INTRODUCTION:

Oral route is the most preferred route for administration of controlled delivery of drugs because of convenience and ease of administration, greater flexibility in dosage form design and ease of production and low cost of such a system¹.

Pharmaceutical products designed for oral delivery are mainly immediate release type or conventional drug delivery systems, which are designed for immediate release of drug for rapid absorption². In order to overcome the drawbacks of conventional drug delivery systems, several technical advancements have led to the development of controlled drug delivery system that could revolutionize method of medication and provide a number of therapeutic benefits.

Controlled Release Dosage form:

The United States Pharmacopoeia (USP) defines the modified-release (MR) dosage form as the one for which the drug release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as solutions, ointments, or promptly dissolving dosage forms”. One class of MR dosage form is an extended-release (ER) dosage form and is defined as the one that allows at least a 2-fold reduction in dosing frequency or significant increase in patient compliance or therapeutic performance when compared with that presented as a conventional dosage form (a solution or a prompt drug-releasing dosage form). The terms “controlled release (CR)”, “prolonged release”, “sustained or slow release (SR)” and “long-acting (LA)” have been used synonymously with “extended release”. Controlled Drug Delivery (CDD) occurs when a polymer, whether natural or synthetic, is judiciously combined with a drug or other active agent in such a way that the active agent is released from the material in a predesigned manner. The release of the active agent may be constant over a long period, it may be cyclic over a long period, or it may be triggered by the environment or other external events. In any case, the purpose behind controlling the drug delivery is to achieve more effective therapies while eliminating the potential for both under and overdosing^3,4.

The rationale for the Controlled Delivery of drugs is to promote therapeutic benefits while at the same time minimizing toxic effects. Controlled, sustained drug delivery can reduce the undesirable fluctuation of drug levels, enhancing therapeutic action and eliminating dangerous side effects⁵. The goal of any drug delivery system is to provide a therapeutic amount of drug to the proper site in the body in order to promptly achieve and there by to maintain the desired concentration. In recent years, various modified drug products have been developed to release the active drug from the product at a controlled rate. Controlled drug delivery systems aim to maintain plasma concentration of drugs within the therapeutic window for a longer period of time, thereby to ensure sustained therapeutic action and for that reason an increasing interest in their development exist. Moreover, many of new therapeutics under development are large molecules such as peptides, proteins, oligonucleotides, and vaccines. Their physical, chemical, and biopharmaceutical attributes distinct from small molecule drugs demand novel controlled release technologies to diminish barriers for oral delivery, such as instability in GI tract and poor absorption⁶. In the present study Cinitapride was chosen as model drug. It is a gastroprokinetic agent and antiulcer agent of the benzamide class. It is used in the treatment gastrointestinal disorders associated with motility disturbances such as gastro esophageal reflux disease, non – ulcer dyspepsia and delayed gastric emptying. The present study is an attempt that has been made to formulate controlled release tablet of Cinitapride by wet granulation method using polymers like carbopol, Methyl cellulose, HPMC K4M, HPMC K15M and HPMC K100M. Considering that an antiulcer drug it is important to improve the patient compliance by making it convenient to take and reduce adverse gastrointestinal reaction.

MATERIAL USED:

Cinitapride was purchased from Alkem Labs, Mumbai. All other reagents and chemicals used were Pharmacopoeial grade.

METHODS:

Drug - Excipient Compatibility Studies:

A successful formulation of a stable and effective solid dosage form depends on careful selection of excipients that are added to facilitate administration, promote the consistent release and bioavailability of the drug and protect it from degradation. If the excipients are new and not been used in formulation containing the active substance, the compatibility studies are of paramount importance. Compatibility of cinitpride with the respective polymers and physical mixture of main formulation was established by Infrared Absorption Spectral Analysis (FTIR). Any changes in the chemical composition after combining with the excipients were investigated with IR spectral analysis

Preparation of Cinitapride CR Tablets:

Cinitapride CR tablets each containing 3 mg of cinitapride were prepared by Wet granulation method. The different polymers used diluents used was Lactose and Dicalcium phosphate were Carbopol, Methyl cellulose, HPMCK 4M, HPMC K 15M and HPMC K 100M in different concentrations. Accurate quantities of cinitapride, polymers and excipients were weighed passed through 24 # and 30 #.

