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The oral route is the most common and preferable route for the delivery of drugs. This may be due to ease of administration, patient compliance and flexibility in formulation . During past few decades, numerous oral controlled drug delivery systems have been investigated and developed to act as drug reservoirs for release of drugs over a defined period of time at a controlled rate. The real challenge in the development of an oral controlled-release drug delivery system is not just to sustain the drug release but also to prolong the presence of the dosage form within the gastrointestinal tract (GIT) until all the drug is completely released at the desired period of time . To overcome these limitations, various gastroretentive systems have been designed to be retained in the gastric region for prolonged time.
Gastric emptying of dosage forms is an extremely variable process and ability to prolong and control emptying time is a valuable asset for dosage forms, which reside in the stomach for a longer period of time than conventional dosage forms.
Floating Drug Delivery Systems (FDDS) or Hydrodynamically Balanced Systems (HBS) are among the several approaches that have been developed in order to increase the gastric residence time (GRT) of dosage forms .Prolonged gastric retention improves bioavailability, reduces drug waste and improves solubility for drugs that are less soluble in a high pH environment. It has applications also for local drug delivery to the stomach and proximal small intestines. Gastro retention helps to provide better availability of new products with new therapeutic possibilities and substantial benefits for patients.
The multiple unit system has been developed to identify the merit over a single unit dosage form because the single unit floating systems are more popular but have a disadvantage owing to their "allâ€orâ€nothing" emptying process, leading to high variability of the gastrointestinal transit time. The synthetic polymer has been used to prepare floating microspheres.The Present study was based on floating microspheres of both hydrophilic and acrylic polymers using Cimetidine as a model drug. It is an antiâ€ulcer drug that has been widely used in treating gastric and duodenal ulceration and also in Zollinger Ellison syndrome. It is poorly absorbed from the lower GIT and has a short elimination half life of 2â€3 hours and bioavailability of 50%.
Cimetidine (CM) was used as model drug. It is an H2-antihistaminic drug that has been widely used in treating gastric and duodenal ulceration and also in Zollinger Ellison syndrome and reflux esophagitis (15). It is poorly absorbed from the lower gastrointestinal tract and has a short elimination half life ( 2 h). The objective of the present study was to develop floating microspheres of CM in order to achieve an extended retention in the upper GIT, which may result in enhanced absorption and thereby improved bioavailability. The prepared microspheres were evaluated for size, in vitro CM release, buoyancy and incorporation efficiency. The effect of various formulation variableson the size and drug release was investigated.
Thus a sustained and controlled release dosage form of cimetidine is desirable. Hence an attempt has been made to design a floating microsphere system of captopril using HPMC K 4M and Ethyl cellulose for prolonged gastric residence time and improve the release profile of drug.
Cimetidine was obtained as a gift sample from ZydusCadila Healthcare (India). Dichloromethane and Tween 80 were obtained from Central Drug House (P) Ltd. (India)Ethyl Cellulose from M/S. Orchid Ltd, and HPMC K 4M cps from M/S. CDH Ltd. All the other chemicals and reagents used were of analytical grade. A UV/Vis spectrophotometer (Schimadzu 1700, Japan) was used for drug analysis.
PREPARATION OF MICROSPHERS
Six batches of microspheres were prepared by taking drug: polymer ratio as 1:1, 1:2 and 1:3 with same drug and two different polymers. The formulation batches were designated as A, B, C for HPMC K 4M (1:1,1:2,1:3 respectively) and D, E, F for Ethyl cellulose(1:1,1:2,1:3 respectively). Drug and polymer in different proportions were weighed and coâ€dissolved at room temperature into a mixture of ethanol and dichloromethane (1:1% v/v) with vigorous agitation to form uniform drug polymer dispersion. This was slowly poured into the dispersion medium consisting of heavy liquid paraffin (50ml) containing 1.5% span 80. The system was stirred using overhead propeller agitator at a speed of 700â€800 rpm at room temperature over a period of 4â€5 hrs, to ensure complete evaporation of the solvent. Liquid paraffin was decanted and the microspheres were separated by filtration through a whatmann filter paper, washed thrice with 180 ml of nâ€Hexane and air dried for 24 hrs.
