Formulation and Evaluation of Mucoadhesive Buccal Tablets for Anti-Hypertensive Drug Valsartan

FORMULATION AND EVALUATION OF MUCOADHESIVE BUCCAL TABLETS FOR ANTI-HYPERTENSIVE DRUG VALSARTAN

M. PharmDissertation Protocol Submitted to

Rajiv Gandhi University of Health Sciences, Karnataka

Bangalore – 560041

By

Mr. VINOD KUMAR.S.M,B. Pharm

Under the Guidance of

Mr. ANUP KUMAR ROY, M. Pharm

Asst. Professor

Department of Industrial Pharmacy,

Acharya & B.M.Reddy College of Pharmacy,

Soladevanahalli, Chikkabanavara (Post),

HesaraghattaMain Road, Bangalore – 560 090

2009-2010

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

KARNATAKA, BANGALORE.

ANNNEXURE– II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / Name and address of candidate / Mr.Vinod kumar S.M.
S/O Dr. S.M.Mallikarjunaiah, Asst. Director,
Veterinary Hospital,
Hosadurga-577527.
Chitradurga Dt
.
2. / Name of institution / ACHARYA & B.M. REDDY COLLEGE OF PHARMACY,
Soldevanahalli, Hesaraghatta Main Road,
Chikkabanavara Post.
Bangalore-560090
3. / Course of study and subject / M.Pharm
(Industrial pharmacy)
4. / Date of admission / 19thJune– 2009
5. / Title of the project / FORMULATION & EVALUATION OF MUCOADHESIVE BUCCAL TABLETS FOR ANTI-HYPERTENSIVE DRUG VALSARTAN
6. / BRIEF RESUME OF THE INTENDED WORK:-
6.1 NEED FOR THE STUDY:
Oral administration is the most convenient, widely utilized, and preferred route of drug delivery for systemic action. However, when administered orally, many therapeutic agents are subjected to extensive presynaptic elimination by gastrointestinal degradation and/or first pass hepatic metabolism, as a result of which low systemic bioavailability and shorter duration of therapeutic activity and/or formation of inactive or toxic metabolites have been reported.1
Delivery of drugs via the absorptive mucosa in various easily accessible body cavities, like the ocular, nasal, buccal, rectal, and vaginal mucosa, has the advantage of bypassing the hepato-gastrointestinal first-pass elimination associated with oral administration. Drugs with hydrophilic and/or lipophillic characteristics can be readily absorbed.2
Both the buccal and sublingual sites have advantages compare with other routes, including rapid onset of action, high blood levels, avoidance of the first-pass effect and the exposure of the drug to the gastrointestinal tract. There is excellent accessibility and the drug can be applied, localized and removed easily.3
Since recent times however, the oral mucosa, as the site for drug administration has been steadily gaining importance. The attractive features of oral mucosa, include excellent accessibility and high patient acceptance and compliance. Moreover, since the oral mucosa is routinely exposed to a multitude of different foreign compounds, it is rather robust and less prone to irreversible irritation or damage by dosage forms, or additives such as absorption promoters.4
Buccal and sublingual tablets are intended to be held in the mouth, where they release their drug contents for the absorption directly through the oral mucosa. These tablets are usually small and somewhat flat, and are intended to be held between the cheek and teeth. Drugs administered by this route are intended to produce systemic drug effects. Drug absorption from the oral mucosa into the blood stream leads directly to the general circulation.5
Valsartan is a tetrazole-byphenyl-valinic derivative of losartan,structurally characterized by the presence of a soleheterocyclic structure. Functionally, valsartan is a highly selective non-competitive angiotensin II-typeI (AT1)receptor antagonist (30,000 times higher affinity for AT1 than for angiotensin II-type 2 receptors –AT2). Valsartan has showed to be effective in decreasing blood pressure values and treating heart failure.Studies performed in animal models of acute myocardial infarction showed that Valsartan decreases both reactive oxygen species production and ventricular remodeling.6
The molecular weight of Valsartan is 435.5, its half life is 6 h, a low bioavailability of approximately 25%, and 95% of drug undergoes protein binding. Valsartan is presently available in tablet dosage form and dose for adult is 40mg once daily.
It has been suggested that drugs with biological half-lives in the range of 2-8 h, are good candidates for sustained-release formulations.20
It has been reported that approximately 70% of the total clearence of Valsartan is accounted for by hepatic clearence. Valsartan undergoes metabolism involving 4-hydroxylation. Valsartan is mainly excreted into the bile in unchanged form, where as 85% of orally administered Valsartin is excreted into feces in unchanged form.7
Hence, considering the half life, and bioavailability of Valsartan, in the present work, an attempt is made to formulate mucoadhesive buccal tablets for Valsartan using suitable polymers, in order to avoid extensive drug elimination, first pass metabolism, reducing the dose and dose related side effects and to increase the bioavailability.
6.2 REVIEW OF LITERATURE:-
Reviews of literatures revealed that number of studies have been carried out on
mucoadhesive buccal tablets using different techniques.

