Sudhamani T. et al. / International Journal of Biopharmaceutics. 2010; 1(2): International Journal of Biopharmaceutics

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1 75 International Journal of Biopharmaceutics Journal homepage: IJB FORMULATION AND EVALUATION OF IBUPROFEN LOADED MALTODEXTRIN BASED PRONIOSOME T. Sudhamani *, V. Ganesan, N. Priyadarsini, M. Radhakrishnan The Erode College of Pharmacy, Erode, Tamil Nadu. ABSTRACT Ibuprofen loaded maltodextrin based proniosome were prepared by slurry method with different surfactant to carrier ratio. The proniosome formulation was evaluated for FT-IR study and scanning electron microscopy. The niosomal dispersion was further evaluated for entrapment efficiency, in-vitro release study, kinetic data analysis, stability study. The result from SEM analysis has showed smooth surface of proniosome. The formulation F4 which showed higher entrapment efficiency of 96.57± 1.08% and invitro cumulative drug release of 92.16% at the end of 12 hr was found to be best among the all 9 formulations. Release was best explained by the zero order kinetics. Kinetic analysis showed that the drug release follows non-fickian release. Proniosome formulation has showed appropriate stability for 60 days by storing the formulations at different conditions. KEYWORDS: Ibuprofen, Proniosomes, Maltodextrin. INTRODUCTION Proniosomes are dry product which could be hydrated immediately before use would avoid many of the problems associated with aqueous niosome dispersions and problems of physical stability (aggregation, fusion, leaking) could be minimized (Rhodes D G et al,1999). These dry formulations of surfactant-coated carrier can be measured out as needed and rehydrated by brief agitation in hot water ( Almira, I et al 2001 ). They are water-soluble carrier particles that are coated with surfactant and can be hydrated to form niosomal dispersion immediately before use on brief agitation in hot aqueous media. Reported methods for preparation of proniosomes were the spraying of surfactant on water-soluble carrier particles and the slurry method (Almira, I et al 2001). * Corresponding author T. Sudhamani tsmkrishv28@yahoo.com This dry, free-flowing, granular product which, upon addition of water, disperses or dissolves to form a multilamellar niosome suspension suitable for administration by oral or other routes. Ibuprofen is considered to be the first-line drug in the symptomatic treatment of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. The successful treatment of arthritis depends on the maintenance of effective drug concentration level in the body, for which a constant and uniform supply of drug is desired. The short biological half-life (about 2 hr) and dosing frequency more than once a day as well as two third (70-80%) of dose is excreted by renal transport. Therefore, an alternative non-invasive mode of delivery of the drug is needed. Transdermal delivery certainly appears to be an attractive route of administration to maintain the drug blood levels of ibuprofen for an extended period of time. The present study involves formulation of a topical ibuprofen gel from malltodextrin based proniosome.

