Development and Evaluation of Metoclopramide Hydrochloride Floating Microspheres for controlled Release

 

Dr. Vaseeha Banu T. S¹, Mohammad Sameer Ansari², Dr. Mohamed Khaleel

¹Professor, Dept. of Pharmaceutics, MMU College of Pharmacy, K.K. Doddi, Ramadevera Betta Road, Ramanagara-562159, Karnataka State, India

²Lecturer, Dept. of Pharmaceutics, MMU College of Pharmacy, K.K. Doddi, Ramadevera Betta Road, Ramanagara-562159, Karnataka State, India

³Principal, M M U College of pharmacy, K. K. Doddi, Ramadevera Betta road, Ramanagara-562159, Karnataka State, India

 

ABSTRACT:

Floating drug delivery system is one of the novel drug delivery system. It has a bulk density less than gastric fluids and thus it remains buoyant in the stomach without affecting gastric emptying rate for a prolonged period of time. Metoclopramide Hydrochloride (MHCl) is a dopamine D2 antagonist that is used as an antiemetic. Floating microspheres of MHCl were prepared by Emulsion solvent evaporation method by using HPMC K4M, HPMC K15M, HPMC K100M, Ethyl cellulose as polymers. The prepared microspheres were evaluated for micromeritic properties, particle size, percentage yield, in vitro buoyancy, incorporation efficiency and in-vitro drug release. From the result it was observed that the concentration of polymer has significant effect on the particle size, percentage yield, in-vitro buoyancy and in-vitro drug release of microspheres; the cumulative drug release with different HPMC grade was found to be HPMC K4M≥HPMC K15M≥HPMC K100M. The micromeritic property was found to be good. Formulation F9 prepared with HPMC K100M: Ethyl cellulose exhibited excellent micromeritic properties, percentage yield, in vitro buoyancy, incorporation efficiency and percentage drug release was 94. 60% for a period of 12 hrs. The data obtained in this study thus suggest that floating microspheres of MHCl are promising for sustained drug delivery, which can reduce dosing frequency.

 

 

 

INTRODUCTION:

Despite tremendous advancements in drug delivery, the oral route remains the preferred route of administration of therapeutic agents because of low cost of therapy and ease of administration lead to high levels of patient compliance. But the issue of poor bioavailability of orally administered drugs is still a challenging one.

 

Gastric emptying is a complex process and makes in-vivo performance of the drug delivery systems uncertain.¹ Drugs that are easily absorbed from the gastrointestinal tract (GIT) have a short half-life and are eliminated quickly from the blood circulation, require frequent dosing. To avoid this problem, the Oral Controlled Release (OCR) formulations have been developed in an attempt to release the drug slowly into the GIT and maintain a constant drug concentration in the serum for longer period of time. Such oral drug delivery devices have a restriction due to the gastric retention time (GRT), a physiological limitation. Therefore, prolonged gastric retention is important in achieving control over the GRT because this helps to retain the OCR system in the stomach for a longer Period of time in a predictable manner.²

 

Floating microspheres have emerged as an efficient means of enhancing the bio-availability and controlled delivery of drugs. Floating drug delivery system has a bulk density lower than gastric fluid and thus remains buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. The increase in sophistication of delivery technology will ensure the development of increase in number of gastro-retentive drug delivery systems to optimize the delivery of molecules that exhibit low bio availability and extensive first pass metabolism. Floating microspheres improves the patient compliance by decreasing dosing frequency, increase the therapeutic effect of short half-life drugs and enhance absorption of drugs which solubilise only in stomach by increasing gastric retention time due to buoyancy.^3,4,5

 

Metoclopramide is used to treat the symptoms of a certain type of stomach problem called gastroparesis in patients with diabetes. It works by increasing the movements or contractions of the stomach and intestines. It relieves symptoms such as nausea, vomiting, heartburn, a feeling of fullness after meals, and loss of appetite. Metoclopramide is also used to treat heartburn for patients with gastro-esophageal reflux disease (GERD). GERD is esophageal irritation from the backward flow of gastric acid into the esophagus.⁶

Hence in the present work an attempt has been made to provide an alternative drug delivery system for better treatment of gastroparesis using Metoclopramide as a model drug in the form of microspheres using biocompatible polymers which will overcome the inherent drawback of existing dosage form.

 

MATERIALS AND METHOD:

Metoclopramide Hydrochloride (MHCl) obtained as gift sample from Agrawal Pharmaceuticals, Delhi, Ethyl Cellulose (EC), Hydroxyl Propyl Methyl Cellulose (HPMC), Ethanol, Dichloro Methane, Tween 80 from Loba Chemicals Mumbai. All other ingredients used were of analytical grade.

