Development and assessment of gastroretentive sustained release captopril tablets
- Authors: Mukozhiwa, Samantha Yolanda
- Date: 2014-04-11
- Subjects: Captopril , Drug delivery systems , Drugs Controlled release , Cardiovascular system Diseases , Cardiovascular agents , Angiotensin converting enzyme Inhibitors
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/480301 , vital:78427
- Description: Cardiovascular diseases (CVD) are the leading cause of death worldwide and global projections predict that the number of deaths due to CVD will continue to increase over the next 17 years [1]. With the growing burden of CVD the design and development of formulations that optimise the delivery of existing therapeutic molecules may be an approach to improving the management of patients with CVD. Captopril (CPT) is an angiotensin converting enzyme (ACE) inhibitor used for the routine management of hypertension, cardiac failure and diabetic nephropathy [2-4]. However it has a relatively short half-life and typical therapeutic dosing regimens require multiple dosing [2]. CPT is a potential candidate for sustained oral drug delivery, however its poor stability profile and high water solubility present significant formulation challenges. CPT exhibits optimal stability at pH < 4 and is unstable in the alkaline environment of intestinal fluids [5]. A sustained release gastroretentive formulation is therefore proposed as an approach that may improve the in vivo stability of CPT in addition to slowly releasing the molecule at a desired rate that may also minimize the occurrence of drug-related adverse effects. A Capillary Zone Electrophoresis (CZE) method for the quantitation of CPT in pharmaceutical dosage forms was developed and optimised using a Central Composite Design (CCD) approach. The CZE method was found to have the necessary linearity, accuracy, precision, sensitivity and specificity for the analysis of CPT in pharmaceutical formulations. Preformulation studies were conducted as part of the preparative work required to manufacture high quality, stable gastroretentive sustained release CPT tablets. The experiments conducted were tailored for the development of CPT sustained release tablets using direct compression manufacture and included an analysis of particle size and shape, powder flow properties and CPT-excipient compatibility studies. The results revealed that there was no definite evidence of interactions between CPT and the excipients to be used to manufacture CPT tablets, and CPT formulations were developed using these excipients. A direct compression procedure was selected for tablet manufacture due to apparent simplicity and to avoid unnecessary exposure of CPT to the heat and moisture that would be encountered if a wet granulation manufacturing process was used. A numerical optimisation approach was used to predict a formulation composition that would produce minimal CPT release initially, a short floating lag time (FLT) and maximum CPT release after 12 hours of dissolution testing. The effect of increasing the agitation speed of USP Apparatus 2 on the release of CPT from the optimised formulation was also investigated. The results revealed that changing the speed of the paddle had only a relatively small impact on the in vitro release behaviour of CPT from the tablets. The optimised formulation was subjected to additional testing in an attempt to investigate the effects of pH and osmolarity on the swelling and erosion characteristics of the dosage form. It was important to evaluate the effects of pH and osmolarity from the perspective of the solubility and stability of CPT. The results generated from swelling studies revealed that the swelling characteristics of the proposed formulation were not significantly altered by a change in pH and osmolarity of the test medium and this is probably due to the non-ionic nature of HPMC. In addition, the results revealed that the solubility and/or stability of CPT in different dissolution media did not affect the water uptake and swelling of the tablet matrices. The results revealed the erosion rate constants were low and suggest that although polymer erosion does occur, the role of this phenomenon in the release of CPT may not be as significant as that of diffusion. The release kinetics of CPT from the tablets was established by fitting in vitro release data to several mathematical models. The in vitro release data were best described using the Korsmeyer-Peppas model and values of release exponent (n) suggest that the majority of the tablets exhibited an anomalous CPT transport mechanism. The short-term stability of the optimised formulation was established by undertaking stability studies at 25°/60% RH and 40°/75% RH. The results revealed that there was no significant change in appearance and physicochemical properties of the tablets over 60 days. In conclusion, gastroretentive sustained release CPT tablets with the potential for further development and optimisation have been successfully developed and assessed in these studies. A basis is thus provided for further development of this technology. , Thesis (MSc (Pharm)) -- Faculty of Pharmacy, 2014
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Formulation and assessment of verapamil sustained release tablets
- Authors: Khamanga, Sandile Maswazi Malungelo
- Date: 2005
- Subjects: Verapamil , Tablets (Medicine) , Drugs -- Administration , Cardiovascular agents , Calcium -- Antagonists , Drugs -- Controlled release
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3869 , http://hdl.handle.net/10962/d1018236
- Description: The oral route of drug administration is most extensively used due to the obvious ease of administration. Verapamil hydrochloride is a WHO listed phenylalkylarnine, L-type calcium channel antagonist that is mainly indicated for cardiovascular disorders such as angina pectoris, supraventricular tachycardia and hypertension. Due to its relatively short half-life of approximately 4.0 hours, the formulation of a sustained-release dosage form is useful to improve patient compliance and to achieve predictable and optimized therapeutic plasma concentrations. Direct compression and wet granulation were initially used as methods for tablet manufacture. The direct compression method of manufacture produced tablets that exhibited formulation and manufacturing difficulties. Mini-tablets containing veraparnil hydrochloride were then prepared by wet granulation using Surelease® E-7-19010.and Eudragit® NE 30D as the granulating agents after which the granules were incorporated with an hydrophilic matrix material, Carbopol® 974P NF. Granule and powder blends were evaluated using the angle of repose, loose and tapped bulk density, Can's compressibility index, Hausner's ratio and drug content. Granules with good flow properties and satisfactory compressibility were used for further studies. Tablets were subjected to thickness, diameter and weight variation tests, crushing strength, tensile strength, friability and content uniformity studies. Tablets that showed acceptable pharmaco-technical properties were selected for further analysis. Drug content uniformity and dissolution release rates were determined using a validated isocratic HPLC method. Initially, USP apparatus 1 and 3 dissolution apparatus were used to determine in-vitro drug release rates from the formulations over a 22-hour period. USP apparatus 3 was finally selected as it offers the advantages of mimicking, in part, the changes in the physicochemical environment experienced by products in the gastro-intestinal tract. Differences in release rates between the test formulations and a commercially available product, Isoptin® SR were observed at different pH's using USP apparatus 1. The release of veraparnil hydrochloride from matrix tablets was pH dependent and was markedly reduced at higher pH values. This may be due, in part, to the poor solubility of veraparnil hydrochloride at these pH values and also the possible interaction of verapamil hydrochloride with anionic polymers used in these formulations. Swelling and erosion behaviour of the tablets were evaluated and differences in behaviour were observed which may be attributed to the physico-chemical characteristics of the polymers used in this study. In-vitro dissolution profiles were characterized by the difference (j1) and similarity factor (j2) and also by a new similarity factor, Sct. In addition, the mechanism of drug release from these dosage forms was mainly evaluated using the Korsmeyer-Peppas model and the kinetics of drug release assessed using other models, including Zero order, First order, Higuchi, HixsonCrowell, Weibull and the Baker-Lonsdale model. Dissolution kinetics were best described by application of the Weibull model, and the Korsmeyer-Peppas model. The release exponent, n, confirmed that drug release from these dosage forms was due to the mixed effects of diffusion and swelling and therefore, anomalous release kinetics are predominant. In conclusion, two test batches were found to be comparable to the reference product Isoptin® SR with respect to their in-vitro release profiles.
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