2 76 MATERIALS AND METHODS Ibuprofen obtained as a gift sample from Swasan pharmaceuticals, India. Maltodextrin, Cholesterol, HPMC and span-60 were purchased from Loba Chem. Pvt. Ltd., Mumbai. All other reagents used were of analytical grade. PREPARATION OF PRONIOSOMES Proniosome were prepared by the slurry method (Mahmoud Mokhtar et al 2008, Fang JY et al, 2001). Different ratios of formulations were prepared and dissolved in chloroform: ethanol (2:1) solution (Table 1). It was then added to a 100ml round bottom flask containing the maltodextrin carrier. Additional chloroform: ethanol solution was added to form slurry in the case of lower surfactant loading. The flask was attached to a rotary flash evaporator to evaporate solvent at 60 to 70 rpm, a temperature of 45 ± 2ºC, and a reduced pressure of 600mmHg until the mass in the flask had become a dry, free flowing product. These materials were further dried overnight in a dessicator under vacuum at room temperature. This dry preparation was referred to as proniosomes and was used for preparations and for further study on powder properties. These proniosomes were stored in a tightly closed container at refrigerator temperature until further evaluated. PREPARATION OF PRONIOSOMAL GEL BY USING HPMC POLYMER The proniosomal powder was dispersed in HPMC polymer solutions (2%) with stirring at 100 rpm, for 1 hour using magnetic stirrer. This was further neutralized with 0.5% triethanolamine amine and 10% glycerine slowly with constant stirring. This proniosomal gel was taken for further studies (Chandra et al 2008, Alsarra, I A et al, 2005). ENTRAPMENT EFFICIENCY To evaluate the loading capacity of proniosomal gels of ibuprofen, 20mg of the proniosomal gel was weighed and dispersed in distilled water and warmed a little for the formation of niosomes. The niosome dispersion so obtained was centrifuged at 18,000 rpm for 40 min at (Remi centrifuge).the clear fraction was used for the determination of free drug at 257 nm UV spectrophotometrically (Ankur Gupta et al, 2007). %EE = [(C t -C f )/C t ] X 100 Where, C t is the concentration of total drug. C f is the concentration of free drug. IN VITRO DRUG RELEASE STUDIES OF THE GELS In vitro release studies were carried out using dialysis membrane employing in two sides open ended cylinder.1 ml of proniosomal gel was placed uniformly in the dialysis membrane previously soaked overnight. The two sides open ended cylinder was placed in the beaker containing 200ml of phosphate buffer saline ph 7.4. Aliquots of 5 ml were withdrawn periodically and replaced with same amount of phosphate buffer saline solution to maintain the sink condition. The samples were analysed by UV spectrophotometrically at a λ max of 257 nm (Unchegbu, I.F et al 1996, Yanhong Yang et al, 2002). DRUG RELEASE KINETIC DATA ANALYSIS The release data obtained from various formulations were studied further for their fitness of data in different kinetic models like Zero order, Higuchi s and peppa s (Korsmeyer R.W et al, 1983, Huguchi.T e al, 1963). SCANNING ELECTRON MICROSCOPY Proniosome powders were affixed to double-sided carbon tape, positioned on an aluminium stub and excess powder was removed. The stubs were stored under vacuum overnight. The samples were sputter-coated with gold. Electron micrographs were obtained using scanning electron microscope. The surface morphology (roundness, smoothness, and formation of aggregates) of proniosomes was studied by Scanning Electron Microscopy (Alsarra, I A et al, 2005). ZETA POTENTIAL ANALYSIS The zeta potential was analyzed (Varaporn Buraphacheep Junyaprasert et al, 2008) for proniosomal powder by MALVERN ZETASIZER in BIRLA INSTITUTE OF TECHNOLOGY, MESRA, (RANCHI). STABILITY STUDIES FOR PRONIOSOMAL GEL Stability study was carried out to investigate the degradation of drug from proniosomal gel during storage. The proniosomal gel formulations composed of span-60 and cholesterol sealed in glass vials and stored in 4 C, 25 C and 40 C temperatures for a period of 2 months Samples from each batch were withdrawn after the definite time intervals and converted into noisome and the residual amount of drug in the vesicles were determined (Ankur Gupta et al, 2007, WHO 2006).

3 77 RESULTS AND DISCUSSION Proniosomes of ibuprofen were prepared by slurry method. In this method drug, non ionic surfactant and cholesterol were mixed in organic solvent and added to maltodextrin carrier. The use of maltodextrin as the carrier in the proniosome preparation permitted flexibility in the amounts of surfactants and other components, which greatly enhances the potential application of proniosomes in a scaled-up production environment. The drug content and entrapment efficiency were studied for all the nine formulations represented in table 2. The entrapment efficiency was found to be highest with the formulation F4 (96.57%), which may have an optimum surfactant, maltodextrin ratio to provide a high entrapment of ibuprofen. The release study was conducted for all the nine formulations as shown in the Figure 2 and 3. Most of the formulations were found to have a linear release and the formulations were found to provide approximately 80%release within a period of 12 hours. The formulation which have optimum ratio F4 was found to sustain the drug release than other formulations. Among all formulations F4 was selected as best formulation because of its highest entrapment efficiency and consistent release profile of ibuprofen. Cholesterol, which has a property to abolish the gel to liquid transition of niosomes, this found to prevent the leakage of drug from the niosomal formulation. The slower release of drug from multilamellar vesicles may be attributed to the fact that multilamellar vesicles consist of several concentric sphere of bilayer separated by aqueous compartment. The zero order plots showed the zero order release characteristics of the formulation, which was confirmed by the correlation value which was found to be nearer to one. Correlation value of Higuchi s plot revealed that the mechanism of drug release was diffusion. The in vitro kinetic data subjected to log time vs log drug release transformation plot (peppa s model), the value lies were found to be n>0.45 this revealed that the drug release follows a non fickian diffusion. Vesicles with smaller diameter are believed to better permeate through the skin as smaller vesicles tend to fuse readily. Shape and surface characteristic of proniosome were examined by Scanning Electronic Microscopy analysis. Surface morphology showed the smooth surface of optimised proniosomal formulation Figure.1. The zeta potential value for the optimised proniosomal powder F4 was found to be-28.3mv Figure 4. A value of ±25 mv (positive or negative) was taken as the arbitrary value that separates low-charged surfaces from highly-charged surfaces. The proniosomal powder showed good stability for F4 formulations. Stability studies of the optimized proniosomal gel were performed. The percentage of drug retained in the span-60 vesicles after a period of 2 months for 4 C, 25 C, 40 C was found to be were 95.72%, 90.45% and 84.65% respectively Figure 5. From this it can be concluded that proniosomes are stable to store under refrigeration temperature with least leakage. CONCLUSION On conclusion, this novel drug delivery system i.e. proniosome as compared to liposome or niosome represent a significant improvement by eliminating physical stability problems, such as aggregation or fusion of vesicles and leaking of entrapped drugs during long-term storage. Proniosomes derived niosomes are superior in their convenience of storage, transport, and dosing as compare to niosomes prepared by conventional method. By these facts study can be concluded by Ibuprofen was successfully entrapped within the lipid bilayer of the vesicles with high efficiency and said that proniosomes based niosomal gel formed from span 60, cholesterol using maltodextrin as a carrier was a promising approach to sustain the drug release for an extended period of time and by that reducing the side effects related to GI irritation. Table.1 Compositions of Proniosome Batches of Ibuprofen. Formulation Code Drug (mg) Span 60 (mg) Cholesterol (mg) Maltodextrin (mg) F F F F F F

