FORMULATION,CHARACTERIZATION AND EVALUATION OF SUSTAINEDRELEASE TABLETSOF VALSARTAN

M. Pharm. Dissertation Protocol

Submitted to

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES KARNATAKA,

BENGALURU

By

Mr. M.VIJAYKANTH

Under the guidance of

Ms. D.AGILANDESWARIM.Pharm

Asst. Professor

DEPARTMENT OF PHARMACEUTICS

CNK REDDY COLLEGE OF PHARMACY

BENGALURU-560 091

(2011-12)

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

KARNATAKA, BANGALORE.

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

1 / NAME OF THE CANDIDATE AND ADDRESS / Mr. VIJAYKANTH,
S/o Mr. RAMACHARY,
GUNGAL(VILLAGE),
YACHARAM(MANDAL),RANGAREDDY(DIST),
ANDHRA PRADESH,PINCODE: 501506.
2 / NAME OF INSTITUTION / CNK REDDY COLLEGE OF PHARMACY
BENGALURU-560091, KARNATAKA.
3 / COURSE OF THE STUDY AND SUBJECT / MASTER OF PHARMACY INPHARMACEUTICS
4 / DATE OF ADMISSION / NOVEMBER 2011
5 / TITLE OF THE PROJECT / FORMULATION, CHARACTERIZATION AND EVALUATION OF SUSTAINED RELEASE TABLETS OF VALSARTAN
6 / BRIEF RESUME OF INTENDED WORK
6.1 / NEED OF THE STUDY
Oral drug delivery has been known for decades as the most widely utilized route of administration among all the routes that have been explored for the systemic delivery of drugs. The reason that the oral route achieved such popularity may be in part attributed to its ease of administration as well as the traditional belief that by oral administration the drug is as well absorbed as the food stuffs that are ingested daily1.
The conventional dosage forms such as tablets and capsules are the major oral preparations among all dosage forms to have a wide acceptance of 50-60%. Solid dosage forms are popular because of ease of administration, accurate dosage, self-medication, pain avoidance and most importantly the patient compliance.
Oral drug delivery has been the most widely utilized route of administration among the all route because of certain advantages such as unit dosage form, low cost, cheapest for packaging etc. In the last two decades the drug delivery technology has developed rapidly and many novel oral drug delivery systems have been invented2. Apart from these advantages this route suffers from certain drawbacks like patient noncompliance, multiple dosing and therapeutic failures. In order to overcome these drawbacks of conventional drug delivery there is a need for development of new drug delivery system or modified drug delivery system1.
Sustained release system is a type of modified drug delivery system that can be used as an alternative to conventional drug delivery system. These systems sustain the release of drug and maintain the plasma drug concentration in therapeutic window except any fluctuation and increase the therapeutic efficacy of drug. They show their action by avoiding peak and trough in dosing and show constant plasma drug concentration in therapeutic window. Sustained release system have benefits like patient compliance, avoid multiple dosing, increase the plasma drug concentration, avoid side effects and overcome the problems associated with conventional system3,4,5.
Valsartan is an angiogenesis II receptor antagonist that is used for the treatment of hypertension. Valsartan acts by blocking the binding of angiotensin II and angiotensin I receptor in many tissues thereby blocking the vasoconstrictor and aldosterone secreting effect of angiotensin II selectively. The most preferred route for this drug is oral delivery in the form of tablets. Valsartan have poor water solubility, low bioavailability (approximately 20-25%), and shorter half-life (nearly 6 hours)6,7. Since Valsartan has low bioavailabilityand shorter half-life, developing a sustained release system can maintain the plasma drug concentration in therapeutic window and increase the therapeutic efficacy of drug. Hence the present work has been proposed. The aim of this proposed work is to formulate, characterize and evaluate sustained release tablets of Valsartan.
6.2 / REVIEW OF LITERATURE
  • Soumyaet al.8 developed and optimized bilayered sustained release matrix tablets of Valsartan. The tablets contained an immediate releasing layer with the loading dose of the drug and a sustaining layer with the maintenance dose of drug prepared by wet granulation method. The optimized batch was selected where the drug from immediate layer was released within 15 minutes and then sustained for a period of 12 hours.
  • Saydamet al.9has summarized the physicochemical properties, analytical determination methods, bioavailablity and pharmacology of Valsartan.
  • Tapas et al.10 enhanced the solubility and dissolution rate of Valsartan, a poorly water soluble antihypertensive by spherically agglomerated solid dispersions using methanol, water and dicholoromethaneas good solvent, poor solvent and bridging liquid respectively. The hydrophilic polymers like polyvinyl pyrrolidone, hydroxypropyl beta-cyclodextrin and hydroxypropyl methylcellulose were used in the agglomeration process.
  • Rajhanset al.11developed a swellable, gastro-retentive drug delivery system using combination of polyethylene oxide (Polyox WSR 303) and HPMC K 100L V by wet granulation process. Based on the release kinetics the authors have concluded that the combination of polyethylene oxide (Polyox WSR 303) and HPMC K 100L V was particularly suitable as gastro-retentive drug delivery system of Valsartan as extended release drug delivery system.
  • Fukuduet al.12investigated the influence of pH, buffer species and ionic strength on the release mechanism of chlorpheniraminemaleate (CPM) from matrix tablets containing chitosan and xanthum gum prepared by hot-melt extrusion process. Drug release from hot-melt extruded (HME) tablets containing either chitosan or xanthum gum was pH and buffer species dependent and the release mechanisms were controlled by the solubility and ionic properties of the polymers.
