Nano Co-Crystal Embedded Stimuli-Responsive Hydrogels: A Potential Approach to Treat HIV/AIDS
- Witika, Bwalya A, Stander, Jessé-Clint, Smith, Vincent J, Walker, Roderick B
- Authors: Witika, Bwalya A , Stander, Jessé-Clint , Smith, Vincent J , Walker, Roderick B
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/183137 , vital:43915 , xlink:href="https://doi.org/10.3390/pharmaceutics13020127"
- Description: Currently, the human immunodeficiency virus (HIV) that causes acquired immunodeficiency syndrome (AIDS) can only be treated successfully, using combination antiretroviral (ARV) therapy. Lamivudine (3TC) and zidovudine (AZT), two compounds used for the treatment of HIV and prevention of disease progression to AIDS are used in such combinations. Successful therapy with 3TC and AZT requires frequent dosing that may lead to reduced adherence, resistance and consequently treatment failure. Improved toxicity profiles of 3TC and AZT were observed when combined as a nano co-crystal (NCC). The use of stimuli-responsive delivery systems provides an opportunity to overcome the challenge of frequent dosing, by controlling and/or sustaining delivery of drugs. Preliminary studies undertaken to identify a suitable composition for a stimulus-responsive in situ forming hydrogel carrier for 3TC-AZT NCC were conducted, and the gelation and erosion time were determined. A 25% w/w Pluronic® F-127 thermoresponsive hydrogel was identified as a suitable carrier as it exhibited a gelation time of 5 min and an erosion time of 7 days. NCC-loaded hydrogels were evaluated using in vitro dissolution and cytotoxicity assays. In vitro dissolution undertaken using membrane-less diffusion over 168 h revealed that 3TC and AZT release from NCC-loaded hydrogels was complete and followed zero-order kinetic processes, whereas those loaded with the micro co-crystal and physical mixture were incomplete and best described using the Korsmeyer–Peppas kinetic model. The release of AZT and 3TC from the physical mixture and MCC-loaded gel exhibited a value for n of 0.595 for AZT release from the physical mixture and 0.540 for the MCC technology, whereas the release exponent for 3TC was 0.513 for the physical mixture and 0.557 for the MCC technology indicating that diffusion and erosion controlled 3TC and AZT release. In vitro cytotoxicity assay data revealed that the addition of NCC to the thermoresponsive hydrogel resulted in an improved cell viability of 88.0% ± 5.0% when compared to the cell viability of the NCC of 76.9% ± 5.0%. The results suggest that the use of a thermoresponsive nanosuspension may have the potential to be delivered as an intramuscular injection that can subsequently increase bioavailability and permit dose reduction and/or permit use of a longer dosing frequency.
- Full Text:
- Date Issued: 2021
- Authors: Witika, Bwalya A , Stander, Jessé-Clint , Smith, Vincent J , Walker, Roderick B
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/183137 , vital:43915 , xlink:href="https://doi.org/10.3390/pharmaceutics13020127"
- Description: Currently, the human immunodeficiency virus (HIV) that causes acquired immunodeficiency syndrome (AIDS) can only be treated successfully, using combination antiretroviral (ARV) therapy. Lamivudine (3TC) and zidovudine (AZT), two compounds used for the treatment of HIV and prevention of disease progression to AIDS are used in such combinations. Successful therapy with 3TC and AZT requires frequent dosing that may lead to reduced adherence, resistance and consequently treatment failure. Improved toxicity profiles of 3TC and AZT were observed when combined as a nano co-crystal (NCC). The use of stimuli-responsive delivery systems provides an opportunity to overcome the challenge of frequent dosing, by controlling and/or sustaining delivery of drugs. Preliminary studies undertaken to identify a suitable composition for a stimulus-responsive in situ forming hydrogel carrier for 3TC-AZT NCC were conducted, and the gelation and erosion time were determined. A 25% w/w Pluronic® F-127 thermoresponsive hydrogel was identified as a suitable carrier as it exhibited a gelation time of 5 min and an erosion time of 7 days. NCC-loaded hydrogels were evaluated using in vitro dissolution and cytotoxicity assays. In vitro dissolution undertaken using membrane-less diffusion over 168 h revealed that 3TC and AZT release from NCC-loaded hydrogels was complete and followed zero-order kinetic processes, whereas those loaded with the micro co-crystal and physical mixture were incomplete and best described using the Korsmeyer–Peppas kinetic model. The release of AZT and 3TC from the physical mixture and MCC-loaded gel exhibited a value for n of 0.595 for AZT release from the physical mixture and 0.540 for the MCC technology, whereas the release exponent for 3TC was 0.513 for the physical mixture and 0.557 for the MCC technology indicating that diffusion and erosion controlled 3TC and AZT release. In vitro cytotoxicity assay data revealed that the addition of NCC to the thermoresponsive hydrogel resulted in an improved cell viability of 88.0% ± 5.0% when compared to the cell viability of the NCC of 76.9% ± 5.0%. The results suggest that the use of a thermoresponsive nanosuspension may have the potential to be delivered as an intramuscular injection that can subsequently increase bioavailability and permit dose reduction and/or permit use of a longer dosing frequency.