 

Preparation of floating microspheres:

Emulsion solvent evaporation method has been employed to prepare floating microspheres of MHCl with ethyl cellulose, hydroxyl propyl methyl cellulose. The drug and polymer in different proportions are weighed; (as shown in table-1) the polymer was co-dissolved into previously cooled mixture of ethanol: dichloromethane at room temperature. The mixture was stir vigorously to form uniform drug polymer dispersion. The above organic phase was slowly added to 100 ml distilled water containing 0.01% tween 80 by maintaining the temperature in between 15 – 20°C and emulsified by stirring at 1200 rpm for 15 min. Microspheres formed were filtered, washed with water and sieved between 50 and 30 mesh size, and dried overnight at 40°C.

 

Table -1 Formulation of floating microspheres of Metoclopramide

Ingredient (mg)	Formulation code
	F1	F2	F3	F4	F5	F6	F7	F8	F9
Ethyl cellulose	0.500	1.334	2.250	0.500	1.334	2.250	0.500	1.334	2.250
HPMC K4M	0.500	0.666	0.750	-	-	-	-	-	-
HPMC K15 M	-	-	-	0.500	0.666	0.750	-	-	-
HPMC K100M	-	-	-	-	-	-	0.500	0.666	0.750
Metoclopramide.HCl	1.000	1.000	1.000	1.000	1.000	1.000	1.000	1.000	1.000
Dichloromethane	30	30	30	30	30	30	30	30	30
Ethanol	30	30	30	30	30	30	30	30	30

 

Physicochemical evaluation of prepared floating microspheres:

The prepared floating microspheres are evaluated for particle size, bulk density, tapped density, carr’s index, Hausners ratio and angle of repose, in vitro buoyancy, incorporation efficiency and in vitro drug release.

 

Particle size:^{7, 8, 9}

The particle size was measured by microscopic technique. In this method suspension of floating microspheres was prepared using castor oil. A drop of suspension was mounted on a slide and observed under optical microscope about 600 particles were measured with the help of the eye piece micrometer.

 

Bulk Density (Db):^{7, 8, 9}

It is the ratio of total mass of microspheres to the bulk volume of microspheres. It was measured by pouring the weighted microspheres into a measuring cylinder and the volume was noted. It is expressed in gm/ml and is given by D_b= M/v; where M is mass of microspheres and bulk volume of microspheres.

 

Tapped density (Dt):^{7, 8, 9}

It is the ratio of total mass of the microspheres to the tapped volume of microspheres. The tapped volume was measured by tapping the microspheres to constant volume. It is expressed in gm/ml and is given by Dt = M/V_t, Where M is the mass of microspheres; V_t is the tapped volume of the microspheres.

Angle of Repose (θ): ^{7, 8, 9}

Weighed quantity (10 g) of microspheres was passed through the funnel from the fixed height on to the graph paper. The height of the heap was measured and circumference of the heap was marked by pencil. The angle of repose was calculated using the above formula. ɵ = tan ^-1 h/r Where, ɵ is the angle of repose, h is the height of heap of microspheres in cm, r is the radius of heap of microspheres.

 

Hausner’s ratio: ^{7, 8, 9}

It indicates the flow properties of the microspheres and is measured by the ratio of tapped density to the bulk density.

 

Carr’s Index (I): ^{7, 8, 9}

It indicates the ease with which a material can be induced to flow. It is expressed in percentage and is given by I = Dt – Db/ Dt × 100 Where, Dt is the tapped density of the microspheres. Db is the bulk density of the microspheres.

 

Yield of Floating microspheres^{10, 11}

The prepared floating microspheres with a size range of 102–420 µm were collected and weighed. The measured weight was divided by total amount of all non-volatile components which were used for the preparation of microspheres.

 

% yield = Actual weight of product/Total weight of excpients and drug X 100

 

In vitro Buoyancy ^12,13

Floating microspheres (equivalent to 150 mg) were dispersed in 900ml of 0.1 (N) hydrochloric acid solution (pH 1.2) containing tween 80 (0.01 W/V%) / tween 20 (0.02 W/V%) to simulate gastric fluid at 37°C. The mixture was stirred with a paddle at 100 rpm and after 12 hr, the layer of buoyant microspheres (Wf) was pipette and separated by filtration simultaneously sinking microsphere (Ws) were also separated; both microspheres type were dried at 40°C over night. The weight of each microsphere were measured and buoyancy was determined by the weight ratio of the floating microspheres to the sum of floating and sinking microspheres. Buoyancy (%) = W_f / W_f + Ws X 100

 

Where, W_f and W_s are the weights of the floating and settled micropshers, respectively.

