Biocompatibility of biomaterials for nanoencapsulation: Current approaches
- Witika, Bwalya A, Makoni, Pedzisai A, Matafwali, Scott K, Chabalenge, Billy, Mwila, Chiluba, Kalungia, Aubrey C, Nkanga, Christian I, Bapolisi, Alain M, Walker, Roderick B
- Authors: Witika, Bwalya A , Makoni, Pedzisai A , Matafwali, Scott K , Chabalenge, Billy , Mwila, Chiluba , Kalungia, Aubrey C , Nkanga, Christian I , Bapolisi, Alain M , Walker, Roderick B
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/183289 , vital:43939 , xlink:href="https://doi.org/10.3390/nano10091649"
- Description: Nanoencapsulation is an approach to circumvent shortcomings such as reduced bioavailability, undesirable side effects, frequent dosing and unpleasant organoleptic properties of conventional drug delivery systems. The process of nanoencapsulation involves the use of biomaterials such as surfactants and/or polymers, often in combination with charge inducers and/or ligands for targeting. The biomaterials selected for nanoencapsulation processes must be as biocompatible as possible. The type(s) of biomaterials used for different nanoencapsulation approaches are highlighted and their use and applicability with regard to haemo- and, histocompatibility, cytotoxicity, genotoxicity and carcinogenesis are discussed.
- Full Text:
- Date Issued: 2020
- Authors: Witika, Bwalya A , Makoni, Pedzisai A , Matafwali, Scott K , Chabalenge, Billy , Mwila, Chiluba , Kalungia, Aubrey C , Nkanga, Christian I , Bapolisi, Alain M , Walker, Roderick B
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/183289 , vital:43939 , xlink:href="https://doi.org/10.3390/nano10091649"
- Description: Nanoencapsulation is an approach to circumvent shortcomings such as reduced bioavailability, undesirable side effects, frequent dosing and unpleasant organoleptic properties of conventional drug delivery systems. The process of nanoencapsulation involves the use of biomaterials such as surfactants and/or polymers, often in combination with charge inducers and/or ligands for targeting. The biomaterials selected for nanoencapsulation processes must be as biocompatible as possible. The type(s) of biomaterials used for different nanoencapsulation approaches are highlighted and their use and applicability with regard to haemo- and, histocompatibility, cytotoxicity, genotoxicity and carcinogenesis are discussed.
- Full Text:
- Date Issued: 2020
Improved Stability of Rifampicin in the Presence of Gastric-Resistant Isoniazid Microspheres in Acidic Media
- Mwila, Chiluba, Walker, Roderick B
- Authors: Mwila, Chiluba , Walker, Roderick B
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/183210 , vital:43929 , xlink:href="https://doi.org/10.3390/pharmaceutics12030234"
- Description: The degradation of rifampicin (RIF) in an acidic medium to form 3-formyl rifamycin SV, a poorly absorbed compound, is accelerated in the presence of isoniazid, contributing to the poor bioavailability of rifampicin. This manuscript presents a novel approach in which isoniazid is formulated into gastric-resistant sustained-release microspheres and RIF into microporous floating sustained-release microspheres to reduce the potential for interaction between RIF and isoniazid (INH) in an acidic environment. Hydroxypropyl methylcellulose acetate succinate and Eudragit® L100 polymers were used for the manufacture of isoniazid-loaded gastric-resistant sustained-release microspheres using an o/o solvent emulsification evaporation approach. Microporous floating sustained-release microspheres for the delivery of rifampicin in the stomach were manufactured using emulsification and a diffusion/evaporation process. The design of experiments was used to evaluate the impact of input variables on predefined responses or quality attributes of the microspheres. The percent degradation of rifampicin following 12 h dissolution testing in 0.1 M HCl pH 1.2 in the presence of isoniazid gastric-resistant sustained-release microspheres was only 4.44%. These results indicate that the degradation of rifampicin in the presence of isoniazid in acidic media can be reduced by encapsulation of both active pharmaceutical ingredients to ensure release in different segments of the gastrointestinal tract, potentially improving the bioavailability of rifampicin.
