were weighed and sifted through a 40 mesh sieve, then were mixed in a rapid mixer granulator for 20 minutes; 2. sodium citrate was weighed and dissolved in about 0.5 ml of water;

3. PVP K-30 was weighed and dissolved in about 0.5 ml of water;

4. the dry mixture of step 1 was granulated using solutions of steps 2 and 3;

5. the granules were dried in a fluidized bed drier at 6O⁰C until the loss on drying at 105⁰C was less than 2.5%;

6.. the granules were mixed with silicon dioxide and magnesium stearate for 5 minutes in a double cone blender; and

7. the mixture of step 7 was compressed into tablets using a rotary tablet compression machine.

EXAMPLE 4

The following ingredients were used to prepare tablets:

The tablets were manufactured using the procedure of Example 2.

EXAMPLE 5

To prepare capsule dosage forms, the procedures of examples 3 and 4 were followed through step 6, then appropriate amounts of the granules to provide either 7.5 or 15 mg of meloxicam were filled into gelatin capsules. EXAMPLE 6

Tablet formulations 1 , 2, and 3 were prepared as described in Example 3, except for the presence or absence of the sodium citrate dihydrate component, and the particle size distribution of the meloxicam.

Formulation 1 was made using coarse meloxicam (D₅₀ « 79 μm), and without the sodium citrate dihydrate.

Formulation 2 was made using coarse meloxicam (D₅₀ « 79 μm) and with the sodium citrate dihydrate.

Formulation 3 was made using fine meloxicam (D₅₀ ~ 4 μm) and with the sodium citrate dihydrate.

The tablets were tested for their dissolution characteristics, using the procedure described in Example 1 , but with a dissolution medium which was simulated gastric fluid having a pH of 2.1 , giving the following results:

The above data show that tablet formulation 3 comprising meloxicam of a mean particle size about 4 μm exhibits a higher rate and extent of drug dissolution, when compared to the formulations 1 and 2 with a mean meloxicam particle size of about 79 μm, either with or without sodium citrate dihydrate.

EXAMPLE 7

Pharmaceutical compositions prepared according to Example 3 and comprising meloxicam having a mean particle size about 2 μm were tested for bioequivalence to the commercially available meloxicam 15 mg tablets (MOBIC^®). An open label single dose crossover study was carried out using thirteen healthy human male volunteers in the fed state. The results of the study are tabulated below:

Claims

CLAIMS:

1. A solid pharmaceutical dosage form prepared from components comprising meloxicam particles having a mean particle size about 2 μm to about 25 μm, and at least one pharmaceutically acceptable excipient.

2. The dosage form of claim 1 , wherein the mean particle size is about 2 μm to about 10 μm.

3. The dosage form of claim 1 , wherein the mean particle size is about 2 μm to about 5 μm.

4. The dosage form of claim 1 , wherein meloxicam particles have a particle size distribution of Dio about 2 μm or less, D₅₀ about 5 μm or less, and Dgo about 15 μm or less.

5. The dosage form of claim 1 , wherein meloxicam particles have a mean particle size about 4 μm,

6. The dosage form of claim 1 , wherein meloxicam particles have a mean particle size about 3 μm.

7. The dosage form of claim 1 , wherein meloxicam particles have a mean particle size about 2 μm.

8. The dosage form of claim 1 , wherein meloxicam particles have a bulk density about 0.2 to about 0.3 g/ml, and a tapped bulk density about 0.4 to about 0.6 g/ml.

9. The dosage form of claim 1 , wherein meloxicam particles have an untapped bulk density about 0.26 g/ml, and a bulk density after tapping about 0.48 g/ml.

10. The dosage form of claim 1 , which comprises a tablet.

11. The dosage form of claim 1 , which comprises a capsule.

12. A process for preparing the dosage form of claim 1 , comprising: a. forming a mixture of the meloxicam particles and at least one pharmaceutically acceptable excipient; b. optionally granulating the mixture, optionally using an aqueous or organic solvent, with or without a binder, and removing solvent to form a granulate; and c. compressing the mixture of a. or the granulate of b. into a tablet, or filling the mixture or granulate into a capsule.

13. A process for preparing a tablet of claim 10, comprising: a. forming a mixture of the meloxicam particles and at least one pharmaceutically acceptable excipient; b. granulating the mixture using an aqueous solution of a binder, and removing solvent to form a granulate; and c. compressing the granulate to form a tablet.

14. The process of claim 13, wherein meloxicam particles have a particle size distribution of D-|₀ about 2 μm or less, D₅₀ about 5 μm or less, and D₉₀ about 15 μm or less.

15. A method of treating at least one of inflammation, pain, fever, and arthritis, comprising administering an effective amount of the dosage form of claim 1.

16. Meloxicam powder having a particle size distribution of D₁₀ about 2 μm or less, D₅₀ about 5 μm or less, and Dg₀ about 15 μm or less.

17. A solid pharmaceutical dosage form prepared using the meloxicam of claim 16.