International Journal of Pharmacy Research and Technology 2012, Volume 2, Issue 4, 19-22 ISSN 2250 0944 (Online) ISSN

N 2250 1150 (Print) Research Article

Formulation and Evaluation of Pulsatile Drug Delivery System of Venlafaxine HCL

Hyma P.*, Tejaswi, Priyanka, Sai Krishna, Abbulu K. Mallareddy Institute of Pharmaceutical Sciences, Dhulapally, Secunderabad-16, India *Corresponding author Email: rk_hyma@yahoo.com Received: 16/10/2012, Revised: 10/11/2012 Accepted: 21/11/2012 ABSTRACT Pulsatile drug delivery system of Venlafaxine Hydrochloride has been successfully prepared for oral delivery of drug. This is a type of controlled drug delivery system which shows sustained therapeutic action; with lag time where there is no release of the drug during initial lag phase of drug administration. Venlafaxine Pulsatile formulations were prepared using sodium alginate, pectin AS104, and sodium bicarbonate for obtaining required lag time. The prepared beads were examined for morphology using scanning electron microscopy, tested for entrapment efficiency and later filled into formaldehyde treated hard gelatin capsules. Drug release studies on the capsules filled with drug loaded beads showed a lag phase of 3hrs, 5hrs and 6 hrs respectively based on concentration of gelling agent used. Thus time delayed capsule device of Venlafaxine Hcl, a highly water soluble drug was prepared to avoid dose dumping and achieve time controlled release for chronotherapeutic delivery of drug. Key words: Venlafaxine HCL, sodium alginate, Pectin AS104, Entrapment efficiency, Lag time; in vitro drug release. INTRODUCTION Controlled drug delivery systems (CDDS) have acquired a major role in drug development and research. The oral CDDS release the drug over prolonged period of time which maintain drug concentration in therapeutic window for longer duration.[1] However there are certain conditions where controlled release pattern does not suit the drug releas hence demand the release of drug after a lag time during which the drug should not be released and the release pattern is known as pulsatile release.[2] Thus following lag time; there should be rapid and complete release of the drug such systems are called pulsatile drug delivery systems, time controlled systems or sigmoidal release system. These types of Novel drug delivery systems have been developed for chrono pharmacotherapy of diseases that show circadian rhythm in their pathophysiology; and targeting drugs to specific sites. Pulsatile devices can be fabricated either in form of tablets, capsules beads [3]. Floating pulsatile beads are prepared by simple process of acid-base reaction and crosslinking of polymers which in turn decides the lag time of the system [4,5]. The lag time is decided based on length of plug, insertion distance for osmotic systems and for water insoluble drugs rapid release is achieved by inclusion of effervescent agents. The hydrogel formulations [6] are governed by nature of polymer used. In the present study the lag time was achieved by using formaldehyde as crosslinking agent on hard gelatine capsules and the prepared drug beads were filled into these capsules. Pulsatile delivery systems have various advantages over conventional delivery with reduced dosage frequency, extended daytime or night time activity, drug targeting and drug adaption to suit circadian rhythms of body functions or diseases. [7] Venlafaxine hydrochloride (VX) is chemically (R/S)1-[2-(dimethylamino)-1-(4-ethoxyphenyl) ethyl] cyclohexanol hydrochloride or ()-1-[-[(dimethylamino) methyl]-p-methoxybenzyl] cyclohexanol hydrochloride. It is a serotonin noradrenaline reuptake inhibitor active orally, used in treatment of various major depressive disorders.[8,9] Its bioavailability is 10 45 % with high water solubility of 572mg/ml (adjusted to ionic strength of 0.2M with NaCl). It is used to treat depression and suicidal tendencies associated with it. Formulating as pulsatile delivery can overcome the circardian tendencies of disease, circardian rhythm is any biological process that displays an endogenous entrainable oscillation of about 24 hrs and depressive suicidal tendencies are more prevalent during early morning hours of the day, hence preferred lag time is selected to achieve desired therapeutic effect.[10] In this study alginate drug loaded beads of VX were developed to prevent the drug release in initial lag time and later rapid release of drug after lag time lapses. For improved lag time calcium pectinate beads were prepared and these beads were filled in hard gelatine capsules treated with formaldehyde vapours. Different formulation parameter like particle size of beads, entrapment efficiency and in vitro drug release were investigated for selecting the optimised formulation of VX pulsatile drug delivery systems. MATERIALS AND METHODS Materials Venlafaxine Hcl was a gift sample from Dr. Reddys laboratory, Hyderabad. Pectin AS 104 was procured from Krishna pectins pvt ltd, Jalgaon, India. Sodium alginate was procured from SD Fine Chemical Ltd, Mumbai, India. All other chemicals and reagents used were either of analytical or pharmaceutical grades. Methods Preparation of VX beads: [11] The hollow porous beads were prepared by dissolving 2gms of alginate and 75 mg of venlaflaxine Hcl (from formulations F1 F6) in 10 ml of deionised water and various amounts of sodium bicarbonate uniformly mixed,

