The role of constraints and information gaps in driving risky medicine purchasing practices in four African countries.

Substandard and falsified (SF) medical products pose a major threat to public health and socioeconomic development, particularly in low- and middle-income countries. In response, public education campaigns have been developed to alert consumers about the risks of SF medicines and provide guidance on 'safer' practices, along with other demand- and supply-side measures. However, little is currently known about the potential effectiveness of such campaigns while structural constraints to accessing quality-assured medicines persist. This paper analyses survey data on medicine purchasing practices, information and constraints from four African countries (Ghana, Nigeria, Sierra Leone and Uganda; n > 1000 per country). Using multivariate regression and structural equation modelling, we present what we believe to be the first attempt to tease apart, statistically, the effects of an information gap vs structural constraints in driving potential public exposure to SF medicines. The analysis confirms that less privileged groups (including, variously, those in rural settlements, with low levels of formal education, not in paid employment, often women and households with a disability or long-term sickness) are disproportionately potentially exposed to SF medicines; these same demographic groups also tend to have lower levels of awareness and experience greater levels of constraint. Despite the constraints, our models suggest that public health education may have an important role to play in modifying some (but not all) risky practices. Appropriately targeted public messaging can thus be a useful part of the toolbox in the fight against SF medicines, but it can only work effectively in combination with wider-reaching reforms to address higher-level vulnerabilities in pharmaceutical supply chains in Africa and expand access to quality-assured public-sector health services.

A qualitative analysis of the COVID-19 vaccination rollout in Lagos, Nigeria: Client and provider perspectives on the plan, the process and the progress.

Mass vaccination has proven useful in the control of COVID-19, though vaccine rollout has met major challenges. The learning curve of this process has been valuable. This qualitative study aimed to assess the plan, the process and the progress of the COVID-19 vaccination rollout in Lagos, Nigeria. This study was conducted at vaccination centers in eight of the 20 Local Government Areas in Lagos State from May to July 2021 among healthcare administrators, health workers and vaccine recipients. Data were collected by conducting three key informant interviews, 24 in-depth interviews and eight focus group discussions to explore the vaccination experiences of participants and the challenges facing the vaccination plan and process. The interviews and discussions were recorded, transcribed verbatim and analyzed using the thematic approach. The four-phased plan for the vaccine rollout was clear to all the key informants because the vaccination process was preceded by training. The process was strengthened by the electronic registration system, though riddled by the frequently unstable electronic and internet data capturing. This was mitigated by a stopgap manual registration and recording of client details. Challenges in the logistics of maintaining supplies of the disposable materials required for the vaccination process were overcome by the creativity of the health professionals. Vaccine hesitancy, fueled by misinformation, myths and misconceptions about the vaccine and its side effects, played a huge role in the community response. The reported vaccine side effects were mild; fever, headaches, pain at the injection site, excessive eating and sleepiness. Though the COVID-19 vaccination process appeared to have largely made progress, the future of vaccination in Nigeria is predicated upon a bottom-up approach to programmatic planning, health education and local vaccine production. Collaborations such as public-private partnerships have the potential of boosting vaccine provision for Nigeria's large population to ensure equitable access to vaccines.

High shear mixing granulation of ibuprofen and beta-cyclodextrin: effects of process variables on ibuprofen dissolution.

The aims of the study were to evaluate the effect of high shear mixer (HSM) granulation process parameters and scale-up on wet mass consistency and granulation characteristics. A mixer torque rheometer (MTR) was employed to evaluate the granulating solvents used (water, isopropanol, and 1:1 vol/vol mixture of both) based on the wet mass consistency. Gral 25 and mini-HSM were used for the granulation. The MTR study showed that the water significantly enhanced the beta-cyclodextrin (beta CD) binding tendency and the strength of liquid bridges formed between the particles, whereas the isopropanol/water mixture yielded more suitable agglomerates. Mini-HSM granulation with the isopropanol/water mixture (1:1 vol/vol) showed a reduction in the extent of torque value rise by increasing the impeller speed as a result of more breakdown of agglomerates than coalescence. In contrast, increasing the impeller speed of the Gral 25 resulted in higher torque readings, larger granule size, and consequently, slower dissolution. This was due to a remarkable rise in temperature during Gral granulation that reduced the isopropanol/water ratio in the granulating solvent as a result of evaporation and consequently increased the beta CD binding strength. In general, the HSM granulation retarded ibuprofen dissolution compared with the physical mixture because of densification and agglomeration. However, a successful HSM granulation scale-up was not achieved due to the difference in the solvent mixture's effect from 1 scale to the other.

