WO2012087256A2

WO2012087256A2 - Pharmaceutical capsule formulations

Info

Publication number: WO2012087256A2
Application number: PCT/TR2011/000275
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Individual
Current assignee: Individual
Priority date: 2010-12-20
Filing date: 2011-12-19
Publication date: 2012-06-28
Anticipated expiration: 2013-06-20
Also published as: WO2012087255A3; TR201010618A2; WO2012087257A3; WO2012087256A3; WO2012087257A2; WO2012087255A2

Abstract

The present invention relates to pharmaceutical imatinib formulations comprising a pharmaceutically acceptable lubricant, glidant and at least one other excipient wherein the ratio of the lubricant and the glidant to each other is minimum 5 by weight; and production methods thereof.

Description

PHARMACEUTICAL CAPSULE FORMULATIONS

The present invention relates to pharmaceutical imatinib formulations comprising a pharmaceutically acceptable lubricant, a glidant and at least one other excipient wherein the ratio of the lubricant and the glidant to each other is minimum 5 by weight, and production methods of said formulations.

Background of the Invention

Imatinib mesylate, which is the methane sulfonic acid addition salt of imatinib, is available on the market under the trade name Glivec by Novartis AG. In the European patent numbered EP0564409, free base and pharmaceutically acceptable salts of imatinib (Formula I) have been disclosed.

(Formula I)

Imatinib, a tyrosine-kinase inhibitor, is effective on BCR-ABL enzyme. Therefore, this compound is indicated for chronic myeloid leukemia and acute lymphoblastic leukemia. Furthermore, it is also known that imatinib inhibits transmembrane receptor KIT and PDGF receptors (Merck Index, 14th edition, no: 4902, page 851).

It is also known that this compound shows polymorphic activity. In the patent application numbered WO9903854, β crystalline form of methane sulphonate salt of the compound has been disclosed. The product produced according to the patent numbered EP0564409 is a crystalline form of imatinib. In the patent application numbered EP 1857454, crystalline form I of the compound has been disclosed.

Imatinib free base and its salts were first disclosed in the patent numbered EP 564409. In the patent numbered WO2004074502, acid addition salts of imatinib and preparation methods thereof have been mentioned. The active agent is available in the form of 100 and 400 mg tablet and 100 mg capsule on the market.

However, during the studies conducted, the inventor has found that homogeneous and effective mixing cannot be provided in the formulations comprising imatinib and suitable excipients; the powder mixture is agglomerated through the production line.

When some situations such as adjustment of active agent dose appropriately, production technology of tablet and capsule are taken into consideration; mixing process is significantly important in preparation of the pharmaceutical formulations. Miscibility of powders basically depends on fluidity of the powders; and the more fluidal powder mass is, the more miscible it is. Aggregation problem which occurs during mixing, on the other hand, emerges after the particles are merged into each other as a result of increase in surface energies and cohesive forces between the particles in the mixture. It is quite hard to provide powder flow and homogeneous mixing in the aggregated mixture.

Failure to provide smooth powder fluidity, therefore content uniformity, causes a change in active agent dose amount in the unit dosage form that an effective treatment cannot be performed. Furthermore, this situation also poses problems at the stages of production and quality control.

In the prior art, these problems are usually tried to be solved by adding pharmaceutically acceptable lubricants into the formulations. Lubricants help to provide substantial fluidity property by reducing friction forces between powder particles.

However, adding lubricant into the formulations is not sufficient in order to solve the problems. Parameters such as adding sequence of the lubricant into the formulation, amount of the lubricant and mixing time etc. can negatively affect important factors such as solubility, physical characteristics of the end dosage form obtained.

In other words, the lubricant which is not used properly and in an appropriate amount causes decrease in solubility of the formulations obtained, constitution of hardly dispersible powder, failure to ensure sufficient physical characteristic (erosion, diffraction, hardness etc.) in dosage forms prepared.

In conclusion, it is seen there is need for new, highly soluble and bioavailable formulations wherein appropriate mixing and therefore appropriate powder fluidity can be provided in the pharmaceutical formulations comprising imatinib and suitable excipients. Detailed Description of the Invention

The present invention relates to pharmaceutical imatinib formulations comprising a pharmaceutically acceptable lubricant, a glidant and at least one other excipient wherein the ratio of the lubricant and glidant to each other is minimum 5 by weight, and production methods thereof.

