Fast Dissolving Drug Delivery System of Cilnidipine using Gelucire 50/13

 

 V. P. Thorat¹*, P. R. Mahaparale²  I. D. Gonjari³

¹Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune, Maharashtra, India 411018

²Government College of Pharmacy, Osmanpura Aurangabad, Maharashtra 431005

³Government College of Pharmacy, Ratnagiri, Maharashtra 415612

 

ABSTRACT:

Cilnidipine is poorly water soluble antihypertensive drug (BCS class II). This study was conducted to increase solubility of drug. An attempt was made to formulate fast dissolving tablet of Cilnidipine by solid dispersion using melting method with Gelucire 50/13. The API: carrier was taken as 1:1, 1:2 and 1:3. Effect of several variables such as concentration of superdisintegrant, drug: carrier ratios were studied. Formulations were analyzed using Differential Scanning Calorimetry (DSC), X-ray Diffraction (XRD) analysis, Fourier Transform-Infrared spectroscopy (FT-IR) and in-vitro release studies followed by various release kinetics. The % drug release NLT 85% was obtained by melting method of Cilnidipine: Gelucire 50/13 (1:3) within 15 minutes. Accelerated stability study was carried out for period of 3 months, which indicated prepared formulations were stable.

 

 

 

INTRODUCTION:

Cilnidipine is a novel dihydropyridine calcium antagonist and its calcium antagonistic activity is lasting longer than those of Nifedipine and Nicardipine. Cilnidipine has been used for the treatment of hypertension and hypertensive-associated vascular disorders. Cilnidipine has a very low solubility (BCS Class-II drug Low solubility high permeability) and compliance to the medication is always very poor The dissolution rate is directly proportional to solubility of drug. Drugs with low aqueous solubility have low dissolution rate and hence suffer from oral bioavailability problems. Solid dispersion technique is widely used to increase intrinsic solubility and dissolution in turns oral bioavailability of poorly water soluble drug. The solid dispersion is defined as dispersion of one or more active ingredients in an inert carrier matrix at solid-state prepared by the melting (fusion), solvent evaporation or melting-solvent method.¹

 

 

 

Gelucires are a family of lipid-based excipients comprising glycerides and esters of (PEG), these two components conferring hydrophobic and hydrophilic properties to the vehicle. Each Gelucire is characterized by two numbers, the first referring to the nominal melting point of the base and the second to the HLB value. Gelucires come in a variety of grades with different melting points (from 33 ºC to 65 ºC) and HLB values (from 1 to 14). Gelucires are reported to be used in solubility enhancement of various drugs.²

 

MATERIALS AND METHODS:

Materials:

Cilnidipine and Neusilin was a gift sample from Emcure Pharmaceuticals Pvt. Ltd. Pune, Gelucire 50/13 from Colorcon Asia Pvt. Ltd., Mumbai, All other ingredients used were of analytical grade and purchased from Research Lab Fine Chem. (Mumbai).

 

Methods:

A)    Preparation of solid dispersion:

Fast dissolving tablets were prepared by using Cilnidipine with variable concentrations of superdisintegrant and drug: carrier ratio. Measured quantity of Gelucire 50/13 was taken separately and heated until they get melted. Then measured quantity of Cilnidipine was added in the molten mass of Gelucire 50/13 with stirring until formed homogeneous mass. Melted mixture was then solidified rapidly in an ice-bath under vigorous stirring. The final solid mass was crushed, pulverized and sieved and stored in desiccators for 24 hours. The solid dispersion was prepared in the ratio of 1:1, 1:2, 1:3. The powder X-ray diffraction (PXRD) patterns were recorded using X-ray diffractometer (Bruker D8 Advance analyser).^3,4

 

B)     Preparation of tablet:

Solid dispersion mass was mixed with excipients thoroughly for 15 minutes. The resulting powder blends were evaluated for flow parameters. The powder blends equivalent to the 10 mg of drug was directly compressed. Tablets were evaluated for various parameters.^{5, 6,26}

Table No.1 Formulation batches of solid dispersion of Drug: Gelucire 50/13

Formulation Batch	Solid dispersion ratios	Drug (mg)	Gelucire 50/13	Crospovidone (mg)	Neusilin (mg)	Total weight (mg)
B1	1:1	10	10	-	80	100
F1	1:1	10	10	4	76	100
F2	1:1	10	10	6	74	100
F3	1:1	10	10	8	72	100
F4	1:2	10	20	4	66	100
F5	1:2	10	20	6	64	100
F6	1:2	10	20	8	62	100
F7	1:3	10	30	4	56	100
F8	1:3	10	30	6	54	100
F9	1:3	10	30	8	52	100

 

Factorial design:

The fast dissolving tablets were prepared using Gelucire 50/13 by 3² full factorial design as shown in Table No.1. The percentage of Gelucire 50/13 (A) and Crospovidone (B) were selected as independent variables and the dependent variables were cumulative % dissolution in 15 min (% DR₁₅) and disintegration time. The study was carried out using Design Expert 8.0.7.1 software.