  • SandhyaRaj et al.13prepared sustained release microcapsules of Valsartan by orifice-ionic gelation method using hydroxypropyl methyl cellulose (viz 50cpc, K4M as mucoadhesive polymer. The optimized formulation showed slow release up to 14 hours. In vitro drug release followed first order kinetics. Fickian diffusion mechanism and the results had proven the release of the best formulation which extended up to 13.5 hours according to t50%. All the microcapsuled formulation exhibited good mucoadhesive property in the in vitro.Accelerated stability studies were carried out for short term studies of formulations according to ICH and Q1A (R2) guidelines.
  • Dindaet al.14formulated a fixed dose combined drug formulation of Valsartan (VAL) as an immediate release layer and Metformin Hydrochloride (MHCL) as a sustained release form using bilayer tablet technology, which enabled biphasic drug release for once daily dosing to get a better therapeutic efficacy. The results indicated that VAL and MHCL could be a potential fixed dose combination form for the simultaneous treatment of hypertension and diabetes and can be developed into suitable bilayer tablets.
  • Anjankumar15designed and evaluated mucoadhesivebilayeredbuccal devices comprised a drug containing mucoadhesive layer and a drug free backing membrane. Bilaminated films composed of mixture of drug (Valsartan) and chitosan, with hydroxypropyl methylcellulose (15 cps) and backing layer (ethylcellulose). A combination of chitosan and hydroxypropyl methylcellulose (1:1) using propylene glycol (50% by weight of polymer) as plasticizer have shown promising results. The optimized film exhibited an in vitro drug release of approximately 90% in 5hours along with satisfactory bio-adhesive strength.
  • Lathaet al.16reviewed the chronobiology and chronotherapy of hypertension and of the various medications used in its management. Evidences clearly pointed to the fact that nocturnal BP is indeed the BP as it is most consistently correlated with prediction of cardiovascular risk and provided more close surveillance of safety. Circardian rhythm is a significant input into the regulation of blood pressure. Hence, a circardian disorder such as hypertension required chronopharmacotherapy.
  • Perezet al.17 evaluated the bioequivalence of two pharmaceutical products whose active principle wasValsartan, based on the comparison of the pharmacokinetic measures of rate and extent (in terms of required time) in which Valsartan reached the sanguineous circulation after a oral dose to 15 volunteers. The study showed no statistically significant differences in the plasma concentration levels after administration of the two formulations of Valsartan: 80 mg tablets and 80 mg capsules. So, the design of the study and the application of the protocols chosen enabled the demonstration of bioequivalence between the products.
  • Pavan Kumar et al.18formulated Valsartan fast dissolving tablets using co-processed superdisintegrant. Crospovidone and SSG were used for preparation of co-processed superdisintegrant by physical mixing and solvent evaporation method in three different ratios (1:1, 1:2, and 1:3). Formulation made with co processed crospovidone and SSG in 1:1 ratio was found to be best out of all formulations. The authors have concluded that the dissolution rate of Valsartan fast dissolving tablets were influenced by ratios of individual superdisintegrants employed for co-processed superdisintegrant and method used for preparation of co-processed superdisintegrant (physical mixing vs solvent evaporation).
  • Parthibanet al.19developed simultaneous estimation of Ramipril and Valsartan in capsule formulation. The separation was achieved by Thermoscientific C18 column (4.6 X 250 mm, particle size 5µm) with a mobile phase consisting of Acetonitrile: water (60:40 v/v, pH 3.6 adjusted with anhydrous disodium hydrogen phosphate), at a flow rate of 1.2ml/min at 235nm. Retention time of Ramipril and Valsartan were found to be 2.46 and 6.37 min, respectively. The linear dynamic range was 1-20µg/ml and 20-100µg/ml Ramipril and Valsartan respectively. The method was validated for accuracy, precision, ruggedness andr. The proposed method was successfully applied for thesimultaneous determination of both drugs in commercialcapsule preparation. The results of the analysis had been validated statistically and by recovery studies.
  • Ibrahim et al.20developed Valsartanorodispersible tablets 40-mg dose, with the intention of facilitating administration to patients experiencing problems with swallowing and hopefully, improving its poor oral bioavailability. A 33full factorial design was adopted for the optimization of the tablets prepared by freeze-drying technique. The effects of the filler type, the binder type, and the binder concentration were studied. Oral bioavailability of two 40mg Valsartanorodispersible tablets was compared to the conventional commercial tablets after administration of a single dose to four healthy volunteers. The relative bioavailability calculated as the ratio of mean total area under the plasma concentration–time curve for the orodispersible tablets relative to the conventional ones was 135%. The results of thein vivostudy revealed that Valsartanorodispersible tablets would be advantageous with regards to improved patient compliance, rapid onset of action, and increase in bioavailability.