• Mucoadhesive buccal tablets of Domperidone were fabricatedwith objective of avoiding first pass metabolism and to improve its bioavailability with reduction in dosing frequency. The mucoadhesive polymers used in the formulation were Carbopol 934P, Methocel K4M, MethocelE15LV and Chitosan. Tablets were prepared by direct compression method using polymer in different ratios. The formulations were characterized for swelling index, in vitrobioadhesion strength and in vitro release studies. The best mucoadhesive performance and in vitro drug release profile were exhibited by the tablet containing Chitosan and Methocel K4M in ratio of 1:1.8

• The bucoadhesive controlled-release tablets for delivery of Nifedipine were prepared by direct compression of Carboxymethyl cellulose(CMC) with Carbomer (CP), which showed biadhesion properties compared to Polyvinylpyrolidine (PVP), Polyvinyl alcohol (PVA), Hydroxypropylmethyl cellulose (HPMC), and Acatia in a modified tensiometry method in vitro. The tablets containing 30 mg of Nifedipine and various amounts of CMC and CP showed a zero order drug release kinetic. The adhesion force was observed at the mixing ratio of 1:0 and 8:2 of the CP:CMC, respectively. The tablets containing 15% CMC and 35% CP adhered for over 8 hrs to the upper gums of six healthy human volunteers. These tablets released about 56% of loaded drug after 8h in vivo with a rate of 2.17h-1 and were perfectly tolerated, while they released about 100% of their content after the same time with a rate of 3.49 h-1in vitro. A good correlation was observed between drug-released in vitro and in vivo.9

• Pharmacokinetics of Verapamil and its metabolite Nonverapamil, from buccal drug formulation administered in a dose 20mg in relation to conventional tablets of Verapamil 40 mg, used in medical practice, was determined. Buccal formulation has previously designed as an alternative form of dosing Verapamil. Bioavailability was determined by means of HPLC with a fluorescence detector. Better parameters of bioavailability of Verapamil from buccal formulation of twice a smaller dose than that in tablet is proved.10

• Extending the residence time of a dosage form at a particular site and controlling the release of drug from the dosage form are useful especially for achieving controlled plasma level of the drug as well as improving bioavailability. The Objective of this study was to extend the GI residence time of the dosage form and controle the release of Rosiglitazone using mucoadhesive tablet to achive controlled plasma levels of the drug. Direct compression method using simplex lattice design, followed by optimization of the evaluation parameters was employed to get final optimized formulation.11

• Oral mucosal bioadhesive tablets of Diltiazem were prepared by direct compression the drug with Chitosan and Sodium alginate. In vitro adhesion studies indicated adhesion properties comparable to those of commercial formulation.Invitro release of Diltiazem found to be rapid and can be modified by changing the mixture ratio. The biavailability was 69% from tablets with a 1:4 Chitosan/alginate.12

• Mucoadhesive buccal tablets of Diltiazem hydrochloride were prepared using carbopol-934, Sodium carboxy methyl cellulose (SCMC),Hydroxy propyl methyl cellulose (HPMC), Sodium alginate and guar-gum as mucoadhesive polymers. Eight formulations were developed with varying concentrations of polymers. The Carbopol-934 was used as a primary polymer and secondary polymers like HPMC, SCMC, sodium alginate and guar-gum were used. The effect of secondary polymer loading on drug release was studied. The formulations were tested for in vitro drug release and in vitro swelling studies. FTIR studies showed no evidence on interaction between drug and polymers.13

• Controlled release buccal patches were fabricated using Eudragit NE40D and studied. Various bioadhesive Polymers, namely Hydroxylpropylmethyl cellulose, Sodium carboxymethyl cellulose and Carbapole of different grades, were incorporated into the patches. The in vitro drug release was determined using the USP 23 dissolution test apparatus 5. Bioadhesiive properties were evaluated using texture analyzer equipment with chicken pouch as the model tissue. Carbopol 700 found satisfactory in modifying the drug release and enhancement of bioadhesive properties.14

• In this study the transporters that mediate the hepatic uptake and biliary excretion of Valsartan was studied. Transporter-expressing systems, human cryopreserved hepatocytes, and MRP2-deficient Eisai hyperbilirubinemic rats were used for study. Valsartan found to be taken up by organic anion- transporting polypeptide (OATP) 1B1 , (OATP1B3). The results suggest that OATP1B1 and OATP1B3 were found hepatic transporters.15