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as shown in formulation table 1. The dispersion was sonicated for 30 min to remove any air bubbles. The resultant dispersion was dropped via 23 guage syringe needle into 100ml of 1% calcium chloride solution. The content was stirred at 100 rpm using magnetic stirrer for 15 minutes. The beads were filtered and washed 3 times with distilled water and oven dried at 50 C for 4 hrs. (Formulations F1 F4) Calcium pectinate beads were prepared similarly replacing with low methoxy pectin 300 mg with various amounts of sodium bi carbonate in 80 ml of 2% w/v calcium chloride solution containing 10% of acetic acid (F5-F8). Low methoxy Pectin is used to prolong the lag Table 1 Composition of Venlafaxine HCL [ratios] Ingredients F1 F2 F3 Venlafaxine Hcl(mg) 75 75 75 Sodium alginate (gm) 2 2 2 Pectin AS 104(mg) Sodium 75 100 125 Bicarbonate(mg) Calcium chloride(gm) 1 1 1 They are treated with formaldehyde for 24 hrs later they are removed and kept in a filter paper for 48 hrs so there is complete reaction between formaldehyde and gelatin. Then the capsules were kept in an open atmosphere for some time so that the residual formaldehyde gets evaporated. Then these capsules were fitted with caps and stored in a polythene bag. The capsules were filled with alginate beads and further evaluated for various tests. EVALUATION TESTS Drug entrapment efficiency [12] 100 mg of beads from each batch was placed in 100 ml conical flask containing 100 ml pH 7.2 phosphate buffer. Beads were agitated in a mechanical shaker for 24 hrs, to promote swelling and breakup of the cross linked structure. The solution was filtered and the drug was quantified at 225nm sphectrophotometrically after appropriate dilution with buffer. The encapsulation efficiency was determined by using the following empirical relationship. Each determination was performed in triplicate manner. Actual % Entrepment ef iciency = 100 theoritical In Vitro drug release [13] In Vitro drug release rate of Venlafaxine HCL beads of different formulations were determined using USP dissolution test apparatus (basket type). Sample of drug equivalent to 75mg were kept in the basket placed into 900ml of preheated dissolution medium at 37 C consisted of pH 1.2 HCL buffer for first 2 hrs, then the medium is replaced with pH 7.2 phosphate buffer. Aliquots of 5ml were withdrawn at regular intervals of time (for every half an hour and the same is replaced with fresh dissolution medium each time. The samples were measured for absorbance at 225nm. Morphology of beads (Scanning electron microscope) [14] Morphological examination of the surface and internal structure of dried beads was carried out using a scanning electron microscope. Each of CaPG and sodium alginate beads of selected formulation were transversely cut with a phase and crosslinking agent concentration is increased for effective hardening of the beads, pectinate beads are stabilised only in presence of acetic acid. [11] Preparation of cross linked Gelatin capsules Hard gelatin capsules about 500 mg were taken and their body was separated from their cap, then the body was placed on a wire mesh. 25 ml of 37% V/V of formaldehyde solution was taken in a in a empty dessicator and a pinch of potassium permanganate was added to it to develop vapors. The wire mesh containing the body of the caps was kept in the dessicator.

F4 75 2 150 1

F5 75 300 0.065 2

F6 75 300 0.22 2

F7 75 300 0.30 2

F8 75 300 0.35 2

steel blade and sputtered with gold to thickness of about 30nm under vaccum and microscopy was performed in scanning mode with magnification ranging from 50X 500X and a spatial resolution of 50nm-100nm. It was viewed for the presence of polymer layer. RESULTS AND DISCUSSIONS Entrapment efficiency Result shows on Table 2 that the entrapment efficiency was in range of 95-92. %; the formulation containing pectin AS and comparable increments of sodium bicarbonate showed high entrapment of 95.6% whereas it was 93.2% and 92.1 %for formulation F4 (VX with sodium alginate as polymer and sodium bicarbonate as effervescent regulator for drug release). The entrapment efficiency values are high for formulations with increase amount of gas forming agent due to formation of thick peripheral boundaries by gas molecules, which prevents the leaching of drug. Table 2 Entrapment efficiency of bead % Entrapment efficiency Formulation code Sodium alginate F1 75.7 F2 79.4 F3 81.2 F4 88 Pectin AS104 F9 77 F10 79.8 F11 81.5 F12 90.9 In vitro drug release Results of dissolution studies of VX loaded alginate beads, pectinate beads and alginate beads filled in capsules are shown in Figure 1, 2 & 3, the formulations containing sodium bicarbonate and sodium alginate showed lag time of 2-3hrs; with % of drug release as 72.1, 89.4, 91.4 and 97.2 %for F1, F2, F3 and F4 formulations at the end of 12 hrs respectively. Next four formulations containing low