4 78 Formulation Code Drug (mg) Span 60 (mg) Cholesterol (mg) Maltodextrin (mg) F F F Table.2 Drug content and Entrapment Efficiency. S.No Formulation Code Average drug content (1ml) Entrapment Efficiency(%) 1 F ± ± F ± ± F ± ± F ± ± F ± ± F ± ± F ± ± F ± ± F ± ± 1.62 Figure.1 SEM PHOTOGRAPHY OF PRONIOSOMAL POWDER FOR F4 FORMULATION

5 79 Figure.2 COMPARATIVE IN VITRO RELEASE STUDIES FROM F1 F5 COMPARATIVE STUDY FROM F1 - F5 90 Percentage Drug Release TIME IN HOURS F1 F2 F3 F4 F5 Figure.3 COMPARATIVE IN VITRO RELEASE STUDIES FROM F6 F9 COMPARATIVE STUDY FROM F6 - F9 Percentage Drug Release TIME IN HOURS F6 F7

6 80 Figure. 4 Zeta potential report of Proniosomal powder for F4 formulation

7 81 Figure.5 Stability study data for F4 Formulation Percentage Drug Retained STABILITY STUDY FOR F4 FORMULATION DAYS 4 degree 25 degree 40 degree REFERENCES Almira I, Blazek-Welsh, Rhodes DG. Maltodextrin-Based Proniosomes. AAPS Pharm SciTech 2001; 3(1); 1. Almira I, Blazek-Welsh1, Rhodes DG. SEM Imaging Predicts Quality of Niosomes from Maltodextrin-Based Proniosomes Pharmaceutical Research. 2001; 18(5): Alsarra IA, Bosela AA, Ahmed SM, Mahrous GM. Proniosomes as a drug carrier for transdermal delivery of ketorolac. European Journal of Pharmaceutics and Biopharmaceutics 2005; 59: Ankur Gupta, Sunil Kumar Prajapati, M Balamurugan, Design and Development of a Proniosomal Transdermal Drug Delivery System for Captopril,Tropical Journal of Pharmaceutical Research, 2007; 6 (2): Chandra and PK Sharma, Proniosome based drug delivery system of piroxicam, African Journal of Pharmacy and Pharmacology Vol. 2008; 2(9): Fang JY, Yu SY, Wu PC, Huang YB, Tsai YH. In vitro skin permeation of estradiol from various proniosome formulations. Int. J. Pharm. 2001; 215: A. Huguchi T. Mechanism of sustained action, medication; Theoretical analysis of rate of release of solid drug dispersed in solid matrix, J.Pham sci, 1963, Korsmeyer RW, Gurny R. Peppas Mechanism of solute release from porous Hydrophilic polymers IJPS, 1983, Pg Mahmoud Mokhtar and Ahmed Ibrahim, In Vitro Evaluation of Proniosomes as a Drug Carrier for Flurbiprofen AAPS PharmSciTech, Vol. 2008; 9(3): Rhodes DG, Chengji UH. Proniosomes: A Novel Drug Carrier Preparation. Int. J. Pharm. 1999; 185: Uchegbu IF, Gianasi E, Cociancinch F, Florence AT, Duncan R. Noisome encapsulation of a doxorubicin polymer conjugates. Eur. J. Pharm. Sci. 1996; 4: S28, Varaporn Buraphacheep Junyaprasert, Effect of Charged and Non-ionic Membrane Additives on Physicochemical Properties and Stability of Niosomes, AAPS Pharm SciTech, 2008; 9 (3): WHO, Draft regional guidelines on stability testing of active substances and pharmaceutical products. 17. Yanhong Yang and Ke an Li. Studies on a high encapsulation of colchicine by a niosome system, International Journal of Pharmaceutics 2002; 244: