Thesis ((M. Pharm. (Pharmaceutics)) -- University of Limpopo, 2019 / Epilepsy is the fourth most common neurological disorder after migraine, stroke and Alzheimer’s disease and it affects about fifty million people worldwide. Careful consideration should be taken when deciding to initiate treatment in epilepsy as it should consider the balance between the possibility of further seizures and their associated risks, including the possible risk of sudden expected death, inconvenience and the risks of taking regular medication for each individual. In the early 1980’s, the first-line treatment for epilepsy was polytherapy. This was due to findings that smaller doses of two drugs rather than larger doses of one drug can achieve synergistic effects or less drug toxicity. However, following more trials on the treatment of epilepsy, this was later changed to monotherapy as first-line treatment. Despite the change, patients remain uncontrolled on a single anti-epileptic drug, thus they are initiated on polytherapy, one such combination being carbamazepine in combination with sodium valproate. The use of these in combination has pharmacological threats such as compliance, the control of side effects and the achievement of synergistic effects. The development of a Fixed Dose Combination (FDC) has often been used to resolve pharmacological threats, and this study aims to develop a fixed dose combination tablet of carbamazepine and sodium valproate to resolve the pharmacological threats in epilepsy. Samples of carbamazepine and sodium valproate and a physical mixture (1:1 w/w) of both drugs and excipients were prepared for compatibility with thermal analysis and spectroscopy techniques. Data was analysed by comparing the DSC curves, FTIR spectra, XRPD peaks and TAM analysis of carbamazepine and sodium valproate alone and in their physical mixture (1:1 w/w) and with excipients. Both carbamazepine and sodium valproate were evaluated for flowability using angle of repose, tapped and bulk density, compressibility index and particle size distribution. To formulate the proposed FDC tablet of carbamazepine and sodium valproate, direct compression and wet granulation methods were employed. The tablets were then evaluated for official and non-official post formulation parameters (weight variation, crushing strength, friability, diameter and thickness, and disintegration) according to BP and USP standards. A standardised HPLC method was developed and validated for analytical procedures. Dissolution studies were conducted xiii according to USP methods to verify and quantify the release of the APIs from the FDC tablet. Carbamazepine and sodium valproate were tested for compatibility with excipients using DSC, FTIR, XRPD and TAM analysis. The overall results confirmed that carbamazepine and sodium valproate are compatible, with each other and the excipients used in the study. Powder flow of carbamazepine and sodium valproate was poor, hence they were subjected to granulation prior to compression to improve flowability. The specifications of the fixed-dose combination were developed in accordance with the FDA’s quality by design concept and WHO recommendations. The tablets were subjected to non-official and official pharmacopoeial tests, and passed all the tests. Dissolution studies according to a USP method were conducted to verify and quantify the release of the APIs in the fixed-dose combination. The initial dissolution rate (DRi) of carbamazepine and sodium valproate in the SLS dissolution medium was rapid as required for an immediate release formulation. The study aimed at developing a fixed dose combination of carbamazepine and sodium valproate to try to reduce the burden of taking more than one tablet for epilepsy. Based on the results obtained from preformulation studies to assay of the final product, the study was successful. / Chieta bursary and HWseta

South Africa has the largest HIV-infected population in the world, with 2015 estimates of 7 million people living with HIV and 180,000 AIDS-related deaths. The South African government began scale-up of a public-sector HIV care and treatment program in 2004, and by the end of 2015, 3.4 million HIV-infected individuals were on antiretroviral therapy (ART). When scale-up began in South Africa, ART was only available to HIV-infected individuals with CD4 counts ≤200 cells/µL or WHO clinical stage 4 disease. In 2010, treatment was extended to patients who were pregnant or who had tuberculosis and a CD4 ≤350 cells/µL, and in 2011, eligibility was extended to all patients with CD4 ≤350 cells/µL. In 2013 patients with WHO clinical stage 3 disease became eligible. In 2015, the eligibility threshold was increased to CD4 ≤500 cells/µL, and in 2016, the South African National Department of Health announced that the country would implement a “test and treat” strategy, offering free ART to all HIV-infected individuals, regardless of CD4 count. This dissertation examines the effectiveness of several expansions and modifications to South Africa’s treatment program. In study 1, we investigated whether the 2011 extension of HIV treatment to patients with CD4 counts ≤350 cells/µL successfully increased the number of