Madhu, S (2016) Formulation Development and Invitro Evaluation of Sustained Release Oral Dosage Forms Containing Cefixime. Masters thesis, J.K.K. Nattraja College of Pharmacy, Kumarapalayam.
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Abstract
AIM AND OBJECTIVES: The aim of the present investigation is to formulate and evaluate matrix tablets of cefixime using a mixture of polymers in view to sustain the drug release, reduce frequency of administration and improved patient compliance. The objectives of the research work undertaken are as follows: (a) To prepare sustained release matrix tablet of cefixime using different polymers. (b) To characterize developed tablets for hardness, thickness, weight variation, dimensions etc., (c) In vitro evaluation of matrix tablets by comparing with marketed products. In the present investigation, efforts were made to develop a sustained release formulation of cefixime for treatment of bacterial infection. The intended formulation was matrix tablet of cefixime, which will provide similar in vitro release profile to that of commercial marketed product. Cefixime is available as 200 mg tablets. It is also available as once daily preparation in the market and hence was a challenge to develop tablets using lesser amount of excipients and polymer, which will give advantage of cost reduction compared to the marketed product.52 The drug chosen for the present investigation is Cefixime, a cephalosporin, an orally active antibacterial agent. It is effective when given as a once-a-day dosing regimen for treating respiratory tract infection, urinary tract infection in children61, adults61-66 and otitis media in children.67 It is active against both gram-negative and gram-positive microorganisms. The acute toxicity of cefixime is comparatively low. It is stable to hydrolysis by many beta-lactamases.68 So, it is more appropriately referred to as bactericidal agent and found to be well-tolerated and safe on chronic use. On oral administration, it is absorbed throughout GI tract and absolute bioavailability of cefixime is approximately 40- 50%.68 Cefixime has 65% binding with plasma proteins. About 20% of an oral dose (or 50% of an absorbed dose) is excreted unchanged in the urine within 24 hours and upto 60% may be eliminated by nonrenal mechanisms. It has a plasma elimination half-life of 3 to 4 hours. Its daily oral dose is 0.2 to 0.4gm per day in two divided doses. Recommended dosage of conventional tablets is 2 to 3 times a day.19 SUMMARY:Conventional dosage forms, which are prompt release in nature, have been used from decades for the treatment of acute and chronic diseases. To maintain drug concentration within the therapeutically effective range, it is necessary to take these types of dosage forms several times a day and which results in the fluctuations in drug levels. Recently, several technical advancements have been made which results in new techniques for drug delivery. These techniques are capable of controlling the rate of drug delivery, sustaining the duration of therapeutic activity and/or targeting the delivery of drug to a tissue. Sustained release pharmaceutical dosage forms may offer one or more advantages over conventional (immediate release) dosage forms of the same drug. Sustained release dosage forms continue to draw attention in the search for improved patient compliance and decreased incidences of adverse drug reactions. Ideally, a sustained release dosage form will provide a therapeutic concentration of the drug in the blood that is maintained throughout the dosing interval with a reduction in a peak concentration ratio. One of the least complicated approaches is to form a tablet in which drug is embedded in matrix core of the polymer. Various types of polymers used as hydrophilic matrices and their modeling aspects have been reviewed. The objectives of the present investigation are: (a) To prepare sustained release matrix tablet of cefixime using different polymers. (b) To characterize developed tablets for hardness, thickness, weight variation, dimensions, etc., (c) In vitro evaluation of matrix tablets by comparing with marketed products. In the present investigation, efforts were made to develop an extended release formulation of cefixime for treatment many bacterial infections. The intended formulation will be matrix tablets of cefixime, which will provide similar in vitro release profile to that of marketed products which can be confirmed by calculating f1 (difference factor) and f2 (similarity factor) values. The chapter “Literature Review” contained general concepts and requirements for sustained release drug delivery system. Classification, advantages and disadvantages of oral sustained release drug delivery systems, factors influencing the design of sustained release products, design and fabrication of matrix drug delivery systems were discussed. Development of matrix tablets was discussed in details. Different types of matrix sustained release formulations were discussed with their principle of working. Extensive literature survey was done on simple matrix tablets for selection of polymer, excipients and method of manufacturing. Different methods for evaluation of performance of matrix system for independent of pH of media, and dependent on agitation intensity of releasing medium, hardness and surface area of the tablets were discussed. A detailed description about cefixime, polymer and excipients were discussed. In order to solve the objectives of this dissertation, suitable analytical method (UV Spectroscopy) was established and validated in phosphate buffer solution pH 7.2 and in 0.1 N HCl. Physical properties of cefixime like loose bulk density, tapped bulk density, compressibility index and angle of repose were determined. Tablet formulations for cefixime 400mg matrix tablets were developed and were evaluated for pharmacopoeial and nonpharmacopoeial (industry specified) tests. Polymer and concentration of polymer were optimized for matrix tablets. Tablets were prepared with different polymers like HPMC (K4, K15, K100), xanthan gum, carbopol in order to optimize one final formula for matrix tablets. Tablets were evaluated for physical and chemical properties. For matrix tablets in vitro release was carried out in 0.1 N HCl for first 2 hours followed by pH 7.2 phosphate buffer