WO2010026467A2

WO2010026467A2 - Controlled release dosage form of high solubility active ingredient

Info

Publication number: WO2010026467A2
Application number: PCT/IB2009/006733
Authority: WO
Inventors: Jaya Abraham; Vinodkumar Gupta; Bhavesh Shah
Original assignee: Torrent Pharmaceuticals Ltd.
Priority date: 2008-09-04
Filing date: 2009-09-03
Publication date: 2010-03-11
Also published as: WO2010026467A3

Abstract

The present invention relates to a solid oral controlled release dosage form comprising high solubility active ingredient, wherein the dosage form is manufactured by single step granulation using at least one hydrophobic release controlling agent. The said dosage form is further coated using at least one hydrophobic release controlling agent. The present invention further discloses the process for preparing the said dosage form. Preferred water soluble drugs are levetiracetam or citicoline.

Description

CONTROLLED RELEASE DOSAGE FORM OF HIGH SOLUBILITY ACTIVE INGREDIENT

FIELD OF THE INVENTION

The present invention relates to a solid oral controlled release tablet dosage form comprising high solubility active ingredient, wherein the dosage form is manufactured by single step granulation using atleast one hydrophobic release controlling agent and compressed tablet is coated with atleast one hydrophobic release controlling agent. The present invention further discloses the process for preparing the said dosage form. BACKGROUND OF THE INVENTION

It is essential that to achieve desired therapeutic response, the blood level of the drug should be maintained within the therapeutic window. Majority of drugs require multiple dosing in a day to maintain the desired therapeutic effect. Such multiple dosing is the main reason for the patient incompliance.

Conventional solid oral pharmaceutical dosage forms are comprised of immediate release (IR) dosages in the form of tablets or capsules. These IR dosage forms release the active drug substance into the body of a subject at a rate that is initially very high followed by a rapid decline. One potential result of an IR dosage form is that the subject may have high degree of blood level fluctuation, which may result in transient therapeutic overdose, followed by a period of therapeutic under dosing and which may some time lead to sub therapeutic blood levels and/or side effects to the patient.

So the overall disadvantages with regard to immediate release dosage form are frequent dosing, which results in poor patient compliance, varying degree of blood level fluctuation and side effects. These problems can be generally overcome by formulating the drug in the controlled release dosage form.

There are number of techniques available to formulate the controlled release system such as matrix, reservoir, osmotic etc. Matrix system using hydrophilic polymeric material is the most preferred method because it is simple, cost effective and easy to manufacture. However, for the drugs having high solubility and high dose, such matrices do not provide adequate control over the release rate, and also require large amounts of polymer to achieve appropriate controlled release profiles. This will increase the size of dosage form. The various techniques to make controlled release dosage form of high solubility active ingredients as described in prior art are as follows:

One method of prolonging the release of a highly water-soluble drug is disclosed in PCT Patent application no. WO99/47128. A biphasic controlled release delivery system for metformin hydrochloride, which has prolonged gastric residence and that swells following hydration. The ratio of inner solid phase to outer continuous phase is 0.5: 1 to about 4: 1. The major limitation of this invention is that it provides a very bulky formulation for higher doses of the metformin hydrochloride that is very inconvenient for human consumption. For instance, example cited provides formulation of 500 mg metformin hydrochloride with tablet weight of about 1.0 gm. Hence restricting to the low dose sustained release tablets of 500 mg or slightly more and making it obligatory to take two tablets of 500 mg each time to provide sustain action. The cited example teaches use of combination of atleast one hydrophilic polymer and which is an essential part for swelling. Non swellable or non erodeble formulations are not included in the invention.

Similarly US patent no. 6340475 B2 assigned to Depomed Inc. describes monolithic controlled release formulation of highly water soluble drugs including metformin hydrochloride. The formulation swells when ingested thus prolonging its residence time in the stomach. The formulations are made of hydrophilic polymers, which results in swellable and erodible matrix.