newly-eligible patients on treatment (those with CD4 counts between 201–350 cells/µL) without crowding out previously-eligible patients with more severe disease (CD4 counts ≤200 cells/µL), focusing on a network of rural clinics in KwaZulu-Natal. We found encouraging results, with newly-eligible patients (CD4 201–350) initiating treatment at a greater frequency (73.0 additional patients per month; 95% CI: 42.1; 103.9) and 47% faster than before (95% CI: 19%; 82%), while previously eligible patients (CD4 ≤200) experienced no decline in the number of patients initiating treatment or the speed of treatment uptake. In study 2, we evaluated whether the introduction of a single-pill fixed-dose combination (FDC) treatment for ART initiators in South Africa had an impact on attrition from care compared to the previously-recommended multiple-pill regimen. We focused on an urban clinic in Johannesburg, using four different clinic attendance measures to define attrition (generally a combined measure of loss to follow-up and mortality). An intention-to-treat analysis revealed an estimated 11.3 percentage point decrease in attrition (95% CI: -22.0; -0.6) associated with the policy change, while a regression discontinuity analysis estimated an 18.0 percentage point drop in attrition (95% CI: -33.6; -2.4) associated with single-pill FDC treatment relative to multiple pills, controlling for unmeasured confounding. In study 3, we used stratified instrumental variable analysis to examine whether the effect of FDCs on attrition varied across subsets of the patient population in the same Johannesburg clinic we evaluated in study 2. We saw larger effects among women (RD -0.25; 95% CI: -0.42; -0.09), non-anemic patients (RD -0.24; 95% CI: -0.41; -0.08), patients with early-stage (as opposed to advanced) clinical disease (RD -0.20; 95% CI: -0.32; -0.07), and those with high CD4 counts (for CD4 ≥350 cells/µL, RD -0.58; 95% CI: -1.58; 0.42). These results suggest that healthier patients saw the greatest improvement in retention in care following the switch from multiple-pill to single-pill regimens. In an era where the healthiest HIV-infected patients are now being targeted for ART treatment, FDCs can play a large role in preventing attrition from care. These three studies depict an HIV program that has successfully grown to treat increasing numbers of patients using up-to-date strategies of care. Given the immense scale and cost of South Africa’s HIV treatment program, it is important to continue to monitor its effectiveness, especially as it introduces new treatments and strategies and adapts to the changing epidemic.

Yes / Polypharmacy is often needed for the management of cardiovascular diseases and is associated with poor adherence to treatment. Hence, highly flexible and adaptable systems are in high demand to accommodate complex therapeutic regimens. A novel design approach is employed to fabricate highly modular 3D printed “polypill” capsules with bespoke release patterns for multiple drugs. Complex structures are devised using combined fused deposition modeling 3D printing aligned with hot-filling syringes. Two unibody highly modular capsule skeletons with four separate compartments are devised: i) concentric format: two external compartments for early release while two inner compartments for delayed release, or ii) parallel format: where nondissolving capsule shells with free-pass corridors and dissolution rate-limiting pores are used to achieve immediate and extended drug releases, respectively. Controlling drug release is achieved through digital manipulation of shell thickness in the concentric format or the size of the rate limiting pores in the parallel format. Target drug release profiles are achieved with variable orders and configurations, hence confirming the modular nature with capacity to accommodate therapeutics of different properties. Projection of the pharmacokinetic profile of this digital system capsules reveal how the developed approach can be applied in dose individualization and achieving multiple desired pharmacokinetic profiles.

Magister Scientiae - MSc (Pharmaceutical Chemistry) / The rapid increase in access to new antiretrovirals (ARVs) worldwide and, especially in sub-Saharan Africa, coupled with the well-documented problem of poor quality ARVs in developing countries has underscored the need for quality assessment of these medicines. South Africa has the worst human immunodeficiency virus (HIV) epidemic profile in the world; consequently, it has rolled out the world's largest antiretroviral ARV programme. With increasing market penetration of generic medicine in South Africa and especially ARVs, there is a call for stringent quality control mechanisms following the marketing approval (post-market quality control) of these medications. Unfortunately, evidence suggests that the World Health Organisation (WHO) recommendations for this aspect of quality assurance is not met by most Medicine Regulatory Authorities. In South Africa and many other countries this is attributed to a lack of physical and financial resources to enforce effective post-marketing surveillance (PMS) of all pharmaceuticals available in the country.

