Preparation, characterization and optimization of carbamazepine based pellets prepared by extrusion-spheronization technique
- Authors: Makoni, Kudzai Gabriella
- Date: 2020-04
- Subjects: Carbamazepine , Pharmacokinetics , Anticonvulsants , Drugs -- Controlled release , Drugs -- Dosage forms , Tablets (Medicine) , Drugs -- Administration , High performance liquid chromatography , International Conference on Harmonisation , Experimental design
- Language: English
- Type: Thesis , Masters , MSc (Pharmacy)
- Identifier: http://hdl.handle.net/10962/140478 , vital:37893
- Description: Carbamazepine (CBZ) is an oral antiepileptic drug (AED) that is prescribed as a first-line treatment for partial seizures. CBZ is a class II compound according to the Biopharmaceutical Classification System (BCS), hence it exhibits low aqueous solubility and high gastrointestinal tract (GIT) permeability...
- Full Text:
- Date Issued: 2020-04
- Authors: Makoni, Kudzai Gabriella
- Date: 2020-04
- Subjects: Carbamazepine , Pharmacokinetics , Anticonvulsants , Drugs -- Controlled release , Drugs -- Dosage forms , Tablets (Medicine) , Drugs -- Administration , High performance liquid chromatography , International Conference on Harmonisation , Experimental design
- Language: English
- Type: Thesis , Masters , MSc (Pharmacy)
- Identifier: http://hdl.handle.net/10962/140478 , vital:37893
- Description: Carbamazepine (CBZ) is an oral antiepileptic drug (AED) that is prescribed as a first-line treatment for partial seizures. CBZ is a class II compound according to the Biopharmaceutical Classification System (BCS), hence it exhibits low aqueous solubility and high gastrointestinal tract (GIT) permeability...
- Full Text:
- Date Issued: 2020-04
Development and assessment of minocycline sustained release capsule formulations
- Sachikonye, Tinotenda Chipo Victoria
- Authors: Sachikonye, Tinotenda Chipo Victoria
- Date: 2010
- Subjects: Drugs -- Controlled release , Drugs -- Dosage forms , Capsules (Pharmacy) , Drugs -- Administration , Acne -- Treatment , Tetracyclines , Antibiotics -- Side effects
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3854 , http://hdl.handle.net/10962/d1013127
- Description: The use of minocycline for the treatment of a broad range of systemic infections and for severe acne has been associated with vestibular side effects. The severity of side effects may lead to poor adherence to therapy by patients. The use of sustained release formulations of minocycline that display slow dissolution of minocycline following administration may be beneficial in reducing the incidence and severity of side effects. Therefore, sustained release capsule dosage forms containing 100 mg minocycline (base) were manufactured and assessed for use as sustained release oral dosage forms of minocycline. Minocycline sustained release capsules were manufactured based on matrix technologies using hydroxypropylmethyl cellulose (HPMC) and Compritol® as release retarding polymers. The rate and extent of minocycline release from the capsules was evaluated using USP Apparatus 1 and samples were analysed using a validated High Performance Liquid Chromatographic (HPLC) method with ultraviolet (UV) detection. Differences in the rate and extent of minocycline release from formulations manufactured using HPMC or Compritol® were influenced by the concentration of polymer used in the formulations. The rate and extent of minocycline release was faster and greater when low concentrations of polymer were used in formulations. The effect of different excipients on the release pattern(s) of minocycline and particularly their potential to optimise minocycline release from experimental formulations was investigated. The use of diluents such as lactose and microcrystalline cellulose (MCC) revealed that lactose facilitated minocycline release when HPMC was used as the polymer matrix. In contrast, the use of lactose as diluent resulted in slower release of minocycline from Compritol® based formulations. The addition of sodium starch glycolate to HPMC based formulations resulted in slower release of minocycline than when no sodium starch glycolate was used. Compritol® based formulations were observed to release minocycline faster following addition of sodium starch glycolate and Poloxamer 188 to experimental formulations. In vitro dissolution profiles were compared to a target or reference profile using the difference and similarity factors, ƒ1 and ƒ2 , and a one way analysis of variance (ANOVA). In addition, the mechanism of minocycline release was elucidated following fitting of dissolution data to the Korsmeyer-Peppas, Higuchi and Zero order models. Minocycline release kinetics were best described by the Korsmeyer-Peppas model and the values of the release exponent, n (italics), revealed that drug release was a result of the combined effects of minocycline diffusion through matrices and erosion of the matrices. These in vitro dissolution profiles were better fit to the Higuchi model than to the Zero order model. Two formulations that displayed a fit to the Zero order model were identified for further studies as potential dosage forms for sustained release minocycline.