Table 1: Formulation design of Cimetidine floating microspheres
S. No. Batch code Drug: Polymer Organic solvent system(1:1)
1 CMâ€1 1:1 Dichloromethane: Ethanol
2 CMâ€2 1:2 Dichloromethane: Ethanol
3 CMâ€3 1:3 Dichloromethane: Ethanol
4 CMâ€4 1:1 Dichloromethane: Ethanol
5 CMâ€5 1:2 Dichloromethane: Ethanol
6 CMâ€6 1:3 Dichloromethane: Ethanol
CHARACTERIZATION OF MICROSPHERES
The microspheres were characterized by their micromeritic properties, such asparticle size, true density, tapped density, compressibility index, hausner ratio, angle of repose. (Sinha V R, 2005 and Whitehead L, 2000)
% Compressibility index = [1- V/Vo] Ã-100
V and Vo are the volumes of the sample after and before the standard tapping Haunser ratio
Angle of repose
The angle of repose (Î¸) of the microspheres, which measures the resistance to particle flow, was determined by the fixed funnel method, using the following equation:
tan Î¸ = H/R
Where, H is the height of the heap that formed after making the microspheres flow from the glass funnel and R is the radius
Scanning electron microscopy (S.E.M)
Scanning electron microscopy has been used to determine particle size distribution, surface topography, texture, and to examine the morphology of fractured or sectioned surface. SEM is probably the most commonly used method for characterizing drug delivery systems, owing in large to simplicity of sample preparation and ease of operation. SEM studies were carried out by using JEOL JSM Tâ€330A scanning microscope (Japan). Dry CM floating microspheres were placed on an electron microscope brass stub and coated with in an ion sputter. Picture of CM floating microspheres were taken by random scanning of the stub.
Particle size analysis
Determination of average particle size of CM floating microspheres was carried out by optical microscopy in which stage micrometer was employed. A minute quantity of CM floating microspheres was spread on a clean glass slide and average size of 300 CM floating microspheres was determined in each batch.
The percentage yield of prepared CM floating microspheres wasdetermined by using the formula.
Fifty milligrams of the floating microspheres were placed in 0.1M HCL, 100 ml containing 0.02 w/v%span 80. The mixture was stirred at 100 rpm in a magnetic stirrer. After 12 hrs, the layer of buoyantmicrospheres was pipette and separated by filtration. Particles in the sinking particulate layer were separated by filtration. Particles of both types were dried in a desiccators until constant weight.
Q f + Qs Where Qf and Qs are the weight of the floating and the settled microspheres, respectively.
Drug entrapment efficiency/encapsulation efficiency (DEE)
Microspheres equivalent to 100 mg of the drug were calculated spectrophotometrically at 218 nm by determining the drug concentration.
In-vitro dissolution studies
In-vitro dissolution of CM fromfloating microspheres was carried out using the USP dissolution test apparatus (Type-I). A weighed amount of floating microspheres of CM were filled into a capsule and placed in the basket. Dissolution media used was 900 ml of 0.1 N HCI (pH 1.2) maintained at 37 ± 0.5°C and stirred at100 rpm. At predetermined time intervals, 10 ml of samplewas withdrawn and replaced with equal amount of 0.1 N HCI (pH 1.2). The collected samples were filtered and suitably diluted with 0.1 N HCI and analyzed spectrophotometrically at 218 nm to determine the amount of drug released in the dissolution medium.
RESULTS AND DISCUSSION
Floating microspheres of cimetidine were prepared by solvent evaporation technique. The prepared microspheres were characterized for particle shape, micromeritic properties, % yield, drug entrapment efficiency, % buoyancy, in vitro drug release study.
Micromeritic properities of the microspheres Angle of repose of microspheres was in the range of 18.35Î„. Shown excellent flow ability as represented in term of angle of repose (<40°). Bulk density values ranged from 0.394 to 0.526 gm/cm3 Tapped density was determined by the tapping method. The tapped density values of the microspheres ranged from 0.431to0.550 gm/cm3 Carr's index values of microspheres was found to be 8.22 %.