Hypertoni är en riskfaktor för allvarliga kardiovaskulära sjukdomar. Olika läkemedelsklasser används vid behandling av hypertoni. Dessa inkluderar angiotensin omvandlade enzymhämmare, angiotensin II-receptorblockerare, kalciumkanalblockerare och tiaziddiuretika. Även om nuvarande läkemedelsterapier kan vara effektiva, är det få som kan uppnå målblodtryck. De flesta patienter med hypertoni kräver minst två antihypertensiva läkemedel för att uppnå sitt målblodtryck. Detta ledde till komplicerade behandlingsmetoder som i sin tur har blivit en stor bidragande faktor till dålig patientföljsamhet. Även om ett stort antal läkemedel finns tillgängliga för behandling, är kontrollen av blodtryck dålig på grund av patienternas dåliga följsamhet till medicinering som vanligtvis är en kombination av flera substanser. Följsamheten minskar med antalet tabletter som en patient behöver ta vilket leder till en komplicerad behandlingsstrategi.  Syftet med detta examensarbete var att undersöka blodtryckssänkande effekt med en enkel tablettform Single-Pill Combination (SPC) som innehåller en kombination av flera antihypertensiva läkemedelsklasser och att undersöka patienternas följsamhet till (SPC) behandling.  Metod det här arbetet är en litteraturstudie utförd i PubMed. Olika sökord användes” single-pill combination in hypertension”, “Fixed dose combination in hypertension “, “Adherence to single-pill combination in hypertension”. Sökningen filtrerades till “Randomized controlled trial”. Nya studier valdes ut som undersökte effekten av SPC och följsamhet till behandling. Resultat Studier 1,2,3 och 4 som undersökte effekten gav positiva resultat som gynnade SPC framför standardmonoterapi och placebo. SPC kunde minska blodtrycket statiskt signifikant i alla studierna. I studie 1 blev den genomsnittliga skillnaden i SBT mellan grupperna (–6,9) mm Hg med (p-värde <0,001). I studie 2 blev skillnaden i genomsnittlig 24-timmars SBT mellan SPC- och placeboperioder (–18,7) mm Hg med p-värde <0,0001. I studie 3 blev SBT-förändringar på klinik -16,5 ± (15,5) mm Hg (p <0,001) med amlodipin/valsartan FDC och -6,9 ± (11,4) mm Hg (p = 0,012) med valsartan monoterapi medan motsvarande förändringar i DBP i Office var -9,8 ± (7,7) mm Hg (p <0,001) respektive -2,5 ± (6,6) mm Hg (p = 0,095). Resultat av studie 4 visade att andelen deltagare som uppnådde målblodtryck efter 6 månader (SBT <140, DBT <90 mm Hg) blev 69% i SPC gruppen och 55,3% i monoterapi gruppen. I studie 5 kunde ingen signifikant skillnad i följsamheten observeras mellan SPC gruppen och FEC gruppen. Följsamhetsgraden var 98% i båda grupperna. Studie 6 rapporterade signifikant resultat där PDT blev 95,1 % i SPC gruppen och 92,1% i kontrollgruppen p-värde <0,05.  Slutsats Alla resultat i studierna 1,2,3 och 4 gynnade signifikant SPC när det gäller effekten. Studie 6 visade att patienternas följsamhet till behandling var bättre i SPC gruppen än kontrollgrupp. Studie 5 kunde inte ge signifikanta resultat avseende följsamheten till SPC jämfört med FEC. Fler RCT studier behövs för att undersöka om SPC kan leda till bättre följsamhet hos hypertonipatienter / Background Hypertension is a risk factor for serious cardiovascular diseases. Different drug classes are used in the treatment of hypertension. These include angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, and thiazide diuretics. Although current drug therapies can be effective, few are able to achieve target blood pressure therefore it has become well-known that most hypertensive patients require at least two antihypertensive drugs to reach their target blood pressure. This led to complicated treatment methods, which in turn has become a significant contributing factor to poor patient compliance. When two or more drug classes are combined, this contributes to improved efficacy, as different mechanisms of action work together to block different pathways to high blood pressure. This leads to lower doses of the individual components being used, which results in a reduced likelihood of side effects. Although a large number of drugs are available for treatment, there is still poor control of blood pressure due to patients' poor adherence to medication, which is usually a combination of several substances. Adherence decreases with the number of tablets a patient needs to take, leading to a complicated treatment strategy. Lower levels of adherence are associated with poorer blood pressure control. Aim The aim of the work is to investigate the blood pressure-lowering effect with a simple tablet form "Single-Pill Combination" (SPC) that contains a combination of several antihypertensive drug classes and to investigate the patients' adherence to this form of treatment (SPC). Method This work is a literature study carried out in Pubmed. Different search terms were used: "single-pill combination for the treatment of hypertension", "Fixed