- Full Text:
- Date Issued: 2020
- Authors: Mwila, Chiluba , Walker, Roderick B
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/183210 , vital:43929 , xlink:href="https://doi.org/10.3390/pharmaceutics12030234"
- Description: The degradation of rifampicin (RIF) in an acidic medium to form 3-formyl rifamycin SV, a poorly absorbed compound, is accelerated in the presence of isoniazid, contributing to the poor bioavailability of rifampicin. This manuscript presents a novel approach in which isoniazid is formulated into gastric-resistant sustained-release microspheres and RIF into microporous floating sustained-release microspheres to reduce the potential for interaction between RIF and isoniazid (INH) in an acidic environment. Hydroxypropyl methylcellulose acetate succinate and Eudragit® L100 polymers were used for the manufacture of isoniazid-loaded gastric-resistant sustained-release microspheres using an o/o solvent emulsification evaporation approach. Microporous floating sustained-release microspheres for the delivery of rifampicin in the stomach were manufactured using emulsification and a diffusion/evaporation process. The design of experiments was used to evaluate the impact of input variables on predefined responses or quality attributes of the microspheres. The percent degradation of rifampicin following 12 h dissolution testing in 0.1 M HCl pH 1.2 in the presence of isoniazid gastric-resistant sustained-release microspheres was only 4.44%. These results indicate that the degradation of rifampicin in the presence of isoniazid in acidic media can be reduced by encapsulation of both active pharmaceutical ingredients to ensure release in different segments of the gastrointestinal tract, potentially improving the bioavailability of rifampicin.
- Full Text:
- Date Issued: 2020
Nano-biomimetic drug delivery vehicles: Potential approaches for COVID-19 treatment
- Witika, Bwalya A, Makoni, Pedzisai A, Mweetwa, Larry L, Ntemi, Pascal V, Chikukwa, Mellisa T R, Matafwali, Scott K, Mwila, Chiluba, Mudenda, Steward, Katandula, Jonathan, Walker, Roderick B
- Authors: Witika, Bwalya A , Makoni, Pedzisai A , Mweetwa, Larry L , Ntemi, Pascal V , Chikukwa, Mellisa T R , Matafwali, Scott K , Mwila, Chiluba , Mudenda, Steward , Katandula, Jonathan , Walker, Roderick B
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/183440 , vital:43991 , xlink:href="https://doi.org/10.3390/molecules25245952"
- Description: The current COVID-19 pandemic has tested the resolve of the global community with more than 35 million infections worldwide and numbers increasing with no cure or vaccine available to date. Nanomedicines have an advantage of providing enhanced permeability and retention and have been extensively studied as targeted drug delivery strategies for the treatment of different disease. The role of monocytes, erythrocytes, thrombocytes, and macrophages in diseases, including infectious and inflammatory diseases, cancer, and atherosclerosis, are better understood and have resulted in improved strategies for targeting and in some instances mimicking these cell types to improve therapeutic outcomes. Consequently, these primary cell types can be exploited for the purposes of serving as a "Trojan horse" for targeted delivery to identified organs and sites of inflammation. State of the art and potential utilization of nanocarriers such as nanospheres/nanocapsules, nanocrystals, liposomes, solid lipid nanoparticles/nano-structured lipid carriers, dendrimers, and nanosponges for biomimicry and/or targeted delivery of bioactives to cells are reported herein and their potential use in the treatment of COVID-19 infections discussed. Physicochemical properties, viz., hydrophilicity, particle shape, surface charge, composition, concentration, the use of different target-specific ligands on the surface of carriers, and the impact on carrier efficacy and specificity are also discussed.
- Full Text:
- Date Issued: 2020
- Authors: Witika, Bwalya A , Makoni, Pedzisai A , Mweetwa, Larry L , Ntemi, Pascal V , Chikukwa, Mellisa T R , Matafwali, Scott K , Mwila, Chiluba , Mudenda, Steward , Katandula, Jonathan , Walker, Roderick B
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/183440 , vital:43991 , xlink:href="https://doi.org/10.3390/molecules25245952"
- Description: The current COVID-19 pandemic has tested the resolve of the global community with more than 35 million infections worldwide and numbers increasing with no cure or vaccine available to date. Nanomedicines have an advantage of providing enhanced permeability and retention and have been extensively studied as targeted drug delivery strategies for the treatment of different disease. The role of monocytes, erythrocytes, thrombocytes, and macrophages in diseases, including infectious and inflammatory diseases, cancer, and atherosclerosis, are better understood and have resulted in improved strategies for targeting and in some instances mimicking these cell types to improve therapeutic outcomes. Consequently, these primary cell types can be exploited for the purposes of serving as a "Trojan horse" for targeted delivery to identified organs and sites of inflammation. State of the art and potential utilization of nanocarriers such as nanospheres/nanocapsules, nanocrystals, liposomes, solid lipid nanoparticles/nano-structured lipid carriers, dendrimers, and nanosponges for biomimicry and/or targeted delivery of bioactives to cells are reported herein and their potential use in the treatment of COVID-19 infections discussed. Physicochemical properties, viz., hydrophilicity, particle shape, surface charge, composition, concentration, the use of different target-specific ligands on the surface of carriers, and the impact on carrier efficacy and specificity are also discussed.
