WO2003011256A1

WO2003011256A1 - Oral controlled release pharmaceutical composition of a prokinetic agent

Info

Publication number: WO2003011256A1
Application number: PCT/IN2002/000161
Authority: WO
Inventors: Dilip Shantilal Shanghvi; Kamlesh Mohanlal Dudhara; Ziauddin Z. Tyebji; Ashwin Bhujanga Rao
Original assignee: Sun Pharmaceutical Industries Limited
Priority date: 2001-07-30
Filing date: 2002-07-29
Publication date: 2003-02-13

Abstract

The present invention provides an oral controlled release dosage form of a prokinetic agent comprising mosapride or its pharmaceutically acceptable salts and release rate controlling pharmaceutically acceptable excipient. The said dosage form is useful for once-a-day therapy in humans and releases mosapride in a controlled manner so as to provide control over mosapride plasma levels, such that the ratio of peak plasma levels to the plasma levels at 24 hours after administration, and the mean residence time of mosapride, are within a desirable range for the once-a-day therapy. The present invention also provides a process for the preparation of said oral controlled release dosage form.

Description

ORAL CONTROLLED RELEASE PHARMACEUTICAL COMPOSITION OF A

PROKINETIC AGENT

The present invention relates to an oral controlled release dosage form of a prokinetic agent, comprising mosapπde or its pharmaceutically acceptable salts and release rate controlling pharmaceutically acceptable excipient It also relates to a process for the preparation of said oral controlled release dosage form

More particularly, the present invention relates to an oral controlled release dosage form, comprising mosapride or its pharmaceutically acceptable salts and a release rate controlling pharmaceutically acceptable excipient, that releases mosapπde in a controlled manner so as to provide control over mosapπde plasma levels, such that the ratio of peak plasma levels to the plasma levels at 24 hours after administration, and the mean residence time of mosapπde, are within a desirable range for once-a-day therapy in humans; and to a process for preparation of said oral controlled release dosage form

BACKGROUND OF THE INVENTION

Gastro esophageal reflux disease (GERD) is among the most common disorders seen by the gastroenterologists and general practicians This disease is characteπzed as the backward flow of the stomach contents into the esophagus One of the most important factors in the pathogenesis of gastro-esophageal reflux disease is a reduction in the pressure banner due to the failure of the lower esophageal sphincter Failure of the lower esophageal sphincter can aπse due to a low basal pressure, sphinctei relaxation, or to a non-compensated increase in intragastπc pressure Other factors in the pathogenesis of the disease are delayed gastπc emptying, insufficient esophageal clearing due to impaired peπstalsis and the corrosive nature of the reflux matenal which can damage esophageal mucosa

Mosapride, I e , 4-amιno-5-chloro-2-ethoxy-N-[[4-(4-fluorophenyl)methyl]-2- morpholιnyl]methyl]-benzamιde, is disclosed in European Patent No. 243959 and United States

Patent No 4870074 as gastrointestinal prokinetic agent Mosapnde is a new 5-HT₄ agonist intended for oral treatment of gastrointestinal motility dysfunction e.g. gastro-esophageal reflux. It is known to exert its action by facilitating acetylcholine release from the enteric cholinergic neurons. With respect to the therapeutic actions mosapride enhances gastric emptying and also improves total acid clearance time. Conditions or symptoms relieved by the promotion of gastric emptying include but are not limited to gastric stasis, flatulence, dyspepsia, peptic ulcer and reflux oesophagitis. Conventionally mosapride is given 5 mg three time's daily for decreasing acid reflux in the esophagus in patients with gastro-esophageal reflux disease. Maintenance therapy is often necessary to prevent recuπent symptoms and oesophagitis. It is more convenient for patients to receive long-term effective controlled release mosapride dosage forms once-a-day than the conventional mosapride dosage forms administered three times a day. Mosapride has a short biological half-life of about 1.4 - 2 hours and shows linear pharmacokinetics upto a dose of 40 mg. Thus, it is suitable for formulation into oral controlled release dosage form. A once-a-day controlled release dosage form eliminates the inconvenience to the patient in taking multiple dosing at different times and thus ensures patient compliance to the prescribed dosage regimen. There is no prior art on controlled release once-a-day dosage form of the prokinetic agent, mosapride, and there is a need for such a dosage form.