Another method of prolonging the release of a highly water-soluble drug is disclosed in International Patent application publication no. WO 96/26718, published Sep. 6, 1996. The method of this publication is the incorporation of the drug into a polymeric matrix to form a tablet that is administered orally. The polymer is water- swellable yet erodible in gastric fluids.

Similarly Chih-Ming Chen in international patent application number WO 02/36100 describes a once a day formulation of metformin hydrochloride which is based on osmotically controlled technique and that is non expandable in nature and has a passage in the coating membrane for release of drug.

Kim et al. in United States patent number 6337091 describes a matrix based controlled release formulation for highly soluble drugs over long periods of time. The release controlling agent is a swellable gum which encapsulates or make granules of drug, which is then disposed in more swellable erodible polymers such as HPMC or poly (ethyleneoxide). CN 1628690 discloses a citicoline sustained and controlled release preparation prepared by matrix system using HPMC as release controlling agent and other conventional adjuvant and process for making the same. The amount of polymer required here almost more than 100% of the amount of citicoline which results in unacceptable size of the dosage form.

IN 193041 discloses preparation of modified release dosage form of high solubility active ingredients, in which micromatrix particles comprises active ingredient and release controlling agent and said micromatrix particles are further coated with release controlling agent. These coated micromatrix particles are then compressed into tablets.

WO/2006080029 discloses an extended release pharmaceutical composition of Levetiracetam with once a day dosage regime and the process of preparing it. The extended release tablet of Levetiracetam with the core comprising of Levetiracetam and water dispersible rate controlling polymer, and the tablet core optionally functional coated comprising a combination of water non-dispersible and/or water dispersible polymer. According to the examples disclosed in the patent application, atleast 45% release controlling polymer is required with respect the active substance to achieve the desired dissolution profile; which results in unacceptable size of the dosage form.

WO/2006123357 discloses oral controlled release pharmaceutical composition comprising a highly soluble high dose active ingredient consisting essentially of therapeutically effective amount of levetiracetam and a rate controlling means comprising a rate-controlling agent and optionally coating selected form (i) a active ingredient permeable coating surrounding the unit dosage form, and (ii) an active ingredient impermeable coating covering one or more surfaces but not all the surfaces of the unit dosage form. The problem associated with the technology discussed in this patent application is non uniform release of active ingredient from one side in coated tablet. This technique is very critical with respect to uniform breaking or opening of tablet coating under all physiological conditions.

WO/2008006528 discloses controlled release pharmaceutical composition in the form of a tablet comprising, levetiracetam and, as excipient within the core of the tablet, 5.0 to 59.0 % per weight of at least one hydrophilic matrix agent, with respect to the total weight of the core of the tablet. WO/2008/062446 discloses an extended release composition of Levetiracetam, which exhibits no adverse food effect, comprising from about 30% w/w to about 85% w/w of Levetiracetam and about 1 % w/w to about 50% w/w of the composition of a water dispersible rate controlling polymer.

In these systems, when a highly soluble active ingredient is used, most of these systems have the disadvantages such as comparatively low payload of active ingredient thus making dosage form bulky, which is particularly problematic for high dose active ingredient. Further, these type of systems also lead to burst effect.

Hence there is an unmet need for controlled release dosage form of high solubility drugs that is simple and easy to manufacture, provide controlled clinical effects and also having acceptable size which further improves the patient compliance.

Inventors of the present application have surprisingly found the controlled release dosage form of high solubility active ingredient, particularly with high dose drugs such as Levetiracetam, which effectively overcome the problems discussed above. SUMMARY OF THE INVENTION

The first embodiment of the present invention is to provide solid oral controlled release tablet dosage form comprising high solubility active ingredient.

Another embodiment of the present invention is to provide solid oral controlled release tablet dosage form comprising high solubility active ingredient, wherein the dosage form is manufactured by single step granulation using atleast one hydrophobic release controlling agent and compressed tablet is coated with atleast one hydrophobic release controlling agent.

Another embodiment of the present invention is to provide solid oral controlled release tablet dosage form comprising Levetiracetam, wherein the dosage form is manufactured by single step granulation using atleast one hydrophobic release controlling agent and compressed tablet is coated with atleast one hydrophobic release controlling agent.