- Full Text:
- Date Issued: 2020
The development, manufacture and evaluation of sustained release gastric-resistant isoniazid and gastroretentive microporous rifampicin microspheres
- Authors: Mwila, Chiluba
- Date: 2018
- Subjects: Biodegradation , Microspheres (Pharmacy) , Drug delivery systems , Rifampin , Isoniazid
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/63497 , vital:28421 , DOI 10.21504/10962/63497
- Description: According to the World Health Organization Global Tuberculosis (TB) 2017 Report, there were an estimated 10.4 million new TB cases worldwide of which, in 2016, 65 % occurred in men, 28.1 % in women and 6.9 % in children. TB is the ninth leading cause of death globally and is the leading cause due to an infectious organism surpassing HIV/AIDS. Treatment is long-term and the use of a combination of medicines is required for success. The concern related to the use of fixed dose combination products for the treatment of TB is the issue of low bioavailability of rifampicin observed from a number of fixed dose combination (FDC) formulations. The hydrolysis of rifampicin, in acidic media, to form insoluble 3-formyl rifamycin SV contributes to poor bioavailability of rifampicin. The degradation of rifampicin to form this poorly absorbed compound is accelerated in the presence of isoniazid via the reversible formation of isonicotinyl hydrazone is a further factor contributing to the poor bioavailability of rifampicin. Therefore, the development of a novel drug delivery technology that prevents interactions between rifampicin and isoniazid in an acidic medium is required. A Box Behnken design was successfully used for the optimisation of a rapid and accurate stability-indicating gradient elution RP-HPLC method for the simultaneous analysis of isoniazid, pyrazinamide and rifampicin. The method was validated using ICH guidelines and the results indicate it can be used for the rapid analysis of commercially available TB FDC formulations containing the active pharmaceutical ingredients, API. The method is precise, sensitive and has the necessary selectivity for use during formulation development and optimisation studies for a combination of rifampicin, isoniazid and pyrazinamide. Initially formulation activities were undertaken with rifampicin and isoniazid for the development of an approach to enhance the effective delivery of these compounds. The characterisation of rifampicin and isoniazid was undertaken using spectroscopic, thermal and microscopic analysis. The studies revealed that the compounds are crystalline and exhibit distinct characteristic sharp peaks in X-ray diffractograms and Differential Scanning Calorimetry thermograms. The thermograms, 13C Nuclear Magnetic Resonance and Fourier Transform Infrared spectroscopy results identified that rifampicin occurs as the form II polymorph however, as there are no significant biopharmaceutic differences between the polymorphic forms of rifampicin this information was used for identification purposes only. The results were used as baseline data for comparative purposes to monitor changes that may occur when rifampicin and isoniazid are used in formulation development, dosage form manufacture and characterisation activities for a FDC technology designed to deliver both compounds simultaneously. Hydroxypropylmethylcellulose acetate succinate (HPMC-AS) and Eudragit® L100 polymers were successfully used for manufacture of isoniazid loaded gastric-resistant sustained release microspheres using an o/o solvent emulsification and evaporation approach. A Hybrid experimental design was used to investigate the influence of input variables viz., homogenisation speed and amount of HPMC-AS and Eudragit® L100 on gastric-resistance, INH release and encapsulation efficiency. The approach of using coating polymers viz., HPMC-AS and Eudragit® L100, to manufacture gastric resistant sustained release microspheres of isoniazid is unique and was efficient for preventing the release of isoniazid in an acidic environment. Only 0.523 % isoniazid was released from the optimised formulation after 2 h exposure to pH 1.2 0.1 M HCl suggesting there is also the possibility of minimising the accelerated degradation of rifampicin that occurs in the presence of isoniazid in acidic media. The microspheres also exhibited sustained release properties without burst release in pH 6.8 0.1 M phosphate buffer as < 5 % isoniazid was released at 0.5 h and only 11 % isoniazid was released at 2 h. The release of isoniazid was sustained over the entire period of dissolution testing with > 85 % isoniazid released at 24 h, implying that the majority of encapsulated isoniazid would be available for absorption. The manufacturing process resulted in the production of hard spherical particles and particle size analysis revealed that the microspheres ranged between 415.76 ± 76.93 μm and 903.35 ± 197.10 μm in diameter. The microspheres exhibited excellent flow properties attributed to the spherical nature of particles. Carr‟s index (CI) was 4.934 ± 0.775 % and the Hausner ratio (HR) was 1.148 ± 0.033 indicating good packability of the microspheres that would help in achieving weight and content uniformity of capsule dosage units. The manufacturing process however produced a low % yield suggesting that scale up difficulties may be encountered. However the high encapsulation efficiency observed may counter the challenges associated with the low yield. The DSC thermograms and FT Raman spectra of 1:1 mixtures of isoniazid, excipients and the microspheres did not reveal any potential detrimental interactions. Microporous floating sustained release