An oral controlled release dosage form of a prokinetic agent, in particular, of mosapride has been found, wherein, the ratio of the peak plasma levels to the plasma levels at 24 hours after administration is within a desirable range to provide once-a-day therapy in humans. A higher ratio of maximum plasma concentration of mosapride to the plasma concentration at 24 hours after oral administration indicates a poorer control and faster release than desired, while a smaller optimum ratio would indicate a control on the release rate over a prolonged duration, however ratio's smaller than optimum may result in accumulation of mosapride at each dosing. An optimum design of an oral controlled release dosage form of mosapride for once-a-day therapy in humans also requires that the dosage form provide a control on the plasma levels such that the mean residence time (i.e. the mean time that a drug spends in the body) is within a desirable range for said once-a-day therapy in humans. Hence, an oral controlled release dosage form for mosapride that releases the mosapride in a controlled manner so as to provide control over mosapride plasma levels, such that the ratio of peak plasma levels to the plasma levels at 24 hours after administration, and the mean residence time of mosapride, are within a desirable range for once-a-day therapy in humans, is thus required.

The prior art does not provide a controlled release dosage form for mosapride.

OBJECT OF THE INVENTION

It is an object of the present invention to provide an oral controlled release dosage form of a prokinetic agent. It is a particular object of the present invention to provide an oral controlled release dosage form for mosapride or its pharmaceutically acceptable salts.

It is a further object of the present invention to provide a process for the preparation of the said oral controlled release dosage form.

A controlled release dosage form has many advantages, such as the reduction of administration times, the decrease of side effects and the retention of effective concentration of the drug in the blood.

SUMMARY OF THE INVENTION

The present invention provides an oral controlled release dosage form of a prokinetic agent. More particularly, the present invention provides an oral controlled release dosage form comprising mosapride or its pharmaceutically acceptable salts and a release rate controlling pharmaceutically acceptable excipient, wherein the said dosage form releases mosapride in a controlled manner so as to provide control over mosapride plasma levels, such that the ratio of peak plasma levels to the plasma levels at 24 hours after administration, and the mean residence time of mosapride, are within a desirable range for once-a-day therapy in humans. The invention also relates to a process for the preparation of an oral controlled release dosage form comprising the steps of mixing a prokinetic agent, for example, mosapride or its pharmaceutically acceptable salt with a release rate controlling pharmaceutically acceptable excipient and forming an oral controlled release dosage form by conventional means, whereby the oral controlled release dosage form releases the mosapride in a controlled manner so as to provide control over mosapride plasma levels, such that the ratio of peak plasma levels to the plasma levels at 24 hours after administration, and the mean residence time of mosapride, are within a desirable range for once-a-day therapy in humans.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the plasma concentration Vs time profile obtained upon administration of one embodiment of the oral controlled release dosage form of the present invention having 15 mg mosapride for once-a-day therapy, in comparison to that obtained for an equivalent dose of an immediate release dosage form.

DETAILED DESCRIPTION OF THE INVENTION

The mosapride or its pharmaceutically acceptable salts may be used in the oral controlled release dosage form of the present invention in the range of amounts equivalent to about 5mg to about 50mg of mosapride. In particular, an oral controlled release dosage form of the present invention may have mosapride or its pharmaceutically acceptable salts in an amount equivalent to 7.5mg or 15mg or 30mg of mosapride.

The oral controlled release dosage form of the present invention comprising mosapride or its pharmaceutically acceptable salts and a release rate controlling pharmaceutically acceptable excipient, releases the mosapride in a controlled manner so as to provide control over mosapride plasma levels, such that the ratio of peak plasma levels to the plasma levels at 24 hours after administration is in the range of 15:1 to 2: 1, preferably within 10:1 to 2:1, more preferably in the range of 6: 1 to 3: 1. The oral administration as referred to herein may be administration of the dosage form in the absence or presence of food, i.e. in the fasted mode or in the fed mode.

