“FORMULATION AND ASSESSMENT OFBIOAVAILABILITYENHANCEMENT OF OLMESARTAN MEDOXOMIL

SUBLINGUAL TABLETS”

MASTER OF PHARMACY DISSERTATION PROTOCOL

SUBMITTED TO THE

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES KARNATAKA, BANGALORE.

By

SUSHAN S. SHETTY

M.PHARM – I

Under The Guidance of

Dr. A.R. SHABARAYA M. Pharm., Ph.D.

DEPARTMENT OF PHARMACEUTICS

SRINIVAS COLLEGE OF PHARMACY, VALACHIL, MANGALORE – 574143

2011-2013

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. SUSHAN.S.SHETTY
1stYEAR M.PHARM,
DEPT. OF PHARMACEUTICS,
SRINIVAS COLLEGE OF PHARMACY,
VALACHIL, MANGALORE-574143.
2. / Name of the Institution: / SRINIVAS COLLEGE OF PHARMACY,
VALACHIL, FARANGIPETE POST, MANGALORE-574143.
3. / Course of Study and Subject: / MASTER OF PHARMACY
INPHARMACEUTICS
4. / Date of Admission: / 5TH APRIL 2011
5. / Title of the Project:
“FORMULATION AND ASSESSMENT OF BIOAVAILABILITYENHANCEMENT OF OLMESARTAN MEDOXOMIL SUBLINGUAL TABLETS”
6.
7.
8. / Brief Resume of the intended work:
6.1 Need of the study:
Systemic drug delivery through the sublingual route had emerged from the desire to provide immediate onset of pharmacological effect. Dysphagia (difficulty in swallowing) is a common problem of all age groups, especially elderly, children and patients who are mentally retarded, uncooperative, nauseated or on reduced liquid intake/diets have difficulties in swallowing these dosage forms1.
Hypertension is a disease that usually needs rapid action. Sublingual tablets of antihypertensive drugs avoids hepatic metabolism due to pregastric absorption of drug, which reduces the dose and increase bioavailability. The medication was bitter tablets have changed by use of flavours and sweeteners in sublingual tablets of antihypertensive drugs and easy to administer for paediatric, geriatric and institutionalized patients. Sublingual tablet of antihypertensive drugs results in quick dissolution and rapid absorption which provide rapid onset of action2.
OlmesartanMedoxomil (OLM) is a selective AT1 subtype angiotensin-II receptor antagonist that is approved for the treatment of hypertension. OLM dose dependently reduces blood pressure through arterial vasodilatation and reduced sodium retention, as do other angiotensin receptor blockers. It is a prodrug that is rapidly de-esterified during absorption from the gastrointestinal tract to produce an active metabolite Olmesartan.Half-life of OlmesartanMedoxomilis 13 hours.Aqueous solubility of OLM is <7.75 µg/ml.Oral bioavailability of this tablet formulation is only 26% in healthy humans due to low aqueous solubility. The unabsorbed drug leads to gastrointestinal side effects such as abdominal pain, dyspepsia, gastroenteritis and nausea. Thus, improving oral bioavailability of OLM can increase clinical efficacy, reduce the oral dose required to achieve the same effect and hence reduce the side effects3.
Prior to absorption, solid oral dosage forms must disintegrate and dissolve because oral bioavailability of a drug depends on its solubility and/or dissolution rate, and dissolution may be the rate determining step for the onset of therapeutic activity. Potential absorption problem occur if the aqueous solubility is less than 1mg/ml. Several methods have been used for the solubility enhancement of poorly
soluble drugs such as solid dispersion, inclusion complex etc. Numerous solid dispersion systems have been demonstrated in the pharmaceutical literature to improve the dissolution properties of poorly water-soluble drugs. Various hydrophilic carriers, such as polyethylene glycols, polyvinylpyrrolidone, hydroxyl propyl methyl cellulose, gums, sugar, mannitol and urea have been used for improvement of dissolution characteristics and bioavailability of poorly aqueous soluble drugs. The formation of inclusion complexes of a drug with nontoxic agent is a promising approach used to improve the dissolution properties of the drugs. Cyclodextrins (CDs) have been recognized as useful pharmaceutical excipients. The most common natural CDs are α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin. Inclusion complex improve stability, solubility, dissolution rate and bioavailability4.