microspheres for the delivery of rifampicin in the stomach have been successfully manufactured using emulsification and a diffusion/evaporation process. A novel approach using solvent mixture of acetone and dichloromethane that has not been reported for the manufacture of rifampicin microspheres was successfully used and resulted in the formation of a stable emulsion and the manufacture of rifampicin-loaded microspheres with uniform characteristics. In addition the manufacturing process was shorter than most other reported methods. A Box-Behnken experimental design was successfully used to study the influence of ethylcellulose, Eudragit® RLPO and d-glucose content on the floating properties, encapsulation efficiency and % yield of microspheres. The optimised formulation did not yield desired floating characteristics as the % buoyancy was low and floating lag times were high. The optimised formulation was modified by addition of NaHCO3 to increase the % buoyancy and reduce the floating lag time. Rifampicin release from the microspheres of the modified batch was 87.10 % at 12 h and the microspheres exhibited a % buoyancy of 87.66 ± 1.28 % (n = 6) and floating lag time of 15 ± 3.2 (n = 6) seconds. The microspheres remained buoyant for up to 12 h and an encapsulation efficiency of 88.26 ± 1.25 % was achieved. SEM images of microspheres following exposure to dissolution fluid revealed that the microspheres had numerous pores on their surface. The mean particle size distribution ranged between 423.19 ± 121.86 μm to 620.07 ± 102.67 μm. The microspheres exhibited similar flow characteristics to isoniazid microspheres with a CI of 1.422 ± 0.074 %, and HR of 1.034 ± 0.002. The excellent flow characteristics indicate that filling of the microspheres into hard gelatin capsules was unlikely to pose a challenge in respect of producing a product with uniform content. Rifampicin-excipient compatibility studies did not reveal any potential or significant interactions suggesting that the excipients used for the manufacture of the microspheres were compatible, although long term stability studies would be required to ascertain this is, indeed the case. The microporous floating sustained release microspheres manufactured in these studies has the potential to increase the bioavailability of rifampicin as they may be retained in the stomach where the solubility of rifampicin is high and from which absorption is best achieved. The degradation of rifampicin after 12 h dissolution testing in pH 1.2 0.1 M HCl in the presence of isoniazid gastric-resistant sustained release microspheres was only 4.44%. These results indicate that the degradation of rifampicin in the presence of isoniazid in acidic media can be overcome by encapsulation of both active pharmaceutical ingredients in a manner that ensure release in different segments of the gastrointestinal tract. The use of sustained release microporous gastroretentive rifampicin microspheres in combination with sustained release isoniazid gastric-resistant microspheres revealed that accelerated degradation of rifampicin in the presence of isoniazid is reduced significantly when using this approach and a FDC of rifampicin and isoniazid microspheres has the potential to improve the bioavailability of rifampicin thereby enhancing therapeutic outcomes. In vivo studies would be required to confirm the potential benefits of using this approach to deliver rifampicin in combination with isoniazid. , Thesis (PhD) -- Faculty of Pharmacy, Pharmacy, 2018
- Full Text:
- Date Issued: 2018
- Authors: Mwila, Chiluba
- Date: 2018
- Subjects: Biodegradation , Microspheres (Pharmacy) , Drug delivery systems , Rifampin , Isoniazid
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/63497 , vital:28421 , DOI 10.21504/10962/63497
- Description: According to the World Health Organization Global Tuberculosis (TB) 2017 Report, there were an estimated 10.4 million new TB cases worldwide of which, in 2016, 65 % occurred in men, 28.1 % in women and 6.9 % in children. TB is the ninth leading cause of death globally and is the leading cause due to an infectious organism surpassing HIV/AIDS. Treatment is long-term and the use of a combination of medicines is required for success. The concern related to the use of fixed dose combination products for the treatment of TB is the issue of low bioavailability of rifampicin observed from a number of fixed dose combination (FDC) formulations. The hydrolysis of rifampicin, in acidic media, to form insoluble 3-formyl rifamycin SV contributes to poor bioavailability of rifampicin. The degradation of rifampicin to form this poorly absorbed compound is accelerated in the presence of isoniazid via the reversible formation of isonicotinyl hydrazone is a further factor contributing to the poor bioavailability of rifampicin. Therefore, the development of a novel drug delivery technology that prevents interactions between rifampicin and isoniazid in an acidic medium is required. A Box Behnken design was successfully used for the optimisation of a rapid and accurate stability-indicating gradient elution RP-HPLC method for the simultaneous analysis of isoniazid, pyrazinamide and rifampicin. The method was validated using ICH guidelines and the results indicate it can be used for the rapid analysis of commercially available TB FDC formulations containing the active pharmaceutical ingredients, API. The method is precise, sensitive and has the necessary selectivity for use during formulation development and optimisation studies for a combination of rifampicin, isoniazid and pyrazinamide. Initially formulation activities were