• Objective of study was made to assess the effect of sublingual Valsartan in a group of patients with hypertension urgency. Patients were given 80 mg of Valsartan sublingually. Blood pressure and heart rate were recorded at 15 min intervals over a 90 min period. The results of the study indicates that sublingual Valsartan is an effective drug in patients with hypertensive urgency.16
• Solid dispersion films were prepared with a highly water soluble medicine Lidocaine hydrochloride (LDC), water insoluble Ethyl cellulose(EC), and water soluble Hydroxylpropylcellulose (HPC). The release profile of Lidocaine hydrochloride was studied. It was found that the release of drug is well controlled at EC/HEC composition ratio of 5/5.17
• The pharmacokinetics and bioavailability of Triamcinalone acetonide were determined to investigate buccal absorption from the mucoadhesive gels in rabbits. The enhancing effect of Sodium deoxycholate as an enhancer on the buccal absorption of Triamcinolone acetonide from the mucoadhesive gels was evaluated in rabbits. Result showed that buccal administration of Triamcinalone acetonide gel containing sodium Deoxycholate as an enhancer showed a relatively constant, sustained blood concentration with minimal fluctuation.18
• The present work was aimed at overcoming poor bioavailability 25-30%, high first pass metabolism. Carried out design of buccal drug delivery system for a poorly soluble drug carvidalol. Drug-Methyl B- Cyclodextrin complex was prepared by knelding method and characterised by FTIR and powder x-ray diffractometry studies. Buccal tablets containing complex showed complete release compare to tablets containing plain drug.19

There is limited reference of the work done about the bucoadhesive tablets using direct compression and/or wet granulation. Thus, we are planning to employ this technique for Valsartenas a model drug.
6.3 OBJECTIVE OF THE STUDY:
The main objective of the present study is to carry out formulation of mucoadhesive buccaltablets for an antihypertensive drug valsartan using suitable polymers to improve its bioavailability and to reduce the dose.
The objectives of the present study are as follows:-
1.Development of spectrophotometric method for the determination of the drug valsartan.
2.Preformulation studies for possible drug/polymer/excipient interaction by FTIRanalysis.
3.Preparation of bucoadhesive tablets using suitable polymers.
4.Evaluation of prepared tablets by different physicochemical studies
5.To perform the in vitro drug Dissolution study and in vitro diffusion study
6.To carry out short term stability studies on the most satisfactory formulation as per
ICH guidelines at 30 ± 20C (65 ± 5 % RH) and 40 ± 20C (75 ± 5 % RH).

7. MATERIALS AND METHODS:

7.1 SOURCE OF DATA:

• Review of literature from:
• Journals such as
• Indian journal of pharmaceutical science.
• Current therapeutic research.
• International journal of pharmacy and pharmaceutical sciences.
• International journal of pharmtech research.
• Europian journal of pharmacology.
• Text books.
• Europian journal of pharmaceutics and biopharmaceutics.
• World Wide Web.
• J-Gate@Helinet.
• Science direct.

7.2 METHODS:
1)To carry out preformulation study:-

1. Drug polymer interaction.
2. Micromeritic study.

a)Angle of repose.
b)Bulk density.
c)Porosity and Percentage compressibility.
2)To formulate mucoadhesive buccal tablets by direct compression/wet granulation methods using various polymers.
3)Evaluation of the various properties of the formulated mucoadhesive buccal tablets:-
a)Physical properties:-

• Diameter and Thickness
• Hardness and Friability
• Uniformity of Weight and drug content