Another embodiment of the present invention is to provide solid oral controlled release tablet dosage form comprising Citicoline, wherein the dosage form is manufactured by single step granulation using atleast one hydrophobic release controlling agent and compressed tablet is coated with atleast one hydrophobic release controlling agent. Another embodiment of the present invention is to provide solid oral controlled release tablet dosage form comprising high solubility active ingredient manufactured by single step granulation using atleast one hydrophobic release controlling agent and compressed tablet is coated with atleast one hydrophobic release controlling agent wherein the said dosage form is substantially devoid of diluent.

Another embodiment of the present invention is to provide solid oral controlled release tablet dosage form comprising high solubility active ingredient manufactured by single step granulation using atleast one hydrophobic release controlling agent and compressed tablet is coated with atleast one hydrophobic release controlling agent wherein the said dosage form is devoid of diluent.

Yet another embodiment of the present invention is to provide a dosage form which controls the release of high solubility active ingredient from the dosage form in a controlled rate and avoid the risk of side effects due to dose dumping because of breakage of the dosage form.

A further embodiment of the present invention is to provide a dosage form, which can be given once or twice daily.

Another embodiment of present invention is to provide process for preparing the controlled release dosage form of high solubility active ingredient.

Yet another embodiment of the present invention is to provide a method of treating an mammal, particularly a human being in need of treatment, comprising administering a said dosage form.

The present invention provides a controlled release dosage form, which comprises of: a) granules comprising high solubility active ingredient and one or more hydrophobic release controlling agent; b) tablet prepared by compressing the granule(s) of step a) with one or more pharmaceutically acceptable excipients; and c) coating of one or more hydrophobic release controlling agent on said tablets.

Thus the present invention using the hydrophobic release controlling agent within the granule(s) and over the tablet as a coating, effectively controls the release of the high solubility active ingredient from the dosage form in controlled manner and also avoid the risk of failure of the system due to rupture of matrix. DETAILED DESCRIPTION

The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

The term "controlled release" as used herein means which is not immediate release and is taken to encompass modified release, sustained release, prolonged release, timed release, retarded release, extended release, and delayed release, etc. in which the active ingredient is released according to a desired profile over an extended period of time. By "extended period of time" it is meant a continuous period of time of greater than about 1 hour, preferably, greater than about 4 hours, more preferably, greater than about 8 hours.

The term "dosage form" denotes any form of the formulation that contains an amount sufficient to produce a therapeutic effect with a single administration. The dosage form used herein is for oral administration. The preferred oral dosage forms are selected from granule, powder, pills, pellets, and more preferred dosage form is tablet.

The term "active ingredient" refers to an agent, active ingredient compound or other substance, or compositions and mixture thereof that provide some pharmacological, often beneficial, effect. Reference to a specific active ingredient shall include where appropriate the active ingredient and it's pharmaceutically acceptable salts.

The term "high dose" as used herein refers to the weight of active ingredient in unit dosage form according to the invention is from 500 mg to 1500 mg.

The term "high solubility" as used herein in relation to active ingredient means that 300 parts of water, preferably 30 parts of water, more preferably 10 parts of water will be required to dissolve 1 part of active ingredient.

The high solubility active ingredient can be present in the form of a free base or in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts forming part of this invention are intended to define but not limited to salts of the carboxylic acid moiety such as alkali metal salts like Li, Na and K salts; alkaline earth metal salts like Ca and Mg salts; salts of organic bases such as lysine, arginine, guanidine, diethanolamine, choline, and the like; ammonium or substituted ammonium salts and aluminium salts. Salts may be acid addition salts which defines but not limited to sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzensulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.

Further, high solubility active ingredient, where applicable, may be present either in the form of one substantially optically pure enantiomer or as a mixture of enantiomers or polymorphs thereof. ^'

The high solubility active ingredients comprises of the following therapeutic classes but not limited to antidiabetics such as biguanides, sulphonylurea, meglitinides, PPAR gamma agonist [insulin sensitisers (thiazolidinedione)] and alpha-glucosidase inhibitors; antiobesity drugs; cardiovascular agents such as diuretics, antihypertensives, antianginals, antithrombotics, anti-cholesterolemics, and antihyperlipidemics; CNS agents such as antipsychotics, neuroleptics, anticonvulsants, anti-depressants, anxiolytic agents, antiparkinsons, cerebral dilators and antialzheimers; anti-viral agents; anesthetics; anti-arthritis; antibiotics; anti-spasmodics; appetite suppressants; cough suppressants; emollients; gastro-intestinal agents such as antiulcers and antacids; growth regulators; anti-histamines; respiratory stimulants; vitamins; anti-asthmatics; anti-diarrhea preparations; anti-infective; anti-inflammatory agents; anti-nauseants; anti-stroke agents; anti-tumor drugs; anti-tussives; anti-uricemic drugs; amino-acid preparations; antiemetics; antiparasitics; analgesics; antipyretics; appetite stimulants; chelating agents; cholecystokinin antagonists; cognition activators; dermatological agents; erythropoietic drugs; fertility agents; synthetic hormones; laxatives; mineral supplements; neuromuscular agents; peripheral vaso-dilators; prostaglandins; vaso-constrictors or vertigo agents.

Examples of high solubility active ingredients comprises of but not limited to aminocaproic acid, acetaminophen, balsalazide disodium, buformin, clindamycin, captopril, citicoline, diltiazem, fexofenadine, erythromycin, hydroxyurea, lisinorpil, metformin, pseudoephedrine, phenformin, potassium chloride, ranitidine, tramadol, vancomycin, ciprofloxacin, ampicillin, sodium valproate, niacin, diltiazem, venlafaxine, isosorbide 5-imononitrate, isosorbide dinitrate, pentoxyphylline, levetiracetam, paliperidone, methyl phenidate, propranolol and quetiapine. Other drugs suitable for use and meeting the solubility criteria described above will be apparent to those skilled in the art. The term "granule(s)" as used herein means individual particles, beads, pellets or agglomerates of individual particles of the high solubility active ingredient with one or more pharmaceutically acceptable excipients.

Granule(s) as used herein can be manufactured by any known method to the person skilled in the art like wet granulation, dry granulation, melt granulation, extrusion, spheronization or by roller compaction and the like. Preferred method for granulation is wet granulation using aqueous or non aqueous solvent. More preferably the granulation method is non aqueous wet granulation.

The term "single step granulation" as used herein means wet granulation, dry granulation including direct compression, melt granulation, extrusion, spheronization or by roller compaction wherein high solubility active ingredient and atleast one pharmaceutically acceptable ingredient are granulated once by above mentioned process.

Compression of granules to the tablet as used herein can be done on usual compression machines. The tablets can be made of various sizes and shapes.

Coating of the tablet as used herein can be done with one or more hydrophobic release controlling agents by any known method, including spray application. Spraying can be carried out using a fluidized bed coating, or in a pan coating system. Alternatively the coating of the tablets with one or more hydrophobic release controlling agents can be done by hot melt process using fluidized bed coating, or in a pan coating system.

A dosage form of the present invention may contain additionally one or more active ingredient.

A dosage form as described herein may comprise one or more pharmaceutically acceptable excipient, during granulation, compression or coating, selected from diluent/filler, glidants, disintegrant, binder, stabilizing agents, lubricant, hydrophobic release controlling agent, plasticizers, film coating agents, opacifiers, stabilizers, anti- tacking agent, and others known to the skilled person in the art. As will be appreciated by those skilled in the art, the exact choice of excipient and their relative amounts will depend to some extent on the final oral dosage form.

Examples of "diluents" or "fillers" includes but not limited to dibasic calcium phosphate, lactose anhydrous, lactose monohydrate, pregelatinized starch, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, starch or other materials known to one of ordinary skill in the art. The diluent may be present in an amount ranging from 0% to 50 % w/w by total weight of dosage form. The term "substantially devoid of diluent" as used herein means that the dosage form comprising less than 5% w/w of diluent by total weight of dosage form.