- Full Text:
- Date Issued: 2021
Top-Down Synthesis of a Lamivudine-Zidovudine Nano Co-Crystal
- Witika, Bwalya A, Smith, Vincent J, Walker, Roderick B
- Authors: Witika, Bwalya A , Smith, Vincent J , Walker, Roderick B
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/183172 , vital:43918 , xlink:href="https://doi.org/10.3390/cryst11010033"
- Description: Lamivudine (3TC) and zidovudine (AZT) are antiretroviral agents used to manage HIV/AIDS infection. A wet media milling top-down approach was used to develop and produce nano co-crystals of 3TC and AZT. Micro co-crystals were prepared by solvent evaporation and subsequently milled in the presence of two surfactants, viz., sodium lauryl sulfate (SLS) and α-tocopheryl polyethylene glycol succinate 1000 (TPGS 1000). Optimisation was undertaken using design of experiments (DoE) and response surface methodology (RSM) to establish and identify parameters that may affect the manufacturing of nano co-crystals. The impact of SLS and TPGS 1000 concentration, milling time, and number of units of milling medium on the manufacturing of nano co-crystals, was investigated. The critical quality attributes (CQA) monitored were particle size (PS), Zeta potential (ZP), and polydispersity index (PDI). Powder X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry, transmission electron microscopy, energy dispersive X-ray spectroscopy scanning electron microscopy, and cytotoxicity assays were used for additional characterization of the optimised nano co-crystal. The mean PS, PDI, and ZP of the optimised top-down nanocrystal were 271.0 ± 92.0 nm, 0.467 ± 0.073, and −41.9 ± 3.94 mV, respectively. In conclusion, a simple, inexpensive, rapid, and precise method of nano co-crystal manufacturing was developed, validated, and optimised using DoE and RSM, and the final product exhibited the target CQA.
- Full Text:
- Date Issued: 2021
- Authors: Witika, Bwalya A , Smith, Vincent J , Walker, Roderick B
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/183172 , vital:43918 , xlink:href="https://doi.org/10.3390/cryst11010033"
- Description: Lamivudine (3TC) and zidovudine (AZT) are antiretroviral agents used to manage HIV/AIDS infection. A wet media milling top-down approach was used to develop and produce nano co-crystals of 3TC and AZT. Micro co-crystals were prepared by solvent evaporation and subsequently milled in the presence of two surfactants, viz., sodium lauryl sulfate (SLS) and α-tocopheryl polyethylene glycol succinate 1000 (TPGS 1000). Optimisation was undertaken using design of experiments (DoE) and response surface methodology (RSM) to establish and identify parameters that may affect the manufacturing of nano co-crystals. The impact of SLS and TPGS 1000 concentration, milling time, and number of units of milling medium on the manufacturing of nano co-crystals, was investigated. The critical quality attributes (CQA) monitored were particle size (PS), Zeta potential (ZP), and polydispersity index (PDI). Powder X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry, transmission electron microscopy, energy dispersive X-ray spectroscopy scanning electron microscopy, and cytotoxicity assays were used for additional characterization of the optimised nano co-crystal. The mean PS, PDI, and ZP of the optimised top-down nanocrystal were 271.0 ± 92.0 nm, 0.467 ± 0.073, and −41.9 ± 3.94 mV, respectively. In conclusion, a simple, inexpensive, rapid, and precise method of nano co-crystal manufacturing was developed, validated, and optimised using DoE and RSM, and the final product exhibited the target CQA.