Dry Mixing:

Mix the material into the blender at slow speed for 10 minutes

Granulation:

The prepared binder solution was added to the above dried mixed ingredients and makes them as wet mass. This wet mass was passed through Sieve No: # 8 and allowed to dry for 1 hour. Then it was rasped using sieve No: # 20

Mixing of extra granular material:

The prepared granules were mixed with extra granular material for 5 min.

Table 1: Composition of cintapride CR Tablets with different polymers

Ingredients (mg/tab)	FORMULATION CODE
Ingredients (mg/tab)	F1	F2	F3	F4	F5	F6	F7	F8	F9	F10	F11	F12	F13
Cinitapride	3	3	3	3	3	3	3	3	3	3	3	3	3
Carbopol	10	15	20	25	30	-	-	-	-	-	-	-	-
Methyl cellulose	-	-	-	-	-	10	15	20	25	30	-	-	-
HPMCK 4 M	-	-	-	-	-	-	-	-	-	-	10	15	20
HPMC K 15M	-	-	-	-	-	-	-	-	-	-	-	-	-
HPMC K 100M	-	-	-	-	-	-	-	-	-	-	-	-	-
Lactose monohydrate	51	46	41	36	31	51	46	41	36	31	51	46	41
Dibasic calcium phosphate	30	30	30	30	30	30	30	30	30	30	30	30	30
PVP K30	2	2	2	2	2	2	2	2	2	2	2	2	2
Sodium starch glycolate	1	1	1	1	1	1	1	1	1	1	1	1	1
Magnesium stearate	1	1	1	1	1	1	1	1	1	1	1	1	1
Talc	2	2	2	2	2	2	2	2	2	2	2	2	2
Total weight (mg)	100	100	100	100	100	100	100	100	100	100	100	100	100

Table 2: Composition of cintapride CR Tablets with different polymers

Ingredients (mg/tab)	FORMULATION CODE
Ingredients (mg/tab)	F14	F15	F16	F17	F18	F19	F20	F21	F22	F23	F24	F25
Cinitapride	3	3	3	3	3	3	3	3	3	3	3	3
Carbopol	-	-	-	-	-	-	-	-	-	-	-	-
Microcrystalline cellulose	-	-	-	-	-	-	-	-	-	-	-	-
HPMC K 4 M	25	30	-	-	-	-	-	-	-	-	-	-
HPMC K 15M	-	-	10	15	20	25	30	-	-	-	-	-
HPMC K 100M	-	-	-	-	-	-	-	10	15	20	25	30
Lactose monohydrate	36	31	51	46	41	36	31	51	46	41	36	31
Dibasic calcium phosphate	30	30	30	30	30	30	30	30	30	30	30	30
PVP K30	2	2	2	2	2	2	2	2	2	2	2	2
Sodium starch glycolate	1	1	1	1	1	1	1	1	1	1	1	1
Magnesium stearate	1	1	1	1	1	1	1	1	1	1	1	1
Talc	2	2	2	2	2	2	2	2	2	2	2	2
Total weight (mg)	100	100	100	100	100	100	100	100	100	100	100	100

Lubrication:

After mixing of extra granular material the blend was lubricated by using magnesium stearate, talc and sodium starch glycolate for 5 min. Before compression, all precompressional parameters were adjusted.3 mg of cinitapride Cr tablets were compressed on single rotary punching machine, each weighing 100mg. the composition of cinitapride CR tablets was given in Table 1 and 2.

EVALUATION OF PRECOMPRESSIONAL PARAMETERS:^7-18

PRECOMPRESSIONAL STUDIES:

1. Angle of repose:

The angle of repose of granules was determined by the funnel method. Accurately weighed granules were placed in a plugged glass funnel which had a distance of 2 cm from the flat surface. The granules was allowed to flow through the 8 mm funnel orifice by removing the cotton plug from the funnel orifice. The height of the heap (h) formed as well as the radius of the heap (r) were noted. The data obtained was used for calculating angle of repose.