Examples of "binder" includes but not limited to polyvinylpyrrolidone, hypromellose, hydroxy methylcellulose, PEG, starch, copovidone, shellac, zein, gelatin, polymethacrylates, synthetic resins, acrylates or other materials known to one of ordinary skill in the art.

Examples of "glidant" includes but not limited to colloidal silica, talc, calcium silicate, magnesium silicate, colloidal silicondioxide or other known to one of ordinary skill in the art.

Examples of "lubricant" includes but not limited to Stearic acid, Polyethylene glycol, Magnesium stearate, Calcium stearate, Zinc stearate, Talc or Silica, Glyceryl behenate, Sodium stearyl fumarate, Hydrogenated caster oil or other materials known to one of ordinary skill in the art.

Examples of 'plasticizer' includes but not limited to Triethyl citrate, PEG 6000, Glyceryl monopalmetostearate / Glyceryl monostearate, Dibutyl phthalate, Macrogol or other materials known to one of ordinary skill in the art.

Examples of opacifier includes but not limited to titanium dioxide or talc.

Examples of solvents used to prepare solution of release controlling agent for the granulation or coating includes but not limited to aqueous or organic solvent preferably organic solvent and more preferably Methanol, Methylene chloride, Acetone, Isopropyl alcohol or combination thereof.

The excipients that can be used as the hydrophobic release controlling agent within the granule(s) and over the tablet as coating are described in greater detail herein below.

The hydrophobic release controlling agents as used herein in the granulation or coating are selected from hydrophobic, pH independent release controlling agents and / or hydrophobic, pH dependent release controlling agents, more preferably hydrophobic, pH independent release controlling agents.

Preferable hydrophobic, pH independent release controlling agent is selected from Ammonio methacrylate copolymers type A and B as described in USP, Polyacrylate dispersion 30% as described in Ph. Eur., Cellulose derivatives, Kollicoat" SR, Kollicoat^® SR 30 D (polyvinyl acetate dispersion stabilised with polyvinylpyrrolidone and sodium lauryl sulphate) or combination thereof. The hydrophobic release controlling agents may be added at intragranular stage, extragranular stage, binder addition stage and tablet coating stage.

The suitable hydrophobic release controlling agents are sold under the Trade name Eudragit® RS (Ammonio Methacrylate Copolymer type B USP), Eudragit® NE 3OD (Polyacrylate dispersion 30% Ph., Eur.), Eudragit® RL (Ammonio Methacrylate Copolymer type A USP), Kollicoat^® SR 30 D (polyvinyl acetate dispersion stabilised with polyvinylpyrrolidone and sodium lauryl sulphate).

Preferred release controlling agent for granulation is Eudragit® RS and for coating of tablet is combination of two ammonio methacrylate co-polymers having different aqueous permeability or Kollicoat^® SR 30 D (polyvinyl acetate dispersion stabilised with polyvinylpyrrolidone and sodium lauryl sulphate).

More preferred combination of ammonio methacrylate co-polymer for tablet coating is Eudragit RS (Ammonio Methacrylate Copolymer type B USP) and Eudragit RL (Ammonio Methacrylate Copolymer type A USP).

In the uncoated tablet, the high solubility active ingredient and one or more hydrophobic release controlling agents are present in a weight ratio of from 100:1 to 100:75, preferably from 100:2.5 to 100:50, more preferably from 100:2.5 to 100:30 and still preferably from 100:2.5 to 100:20, most preferably from 100: 1 to 100:10.

In tablet coating stage, the high solubility active ingredient and one or more hydrophobic, release controlling agents are preferably in a weight ratio of from 100: 0.1 to 100:30, particularly from 100:0.1 to 100:20, more particularly from 100:0.1 to 100:10, still more preferably from 100:0.25 to 100:10.

