International Journal of Drug Research and Technology

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1 Int. J. Drug Res. Tech. 2016, Vol. 6 (3), ISSN International Journal of Drug Research and Technology Available online at Original Research Paper FORMULATION AND EVALUATION OF PH INDUCED IN-SITU NASAL GEL OF LEVOCETIRIZINE HYDROCHLORIDE S.Z. Chemate and Y.W. Meshram* Department of Pharmaceutics, P.D.V.V.P.F s College of Pharmacy Vilad Ghat, Ahmednagar, Maharashtra , India ABSTRACT Nasal delivery is a feasible alternative to oral or parenteral administration for some Drugs because of the high permeability of the nasal epithelium, rapid drug absorption across this membrane and avoidance of hepatic first-pass metabolism. Nasal solution of levocetirizine hydrochloride was prepared for sustaining its release and improving its bioavailability. Carbapol was used as key ingredients to effect ph induce sol to gel conversion of the formulation. Different formulations were prepared by varying the concentration of carbapol 934 and Hydroxy Propyl Methyl Cellulose. These formulation were evaluated for parameter like ph, drug contain, viscosity, gel strength and drug release. At extreme low concentration of the polymer, the formulation drained out due to poor viscosity and higher concentration of the same formulation formed stiff gel and show slowed released of the drug. Finally optimized formulation with specific concentration 934 and Hydroxy Propyl Methyl cellulose showed ph induced sol-gel conversion, sustained release and higher bioavailability. Keywords: ph induced sol to gel conversion, Carbapol 934, HPMC, Levocetirizine hydrochloride, Sustained release. INTRODUCTION Intranasal delivery is one of the most interesting and challenging endeavors facing pharmaceutical scientists. The conventional nasal drug delivery systems including solutions, suspensions, and ointments show drawbacks such as short residence in the nasal cavity, highly variable efficiency, low permeability, and inconvenient administration. In situ gel-forming systems are an interesting polymeric system that exists as flowing aqueous solution before administration and undergoes phase transition to form a viscoelastic gel in a physiologic environment. Benefiting from the merits of both a solution and a gel, an impressive number of in situ gel-forming systems induced by temperature, ph and ions have been prepared for use in nasal drug delivery in the past few years. In situ gel-forming systems increase the retention of drugs in the nasal cavity, and some of them also show permeation enhancing capabilities. This article reviews the in situ gel-forming systems used for nasal drug delivery and introduces their gelling mechanisms and other favorable features for intranasal delivery. It also describes the release patterns and drug stability of in situ gels as well as their in vivo performances and local In situ gelation is a process of gel formation at the site of action after the formulation has been applied at the site. In situ gel phenomenon based upon liquid solution of drug formulation and converted into semi-solid mucoadhesive key depot. It permits the drug must be delivered in a liquid form to solution form. Intranasal route is considered for the drugs that are ineffective orally and are used chronically where rapid entry into the circulation is desired and they require small doses. The absorption of drugs from the nasal mucosa most probably takes place via the aqueous 120

