FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10; rule 13)
1. Title of the invention - EXTENDED RELEASE ORAL FORMULATION OF
CINITAPRIDE

2. Applicant(s)
(a) NAME: CADILA HEALTHCARE LIMITED.
(b) NATIONALITY: INDIAN
(c) ADDRESS: SARKHEJ-BAVLA N.H. No. 8A, MORAIYA, Tal. SANAND, Dist.: AHMEDABAD-382 210, GUJARAT, INDIA
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention

Field of the invention:
The present invention relates to extended release formulations of Cinitapride, which are suitable for oral administration. The present invention describes formulations with Cinitapride for once a day administration & processes for preparation thereof.
Cinitapride is a gastroprokinetic agent and is approved for the treatment of gastroesophageal reflux disease and functional inconvenience of the gastrointestinal motility. It belongs to the chemical class of substituted benzamide. The chemical name is 4-Amino-N-[l-(3-cyclohexen-l-ylmethyl)-4-piperidinyl]-2-ethoxy-5-nitrobenzamide. Its molecular formula is C21H30N4O4 and its molecular weight is 402.49. Cinitapride is represented in as below.

Cinitapride is a substituted benzamide gastroenteric prokinetic agent acting via complex, but synergistic effects on serotonergic 5-HT2 (inhibition) and 5-HT4 (stimulation) receptor and dopaminergic D2 (inhibition) receptors in the neuronal synapses of the myenteric plexus. Cinitapride is available in India under the trade name Cinitapro® as 1 mg immediate release tablet. Cinitapride has been marketed in Spain under the trade names Cidine and Blaston since November 1990, and is available in Mexico under the name Pemix. The current indications include gastroesophageal reflux and functional disorders in gastrointestinal motility (delayed gastric emptying).
The present invention relates to extended release formulations containing Cinitapride for oral administration and processes of preparation thereof.
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Background of the invention:
The compound, 4-Amino-N-[l-(3-cyclohexen-l-ylmethyl)-4-piperidinyl]-2-ethoxy-5-nitrobenzamide, "Cinitapride" is disclosed in U.S. Pat. No. 5,026,858 having the following structure:
O

