Enhancement of Dissolution Rate and Bioavailablity of Eprosartan Mesylate by Sold Dispersion

“ENHANCEMENT OF DISSOLUTION RATE AND BIOAVAILABLITY OF EPROSARTAN MESYLATE BY SOLD DISPERSION.”

M. PHARM DISSERTATION PROTOCOL

SUBMITTED TO THE

RAJIVGANDHIUNIVERSITY OF HEALTH

SCIENCES, BANGALORE,KARNATAKA

BY

KULAKARNI MANGESH UMESH

B.Pharm

UNDER THE GUIDANCE OF

Mr.VENKATESHJ.S.

B.Sc., M.Pharm.

PROFESSOR

P. G. DEPARTMENT OF PHARMACEUTICS

S. C. S. COLLEGE OF PHARMACY,

HARAPANAHALLI-583131

2009-10

RajivGandhiUniversity of Health Sciences,

Karnataka, Bangalore.

Annexure – II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

T. M. A. E. SOCIETY’S

ENCLOSURE: I

06. Brief resume of the intended work

6.1. Need for the study

Up to 40 percent of new chemical entities discovered by the pharmaceutical industry today are poorly soluble or lipophilic compounds. The solubility issues complicating the delivery of these new drugs also affect the delivery of many existing drugs. Poorly water-soluble drugs show unpredictable absorption, since their bioavailability depends upon dissolution in the gastrointestinal tract. The dissolution characteristics of poorly soluble drugs can be enhanced by several methods. Solid dispersion is one of the effective and widely used techniques for dissolution enhancement.1

The formulation of poorly soluble compounds for oral delivery now presents one of the most frequent and greatest challenges to formulation scientists in the pharmaceutical industry. However, the most attractive option for increasing the release rate is improvement of the solubility through formulation approaches. Although salt formation, solubilisation, and particle size reduction have commonly been used to increase dissolution rate and thereby oral absorption and bioavailability of low water soluble drugs, there is practical limitation of these techniques. In 1961, Sekiguchi and Obi developed a practical method whereby many of the limitations with the bioavailability enhancement of poorly water-soluble drugs can be overcome. This method, which was later termed solid dispersion, involved the formation of eutectic mixture of drugs with water-soluble carriers by the melting of their physical mixtures.2

Eprosartan mesylate a Angiotensin II type 1 Receptor Blockers and Antihypertensive Agent.Experimentally it is water insoluble. The bioavailability is approximately 15% with a single 300 mg oral dose. Elimination half life of the drug following oral administration is typically 5 to 9 hours.3Hence in the present study an effort will be made to improve the dissolution rate and thereby increase the bioavailability of eprosartan mesylate by solid dispersion techniques.

ENCLOSURE: II

6.2 Review of the Literature

M.M.Kamila, N.Mondal, L.K.Ghosh.4:A simple sensitive method has been developed for determination of eprosartan mesylate in raw material and experimental tablets a survey of literature revealed that uv spectrometric method for determination of drug in pharmaceutical formulations has not been reported. Currently no pharmaceutical formulation of eprosartan mesylate is available in India. Since our research involves the development and evaluation of conventional tablet formulation containing eprosartan mesylate.

Narendra Kumar, Akhilesh K Jain, et.al.5:Terbinafie HCl (poorly water soluble drug), when prepared as solid dispersion showed improved solubility and dissolution. So the main purpose of this investigation was to increase the solubility and dissolution rate of terbinafine HCl by the preparation of its solid dispersion with polyvinyl pyrrolidone K30 solvent evaporation methods. FT-IR spectra revealed no chemical incompatibility between drug and polyvinyl pyrrolidone K30. Drug –polymer interactions were investigated using differential scanning calorimetry (DSC), X-Ray Diffraction (PXRD).

Ganesh Chaulang, Piyush Patel, et.al.6: Solid dispersion of furosemide in SSG (sodium starch glycolate) was prepared in ratios of 1:1 and 1 (furosemide):2 (SSG) by kneading method. In each case, the solid dispersion was characterized by Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), and X-ray diffraction (XRD) to ascertain if there were any physicochemical interactions between drug and carrier that could affect dissolution. Tablets containing the solid dispersion were formulated and their dissolution characteristics compared with commercial furosemide tablets. XRD, DSC, FTIR spectroscopy and dissolution studies indicated that the solid dispersion formulated in 1:2 ratio showed a 5.40-fold increase in dissolution and also exhibited superior dissolution characteristics to commercial furosemide tablets.