The oral controlled release dosage form of the present invention is designed to increase the mean residence time of mosapride in the body to a range from about 4 hours to about 15 hours, preferably about 6 hours to about 13 hours. The mean residence time is preferably increased about 4 to 5 times as compared to an immediate release dosage form. The oral controlled release dosage form of the present invention compπses a prokinetic agent, more particularly compπses of mosapπde or its pharmaceutically acceptable salts and a release rate controlling pharmaceutically acceptable excipient, such that the mosapπde is released according to the following dissolution profile -

(a) Not less than 15% of the mosapπde is released after 4 hours;

(b) Between 30% and 70% of the mosapπde is released after 8 hours; and

(c) Not less than 90% of the mosapπde is released after 24 hours. when tested in vitro in United States Pharmacopoeia Type II apparatus at 75 rpm using 0. IN HC1 as dissolution medium at 37 ±1°C.

More particularly, the oral controlled release dosage form compπses mosapride or its pharmaceutically acceptable salts and a release rate controlling pharmaceutically acceptable excipient, wherein mosapπde is released as per the following the dissolution profile- (a) Not less than 15% of the mosapπde is released after 4 hours, (b) Between 35% and 55% of the mosapπde is released after 8 hours;

(c) Between 50% and 75% of the mosapπde is released after 12 hours, and

(d) Not less than 90% of the mosapπde is released after 24 hours. when tested in vitro in United States Pharmacopoeia Type II apparatus at 75 rpm using 0 IN HC1 as dissolution medium at 37 ±1°C

The oral controlled release dosage form of the present invention may be in the form of a matπx formulation, a coated composition, an ion exchange composition, an osmotic system compπsing a core covered with a semi permeable membrane, and vanous other controlled release compositions known to a person skilled in the art. A matπx formulation for the present invention compπses a core compπsing mosapπde or its pharmaceutically acceptable salts, a release rate controlling pharmaceutically acceptable excipient and other pharmaceutically acceptable excipients. A coated composition that provides a controlled release of mosapπde is obtained by coating a drug-containing core with release rate controlling excipients, using techniques known to a person skilled in the art. The osmotic system for the controlled release of mosapπde compπses a core compπsing the drug and other pharmaceutically acceptable excipients, covered with a semi permeable membrane, the membrane having an orifice for the release of mosapride in a controlled manner over a defined period of time.

The conversion of the mixture of mosapride or its phaπnaceutically acceptable salts and pharmaceutically acceptable excipients into an oral controlled release dosage form is preferably effected by one of the following methods:

(a) including in the mixture at least one release rate controlling excipient and filling the mixture into capsules,

(b) including in the mixture at least one release rate controlling excipient, granulating or pelletizing the mixture by conventional means and filling into capsules, and

(c) including in the mixture at least one release rate controlling excipient, granulating or pelletizing the mixture by conventional means and compressing the granules or pellets so obtained into tablets.

Yet another process for the conversion of the mixture of mosapride or its pharmaceutically acceptable salts and pharmaceutically acceptable excipients which may or may not include release rate controlling pharmaceutically acceptable excipient into an oral controlled release dosage form is effected by one of the following methods:

(a) filling the mixture into capsules and coating the capsules with a composition comprising at least one release rate controlling excipient, (b) granulating or pelletizing the mixture by conventional means and filling into capsules and coating the capsules with a composition comprising at least one release rate controlling excipient, and (c) granulating or pelletizing the mixture by conventional means and compressing the granules or pellets so obtained into tablets and coating the tablets with a composition comprising at least one release rate controlling excipient.