θ = tan^-1(h/r)

2. Bulk Density and Tapped Density:

Accurately weighed granules were previously passed through 20 # sieve, was transferred in 100 ml graduated cylinder. The powder in the cylinder was leveled without compacting, and the unsettled apparent volume was noted. The cylinder was dropped on a wooden platform from a height of 2.5 cm, three times at 2s interval. The volume occupied by the granules was recorded as the bulk volume. The cylinder was then tapped on the wooden platform until the volume occupied by the granules was remained constant. This was repeated three times for granules. The data generated were used in calculating the Carr’s compressibility index and Hausner’s ratio. The LBD and TBD were calculated in g/ml by the following formula

Bulk density = Weight of powder / Bulk volume

Tapped Density = Weight of powder / Tapped volume

3. Carr’s Index:

The Compressibility Index of the powder blend was determined by Carr’s compressibility index. It was a simple test to evaluate the BD and TD of a powder and the rate at which it was packed down. The formula for Carr’s Index is as below

Carr’s Index (%) = [(TD-BD) x100]/TD

4. Hausner’s Ratio:

The Hausner’s ratio is a number that is correlated to the flowability of a powder or granular material.

Hausner’s Ratio = Tapped Density / Bulk Density

POST-COMPRESSIONAL STUDIES:^7-18

A. Tablet thickness:

The thickness of 10 tablets of each selected at random from the formulated tablets was determined using a vernier caliper and the mean of these readings was taken as the mean tablets thickness.

B. Tablet weight uniformity:

Twenty tablets were weighed individually using a digital balance with the precision of 0.05 mg and readability of 0.1 mg, from which the mean was calculated and percentage deviations determined.

C. Hardness (Crushing strength):

The crushing strengths of tablets were determined individually with the Monsanto hardness tester. 6 tablets were used and the mean crushing strength was calculated.

D. Friability:

For each tablet formulation the friability of 10 tablets were determined. Friability can be determined by the following equation

W(I) – W(F)

F = ------------------------ X 100

W(I)

E. Drug content uniformity:

The drug content of the matrices determined by equilibrating an accurately weighed quantity of the tablet in appropriate dissolution medium. The samples were filtered, suitably diluted and assayed spectrophotometrically.

F. Tablet dosage forms assay:

Tablet containing 3 mg of drug was dissolved in 100 ml of 0.1N HCl .The drug was allowed to dissolve in the solvent, the solution was filtered, and 1ml of filtrate was suitably diluted with phosphate buffer pH 6.8 and analyzed spectrophotometrically at 264 nm. The amount of cinitapride was estimated by using standard calibration curve of the drug. Drug content studies were carried out for each batch of formulation

G. In-vitro drug release studies of tablets:

Drug release studies of tablets were carried out using a USP II dissolution rate test apparatus (50 rpm, 37 °C) for 2 hr in 0.1 N HCl (900 ml) as the average gastric emptying time is about 2 hr. Then the dissolution medium was replaced phosphate buffer pH-6.8 (900 ml) for 12 hrs tested for drug release up to complete drug release. At the end of the time period 10 ml of the samples were taken and analyzed for cinitapride content. A 10 ml Volume of fresh and filtered dissolution medium was added to make the volume after each sample withdrawal. Sample was analyzed using UV spectrophotometer at 264 nm.

H. Comparison of in-vitro dissolution of formulation with the marketed product:

Comparison of dissolution profile of optimized formulation (F23) with marketed product (Cintapro OD) was done.

I. Stability study of optimized formulation:

The purpose of stability testing was to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, light, to establish re-set period for drug substances or a shelf life for the drug product and recommended storage conditions. The storage condition used for stability studies were 40°C, 75±5% RH, for 3 months. The tablets were withdrawn for analysis of following parameters:

1. Physical characteristics

2. Assay

3. Dissolution

Tablets were evaluated for physical characteristics; Assay, and in-vitro drug release after 3 months.

RESULTS AND DISCUSSION:

The present study was to formulate controlled release tablets of cinitapride using different polymers in different concentrations and diluent Lactose and DCP along with other excipients by wet granulation method. The prepared tablets were evaluated for physic chemical properties, in-vitro dissolution studies and stability studies.

DRUG- EXCIPIENT COMPATIBILITY STUDIES:

The optimized formulation F23 was subjected for IR Spectroscopic analysis to ascertain whether there was any interaction between drug and excipients used. The IR Spectra showed similar characteristic peaks at their respective wavelength with minor difference. The similarity in the peaks indicated the compatibility of drug with formulation excipients.