Saurabh Bhutani, S.N.Hiremath, et.al.7:Inclusion behaviour of hydroxylproyl beta cyclodextrin was studied towords carvedilol, an antihypertensive agent in order to develop a new dosage form with enhanced dissolution rate and bioavailability following cyclodextrin complexation formation of inclusion complexes with HP beta cyclodextrin in the solid state was confirmed by DSC and FTIR and comparative studies on invitro dissolution were carried out phase solubility studies indicated formation of 1:1M complex poor HP beta cyclodextrin. Apparent stability constant was found to be 582.78M+ for HP beta cyclodextrin complexes DSC studies indicated formation of solid inclusion complexes of carvedilol –HPB cyclodextrin at 1:2 M ratio prepared by kneading method solid complex of carvedilol HP beta cyclodextrin at 1:2M prepared by physical and kneading method exhibited higher dissolution rate and dissolution efficiency value then the pure drug and other complexes.

Tanuja SaveandPadma Venkitachalam.8:Nifedipine-Polyethylene glycol solid dispersions were prepared by melting or fusion method in order to improve nifedipine solubility in the aqueous body fluids. The dissolution rate of the drug was markedly increased in these solid dispersion ratios of 1:1 and 1 (furosemide):2 (SSG) by kneading method. In each case, the solid dispersion was characterized by (FTIR) spectroscopy, (DSC), and (XRD) to ascertain if there were any physicochemical interactions between drug and carrier that could affect dissolution. Tablets containing the solid dispersion were formulated and their dissolution characteristics compared with commercial furosemide tablets. XRD, DSC, FTIR spectroscopy and dissolution studies indicated that the solid dispersion formulated in 1:2 ratio showed a 5.40-fold increase in dissolution and also exhibited superior dissolution characteristics to commercial furosemide tablets.

Ding JS, Gao R, Li D, Peng Jet.al.9: It was reported previously that rutaecarpine produced a hypotensive effect in phenol-induced and 2-kidney,1-clip hypertensive rats. However, the same dose of crude rutaecarpine did not produce significant hypotensive effects when applied to spontaneously hypertensive rats (SHR). In the present study, a different dose of rutaecarpine solid dispersion was administered intra gastrically to SHR. The systolic blood pressure was monitored by the tail-cuff method with an electro-sphygmomanometer. The plasma concentration of rutaecarpine, calcitonin gene-related peptide (CGRP) and the mRNA levels of CGRP in dorsal root ganglion were determined. The results showed that administration of the solid dispersion significantly increased the blood concentration of rutaecarpine, accompanied by significant hypotensive effects in SHR in a dose-dependent manner. It was concluded that a change of the dosage from the crude drug to solid dispersion could improve significantly the efficiency of rutaecarpine absorption and increase its plasma concentration.

Mohamed Rahamathulla, Gangadharappa H. V. et.al.10: Rofecoxib (RXB) is a potent and selective cyclo-oxygenase-2 (COX-2) inhibitor, highly effective in the treatment of various pains, inflammatory condition, post-operative pain, rheumatoid arthritis, other musculoskeletal and joint disorders. Although they are completely absorbed upon oral administration, the peak plasma concentration is reached 2-3 hours after oral ingestion. The reason for delay being slow rate of absorption due to poor aqueous solubility. An attempt has been made to enhance solubility and dissolution of rofecoxib by solid dispersion (SD) technique using various hydrophilic excipients like PEG 4000, PEG 6000, PVP at different ratios by melting method and solvent evaporation method. The prepared SD of RXB were characterized to various physico-chemical properties and in vitro drug dissolution studies. The drug dissolution was found to enhance percent in PEG 4000, PEG 6000 and PVP, after 90mins of dissolution study 79.02%, 88.02%, 98.57% respectively. On comparison of various polymers used at varied concentrations PVP at 75:25 ratio by fusion method was found to be best suitable for the enhancement of dissolution and solubility of RXB.

Sarasija Suresh, H. N. Shivakumar et.al.11:Carbamazepine was complexed with β-cyclodextrin in an attempt to enhance the solubility features of the drug. Phase solubility studies revealed a linear relationship between carbamazepine solubility and β-cyclodextrin concentration. The 3value of the stability constant (405.42 M-1) calculated from the phase solubility diagram indicated that the complexes were adequately stable. Carbamazepine-β-cyclodextrin complex prepared by kneading method was used to produce dispersible tablets. A 23 factorial design was employed to investigate the effect of factors such as amount of binder, hardness and type of disintegrant on the tablet disintegration time and dissolution rate. Type of disintegrant emerged as the main effect with the highest statistical significance affecting both the responses. Two formulations with a combination of factors within the experimental domain were developed and evaluated to validate the mathematical models. The predicted values were found to agree with the experimental values, confirming the forecasting ability of multi-linear regression and ANOVA.