Cinitapride has a short half life of about 3 to 5 hours also the currently available immediate release formulation of 1 mg needs to be given thrice daily for the therapeutic effect. Due to this, cinitapride is a typical candidate for an extended release formulation. By developing an extended release formulation, the dosage regimen can be reduced to once daily, thereby improving patient compliance. Optimized controlled therapy, reduced fluctuation in blood level, a relative reduction in the maximum concentration achieved in the blood thereby resulting in reduced side effects are the other advantages of an extended release formulation.
Other drugs belonging to the category of gastroenteric prokinetic known in the art such as Cisapride, Mosapride have a daily maximum dose of 10 mg or more against Cinitapride that has maximum daily dose of 3 mg (less than 10 mg). Cinitapride 1 mg immediate release tablet is the highest dose of the drug available in the market. Cisapride is available as 10 mg and 20 mg tablet.
WO2004071374 discloses a bilayered tablet of mosapride consisting of an immediate and a sustained release portion. In example 1 of this application, a sustained release portion of mosapride bilayered tablet is prepared by mixing 13.9 %w/w of mosapride with 31.25 % w/w of hydroxypropylmethyl cellulose K4M.
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US Patent No.7,338,667 discloses in example 5 an extended release formulation of cisapride maleate, wherein 40 mg of cisapride maleate is mixed with 25 mg of hydroxyethyl cellulose and 7.8 mg of hydroxypropyl cellulose.
The above cited prior arts, teach us that extended or sustained release of this particular category of drug ie. Gastroprokinetic agents could be achieved by mixing the drug with a rate controlling agent in the ratio of from about 1:<1 to about 1:3. Surprisingly, we have found that such low concentration of polymers for making an extended release formulation of Cinitapride is not effective and a certain minimum drug to polymer ratio is essential to formulate an extended release formulation of Cinitapride or salt thereof although cinitapride belonged to the same category of the drugs as mentioned in the art.
Thus, it is long felt need to design an extended release formulation of cinitapride, which will be intended to administer once a day, so as to achieve the desired therapeutic concentration in the blood by controlling the release of the drug from the formulation.
After considerable trial and errors, it was found that to attain an extended release action of cinitapride the amount of the rate controlling agent is crucial. It was found that the rate controlling agent required to achieve an extended release of cinitapride was much higher than the teaching known in the art.
According to the ICH guidelines, for the purpose of calculating degradation products in new drug products, the drugs are classified according to their maximum daily doses. These categories are less than 1 mg, 1 mg to <10 mg, 10 mg to 100 mg and above 100 mg. Thus it is known in the art that study of stability parameters is highly dependent on maximum daily dose. Also, person skilled in art would appreciate that
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manufacturing various dosage forms of drugs having different doses is dealt differently. For the purpose of this application, we consider all drugs having maximum daily dose below 10 mg to be low dose drugs. The problems faced in manufacturing low dose formulations are crucial and to be addressed with more care and diligence.
Cinitapro Tablets Leaflet mentions following,
"The elimination profile in man was similar by either route of administration, with a half life of some 3-5 h during the first 8 h and a residual half-life greater than 15 h thereafter. The plasma levels during this slow phase were, however negligible and the overall pharmacokinetic profile is indicative of 3 times daily dosing schedule being the most appropriate...."
This clearly indicates that there is a need of repeated administration of every 8 hrs of Cinitapride to maintain its level in therapeutic concentration in plasma. Repeated administration leads to patient non-compliance. In first 8 hours there is rapid elimination of Cinitapride from the body in 3-5 hours, as a result of which it is difficult to maintain therapeutic concentration over longer period.
fn E-Journal of Chemistry Vol. 5, No. 3, pp. 453-460, July 2008 "Determination of Free Levels of Cinitapride in Human plasma by liquid Chromatography-Tandem Mass Spectrometry" Shikha M.N. Roy et al gives the Mean Plasma concentration plot of Cinitapride in pg/ml versus time over a period of 24 hours when single dose of Cinitapride 1 mg in tablet form is administered to 12 healthy volunteers by administering Reference and Test product. This plot clearly indicates that peak plasma concentration of Cinitapride when Cinitapride is administered as immediate release single dose tablet is around 500 -600 pg/ml is achieved around 2.5 hours. Thereafter it reduces rapidly and around 12 hours it reaches 50 pg/ml. Thus there is a