Development of topical ophthalmic In Situ gel-forming estradiol delivery system intended for the prevention of age-related cataracts.

The goal of this study was to develop and characterize an ion-activated in situ gel-forming estradiol (E2) solution eye drops intended for the prevention of age-related cataracts. Accordingly, in situ gelling eye drops were made using gellan gum as an ion-activated gel-forming polymer, polysorbate-80 as drug solubilizing agent, mannitol as tonicity agent, and combination of potassium sorbate and edetate disodium dihydrate (EDTA) as preservatives. The formulations were tested for the following characteristics: pH, clarity, osmolality, antimicrobial efficacy, rheological behavior, and in vitro drug release. Stability of the formulation was also monitored for 6 months at multiple storage conditions per ICH Q1A (R2) guidelines. The solution eye drops resulted in an in-situ phase change to gel-state when mixed with simulated tear fluid (STF). The gel structure formation was confirmed by viscoelastic measurements. Drug release from the gel followed non-fickian mechanism with 80% of drug released in 8 hr. The formulations were found to be clear, isotonic with suitable pH and viscoelastic behavior and stable at accelerated and long-term storage conditions for 6 months. In vitro results suggest that the developed formulation is suitable for further investigation in animal models to elucidate the ability of estrogen to prevent and delay cataracts.

Development of repaglinide microspheres using novel acetylated starches of bitter and Chinese yams as polymers.

Tropical starches from Dioscorea dumetorum (bitter) and Dioscorea oppositifolia (Chinese) yams were acetylated with acetic anhydride in pyridine medium and utilized as polymers for the delivery of repaglinide in microsphere formulations in comparison to ethyl cellulose. Acetylated starches of bitter and Chinese yams with degrees of substitution of 2.56 and 2.70 respectively were obtained. Acetylation was confirmed by FTIR, 1H NMR spectroscopy. A 32 factorial experimental design was performed using polymer type and drug-polymer ratio as independent variables. Particle size, swelling, entrapment and time for 50% drug release (t50) were dependent variables. Contour plots showed the relationship between the independent factors and the response variables. All variables except swelling increased with drug: polymer ratio. Entrapment efficiency was generally in the rank of Bitter yam>Ethyl cellulose>Chinese yam. Repaglinide microspheres had size 50±4.00 to 350±18.10µm, entrapment efficiency 75.30±3.03 to 93.10±2.75% and t50 3.20±0.42 to 7.20±0.55h. Bitter yam starch gave longer dissolution times than Chinese yam starch at all drug-polymer ratios. Drug release fitted Korsmeyer-Peppas and Hopfenberg models. Acetylated bitter and Chinese yam starches were found suitable as polymers to prolong release of repaglinide in microsphere formulations.

A randomized two-way crossover bioequivalence study in healthy adult volunteers of paediatric zidovudine/lamivudine/nevirapine fast-disintegrating fixed-dose combination tablet.

OBJECTIVE: The bioequivalence study was conducted to compare the developed paediatric fixed-dose combination (FDC) zidovudine/lamivudine/nevirapine (60/30/50 mg) tablet - the test formulation - with the combined mixture of single-entity innovator products (reference product). METHODS: A single-dose open-label randomized two-way crossover study was conducted in healthy adult African volunteers after an informed consent was obtained. The 24 volunteers, divided into two groups, were administered the products after an overnight fast on two treatment days with 14 days of washout period. Blood samples were collected for 96 h and analysed using a validated RP-HPLC-UV assay method. Pharmacokinetic (PK) parameters (non-compartmental model) were assessed with WinNonlin® software. Analysis of variance (ANOVA) and FDA bioequivalence statistical criterion of 90% CI or 80% to 125% range (set at P < 0.05) of least square geometric means (LSGM) ratios of test: reference product for Cmax , AUC0-t , and AUC0-∞ were determined. RESULTS: ANOVA indicated that the period, sequence and formulation had no significant effect on the PK parameters (P > 0.05). The 90% CIs for all the drugs were within the 80% to 125% range. CONCLUSION: The developed FDC tablet is bioequivalent to the reference product.