The matrix formulations containing release rate controlling pharmaceutically acceptable excipient may be prepared by mixing the active ingredient with a rate controlling pharmaceutically acceptable excipient and optionally other pharmaceutically acceptable excipients. The rate controlling pharmaceutically acceptable excipient is any material that slows the rate of release of the drug from the dosage form. Usually, the rate controlling pharmaceutically acceptable excipient is a polymer or a fatty compound or a mixture thereof. It may also comprise an ion-exchange resin. Examples of rate controlling polymers that may be used in the present invention include but are not limited to:

• cellulose ethers such as methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl ethylcellulose (HPEC), carboxymethyl cellulose (CMC), crosslinked carboxymethyl cellulose (croscarmellose) and its alkali salts, cellulose acetate, ethylhydroxyethylcellulose (EHEC), hydroxyethyl methylcellulose (HEMC), hydrophobically modified hydroxyethyl cellulose (HMHEC), hydrophobically modified ethylhydroxyethylcellulose (HMEHEC), carboxymethyl hydroxyethylcellulose (CMHEC), carboxymethyl hydrophobically modified hydroxyethyl cellulose (CMHMHEC), and the like; • vinyl pyrrolidone polymers such as crosslinked polyvinyl pyrrolidone or crospovidone, copolymers of vinyl pyrrolidone and vinyl acetate;

• alkylene oxide homopolymers such as polypropylene oxide, such as ethylene oxide homopolymers

• a superdisintegrant polymer such as cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethylcellulose, carboxymethyl starch, sodium carboxymethyl starch, potassium methacrylate-divinylbenzene copolymer, polyvinyl alcohols, amylose, cross- linked amylose, starch derivatives, microcrystalline cellulose and cellulose derivatives, alpha-, beta-and gamma-cyclodextrin and dextrin derivatives such as cross-linked carboxymethylcellulose • gums of plant, animal, mineral or synthetic origin such as (i) agar, alginates, caπageenan, furcellaran derived from marine plants, (ii) guar gum, gum arabic, gum tragacanth, karaya gum, locust bean gum, pectin derived from terrestrial plants, (iii) microbial polysaccharides such as dextran, gellan gum, rhamsan gum, welan gum, xanthan gum, and (iv) synthetic or semi -synthetic gums such as propylene glycol alginate, hydroxypropyl guar and modified starches like sodium starch glycolate, and the like; and • an acrylic acid polymer such as cross-linked polymer available under the trade name Carbopol^® or homopolymers and co-polymers of acrylate or methacrylate monomers for example polymethacrylates marketed under the brand names of Eudragit^® particularly Eudragit^® RS and Eudragit^® RL.

Examples of fatty compounds that may be used as the rate controlling excipients in the present invention include various waxes such as digestible, long chain (C₈ -C₅₀, especially Cι₂ -C₄₀), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and waxes.

An oral controlled release dosage form may also be obtained by coating particles, pellets, granules or tablets of mosapride with rate controlling excipients, such as hardened gelatin, methyl cellulose, ethyl cellulose or ethyl cellulose in combination with hydrophilic polymers like hydroxypropyl methylcellulose, methacrylates such as anionic polymer of methacrylic acid and methacrylates with a carboxylic group, cationic polymer with a dimethylaminoethyl ammonium group, copolymers of acrylates and methacrylates with quaternary ammonium group in combination with sodium carboxymethylcellulose, copolymers of acrylate and methacrylates with quaternary ammonium group and the like, commercially available as Eudragit^®, for example Eudragit^® RS, Eudragit^® RL, Eudragit^® L, Eudragit^® E, Eudragit^® S, Eudragit^® RD and the like; hydroxypropyl cellulose, polyvinyl acetate, polyvinyl acetate phthalate, shellac, various waxes and the like.