In present study, attempt is made to enhance the bioavailability of OlmesartanMedoxomil sublingual tablet by using solid dispersion and inclusion complex methods like fusion method, solvent evaporation method, kneading method etc by using various carriers like cyclodextrin, PEG 6000, urea etc in different ratios.
6.2– Review of literature:
  • NehaNarang, Jyoti Sharma has made a review on sublingual mucosa as a route for systemic drug delivery. They concluded that sublingual dosages areconvenient for young children, the elderly and patients withswallowing difficulties, and in situations where potable liquids arenot available1.
  • YukselGokel, SalimSatar, SaimePaydas has compared the effectiveness of sublingual Losartan, Captopril and Nifedipine hypertensive emergency andconcluded that the hypotensive effects ofsublingual captopril and losartan were more powerfulthan those of sublingual Nifedipine. They also concludedthat Losartan sublingually administered is an effective andsafe alternative drug for managing hypertensive urgency2.
  • HetalPareshThakkar, Bindesh V Patel, Sneha P Thakkar has enhanced the bioavailability of OlmesartanMedoxomil by developing a nanosuspension. This seems to be a promising approach for bioavailability enhancement because of simple method of preparation and its universal applicability3.
  • Gupta Sachin, SrivastavShruti, VajpaiMeenakshi has compared the solubility enhancement of poorly soluble drugs by solid dispersion and inclusion complex and found that the kneading method shows the better enhancement of solubility in comparisonto the solvent evaporation and physical mixing method4.
  • P. S Mohanchandran, P. G Sindhmol, T. S Kiran has made an overview on enhancement of solubility and dissolution rate of poorly soluble drugs by various methods like physical modifications, chemical modifications, cocrystallisation, solvent deposition etc and concluded thatdissolution enhancement of poorly water soluble drugs constitute an innovative approach, which overcome the problems of solubility and dissolution rate limiting step and provide a quick onset of action5.
  • Vineet B, Vikesh S, Narendra G, Salim MD, Sharma PK have formulated and evaluated fast disintegrating sublingual tablets of AmlodipineBesylate. This is used in potential emergency treatment of angina and hypertension. The tablets were evaluated for weight variation, hardness, friability, wetting time, disintegrating time and dissolution study. The above study shows that dissolution rate of AmlodipineBesylate can be enhanced to a great extent by direct compression technique with the addition of super disintegrants6.
  • Y.Lalitha, P. K. Lakshmihas studied on enhancing the dissolution of Nifedipine by using surface solid dispersion technique. This enhancement in dissolution rate helped in providing rapid onset of drug. The sublingual administration prepared of surface solid dispersion tablet helps in bypassing the first pass effect7.
  • Sindhu Abram, Basavaraj BV, Bharath S, Deveswaran R, Sharon F, Madhavanhave formulated and optimize sublingual tablets of Rabeprazole sodium. It is a class of proton pump inhibitors used in the treatment of acid peptic disorder. In this they prepared the tablets by wet granulation method. The effect of formulation variable on wetting time and invitro dispersion time can be studied by applying optimization technique. Here super disintegrating like cross povidone, croscaremellose sodium etc.is used8.