6.3 / OBJECTIVE OF STUDY
The present work is planned with the following objectives
1) To develop a new formulation of sustained release tablets of Valsartan by wet granulation method.
2) To evaluate the pre-compression parameters.
4) To evaluate the post-compression parameters.
5) To perform invitro dissolution studies.
6) To perform stability studies as per ICH guidelines.
7 / MATERIALS AND METHODS
7.1 / REVIEW OF LITERATURE FROM
1.Standard Books : Books on Advances in Drug Delivery Systems.
2.Journals : Indian and International journals.
3.Web Resources : Science direct, Pub med, Scirus.
7.2 / MATERIALS
1)Drug: Anti-hypertensive drug- Valsartan
2)Polymers: Ethylcellulose and Methacrylic acids
7.3 / METHODS OF PREPARATION
1)Drug excipients compatibility studies by FTIR spectrophotometry.
2)To evaluate the pre-compression parameters i.e.
Angle of repose,
Tapped density,
Bulk density,
Carr’s index,
Hauser Ratio.
3)Preparation of sustained release tablets by wet granulation method.
4)To evaluate tablets for post compression studies i.e.
Hardness,
Friability,
Weight variation,
Thickness,
Drug content,
Tablet Size and Shape,
Content Uniformity,
In vitro dissolution studies.
5)Stability studies as per ICH guidelines.
7.4 / DOES THE STUDY REQUIRE ANY INVESTIGATION OR INTERVENTIONS TO BE CONDUCTED ON PATIENTS OR OTHER HUMANS OR ANIMALS? / -No-
7.5 / HAS ETHICAL CLEARANCE HAS BEEN OBTAINED FROM YOUR INSTITUTION IN CASE 7.3? / -Not Applicable-
8 / LIST OF REFERENCES:
  1. Chien YW. Novel Drug Delivery Systems, Volume 2, 2ndedition, New York: Dekker, 1997.
  1. Vyas SP, Khar RK. Controlled Drug Delivery and Advances, 1stedition, New Delhi: VallabhPrakashan, 2005.
  1. Lachman L, Liberman H, Kanig JL, Pharmaceutical Dosage Forms-Tablets. In: Gilbert S Banker, Neil R Anderson, editors, The Theory and Practice of Industrial Pharmacy, 3rd edition. Varghese Publishing House, 1991:430-56.
  1. Mahajan P, Mahajan SC, Mishra DK, Valsartan release from sustained release matrix tablet and effect of cellulose derivatives. International Journal of Pharmacy and Life Science 2011; 2:521-30.
  1. Lachman L, Liberman H, Kanig JL, Pharmaceutical Dosage Forms-Tablets. In: Gilbert S Banker, Neil R Anderson, editors, The Theory and Practice of Industrial Pharmacy, 3rd edition. Varghese Publishing House, 1987:296-303.
  1. Rockville MD.United States Pharmacopeia. 30/NF25, United State PharmacopoeiaConvention Inc., 2007: 616, 1174.
  1. RxListThe Internet Drug Index [online]. 2012 [cited 2012 June 14]. Available from: URL:
  1. Soumya M, Saritha M, Preparation and optimization of Valsartanbilayeredsustained release matrix tablets. International Journal of Pharmaceutical and Biological Archives 2011; 2:914-20.
  1. Saydam M, Takk S, Bioavailability file: Valsartan. FABAD Journal of Pharmaceutical Sciences 2007; 32:185-96.
  1. Tapas AR, Kawtikwar PS, Sakarkar DM, Spherically agglomerated solid dispersions of Valsartan to improve solubility, dissolution rate and micromeritic properties. International Journal of Drug Delivery 2010; 2:304-13.
  1. RajhansS, Gupta MK, Sharma S, Swellable gastro retentive drug delivery system of poorly soluble antihypertensive agent. International Journal of Drug Formulation and Research 2011; 2:151-65.
  1. Fukuda M, Peppas NA, McGinity JW, Properties of sustained release hot-melt extruded tablets containing chitosan and xanthum gum. International Journal of Pharmaceutics 2006; 310:90-100.
  1. Sandhya Raj S, Sundaramoorthy K, Vetrichelvan T, Formulation, development and in-vitro evaluation of Valsartanmucoadhesive microcapsules. International Journal of Pharmacy and Technology 2012 2:1315-27.
  1. Dinda SC, DurgaP, Pattanayak, Narayan UL, Design and evaluation of a fixed dose combination formulation of Valsartan and MetforminHcl for biphasic drug release: A novel approach to increase therapeutic efficacy. International Journal of Pharmaceutical Science and Technology 2011; 6:44-63.
  1. Anjankumar PB, Design and evaluation of buccal patches of Valsartan. Journal of Pharmaceutics and Cosmetaology2011; 1:51-5.
  1. Latha K, Uhumwangho MU, Sunil SA, Srikanth MV, Ramana Murthy KV, Chronobiology and chronotherapy of hypertension – a review. International Journal of Health Research 2010; 3:121-31.
  1. Perez M, Cardenas W, Ramirez G, Perez M, Restrepo P, A comparative, cross-over, double blind, randomized study for bioequivalence assessment between two formulations of Valsartan capsules vs. tablets.Colombia Medica2006; 37:107-13.
  1. Pavan Kumar A, SaiKishore V, Gopala Krishna Murthy TE, MadhuBabu K, Formulation of Valsartan fast dissolving tablets using novel co-processed superdisintegrants. Research Journal of Pharmaceutical Dosage Forms and Technology 2012; 4:52-5.
  1. Parthiban C, BhagavanRaju M, Sudhakar M, A validated RP-HPLC method for simultaneous estimation of Ramipril and Valsartan in pharmaceutical dosage form. Research Journal of Pharmaceutical, Biological and Chemical Sciences 2012; 3:198-205.
  1. Ibrahim HK, El-Setouhy DA, Valsartanorodispersible tablets: formulation,in vitro/in vivocharacterization. AAPS PharmSciTech, 2010; 11:189-96.

