Formulation and Evaluation of Floating beads of Verapamil hydrochloride

نویسندگان

  • Azhar Danish Khan
  • Meenakshi Bajpai
چکیده

To develop a multi-unit gastroretentive sustained release dosage form of a water-soluble drug, Verapamil hydrochloride, from a completely aqueous environment. avoiding the use of any organic solvent, thus releasing the drug for a prolonged duration of time. Emulsion gelation technique was used to prepare emulsion gel beads using sodium alginate as the polymer. The gel beads containing oil was prepared by gently mixing and homogenizing oil and water phase containing sodium alginate which was then extruded in to calcium chloride solution. The effects of factors like concentration of oil, drug: polymer ratio and alginate: pectin ratio on drug entrapment efficiency, floating lag time and morphology and drug release was studied. The use of sodium alginate and combinations of sodium alginate and pectin were used to study the effect on the sustaining property of the formed beads. It was found that sodium alginate was not sufficient to sustain the drug release at gastric pH. Instead of it, appropriate combination of alginate and pectin could provide the sustain release of drug. The results show that these beads can entrap even a water soluble drug as Verapamil hydrochloride in sufficient amount and also can successfully deliver the drug in stomach for a prolong duration of time without using any organic solvent and any time consuming step in the preparation. Key words; Floating beads, Verapamil hydrochloride, Formulation. INTRODUCTION Historically, the oral delivery of drugs is by far the most preferable route of drug delivery due to the ease of administration, patient compliance and flexibility in formulation, etc. From immediate release to sitespecific delivery, oral dosage forms have really progressed. However, it is a well-accepted fact that it is difficult to predict the real in vivo time of release with solid, oral controlled release dosage forms. Thus, drug absorption in the gastrointestinal (GI) tract may be very short and highly variable in certain circumstances. (1) Despite tremendous advancement in drug delivery, oral route remains the preferred route for the administration of therapeutic agents and oral drug delivery is by far the most preferable route of drug delivery because of low cost of therapy and ease of administration leads to high levels of patient compliance as well as the fact that gastrointestinal physiology offers more flexibility in dosage form design than most other routes, consequently much effort has been put into development of strategies that could improve patient compliance through oral route (2) The de novo design of an oral controlled drug delivery system (DDS) should be primarily aimed at achieving more predictable and increased bioavailability of drugs. However, the development process is precluded by several physiological difficulties, such as an inability to restrain and localize the DDS within desired region of the gastrointestinal tract and the highly variable nature of gastric emptying process. It can be anticipated that, depending upon the physiological state of the subject and the design of pharmaceutical formulation, the emptying process can last from a few minute to 12 hr. This variability may lead to unpredictable bioavailability and times to achieve peak plasma levels, since the majority of drugs Azhar Danish Khan et al /Int.J. PharmTech Res.2011,3(3) 1538 are preferentially absorbed in upper part of small intestine. Furthermore, the relatively brief gastric emptying time (GET) in humans, which normally average 2-3 hr through the major absorption zone (stomach or upper part of intestine), can result in incomplete drug release from the DDS leading to diminished efficacy of the administered dose. Thus, control of placement of DDS in a specific region of the GI tract offers numerous advantages, especially for drugs exhibiting an absorption window in the GI tract or drugs with a stability problem. Overall, the intimate contact of the DDS with the absorbing membrane has the potential to maximize drug absorption and may also influence the rate of drug absorption . Conventional oral dosage forms such as tablets, capsules etc provide specific drug concentration in systemic circulation without offering any control over drug delivery and also great fluctuations in plasma drug levels, by comparison oral controlled drug delivery systems provide a release profile predominantly controlled by the design of the system itself (4-5) .It is evident from the recent scientific and patent literature that an increased interest in novel dosage forms that are retained in the stomach for a prolonged and predictable period of time exists today in academic and industrial research groups. One of the most feasible approaches for achieving a prolonged and predictable drug delivery profile in the GI tract is to control the gastric residence time (6-7) These considerations have led to the development of oral controlled release (CR) dosage forms possessing gastric retention capabilities. Thus when a drug possesses a narrow ‘absorption window’ design of sustained release preparation require both prolongation of gastrointestinal transit time of dosage forms and controlled drug release. Extended release dosage form with prolonged residence time in stomach is highly desirable for drug (8) That are locally active in stomach That have absorption window in stomach or in upper small intestine. That are unstable in intestinal or colonic environment Have low solubility at high pH value. The patient always wants to minimize the frequency of dosing without compromising the therapeutic benefit. Use of sustained release dosage forms can fulfill this requirement. Verapamil hydrochloride is a Calcium Channel blocker. The primary absorption