Yalc in O zkan, Tamer Atay et.al.12:Inclusion complexes of gliclazide with b-cyclodextrin were prepared using different two methods: neutralization and recrystalization. Host–guest interactions were studied in the solid state by X-ray diffractometry and infrared spectroscopy. The stability constant between gliclazide and b-cyclodextrin was calculated from the phase solubility diagram. It was found that the neutralization technique and a solid complex of gliclazide with b-cyclodextrin in a molar ratio of 1.5:1 could be used to prepare the amorphous state of drug inclusion complexes. The dissolution rates of gliclazide from the inclusion complex made by neutralization were much faster than the pure drug, physical mixture of drug and cyclodextrin, recrystalization system and also comparable to the data reported in literature. Results of this report indicate that b-cyclodextrin could be useful for the solid gliclazide formulations as it may results in a more rapid and uniform release of the drug.

H.O. Ammara, H.A. Salama et.al.13: Glimepiride is one of the third generation sulfonylurea used for treatment of type 2 diabetes. Poor aqueous solubility and slow dissolution rate of the drug lead to irreproducible clinical response or therapeutic failure in some cases due to sub therapeutic plasma drug levels. Consequently, the rationale of this study was to improve the biological performance of this drug through enhancing its solubility and dissolution rate. Inclusion complexes of glimepiride in -cyclodextrin (-CyD), hydroxypropyl--cyclodextrin (HP-CyD) and sulfobutylether--cyclodextrin (SBE-CyD), with or without water soluble polymers were prepared by the kneading method. Binary systems were characterized by thermo gravimetric analysis, IR spectroscopy and X-ray diffractometry. Phase solubility diagrams revealed increase in solubility of the drug upon cyclodextrin addition. In conclusion, the association of water soluble polymers with glimepiride–CyD systems leads to great enhancement in dissolution rate, increased duration of action and improvement of therapeutic efficacy of the drug.

Mohammad Ali Dabbagh, Behzad Taghipour14: Ibuprofen solid dispersions were prepared by the solvent and fusion-solvent methods using polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), eudragit RS PO, eudragit RL PO and hydroxypropylmethylcellulose (HPMC) as carriers to improve physicochemical characteristics of ibuprofen. The prepared solid dispersions were evaluated for the flow ability, solubility characteristics and dissolution behaviour. Flow ability studies of powders showed that solid dispersion technique improve flow properties compared with the physical mixtures. Solid dispersion technique found to be effective in increasing the aqueous solubility of ibuprofen. The dissolution of ibuprofen and polymers (PVP, HPMC, eudragit and PEG-6000) were investigated using UV spectroscopy. Dissolution was carried out in phosphate buffer (pH 6.8) using a standard USP II dissolution apparatus. In vitro dissolution studies showed that in the dispersion systems containing eudragit or HPMC, dissolution of ibuprofen were retarded, which attributed to ionic interaction and gel forming, respectively. But solid dispersion containing PEG, as a carrier, gave faster dissolution rates than the physical mixtures. Finally, solid dispersion of ibuprofen:PEG 6000 prepared in 1:1.5 ratio showed excellent physicochemical characteristics and was found to be described by the zero order kinetic, and was selected as the best formulation in this study.

ENCLOSURE:III

6.3 Objectives of the study

1. To evaluate the potential of various suitable hydrophilic polymers / beta cyclodextrin, suitable drug carrier system for enhancement of dissolution and bioavailability.

2. Determine the effect of change in polymer and polymer composition and drug polymer ratio on solubility of eprosartan mesylate.

3. Study of in vitro dissolution kinetics of Eprosartan Mesylate from the formulated solid dispersion.

4. Stability study at various temperature.

ENCLOSURE: IV

7. Materials and methods.

7.1 Source of Data:

I. Review of Literature from

a. Journals - such as

• Advanced Drug Delivery Reviews.
• International Journal of Pharmaceutical Sciences.
• Journal of Pharmaceutical Sciences.
• European Journal of Pharmaceutical Science.

b. Internet Browsing.

c. CD-ROM Search.