- Full Text:
- Date Issued: 2010
- Authors: Sachikonye, Tinotenda Chipo Victoria
- Date: 2010
- Subjects: Drugs -- Controlled release , Drugs -- Dosage forms , Capsules (Pharmacy) , Drugs -- Administration , Acne -- Treatment , Tetracyclines , Antibiotics -- Side effects
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3854 , http://hdl.handle.net/10962/d1013127
- Description: The use of minocycline for the treatment of a broad range of systemic infections and for severe acne has been associated with vestibular side effects. The severity of side effects may lead to poor adherence to therapy by patients. The use of sustained release formulations of minocycline that display slow dissolution of minocycline following administration may be beneficial in reducing the incidence and severity of side effects. Therefore, sustained release capsule dosage forms containing 100 mg minocycline (base) were manufactured and assessed for use as sustained release oral dosage forms of minocycline. Minocycline sustained release capsules were manufactured based on matrix technologies using hydroxypropylmethyl cellulose (HPMC) and Compritol® as release retarding polymers. The rate and extent of minocycline release from the capsules was evaluated using USP Apparatus 1 and samples were analysed using a validated High Performance Liquid Chromatographic (HPLC) method with ultraviolet (UV) detection. Differences in the rate and extent of minocycline release from formulations manufactured using HPMC or Compritol® were influenced by the concentration of polymer used in the formulations. The rate and extent of minocycline release was faster and greater when low concentrations of polymer were used in formulations. The effect of different excipients on the release pattern(s) of minocycline and particularly their potential to optimise minocycline release from experimental formulations was investigated. The use of diluents such as lactose and microcrystalline cellulose (MCC) revealed that lactose facilitated minocycline release when HPMC was used as the polymer matrix. In contrast, the use of lactose as diluent resulted in slower release of minocycline from Compritol® based formulations. The addition of sodium starch glycolate to HPMC based formulations resulted in slower release of minocycline than when no sodium starch glycolate was used. Compritol® based formulations were observed to release minocycline faster following addition of sodium starch glycolate and Poloxamer 188 to experimental formulations. In vitro dissolution profiles were compared to a target or reference profile using the difference and similarity factors, ƒ1 and ƒ2 , and a one way analysis of variance (ANOVA). In addition, the mechanism of minocycline release was elucidated following fitting of dissolution data to the Korsmeyer-Peppas, Higuchi and Zero order models. Minocycline release kinetics were best described by the Korsmeyer-Peppas model and the values of the release exponent, n (italics), revealed that drug release was a result of the combined effects of minocycline diffusion through matrices and erosion of the matrices. These in vitro dissolution profiles were better fit to the Higuchi model than to the Zero order model. Two formulations that displayed a fit to the Zero order model were identified for further studies as potential dosage forms for sustained release minocycline.