 

Evaluation of tablets:

Drug content uniformity:

Five tablets were weighed individually and crushed in a mortar. Quantity of powder equivalent to 10 mg of Cilnidipine was weighed accurately and dissolved in methanol. The volume was made to 100 ml with Distilled water. Appropriate dilutions of the resulting solutions were done. The drug contents of the resulting solutions were calculated from UV absorbance at 253 nm.^{7, 8, 9,27}

 

Disintegration time:

The in vitro disintegration studies were carried out using Digital Tablet Disintegration Test Apparatus (Veego Scientific Pvt Ltd, Mumbai). One tablet was placed in each of the six tubes of the basket assembly and disk was added to each tube. This assembly was then suspended in beaker containing 0.1 % SLS in distilled water maintained at 37±2⁰C. The basket was then moved up and down through a distance of 5 to 6 cm. at a frequency of 28 to 32 cycles per minutes. The time required for complete disintegration of tablets was recorded. The test was performed for tablets of all type of formulation.^{10,11,12,23,28}

 

In Vitro Dissolution studies:

The dissolution study was carried out in 900 ml 0.1% SLS in distilled water at 50 rpm at temperature 37±0.5⁰C for 15 minutes using USP apparatus type-II (Veego Scientific Pvt. Ltd, India). Appropriate aliquots (10 ml sample volume) were withdrawn from the dissolution medium at predetermined intervals (2, 4, 6, 8, 10, 15 min). The samples were filtered through whatman filter paper. Samples were then analyzed at λmax of 253 nm using UV/VIS double beam Spectrophotometer.^{13 ,14,24,29}

 

Stability studies:

Stability studies on the optimized formulation of fast dissolving tablet were carried out to determine the effect of temperature and humidity on the stability of the drug. The tablet (optimized batch F9) was stored in stability chamber at a 40°C±2°C/ 75%RH. The sample was withdrawn at 30 days, 90 days and subjected for visual inspection, disintegration test and in vitro dissolution ^{15, 16,30} (Table 2).

 

RESULT AND DISCUSSION:

Powder X ray Diffraction:

PXRD pattern of the solid dispersion prepared with Gelucire was characterized by less intensity of diffraction peaks as compared to pure drug, suggesting conversion of microcrystalline form of the drug to an amorphous state, which may helps to improve solubility and dissolution of drug (Fig. 1 and 2).^{17, 18,19,22,25}

 

Figure No. 1 PXRD of Cilnidipine

 

 

Figure No. 2 PXRD pattern for Cilnidipine – Gelucire 50/13 solid dispersion

 

Factorial Design:

Response surface plot for cumulative % drug release in 15 minutes and for disintegration time is as shown in Figure No.3, 4.

 

 

Figure No. 3 Response surface plot for cumulative % drug dissolved in 15 mins

 

Final equation in terms of coded factors for % drug dissolved

 

Cumulative % drug  dissolved in 15 min=+ 58.03+ 27.04A +4.02B

Response surface plots were generated for each response. Coefficient of A was found to be more as compared to B which indicated concentration of Gelucire was more significant than concentration of crospovidone on dissolution of drug. Gelucire was found to increase solubility and dissolution of drug.

 

Figure No.4 Response surface plot for disintegration time

Final equation in terms of coded factors for disintegration time

Disintegration time = +52.33-11.17 A-5.17 B

Response surface plots were generated for each response. Negative sign indicates increase in concentration of gelucire and crospovidone decreases disintegration time.

 

DRUG GELUCIRE SOLID DISPERSION:

From dissolution profile it was observed that the increasing ratio of drug: gelucire complex leads to increase in the drug release. The 1:1 ratio showed 40%, 1:2 ratio 70% and 1:3 ratio 93% drug release in 15 minutes (Fig. 5). The enhanced drug release rates of solid dispersions (SDs) may be due to many factors such as decreased particle size of drug, specific form of drug in these SDs, in addition to the increase in drug wettability.

 

Figure No.5 Effect of Drug Gelucire 50/13 ratio on dissolution of drug

 

Comparative Dissolution Profile of optimized formulations with Marketed tablet M1:

From the graph it was observed that the marketed formulation of Cilnidipine showed 60% dissolution within 60 min. Our all selected ratios showed much faster dissolution as compared to marketed formulations (Fig. 6).

 

Figure No.6 Comparative Dissolution Profile of Marketed tablet M1 with F9 formulation

 

Stability studies:

Stability studies carried out at 40 ± 2⁰C/ 75± 5% RH for 90 days shown no significant change in colour, disintegration time, and cumulative % dissolution of optimized formulations. It indicated that formulation was stable.

 

Table No.2 Stability studies

Formulation Batch	Time	Appearance	Disintegration Time  (seconds)	Cumulative %Drug Dissolved within 15 minutes
F7	Initial	White	53±3	84.30±1.16
	30days	White	53±3	84.20±1.16
	90days	White	52±2	84.10±2.34
	Initial	White	50±2	87.22±0.85
F8	30days	White	49±1	87.22±1.62
	90days	White	48±1	87.22±1.91
F9	Initial	White	26±3	93.41±1.16
	30days	White	25±2	93.21±2.34
	90days	White	25±2	93.11±2.34

 

CONCLUSION:

The solid dispersion prepared using Gelucire showed increase in dissolution of drug. Increase in concentration of Gelucire showed increase in dissolution of drug. The superdisintegrant used shown decrease in disintegration time and increase in dissolution rate of drug. The drug: Gelucire 1:3 and 8% crospovidone was found to be good in terms of dissolution rate and disintegration time.

 

The formulations F7, F8 and F9 were found better in terms of disintegration time and dissolution profile (DT<3 minutes and drug release NLT 85% in 15 min).

 

ACKNOWLEDGEMENT:

This work was supported by Dr. D. Y. Patil College of Pharmacy, Akurdi, Pune.

 

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Received on 20.12.2018          Modified on 20.01.2019

Accepted on 16.02.2019        © RJPT All right reserved