In one embodiment of the present invention, the oral controlled release dosage form of mosapride is obtained in the form of a tablet comprising mosapride or its pharmaceutically acceptable salts, a hydrophilic swellable polymer as the release rate controlling pharmaceutically acceptable excipient and other pharmaceutically acceptable excipients. Example of a hydrophilic swellable polymer that may be used include above-mentioned swellable polymers from the class of cellulose ethers, vinylpyπolidone polymers, alkylene oxide homopolymers, superdisintegrant polymer, natural gum, an acrylate polymer or mixtures thereof. The prefeπed hydrophilic swellable polymer is a cellulose ether, more preferably a hydroxypropyl methylcellulose (HPMC), which is commercially available as Methocel^®, Pharmacoat^®, Benecel^®, Metolose^®. It is available in several grades, which vary in viscosity and the extent of substitution. The molecular weight of HPMC ranges between 10,000 and 1,500,000. Different grades of HPMC are characterized by the viscosity of a 2% w/v aqueous solution at 20°C. HPMC may be used in an amount from about 10% to about 50% by weight of the tablet. In a particularly preferred embodiment the hydrophilic swellable polymer is a mixture of a high viscosity grade of HPMC having a viscosity greater than about 10,000 mPas; and a low viscosity grade of HPMC having a viscosity equal to or less than about 10,000 mPas. In one embodiment of the present invention, one of the grades of the HPMC used has an average molecular weight of about 86,000, with a viscosity of about 4000 mPas, and is commercially available as Methocel^® K4M, and the other grade of HPMC used has an average molecular weight of about 250,000, with a viscosity of about 100,000 mPas, and is commercially available as Methocel^® K100M. In a preferred embodiment of the present invention, Methocel^® K4M is used in an amount from about 10 to 30% and Methocel^® K100M is used in an amount from about 4 to 15% by weight of the tablet.

The oral controlled release dosage form of the present invention may also include various pharmaceutically acceptable excipients, for example wicking agents such as microcrystalline cellulose; disintegrants such as starch, cellulose derivatives, gums, crosslinked polymers and the like; binders such as starch, gelatin, sugars, cellulose derivatives, polyvinyl pyrrolidone and the like; lubricants such as talc, magnesium stearate, colloidal silicon dioxide, polyethylene glycol and mixtures thereof.

In one embodiment of the present invention, polyvinyl pyrrolidone is present as a binder and microcrystalline cellulose is present as a wicking agent. The polyvinyl pyrrolidone and microcrystalline cellulose are dispersed in the matrix of the hydrophilic swellable polymer, preferably the mixture of high viscosity grade and low viscosity grade HPMC's.

A matrix formulation for the present invention comprises a core comprising mosapride or its pharmaceutically acceptable salts and a release rate controlling pharmaceutically acceptable excipient, preferably a hydrophilic swellable polymer, more preferably HPMC, particularly preferably a mixture of high viscosity grade of HPMC and a low viscosity grade of HPMC and still more particularly preferably a mixture of Methocel^® K100M and Methocel^® K4M and other pharmaceutically acceptable excipients.

In another embodiment, the said oral controlled release dosage form of the present invention, obtained in the form of a tablet comprising mosapride or its pharmaceutically acceptable salts, a hydrophilic swellable polymer as the release rate controlling pharmaceutically acceptable excipient and other pharmaceutically acceptable excipients, is further coated with release rate controlling excipient. Example of a release rate controlling excipient that may be used include above-mentioned methacrylates, commercially available as Eudragit^®. The methacrylates also refeπed to as methacrylic acid copolymer is fully polymerized copolymer of methacrylic acid and an acrylic or methacrylic ester, defined in the USP monograph as of three types, Type A, Type B, and Type C. The preferred methacrylic acid copolymer is ammoniomethacrylate copolymers consisting of fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups, referred to as Type A and Type B methacrylic acid copolymers, more preferably the Type A methacrylic acid copolymer which is commercially available as Eudragit^® RL. Eudragit^® RL is referred in the USP monograph as ammoniomethacrylate copolymer and is synthesized from acrylic acid and methacrylic acid esters having 10% of functional quaternary ammonium groups. In a particularly preferred embodiment of the present invention, the Eudragit^® RL used is the solvent-free granules available as Eudragit^® RL 100, containing > 97% of the dried weight content of the polymer, used in an amount from about 1% to about 10% by weight of the tablet.