  • Noushin B, Naghmesh H, SeyedMohsen F, Bijan S have formulated and optimize of Captopril sublingual tablet using D-optimal design. Captopril which is an effective drug in the treatment of hypertension. Here the tablets were prepared by direct compression method using different ingredients such as polyvinylpyrrolidone, starch1500, sodium starchglycolate etc. According to this study PVP has a significant effect on tablet hardness; on the other hand, fast disintegrating Captopril sublingual tablets could be achieved by using higher amount of sodium starch glycolate as well as starch 15009.
  • Saadia A Tayel, Imran I Soliman, Dina Louishas made a study to prepare sublingual tablet of antiasthmatic drug KetotifenFumarate which suffers an extensive first pass effect using fast melt granulation technique. This showed the presence of permeability enhancer polyethylene glycol, which favoured rapid uptake of drug through the buccal cavity rather than swallowing and loss by first pass effect10.
  • Dhirendra K, Lewis S, Udupa N, Atin K has made a review on solid dispersion technique to enhance solubility, dissolution and bioavailability by the use of various carriers like urea, PEG 6000, β-cyclodextrinetc and said that solid dispersion systems have been realized as extremely useful tool in improving the dissolution properties ofpoorly water soluble drugs11.
  • SuchetaBhise, DyandeviMathure, Mithun V.K Patil, Rajendra. D Patankar has made a study on enhancing the solubility of Antihypertensive agent Telmisartan using solid dispersion technique fusion method. They found that solubility of Telmisartan was increased by solid dispersion of the carriers. The solubility was found to be increased in not only water but also in fasted state and fed state simulated intestinal fluids12.
  • SunitaDahiya has made study on formulation development of a poorly soluble drug Aceclofenacby solid dispersion technique using water soluble carriers like PEG 6000 and β-cyclodextrin. She concluded thatPEG 6000 was found more effective carrier as compared to β-CD for improving the dissolutionproperties of Aceclofenac at higher ratio and the melt-solvent
    method was effective to achieve Aceclofenac: PEG 6000 binary system with good flow properties and compressibility13.
  • Tejas Patel, L D Patel, Timir Patel, Tushar Patel, Sunil Makwana has enhanced the dissolution of Fenofibrate by solid dispersion technique using PEG 6000, Poloxamer 407 and the combination of PEG 6000 and Poloxamer 407.In conclusion, physical mixtures, solid dispersions and lyophilized solid dispersions increase dissolution of Fenofibrate. Lyophilized solid dispersions of Poloxamer 407 had the maximum effect on the rate and extent of dissolution of Fenofibrate14.
  • KamalDua, M V Ramana, U V Singh Sara, M Himaja, AbhinavAgrawal, VaibhavGarg and KavitaPabrejahave investigated the enhancement of solubility ofNorfloxacin β cyclodextrin in presence of acidic solubilizing additives. This study concludes that complexation of Norfloxacin with β-cyclodextrin can enhance the dissolution rate of Norfloxacin. Dissolution rate of Norfloxacin can be enhanced further by incorporating acidic substances like ascorbic acid and citric acid into the formulations and thereby improve its bioavailability and have the potential to produce a faster onset of action15.
  • Gaurav Swami, Koshy M K, ManishaPandey, Shubhini A Saraf has prepared and characterized Domperidone by complexing with β-cyclodextrin by kneading method.The study shows that the dissolution rate of Domperidonemay be enhanced to a great extent by solid dispersion technique using kneading method16.