9 / SIGNATURE OF THE CANDIDATE
10 / REMARK OF THE GUIDE / The topic selected for dissertation is satisfactory. Adequate equipment’s and chemicals are available to carry out the project work.
11 / DESIGNATION OF GUIDE / D.AgilandeshwariM.Pharm.,
Asst. Professor,
DEPARTMENT OF PHARMACEUTICS,
CNK REDDY COLLEGE OF PHARMACY,
BENGALURU-560091, KARNATAKA.
11.1 / SIGNATURE OF THE GUIDE
11.2 / HEAD OF DEPARTMENT / Prof.Manjunath.U.MachaleM.Pharm.,
DEPARTMENT OF PHARMACEUTICS,
CNK REDDY COLLEGE OF PHARMACY,
BENGALURU -560091, KARNATAKA.
11.3 / SIGNATURE OF HOD
12
12.1 / REMARKS OF THE PRINCIPAL / All the required facilities will be provided to carry out dissertation work under the supervision of the guide.
12.2 / PRINCIPAL / Prof.SyedAsadulla. M.Pharm., (Ph.D),
PRINCIPAL,
CNK REDDY COLLEGE OF PHARMACY,
BENGALURU-560091,
KARNATAKA.
12.3 / SIGNATURE OF THE PRINCIPAL