Figure 1: FTIR Spectra of Cinitapride

Figure 2: FTIR Spectra of drug and F23

_T_{able 3: Pre-compressional studies of Cinitapride
granules}

Formulation	Angle of Repose	Bulk Density	Tapped Density	Compressibility Index	Hausner's Ratio	LOD
F1	28.02	0.5581	0.6775	17.62	1.214	2.0234
F2	28.80	0.5665	0.6813	16.85	1.203	2.0202
F3	28.65	0.5562	0.6714	16.36	1.207	2.0240
F4	28.70	0.5602	0.6698	17.11	1.196	2.0002
F5	28.71	0.5620	0.6787	17.19	1.207	2.0198
F6	28.40	0.5702	0.6782	15.92	1.189	2.02
F7	28.46	0.5725	0.6909	17.14	1.206	1.9952
F8	28.48	0.5698	0.6701	14.96	1.176	1.998
F9	28.46	0.5710	0.6897	17.21	1.121	2.012
F10	28.48	0.5711	0.6780	15.76	1.187	2.032
F11	27.855	0.5612	0.6616	15.107	1.178	1.88
F12	27.85	0.5642	0.6592	14.41	1.168	2.002
F13	27.96	0.5602	0.6680	16.13	1.1922	1.98
F14	27.90	0.5600	0.6596	15.10	1.178	1.970
F15	27.77	0.5611	0.6593	14.89	1.175	2.011
F16	26.70	0.5590	0.6618	15.53	1.183	1.985
F17	25.98	0.5602	0.6603	15.15	1.178	1.9086
F18	26.12	0.5597	0.6660	15.96	1.189	1.889
F19	26.04	0.5600	0.6596	15.10	1.178	1.980
F20	26.34	0.5610	0.6627	15.34	1.181	1.995
F21	26.03	0.5604	0.6603	15.13	1.178	2.002
F22	25.95	0.5661	0.6599	14.21	1.165	1.877
F23	26.91	0.5624	0.6591	14.67	1.171	1.903
F24	26.73	0.5654	0.6603	14.37	1.167	1.930
F25	26.11	0.5655	0.6589	14.17	1.165	1.919

_Tab_l_{e 4: Post-compression evaluation of the prepared Tablets
F1 – F25}

Formulation	Thickness (mm)	Weight of Tablet (mg)	Friability (%)	Hardness (kg/cm²)	Assay (%)
F1	3.53±0.18	99.84 ± 1.43	0.215	5.75 ± 0.6	98.39
F2	3.48± 0.17	99.06 ± 1.95	0.120	5.80 ±0.72	99.53
F3	3.48± 0.17	99.46 ± 1.33	0.094	5.83 ±0.91	99.80
F4	3.52±0.18	99.18 ± 2.00	0.117	5.84±0.17	99.68
F5	3.53±0.18	98.78 ± 2.05	0.276	5.92 ±0.80	98.50
F6	3.48± 0.14	99.87 ± 1.43	0.295	5.60 ± 0.6	100.36
F7	3.62±0.17	99.17 ± 1.80	0.164	5.72 ±0.53	99.82
F8	3.57 ±0.14	99.26 ± 1.33	0.305	5.70± 0.65	98.88
F9	3.60±0.18	99.18 ± 2.10	0.229	5.75±0.70	99.18
F10	3.54 ±0.18	99.86 ± 1.62	0.177	5.78 ±0.80	98.70
F11	3.62±0.15	99.27 ± 1.43	0.175	5.90 ± 0.6	99.26
F12	3.60 ±0.17	99.26 ± 1.85	0.098	5.86 ±0.72	99.72
F13	3.62±0.14	99.46 ± 1.30	0.087	5.97 ±0.65	100.80
F14	3.58± 0.17	99.28 ± 1.68	0.131	6.12±0.70	99.68
F15	3.58± 0.17	99.26 ± 1.32	0.108	6.19 ±0.90	99.12
F16	3.62±0.16	99.07 ± 1.63	0.085	5.90 ± 0.6	99.16
F17	3.60±0.18	99.26 ± 1.93	0.093	5.98 ±0.47	99.12
F18	3.53±0.19	98.90 ± 2.03	0.139	5.99 ±0.45	101.0
F19	3.58± 0.14	98.98 ± 2.22	0.106	6.02±0.72	99.68
F20	3.60± 0.15	99.16 ± 1.32	0.089	6.17 ±0.04	100.32
F21	3.63±0.18	99.27 ± 1.43	0.085	6.0 ± 0.6	99.36
F22	3.58± 0.16	99.26 ± 1.85	0.086	6.10 ±0.77	99.42
F23	3.60± 0.17	99.56 ± 1.33	0.086	6.37 ± 0.65	100.30
F24	3.62±0.15	98.98 ± 2.10	0.088	6.30±0.70	99.28
F25	3.58±0.18	99.66 ± 1.32	0.097	6.31±0.80	98.98

e) Friability test:

Friability values for each batch were found to be lies between 0.085% to 0.305% respectively. The obtained results were found to be well within the approved range (<1%) in all the designed formulations. That indicated tablets possess good mechanical strength.

f) Tablet dosage form assay:

Tablet dosage form assay for both the formulations was carried out. In assay of formulations lies in between 98.39 % to 101 % drug content respectively. The cumulative percentage drug released from each tablet in the in-vitro release studies was based on the average drug content present in the tablet.

The In-vitro release studies:

The in-vitro release studies were carried out using – USP II dissolution assembly. The results obtained in the in-vitro drug release study are shown in Figure 3 to Figure 7.

Figure 3: In-vitro drug release profile of Cinitapride trial batches F1 to F5

Figure 4: In-vitro drug release profile of Cinitapride trial batches F6 to F10

Figure 5: In-vitro drug release profile of Cinitapride trial batches F11 to F15

Figure No. 6: In-vitro drug release profile of Cinitapride trial batches F16 to F20

Figure 7: In-vitro drug release profile of Cinitapride trial batches F21 to F25

Stability study of Cinitapride controlled release tablets:

The stability study was carried out at 40°C/75% RH for formulation F23 up to 90 days. At every 30 days time interval, the devices were analyzed for Physical Properties and in-vitro drug release. Release profile of F23 after stability study is plotted as shown in the Figure 13.The results of accelerated stability study showed that there was no change in the formulation after 3 months. In-vitro drug release study throughout 2 hours, after 30, 6 0 and 9 0 days, showed the values 21.88, 21.33 and 22.09 respectively. The drug release throughout 2 hours obtained the values within range of targeted release profile. In-vitro drug release study throughout 12 hours, after 30, 6 0 and 90 days, showed the values 98.07%, 97.91% and 98.76% respectively. The drug release throughout 12 hours obtained the values within range of targeted release profile. Assay result after 30, 60 and 9^{0 days, showed the values}99.78%^,99.15%^and99.07%^{respectively.}After 90 days accelerated stability study the assay result was stable.

Figure 8: Comparison of In-vitro drug release of Cinitapride CR formulation (F23) before and after stability studies

CONCLUSION:

The study was undertaken with an aim of Formulation, Development and Evaluation of Cinitapride controlled release tablets, using different polymers as release retarding agent. Preformulation study was done initially and results directed for the further course of formulation. Based on preformulation studies different batches of Cinitapride were prepared using selected excipients. Granules were evaluated for Bulk density, Tapped density, Compressibility index, and Hausner’s ratio. Tablets were tested for weight variation, thickness, hardness and friability as per official procedure. Dissolution was carried out in phosphate buffer pH 6.8. Based on dissolution tests, it was concluded that F23 satisfactorily release drug through 12 hrs. From the above results and discussion, it was concluded that formulation of controlled release tablet Cinitapride of formulation F23 can be taken as an ideal formulation of controlled release tablets for 12 hour release, as it fulfills all the requirements for controlled release tablet and our study encourages for in-vivo studies. Stability study was carried out after 3 months of time. Stability study report confirmed that formulation was not shown any colour change and no significant release profile, assay from initial period. Thus it confirms that prepared formulation was stable.

ACKNOWLEDGEMENT:

The authors are thankful to the Management and Principal of Karavali college of Pharmacy, Mangalore for providing all the facilities to conduct the research work and the authors are also thankful to Alkem Labs, Mumbai, for generous gift sample of Cinitapride.

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Received on 16.03.2016 Accepted on 08.04.2016

Asian J. Pharm. Res. 2016; 6(2): 87-94

DOI: 10.5958/2231-5691.2016.00015.0