Valproic acid uptake by bovine brain microvessel endothelial cells: role of active efflux transport.

The basis for low brain permeability of valproic acid (VPA) appears to be the result of efflux transport at the blood-brain barrier (BBB); however, the identity of the putative efflux transporter has not been investigated. The objective of our studies was to determine whether the multidrug resistance-associated protein (MRP) might be involved in efflux transport of VPA. Brain microvessel endothelial cells (BMEC) were isolated from cow brains and grown to confluence. MRP messenger RNA (mRNA) in BMEC were verified by reverse transcriptase-polymerase chain reaction (RT-PCR). Functional activity was demonstrated using the steady-state retention of calcein and MRP inhibitors, indomethacin (IND) and probenecid (PRB). Probenecid (0.50 mM) and indomethacin (10 microM) produced a 26 and 13% ( P<0.05 ) elevation in steady-state cellular VPA uptake following a 30-min-incubation with tracer 3H-VPA and 30 microM cold VPA. In contrast, at higher concentrations of probenecid (2 mM) and indomethacin (500 microM), an 11 and 31% reduction in VPA uptake was observed. The biphasic pattern of VPA uptake suggested concurrent inhibition of uptake and efflux transporters by the inhibitor with differing sensitivities, i.e. the efflux transporter being more susceptible to inhibition than the influx transporter. Similar results were obtained in the MRP overexpressing cell line A549. Overall, the results suggest that MRP(s) is(are) involved in the efflux transport of VPA, but do not preclude the possible contribution(s) of other organic anion transporters. The findings also adds to the growing evidence that up-regulation of active drug efflux transporters at the BBB may contribute to the development of drug resistance to antiepileptic drug therapy.

Enhanced bioavailability of process-induced fast-dissolving ibuprofen cogranulated with beta-cyclodextrin.

The objectives of this study were to evaluate the bioavailability of cogranulated and oven-dried ibuprofen (IBU) and beta-cyclodextrin (betaCD), in comparison to a physical mixture, and to examine the effect of endogenous bile on the bioavailability of the drug. In vitro dissolution studies were performed using USP type 2 apparatus. The granules and physical mixture were administered perorally in a crossover fashion, to male Wistar bile duct-nonligated rats. The granules were also perorally administered to bile duct-ligated rats. Blood samples were taken at different time intervals and the plasma analyzed for IBU. Dissolution of granules was faster than the physical mixture due to faster IBU-betaCD complex formation in solution from the former than the latter. The in vivo study showed that C(max), AUC(0-8), and the absolute bioavailability for the granules (49.0 microg/mL, 57.0 h x microg/mL and 80.6%, respectively) were almost one and half times that of the physical mixture (32.2 microg/mL, 38.4 h x microg/mL and 53.1%, respectively). However, in bile duct-ligated rats, lower C(max) and AUC(0-8) (15.9 microg/mL and 14.4 h x microg/mL, respectively) were obtained for the granules. Phase solubility study of IBU in an aqueous betaCD solution in the presence of the bile salt (sodium cholate), showed an increase in the solubility of IBU. Moreover, the stability constant value for the IBU-betaCD complex was also found to decrease as the sodium cholate concentration increased. These results indicated that the enhancement in the bioavailability of IBU was due to faster in-solution complex formation, and micelllar solubilization by the bile salt.

Development and in vivo evaluation of buccal tablets prepared using danazol-sulfobutylether 7 beta-cyclodextrin (SBE 7) complexes.