One embodiment of the process for the preparation of the oral controlled release dosage form of the present invention comprises the steps of mixing mosapride or its pharmaceutically acceptable salt with the pharmaceutically acceptable excipients and forming a pharmaceutical dosage form by conventional means. The release rate controlling excipient may be one of the pharmaceutically acceptable excipients admixed with the mosapride or its pharmaceutically acceptable salt. In an alternative embodiment, a core may be formed from the mixture of mosapride or its pharmaceutically acceptable salt and the pharmaceutically acceptable excipients, which may or may not include a release rate controlling excipient; and then the core is coated by conventional methods with a coating composition comprising the release rate controlling excipient. In the present invention the oral controlled release dosage form may be formed by any of the various methods known in the art. It may be formed into capsules by filling the mixture of mosapride or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients into capsules. Alternatively, the mixture may be formed into granules or pellets by conventional means such as dry granulation, wet granulation, extrusion, spheronization and the like. The granules or pellets may be filled into capsules or may be compressed into tablets.

The oral controlled release dosage form as herein described is orally administered to humans to provide desired control over mosapride plasma levels in humans for once-a-day therapy of the prokinetic agent. The oral controlled release dosage form may be administered to the patient on an empty stomach or with meals.

The examples that follow do not limit the scope of the invention and are presented as illustrations.

Example 1

This example illustrates one embodiment of the oral controlled release dosage form of the present invention. Tablets were prepared as per the formula given in Table 1 below.

Table 1

Stage A: Mosapride citrate dihydrate was mixed with starch and passed through # 100 sieve (as defined by American Society for Testing and Materials, ASTM). The rest of the ingredients of

Stage A comprising microcrystalline cellulose, lactose monohydrate, maize starch, hydroxypropyl methyl cellulose K4M, hydroxypropyl methyl cellulose K100M and polyvinyl pyπolidone K-30 in the amounts mentioned in Table 1 were passed through a # 40 sieve (as defined by American Society for Testing and Materials, ASTM). The Mosapride citrate di hydrate-starch blend was geometrically mixed with the rest of the ingredients.

Stage B: Sufficient quantity of isopropyl alcohol was used to granulate the dry powder blend.

The granules were dried in fluid bed dryer and passed through a mill.

Stage C: A mixture of talc, magnesium stearate and colloidal silicon dioxide, passed through a #

60 sieve, was then used to lubricate the dry granules. This lubricated mass was then compressed at a weight of 130 mg using 7mm standard concave punches to obtain the final tablets.

The compressed tablets were further coated using the coating solution of the formula given in

Table 2 below.

Table 2

Stage D: Methocel E5 was dispersed in isopropyl alcohol and methylene chloride added to the dispersion while stirring.

Stage E: Polyethylene glycol 6000 dissolved in purified water was added to the dispersion of stage D. Stage F: Talc, titanium dioxide and yellow oxide of iron were dispersed in isopropyl alcohol, milled and was added to the dispersion of stage D to obtain the coating solution.

The tablets so obtained were subjected to dissolution testing using United States Pharmacopoeia type π dissolution apparatus at 75 rpm. The dissolution medium used was 900ml of 0.1N HCl. The results of the dissolution test are mentioned in Table 3 below.

Table 3

Example 2

This example illustrates another embodiment of the oral controlled release dosage form of the present invention and a process for its preparation. The controlled release formulation was made as per the formula given in Table 4 below.

Table 4

Stage A comprising microcrystalline cellulose, lactose monohydrate, starch, hydroxypropyl methyl cellulose K4M, hydroxypropyl methyl cellulose K100M and polyvinyl pyrrolidone K-30 in the amounts mentioned in Table 4 were passed through a # 40 sieve (as defined by American

Society for Testing and Materials, ASTM). The Mosapride citrate dihydrate-starch blend was geometrically mixed with the rest of the ingredients.

The granules were dried in fluid bed dryer and passed through a mill.

60 sieve, was then used to lubricate the dry granules. This lubricated mass was then compressed at a weight of 75 mg using 5.5mm standard concave punches to obtain the final tablets.