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methoxy grade pectin with sodium bicarbonate showed lag time of 5 hrs with % drug release of 84.1, 88.9, 97.2, 99.7 % for formulations F5, F6, F7 and F8 at the end of 12 hrs respectively and final four formulations developed by filling drug loaded alginate beads in formaldehyde treated capsules showed prolonged lag time of 6 hrs with % drug release of 89.1, 94.6, 96.1, 99.8 % at the end of 12 hrs. The release rate was found to increase steadily after lag phase and 99 % release was achieved later. The above results were compared to conventional tablets of VX and the release rate clearly indicates the lag phase of release where there was almost zero release of drug and subsequent rapid release of drug later. Whereas marketed sustained release eted tablets of VX released drug steadily with 94.2 % release at the end of 12 hrs with no lag time in release profile. SEM. The pectin ate beads SEM Figure 5 is observed to have more increase in surface area compared to alginate beads in Figure 4, with satisfactory regular spherical shape , and well separated particles with no agglomeration.

Figure 4 SEM of alginate beads of Venlafaxine.

Figure 1 Rate of drug release of different formulations of alginate beads. Figure 5 SEM of pectinate beads of Venlafaxine CONCLUSION Venlafaxine Hcl is anti depressant drug and highly water soluble,(534mg/ml in water, to avoid dose dumping 534mg/ml and achieve time controlled release timed delayed capsule device for chronotherapeutic delivery of drug was successfully developed. F12 formulation is recommended as the better formulation. The lag time achieved whe where almost the release of drug was negligible was due to combined effect of sodium alginate; sodium bicarbonate, pectin and formaldehyde in varying proportions. Formulations F4, F8 and F12 burst release after lag hrs time 3, 5, 6 which is applicable pulsat drug delivery of pulsatile Venlafaxine for anti suicidal and anti depressant actions. The lag time criterion of 5hrs was satisfied by formulation 12. The dosage form can be taken at bed time and will release the contents in the early morning hours when depressant attacks are more potent. t REFERENCES 1. Krogel I, Bodmeier R. Pulsatile drug release from an insoluble capsule body controlled by an erodible plug, Pharm Res. 5,474-478 ( (1998) . 2. Krogel I, Bodmeier R. Evaluation of an enzyme containing capsular shaped pulsatile drug delivery system Pharm Res. 16,1424-29 (1999). 29 3. Krgel I, Roland B, Floating or pulsatile drug delivery systems based on coated effervescent cores, Int. J. Pharm, 187, 175-184 (1999). 4. Kataoka K, Harada A, Harada A, Nagasaki Y, Block copolymer micelles for drug delivery: design, characterization and biological significance, Adv. Drug Del. Rev. 47, 113-131 (2001 2001).

Figure 2 Rate of drug release of different formulations of erent alginate beads filled in capsules

Figure 3 Rate of drug release of different formulations of calcium pectinate beads filled in capsules Scanning electron microscopy The SEM photomicrographs of beads show a characteristic surface area increment which favours effective surface area increment which favours effective dissolution of the drug. Efficient polymerization of drug and polymer is observed: which is clearly depict depicted by

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5. A. Kikuchi, T. Okano, Pulsatile drug release control using linear region of the current versus drug release curve hydrogels, Adv. Drug Deliv. Rev. 54, 5377 (2002). 6. Nitin S, Satarkar, Zach Hilt S. Magnetic hydrogel nanocomposite for remote controlled pulsatile drug release. J Cont Release .130, 246-251 (2008). 7. Veena S Belgamwar, Madhavi V. Gaikwad, Ganesh B Patil , Sanjay Surana. Pulsatile Drug Delivery System Asian J. Pharmaceutics. 2(3), 141-145 (2008). 8. Dollery Collin, Therapeutic Drugs. Churchill livingstone, Edinburg, 2, V16-V20 (1996). 9. Thomson, Physicians Desk Reference, Thomson PDR, Motvale, NJ. 58, 3413-3424 (2004). 10. Shan-Yang Lin, Yoshiaki Kawashima, Current trends and approaches to developing press coated chronodelivery drug systems, J. Control. Rel. 157 (3): 331-353 (2012). 11. Somani V G, Shahi S R, Udavant Y K, Atram S C, Satpute R, Shinde N M, A floating pulsatile drug delivery system based on hollow calcium pectinate beads , Asian J. Pharmaceutics. 2 (3), 120-124 (2009). 12. Shraddha S. Badve, Praveen Sher, Aruna Korde, Atmaram P. Pawar, Development of hollow / porous calcium pectinate beads for floating pulsatile drug delivery; European. J. Pharm & Biopharm. 65 (1), 8593 (2007). 13. Maryam Maghsoodi, Elham Hemati, Bahram Qadermazi, Zahra Yari, Hollow microspheres for gastroretentive floating- pulsatile drug delivery: preparation and in vitro evaluation, Advanced pharmaceutical Bulletin. 1 (2), 55-61 (2011). 14. Sameer Sharma, Atmaram Pawar, Low density multiparticulate system for pulsatile release of meloxicam , Int. J. Pharm. 313(1-2); 150-158 (2006).

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