2 channels of the membrane. Therefore, as long as the drug is in the form of solution and the molecular size is small, the drug will be absorbed rapidly via the aqueous path of the membrane. The absorption from the nasal cavity decrease safety following nasal administration. The formation of gels depends on factors like temperature modulation, ph change, presence of ions and ultra violet irradiation, from which the drug gets released in a sustained and controlled manner. Various polymers that are used for the formulation of in situ gels include gellan gum, alginic acid, xyloglucan, pectin, chitosan, poly (DL-lactic acid), poly (DL-lactide-co-glycolide) and poly-caprolactone. The choice of solvents like water, dimethylsulphoxide, N-methyl pyrrolidone, triacetin and 2-pyrrolidone for these formulations depends on the solubility of polymer used. Mainly in situ gels are administered by oral, ocular, rectal, vaginal, injectable and intraperitoneal routes. The in situ gel forming polymeric formulations offer several advantages like sustained and prolonged action in comparison to conventional drug delivery systems. The efficacy of a treatment mostly depends on the techniques by which the drug is delivered and optimum concentration of the drug, above or below this range can be toxic or produce no therapeutic benefit at all. The slow progress in the efficacy of the treatment of severe diseases, has suggested a growing need for a multidisciplinary approach to the delivery of therapeutic agents to targets in tissues. The efficacy of the drug and its treatment can be achieved from the new ideas on controlling the pharmacokinetics, pharmacodynamics, immunogenicity, and bio recognition. These new strategies based on interdisciplinary approaches such as polymer science, pharmaceutical technology, bio conjugate chemistry, and molecular biology, are often called novel/advanced drug delivery systems. Different drug delivery/drug targeting systems already exist and currently under development can be efficiently used to minimize the drug degradation and loss, to prevent harmful side effects and to increase drug bioavailability. For over 20 years, the potential benefit of nanotechnology is appreciated by most of the researchers and it is providing vast improvements in drug delivery and drug targeting. New advancements in the drug delivery strategies are minimizing the unwanted toxicities and improving the efficacy of the treatments. MATERIAL AND METHODS Materials Levocetirizine Hydrochloride was obtained as a gift sample from Macleods Pharmaceuticals Baddi India, Hydroxy propyl methyl cellulose K 4 M from M/S Yarrow Chem. Product Mumbai. Carbapol from Rajesh Chemical Co. Mumbai. Benzoalkonium chloride from Rajesh Chemical Co. Mumbai, Sodium Metabisulphide from M/S Balaji Drugs Surat (Gujarat). Methods Preparation of standard curve of levocetrizine hydrochloride Standard Curve of Levocetirizine Hydrochloride was prepared in phosphate buffer solution ph 6.5 From standard stock solution 0.5,1.0, 1.5, 2.0, 2.5 ml was withdrawn in 10 ml volumetric flask and diluted to 10 ml with distilled water to produce concentration 5,10,15,20,25 ug/ml respectively. The solution was analysed by UV-Visible Spectrophotometer (Jasco V-630) at 231 nm and results were recorded. The calibration graph was plotted as concentration on x-axis and absorbance at y-axis (table 1: Calibration curve). Formulation of In Situ Gel The formulation as given in table 2 were prepared by dispersing Carbapol in distilled water with continuous stirring (Thermostatic hot plate with magnetic stirrer) until completely dissolved and allow to hydrate overnight. For the preparation of solution, First HPMC K 4 M was dissolved in distilled water and allows hydrating. Then carbapol was slowly added and allow hydrating overnight. After complete hydration of polymer a separate solution of Levocetirizine Hydrochloride and sodium chloride was added to polymeric solution. And then added Benzoalkonium Chloride and Sodium Metabisulphide and mixing were confirmed until a uniform and clear solutions were formed. Final volume was made 121

3 by adding required volume if distilled water. All formulation was adjusted to ph 5.5 by 0.5 M sodium Hydroxide solution (table no.2). Evaluation of In situ Gels Appearance The develop formulation were inspected visually for clarity in sol and gel form. ph of the gel ph of the each formulation was determined by using ph meter. The ph meter was first calibrated using solution of ph 5 and 7. Gelation studies Gelation studies were carried out in gelation cells these cells were cylindrical reservoirs holding 3 ml of gelation solution. Within the cells at the bottom, a 400 ul transparent plastic cup was hold to gel sample in place after its formation. The studies were carried out by 0.5 M sodium hydroxide which resembles the nasal fluid. The formulation (250ul) was placed into the cavity of cup using a micropipette and 2 ml of gelation solution was added slowly. Gelation was assessed by visual examination. Drug content Uniform distribution of active ingredient is important to get dose uniformity. 1.0 ml was transferred into a 100-ml volumetric flask and 50 ml of simulated nasal fluid was added. The formed gel was completely crushed with the help of a glass rod, followed by vigorous shaking until the formed gel got completely dispersed to give a clear solution. The volume was adjusted to 100 ml with simulated tear fluid. The solution was filtered through a 0.45-mm filter membrane and the drug concentration was determined with a UV-Visible spectrophotometer at 231 nm. Viscosity measurement The viscosity values were measured with Brookfield digital viscometer. Viscosity was measured at 10 rpm for 30 seconds for liquid formulation and gel Measurement of gel strength A sample of 50 gm. of formulation was placed in 100 ml graduated cylinder and gelled by neutralizing by 0.5 M NaoH. A weight of 35 gm. was placed onto gel; the gel strength which is the indication for viscosity of nasal insitu gel at physiological condition was determined by time in seconds the weight took to peneterate 5 cm down through the gel. In vitro release study Tissue samples are inserted in Franz diffusion cells displaying a permeation area of cm2. 20 ml phosphate buffer saline (PBS) ph 6.8 at 34 C was added in the acceptor chamber. The temperature within the chambers is maintained at 34 C. Formulation equivalent to 25mg was placed in the donor chamber. At predetermined time points, 1ml sample was withdrawn from the acceptor compartment, replacing the sampled volume with PBS ph 6.8 after each sampling for four hours. Samples withdrawn were filtered and analyzed spectrophotometrically. Blank samples can be run simultaneously throughout the experiment to check for any interference. The amount of permeated drug was determined using UV visible spectrophotometer at 231nm; table 6. Content of the receiver compartment was stirred using magnetic stirrer. The Position of the donor compartment was adjusted so that dialysis membrane just touches the diffusion medium. An aliquot of 1 ml was withdrawn from receiver compartment initially after 15 and 30 min and then at 1- hr interval and replaced with same amount of fresh medium. Aliquot so withdrawn were suitably diluted and analyzed using UV release study was carried out for 6 hrs; table 3. RESULT AND DISCUSSION The in situ formulation is colorless liquid. The 122

4 percentage yields of the batches were found between to 95.75%.Insitu gel formulations prepared by using various concentrations of polymers ratios. The API and excipients does not show any incompatability as interpreted from drug excipients compatability studies. Besides that the formulation was found to pass various preformulation tests like solubility analysis, melting point, DSC, FT-IR, compatability tests. And show satisfactory results in development batches for release specifications. The F3 formulation shows 92.36% drug release from the insitu gel formulation at 6 th hr; table no.4,5,6; (fig.no.2). From the result it was found that standard calibration curve at 231 nm followed Beer-Lamberts law in the concentration ranging from µ/ml. For the formulation of in situ gel, Carbapol 934 was selected as ph inducing gelling. HPMC K 4 M was added as viscosity builder and mucoadhesive agent in order to reduce concentration of carbapol just sufficient to induce gelation while retaining the same mucoadhesion as that of higher concentration of carbapol. All the formulation had clearance appearance. All the formulation had ph values in the nasal ph range. Amongst these formulations formulation f3 was considered as optimized formulation as it showed the best in-vitro release profile i.e % CONCLUSION From the results it can be concluded that Levocetirizine Hydrochloride was successfully formulated as a ph induced in situ nasal gelling system using Carbapol 934 and HPMC k4m.the optimized formulation F3 Provided sustain in vitro release of drug over an extended period of 6hrs.The optimized formulation can be a competent alternative to conventional nasal drops. As a consequence of its enhanced bioavailability and longer residence time, it avoids the first pass effect and reduces the dosing frequency as well. Table 1: Analytical data for calibration curve of levocetirizine (HCL) Sr.No. Concentration µg/ml Absorbance (nm) Table 2: Formulation design Ingredients Formulations F1 F2 F3 F4 F5 Levocetirizine (%w/v) HPMC (K4M) (%w/v) Carbapol (934) (%w/v) Benzalkonium chloride (%w/v) Sodium metabisulphide (%w/v) Nacl (%w/v) Distilled water (ml) q.s q.s q.s q.s q.s 123

5 Table 3: Absorbance values of Levocetrizine Hydrochloride in PBS 6.4 at 231 nm for preparation of standard curve Sr.No. Concentration µg/ml Absorbance (nm) Table 4: Various physical evaluation parameters and gelling capacities of all formulations Formulation Appearance Fragrance efficiency Ph Gelling capacity F1 Colourless Pleasant Odour F2 Colourless Pleasant Odour F3 Colourless Pleasant Odour F4 Colourless Pleasant Odour F5 Colourless Pleasant Odour Gelation occurred immediately and remained for a few hrs. +++ Gelation occurred immediately and remained for extend period. Table 5: Drug content viscosity and gel strength of prepared formulation Formulation Drug content (%w/w) Viscosity of liquid Formulation(Pa.S) Viscosity of Gel (Pa.S) Gel strength (seconds) F % F % F % F % F % Table 6: In vitro release profile of drug prepared formulation Sr. No. Time (hrs.) Cumulative percent drug released F1 F2 F3 F4 F

6 Figure1: Standard calibration curve of Levocetrizine Hydrochloride Figure 2: Comparative Effect on Drug Release of various Formulations (f1, f2, f3, f4, f5) REFERENCES 1. Nirmal, HB; Bakliwal, SR and Pawar, SP (2010), In-Situ Gel: New trends in controlled and Sustained Drug Delivery System, International Journal of Pharmatech Research, 2(2), Shah, H and Patel, M (2012), In situ Gelling System: An Insight, Inventi Impact, (3), Kute, JU; Darekar, AB and Saudagar, RB(2013), In situ Gel-Novel Approach For Nasal Delivery, World Journal of Pharmacy and Pharmaceutical Sciences, 3(1), Peppas, N and Langer, R (1994), New Challenges In Biomaterials Science, 263, Nerkar, TS; Gujarathi, N; Rane, BR; Bakliwal, SR and Pawar, SP (2013), In situ gel: Novel Approach in Sustained and Controlled Drug Delivery System, International Journal of Pharmaceutical Sciences, 4 (4), Upadhyay, S; Parikh, A; Joshi, P; Upadhyay, UM and Chotai, NP (2011), Intranasal Drug Delivery System- A glimpse to become maestro, Journal of Applied Pharmaceutical Science, 01,03), Chhajed, S; Sangale, S and Barhate, SD (2011), Advantageous Nasal Drug Delivery System: A Review, International Journal of 125

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