II References from library:-

SCSCOLLEGE OF PHARMACY, HARAPANAHALLI-583131.

Textbook and standard reference books.

ENCLOSURE: V

7.2 METHOD OF COLECTION OF DATA-

PART-I:

1. Extensive literature survey.

2. Procurement of raw materials and drug.

3. Standardization of raw materials and drugs.

PART-II:

Preparation of solid dispersions using different carrier systems by physical mixture, solvent evaporation method and fusion method.

Carrier Systems Used:

1. Polyethylene glycol 6000.

2. Polyvinyl pyrrolidone.

3. Crosscarmellose sodium.

4 .Beta cyclodextrin.

PART-III: Evaluation of eprosartan Solid Dispersions:

1. Physical appearance.

2. Solubility study.

3. Drug-content uniformity.

PART-IV:

1. In vitro drug release studies.

2. Stability study.

PART-V: Statistical Analysis, Data Interpretation and Conclusions.

ENCLOSURE: VI

8. References

1)Moreshwar P. Patil, Naresh J. Gaikwad. “Preparation and characterization of gliclazide-

polyethylene glycol 4000 solid dispersions” Original research paper Acta Pharm., 2009; 59: 57–65.

2)Jani Rupal, Jani Kaushal, Setty C. Mallikarjuna,Patel Dipti“Preparation and evaluation of

solid dispersion of aceclofenac”

International Journal of Pharmaceutical Sciences and Drug Research, 2009; 1(1):32-35.

3)Ruilope L, Jäger B, Prichard B. "Eprosartan versus enalapril in elderly patients with

hypertension: a double-blind, randomized trial". Blood Press. 2001; 10(4) 223–9.

4)M. M. Kamila, N. Mondal, L. K. Ghosh“Spectrometric determination of eprosartan

mesylate in raw material and experimental tablets” Indian Journal of Chemical Technology, 2008;15:194-196.

5)Narendra Kumar, Akhilesh K Jain, Chhater Singh, Rajesh Kumar “Development,

characterization and solubility study of solid dispersion of terbinafine hydrochloride by solvent evaporation method”July-Sept 2008.,154-158

6)Ganesh Chaulang, Piyush Patel, Sharwaree Hardikar, Mukul Kelkar, Ashok Bhosale,

Sagar Bhise “Formulation and Evaluation of Solid Dispersions of Furosemide in Sodium Starch Glycolate” Tropical Journal of Pharmaceutical Research, 2009;8(1):43-51.

7)Saurabh Bhutani, S.N.Hiremath, P.V.Swamy, S.A.Raju“Preparation and Evaluation of

inclusion complexes of carvedilol “Journal of Scientific and Industrial Research, 2007; 66: 830-834.

8)Tanuja Save and Padma Venkitachalam, Drug development and Industrial Pharmacy

1992; 18:No.15, 1663-1679

9)Ding JS, Gao R, Li D, Peng J,Ran LL,Li YJ. “Solid dispersion of rutaecarpine improved

its antihypertensive effect in spontaneously hypertensive rats“Biopharm drug dispos.,2008; 29(9):495-500.

10)Mohamed Rahamath Ulla, Gangadharappa H V, Neelkant Rathod“Solubility and

dissolution improvement of rofecoxib using solid dispersion technique” Pak. J. Pharm. Sci., 2008; 21(4):350-355.

11)Sarasija Suresh, H. N. Shivkumar, and G. Kiran Kumar “Effect of beta cyclodextrin

complexation on the solubility and dissolution rate of carbamazepine from tablets.” Indian Journal of Pharmaceutical Sciences, May-June 2006;301-307

12)Yalc¸ in O zkan , Tamer Atay , Necati Dikmen , Askin Ismer , Hassan Y. Aboul-Enein

“Improvement of water solubility and in vitro dissolution rate of gliclazide by complexation with b-cyclodextrin.” Pharmaceutica Acta Helvetiae, 2000; 74: 365–370.

13)H.O. Ammar, H.A. Salama, M. Ghorab, A.A. Mahmoud “Formulation and biological

evaluation of glimepiride–cyclodextrin–polymer systems.” International Journal of Pharmaceutics, 2006; 309: 129–138.

14)Mohammad Ali Dabbagh, Behzad Taghipour. “Investigation of Solid Dispersion

Technique in Improvement of Physicochemical Characteristics of Ibuprofen Powder.” Iranian Journal of Pharmaceutical Sciences Spring, 2007; 3(2): 69-76.