undertaken with rifampicin and isoniazid for the development of an approach to enhance the effective delivery of these compounds. The characterisation of rifampicin and isoniazid was undertaken using spectroscopic, thermal and microscopic analysis. The studies revealed that the compounds are crystalline and exhibit distinct characteristic sharp peaks in X-ray diffractograms and Differential Scanning Calorimetry thermograms. The thermograms, 13C Nuclear Magnetic Resonance and Fourier Transform Infrared spectroscopy results identified that rifampicin occurs as the form II polymorph however, as there are no significant biopharmaceutic differences between the polymorphic forms of rifampicin this information was used for identification purposes only. The results were used as baseline data for comparative purposes to monitor changes that may occur when rifampicin and isoniazid are used in formulation development, dosage form manufacture and characterisation activities for a FDC technology designed to deliver both compounds simultaneously. Hydroxypropylmethylcellulose acetate succinate (HPMC-AS) and Eudragit® L100 polymers were successfully used for manufacture of isoniazid loaded gastric-resistant sustained release microspheres using an o/o solvent emulsification and evaporation approach. A Hybrid experimental design was used to investigate the influence of input variables viz., homogenisation speed and amount of HPMC-AS and Eudragit® L100 on gastric-resistance, INH release and encapsulation efficiency. The approach of using coating polymers viz., HPMC-AS and Eudragit® L100, to manufacture gastric resistant sustained release microspheres of isoniazid is unique and was efficient for preventing the release of isoniazid in an acidic environment. Only 0.523 % isoniazid was released from the optimised formulation after 2 h exposure to pH 1.2 0.1 M HCl suggesting there is also the possibility of minimising the accelerated degradation of rifampicin that occurs in the presence of isoniazid in acidic media. The microspheres also exhibited sustained release properties without burst release in pH 6.8 0.1 M phosphate buffer as < 5 % isoniazid was released at 0.5 h and only 11 % isoniazid was released at 2 h. The release of isoniazid was sustained over the entire period of dissolution testing with > 85 % isoniazid released at 24 h, implying that the majority of encapsulated isoniazid would be available for absorption. The manufacturing process resulted in the production of hard spherical particles and particle size analysis revealed that the microspheres ranged between 415.76 ± 76.93 μm and 903.35 ± 197.10 μm in diameter. The microspheres exhibited excellent flow properties attributed to the spherical nature of particles. Carr‟s index (CI) was 4.934 ± 0.775 % and the Hausner ratio (HR) was 1.148 ± 0.033 indicating good packability of the microspheres that would help in achieving weight and content uniformity of capsule dosage units. The manufacturing process however produced a low % yield suggesting that scale up difficulties may be encountered. However the high encapsulation efficiency observed may counter the challenges associated with the low yield. The DSC thermograms and FT Raman spectra of 1:1 mixtures of isoniazid, excipients and the microspheres did not reveal any potential detrimental interactions. Microporous floating sustained release microspheres for the delivery of rifampicin in the stomach have been successfully manufactured using emulsification and a diffusion/evaporation process. A novel approach using solvent mixture of acetone and dichloromethane that has not been reported for the manufacture of rifampicin microspheres was successfully used and resulted in the formation of a stable emulsion and the manufacture of rifampicin-loaded microspheres with uniform characteristics. In addition the manufacturing process was shorter than most other reported methods. A Box-Behnken experimental design was successfully used to study the influence of ethylcellulose, Eudragit® RLPO and d-glucose content on the floating properties, encapsulation efficiency and % yield of microspheres. The optimised formulation did not yield desired floating characteristics as the % buoyancy was low and floating lag times were high. The optimised formulation was modified by addition of NaHCO3 to increase the % buoyancy and reduce the floating lag time. Rifampicin release from the microspheres of the modified batch was 87.10 % at 12 h and the microspheres exhibited a % buoyancy of 87.66 ± 1.28 % (n = 6) and floating lag time of 15 ± 3.2 (n = 6) seconds. The microspheres remained buoyant for up to 12 h and an encapsulation efficiency of 88.26 ± 1.25 % was achieved. SEM images of microspheres following exposure to dissolution fluid revealed that the microspheres had numerous pores on their surface. The mean particle size distribution ranged between 423.19 ± 121.86 μm to 620.07 ± 102.67 μm. The microspheres exhibited similar flow characteristics to isoniazid microspheres with a CI of 1.422 ± 0.074 %, and HR of 1.034 ± 0.002. The excellent flow characteristics indicate that filling of the microspheres into hard gelatin capsules was unlikely to pose a challenge in respect of producing a product with uniform content. Rifampicin-excipient compatibility studies did not reveal any potential or significant interactions suggesting that the excipients used for the manufacture of the microspheres were compatible, although long term stability studies would be required to ascertain this is, indeed the case. The microporous floating sustained release microspheres manufactured in these studies has the