real need to provide a second dose around 8 hours to maintain the concentration of cinitapride above 50 pg/ml. See Figure 1.
The inventors of present invention have surprisingly formulated extended release formulations of Cinitapride to take care of all problems associated with immediate release tablets that need to be administered thrice.
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Object of the invention:
The principal object of the invention is to provide an extended release oral formulation of cinitapride. Another object is to provide a stable extended release oral formulation of cinitapride. Another object is to provide processes for manufacturing extended release formulations of cinitapride. Yet another object is to provide an extended release oral formulation of cinitapride that can be administered once a day.
Detailed description of the invention:
For the purpose of this invention, cinitapride includes all its pharmaceutically acceptable salts, solvates, polymorphs, enantiomers or mixtures thereof. The present invention relates to extended release oral formulations of cinitapride. For the purpose of this invention, wherever cinitapride to rate controlling agent ratio is described herein, it is applicable to cinitapride base.
First aspect of the present invention relates to an extended release formulation of cinitapride so as to achieve the desired therapeutic concentration in the blood by controlling the release of the drug from the formulation and to achieve patient compliance by providing once a day therapy of Cinitapride..
Inventors of present invention have invented an extended release formulation of Cinitapride 3 mg to solve this problem of plasma variations and fluctuations and to enhance patient compliance. This variability can be concluded from following plot (Figure 2) where mean plasma concentration versus time is plotted for an immediate release tablet (R) and an extended release tablet of cinitapride of present invention (T). When cinitapride extended release formulation is administered, the mean plasma concentration remains substantially above 100 pg/rnl for around 15 hours and within 50 - 250 pg/ml over a period of 24 hours. When 1 mg of Cinitapride is administered
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every 8 hrs for 24 hours period, concentration of Cinitapride varies drastically and mean plasma concentration varies from around 50 pg/ml to above 300 pg/ml over 24 hours. See Figure 2 and 3
The most significant advantage of present invention is lowering frequency of administration of Cinitapride from every 8 hrs to once a day. Patient compliance to therapy is one of the biggest threat for effectiveness of any treatment. The changed lifestyle and eating habits and fast paced life poses significant problem to therapy. Administration of accurate doses on time may not be so challenging for hospitalized patients, however some indications such as for the treatment of gastroesophageal reflux disease and functional inconvenience of the gastrointestinal motility which are treated with Cinitapride where patients may not be hospitalized require lot of persuasions to take correct daily doses.
In one embodiment of the said aspect of the present invention, the Cmax (maximum concentration of the drug achieved in the blood) achieved through the extended release formulation (test product) has a lower Cmax compared to the conventional immediate release formulation (reference product). See Figure 2 and 3.
Second aspect of the present invention relates to an extended release oral formulation consisting of cinitapride, a rate controlling agent and optionally pharmaceutically acceptable excipients from the class of filler, binder, disintegrant, lubricant and other process aids. In the resulting formulation, the release of the drug is controlled by use of a suitable rate controlling agent used in from about 15 %w/w to about 60 % w/w of the formulation, wherein the ratio of Cinitapride to rate controlling agent is from about 1:5 to about 1:20. More preferably, the rate controlling agent may be used in concentration from 18 %w/w to 50 %w/w of the formulation.

According to this aspect, the rate controlling agent is hydrophilic or hydrophobic or lipophilic polymer. The hydrophilic rate controlling agent may be selected from the class consisting of polymers selected from celluloses, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, xanthan gum, starches, alginic acid, alginates, polyethylene oxides. Hydrophobic rate controlling agents may be selected from class of excipients selected from ethyl cellulose, polymethyacrylates, acyrlates, cellulose acetate, cellulose acetate propionate, cellulose ethyl butyrate. Lipophilic rate controlling excipients may be selected from waxes, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, glyceryl monostearate, hydrogenated castor oil, glyceryl behenate, low melting substances. Rate controlling agent may also be low melting substances such as cetyl alcohol, stearyl alcohol, cetostearyl alcohol, beeswax, carnauba wax, gelatin, white wax, paraffin wax, glyceryl monostearate, poloxamers, polyethylene glycols or mixture thereof. Rate controlling agent can be used alone or as mixtures of polymers.
In one embodiment, the rate controlling agent is used in concentration of about 30 %w/w of the formulation. The ratio of cinitapride to rate controlling agent is 1:10.
In one of the preferred embodiment, the hydrophilic polymer is hydroxypropylmethyl cellulose (Benecel® K100M). The Cinitapride to hydroxypropylmethyl cellulose ratio is 1:10.
Polyethylene oxide is yet another rate controlling agent used in the present invention; it may be added from 20 to 40 %w/w of the formulation. In one embodiment, the hydrophilic polymer is polyethylene oxide used in concentration of about 24 % w/w of the formulation and the ratio of cinitapride to polyethylene oxide is 1:8.