- Full Text:
- Date Issued: 2021
A comparative study of the effect of different stabilizers on the critical quality attributes of self-assembling nano co-crystals
- Witika, Bwalya A, Smith, Vincent J, Walker, Roderick B
- Authors: Witika, Bwalya A , Smith, Vincent J , Walker, Roderick B
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/183224 , vital:43931 , xlink:href=" https://doi.org/10.3390/pharmaceutics12020182"
- Description: Lamivudine (3TC) and zidovudine (AZT) are antiviral agents used orally to manage HIV/AIDS infection. A pseudo one-solvent bottom-up approach was used to develop and produce nano co-crystals of 3TC and AZT. Equimolar amounts of 3TC dissolved in de-ionized water and AZT in methanol were rapidly injected into a pre-cooled vessel and sonicated at 4 °C. The resultant suspensions were characterized using a Zetasizer. The particle size, polydispersity index and Zeta potential were elucidated. Further characterization was undertaken using powder X-ray diffraction, Raman spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, and energy dispersive X-ray spectroscopy scanning electron microscopy. Different surfactants were assessed for their ability to stabilize the nano co-crystals and for their ability to produce nano co-crystals with specific and desirable critical quality attributes (CQA) including particle size (PS) less than 1000 nm, polydispersity index (PDI) less than 0.500 and Zeta potential (ZP) less than −30 mV. All surfactants produced co-crystals in the nanometer range. The PDI and PS are concentration-dependent for all nano co-crystals manufactured while only ZP was within specification when sodium dodecyl sulfate was used in the process.
- Full Text:
- Date Issued: 2020
- Authors: Witika, Bwalya A , Smith, Vincent J , Walker, Roderick B
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/183224 , vital:43931 , xlink:href=" https://doi.org/10.3390/pharmaceutics12020182"
- Description: Lamivudine (3TC) and zidovudine (AZT) are antiviral agents used orally to manage HIV/AIDS infection. A pseudo one-solvent bottom-up approach was used to develop and produce nano co-crystals of 3TC and AZT. Equimolar amounts of 3TC dissolved in de-ionized water and AZT in methanol were rapidly injected into a pre-cooled vessel and sonicated at 4 °C. The resultant suspensions were characterized using a Zetasizer. The particle size, polydispersity index and Zeta potential were elucidated. Further characterization was undertaken using powder X-ray diffraction, Raman spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, and energy dispersive X-ray spectroscopy scanning electron microscopy. Different surfactants were assessed for their ability to stabilize the nano co-crystals and for their ability to produce nano co-crystals with specific and desirable critical quality attributes (CQA) including particle size (PS) less than 1000 nm, polydispersity index (PDI) less than 0.500 and Zeta potential (ZP) less than −30 mV. All surfactants produced co-crystals in the nanometer range. The PDI and PS are concentration-dependent for all nano co-crystals manufactured while only ZP was within specification when sodium dodecyl sulfate was used in the process.
- Full Text:
- Date Issued: 2020
Quality by Design Optimization of Cold Sonochemical Synthesis of Zidovudine-Lamivudine Nanosuspensions:
- Witika, Bwalya A, Smith, Vincent J, Walker, Roderick B
- Authors: Witika, Bwalya A , Smith, Vincent J , Walker, Roderick B
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148424 , vital:38738 , https://doi.org/10.3390/pharmaceutics12040367
- Description: Lamivudine (3TC) and zidovudine (AZT) are antiviral agents used to manage HIV/AIDS infection. The compounds require frequent dosing, exhibit unpredictable bioavailability and a side effect profile that includes hepato- and haema-toxicity. A novel pseudo one-solvent bottom-up approach and Design of Experiments using sodium dodecyl sulphate (SDS) and α-tocopheryl polyethylene glycol succinate 1000 (TPGS 1000) to electrosterically stablize the nano co-crystals was used to develop, produce and optimize 3TC and AZT nano co-crystals. Equimolar solutions of 3TC in surfactant dissolved in de-ionised water and AZT in methanol were rapidly injected into a vessel and sonicated at 4 °C.
- Full Text:
- Date Issued: 2020
- Authors: Witika, Bwalya A , Smith, Vincent J , Walker, Roderick B
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148424 , vital:38738 , https://doi.org/10.3390/pharmaceutics12040367
- Description: Lamivudine (3TC) and zidovudine (AZT) are antiviral agents used to manage HIV/AIDS infection. The compounds require frequent dosing, exhibit unpredictable bioavailability and a side effect profile that includes hepato- and haema-toxicity. A novel pseudo one-solvent bottom-up approach and Design of Experiments using sodium dodecyl sulphate (SDS) and α-tocopheryl polyethylene glycol succinate 1000 (TPGS 1000) to electrosterically stablize the nano co-crystals was used to develop, produce and optimize 3TC and AZT nano co-crystals. Equimolar solutions of 3TC in surfactant dissolved in de-ionised water and AZT in methanol were rapidly injected into a vessel and sonicated at 4 °C.