The aim of the present work was to develop a mucoadhesive controlled-release formulation of danazol-sulfobutylether 7 beta-cyclodextrin (SBE 7) complex and to evaluate the feasibility of improving the bioavailability of danazol via the buccal route. Different types of polymers, polycarbophil (PC) and hydroxypropylmethyl cellulose (HPMC) were mixed with danazol-SBE 7 complex and compressed into tablets. These tablets were evaluated for their dissolution and mucoadhesion properties and for drug absorption in female beagle dogs. Increased mucoadhesion was observed for PC-containing tablets compared with HPMC tablets. As the concentration of polymer increased, drug release decreased, and PC-containing tablets gave slower release compared to HPMC tablets. In vivo bioavailability performed in dogs showed that the perorally administered danazol-SBE 7 complex and the danazol-SBE 7 (in PC matrix) buccal tablets had absolute bioavailabilities of 64% and 25%, respectively, that are significantly greater than 1.8% observed for the commercial formulation Danocrine. The increased bioavailability was attributed to the enhanced solubility consequent to complexation, and the possible avoidance of first-pass metabolism upon buccal administration.

Feasibility studies in spheronization and scale-up of ibuprofen microparticulates using the rotor disk fluid-bed technology.

The aim of this study was to develop spheronized microparticulates as a drug delivery system using the 1-step closed rotor disk fluid-bed technology, and to scale up the batch spheronization process. Ibuprofen was used as the model drug and microcrystalline cellulose/sodium carboxymethyl cellulose hydrocolloid (Avicel(R) RC-581 or CL-611) was present as the diluent/binder. The mixture, in 1:1 ratio, was blended with and without 1% sodium lauryl sulfate (SLS) and spheronized with the rotor disk insert, using either water or hydroxypropylmethyl cellulose (HPMC) as binder. Fluid-bed machines (Vector/Freund Flo-Coater model) FLM-1 (with 9-inch rotor insert for 0.75 kg) and FLM-15 (with a 12-inch and 19-inch rotor inserts for 1 kg and 5, 10 kg, respectively) were used. The critical process parameters included inlet air temperature, rotor disk speed and configuration, air flow, and rate of binder application. The 1 kg batch containing SLS that was made with 12-inch smooth stainless steel or waffle teflon plates rotating at 500 rpm had desirable characteristics. The sphericity values were 0.88 and 0.91, with percent yield of 85.4 and 91.2 and drug content values of 94.47% and 91.44%, respectively. The spheroids showed good flow properties with respective rapid drug release (Q20 = 83.27 and 91.75). No difference was seen in the Avicel RC-581 and CL-611. Based on the 1 kg data, Avicel RC-581 and smooth stainless steel and waffle teflon plates (12 inch and 19 inch), the batch was scaled up to 5 and 10 kg. The scale-up parameters included rotor speed (124 -300 rpm) and spray rate (90-140 g/min). The scale-up batches had similar flow characteristics, release rate, and size distribution. The geometric mean diameter increased as batch size increased, and slightly bigger spheroids were obtained using the waffle teflon plate. Ibuprofen spheres with very good physical characteristics were developed using the rotor disk fluid-bed technology, a 1-step closed process that did not require additional unit processes.

Viscoelastic evaluation of topical creams containing microcrystalline cellulose/sodium carboxymethyl cellulose as stabilizer.

The purpose of this study was to examine the viscoelastic properties of topical creams containing various concentrations of microcrystalline cellulose and sodium carboxymethyl cellulose (Avicel(R) CL-611) as a stabilizer. Avicel CL-611 was used at 4 different levels (1%, 2%, 4%, and 6% dispersion) to prepare topical creams, and hydrocortisone acetate was used as a model drug. The viscoelastic properties such as loss modulus (G"), storage modulus (G'), and loss tangent (tan delta) of these creams were measured using a TA Instruments AR 1000 Rheometer and compared to a commercially available formulation. Continuous flow test to determine the yield stress and thixotropic behavior, and dynamic mechanical tests for determining the linear viscosity time sweep data, were performed. Drug release from the various formulations was studied using an Enhancer TM Cell assembly. Formulations containing 1% and 2% Avicel CL-611 had relative viscosity, yield stress, and thixotropic values that were similar to those of the commercial formulation. The elastic modulus (G') of the 1% and 2% formulation was relatively high and did not cross the loss modulus (G"), indicating that the gels were strong. In the commercial formulation, G' increased after preshearing and broke down after 600 seconds. The strain sweep tests showed that for all formulations containing Avicel CL-611, the G' was above G" with a good distance between them. The gel strength and the predominance of G' can be ranked 6% > 4% > 2%. The strain profiles for the 1% and 2% formulations were similar to those of the commercial formulation. The delta values for the 1% and 2% formulations were similar, and the formulations containing 4% Avicel CL-611 had lower delta values, indicating greater elasticity. Drug release from the commercial preparation was fastest compared to the formulations prepared using Avicel CL-611, a correlation with the viscoelastic properties. It was found that viscoelastic data, especially the strain sweep profiles of products containing Avicel CL-611 1% and 2%, correlated with the commercial formulation. Rheological tests that measure the viscosity, yield stress, thixotropic behavior, other oscillatory parameters such as G' and G" are necessary tools in predicting performance of semisolids.