Pharmaceutical capsule formulations of the present invention comprise imatinib minimum 80% by weight, preferably in the range of 80% to 99% by weight, more preferably in the range of 80% to 98% by weight.

The term "imatinib" used herein refers to pharmaceutically acceptable salts, enantiomers, racemates, solvates, hydrates, different polymorphic forms, amorphous forms and crystalline forms of the active agent or the combinations thereof.

One characteristic feature of the pharmaceutical formulations of the present invention is that the active agent comprised in the formulations is imatinib mesylate salt.

Another characteristic feature of the pharmaceutical formulations of the present invention is that mesylate salt of the active agent comprised in the formulations is in alpha or beta crystalline form, more preferably in alpha crystalline form.

One characteristic feature of the pharmaceutical formulations comprising imatinib as active agent is that the formulations are composed of a pharmaceutically acceptable lubricant, a glidant and at least one other excipient in addition to the active agent.

One characteristic feature of the formulation comprising imatinib as active agent and a pharmaceutically acceptable lubricant, a glidant and at least one other excipient is that the ratio of the lubricant and the glidant to each other comprised in the formulations is minimum 5 by weight.

One characteristic feature of the formulation comprising imatinib as active agent and a pharmaceutically acceptable lubricant, a glidant and at least one other excipient is that the ratio of the lubricant and the glidant to each other comprised in the formulations is in the range of 5 to 10 by weight.

One characteristic feature of the formulation comprising imatinib as active agent and a pharmaceutically acceptable lubricant, a glidant and at least one other excipient is that the ratio of the lubricant and the glidant to each other comprised in the formulations is in the range of 6 to 8 by weight.

The inventor has seen that use of lubricant and glidant in the amount given in imatinib formulations of the present invention provides more superior ease of mixing and fluidity than expected in the formulations. This unexpected positive effect positively affects content uniformity of the formulations obtained and therefore efficiency of the treatment.

In addition, ensuring appropriate mixing and fluidity property enables production of the formulations by one of the methods in the prior art, particularly by dry blending method easily.

In addition, pharmaceutical dosage forms produced with the formulations of the present invention possess the features required in terms of solubility and physical characteristics.

The lubricants that can be used in the formulations of the present invention comprising imatinib as active agent and a pharmaceutically acceptable lubricant, a glidant and at least one other excipient can be selected from a group comprising metallic stearates (such as magnesium stearate, calcium stearate, aluminium stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oil, leucine, polyethylene glycols (PEG), metallic lauryl sulphate (such as sodium lauryl sulphate, magnesium lauryl sulphate), sodium chloride, sodium benzoate, sodium acetate, talc, siliconized talc and/or hydrates or the combinations thereof.

One characteristic feature of the formulation of the present invention comprising imatinib as active agent and a pharmaceutically acceptable lubricant and a glidant and at least one other excipient is that the amount of the lubricant comprised in the formulations is in the range of 1 to 3% by weight, preferably in the range of 1 to 2 % by weight.

The lubricant which is particularly preferred is magnesium stearate in the formulations of the present invention comprising imatinib as active agent and a pharmaceutically acceptable lubricant, a glidant and at least one other excipient.

The glidants that can be used in the formulations of the present invention comprising imatinib as active agent and a pharmaceutically acceptable lubricant, a glidant and at least one other excipient can be selected from a group comprising silica, talc, colloidal silicone dioxide (Aerosil® 200, Syloid®, Cab-OSil®), magnesium trisilicate, cellulose powder, magnesium stearate and corn starch or the combinations thereof. One characteristic feature of the formulation comprising imatinib as active agent and a pharmaceutically acceptable lubricant and a glidant and at least one other excipient is that the amount of the glidant comprised in the formulations is in the range of 0.1 to 1 % by weight, preferably in the range of 0.1 to 0.5 % by weight.

On the other hand, it has been seen that specific surface area and particle size features of the glidant used in the formulations of the present invention also affects mixing and fluidity property of the end formulation.