 

Incorporation efficiency^14,15,16

Floating microspheres were dissolved in a minimum amount of water and drug was extracted into 0.1N hydrochloric acid. The solution was filtered through whatman filter paper, diluted suitably and analyzed for drug content spectrophotometrically at 272 nm using 0.1N hydrochloric acid as blank and it is calculated by using formula % Incorporation efficiency = Actual drug content/Theoretical content × 100                                                  

 

In vitro Drug release^{14, 17,}

Drug release from floating microspheres having a size range between 102 - 420 µm was carried out by taking microspheres equivalent to 150 mg of drug using paddle method at 100 rpm, the study was carried out for the 12 hrs; for  first 2 hrs in pH 1.2 with tween 80 (0.01 W/V%) / tween 20 (0.02 W/V%) to simulate gastric fluid and for remaining 10 hrs in phosphate buffer pH 7.2 with tween 80 (0.01 W/V%) / tween 20 (0.02 W/V%) to simulate gastric fluid. 5 ml of sample were withdrawn at different time intervals and replaced with fresh phosphate buffer, the amount of drug release was analyzed at 272 nm using shimadzu UV visible spectrophotometer.

 

RESULTS AND DISCUSSION:

The aim of present study was to develop floating microspheres of MHCl by emulsion solvent evaporation method by using different grades of HPMC and EC as polymers the emulsion was stabilized by tween-80 and the volatile solvent get evaporated leaving a solidified thin film at the interface between aqueous phase and organic phase, where drug get encapsulated in the core-coat of polymers. The effect of polymer concentration on the particle size of microspheres was determined. The mean particle size of the microspheres was found to increase with increasing EC concentration. The viscosity of the medium increases at a higher EC concentration resulting in enhanced interfacial tension. Shearing efficiency is also diminished at higher viscosities. This results in the formation of larger particles. From the values of angle of repose and carr´s index it was found that prepared microspheres has the good to excellent flow property.

 

Further to known the effect of polymer concentration on the formulation percentage yield of the floating microspheres was carried out and it was observed that as the concentration of polymer increases the yield of the floating microspheres increased. At low concentration of  EC part of the polymer solution aggregated in a fibrous structure, as it solidified prior to forming droplets or the transient droplets were broken before solidification was complete due to poor mechanical strength resulting into low yield. The purpose of preparing floating microspheres was to extend the gastric residence time of a drug. The buoyancy test was carried out to investigate the floatability of the prepared microspheres. Among all formulation F9 was found to be highest in-vitro buoyancy 94.95±1.43. The results also showed a tendency that the larger the particle size, the longer floating time. The drug entrapment efficiency was found to be good in all the formulation; among all formulation F9 (96.38±2.34) found to be best, further the  results demonstrated that increase in concentration of EC  increased the entrapment of the drug. In-vitro drug release data revealed that among all the formulations, F9 was found to be the best formulation as it release MHCl  94.60% in a sustained manner with constant fashion over extended period of time (after 12 hr.). It was observed as the concentration of EC was increased percent release of MHCl decreases; this might be due to the increase in EC concentration leads to the increased density of polymer matrix into the microspheres which result in an increased diffusional path length. This may decrease the overall drug release from polymer matrix. Furthermore smaller microspheres are formed at lower polymer concentration and have larger surface area exposed to dissolution medium. In vitro release data fitted into various kinetic models suggest that the release obeyed mixed order kinetic, higuchi diffusion mechanism and non fickian control (anomalous diffusion) with swelling.

 

Table- 2 Micromeritic property of floating microspheres of Metoclopramide

Formulation Code	Mean particle size(µm)	Bulk density (gm/cm3)	Tapped density (gm/cm3)	Hauseners ratio	Carrr’s index	Angle of repose
F1	387.32±2.54	0.3572±0.010	0.4019±0.018	0.8902±0.04	11.13±0.11	32.49±1.71
F2	452.9 ±2.52	0.41240±0.012	0.4647±0.015	0.8840±0.05	12.03±0.64	27.72±1.89
F3	479.52±3.25	0.4308±0.007	0.4955±0.014	0.8681±0.03	13.46±0.24	31.88±2.78
F4	389.5±3.88	0.3575±0.014	0.4026±0.014	0.8879±0.01	11.3±0.33	27.00±1.93
F5	456.84±2.27	0.4150±0.015	0.4678±0.015	0.8871±0.02	11.4±0.26	26.02±1.80
F6	480±2.25	0.4319±0.012	0.4973±0.021	0.8684±0.01	13.2±0.33	26.56±1.43
F7	476.9±2.36	0.3889±0.018	0.4375±0.022	0.8889±0.03	12.7±1.5	26.80±1.68
F8	485.82±2.3	0.4568±0.015	0.5160±0.027	0.8852±0.01	12.4±0.86	27.11±1.59
F9	489.24±3.43	0.5763±0.017	0.6508±0.015	0.8855±0.02	12.8±1.5	26.56±1.68

*mean±SD, n=3

 

Table - 3 Percentage yield, in-vitro buoyancy and incorporation efficiency of floating microspheres of MHCl