- Full Text:
- Date Issued: 2020
Synthesis, structure and in vitro anti-trypanosomal activity of non-toxic Arylpyrrole-Based Chalcone derivatives:
- Zulu, Ayanda I, Oderinlo, Ogunyemi O, Kruger, Cuan, Isaacs, Michelle, Hoppe, Heinrich C, Smith, Vincent J, Veale, Clinton G L, Khanye, Setshaba D
- Authors: Zulu, Ayanda I , Oderinlo, Ogunyemi O , Kruger, Cuan , Isaacs, Michelle , Hoppe, Heinrich C , Smith, Vincent J , Veale, Clinton G L , Khanye, Setshaba D
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/179017 , vital:40096 , https://doi.org/10.3390/molecules25071668
- Description: With an intention of identifying chalcone derivatives exhibiting anti-protozoal activity, a cohort of relatively unexplored arylpyrrole-based chalcone derivatives were synthesized in moderate to good yields. The resultant compounds were evaluated in vitro for their potential activity against a cultured Trypanosoma brucei brucei 427 strain. Several compounds displayed mostly modest in vitro anti-trypanosomal activity with compounds 10e and 10h emerging as active candidates with IC50 values of 4.09 and 5.11 µM, respectively. More importantly, a concomitant assessment of their activity against a human cervix adenocarcinoma (HeLa) cell line revealed that these compounds are non-toxic.
- Full Text:
- Date Issued: 2020
- Authors: Zulu, Ayanda I , Oderinlo, Ogunyemi O , Kruger, Cuan , Isaacs, Michelle , Hoppe, Heinrich C , Smith, Vincent J , Veale, Clinton G L , Khanye, Setshaba D
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/179017 , vital:40096 , https://doi.org/10.3390/molecules25071668
- Description: With an intention of identifying chalcone derivatives exhibiting anti-protozoal activity, a cohort of relatively unexplored arylpyrrole-based chalcone derivatives were synthesized in moderate to good yields. The resultant compounds were evaluated in vitro for their potential activity against a cultured Trypanosoma brucei brucei 427 strain. Several compounds displayed mostly modest in vitro anti-trypanosomal activity with compounds 10e and 10h emerging as active candidates with IC50 values of 4.09 and 5.11 µM, respectively. More importantly, a concomitant assessment of their activity against a human cervix adenocarcinoma (HeLa) cell line revealed that these compounds are non-toxic.
- Full Text:
- Date Issued: 2020
New thiazolidine-2,4-dione derivatives combined with organometallic ferrocene: Synthesis, structure and antiparasitic activity
- Oderinlo, Ogunyemi O, Tukulula, Matshawandile, Isaacs, Michelle, Taylor, Dale, Smith, Vincent J, Khanye, Setshaba D, Hoppe, Heinrich C
- Authors: Oderinlo, Ogunyemi O , Tukulula, Matshawandile , Isaacs, Michelle , Taylor, Dale , Smith, Vincent J , Khanye, Setshaba D , Hoppe, Heinrich C
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/122978 , vital:35382 , https://doi.org/10.1002/aoc.4385
- Description: Favourable physicochemical properties of an organometallic ferrocene and antiplasmodial potency of compounds containing the thiazolidine‐2,4‐dione framework (TZD‐4) prompted us to explore compounds containing both the thiazolidine‐2,4‐dione core and the ferrocenyl unit with the primary aim of identifying compounds with promising antiprotozoal activities. Thus, a new series of rationally designed ferrocene‐based thiazolidine‐2,4‐dione derivatives, containing a selection of secondary cyclic amines, was synthesised and fully characterised using standard spectroscopic techniques. The resulting compounds were screened for their antiplasmodial and antitrypanosomal activities against both the chloroquine‐resistant (Dd2) strain of Plasmodium falciparum and the Nagana Trypanosoma brucei brucei 427. The general trend that emerged indicated that the target compounds were more selective towards T. b. brucei compared to the P. falciparum parasite. Moreover, the analogues bearing methylpiperazine (8a) and piperidine (8b) rings were more active against T. b. brucei compared to hit compound TZD‐4. Except compound 8b, which appeared promising, none of the synthesised compounds showed better activity than TZD‐4 against the P. falciparum parasite. All the synthesised compounds were non‐toxic and often showed >90% viability of the HeLa cell line screened.