dose combination in hypertension", and "Adherence to single-pill combination for hypertension". The search was filtered to "Randomized controlled trial". New studies were selected that investigated the effect of single-pill combination and blood pressure control and adherence to treatment. Results Studies 1, 2, 3, and 4 investigating the efficacy produced positive results favoring SPC over standard monotherapy and placebo. SPC was able to reduce blood pressure statically significantly in all studies. In Study 1, the primary outcome variable was the mean difference in SBT between groups (–6.9) mm Hg with (p-value <0.001). In Study 2, the difference in mean 24-hour SBT between SPC and placebo periods was (–18.7) mm Hg with a p-value <0.0001. Whereas in Study 3, in-clinic SBT changes were -16.5 ± (15.5) mm Hg (p < 0.001) with amlodipine/valsartan FDC and -6.9 ± (11.4) mm Hg (p = 0.012) with valsartan monotherapy while the corresponding changes in DBP in Office were -9.8 ± (7.7) mm Hg (p <0.001) and -2.5 ± (6.6) mm Hg (p = 0.095), respectively. The results of study 4 were that the percentage of participants who achieved target blood pressure after 6 months (SBT <140, DBT <90 mm Hg) was 69% in the SPC group and 55.3% in the monotherapy group. In study 5, no significant difference in compliance could be observed between the SPC group and the FEC group. The compliance rate was 98% in both groups. While study 6 reported significant results where PDT was 95.1% in the SPC group and 92.1% in the control group p-value <0.05. Conclusion All results in studies 1,2,3and 4 significantly favored SPC in terms of efficacy. Study 6 showed that patients’ adherence to treatment was better in the SPC group than in the control group. While study 5 which was the first RCT study in this area could not provide positive and significant results regarding the adherence to SPC compared to FEC. More RCT studies are needed to investigate whether SPC can lead to better adherence in hypertensive patients.

Made available in DSpace on 2016-04-04T12:26:00Z (GMT). No. of bitstreams: 2 2.pdf: 3729000 bytes, checksum: 78661b59dc7c742033ca6ce5a153cc47 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2013 / Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos/Farmanguinhos. Rio de Janeiro, RJ, Brasil. / O crescimento do número de casos de tuberculose no Brasil fez com que o Governo Federal desenvolvesse uma política nacional de controle da tuberculose que possibilitasse melhorar e prolongar a qualidade de vida dos indivíduos infectados. Esta política inclui, entre várias outras iniciativas, o aumento na adesão de pacientes com um tratamento terapêutico adequado utilizando Formulações de Doses Fixas Combinadas (FDC), contendo os fármacos aos quais o bacilo de Koch é mais sensível. Um dos pontos críticos para o desenvolvimento de tuberculostáticos é o desenvolvimento de metodologias analíticas para seu controle que sejam viáveis, eficazes e robustas, uma vez que a rifampicina um dos insumos farmacêuticos ativos (IFAs) da associação apresenta características peculiares como a sua baixa estabilidade em solução, o que pode levar à formação de muitos produtos de degradação. O presente estudo tem por objetivo otimizar e validar uma metodologia analítica que seja adequada à rotina de um laboratório de controle de qualidade para a determinação dos fármacos isoniazida e rifampicina (ambos IFAs da formulação) e suas substâncias relacionadas, associados em comprimidos de dose fixa combinada para serem utilizados no tratamento dos casos da tuberculose e serem distribuídos pelo Sistema Único de Saúde. Para tanto, foi otimizada e validada uma metodologia analítica utilizando a técnica de cromatografia líquida de alta eficiência (CLAE) capaz de determinar não só o teor dos insumos farmacêuticos ativos (IFAs) presentes na formulação, mas também de quantificar as suas substâncias relacionadas. Um estudo de estabilidade de longa e acelerada durações também foi conduzido e a metodologia analítica otimizada e validada foi usada para avaliação dos comprimidos, mostrando sua capacidade de detectar o esperado decaimento do teor dos IFAs e o aumento no teor de suas substâncias relacionadas. Posteriormente, houve a transferência do método para a técnica de cromatografia líquida de ultraeficiência (CLUE), visando uma análise cromatográfica em tempo mais curto e uma maior sensibilidade do método. Essa metodologia utilizando a técnica de CLUE também foi validada. / As the number of tuberculosis (TB) cases in Brazil is rising, the brazilian Government implemented a national policy for TB control that would enable to improve and endure the quality of life in infected individuals. This policy includes, among many actions, the increase of the patient’s adhesion by a therapeutic treatment using suitable formulations of Fixed Dose Combination (FDC) including drugs