Table 5 below.

Table 5

Stage D: Eudragit RL 100 was dissolved in a mixture of isopropyl alcohol and acetone and triethyl citrate was added to the solution. Stage E: Talc, titanium dioxide and yellow oxide of iron were dispersed in isopropyl alcohol, milled and was added to the solution of stage D to obtain the coating solution. The tablets so obtained were subjected to dissolution testing using United States Pharmacopoeia type π dissolution apparatus at 75 rpm. The dissolution medium used was 900ml of 0.1N HCl. The results of the dissolution test are mentioned in Table 6 below.

Table 6

Example 3

Mosapride Citrate OD (SPARC, Baroda, Lot no. EXP001, Mfg. Date : April 2002) 15 mg tablets was used as the controlled release test product and Mozasef (SPIL, Silvasa, Lot no. BK20237, Exp. Date : Feb 2004) 15 mg (3 x 5 mg) tablets was used as the immediate release reference product. A single and multiple-dose, open label, randomized, comparative and two-way crossover pharmacokinetic study, with a nine-day washout period between the dose(s) was undertaken for the same.

The pharmacokinetic assessment was based on the plasma levels of mosapride measured by blood sampling. Blood samples were obtained before dosing and at the following times after administration of the test product at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20 and 24 hrs and at 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 5, 6, 8, 8.25, 8.5, 8.75, 9, 9.5, 10, 12, 14, 16, 16.25, 16.5, 16.75, 17, 17.5, 18, 20 and 24 hrs for the reference product.

Sixteen healthy male volunteers were enrolled for the study and fifteen of them completed the two-way crossover study. The subjects were fasted overnight before dosing and for 4 hours thereafter. Drinking water was prohibited 2 hours before dosing and 2 hours thereafter. Standard meals were provided at 4 hours and 8 hours after dosing and at appropriate times thereafter. Meal plans were identical for both the periods.

Subjects received a single controlled release tablet of mosapride (15 mg) with 240 ml of drinking water at ambient temperature after the overnight fast, as the test product, while the reference product was administered as a multiple, three tablets of Mozasef (SPIL), each of 5 mg.

The plasma concentration of mosapride was determined for samples collected at different time points and averaged over the fifteen volunteers. The data is given in Table 7 below. The plasma concentration versus time profile is illustrated in Figure 1.

Table 7

For the oral controlled release dosage form the ratio of peak plasma level to the plasma level at 24 hours after administration, when calculated from the above averaged plasma concentration was about 3.96, which is comparatively less than the same calculated for the immediate release formulation which is about 7.78.

Single oral dose of (15 mg mosapride citrate OD) test product show a sustained concentrations up to 24 hours.

The other pharmacokinetic parameters calculated include area under the curve

(AUC₀. _4hr) and area under the moment curve (AUMCo-₂₄hr)- The AUCo_-24hr is calculated using the trapezoidal rule on the plasma-concentration time profile (Cp vs. t); and the AUMCo-₂₄hr is calculated using trapezoidal rule on the first moment of the plasma-concentration time profile (Cp x t vs. t) using the Win Nonlin software.

The mean residence time (MRT) was calculated using the formula:

MRT = AUM _t2 hr

The mean residence time for the controlled release formulation was found to be 9.23 ± 2.75 hours, as compared to 2.06 ± 0.60 hours for the immediate release formulation.

While the invention has been described with reference to specific embodiments, this was done for purposes of illustration only and should not be considered to limit the spirit or the scope of the invention.

Claims

1. An oral controlled release dosage form of a prokinetic agent comprising mosapride or its pharmaceutically acceptable salt and a release rate controlling pharmaceutically acceptable excipient.

2. An oral controlled release dosage form as claimed in claim 1, wherein the said dosage form releases mosapride in a controlled manner so as to provide control over mosapride plasma levels, such that the ratio of peak plasma levels to the plasma levels at 24 hours after administration, and the mean residence time of mosapride, are within a desirable range for once-a-day therapy in humans.