up to 24 hours using USP type I apparatus at 100 rpm. To study the effect of pH of medium on release in vitro, release studies were carried using pH change method and in phosphate buffer, pH 7.2. To study effect of agitational intensity of medium on release, in vitro release was conducted at different rpm (50, 75, and 100). To evaluate the effect of the physical properties of the tablets on release, in vitro release was conducted using different hardness tablets. Short-term accelerated stability study of optimized formulations of cefixime 400 mg matrix tablets were carried out at 40 ± 2oC and at 75 ± 5% RH for one month. The results and discussion of different methods of this thesis were described under different headings using graphs and tables. No interference due to additives in the estimation of cefixime was observed (Figure 8). Different polymers were used to get a suitable formulation of matrix tablets and finally were optimized to get optimized tablet formulations. The optimized formulation consists of xanthan gum (7.5% of total tablet weight). Tablets were evaluated for pharmacopoeial and nonpharmacopoeial (industry specified) tests and were found to be within the prescribed limits. Cefixime matrix tablets were prepared with different formulae for optimized formulations that show f1 and f2 in prescribed limits when using commercially available marketed sustained release products as reference standards. The average f1 and f2 values of optimized formulation were found to be 5.41 and 66.20 for matrix tablets respectively. The R2 = 0.9894 for the first order release (Figure 24) and for zero order release R2 = 0.9173 (Figure 23). Hence the release of cefixime from developed formulations was considered to be first order. The drug release from the matrix tablets developed in this thesis was largely found to be independent of pH of medium. The release was found to be highly dependent on the agitational intensity, and physical properties of the tablets like hardness. The Higuchi’s equation showed R2 = 0.9948 (Figure 25) and also when the data was fitted in to Korsmeyer et al equation it showed R2 = 0.9978 with slope (n) value of 0.4 (Figure 26) which is less than 0.5. Thus, diffusion of the drug was the main mechanism for drug release for the optimized formulation. Manufacturing procedure was found to be reproducible and formulation was found to be stable for one month under accelerated stability condition. The conclusions drawn from the present investigation were given below 1. Suitable analytical method based on UV-Visible spectrophotometer was developed for cefixime. lmax of 288 nm and 285 nm was identified in phosphate buffer pH 6.8 , and 0.1 N HCl solution respectively. 2. Procedure to manufacture matrix tablets by direct compression was established. 3. Matrix tablets of cefixime (F-X) were successfully prepared using xanthan gum by direct compression method. 4. The tablets were evaluated for pharmacopoeial and non-pharmacopoeial (industry specified) tests. Based on the results, F-X was identified as better formulation amongst all formulations for matrix tablets. 5. Tablets of F-X passed all official and unofficial quality control tests. Drug release from the developed formulation follows first- order kinetics. 6. In vitro release profiles of optimized formulations of cefixime matrix tablets (F-X) was found to be similar to that of commercial marketed product. The average f1 and f2 values were found to be 5.41 and 66.20 for matrix tablets respectively. Thus, the objectives of the thesis are achieved.CONCLUSION: The conclusions drawn from the present investigation were given below : 1. Suitable analytical method based on UV-Visible spectrophotometer was developed for cefixime. lmax of 288 nm and 285 nm was identified in phosphate buffer pH 6.8 , and 0.1 N HCl solution, respectively. 2. Procedure to manufacture matrix tablets by direct compression was established. 3. Matrix tablets of cefixime (F-X) were successfully prepared using xanthan gum by direct compression method. 4. The tablets were evaluated for pharmacopoeial and non-pharmacopoeial (industry specified) tests. Based on the results, F-X was identified as better formulation amongst all formulations for matrix tablets. 5. Cefixime release from the developed matrix tablets has been observed to decrease at the amount of polymer increases in the tablets. 6. Cefixime release from the matrix tablets was independent of pH of the dissolution medium, assuring the release to be fairly independent of pH of the GIT. 7. Cefixime release from the matrix tablet was inversely proportional to the agitational intensity of the dissolution medium. 8. Cefixime release from the matrix tablet was inversely proportional to the hardness of tablets, confirms physical properties of tablets contributes for mechanism for drug release. 9. Tablets of F-X passed all official and unofficial quality control tests. Drug release from the developed formulation follows first- order kinetics. 10. The manufacturing procedure was standardized and found to be reproducible. 11. After one month accelerated stability developed formulations were found to be stable. 12. In vitro release profiles of optimized formulations of cefixime matrix tablets (F-X) by using Xantham gum was found to be similar to that of commercial marketed product. The average f1 and f2 values were found to be 5.41 and 66.20 for matrix tablets respectively. The conclusions arrived in this thesis indicated that the sustained release formulations of cefixime trihydrate developed in this investigation was found to be equivalent to commercial market product, based on in vitro release studies. Thus the objectives envisaged in this thesis were achieved. Further studies are needed to investigate these formulations for its performance in vivo and its bioequivalence with the available commercial products.
| Item Type: | Thesis (Masters) |
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| Uncontrolled Keywords: | Formulation Development ; Invitro Evaluation ; Sustained Release Oral Dosage Forms ; Cefixime |
| Subjects: | PHARMACY > Pharmaceutics |
| Depositing User: | Ravindran C |
| Date Deposited: | 20 Dec 2017 07:03 |
| Last Modified: | 20 Dec 2017 07:03 |
| URI: | http://repository-tnmgrmu.ac.in/id/eprint/4530 |
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