  • NitinMaski, ArulKumaran, KundlikGirhepunje, PrashantGhode, SurajKumarRandive, Ranju Pal has studied on preparation, characterization and solubility of β-cyclodextrin-Diacerein inclusion complexes.Diacerein is a poor water soluble drug with relatively low bioavailability. This was enhanced by inclusion complex method using β cyclodextrin17.
  • Haresh M Patel, Bhanubhai N Suhagia, Shailesh A Shah, IshwarSinhRathod, Vijay K Parmar has prepared and characterized Etoricoxib by complexing with β-cyclodextrin by kneading method.The dissolution profile of the kneaded complex (1:1 molar ratio) showed more than 75%
    drug released in 30 min. Further study is required to prepare a prompt release oral formulation of Etoricoxib by utilizing this complex18.
6.3 – Objectives of the study:
a)To enhance the solubilityof OlmesartanMedoxomilsublingual tabletsto achieve increased bioavailability and quick onset of action by solid dispersion and inclusion complex methods using various carriers.
b)To prepare sublingual tablet of OlmesartanMedoxomil.
c)To evaluate the formulated sublingual tablets.
d)To check drug excipients compatibility.
Materials and Methods:
Materials:
a)Drug : OlmesartanMedoxomil
b)Carrier : PEG 6000, β-cyclodextrin
c)Disintegrant : Croscaremellos
d)Methods:To increase the bioavailability of OlmesartanMedoxomil by solid dispersion and inclusion complex methods like fusion method, solvent evaporation method, kneading method etc using various carriers in different ratios and then preparing sublingual tablet by direct compression.
7.1 Source of data:
Review of literature from
a)Journals such as
  • International Journal of ChemTech Research
  • International Journal of Research in Pharmaceutical and Biomedical Sciences
  • International Journal of Pharmacy and Life Sciences
  • International Journal of PharmTech Research
  • Journal of Chemical and Pharmaceutical Research
  • Indian Journal of Pharmaceutical Sciences
  • International Journal of Pharmaceutical Sciences Review and Research
  • Journal of Pharmacy Research
  • International Journal of Pharmacy and Pharmaceutical Sciences
  • International Journal of Comprehensive Pharmacy
  • Iranian Journal of Pharmaceutical Research
b)Internet Browsing.
c)Laboratory based studies.
7.2 – Method of Collection of Data:
a)An Overview of sublingual Tablets.
b)Formulation of sublingual Tablets.
c)Evaluation of formulated antihypertensive sublingual tablets, as follows:
  • Drug-Excipient interaction studies4.6
  • Hardness4,6
  • Friability4,6
  • Weight variation4,6
  • Drug content4,6
  • Wetting time and Water absorption ratio4,6
  • In-vitro disintegration time4,6
  • In-vitro dissolution study4,6
  • Stability studies as per ICH guidelines
  • Drug and excipients interaction:
By F.T.I.R Spectroscopy
  • In vitro drug release study:
 USP II dissolution by paddle method
7.3 Does the study require any investigations or interventions to beconducted on patients or other humans or animals? If so, please describe briefly.
- Not applicable
7.4Has ethical clearance been obtained from your institution in case of 7.3?
-Not applicable
LIST OF REFERENCES:
  1. Neha N, Jyoti S. Sublingual mucosa as a route for systemic drug delivery. Int J PharmPharmSci 2011; 3(2):18-22.
  1. YukselGokel, SalimSatar, SaimePaydas. A comparison of the effectiveness of sublingual Losartan, sublingual Captopril and sublingual Nifedipine in hypertensive emergency. Tr. J. of Medical Sciences 1999; 29: 655-660.
  1. HetalPareshThakkar, Bindesh V Patel, Sneha P Thakkar. Development and characterization ofnano suspension of OlmesartanMedoxomil for bioavailability enhancement. Journal of Pharmacy and Bioallied Sciences 2011; 3(3):426-434.