to which M. tuberculosis is more sensitive. One critical point for FDC formulation development is the establishment of viable, effective and robust analytical methods for its quality control, since rifampicin – one of the formulation’s active pharmaceutical ingredient (API) – has particular characteristics such as its low stability in aqueous solution, which can lead to formation of many degradation products. This study aims to optimize and validate an analytical methodology for the determination of isoniazid and rifampicin (both APIs in the formulation) and their related substances en tablets with fixed dose. This medicines will be distributed by the national health system for the treatment of tuberculosis patients. Therefore, an analytical method was optimized and validated using the technique of high performance liquid chromatography (HPLC) that can evaluate not only the dosage of APIs in the formulation, but also to determine their related substances. A stability study of accelerated and long durations was also conducted and the optimized analytical method was used to evaluate the tablet, showing its ability to detect the expected reduction of API dosage and the increase in the amount of its related products. Later, an upgrade of the optimized and validated method to ultra-high performance liquid chromatography (UPLC) was succefully performed, with the reduced chromatographic analysis time and increased sensitivity. This UPLC methodology has also been validated.

Malaria affects about forty percent of the world’s population. Annually more than 1.5 million fatalities due to malaria occur and parasite resistance to existing antimalarial drugs such as mefloquine has already reached disturbingly high levels in South-East Asia and on the African continent. Consequently, there is a dire need for new drugs or formulations in the prophylaxis and treatment of malaria. Artesunate, an artemisinin derivative, represents a new category of antimalarials that is effective against drug-resistant Plasmodium falciparum strains and is of significance in the current antimalarial campaign. As formulating an ACT double fixed-dose combination is technically difficult, it is essential that fixed-dose combinations are shown to have satisfactory ingredient compatibility, stability, and dissolution rates similar to the separate oral dosage forms. Since the general deployment of a combination of artesunate and mefloquine in 1994, the cure rate increased again to almost 100% from 1998 onwards, and there has been a sustained decline in the incidence of Plasmodium falciparum malaria in the experimental studies (Nosten et al., 2000:297; WHO, 2010:17). However, the successful formulation of a solid oral dosage form and fixed dosage combination of artesunate and mefloquine remains both a market opportunity and a challenge. Artesunate and mefloquine both exhibited poor flow properties. Furthermore, different elimination half-lives, treatment dosages as well as solubility properties of artesunate and mefloquine required different formulation approaches. To substantiate the FDA’s pharmaceutical quality by design concept, the double fixed-dose combination of artesunate and mefloquine required strict preliminary formulation considerations regarding compatibility between excipients and between the APIs. Materials and process methods were only considered if theoretically and experimentally proved safe. Infrared absorption spectroscopy (IR) and X-ray powder diffraction (XRPD) data proved compatibility between ingredients and stability during the complete manufacturing process by a peak by peak correlation. Scanning Electron Micrographs (SEM) provided explanations for the inferior flow properties exhibited by the investigated APIs. Particle size analysis and SEM micrographs confirmed that the larger, rounder and more consistently sized particles of the granulated APIs contributed to improved flow under the specified testing conditions. A compressible mixture containing 615 mg of the APIs in accordance with the WHO recommendation of 25 mg/kg of mefloquine taken in two or three divided dosages, and 4 mg/kg/day for 3 days of artesunate for uncomplicated falciparum malaria was developed. Mini-tablets of artesunate and mefloquine were compressed separately and successfully with the required therapeutic dosages and complied with pharmacopoeial standards. Preformulation studies eventually led to a formula for a double fixed-dose combination and with the specific aim of delaying the release of artesunate due to its short half-life. A factorial design revealed the predominant factors contributing to the successful wet granulation of artesunate and mefloquine. A fractional factorial design identified the optimum factors and factor levels. The application of the granulation fluid (20% w/w) proved to be sufficient by a spraying method for both artesunate