region of this drug is stomach. Its oral bioavailability is 22% and half-life is 4 hours and its absorption takes place in upper part of GIT (mainly small intestine). However, bioavailability of drug has been found to be reduced further due to first pass metabolism. Verapamil hydrochloride is absorbed from stomach and upper part of small intestine The incorporation of Verapamil in an extended-release oral dosage form would have many advantages such as improving the patient compliance by reducing dosing frequency, since the drug is indicated in chronic diseases. In addition, some reports showed that side effects and therapeutic responses were beneficially modified when sustained release forms were used . It was also found that solubility of Verapamil HCl is high in acidic environment. The Pharmacokinetic studies show that floating dosage form is better as compared to conventional dosage form . The design of gastroretentive drug delivery systems depends upon physicochemical properties, dose and purpose of controlling the drug release, constraining gastrointestinal factors. Various approaches have been pursued including low density dosage form that remains buoyant above gastric fluid or high density dosage form that is retained at the bottom of the stomach, imparting bioadhession to the stomach mucosa, utilizing ion-exchange resin which adheres to mucosa, expending the dosage form by swelling or unfolding to a large size which limits emptying of dosage form through pyloric sphincter, using modified shape system, or other effervescent systems using a gas generating material like sodium bicarbonate and calcium carbonate or the same with citric acid . Preparation of floating alginate beads is more suitable because it is a multiparticulate system, utilizes cheap and nontoxic polymers and there is no use of any organic solvent. These beads having a sustained release composition and formulation of ranitidine hydrochloride capable of providing release drug release over 12 hr was formulated using expandable, gelling, swellable, hydrocolloid polymer along with light liquid paraffin. Sodium alginate has been used as thickening and gelling agent. Additionally it also reduces interfacial tension between an oil and water phase and is efficient for preparation of emulsion. Alginate is a linear co-polymer composed of two monomeric units, D-mannuronic acid and Lguluronic acid. They occur in alginate molecule as regions made up exclusively of one unit or the other referred to M block or G block or as a region in which monomer approximates an alternating sequence. Gels form when a calcium salt is added to a solution of sodium alginate in water. The gel forms by chemical reaction, the calcium displaces the sodium from the alginate, holds the long alginate molecules together and a gel is the result . No heat is required and the gels do not melt when heated. The polyguluronate block of alginate is known to be responsible for this gelling feature . Pectin was also used in combination Azhar Danish Khan et al /Int.J. PharmTech Res.2011,3(3) 1539 with alginate to study its effect on different parameters. It is mainly complex polysaccharide comprising mainly esterified Dgalactouronic acid residues in an alpha (1-4) chain; it is also gelled after coming in contact with calcium ions. MATERIAL AND METHODS Material Gift sample of Verapamil hydrochloride (VPHCL) was obtained from Torrent Research Labs Gujarat, India. Sodium alginate, Pectin-pure (poly D-galarturonic acid methyl ester, methoxy content 6%) light liquid paraffin, Calcium chloride (anhydrous) were purchased from Central Drug House New Delhi. All other ingredients used were of analytical grade. Preparation of Verapamil hydrochloride floating emulsion gel beads with sodium alginate The technique involved in the preparation of oil entrapped floating alginate beads was emulsion gelation technique. Polymer was dissolved in water with stirring. Oil was added to polymer solution and the drug was then added. The mixture was homogenized for 15 minutes and was extruded via a needle having diameter of 0.8 mm from a distance of 5 cm in to 5% calcium chloride solution with gentle agitation at room temperature. The dropping rate was kept 2ml/min. After washing the beads, they were dried in a tray dryer at temperature of 40C. The time of drying was optimized by weighing the beads repeatedly, until they obtained a constant weight. The formulations of the different batches (A-1 to E-2) are shown in Table-1. Preparation of Verapamil hydrochloride floating emulsion gel beads with sodium alginate and pectin blend The technique involved was similar, only the different combination of sodium alginate and pectin in each drug polymer ratio was added. When only pectin was taken no beads were formed. Homogenizing time, needle diameter, distance of needle from the surface of solution, strength of calcium chloride solution and dropping rate were kept constant.. After washing the beads, they were dried in a tray dryer at temperature of 40C. The time of drying was optimized by weighing the beads repeatedly, until they obtained a constant weight. The formulations of these batches (F1 to K2) are shown in Table2. Study of size and morphology of emulsion gel beads The beads formed were viewed under Scanning Electron Microscope (Fig1). The diameter of beads was determined by screw gauge (17) For this purpose, 20 dried beads were randomly selected from each batch and the mean diameter was determined by screw gauge. The least count of screw gauge was 0.005 mm. Colour and shape of dried beads of each batch was noted. Table 1: Formulation of Verapamil Hydrochloride Floating Emulsion Gel Beads with sodium alginate Batch No. Polymer conc. (%) w/v Drug :Polymer Oil conc. (%) w /v Curing time minutes)

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تاریخ انتشار 2011