Table 2: Evaluation parameters of different formulations
Formulation Bulk Density Tapped Density Carr's Index Angle of repose
Code (g/cm3) (g/cm3) (Å¸)
CM1 0.394± 0.03 0.431± 0.01 9.23± 0.65 14.12± 1.65
CM2 0.424± 0.08 0.451± 0.03 8.21± 1.45 18.35± 1.23
CM3 0.514± 0.06 0.531± 0.03 8.16± 1.30 21.61± 1.11
CM4 0.398± 0.07 0.429± 0.02 9.22± 0.68 14.23± 1.59
CM5 0.454± 0.03 0.473± 0.04 8.19± 1.34 18.55± 1.27
CM6 0.526± 0.08 0.550± 0.01 8.14± 1.23 21.53± 1.64
Surface morphology of Cimetidine microspheres (SEM)
The surface morphology of the CM floating microspheres was studied by SEM. Surface smoothness of the CM floating microspheres was increased by increasing the polymer conc., which was confirmed by SEM. Microspheres with HPMC K 4M contain smooth surface and smaller in size compare to the microspheres with ethyl cellulose.
The microspheres floated for prolonged time over the surface of the dissolution medium without any apparent gelation. As the polymer concentration increases the buoyancy time increases.
Table 3: Buyounancy percentage of Cimetidine floating microspheres
Sr No. Formulation code % Buoyancy time
1 CM1 78.40 ± 1.02
2 CM2 83.45 ± 1.8
3 CM3 91.15 ± 1.01
4 CM4 67.30 ± 1.01
5 CM5 74.32 ± 1.69
6 CM6 79.30 ± 1.60
Drug entrapment efficiency of floating Microspheres of cimetidine
As the CM to polymer ratio was increased, the mean particle size of CM floating microspheres was also increased Table 4 . The significant increase may be because of the increase in the viscosity of the droplets (may be due to the increase in concentration of polymer solution). CM floating microspheres with HPMC K 4M having a sizerange less when compared to that of ethyl cellulose which wasshown in table 4.
Entrapment efficiency increases with increase in the polymer concentration. From the results it can be inferred that there is a proper distribution of CM in the microspheres and the deviation is within the acceptable limits. A maximum of 87% drug entrapment efficiency was obtained in the CM floating microspheres which were prepared by using HPMC K 4M. A maximum of 81.42% drug entrapment efficiency was obtained in the CM floating microspheres which were prepared by using Ethyl cellulose. It was further observed that the drug entrapment was proportional to the CM: polymer ratio and size of the CM floating microspheres. By increasing the polymer concentration, the encapsulation efficiency was increased. Results shown in table 4.
Table 4: Percentage yield, Mean particle size and incorporation efficiency of floating microspheres
Formulation Percentage Mean Particle Entrapment
Code yield size(µm) efficiency(%)
CM1 85.02 242 69.80±1.10
CM2 89.67 258 77.48±0.98
CM3 93.88 273 87.52±1.12
CM4 70.00 288 57.74±1.02
CM5 77.01 262 66.12±1.11
CM6 82.33 286 81.42±2.25
In-Vitro dissolution studies
Dissolution studies on all the six formulations of CM floating microspheres were carried out using a USP dissolution apparatus Type I. 0.1N HCl was used as the dissolution medium.
The in vitro performance of CM floating microspheres showed prolonged and controlled release of CM. The results of the in vitro dissolution studies shows controlled and predictable manner as the polymer concentration increases the drug release from the floating microsphere decreases. The formulations with HPMC K 4M i.e.CM1 82.26% to CM3 74.35% are shown in Table 5 and Figure 7. The formulations with Ethyl cellulose i.e.CM4 86.48% to CM6 78.35%
are shown in Table 5 and Figure 8.
Fig: Percentage cumulative release of Cimetidine floating microspheres with HPMC K4M
Fig: Percentage cumulative release of Cimetidine floating microspheres
In vitro data obtained for floating microspheres of cimetidine showed good buoyancy, entrapment efficiency, and prolonged drug release. The concept of formulating floating microspheres containing CM offers a suitable, practical approach to achieve a prolonged therapeutic effect by continuously releasing the medication over extended period of time. Floating microspheres of CM were prepared successfully by emulsion solvent evaporation method using the different concentration of individual polymers like HPMC K4M, and EC by means of prolonging its gastric retention thus improving the oral bioavailability of the drug. It would be faster and more economical to alter beneficially the properties of the existing drugs than developing new drug entities hence this formulation will be boon to novel drug dosage forms.