According to this, the glidant comprised in the formulations has a specific surface area in the range of 150 to 300 m² /g; and an average particle size is in the range of 1 to 50 nm, preferably in the range of 1 to 40 nm, more preferably in the range of 1 to 30 nm.

The term "Average particle size" used herein signifies volumetric average particle size and it is also shown as d ₀ in short_. In this sense, the term d₅₀ refers that one half of said substance by volume has a particle size over the value stated with d₅₀, the other half of the substance has a particle size under the value stated with d₅₀.

The average particle size in the formulations of the present invention has been measured with a device which measures particle distribution by laser diffraction (Malvern Mastersizer etc.); as for the specific surface area, it has been measured with a BET (Micromeritics ASAP 2400) device which was calibrated properly.

The glidant which is particularly preferred is silicone dioxide in the formulations of the present invention comprising imatinib as active agent and a pharmaceutically acceptable lubricant, a glidant and at least one other excipient.

The excipients which can be used in the pharmaceutical formulations of the present invention in addition to the lubricant and glidant can be selected from a group comprising disintegrant, binders, viscosity enhancing components, filling agents, drying agents, surfactants, stabilizing agents, diluents, glidants, wetting agents, coating agents designed in order to provide various release properties, pH regulators, effervescent acids, effervescent bases, gelling agents, flavouring agents, sweeteners, emulgators, antifoaming agents, protective agents, solvents or solvent combinations, colouring agents and complexing agents or the combinations thereof.

The excipients that can be used in the pharmaceutical formulations of the present invention in addition to the lubricant and the glidant are preferably selected from a group comprising disintegrants, diluents, binders or the combinations thereof. According to this, the diluents that can be used in the formulations of the present invention can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch and starch derivatives (for instance corn starch), sodium chloride, sucrose, talc, xylitol or the combinations thereof.

The binders that can be used in the formulations of the present invention can be selected from a group comprising potato starch, wheat starch or corn starch; microcrystalline cellulose (Avicel®, Filtrak®, Heweten® or Pharmacel®), hydroxypropyl cellulose, hydroxyethyl cellulose; hydroxypropyl methyl cellulose (hydroxypropyl methyl cellulose-Type 2910 USP, hypromellose) and polyvinylpyrrolidone (for instance, Povidone® K30(BASF)), lactose, guar gum, pectin, gelatine, sodium alginate or the combinations thereof.

According to this, the disintegrants that can be used in the formulations of the present invention can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate or the combinations thereof.

The formulations of the present invention comprising imatinib as active agent and a pharmaceutically acceptable lubricant, a glidant and at least one other excipient are powder form.

The powder formulations of the present invention comprising a pharmaceutically acceptable disintegrant in the range of 0.1 to 5% by weight together with imatinib as active agent can be prepared in any one of the solid forms including tablet; layered tablet (for instance bilayer tablet); capsule; enterically coated or modified release tablet; controlled release tablet; prolonged release tablet; delayed release tablet; slow or fast release tablet; fast soluble tablet; effervescent tablet; fast soluble powder mixture; water soluble powder; pellet; mini tablet; micro tablet; granule in capsule; pellet in capsule; mini tablet in capsule; micro tablet in capsule or dry powder mixture to prepare syrup; dragee; orodispersible tablet; film coated tablet or a combination thereof.

The powder formulations of the present invention comprising a pharmaceutically acceptable disintegrant in the range of 0.1 to 5% by weight together with imatinib as active agent is preferably in tablet or capsule dosage form. In the case that the powder formulations of the present invention are prepared in capsule dosage form, the capsule that can be used can be made of a substance selected from a group comprising gelatine, chitosan, starch and/or starch derivatives, cellulose and/or cellulose derivatives or synthetic polymers. Furthermore, the capsule is composed of telescoping body and cap parts. The body and cap parts of said capsule can be made of the same or different materials.

According to the present invention, in the case that the capsule is made of cellulose and its derivatives; capsule material can be selected from a group comprising hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose or the combinations thereof.

According to the present invention, in the case that capsule is synthetic polymer; capsule material can be selected from a group comprising polyethylene, polyester, polyethylene terephthalate, polycarbonate or polypropylene or the combinations thereof.