potential to increase the bioavailability of rifampicin as they may be retained in the stomach where the solubility of rifampicin is high and from which absorption is best achieved. The degradation of rifampicin after 12 h dissolution testing in pH 1.2 0.1 M HCl in the presence of isoniazid gastric-resistant sustained release microspheres was only 4.44%. These results indicate that the degradation of rifampicin in the presence of isoniazid in acidic media can be overcome by encapsulation of both active pharmaceutical ingredients in a manner that ensure release in different segments of the gastrointestinal tract. The use of sustained release microporous gastroretentive rifampicin microspheres in combination with sustained release isoniazid gastric-resistant microspheres revealed that accelerated degradation of rifampicin in the presence of isoniazid is reduced significantly when using this approach and a FDC of rifampicin and isoniazid microspheres has the potential to improve the bioavailability of rifampicin thereby enhancing therapeutic outcomes. In vivo studies would be required to confirm the potential benefits of using this approach to deliver rifampicin in combination with isoniazid. , Thesis (PhD) -- Faculty of Pharmacy, Pharmacy, 2018
- Full Text:
- Date Issued: 2018
Development and assessment of a USP Apparatus 3 dissolution test method for sustained-release Nevirapine matrix tablets
- Mwila, Chiluba, Khamanga, Sandile M M, Walker, Roderick B
- Authors: Mwila, Chiluba , Khamanga, Sandile M M , Walker, Roderick B
- Date: 2016
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/184779 , vital:44271 , xlink:href="https://doi.org/10.14227/dt230316p22"
- Description: Dissolution testing is a quality control tool used to assess batch-to-batch performance of dosage forms, thereby providing continued assurance of product quality. Analytical methods for the assessment of pharmaceutical product quality must be validated according to regulatory guidelines to ensure that tests are reliable and valid. Agitation rate, mesh pore size, surfactant concentration, and dissolution medium molarity are experimental parameters that may affect nevirapine (NVP) release and were investigated and optimized to ensure that consistent, reliable, and valid results using Apparatus 3 were produced. Agitation rate was investigated to establish an equivalent response to that observed for NVP release using Apparatus 2 at 50 rpm. A reciprocation rate of 5–10 dpm produced dissolution profiles that were similar to those observed using Apparatus 2. An increase in the molarity of the dissolution medium slightly increased the release rate of NVP, and a 50 mM buffer maintained at pH values mimicking gastrointestinal tract (GIT) conditions was selected for all experiments. With the addition of 2% sodium lauryl sulfate (SLS) to the dissolution medium, >80% NVP was released from the tablets over the test period. The NVP release rate increased with an increase in the mesh pore size; however, the extent of release was not affected by this parameter. Dissolution test samples were analyzed using HPLC, and dissolution methods were validated for NVP stability in the dissolution medium, specificity, linearity and range, repeatability, intermediate precision, and accuracy as defined by ICH. The dissolution method used for testing NVP tablets can be regarded as an appropriate tool for the evaluation of sustained-release (SR) NVP formulations and the impact of formulation composition and product quality attributes on drug release.
- Full Text:
- Date Issued: 2016
- Authors: Mwila, Chiluba , Khamanga, Sandile M M , Walker, Roderick B
- Date: 2016
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/184779 , vital:44271 , xlink:href="https://doi.org/10.14227/dt230316p22"
- Description: Dissolution testing is a quality control tool used to assess batch-to-batch performance of dosage forms, thereby providing continued assurance of product quality. Analytical methods for the assessment of pharmaceutical product quality must be validated according to regulatory guidelines to ensure that tests are reliable and valid. Agitation rate, mesh pore size, surfactant concentration, and dissolution medium molarity are experimental parameters that may affect nevirapine (NVP) release and were investigated and optimized to ensure that consistent, reliable, and valid results using Apparatus 3 were produced. Agitation rate was investigated to establish an equivalent response to that observed for NVP release using Apparatus 2 at 50 rpm. A reciprocation rate of 5–10 dpm produced dissolution profiles that were similar to those observed using Apparatus 2. An increase in the molarity of the dissolution medium slightly increased the release rate of NVP, and a 50 mM buffer maintained at pH values mimicking gastrointestinal tract (GIT) conditions was selected for all experiments. With the addition of 2% sodium lauryl sulfate (SLS) to the dissolution medium, >80% NVP was released from the tablets over the test period. The NVP release rate increased with an increase in the mesh pore size; however, the extent of release was not affected by this parameter. Dissolution test samples were analyzed using HPLC, and dissolution methods were validated for NVP stability in the dissolution medium, specificity, linearity and range, repeatability, intermediate precision, and accuracy as defined by ICH. The dissolution method used for testing NVP tablets can be regarded as an appropriate tool for the evaluation of sustained-release (SR) NVP formulations and the impact of formulation composition and product quality attributes on drug release.
