“FORMULATION AND EVALUATION OF SUSTAINED RELEASE …
“FORMULATION AND EVALUATION OF FAST DISSOLVING TABLETS OF LOSARTAN POTASSIUM”
DISSERTATION PROTOCOL
SUBMITTED TO
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
BANGALORE, KARNATAKA.
BY
SHAILAJA.C.JOGUR
I Year M. PHARM,
DEPARTMENT OF PHARMACEUTICS,
NARGUND COLLEGE OF PHARMACY,
BANGALORE- 85. KARNATAKA.
(2010-2012)
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
BANGALORE, KARNATAKA.
ANNEXURE – II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR pg DISSERTATION
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|1. |Name of the Candidate & Address (In |SHAILAJA.C.JOGUR |
| |block letters) |NARGUND COLLEGE OF PHARMACY, |
| | |DATTATREYA NAGAR,2nd main, |
| | |100 ft ring road,BSK 3rd stage |
| | |BANGALORE-560085 |
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|2. |Name of the |NARGUND COLLEGE OF PHARMACY, |
| |Institution |DATTATREYA NAGAR,2nd main, |
| | |100 ft ring road,BSK 3rd stage |
| | |BANGALORE-560085 |
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|3. |Course of Study and Subject |Master of pharmacy in |
| | |pharmaceutics |
| | |7thJULY 2010 |
|4. |Date of Admission to Course | |
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|5. |Title of the Topic |“FORMULATION AND EVALUATION OF FAST DISSOLVING TABLETS OF LOSARTAN POTASSIUM” |
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|6 |BRIEF RESUME OF THE INTENDED WORK |
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| |6.1 NEED FOR THE STUDY |
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| |Oral drug administration has been one of the most convenient and widely accepted delivery system for most therapeutic drugs. Various dosage forms like |
| |tablets, capsules, liquid preparation has been given by oral route. But, due to some unfavorable physiological environment of the gastro-intestinal |
| |tract like relatively poor absorption, presence of various digestive enzymes of the gastro-intestinal lumen and epithelium, poor absorption efflux (i.e. |
| |by P-glycoprotein, etc.) and first pass metabolism by hepatic enzymes oral route has limited scope for some drugs. Also, it limits many drugs to reach |
| |into the therapeutic level. Difficulty in swallowing is experienced by patient such as pediatric, geriatric, bedridden, disabled and mentally ill, |
| |including motion sickness and sudden episodes of allergic attacks, hence resulting in higher incidence of non-compliance and ineffective therapy. |
| |To improve the quality of life, to minimize the problems associated with drug- absorption through gastro-intestinal membrane and treatment compliances of|
| |such patients, intraoral drug delivery systems that will enhance the therapeutic drug level, avoids first-pass and gut-wall metabolism, increases the |
| |bioavailability of active medicament or improve convenience of dosing is a better alternative for oral medication. The target sites for local drug |
| |delivery in the oral cavity include the following: buccal, sublingual, periodontal region, tongue and gum. Within the oral cavity, delivery of drugs via |
| |the buccal mucosal membranes is convenient. |
| |Thus to overcome drawbacks, fast dissolving tablets (FDT) or orally disintegrating tablets emerged as alternative oral dosage forms. These are novel |
| |types; of tablets that disintegrate/dissolve /disperse in saliva within few seconds. Fast dissolving drug delivery system, in most cases, is a tablet |
| |that dissolves or disintegrates in the oral cavity without the need of water or chewing. These tablets are also called as melt-in-mouth tablet, |
| |repimelts, porous tablet, oro-dispersible, quick dissolving or rapid disintegrating tablets. |
| |The basic approach used in development of FDT is the use of superdisintegrants like Cross linked carboxymelhylcellulose (Croscarmellose), Sodium starch |
| |glycolate (Primogel, Explotab). Polyvinylpyrrolidone (Polyplasdone) etc. which provide instantaneous disintegration of tablet after putting on tongue, |
| |thereby releasing the drug in saliva. The bioavailability of some drugs may be |
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| |increased due to absorption of drugs in oral cavity and also due to pregastric absorption of saliva containing dispersed drugs that pass down into the |
| |stomach. Moreover, the amount of drug that is subject to first pass metabolism is reduced as compared to standard tablets. |
| |Recent advance in novel drug delivery system aims to enhance the safety and efficacy of the drug molecule by formulating a dosage form being for the |
| |administration. So designing fast dissolving tablets is one of approach to enhance the onset of action of antihypertensive drugs. As the patients with |
| |sudden increase blood pressure, have markedly reduced function ability and extremely restless, in such cases rapid onset of action is of prime |
| |importance. So the patients would be benefited from acute treatment by using proposed drug delivery system. This may help them to return to normal state |
| |and resume their functional activities. Some of the angiotensin-II receptor antagonists are Valsartan, Irbesartan, Olmesartan, Telmisartan etc. |
| |Losartan Potassium is an Antihypertensive drug (angiotensin II receptor (type AT1) antagonist). |
| |It suppresses the effects of angiotensin II at its receptors, thereby blocking the rennin‐ angiotensin system. The rennin‐angiotensin system plays a |
| |crucial role in the control of blood pressure, and in particular it is felt to play crucial role in hypertension. Losartan has been demonstrated to be |
| |superior to previous peptide receptor antagonists and angiotensin converting enzyme (ACE) inhibitors because of its enhanced specificity, selectively, |
| |and tolerability. Generally, losartan potassium is employed in the management of essential hypertension with lower incidence of side‐effects like cough. |
| |It is readily absorbed and undergoes rapid hepatic metabolism to an active metabolite, EXP‐3174, via cytochrome P‐450 system. |
| |The molecular weight of losartan potassium is 461.01. It is freely soluble in water and soluble in alcohols. It has low bioavailability due to its first |
| |pass metabolism. Systemic bioavailability is about 33%. Thus the purpose of this research project is to formulate and evaluate fast dissolving tablets of|
| |losartan potassium for rapid dissolution of drug and absorption, which may produce the rapid onset of action in the treatment of hypertension. |
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| |6.2 REVIEW OF LITERATURE |
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| |Rahul G et al., presented a complete overview on the fast dissolving tablets. Pediatric and geriatric patients find it difficult to swallow solid dosage |
| |forms like tablets. Mouth dissolving tablet that dissolve or disintegrate rapidly in oral cavity result in solution, is an ultimate remedy for this |
| |problem. MDTs have advantages such as patient compliance, quick onset of action, improved bioavailability, etc. Therefore, mouth dissolving tablets are |
| |attractive alternative to liquid and conventional tablet dosage forms.1 |
| |Shailesh S. has given a complete overview on the conventional techniques used for the formulation of fast dissolving tablets. Such as disintegrant |
| |addition, freeze drying, molding, sublimation etc.2 |
| |Suhas MK et al., designed mouth dissolving tablets of Losartan potassium to provide a quick onset of action. Mouth dissolving tablets prepared by direct |
| |compression and using super disintegrants like Polyplasdone XL 10, Croscarmellose sodium and Explotab in different concentration and evaluated for the |
| |pre & post-compression parameters. The prepared batches of tablets were evaluated for hardness, weight variation, friability, drug con-tent, |
| |disintegration time and in-vitro dissolution profile and found satisfactory.3 |
| |Shailesh S et al., formulated & evaluated mouth dissolving Losartan potassium tablets by co-processing. Co-processing excipients like Ac-di-Sol and |
| |Crospovidone were used as direct compressible excipients in mouth dissolving tablet formulation. A decrease in disintegration time and wetting time was |
| |noted with tablet prepared by processed superdisintegrants when compared with tablet formulated using Ac-di-sol, Crospovidone alone; however there was no|
| |significant change in tablet hardness and percent friability.4 |
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| |Debjit B et al., prepared fast dissolving tablets of Telmisartan by using super disintegrants– Crospovidone, Ac-di-sol and sodium starch glycolate, |
| |level of addition to increase the rate of drug release from dosage form to increase the dissolution rate and hence its bioavailability. The tablets were |
| |prepared by direct compression method. The disintegration time of fast dissolving tablets were increased by the addition of concentration of |
| |superdisintegrants.5 |
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| |Jain CP et al., investigated fast dissolving tablets of Valsartan using different superdisintegrants by direct compression method. Fast dissolving |
| |tablets were evaluated for physicochemical properties and in vitro dissolution. Wetting time of formulations containing Crospovidone was least and |
| |tablets showed fastest disintegration. The drug release from fast dissolving tablets increased with increasing concentration of superdisintegrants and |
| |was found to be highest with formulations containing Crospovidone.6 |
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| |Vasanthakumar S et al., have been made an attempt to prepare immediate release tablets of Telmisartan by using Polyplasdone XL-10 (Crospovidone) at |
| |intragranular, extragranular and partly intra and extragranular level of addition to increase the rate of drug release from dosage form to increase the |
| |dissolution rate and hence its bioavailability. The prepared granules and tablets were evaluated for their physiochemical properties and in-vitro |
| |dissolution study was conducted for the prepared tablets. It was concluded that the immediate release tablets with proper hardness, disintegration time |
| |and with increase rate of dissolution can be made using Polyplasdone XL-10.7 |
| |Kothawade SN et al., shown that solubility of drug also affect the dissolution profile. In the present investigation, an attempt was made to improve the |
| |solubility and dissolution rate of a poorly soluble drug; Telmisartan solid dispersions were prepared using polyvinyl pyrrolidone (PVP), Polyethylene |
| |glycol-1500 (PEG-1500) and Polyethylene glycol-4000(PEG-4000) to increase its aqueous solubility. Telmisartan solid dispersions were prepared using |
| |solvent evaporation method. The formulations were characterized for solubility parameters, drug content studies, drug release studies and drug-polymer |
| |interactions by using FTIR spectrum. Formulation containing 1:2 ratio of drug: PEG-4000 showed the best release |
| |with a cumulative release of 99.49% as compared to 35.82 % for the pure drug. The interaction studies showed no interaction between the drug and polymer.|
| |It was concluded that PEG-4000 as a carrier can be very well utilized to improve the solubility of poorly soluble drugs.8 |
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| |Howida KI et al., have been developed Valsartan orodispersible tablets of 40-mg dose. Work started with selecting drug compatible excipients depending on|
| |differential scanning calorimetric analysis. A 33 full 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. The different tablet formulas were characterized |
| |for their physical properties, weight variation, disintegration time, surface properties, wetting properties, and in vitro dissolution. Oral |
| |bioavailability of two 40 mg Valsartan orodispersible tablets was higher than that of the conventional tablets.9 |
| |Mehdi A et al., have given Derivative Spectrophotometric Method for determination of Losartan in Pharmaceutical Formulations. A first derivative UV |
| |spectroscopic method was developed for determination of Losartan in the tablet dosage form. The first derivative spectrum recorded between 220 and 320 |
| |nm, and a zero-crossing technique for first derivative measurement at 232.5 nm was selected. It was found that the selectivity and sensitivity of method |
| |to be in desirable range. In comparison with the direct UV method, the first derivative UV spectroscopy has a definite through without any interference |
| |from UV absorbing excipients. This method is also fast and economical in comparison to the more time consuming HPLC.10 |
| |Behera AK et al., their investigation highlighted that formulation and optimization of Losartan potassium tablets. To achieve this goal, various |
| |formulations of Losartan potassium tablets were prepared and evaluated with respect to the various quality parameters both in process parameters for |
| |granules and parameters for finished products. On the basis of these parameters, the formula was optimized and compared with the innovator. It was |
| |observed that the optimized Losartan potassium tablets were pharmaceutically equivalent with the innovator. The stability of optimized tablets at various|
| |atmospheric conditions was done and stability parameters were satisfactory. It was observed that the optimized Losartan potassium tablets were |
| |pharmaceutically equivalent with the innovator tablet (U.S. market product). Again, the optimized Losartan potassium tablet may provide immediate release|
| |of drug than the innovator brand.11 |
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| |6.3 OBJECTIVE OF STUDY |
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| |The purpose of this research project is to prepare fast dissolving tablets containing Losartan Potassium .The work will be scheduled as: |
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| |Step Ι: To develop suitable analytical method for the estimation of the drugs. |
| |Step ΙΙ: Preformulation studies, drug-excipient compatibility studies for selection of excipients. |
| |Step ΙΙΙ: To evaluate the powder mix for precompression characteristic and tableting characteristics. |
| |Step IV: To compress the formulation according to compatibility study. |
| |Step V: Evaluation of the prepared formulation by different physicochemical characterization studies such as General appearance, Size & Shape, Uniformity|
| |of weight, Wetting time, Disintegrating time, Weight variation, Thickness, Hardness, Friability, |
| |Drug content & In vitro studies etc. |
| |Step VI: Best formulation will be subjected for stability studies as per ICH guidelines. |
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| |MATERIALS AND METHODS |
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| |Source of data |
| |1. Library and e-library of Nargund college of pharmacy. |
| |2. RGUHS Library, Bangalore. |
| |3. International Pharmaceutical abstracts etc. |
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| |A. Journals & articles |
| |International Journal of Research Pharma Science. |
| |International Journal of Pharmaceutical & Biological Archieves 2010. |
| |International Journal of Pharma Recent Research. |
| |International Journal of Pharmacy & Pharmaceutical Science. |
| |International Journal of PharmaTech Research. |
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| |AAPS PharmSciTech. |
| |Iranian Journal of Pharmacology & Therapeutics. |
| |International Journal of Applied Pharmaceutics. |
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| |B. Internet Browsing |
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| |ijrps.iums.ac.ir |
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| |C. Text books |
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| |Rowe RC, Sheskey PJ and Owen SC. Hand book of pharmaceutical |
| |Excipients. 5th ed. |
| |Banker GS and Rhodes CT. Modern pharmaceutics. |
| |4th ed. Revised and Expanded. |
| |Lieberman HA, Lachman L and Schwartz JB. Pharmaceutical dosage |
| |Forms. Tablets volume 1, 2 & 3. |
| |Goodman & Gilmann. Pharmacological Basics of Therapeutics. |
| |Tripathi KD. Essentials of Medical of pharmacology. 6th Ed. |
| |Lachman L, Lieberman HA and Kanig JL. The theory and practice of Industrial Pharmacy. 3rd Ed. |
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| |7.2. Materials |
| |1) Drug-Losartan potassium |
| |2) Super disintegrants- Sodium starch glycolate, Crospovidone, Croscarmellose sodium, |
| |Polyplasdone XL-10, Explotab, Acrylic acid derivatives, Ac-di-sol, Sodium alginate, L-HPC, |
| |etc. |
| |3) Polymers-HPMC (Hydroxy Propyl Methyl Cellulose), CMC (Carboxy Methyl Cellulose), MCC |
| |(Micro Crystalline Cellulose),Poly vinyl pyrrolidene(PVP) etc. |
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| |4) Permeation Enhancer-Sodium Lauryl Sulfate etc. |
| |5) Binders-Different grades of Poly Ethylene Glycols like PEG-4000, PEG-1500 & PEG-6000 etc. |
| |6) Sweetners- Mannitol, Sorbitol, Glycerin, Sodium saccharin etc. |
| |7) Flavors- Menthol, Lemon oil, Mint etc. |
| |8) Colouring Agents- Sunset Yellow, Orange etc. |
| |9) Other Additives-Talc, Lactose, Dextrose, Magnesium stearatte etc. |
| |10) Chemicals- Isopropyl alcohol, Dichloromethane, Acetonitrile, Potassium dihydrogen phosphate |
| |etc. |
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| |Methods |
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| |Some conventional techniques used for the formulation of fast dissolving tablets. |
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| |1) Freeze drying |
| |2) Molding |
| |3) Sublimation |