According to the present invention, in the case that capsule material is gelatine; various molecular-weighted polyethylene glycol, sorbitol, glycerol, propylene glycol, titanium dioxide, polyethylene oxide- polypropylene oxide block copolymers and /or other polyalcohols and polyethers can be used as excipient.

In the case that the powder formulations of the present invention are prepared as capsule dosage forms, the preferred capsule is preferably gelatine capsule and said capsule can be in any shape and colour.

In the case that the powder formulations of the present invention is prepared as tablet dosage forms, said tablet dosage form can be coated with protective coating, enteric coating, film coating and/or coatings designed in order to provide various release properties (such as fast release, slow release, controlled release).

The film coating agents that can be used in the present invention can be selected from a group comprising cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose; polyvinyl alcohols such as iron oxides, titanium dioxide, polyethylene glycol; synthetic polymers such as polyvinyl acetal diethyl aminoacetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone and polysaccharides such as pullulan or the combinations thereof. The sugar based coating agents that can be used in the present invention can be selected from saccharose alone or optionally from a group comprising any of the agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatine, gum Arabic, polyvinylpyrrolidone and pullulan or any combination thereof.

The enteric coating agents that can be used in the present invention can be selected from a group comprising cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate; acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S; natural substances such as shellac or the combinations thereof.

Effective daily dose amount differs according to various factors such as patient's age, individual conditions, stage of the disease, mode of administration. For instance, daily imatinib dose required for adults varies in the range of 400 mg to 800 mg. According to this, in the case that the active agent is imatinib free base, amount of active agent in the oral dosage form is in the range of 50 mg to 800 mg, preferably in the range of 100 mg to 600 mg, more preferably in the range of 100 mg to 400 mg in another embodiment of the invention. In the case that active agent is a pharmaceutically acceptable derivative of imatinib, these substances are used in the amounts corresponding to 50 mg-800 mg, preferably to 100 mg-600 mg, more preferably to 100 mg-400 mg of imatinib free base.

According to this, the amount of imatinib comprised in the pharmaceutical formulations of the present invention corresponds to imatinib free base in the range of 50 mg to 800 mg, preferably in the range of 100 mg to 600 mg, more preferably in the range of 100 mg and 400 mg.

In another embodiment of the invention, the oral dosage form comprising an effective amount of alpha crystalline form of imatinib mesylate can be administered separately, sequentially and simultaneously with dosage forms comprising active agents belonging to groups such as rapamycin, cyclosporine, ascomycine, corticosteroid, cyclophosphamide, azathioprine, methotrexate, brequinar, leflunomide, mizoribine, mycophenolic acid and/or mycophenolate mofetil.

The formulation of the present invention comprising imatinib as active agent and a pharmaceutically acceptable lubricant, a glidant and at least one other excipient is preferably produced by dry blending method. Dry blending method which is used in order to produce the formulation of the present invention comprising imatinib as active agent and a pharmaceutically acceptable lubricant, a glidant and at least one other excipient is preferably composed of the following steps:

1. The active agent, glidant and at least one other excipient are mixed dryly,

2. The mixture obtained is sieved,

3. The lubricant is added into the mixture and mixed again,

4. Final mixture is optionally compressed in tablet form or filled into capsules.

The formulations of the present invention comprising imatinib as active agent and a pharmaceutically acceptable lubricant, a glidant and at least one other excipient are used in the treatment of acute lymphocytic leukemia, gastrointestinal stromal tumors (GIST), hypereosinophilic syndrome, chronic myelogenous leukemia (CML), myelodysplastic syndrome and systemic mastocytosis.

The examples below are given only in order to render the invention more comprehensible. To this respect, the scope of the invention is not limited to these examples.

EXAMPLE 1: Imatinib Capsule Formulation

Imatinib mesylate, the disintegrant and the glidant are mixed for production of the formulation given; the lubricant is added into the mixture and the mixture is mixed again. The mixture is presented as filled into a hard gelatine capsule which is preferably made of titanium dioxide and gelatine.

EXAMPLE 2: Imatinib Tablet Formulation

Imatinib mesylate, the disintegrant and the glidant are mixed for production of the formulation given; the lubricant is added into the mixture and the mixture is mixed again. The mixture is compressed in tablet form and coated with film coating material.