A randomized pahse I bioequivalence clinincal trial of a paediatric fixed-dose combination antiretroviral reconstitutable suspension in healthy adult volunteers.

BACKGROUND: This study aimed to test the hypothesis that the paediatric fixed-dose combination granule for reconstitution (comprising lamivudine/zidovudine/nevirapine 30/60/50 mg per 5 ml) as a test product is bioequivalent to the coadministered single entities of the referenced products. Fixed-dose combination anti-retroviral therapy provides adequate suppression of HIV-1 replication, provides barrier to the development of resistance, simplifies dosage regimen and improves adherence. METHODS: An open label, randomized, two-way crossover study was conducted on 24 health adults under fasted conditions, with a washout period of 14 days between treatments. A total of 15 blood samples were collected before dosing and up to 96 h post dosing. The drugs were extracted from plasma and anlaysed using a validated high performance liquid chromatography- ultraviolet method. Non- compartmental pharmacokinetic (PK) analysis was performed to obtain the PK parameters, maximum plasma concentration (C max), area under the curve of plasma concentration-time curves from the time zero to last measurable concentration (AUC0-t) and the area under the curve extrapolated to infinity (AUC 0-∞) ANOVA test was performed to determine the effect of model factors on the PK parameters. The two one-sided t-tests were performed on the log-transformed data to determine the 90% CL for the ratio of test to reference PK parameters. RESULTS: The drugs were well tolerated and safe with minimal adverse events. The ANOVA test indicated the absence of any significant effects ( P>0.05) due to the model parameters. The 90% Cl for the geometric mean ratio of the test/reference for the Cmax, AUC0-t and the AUC0-∞ for lamivudine, zidovudine and nevirapine were within 80-125% bioequivalence limits. CONCLUSIONS: This single dose randomized study found that the test and reference products met the criteria for bioequivalence in the fasting healthy adult volunteers.

Bacteria and pH-sensitive polysaccharide-polymer films for colon targeted delivery.

The colon provides drug delivery opportunities for colon-specific and systemic delivery of various therapeutic agents. Different strategies have been utilized in targeting drugs to the colon. Recently, integrated systems which incorporate dual mechanisms in colon targeted delivery have received a lot of attention. Of particular interest is bacteria-aided biomaterials and pH-sensitive polymeric film (BPSF) coating for colon targeted drug delivery. The major constituents of these films are polysaccharides and pH-sensitive polymers. The pH-sensitive polymer retards drug release in the stomach and small intestine, while the polysaccharide is digested by colonic enzymes. Digestion of the polysaccharides by bacterial glycosidic enzymes increases the pore density in the film to facilitate drug release. Generally, bacteria-aided biomaterials and pH-sensitive films can be applied to the delivery of most small organic molecules to the colon. The review encompasses the pharmaceutical design parameters such as film digestibility, swelling index and dry mass loss (that provide molecular mechanistic analysis of film permeability) as well as tensile strength, elastic modulus, and elongation at break (that describe the desirable mechanical properties of the films). A critical analysis of formulation, techniques for characterization of film properties and drug-release kinetics from these systems are emphasized.

Gastroretentive floating drug-delivery systems: a critical review.