and mefloquine. A compatible acrylic polymer and coating agent for artesunate, Eudragit® L100 was employed to delay the release of approximately half of the artesunate dose from the double fixed-dose combination tablet until a pH of 6.8. A compressible mixture was identified and formulated to contain 200 mg of artesunate and 415 mg of mefloquine per tablet. The physical properties of the tablets complied with BP standards. An HPLC method from available literature was adapted and validated for analytical procedures. Dissolution studies according to a USP method were conducted to verify and quantify the release of the APIs in the double fixed-dose combination. The initial dissolution rate (DRi) of artesunate and mefloquine in the acidic dissolution medium was rapid as required. The enteric coated fraction of the artesunate exhibited no release in an acidic environment after 2 hours, but rapid release in a medium with a pH of 6.8. The structure of the granulated particles of mefloquine may have contributed to its first order release profile in the dissolution mediums. A linear correlation was present between the rate of mefloquine release and the percentage of mefloquine dissolved (R2 = 0.9484). Additionally, a linear relationship was found between the logarithm of the percentage mefloquine remaining against time (R2 = 0.9908). First order drug release is the dominant release profile found in the pharmaceutical industry today and is coherent with the kinetics of release obtained for mefloquine. A concept pre-clinical phase, double fixed-dose combination solid oral dosage form for artesunate and mefloquine was developed. The double fixed-dose combination was designed in accordance with the WHO’s recommendation for an oral dosage regimen of artesunate and mefloquine for the treatment of uncomplicated falciparum malaria. The specifications of the double fixed-dose combination were developed in close accordance with the FDA’s quality by design concept and WHO recommendations. An HPLC analytical procedure was developed to verify the presence of artesunate and mefloquine. The dissolution profiles of artesunate and mefloquine were investigated during the dissolution studies. / PhD (Pharmaceutics), North-West University, Potchefstroom Campus, 2014

Advancements in pulmonary drug delivery technologies have improved the use of dry powder inhalation therapy to treat respiratory and systemic diseases. Despite remarkable improvements in the development of dry powder inhaler devices (DPIs) and formulations in the last few years, an optimized DPI system has yet to be developed. In this work, we hypothesize that Thin Film Freezing (TFF) is a suitable technology to improve inhalation therapies to treat lung and systemic malignancies due to its ability to produce brittle powder with optimal aerodynamic properties. Also, we developed a performance verification test (PVT) for the Next Generation Cascade Impactor (NGI), which is one of the most important in vitro characterization methods to test inhalation. In the first study, we used TFF technology to produce amorphous and brittle particles of rapamycin, and compared the in vivo behavior by the pharmacokinetic profiles, to its crystalline counterpart when delivered to the lungs of rats via inhalation. It was found that TFF rapamycin presented higher in vivo systemic bioavailability than the crystalline formulation. Subsequently, we investigated the use of TFF technology to produce triple fixed dose therapy using formoterol fumarate, tiotropium bromide and budesonide as therapeutic drugs. We investigated applications of this technology to powder properties and in vitro aerosol performance with respect to single and combination therapy. As a result, the brittle TFF powders presented superior properties than the physical mixture of micronized crystalline powders, such as excellent particle distribution homogeneity after in vitro aerosolization. Lastly, we developed a PVT for the NGI that may be applicable to other cascade impactors, by investigating the use of a standardized pressurized metered dose inhaler (pMDI) with the NGI. Two standardized formulations were developed. Formulations were analyzed for repeatability and robustness, and found not to demonstrate significant differences in plate deposition using a single NGI apparatus. Variable conditions were introduced to the NGI to mimic operator and equipment failure. Introduction of the variable conditions to the NGI was found to significantly adjust the deposition patterns of the standardized formulations, suggesting that their use as a PVT could be useful and that further investigation is warranted. / text