- Full Text:
- Date Issued: 2010
The evaluation of indomethacin and theophylline oral controlled/modified-release dosage forms in vitro-in vivo correlations
- Tandt, Ludo Alfons Germaan Luc
- Authors: Tandt, Ludo Alfons Germaan Luc
- Date: 1992
- Subjects: Theophylline , Indomethacin , Drugs -- Controlled release , Drugs -- Dosage forms
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3794 , http://hdl.handle.net/10962/d1003272 , Theophylline , Indomethacin , Drugs -- Controlled release , Drugs -- Dosage forms
- Description: Over the past few decades many researchers have investigated the utility of in vitro - in vivo correlations for the assessment of dosage forms. These investigations are, however, dependent on reproducible dissolution data and well conducted biostudies in order to establish meaningful and robust correlations. Despite the fact that the establishment of such correlations is perhaps idealistic, considerable interest has still been shown in this area of research. Various Controlled/Modified Release Dosage Forms (CMRD's) of theophylline, a weakly basic drug, and indomethacin, a weakly acidic drug, were assessed in order to establish in vitro - in vivo correlations. Dissolution rate studies were carried out using either the USP basket or paddle apparatus. The dissolution rate studies were conducted in a range of dissolution media of varying pH. Bioavailability studies were conducted on the dosage forms used by the Biopharmaceutics Research Institute at Rhodes University. The results of these biostudies were kindly made available for use in this research project. Type A correlations were established using a mathematical simulation process whereby expected in vivo responses are simulated and compared to actual profiles obtained for the dosage forms. In order to perform the simulations the dissolution rate profiles were stripped and using linear regression and the methods of residuals the dissolution rate order and the relevant dissolution rates were obtained. The results of the s imulations indicated that the in vivo serum concentration-time curves could be accurately predicted for the theophylline dosage forms but to a lesser extent, for the indomethacin formulations. The dissolution rate studies indicated that the paddle method is a suitable method for dissolution rate studies of theophylline CMRD's, although it appeared that the optimum pH of the dissolution medium was formulation dependent. Dissolution rate studies conducted on indomethacin formulations indicated that the USP specified basket method for extended-release indomethacin formulations was not able to distinguish between two formulations which exhibited different in vivo profiles. The conversion to the paddle method was, however, able to highlight the differences between these formulations. The use of three dimensional topographs to depict dissolution rate profiles was demonstrated for formulations of both theophylline and indomethacin. The topographs enabled the successful differentiation between bioinequivalent formulations. The dissolution rate profiles were also fitted to the Wei bull equation and the parameters obtained from this were compared to the Weibull parameters obtained from the in vivo absorption plots obtained using the Wagner-Nelson method. The results indicated that the Weibull function was suitable to describe both the in vivo and in vitro data. The following recommendations for the preformulation dissolution studies of weakly acidic and weakly basic drugs are proposed. The dissolution rate studies of weakly acid drugs, such as indomethacin, should be carried out over a range of pH utilising the paddle apparatus. Three dimensional topographs based on the dissolution data should be constructed and used as a comparative tool for different formulations. Based on these comparisons the appropriate formulation can then be selected for a pilot scale in vivo bioavailability study. The dissolution rate studies of weakly basic drugs, such as theophylline, should be carried out over a range of pH utilising the paddle apparatus. The dissolution data should then be used to simulate the expected in vivo profile and on this basis the appropriate formulation selected for a pilot scale bioavailability study. The above approach to the preformulation studies of new CMRO's would allow for the more careful selection of new dosage forms and could thus eliminate costly and unnecessary bioavailability studies performed on inferior formulations.