Claims

1. Pharmaceutical formulations comprising imatinib characterized in that said formulations comprise a pharmaceutically acceptable lubricant, a glidant and at least one other excipient; and the ratio of the lubricant and the glidant comprised in the formulations to each other is minimum 5 by weight.

2. The pharmaceutical formulation according to claim 1 characterized in that the ratio of the lubricant and the glidant comprised in the formulations to each other is in the range of 5 to 10 by weight.

3. The pharmaceutical formulation according to claims 1-2 characterized in that the ratio of the lubricant and the glidant comprised in the formulations to each other is in the range of 6 to 8 by weight.

4. The pharmaceutical formulation according to claims 1-3 characterized in that the lubricants comprised in the formulations are selected from a group comprising metallic stearates (such as magnesium stearate, calcium stearate, aluminium stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids ( such as stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols (PEG), metallic lauryl sulphate (such as sodium lauryl sulphate, magnesium lauryl sulphate), sodium chloride, sodium benzoate, sodium acetate, talc, siliconized talc and/or hydrates or combinations thereof.

5. The pharmaceutical formulation according to claims 1-4 characterized in that the amount of the lubricant comprised in the formulations is in the range of 1 to 3 % by weight.

6. The pharmaceutical formulation according to claims 1-5 characterized in that the amount of the lubricant comprised in the formulations is in the range of 1 to 2 % by weight.

7. The pharmaceutical formulation according to claims 1-6 characterized in that the lubricant comprised in the formulations is magnesium stearate.

8. The pharmaceutical formulation according to claims 1-7 characterized in that the glidants comprised in the formulations can be selected from a group comprising silica, talc, colloidal silicone dioxide (Aerosil® 200, Syloid®, Cab-OSil®), magnesium trisilicate, cellulose powder, magnesium stearate and corn starch or the combinations thereof.

9. The pharmaceutical formulation according to claims 1-8 characterized in that the amount of the glidant comprised in the formulations is in the range of 0.1 to 1 % by weight.

10. The pharmaceutical formulation according to claims 1-9 characterized in that the amount of the glidant comprised in the formulations is in the range of 0.1 to 5 % by weight.

11. The pharmaceutical formulation according to claims 1-10 characterized in that the specific surface area of the glidant comprised in the formulations is in the range of 150 m2/g to 300 m2/g.

12. The pharmaceutical formulation according to claims 1-11 characterized in that the average particle size of the glidant comprised in the formulations in the range of 1 to 50 nm.

13. The pharmaceutical formulation according to claims 1-12 characterized in that the average particle size of the glidant comprised in the formulations is in the range of 1 to 30 nm.

14. The pharmaceutical formulation according to any preceding claims characterized in that said formulations comprise at least one other excipient selected from a group comprising disintegrant, binders, viscosity enhancing components, filling agents, drying agents, surfactants, stabilizing agents, diluents, glidants, wetting agents, coating agents designed to provide various release properties, pH regulators, effervescent acids, effervescent bases, gelling agents, flavouring agents, sweeteners, emulgators, antifoaming agents, protective agents, solvent or solvent mixtures, colouring agents and complexing agents or the combinations thereof in addition to the lubricant and the glidant.

15. The pharmaceutical formulation according to claim 14 characterized in that the excipients that can be used in the formulations in addition to lubricant and glidant are selected from a group comprising disintegrants, diluents, binders or the combinations thereof.

16. The pharmaceutical formulation according to any preceding claims characterized in that said formulation is in capsule dosage form.

17. The pharmaceutical formulation according to any preceding claims characterized in that said formulations are in tablet dosage form.

18. A method for production of the pharmaceutical formulation comprising imatinib, a pharmaceutically acceptable lubricant, a glidant and at least one other excipient characterized in that said method is dry blending method.

19. The method according to claim 18 characterized in that said method comprises the steps of:

a) Mixing imatinib, the glidant and at least one other excipient dryly,

b) Sieving the mixture obtained, c) Adding lubricant into the mixture and mixing it again,

d) Optionally compressing the final mixture in tablet form or filling it into capsules.