- Full Text:
- Date Issued: 2018
- Authors: Oderinlo, Ogunyemi O , Tukulula, Matshawandile , Isaacs, Michelle , Taylor, Dale , Smith, Vincent J , Khanye, Setshaba D , Hoppe, Heinrich C
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/122978 , vital:35382 , https://doi.org/10.1002/aoc.4385
- Description: Favourable physicochemical properties of an organometallic ferrocene and antiplasmodial potency of compounds containing the thiazolidine‐2,4‐dione framework (TZD‐4) prompted us to explore compounds containing both the thiazolidine‐2,4‐dione core and the ferrocenyl unit with the primary aim of identifying compounds with promising antiprotozoal activities. Thus, a new series of rationally designed ferrocene‐based thiazolidine‐2,4‐dione derivatives, containing a selection of secondary cyclic amines, was synthesised and fully characterised using standard spectroscopic techniques. The resulting compounds were screened for their antiplasmodial and antitrypanosomal activities against both the chloroquine‐resistant (Dd2) strain of Plasmodium falciparum and the Nagana Trypanosoma brucei brucei 427. The general trend that emerged indicated that the target compounds were more selective towards T. b. brucei compared to the P. falciparum parasite. Moreover, the analogues bearing methylpiperazine (8a) and piperidine (8b) rings were more active against T. b. brucei compared to hit compound TZD‐4. Except compound 8b, which appeared promising, none of the synthesised compounds showed better activity than TZD‐4 against the P. falciparum parasite. All the synthesised compounds were non‐toxic and often showed >90% viability of the HeLa cell line screened.
- Full Text:
- Date Issued: 2018
A ring-closing metathesis approach to eight-membered benzannelated scaffolds and subsequent internal alkene isomerizations
- Taher, Abu, Aderibigbe, Blessing A, Morgans, Garreth L, Madeley, Lee G, Khanye, Setshaba D, Van der Westhuizen, Leandi, Fernandes, Manuel A, Smith, Vincent J, Michael, Joseph P, Green, Ivan R, Van Otterlo, Willem A L
- Authors: Taher, Abu , Aderibigbe, Blessing A , Morgans, Garreth L , Madeley, Lee G , Khanye, Setshaba D , Van der Westhuizen, Leandi , Fernandes, Manuel A , Smith, Vincent J , Michael, Joseph P , Green, Ivan R , Van Otterlo, Willem A L
- Date: 2013
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66252 , vital:28925 , https://doi.org/10.1016/j.tet.2012.12.043
- Description: publisher version , A set of eight-membered benzannelated heterocycles containing two heteroatoms (O,O, NR,NR and O,NR where R=protecting group) was synthesized by ring-closing metathesis from the corresponding ortho-bis-allyl precursors. In this manner, 7-methoxy-2,5-dihydro-1,6-benzodioxocine, 1,2,5,6-tetrahydro-1,6-benzodiazocines, 5,6-dihydro-2H-1,6-benzoxazocines and 5,6,9,10-tetrahydropyrido[2,3-b][1,4]diazocine were synthesized. A number of these compounds were then treated with the catalyst [RuClH(CO)(PPh3)3] to facilitate isomerization of the alkene into conjugation with the heteroatoms in the eight-membered ring. Quite surprisingly, an equal ratio of regioisomers was obtained, even if the heteroatoms were different.
- Full Text: false
- Date Issued: 2013
- Authors: Taher, Abu , Aderibigbe, Blessing A , Morgans, Garreth L , Madeley, Lee G , Khanye, Setshaba D , Van der Westhuizen, Leandi , Fernandes, Manuel A , Smith, Vincent J , Michael, Joseph P , Green, Ivan R , Van Otterlo, Willem A L
- Date: 2013
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66252 , vital:28925 , https://doi.org/10.1016/j.tet.2012.12.043
- Description: publisher version , A set of eight-membered benzannelated heterocycles containing two heteroatoms (O,O, NR,NR and O,NR where R=protecting group) was synthesized by ring-closing metathesis from the corresponding ortho-bis-allyl precursors. In this manner, 7-methoxy-2,5-dihydro-1,6-benzodioxocine, 1,2,5,6-tetrahydro-1,6-benzodiazocines, 5,6-dihydro-2H-1,6-benzoxazocines and 5,6,9,10-tetrahydropyrido[2,3-b][1,4]diazocine were synthesized. A number of these compounds were then treated with the catalyst [RuClH(CO)(PPh3)3] to facilitate isomerization of the alkene into conjugation with the heteroatoms in the eight-membered ring. Quite surprisingly, an equal ratio of regioisomers was obtained, even if the heteroatoms were different.
- Full Text: false
- Date Issued: 2013
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