- Full Text:
- Date Issued: 1992
- Authors: Tandt, Ludo Alfons Germaan Luc
- Date: 1992
- Subjects: Theophylline , Indomethacin , Drugs -- Controlled release , Drugs -- Dosage forms
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3794 , http://hdl.handle.net/10962/d1003272 , Theophylline , Indomethacin , Drugs -- Controlled release , Drugs -- Dosage forms
- Description: Over the past few decades many researchers have investigated the utility of in vitro - in vivo correlations for the assessment of dosage forms. These investigations are, however, dependent on reproducible dissolution data and well conducted biostudies in order to establish meaningful and robust correlations. Despite the fact that the establishment of such correlations is perhaps idealistic, considerable interest has still been shown in this area of research. Various Controlled/Modified Release Dosage Forms (CMRD's) of theophylline, a weakly basic drug, and indomethacin, a weakly acidic drug, were assessed in order to establish in vitro - in vivo correlations. Dissolution rate studies were carried out using either the USP basket or paddle apparatus. The dissolution rate studies were conducted in a range of dissolution media of varying pH. Bioavailability studies were conducted on the dosage forms used by the Biopharmaceutics Research Institute at Rhodes University. The results of these biostudies were kindly made available for use in this research project. Type A correlations were established using a mathematical simulation process whereby expected in vivo responses are simulated and compared to actual profiles obtained for the dosage forms. In order to perform the simulations the dissolution rate profiles were stripped and using linear regression and the methods of residuals the dissolution rate order and the relevant dissolution rates were obtained. The results of the s imulations indicated that the in vivo serum concentration-time curves could be accurately predicted for the theophylline dosage forms but to a lesser extent, for the indomethacin formulations. The dissolution rate studies indicated that the paddle method is a suitable method for dissolution rate studies of theophylline CMRD's, although it appeared that the optimum pH of the dissolution medium was formulation dependent. Dissolution rate studies conducted on indomethacin formulations indicated that the USP specified basket method for extended-release indomethacin formulations was not able to distinguish between two formulations which exhibited different in vivo profiles. The conversion to the paddle method was, however, able to highlight the differences between these formulations. The use of three dimensional topographs to depict dissolution rate profiles was demonstrated for formulations of both theophylline and indomethacin. The topographs enabled the successful differentiation between bioinequivalent formulations. The dissolution rate profiles were also fitted to the Wei bull equation and the parameters obtained from this were compared to the Weibull parameters obtained from the in vivo absorption plots obtained using the Wagner-Nelson method. The results indicated that the Weibull function was suitable to describe both the in vivo and in vitro data. The following recommendations for the preformulation dissolution studies of weakly acidic and weakly basic drugs are proposed. The dissolution rate studies of weakly acid drugs, such as indomethacin, should be carried out over a range of pH utilising the paddle apparatus. Three dimensional topographs based on the dissolution data should be constructed and used as a comparative tool for different formulations. Based on these comparisons the appropriate formulation can then be selected for a pilot scale in vivo bioavailability study. The dissolution rate studies of weakly basic drugs, such as theophylline, should be carried out over a range of pH utilising the paddle apparatus. The dissolution data should then be used to simulate the expected in vivo profile and on this basis the appropriate formulation selected for a pilot scale bioavailability study. The above approach to the preformulation studies of new CMRO's would allow for the more careful selection of new dosage forms and could thus eliminate costly and unnecessary bioavailability studies performed on inferior formulations.
- Full Text:
- Date Issued: 1992
Design, development and evaluation of encapsulated oral controlled release theophylline mini-tablets
- Authors: Munday, Dale Leslie
- Date: 1991
- Subjects: Drugs -- Administration , Drugs -- Bioavailability , Drugs -- Controlled release , Drugs -- Dosage forms , Tablets (Medicine) , Biopharmaceutics , Drugs -- Testing
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3777 , http://hdl.handle.net/10962/d1003255 , Drugs -- Administration , Drugs -- Bioavailability , Drugs -- Controlled release , Drugs -- Dosage forms , Tablets (Medicine) , Biopharmaceutics , Drugs -- Testing