Malaria affects about forty percent of the world’s population. Annually more than 1.5 million fatalities due to malaria occur and parasite resistance to existing antimalarial drugs such as mefloquine has already reached disturbingly high levels in South-East Asia and on the African continent. Consequently, there is a dire need for new drugs or formulations in the prophylaxis and treatment of malaria. Artesunate, an artemisinin derivative, represents a new category of antimalarials that is effective against drug-resistant Plasmodium falciparum strains and is of significance in the current antimalarial campaign. As formulating an ACT double fixed-dose combination is technically difficult, it is essential that fixed-dose combinations are shown to have satisfactory ingredient compatibility, stability, and dissolution rates similar to the separate oral dosage forms. Since the general deployment of a combination of artesunate and mefloquine in 1994, the cure rate increased again to almost 100% from 1998 onwards, and there has been a sustained decline in the incidence of Plasmodium falciparum malaria in the experimental studies (Nosten et al., 2000:297; WHO, 2010:17). However, the successful formulation of a solid oral dosage form and fixed dosage combination of artesunate and mefloquine remains both a market opportunity and a challenge. Artesunate and mefloquine both exhibited poor flow properties. Furthermore, different elimination half-lives, treatment dosages as well as solubility properties of artesunate and mefloquine required different formulation approaches. To substantiate the FDA’s pharmaceutical quality by design concept, the double fixed-dose combination of artesunate and mefloquine required strict preliminary formulation considerations regarding compatibility between excipients and between the APIs. Materials and process methods were only considered if theoretically and experimentally proved safe. Infrared absorption spectroscopy (IR) and X-ray powder diffraction (XRPD) data proved compatibility between ingredients and stability during the complete manufacturing process by a peak by peak correlation. Scanning Electron Micrographs (SEM) provided explanations for the inferior flow properties exhibited by the investigated APIs. Particle size analysis and SEM micrographs confirmed that the larger, rounder and more consistently sized particles of the granulated APIs contributed to improved flow under the specified testing conditions. A compressible mixture containing 615 mg of the APIs in accordance with the WHO recommendation of 25 mg/kg of mefloquine taken in two or three divided dosages, and 4 mg/kg/day for 3 days of artesunate for uncomplicated falciparum malaria was developed. Mini-tablets of artesunate and mefloquine were compressed separately and successfully with the required therapeutic dosages and complied with pharmacopoeial standards. Preformulation studies eventually led to a formula for a double fixed-dose combination and with the specific aim of delaying the release of artesunate due to its short half-life. A factorial design revealed the predominant factors contributing to the successful wet granulation of artesunate and mefloquine. A fractional factorial design identified the optimum factors and factor levels. The application of the granulation fluid (20% w/w) proved to be sufficient by a spraying method for both artesunate and mefloquine. A compatible acrylic polymer and coating agent for artesunate, Eudragit® L100 was employed to delay the release of approximately half of the artesunate dose from the double fixed-dose combination tablet until a pH of 6.8. A compressible mixture was identified and formulated to contain 200 mg of artesunate and 415 mg of mefloquine per tablet. The physical properties of the tablets complied with BP standards. An HPLC method from available literature was adapted and validated for analytical procedures. Dissolution studies according to a USP method were conducted to verify and quantify the release of the APIs in the double fixed-dose combination. The initial dissolution rate (DRi) of artesunate and mefloquine in the acidic dissolution medium was rapid as required. The enteric coated fraction of the artesunate exhibited no release in an acidic environment after 2 hours, but rapid release in a medium with a pH of 6.8. The structure of the granulated particles of mefloquine may have contributed to its first order release profile in the dissolution mediums. A linear correlation was present between the rate of mefloquine release and the percentage of mefloquine dissolved (R2 = 0.9484). Additionally, a linear relationship was found between the logarithm of the percentage mefloquine remaining against time (R2 = 0.9908). First order drug release is the dominant release profile found in the pharmaceutical industry today and is coherent with the kinetics of release obtained for mefloquine. A concept pre-clinical phase, double fixed-dose combination solid oral dosage form for artesunate and mefloquine was developed. The double fixed-dose combination was designed in accordance with the WHO’s recommendation for an oral dosage regimen of artesunate and mefloquine for the treatment of uncomplicated falciparum malaria. The specifications of the double fixed-dose combination were developed in close accordance with the FDA’s quality by design concept and WHO recommendations. An HPLC analytical procedure was developed to verify the presence of artesunate and mefloquine. The dissolution profiles of artesunate and mefloquine were investigated during the dissolution studies. / PhD (Pharmaceutics), North-West University, Potchefstroom Campus, 2014