Carbopol is yet another rate controlling agent used in the present invention. It may be added from about 15 %w/w to about 35 %w/w of the formulation. In one embodiment, the carbopol is used in the quantity of 18 %w/w of the formulation and the ratio of cinitapride to carbopol is 1:6.
Mixture of rate controlling agents can be used to formulate extended release formulation of cinitapride. Preferred rate controlling agent that may be used are hydroxyethyl cellulose and hydroxypropyl cellulose. Preferred ranges are in the range from about 10 to 40 %w/w for hydroxyethyl cellulose and 1 to 20 %w/w for hydroxypropyl cellulose. In a preferred embodiment, mixture of hydroxyethyl cellulose and hydroxypropyl cellulose is used, wherein hydroxyethyl cellulose is 40 %w/w and hydroxypropyl cellulose is 11 %w/w of the formulation and wherein the ratio of cinitapride to mixture of hydroxyethyl cellulose and hydroxypropyl cellulose is 1:17.
Third aspect of the present invention relates to release profile achieved by the extended release formulation of the present invention. The in vitro dissolution of the formulation of the present invention is carried out in 900 ml of 0.1 N HCI, using USP II (Paddle) type apparatus at 50 rpm, temperature being 37 °C + 0.5 °C. The release profile of the fonnulation of the present invention is as follows:

Time (hr) Percent drug release
1 <30
4 30-70
8 55-95
12 >80

In one embodiment, the dissolution profile of the formulation of the present invention, prepared in accordance with example 1 is found to be:

Time (hr) Percent drug release
1 18.6
4 52.1
8 79.3
12 93.0
as against the conventional immediate release formulation that shows substantially complete release of the drug in about 45 minutes.
Fourth aspect of the present invention relates to a stable extended release formulation of cinitapride.
According to this aspect, stability test is performed on cinitapride extended release formulation of the present invention, prepared in accordance with example 1. See figure 4.
In one embodiment, the total impurity at 40 °C and 75 %RH for 3 months in the final PVDC blister pack-90 gsm of the formulation is within 0.5 %.
In another embodiment, the total impurity at 40 °C and 75 %RH for 3 months in the final PVDC blister pack-90 gsm of the formulation is within 0.05 %.
Fifth aspect of the present invention relates to method of producing extended release formulation of cinitapride. The process comprises of either-
(a) preparing granules of cinitapride and mixing the said granules with an extragranular rate controlling agent and compressing blend in to tablets or
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(b) geometrically mixing cinitapride with diluent, further, blending with a rate controlling agent and directly compressing the blend in to tablets or
(c) preparing granules of cinitapride and rate controlling agent and mixing the said granules with extragranular pharmaceutically acceptable excipients and then compressing the blend in to tablets to form an extended release formulation.
According to this aspect, the ratio of cinitapride to rate controlling agent is from 1:5 to about 1:20.
In one embodiment, cinitapride granules are prepared and mixed with hydroxypropylmethyl cellulose (Benecel Kl OOM) in the ratio of 1:10 and subsequently compressed in to tablets.
In another embodiment, cinitapride is geometrically mixed with diluent, blended with carbopol and compressed in to tablet wherein, ratio of cinitapride to carbopol is 1:6.
In yet another embodiment, cinitapride is granulated with polyethylene oxide by using a binder solution and the resulting granules is compressed in to tablets wherein, the ratio of cinitapride to polyethylene oxide is 1:8.
In one of the preferred embodiment of the present invention, cinitapride used is cinitapride hydrogen tartrate.
In one of the embodiment of the present invention, the ratio of drug to the rate controlling agent is 1:10.

The fillers may be selected from commonly used pharmaceutical diluents such as dicalcium phosphate, microcrystalline cellulose, powdered microcrystalline cellulose, pregelatinised starch, lactose, mannitol, dextrose, sugars and other such pharmaceutically acceptable substances that can be used as diluents known to a person skilled in the art.
Suitable binders may be selected povidone, hypromellose, gelatin, gum acasia, xanthan gum, carboxy methylcellulose, polyvinyl alcohol, starch, pregelatinised starch sodium carboxymethyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose and any suitable binder known to a person skilled in the art.
Disintegrates can be seJected from carboxymethyl cellulose salt such as caJcium, sodium; cellulose, microcrystalline cellulose, crosscarmellose sodium, Cross-linked polyvinyl pyrrolidone used in the present invention is commercially available under the trade name Crosspovidone, guar gum, low substituted hydroxypropylcellulose, magnesium aluminum silicate, methyl cellulose, sodium starch glycolate, starch and mixtures thereof.
Lubricants can be selected from magnesium stearate, magnesium lauryl sulfate, sodium lauryl sulfate, sodium stearyl fumarate, calcium stearate, microcrystalline cellulose and silicone dioxide and mixtures thereof.
The examples of cinitapride extended release oral formulations described herein are illustrative of the invention and should not be read as limiting the scope of the present invention.