- Description: Conventional solid dosage forms often lead to fluctuations which exceed the maximum safe therapeutic level and/or decline below the minimum effective level. It is recognised that many drugs for chronic administration should be administered on a schedule that maintains plasma drug concentration within the therapeutic window. Research in controlled release dosage forms aims at designing a system with a zero-order input (eg, ideally to deliver 8.33% of the dose per hour over a 12 hour duration), producing steady state plasma drug levels. Oral dministration of drugs prepared as a controlled release formulation is extremely popular, and has attracted the attention of pharmaceutical scientists during the last decade. This has been due to the simultaneous convergence of various factors (eg, discovery of novel polymers and devices, better understanding of formulation and physiological constraints, expiration of existing patents, prohibitive cost of developing new drug entities), involved in the development of these delivery systems. Controlled release oral products can be formulated as single or multiple unit dosage forms and the relative merits of multiple unit forms with their own rate controlling systems are well established. This work describes the development of a relatively inexpensive multiple-unit capsule dosage form of theophylline containing coated mini-tablets for drug delivery throughout the gastrointestinal tract. Preformulation studies on theophylline anhydrous included solubility and dissolution rate determinations. Techniques including X-ray powder diffraction, differential scanning colorimetry and infrared spectroscopy provided no evidence of true polymorphism after recrystallisation from various solvents. However, scanning electron micrographs showed the effects of solvent polarity and cooling rate on the size and shape of recrystallised particles. Theophylline granules were manufactured by using various binders and were film coated by fluidised bed technology with various proportions of ethylcellulose, containing varying amounts of PEG 1540. In vitro release rates were dependent upon coating thickness and the proportion of PEG, which, being water soluble, created pores in the coating during dissolution studies as observed by a scanning electron microscope. However, substantial proportions of the drug remained unreleased from the granules. In order to overcome the problems of drug retention, plain granules were used and theophylline mini-tablets (3 mm diameter, weighing 15 - 20 mg) were manufactured and film coated with various Eudragits ® and other polymeric mixtures (soluble and insoluble). In vitro dissolution profiles from samples enclosed in hard gelatin capsules were determined using the USPXXI paddle apparatus in test media at pH 1.2 (HCI), pH 5.4 and 7.4 (phosphate buffers) at 37'C. Monitoring of in vitro theophylline release over 12 h, under identical hydrodynamic conditions, showed that the dissolution rate at pH 1.2 is substantially greater (95% of total drug content released in < 10 h) than that in phosphate buffers. The maximum release after 12 h was approximately 20 and 30% of total drug content of the tablet at pH 5.4 and 7.4, respectively. However, in vivo bioavailability after oral administration of tablets to rabbits corresponded to over 95% of total drug, compared with the same dose administered intravenously. The retarded drug release during in vitro dissolution in phosphate buffer was attributed to a possible interaction of phosphate ions with theophylline molecules at the tablet core-coat interface. These findings indicate that both rate and extent of theophylline release from the slow release coated mini-tablets are highly sensitive to phosphate buffers. The data also emphasise the usefulness of an animal model for assessment of in vivo drug release and subsequent absorption during the development of modified release dosage forms. Mini-tablets were subjected to isothermal and cyclic stresses to reach conditions for up to 6 months at different temperatures and relative humidity. The film integrity was maintained but ageing of the coating occurred which impeded dissolution. Reduced drug release was temperature related while the effect of relative humidi% was insignific~t. Encapsulated mini-tablets (uncoated and coated with Eudragit RL and RS 2% w/w) equivalent to a 300 mg dose, were evaluated both in vitro and in vivo using beagle dogs. The pharmacokinetic parameters from single and multiple dose studies showed several advantages over Theo-Dur® 300 mg tablets. Precise dosage titration is possible by careful adjustment of the number of encapsulated mini-tablets. This multiple unit mini-tablet delivery system will allow for greater flexibility in dosage adjustment compared to the currently available preparations, allowing individualised fine dose titration in those patients requiring therapeutic drug monitoring. The developmentof the multiple unit mini-tablet formulation appears to provide an optimal dosage form with maximum flexibility in respect of dose, duration range and ease of production.