- Full Text:
- Date Issued: 2016
The development and assessment of sustained release nevirapine tablets
- Authors: Mwila, Chiluba
- Date: 2013
- Language: English
- Type: text , Thesis , Masters , MPharm
- Identifier: http://hdl.handle.net/10962/54667 , vital:26598
- Description: The use of antiretroviral (ARV) agents in the management of HIV/AIDS has significantly improved the lifestyle and wellbeing of patients. Despite the success that has been achieved with the use of ARV therapy, the occurrence of adverse effects and unpredictable bioavailability associated with most of these drugs remains a major concern. Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that is used in combination with other ARV compounds for the treatment of HIV-1 infections. It is also used for the prevention of mother to child transmission of the HIV-1 virus. NVP is a Biopharmaceutics Classification System (BCS) Class II compound. Although NVP exhibits good oral absorption, it induces self-metabolism leading to low and sometimes unpredictable bioavailability. NVP is commercially available as an immediate release and extended release dosage form, viz., Viramune® XR. Formulation of a generic sustained release (SR) dosage form for once daily dosing would result in delivery of constant amount of the drug to the circulation, reduce dose related adverse effects, improve patient compliance to medication and reduce the costs of therapy. A simple RP-HPLC method was developed and optimised using a central composite design approach. The method was validated using ICH guidelines and was found to be linear, precise, specific and accurate for the analysis of NVP both in bulk and dosage forms. Direct compression was used as the method of tablet manufacture. Different polymers were assessed for suitability as rate retarding polymers and included Methocel® K4M, Carbopol® 71G NF and Eudragit® RSPO. Powder blends were assessed for flow properties using the angle of repose, bulk and tapped density, Carr’s Compressibility index and Hausner’s ratio. The traditional approach of changing the amount of polymers and diluents systematically to achieve a desired NVP release profile was used for the development of a preliminary formulation. Response surface methodology was used for the optimisation of the formulation using a Box-Behnken quadratic design. Physical characteristics of the tablets such as thickness, weight, hardness, tensile strength and friability were assessed and the tablets passed Pharmacopoeial testing. NVP assay and content uniformity were assessed using a validated RP-HPLC method. Initially, USP Apparatus 2 was used to study NVP release over a 24 hour period and subsequently dissolution studies were performed using USP Apparatus 3 as it can be used to simulate GIT conditions. The dissolution profiles generated were used to determine the agitation rate for USP Apparatus 3 that would be equivalent to an agitation rate of 50 rpm when using USP Apparatus 2. The effect of the mesh screen pore size, buffer molarity strength and concentration of surfactant on NVP release were also investigated in order to select discriminatory dissolution test conditions for the test formulation. Dissolution profiles were compared to those of the commercially available Viramune® XR using the FDA recommended difference (f1) and similarity (f2) factors. The calculated values for f1 and f2 revealed that the dissolution profile for the optimised formulation that was identified was statistically similar to Viramune® XR. In vitro release data were fitted to different kinetic models to study the release kinetics of NVP. The overall mechanism of NVP release was best described using the Korsmeyer-Peppas diffusion exponent value, n. NVP release was found to be anomalous, implying that the release was influenced by a combination of diffusion, swelling and polymer chain relaxation. The Hixson-Crowell model revealed that there was constant change in surface area of the dosage form suggesting that erosion and swelling were significant factors affecting NVP release from the hydrophilic matrix technology. The release kinetics data were also used to design the optimised formulation. Tablets manufactured using the optimised formulation were subjected to water uptake and erosion studies and the results revealed that swelling and erosion occur simultaneously. The effects of pH and molarity on the swelling and erosion of the tablets were also investigated. The data suggest that increase in pH resulted in a slight increase in swelling while an increase in molarity did not have a significant effect on swelling. The change in pH did not have a significant effect on erosion while an increase in molarity strength resulted in a decrease in matrix erosion. The effect of HPMC grade on swelling, erosion and NVP release revealed that the grade of HPMC used had a significant effect on NVP release, with the release rate decreasing, swelling increasing and erosion decreasing as the viscosity of the HPMC grade increased. The effect of the particle size of MCC on NVP release was also studied by manufacturing tablets containing different grades of MCC and these studies revealed that particle size did not appear to have a significant effect on NVP release. Similarly the use of different types of lactose did not appear to have a significant impact on NVP release. In conclusion a sustained release NVP tablet formulation that has the potential for further development and optimisation has been developed, assessed and manufactured successfully and has been shown to exhibit similar dissolution behaviour to Viramune® XR, a commercially available NVP extended release product.