Example 1

Ingredient % w/w
Cinitapride Hydrogen Tartrate eq. to Cinitapride 3 mg 4.34
Lactose DCL - 21 52.14
Microcrystalline cellulose (Avicel) 10.53
BenecelKlOOM 31.58
Silicon dioxide (Aerosil) 0.37
Magnesium stearate 1.04
Purified water q.s
Process:
Step 1: Cinitapride hydrogen tartrate was geometrically mixed with
microcrystalline cellulose in a polybag for 5 minutes.
Step 2: Lactose was dry mixed with the blend of step 1 in a rapid mixer
granulator (RMG) for 10 min with impeller speed at 150 rpm and with chopper
off.
Step 3: The blend of step 2 was granulated with purified water as granulating
solvent in RMG with impeller speed at 150 rpm and chopper speed at 1500 rpm
for 45 seconds.
Step 4: The granulated mass of step 3 was dried in a tray drier at 60-65 °C.
Step 5: The granules obtained in step 5 were sized through 30 # mesh.
Step 6: The sized granules of step 5 were blended with aerosil in a cage blender
for 10 min and sieved again through 30 # mesh.
Step 7: The granules of step 6 were lubricated in a cage blender for 3 min.
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Step 8: The granules of step 7 were compressed with 6 mm punch in to tablets. Example 2:

Ingredient % w/w
Cinitapride Hydrogen Tartrate eq. to Cinitapride 3 mg 4.34
Lactose 48.16
Microcrystalline cellulose 22
Carbopol 71 G 18
Copovidone (Plasdone S 630) 3
Silicon dioxide (Aerosil) 3
Magnesium stearate 1.5
Process:
Step 1: Mix Cinitapride hydrogen tartrate geometrically with microcrystalline
cellulose in a polybag for 5 minutes.
Step 2: Dry mix Lactose with the blend of step 1 in a rapid mixer granulator
(RMG) for 10 min with impeller speed at 150 rpm and with chopper off.
Step 3: Blend the blend of step 2 with aerosil, plasdone and carbopol in a blender
for a prescribed time.
Step 4: Sift through 30 # mesh on a sifter blend of step 3.
Step 5: Lubricate the blend of step 4 with magnesium stearate in a blender for
prescribed time.
Step 6: Compress the blend of step 5 in to tablets.

Example 3:

Ingredient % w/w
Cinitapride Hydrogen Tartrate eq. to Cinitapride 3 mg 4.34
Polyethylene oxide (Polyox WSR-303, Dow) 24
Microcrystalline cellulose (Avicel PHI01) 69.66
Plasdone 1
Magnesium stearate 1
Isopropyl alcohol q.s
Process:
Step 1: Mix Cinitapride hydrogen tartrate geometrically with microcrystalline
cellulose in a polybag for 5 minutes.
Step 2: Mix the blend of step 1 with polyethylene oxide
Step 3: Prepare a binder solution of plasdone in isopropyl alcohol.
Step 4: Granulate blend of step 2 with binder solution of step 3
Step 5: Dry the granulate of step 4
Step 6: Sift the dried granules through 1 mm sieve
Step 7: Lubricate the granules of step 6 with magnesium stearate in a blender for
prescribed time.
Step 8: Compress the lubricated blend into tablets.
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Figure 1


Group

Time in hours □ ■a-G Referenc

Test

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Figure 2: Linear Plot of Mean Plasma Concentrations versus Time Curves of Cimtapride after Administration of Test (T) [single dose] and Reference (R) [three times at equal interval of 8 hrs] Formulations to Healthy, Adult, Male and human Subjects under Fasting Condition (n=13)

350 T

10

20

30 40 50
Time