- Full Text:
- Date Issued: 1991
Design, development and evaluation of encapsulated oral controlled release theophylline mini-tablets
- Authors: Munday, Dale Leslie
- Date: 1991
- Subjects: Drugs -- Administration , Drugs -- Bioavailability , Drugs -- Controlled release , Drugs -- Dosage forms , Tablets (Medicine) , Biopharmaceutics , Drugs -- Testing
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3777 , http://hdl.handle.net/10962/d1003255 , Drugs -- Administration , Drugs -- Bioavailability , Drugs -- Controlled release , Drugs -- Dosage forms , Tablets (Medicine) , Biopharmaceutics , Drugs -- Testing
- Description: Conventional solid dosage forms often lead to fluctuations which exceed the maximum safe therapeutic level and/or decline below the minimum effective level. It is recognised that many drugs for chronic administration should be administered on a schedule that maintains plasma drug concentration within the therapeutic window. Research in controlled release dosage forms aims at designing a system with a zero-order input (eg, ideally to deliver 8.33% of the dose per hour over a 12 hour duration), producing steady state plasma drug levels. Oral dministration of drugs prepared as a controlled release formulation is extremely popular, and has attracted the attention of pharmaceutical scientists during the last decade. This has been due to the simultaneous convergence of various factors (eg, discovery of novel polymers and devices, better understanding of formulation and physiological constraints, expiration of existing patents, prohibitive cost of developing new drug entities), involved in the development of these delivery systems. Controlled release oral products can be formulated as single or multiple unit dosage forms and the relative merits of multiple unit forms with their own rate controlling systems are well established. This work describes the development of a relatively inexpensive multiple-unit capsule dosage form of theophylline containing coated mini-tablets for drug delivery throughout the gastrointestinal tract. Preformulation studies on theophylline anhydrous included solubility and dissolution rate determinations. Techniques including X-ray powder diffraction, differential scanning colorimetry and infrared spectroscopy provided no evidence of true polymorphism after recrystallisation from various solvents. However, scanning electron micrographs showed the effects of solvent polarity and cooling rate on the size and shape of recrystallised particles. Theophylline granules were manufactured by using various binders and were film coated by fluidised bed technology with various proportions of ethylcellulose, containing varying amounts of PEG 1540. In vitro release rates were dependent upon coating thickness and the proportion of PEG, which, being water soluble, created pores in the coating during dissolution studies as observed by a scanning electron microscope. However, substantial proportions of the drug remained unreleased from the granules. In order to overcome the problems of drug retention, plain granules were used and theophylline mini-tablets (3 mm diameter, weighing 15 - 20 mg) were manufactured and film coated with various Eudragits ® and other polymeric mixtures (soluble and insoluble). In vitro dissolution profiles from samples enclosed in hard gelatin capsules were determined using the USPXXI paddle apparatus in test media at pH 1.2 (HCI), pH 5.4 and 7.4 (phosphate buffers) at 37'C. Monitoring of in vitro theophylline release over 12 h, under identical hydrodynamic conditions, showed that the dissolution rate at pH 1.2 is substantially greater (95% of total drug content released in < 10 h) than that in phosphate buffers. The maximum release after 12 h was approximately 20 and 30% of total drug content of the tablet at pH 5.4 and 7.4, respectively. However, in vivo bioavailability after oral administration of tablets to rabbits corresponded to over 95% of total drug, compared with the same dose administered intravenously. The retarded drug release during in vitro dissolution in phosphate buffer was attributed to a possible interaction of phosphate ions with theophylline molecules at the tablet core-coat interface. These findings indicate that both rate and extent of theophylline release from the slow release coated mini-tablets are highly sensitive to phosphate buffers. The data also emphasise the usefulness of an animal model for assessment of in vivo drug release and subsequent absorption during the development of modified release dosage forms. Mini-tablets were subjected to isothermal and cyclic stresses to reach conditions for up to 6 months at different temperatures and relative humidity. The film integrity was maintained but ageing of the coating occurred which impeded dissolution. Reduced drug release was temperature related while the effect of relative humidi% was insignific~t. Encapsulated mini-tablets (uncoated and coated with Eudragit RL and RS 2% w/w) equivalent to a 300 mg dose, were evaluated both in vitro and in vivo using beagle dogs. The pharmacokinetic parameters from single and multiple dose studies showed several advantages over Theo-Dur® 300 mg tablets. Precise dosage titration is possible by careful adjustment of the number of encapsulated mini-tablets. This multiple unit mini-tablet delivery system will allow for greater flexibility in dosage adjustment compared to the currently available preparations, allowing individualised fine dose titration in those patients requiring therapeutic drug monitoring. The developmentof the multiple unit mini-tablet formulation appears to provide an optimal dosage form with maximum flexibility in respect of dose, duration range and ease of production.
- Full Text:
- Date Issued: 1991
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