The oral delivery of drugs with a narrow absorption window in the gastrointestinal tract (GIT) is often limited by poor bioavailability with conventional dosage forms due to incomplete drug release and short residence time at the site of absorption. To overcome this drawback and to maximize the oral absorption of these drugs, gastroretentive systems such as mucoadhesive, high-density, expandable, and floating systems have been developed. These systems provide controlled delivery of drugs with prolonged gastric residence time. However, in humans, differences in various physiological and biological factors can affect the gastric residence time and drug-delivery behavior from gastroretentive systems. Some floating drug-delivery systems (FDDS) have shown the capability to accommodate these variations without affecting drug release. This review mainly focuses on various physiological considerations for development of FDDS, and highlights recent technological developments including new dosage forms and their production techniques (e.g., holt-melt extrusion, melt pelletization, and pulsed plasma-irradiation processes). Alternatives to the existing in vitro compendial methods for evaluating floating dosage forms will be discussed, and a critical analysis of the existing literature on FDDS, identifying the potential areas for future research, is provided.

Postmarketing in vitro/in vivo assessment of fixed dose combination products of first line antiretrovirals.

The purpose of this study was to evaluate the postmarket pharmaceutical equivalence, stability and bioequivalence of generic and innovator fixed dose combination products of lamivudine (3TC) and zidovudine (AZT) 150/300 mg tablets available in Nigeria. An isocratic HPLC-UV method was developed and validated for the quantitative determination of 3TC and AZT in human plasma and pharmaceutical samples. The model independent f(2) similarity factor was used to compare the dissolution profiles of the two products stored at accelerated and long-term stability conditions for 6 months. The f(2) values for 3TC and AZT in both products were found to be greater than 51. Also, the tablets were stable according to the USP potency and drug dissolution criteria with more than 80% of drug dissolution in 30 min indicating the pharmaceutical equivalence of the two products. The 90% confidence interval for the ratios of generic/innovator pharmacokinetic parameters for 3TC/AZT were 73.5-112.6/63.4-95.8 (C(max)); 68.5-105.6/68.0-114.8 (AUC(0-t)); and 64.2-106.2/80.1-120.3 (AUC(0-infinity)) respectively. The pharmacokinetic parameters failed to fully demonstrate bioequivalence between the products. The results underscored the importance of assessing the quality of the combination drug products that would ensure the safety and efficacy of the generic drug products available in the market.

Factorial design in the spheronization of ibuprofen microparticulates using the rotor disk fluid-bed technology.

The aim of this study was to statistically evaluate the effects of some formulation and process variables in the spheronization of microparticulates of ibuprofen using the rotor disk fluid-bed technology and water as binder. Preliminary studies revealed that presence of surfactant, plate material type, and nature and content of binder influenced the process and quality of the spheronized material. A 2 x 2 x 3 full factorial randomized experiment was designed, demonstrating the influence of these factors on properties such as percent yield, particle size distribution, densities, ibuprofen release, moisture content, etc., as well as their interactions in the experimental response. A response known as the usable fraction was created representing microparticulates of 250 to 850 microm sizes (mesh size 20-60). The reproducibility of the spheronization process was assessed by blocking the experiments with the experiments within the blocks randomly replicated. The main effects included two binder levels (X1), two surfactant levels (X2), and a three-level plate type (X3) in which 2 two-level factors were collapsed into a single three-level factor. The results from the statistical analysis (general linear model, JMP 4) showed that the variables studied had a significant influence on most of the response variables evaluated (p < 0.05), with the binder level proving to be the most significant of the three. There was also significant interaction (p<0.05) between binder level and plate type with the drug content, friability, sphericity, loss on drying (LOD), and usable fraction response variables, and between the binder and the surfactant levels with the drug content, Q20, true density, geometric mean diameter, LOD, and usable fraction responses. High levels of surfactant and binder increased the sphere size, while low levels decreased it. Significant (p < 0.05) interaction was also observed between the plate type and surfactant level with the drug content, geometric mean diameter, and more or less with Q20 and bulk density response variables. Blocking of the experiments had no significant effect on the process and product characteristics analyzed, indicating the reproducibility of the process.