3. An oral controlled release dosage form as claimed in claim 2, wherein the amount of mosapride or its pharmaceutically acceptable salts expressed as mosapride, is in the range from about 5 mg to about 50 mg.

4. An oral controlled release dosage form as claimed in claim 3, wherein the ratio of peak mosapride plasma levels to mosapride plasma levels at 24 hours, after oral administration to human subjects, is in the range of 15:1 to 2:1.

5. An oral controlled release dosage form as claimed in claim 4, wherein the ratio of peak mosapride plasma levels to mosapride plasma levels at 24 hours, after oral administration to human subjects, is in the range of 10:1 to 2:1.

6. An oral controlled release dosage form as claimed in claim 5, wherein the ratio of peak mosapride plasma levels to mosapride plasma levels at 24 hours, after oral administration to human subjects, is in the range of 6:1 to 3:1.

7. An oral controlled release dosage form as claimed in claim 3, wherein the mean residence time of mosapride is in the range of about 4 hours to about 15 hours.

8. An oral controlled release dosage form as claimed in claim 7, wherein the mean residence time of mosapride is in the range of about 6 hours to about 13 hours.

9. An oral controlled release dosage form as claimed in claim 3, wherein the mean residence time of mosapride is increased by about 4 to 5 times as compared to the immediate release dosage form.

10. An oral controlled release dosage form as claimed in claim 1 wherein the release rate controlling pharmaceutically acceptable excipient is a hydrophilic swellable polymer.

11. An oral controlled release dosage form as claimed in claim 10, wherein the hydrophilic swellable polymer is hydroxypropyl methylcellulose (HPMC).

12. An oral controlled release dosage form as claimed in claim 11, wherein the hydrophilic swellable polymer is a mixture of high viscosity grade of HPMC, having a viscosity greater than about 10,000 mPas for a 2% w/v aqueous solution and a low viscosity grade of HPMC, having a viscosity equal to or less than about 10,000 mPas for a 2% w/v aqueous solution.

13. An oral controlled release dosage form as claimed in claim 12, wherein the high viscosity grade HPMC has viscosity of about 100,000 mPas for a 2% w/v aqueous solution and molecular weight of about 250,000 and the low viscosity grade HPMC has viscosity of about 4,000 mPas for a 2% w/v aqueous solution and molecular weight of about 86,000.

14. An oral controlled release dosage form as claimed in claim 13, wherein the high viscosity grade HPMC is Methocel^® K100M and the low viscosity grade HPMC is Methocel^® K4M.

15. An oral controlled release dosage form as claimed in claim 1, further comprising a wicking agent.

16. An oral controlled release dosage form as claimed in claim 15, wherein the wicking agent is microcrystalline cellulose.

17. An oral controlled release dosage form as claimed in claim 1, wherein the said dosage form is a matrix formulation comprising of a core comprising mosapride or its pharmaceutically acceptable salts dispersed homogeneously in the said release rate controlling pharmaceutically acceptable excipient.

18. An oral controlled release dosage form as claimed in claim 1, wherein mosapride is released according to the following dissolution profile -

(a) Not less than 15% of the mosapride is released after 4 hours;

(b) Between 30% and 70% of the mosapride is released after 8 hours; and (c) Not less than 90% of the mosapride is released after 24 hours. when tested in vitro in United States Pharmacopoeia Type II apparatus at 75 rpm using 0.1N HCl as dissolution medium at 37 ±1°C.

19. An oral controlled release dosage form as claimed in claim 18, wherein mosapride is released according to the following dissolution profile - (a) Not less than 15% of the mosapride is released after 4 hours;

(b) Between 35% and 55% of the mosapride is released after 8 hours; (c) Between 50% and 75% of the mosapride is released after 12 hours; and

(d) Not less than 90% of the mosapride is released after 24 hours. when tested in vitro in United States Pharmacopoeia Type π apparatus at 75 m using 0.11 HCl as dissolution medium at 37 ±1°C.