Malaria is a life–threatening disease caused by Plasmodium spp and causes over one million deaths annually. The complex life cycle of the malaria parasite offers several points of attack for the antimalarial drugs. The rapid spread of resistance against antimalarial drugs, especially chloroquine and pyrimethamine–sulphadoxine, emphasises the need for new alternatives or modification of existing drugs. Artemisinin–based combination therapies (ACT’s) with different targets prevent or delay the development of drug resistance and therefore have been adopted as first–line therapy by all endemic countries. Proguanil–dapsone, an antifolate combination is more active than pyrimethamine–sulphadoxine and is being considered as an alternative to pyrimethamine–sulphadoxine. Artesunate–proguanil–dapsone is a new ACT that has wellmatched pharmacokinetics and is relatively rapidly eliminated; therefore there is a reduced risk of exposure to any single compound and potentially a decreasing risk of resistance. A few studies have been done on a triple fixed–dose combination therapy for malaria treatment and such a combination for artesunate, proguanil and dapsone are not currently investigated, manufactured or distributed. The aim of this study was to develop a triple fixed–dose combination for artesunate, proguanil and dapsone. The formulation was developed in three phases; basic formulation development, employing factorial design to obtain two possible optimised formulations and evaluating the optimised formulations. During the formulation development the most suitable manufacturing procedure and excipients were selected. A full 24 factorial design (four factors at two levels) was used to obtain the optimised formulations. As end–points to identify the optimised formulations, weight variation, friability, crushing strength and disintegration of the tablets, were used. Statistical analysis (one way ANOVA) was used to identify optimal formulations. To identify any interaction between the active pharmaceutical ingredients (API’s) and the API’s and excipients, differential scanning calorimetry was done. Flow properties of the powder mixtures (of the optimised formulations) were characterised by means of angle of repose; critical orifice diameter (COD); bulk density and tapped density; and flow rate. Tablets of the two optimised powder formulations were compressed. The tablets were evaluated and characterised in terms of weight variation, friability, crushing strength, disintegration and dissolution behaviour. Initial formulation development indicated that wet granulation was the most suitable manufacturing method. The results from the factorial design indicated that different amounts (% w/w) of the lubricant and binder as well as two different fillers influenced the weight variation, crushing strength and disintegration statistically significant. Two formulations containing two different fillers (microcrystalline cellulose or Avicel® PH 101, and lactose or Granulac® 200) were found to be within specifications and ideal for manufacturing. Tablets prepared from the FA formulation (formulation containing Avicel® PH 101) complied with the standards and guidelines for weight variation, friability, crushing strength and disintegration as set by the British Pharmacopoeia (BP). Tablets had an average crushing strength of 121.56 ± 0.022 N. Tablets disintegrated within 52.00 seconds and a maximum weight loss of 0.68% occurred during the friability test. Weight variation of the tablets prepared from the FG formulation (formulation containing Granulac® 200) complied with the standards. Average crushing strength was 91.99 ± 6.008 N and the tablets disintegrated within 140.00 seconds. Percentage friability (1.024%) did not comply with the guideline of a percentage friability of less than 1%, however, no cracked or broken tablets were seen. Dissolution showed that 98, 93 and 94% of artesunate, proguanil and dapsone were respectively released (of the label value) within 15 minutes for the FA formulations. Release of artesunate, proguanil and dapsone for the FG formulation was 62, 85 and 92% for the same time period. The release of the three API’s (the FG formulation) increased to 78, 89 and 92%, respectively, after 45 minutes. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2012.