- Full Text:
- Date Issued: 2013
- Authors: Mwila, Chiluba
- Date: 2013
- Language: English
- Type: text , Thesis , Masters , MPharm
- Identifier: http://hdl.handle.net/10962/54667 , vital:26598
- Description: The use of antiretroviral (ARV) agents in the management of HIV/AIDS has significantly improved the lifestyle and wellbeing of patients. Despite the success that has been achieved with the use of ARV therapy, the occurrence of adverse effects and unpredictable bioavailability associated with most of these drugs remains a major concern. Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that is used in combination with other ARV compounds for the treatment of HIV-1 infections. It is also used for the prevention of mother to child transmission of the HIV-1 virus. NVP is a Biopharmaceutics Classification System (BCS) Class II compound. Although NVP exhibits good oral absorption, it induces self-metabolism leading to low and sometimes unpredictable bioavailability. NVP is commercially available as an immediate release and extended release dosage form, viz., Viramune® XR. Formulation of a generic sustained release (SR) dosage form for once daily dosing would result in delivery of constant amount of the drug to the circulation, reduce dose related adverse effects, improve patient compliance to medication and reduce the costs of therapy. A simple RP-HPLC method was developed and optimised using a central composite design approach. The method was validated using ICH guidelines and was found to be linear, precise, specific and accurate for the analysis of NVP both in bulk and dosage forms. Direct compression was used as the method of tablet manufacture. Different polymers were assessed for suitability as rate retarding polymers and included Methocel® K4M, Carbopol® 71G NF and Eudragit® RSPO. Powder blends were assessed for flow properties using the angle of repose, bulk and tapped density, Carr’s Compressibility index and Hausner’s ratio. The traditional approach of changing the amount of polymers and diluents systematically to achieve a desired NVP release profile was used for the development of a preliminary formulation. Response surface methodology was used for the optimisation of the formulation using a Box-Behnken quadratic design. Physical characteristics of the tablets such as thickness, weight, hardness, tensile strength and friability were assessed and the tablets passed Pharmacopoeial testing. NVP assay and content uniformity were assessed using a validated RP-HPLC method. Initially, USP Apparatus 2 was used to study NVP release over a 24 hour period and subsequently dissolution studies were performed using USP Apparatus 3 as it can be used to simulate GIT conditions. The dissolution profiles generated were used to determine the agitation rate for USP Apparatus 3 that would be equivalent to an agitation rate of 50 rpm when using USP Apparatus 2. The effect of the mesh screen pore size, buffer molarity strength and concentration of surfactant on NVP release were also investigated in order to select discriminatory dissolution test conditions for the test formulation. Dissolution profiles were compared to those of the commercially available Viramune® XR using the FDA recommended difference (f1) and similarity (f2) factors. The calculated values for f1 and f2 revealed that the dissolution profile for the optimised formulation that was identified was statistically similar to Viramune® XR. In vitro release data were fitted to different kinetic models to study the release kinetics of NVP. The overall mechanism of NVP release was best described using the Korsmeyer-Peppas diffusion exponent value, n. NVP release was found to be anomalous, implying that the release was influenced by a combination of diffusion, swelling and polymer chain relaxation. The Hixson-Crowell model revealed that there was constant change in surface area of the dosage form suggesting that erosion and swelling were significant factors affecting NVP release from the hydrophilic matrix technology. The release kinetics data were also used to design the optimised formulation. Tablets manufactured using the optimised formulation were subjected to water uptake and erosion studies and the results revealed that swelling and erosion occur simultaneously. The effects of pH and molarity on the swelling and erosion of the tablets were also investigated. The data suggest that increase in pH resulted in a slight increase in swelling while an increase in molarity did not have a significant effect on swelling. The change in pH did not have a significant effect on erosion while an increase in molarity strength resulted in a decrease in matrix erosion. The effect of HPMC grade on swelling, erosion and NVP release revealed that the grade of HPMC used had a significant effect on NVP release, with the release rate decreasing, swelling increasing and erosion decreasing as the viscosity of the HPMC grade increased. The effect of the particle size of MCC on NVP release was also studied by manufacturing tablets containing different grades of MCC and these studies revealed that particle size did not appear to have a significant effect on NVP release. Similarly the use of different types of lactose did not appear to have a significant impact on NVP release. In conclusion a sustained release NVP tablet formulation that has the potential for further development and optimisation has been developed, assessed and manufactured successfully and has been shown to exhibit similar dissolution behaviour to Viramune® XR, a commercially available NVP extended release product.
- Full Text:
- Date Issued: 2013
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