The controlled release dosage form of the present invention can be manufactured by the following procedure: a) granules comprising high solubility active ingredient and one or more hydrophobic release controlling agent; b) tablet prepared by compressing the granule(s) of step a) with one or more pharmaceutically acceptable excipients; and c) coating of one or more hydrophobic release controlling agent on said tablets. EXAMPLES

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare the various dosage forms and/or perform the various processes of the invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever: Example 1

Table 1

* Solid content per tablet Manufacturing Procedure:

Levetiracetam and Microcrystalline cellulose were mixed and granulated with the solution of Eudragit® RSPO in acetone and dried and sized. The sized granules were blended with Colloidal silicon dioxide and Glyceryl behenate. These lubricated granules were compressed using suitable tablet compression machine. The compressed tablets were coated with the coating solution of Eudragit® RSPO and Eudragit® RLPO in purified water with talc, titanium dioxide and Triethyl citrate. Dissolution data of Example 1

The dissolution of the present invention was determined by following method:

Table 2

Example 2

Table 3

Mix Citicoline sodium and Eudragit" RSPO thoroughly. Granulate the drug blend with the solution of Eudragit^® RSPO in acetone. Dry and Size the granulated drug mass. Blend the dried and sized granules with colloidal silicone dioxide and magnesium stearate. Compress the lubricated granules using suitable tablet compression machine. Coat the compressed tablet with the coating solution of Eudragit^® RSPO and Eudragit^® RLPO in acetone-Isopropyl alcohol with talc, titanium dioxide and Triethyl citrate. Example 3

Table 4

* Solid content per tablet Manufacturing Procedure:

Levetiracetam and Microcrystalline cellulose were mixed and granulated with the solution of Eudragit® RSPO in acetone and dried and sized. The sized granules were blended with Colloidal silicondioxide and Glyceryl behenate. These lubricated granules were compressed using suitable tablet compression machine. The compressed tablets were coated with the coating solution of Kollicoat SR 30 D and HPMC (3 cps) in purified water with talc and Triethyl citrate. Dissolution data of Example 3

The dissolution of the present invention was determined by following method:

Table 5

Claims

We Claim:

1. A solid controlled release tablet dosage form comprising of a high solubility active ingredient, characterized in that the said dosage form is manufactured by single step granulation using atleast one hydrophobic release controlling agent and compressed tablet is coated with atleast one hydrophobic release controlling agent.

2. The dosage form according to claim 1, which is substantially free from diluent.

3. The dosage form according to claim 1 or 2, wherein the hydrophobic release controlling agents employed during granulation and/or coating are selected from the group comprising of pH independent release controlling agents and/or pH dependent release controlling agents.

4. The dosage form according to claim 3, wherein said hydrophobic release controlling agents are selected preferably from Ammonio methacrylate copolymers type A and B as described in USP, Polyacrylate dispersion 30% as described in Ph. Eur., Cellulose derivatives, Kollicoat^® SR, Kollicoat^® SR 30 D (polyvinyl acetate dispersion stabilised with polyvinylpyrrolidone and sodium lauryl sulphate) or combination thereof.

5. The dosage form according to claim 1 or 2, wherein the high solubility active ingredient is levetiracetam.

6. The dosage form according to claim 1 or 2, wherein the high solubility active ingredient is citicoline.

7. A process for preparing solid controlled release tablet dosage form comprising the steps of: a) preparing granules comprising high solubility active ingredient and one or more hydrophobic release controlling agent; b) compressing the granule(s) of step a) with one or more pharmaceutically acceptable excipients in to tablet; and c) coating said tablet with one or more hydrophobic release controlling agent.

8. A process for preparing solid controlled release tablet dosage form comprising the steps of: a) preparing granules comprising levetiracetam and one or more hydrophobic release controlling agent; b) compressing the granule(s) of step a) with one or more pharmaceutically acceptable excipients in to tablet; and c) coating said tablet with one or more hydrophobic release controlling agent.

9. A controlled release dosage form comprising high solubility active ingredient as substantially herein described and illustrated with reference to the examples.