  1. Gupta Sachin, SrivastavShruti, VajpaiMeenakshi. Comparative studyof solubility enhancement of poorly soluble drug by solid dispersion and inclusion complex. Journal of Pharmacy Research 2010; 3(4): 692-696.
  1. P. S Mohanchandran, P. G Sindhmol, T. S Kiran. Enhancement of solubility and dissolution rate. International Journal of Comprehensive Pharmacy 2010; 4(11): 01-10.
  2. Vineet B, Vikesh S, Narendra G, Salim MD, Sharma PK. Formulation and evaluation of fast disintegrating sublingual tablets of AmlodipineBesylate using different super disintegrants. Into J PharmPharmSci 2010; 2(3):89-92.
  3. Y.Lalitha, P K Lakshmi. Enhancement of dissolution of Nifedipine by surface solid dispersion technique. International Journal of Pharmacy and Pharmaceutical Sciences 2011; 3(3): 41-46.
  4. Sindhu Abram, Basavaraj BV, Bharath S, Deveswaran R, Sharon F, MadhavanV.Formulation and Optimization of Sublingual tablets of Rabeprazole Sodium. Int J PharmSci Res 2010;5(2):50-54.
  5. Noushin B, Naghmesh H, SeyedMohsen F, Bijan S. Formulation and optimization of Captopril sublingual tablet using D-optimal Design. Iranian J Pharm Res 2008;7(4):259-67.
  6. Saadia A Tayel, Imran I Soliman, Dina Louis. Formulation of KetotifenFumarate fast melt granulation sublingual tablet.AAPS PharmSciTech2010; 11(2): 679-685.
  7. Dhirendra K, Lewis S, Udupa N, Atin K. Solid dispersion: A Review. Journal of Pharm. Science;2009; 22(2);234-246.
  8. SuchetaBhise, DyandeviMathure, MithunV.KPatil, Rajendra. D Patankar. Solubility enhancement of antihypertensive agent by solid dispersion technique. International Journal of Pharmacy and Life Sciences 2011;2(8): 970-975.
  1. SunitaDahiya. Studies on formulation development of poorly water soluble drug through solid dispersion technique. Thai Journal of Pharmaceutical Sciences 2010; 34: 77-87.
  2. Tejas Patel, L D Patel, Timir Patel, Tushar Patel, Sunil Makwana. Enhancement of dissolution of Fenofibrate by solid dispersion technique. International Journal of Research and Pharmaceutical Sciences 2010; 1(2): 127-132.
  3. KamalDua, M V Ramana, U V Singh Sara, M Himaja, AbhinavAgrawal, VaibhavGarg et al. Investigation of enhancement of solubility of Norfloxacinβ-cyclodextrin in presence of acidic solubilizing additives. Current Drug Delivery 2007; 4: 21-25.
  4. GauravSwami, Koshy M K, ManishaPandey, Shubhini A Saraf. Preparation and characterization of Domperidone-β-cyclodextrin complexes prepared by kneading method. International Journal of Advances in Pharmaceutical Sciences 2010; 1: 68-74.
  5. NitinMaski, ArulKumaran, KundlikGirhepunje, PrashantGhode, SurajKumarRandive, Ranju Pal. Studies on preparation, characterization and solubility of β-cyclodextrin-Diacerein inclusion complexes. International Journal of Pharmacy and Pharmaceutical Sciences 2009; 1(2): 121-135.
  6. Haresh M Patel, Bhanubhai N Suhagia, Shailesh A Shah, IshwarSinhRathod, Vijay K Parmar. Preparation and characterization of Etoricoxib-β-cyclodextrin complexes prepared by kneading method. ActaPharma 2007; 57: 351-359.

9. / Signature of the candidate / (SUSHAN.S.SHETTY)
10. / Remarks of the Guide / The work, which is assigned to
Mr. SUSHAN.S.SHETTY is under my guidance.
11. / 11.1 Name and Designation of the
Guide / Dr.A.R. SHABARAYA M.Pharm., Ph.D.
Principal and Director,
Professor of Pharmaceutics
Srinivas College of Pharmacy
Valachil, Mangalore- 574143
11.2 Signature / (Dr. A. R. SHABARAYA)
11.3 Name and Designation of the
Co-Guide / ------
11.4 Signature / ------
11.5 Head of the Department / Dr. A. R. SHABARAYA M.Pharm.,Ph.D.
Principal and Director,
Professor of Pharmaceutics,
SrinivasCollege of Pharmacy,
Valachil, Mangalore- 574143
11.6 Signature / (Dr. A. R. SHABARAYA)
12. / 12.1 Remarks of the Principal / Recommended and forwarded for favourable consideration.
12.2 Signature / (Dr. A. R. SHABARAYA)