| |4) Spray drying |
| |5) Direct compression |
| |6 ) Melt granulation |
| |7) Phase transition process |
| |8) Melt extrusion method |
| |9) Cotton candy process |
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| |Methods of collection of data |
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| |The formulation evaluated for the compatibility studies using DSC techniques and thermal analysis. |
| |Formulation development and evaluation. |
| |Pre & Post-compression and in-vitro dissolution studies for the developed formulation. |
| |UV Spectrophotometery, HPLC method for the estimation of drug and for analysis of in-vitro dissolution samples. |
| |Statistical analysis of all the results. |
| |Stability studies. |
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| |Does the study require any investigation or intervention to be conducted on patients or other humans or animals? If so please describe briefly. |
| |- No - |
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| |Has ethical clearance been obtained from your institution in case of 7.3? |
| |-Not applicable- |
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| |LIST OF REFERENCES: |
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| |1) Rahul G, Dhanykumar D.C, Dhanjay G. S, Rohit S. R, Fast Dissolving Tablets: An Overview. |
| |. 2010 June 9; 8(2). |
| |2) Shailesh S, New Generation of Tablet: Fast Dissolving Tablet. . 2008 Jan 29; |
| |6(1). |
| |3) Suhas K. M, Vinodh M.S, Ketan R.B, Ayaz D.A, Chirag N.V, Avinash B, Formulation and |
| |evaluation of mouth dissolving tablets of losartan potassium by direct compression techniques. |
| |International Journal of Research Pharma Science. 2010; 1(3): 290-5. |
| |4) Shailesh S, Puneet B, Gupta G.D, Formulation, Evaluation & Optimization of Mouth Dissolving |
| |Tablets of Losartan Potassium: Effect of Co-processed Superdisintegrants. International Journal |
| |Of Pharmaceutical & Biological Archives. 2010; 1(1): 76-83. |
| |5) Debjit B, Jayakar B, Sampathkumar.K, Design And Characterization of Fast Dissolving Tablet |
| |of Telmisartan. International Journal of Pharma Recent Research. 2009; 1(1): 31-40. |
| |6) Jain C.P. And Naruka P.S, Formulation And Evaluation Of Fast Dissolving Tablets Of |
| |Valsartan. Indian Journal Of Pharmacy & Pharmaceutical Science.2009 July-Sep; 1(1). |
| |7) Vasanthakumar S, Vijaya R. C, Immediate Release Tablets of Telmisartan Using |
| |Superdisintegrants-formulation, Evaluation and Stability Studies. Pharmaceutical Society Of |
| |Japan, Chem. Pharm. Bull. 2008 Jan 8; 56(4): 575—7. |
| |8) Kothawade S. N, Kadam N. R, Ar agade P. D, Baheti D. G. Formulation And Characterization |
| |Of Telmisartan Solid Dispersions. International Journal of PharmTech Research. 2010 Jan-Mar; |
| |2 (1): 341-7. |
| |9) Howida K.I and Doaa A. El-Setouhy, Valsartan Orodispersible Tablets: Formulation, In vitro/In |
| |vivo Characterization. AAPS PharmSciTech. 2010 March; l 1.(1). |
| |10) Mehdi A, Maryamkazemipour, Mehdi B, Hassan A.J, Derivative Spectrophotometric Method |
| |for determination of Losartan in Pharmaceutical Formulations. Iranian Journal Of |
| |Pharmacology & Therapeutics, 2004 June 1. |
| |11) Behera A. K, Nayak A. K, Mohanty B. R , Barik B. B, Development And Optimization Of |
| |Losartan Potassium Tablets. International Journal of Applied Pharmaceutics. 2010 Feb 21; |
| |2(2). |
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|9. |Signature of the candidate | |
| | | |
| | |(SHAILAJA.C.JOGUR) |
|10. |REMARKS OF THE GUIDE |RECOMMENDED FOR DISSERTATION WORK. |
| | | |
|11. |NAME AND DESIGNATION OF | |
| 11.1 | GUIDE |PREETI KARWA |
| | |ASST.PROFESSOR |
| | |DEPT. OF PHARMACEUTICS |
| | |NARGUND COLLEGE OF PHARMACY |
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|11.2 |SIGNATURE | |
|11.3 |CO-GUIDE |P.PARIMALA |
| | |SR.MANAGER |
| | |KARNATAKA ANTIBIOTICS & |
| | |PHARMACEUTICALS LIMITED. |
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| |SIGNATURE | |
| |11.4 HEAD OF THE DEPT. |Dr. CSR LAKSHMI |
| | |PROFESSOR AND HEAD |
| | |DEPT. OF PHARMACEUTICS |
| | |NARGUND COLLEGE OF PHARMACY, |
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| |SIGNATURE | |
|12. |REMARKS OF THE PRINCIPAL | FORWARDED AND RECOMMENDED FOR |
| | |FAVORABLE CONSIDERATION. |
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| |SIGNATURE | |
| | |(D.S.PURANIK) |
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