b)Mucoadhesive properties:-

• Mucoadhesive strength
• Surface pH of the tablets
• Swelling characteristics

c) In vitro drug release studieswill be carried out on a fresh bovine cheek pouch
washed withIPB pH 6.6 at 37°C.
4)To carry out short term stability studies on the most satisfactory formulation as perICH guidelines at 30 ± 20C (65 ± 5 %RH) and 40 ± 20C (75 ± 5 %RH) for 2 months.
7.3DOES THE STUDY REQUIRE ANY INVESTIGATION OR
INVESTIGATIO TO BE CONDUCTED ON PATIENT OR OTHER
HUMANS OR ANIMALS?
“NO”
7.4 HAS ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR
INSTITUTION IN CASE 7.3?
“NOT APPLICABLE”
8. / REFERENCES:-
1.Shiva Krishna S, Subhabrata Ray, Thakur RS. Formulation And Evaluation Of
Mucoadhesive Dosage Form Containing Rosiglitazone Maleate. Pak J Pharm Sci2006;
19(3):208-13.
2.Chien YW. Novel drug delivery system.2nd ed. New York: Marcel Dekker;1992.p.197.
3. Miyazaki S, Nakayama A, Oda M, Takada M, Attawood D. Drug Release from oral mucosal
adhesive tablets of chitosan and sodium alginate. Int J pharm 1995; 118:257-63.
4. Jain NK. Controlled and novel drug delivery. 5th ed. New Delhi(India): Satish kumar jain,CBS
publishers; 1997.p. 52-53.
5.Leon lachman, Herbert liberman A. The theory and practice of industrial pharmacy, Special
Indian edition. New Delhi: Satish jain & Vinod jain, CBS publishers; 2009.p. 333.
6.Pedro M, Anna ID, Lino Goncaves M, Luis Pprovidencia A. Valsartanimproves mitochondrial
function. Euro J Pharm Colo2005; 518: 158-64.
7. Wakaba Y, Kazuya M, Masakazu H, Yasuhisa A, Zhuohan H, Yuichi S.Involvement of
transporters in the hepatic uptake andbiliaryexcretion of Valsartan. Ame Soc Pharm cology
Exper Ther2006; 34: 1247-54.
8. Balamurugan M, Saravanan VS, Ganesh P, Senthil SP, Hemalatha PV, Sudhir Pandya.
Development and in-vitro evaluation of mucoadhesive buccal tablets of domperidone.
Res J Pharm Tech2008; 1(4).
9. Varshosaz J, Dehghan Z. Development and characterisation of bucoadhesivenifedipine tablets.
Euro J Pharm Ceu biopharm 2002; 54: 135-41.
10.Wieslaw Sawicki, Stanislaw Janicki. Pharmacokinetics of verapamil and its metabolite
nonverapamil from a buccal drug formulation.InterJ pharm ceu2002; 238: 181-9.
11.Shivas Krishna S, Subhabrata Ray, Thakur RS. Formulation and evaluation of mucoadhesive
dosage form containing rosiglitazone maleate.Pak J Pharm Sci2006; 19(3):208-13.
12. Miyazaki S, Nakayama A, Oda M, Takada M, Attwood D. Drug release from oral mcosal
adhesive tablets of chitosan and sodium alginate.Inter J Pharm Ceu1995; 118: 257-63.
13.Manivannan R, Balasubramaniam A, Prem Anand DC, Sandeep G, Rajkumar N. Formulation
and evaluation of mucoadhesive buccal tablets of diltiazem hydrochloride.Res J Pharm Tech
2008; 1(4): 478-80.
14.Choy FW, Kah HY, Kok KP. Formulation and evaluation of controlled release eudragit buccal
patches. Inter J Pharm Ceu 1999;178: 11-12.
15. Wakaba Y, Kazuya M, Masakazu H, Yasuhisa A, ZhuohanH, Yuichi S.Involvement of
transporters in the hepatic uptake and biliary excretion of valsartan. Amer Soc Pharm col
Exper Ther2006; 34(7): 1247-54.
16. Yuksel G, Saime P, Guven K, Nazan A.Sublingual valsartan in hypertensive urgency. Turk J
Med Sci 2001; 31: 565-7.
17. Yukinao K, Hitoshi K, Yasuyuki B, Hiroshi Y,Tetsuya O, Yoshio K, Etsuro S. Controlled
release of lidocaine hydrochloride from buccal mucosa-adhesive films with solid dispersion.
Inter J Pharm Ceu 1997; 158:147–55.
18. Sang-Chul S, Jin-Pil B, Jun-Shik C. Enhanced bioavailability by buccal administration of
triamcinolone acetonide from the bioadhesive gels in rabbits. Inter J Pharm ceu 2000; 209:
37–43.
19. Hirlekar RS, Kadam VJ. Design of buccal drug delivery system for a poorly soluble drug.
Asi J Pharm Ceu Cli Res 2009; 2(3).
20.Longer MA, Ch’ng HS, Robinson JR, Bioadhesive polymers as platforms for oral controlled
drug delivery, J Pharm Sci 1985; 74: 406-11.
9 / Signature of the candidate:
10 / Remarks of the Guide:
11 / Name and Designation of:

11.1 Institutional Guide: / Mr. Anup Kumar Roy
Asst. Professor
Dept. of Industrial pharmacy,
11.2 Signature:
11.3 Co-Guide: / Mr. Venkatesh D.P.
Sr. Lecturer
Dept. of Industrial pharmacy
11.4 Signature:
11.5 Head of the Department: /

Dr. B.Prakash Rao

Professor & HOD
Dept. of Industrial pharmacy
11.6 Signature
12 / 12.1 Remarks of the Principal
12.2 Signature /

Dr. Goli Divakar

Principal

Acharya & B.M.Reddy College Of Pharmacy,
Bangalore-560 090.

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