Formulation code	Percentage yield Mean±SD*	In vitro- buoyancy Mean±SD* (%)	Incorporation efficiency Mean±SD*(%)
F1	67.840.64	76.66±1.52	77.43±2.72
F2	85.59±0.69	82.39±2.07	87.34±2.84
F3	92.5±0.51	89.96±1.04	91.94±2.17
F4	70.67±0.66	75.43±2.02	67.11±3.01
F5	82.26±0.43	83.96±1.07	88.11±2.59
F6	89.84±0.72	90.39±2.00	92.30±2.88
F7	88.63±0.65	79.33±1.32	79.76±1.58
F8	92.29±0.74	87.12±1.00	93.91±2.02
F9	93.780±0.55	94.95±1.43	96.38±2.34

 

Table – 4  In-vitro Drug release from formulation F1 to F3

Time	F1	F2	F3	F4	F5	F6	F7	F8	F9
1	0.926 ±0.21	0.926 ±1.18	1.158 ±0.38	0.926 ±1.18	2.084 ±0.21	1.853 ±0.38	1.158 ±0.67	1.853 ±0.30	5.328 ±0.36
2	7.413 ±0.49	22.00 ±0.28	11.583 ±0.4	9.034 ±0.28	7.876 ±0.49	12.046 ±0.45	8.1088 ±0.29	17.606 ±0.29	13.899 ±0.19
3	22.472 ±1.30	34.75 ±1.67	24.093 ±1.54	22.240 ±1.67	23.168 ±1.30	25.484 ±1.54	22.472 ±0.98	31.971 ±0.21	31.280 ±0.19
4	32.906 ±3.64	49.138 ±1.11	38.471 ±1.82	32.676 ±1.11	36.615 ±3.64	39.399 ±1.82	33.370 ±3.45	40.332 ±1.61	41.031 ±2.10
5	42.900 ±3.92	56.151 ±1.89	47.082 ±3.5	40.819 ±1.89	47.167 ±3.92	45.927 ±3.50	41.744 ±1.67	58.457 ±1.48	51.969 ±2.10
6	51.070 ±2.80	59.487 ±1.53	54.796 ±1.81	51.073 ±1.53	53.859 ±2.80	56.888 ±1.81	51.999 ±1.02	62.939 ±1.74	59.231 ±1.10
7	55.555 ±2.09	64.237 ±1.39	59.061 ±1.95	56.946 ±1.39	60.902 ±2.09	60.920 ±1.95	58.801 ±1.82	67.450 ±2.37	66.284 ±1.25
8	59.830 ±1.69	69.694 ±1.61	67.282 ±1.67	61.681 ±1.61	68.427 ±1.68	66.363 ±1.67	64.696 ±1.29	75.229 ±1.67	70.577 ±1.55
9	64.813 ±1.96	75.159 ±1.53	74.821 ±2.1	66.434 ±1.53	74.577 ±1.96	72.748 ±2.10	69.684 ±1.72	82.555 ±0.91	78.824 ±2.15
10	71.427 ±2.1	79.245 ±1.47	80.984 ±1.35	73.051 ±1.47	79.354 ±2.10	79.839 ±1.35	76.539 ±2.32	86.651 ±1.20	83.840 ±1.10
11	77.819 ±2.05	86.123 ±1.67	86.238 ±2.35	80.606 ±1.67	84.145 ±1.10	88.564 ±2.35	85.953 ±1.01	89.374 ±1.35	89.565 ±1.05
12	84.919 ±1.10	91.158 ±1.20	92.896±2.20	88.637±1.12	91.728	92.670 ±2.20	90.285 ±1.65	93.962 ±3.30	94.609 ±1.00

*Standard deviation (SD), n=3

 

 

 

CONCLUSION:

The Pharmacokinetic parameter of MHCl found to feasible for the formulation as floating microspheres. The method selected to prepare was emerged as a best and economical method by promising the release of drug in a sustained manner for 12hrs. The selection and combination of the polymers also helped the formulation to release the drug and in sustain manner by using its GRT Physicochemical evaluation of prepared microspheres data further revealed and confirmed the suitability of the selected method and polymers. Hence, finally it was concluded that the prepared floating microspheres of MHCl may prove to be potential candidate for safe and effective sustained drug delivery over an extended period of time which can reduce dosing frequency, thereby increasing patient compliance and can be used effectively in treatment of GERD and certain stomach problem in diabetic patients which is the main aim of this research work.

 

Figure-1. CPR of MHCl formulation F1 to F3

 

Figure-2. CPR of MHCl formulation F4 to F6

 

Figure-3. CPR of MHCl formulation F7 to F9

 

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Received on 20.05.2019         Modified on 21.06.2019

Accepted on 10.07.2019       ©A&V Publications All right reserved