Responding to the need: An evaluation of the subspecialty units in a pediatric surgical department in a limited resource setting using selected optimal resources for children's surgery strategies.

BACKGROUND: The Global Initiative for Children's Surgery group published the Optimal Resources for Children's Surgery (OReCS) document outlining the essential criteria and strategies for children's surgical care in low-resource settings. Limited data exist on subspecialties in pediatric surgery and their contribution to global surgery efforts. The study aimed to evaluate the development of subspecialty units within Chris Hani Baragwanath Academic Hospital (CHBAH) Department of Pediatric Surgery (DPS) from January 1, 2018 to December 31, 2021 using selected OReCS strategies for the improvement of pediatric surgery. METHODS: A retrospective descriptive research design was followed. The study population consisted of CHBAH PSD records. The following data were collected: number of patients managed in PSD subspecialty unit (the units) clinics and surgeries performed, number of trainees, available structures, processes and outcome data, and research output. RESULTS: Of the 17,249 patients seen in the units' outpatient clinics, 8275 (47.9%) burns, 6443 (37.3%) colorectal, and 2531 (14.6%) urology. The number of surgeries performed were 3205, of which 1306 (40.7%) were burns, 644 (20.1%) colorectal, 483 (15.1%) urology, 341 (10.6%) hepatobiliary, and 431 (12.8%) oncology. Of the 16 selected strategies evaluated across the 5 units, 94% were available, of which 16.4% was partly provided by Surgeons for Little Lives. Outcome data in the form of morbidity and mortality reviews for all the units is available, but there is no data for timeliness of care with waiting lists. There were 77 publications and 41 congress presentations. CONCLUSION: The subspecialty units respond to the global surgical need by meeting most selected OReCS resources in the clinical service provided.

In vitro evaluation of metal chelators as potential metallo- ß -lactamase inhibitors.

AIMS: This study aimed at investigating the use of metal chelators as potential metallo-ß-lactamase inhibitors (MBL). METHODS AND RESULTS: The minimum inhibitory concentration (MIC) of meropenem was ascertained alone and in combination with various concentrations of macrocyclic (1,4,7- triazacyclononane-1-glutaric acid-4,7-diacetic acid = NODAGA) peptide derivatives and acyclic (N,N,N',N'-Tetrakis(2-pyridylmethyl)ethylenediamine = TPEN and di-(2-picolyl)amine = DPA) metal chelators using the broth microdilution method. MICs of meropenem against carbapenem-resistant enterobacteriaceae (CRE) producing MBLs were decreased to concentrations as low as 0·06 mg l(-1) in the presence of some metal chelators. TPEN at 4 and 8 mg l(-1) showed the best activity by decreasing meropenem MICs to 0·5 and 0·06 mg l(-1) , respectively, for some New Delhi Metallo-beta-lactamase (NDM) and Verona integron-encoded metallo-ß-lactamase (VIM) -producing enterobacteriaceae. DPA at 8 and 16 mg l(-1) was also able to decrease meropenem MICs to 1 and 0·125 mg l(-1) , respectively, for these CREs. NODAGA peptide derivatives showed the least inhibition as 32 mg l(-1) was required for meropenem MICs to be decreased to 0·06 mg l(-1) against an NDM-1 producing isolate. CONCLUSION: The various metal chelators, TPEN, DPA and NODAGA peptide derivatives were able to inhibit the MBLs in decreasing order of activity, rendering CREs susceptible to meropenem. SIGNIFICANCE AND IMPACT OF THE STUDY: In the absence of new antibiotics, this study evaluated metal chelators as potential MBL inhibitors.

An analysis of referral patterns of traumatic brain injury at Groote Schuur Hospital Trauma Centre.

BACKGROUND: Traumatic brain injury (TBI) can result in significant morbidity and mortality if not diagnosed in a timely manner. Brain computed tomography (CT) is the diagnostic gold standard but is of limited availability in most South African public hospitals, resulting in transfer of TBI patients to tertiary hospitals. OBJECTIVE: To describe the referral patterns and outcomes of patients with TBI referred to Groote Schuur Hospital Trauma Centre. METHODS: This was a retrospective audit of all patients admitted to the Trauma Centre who had a brain CT scan for suspected TBI between 1 February 2022 and 31 March 2022. Demographic data (age, sex), mechanism of injury and Glasgow Coma Score were recorded. Referral pathways were determined, and final disposition of patients was recorded. RESULTS: A total of 522 patients had a brain CT for TBI. Of these, 314 (60.1%) were referred from other hospitals. CT scan was abnormal in 178 (34.1%) patients. Three hundred and two (58.6%) were discharged home within 24 hours. The mean time between referral and CT scan was 13 hours. CONCLUSION: More than half of patients referred for a CT scan were discharged from the Trauma Centre within 24 hours of admission, which indicates additional costs and inefficiencies in the health system. These data are useful to guide resource planning and allocation for district hospitals, since less expensive point-of-care modalities now exist to diagnose TBI, and which are useful in indicating the prognosis of patients.

Laparoscopic repair of a delayed traumatic bladder injury.

SUMMARY: Isolated bladder injuries from falls are not common; we report a laparoscopic bladder repair in a patient with delayed presentation. There are about 20 case reports of laparoscopic repair of traumatic bladder reported in the literature, but none with such a delayed presentation. We describe the technique of laparoscopic bladder repair. The delay in the presentation might have facilitated laparoscopic repair as it might have excluded bowel injuries.

Expanding the use of dolutegravir-based antiretroviral therapy in multidrug-resistant TB.

The wider availability of dolutegravir (DTG) containing HIV therapy for patients living with multidrug-resistant TB (MDR-TB) presents several advantages. DTG-based antiretroviral therapy (ART) has superior potency, reduces pill burden, and may reduce overall treatment-related toxicity, giving it the potential to improve outcomes in both diseases. While the uptake of DTG-based ART in programs where drug-resistant TB is treated remains unknown, there is early evidence from three programs that uptake is increasing. The use of DTG-based ART should be scaled-up, beginning with antiretroviral-naïve or virologically suppressed patients initiating MDR-TB treatment.

Variation in training requirements within general surgery: comparison of 23 countries.

Background: Many differences exist in postgraduate surgical training programmes worldwide. The aim of this study was to provide an overview of the training requirements in general surgery across 23 different countries. Methods: A collaborator affiliated with each country collected data from the country's official training body website, where possible. The information collected included: management, teaching, academic and operative competencies, mandatory courses, years of postgraduate training (inclusive of intern years), working-hours regulations, selection process into training and formal examination. Results: Countries included were Australia, Belgium, Canada, Colombia, Denmark, Germany, Greece, Guatemala, India, Ireland, Italy, Kuwait, the Netherlands, New Zealand, Russia, Saudi Arabia, South Africa, South Korea, Sweden, Switzerland, UK, USA and Zambia. Frameworks for defining the outcomes of surgical training have been defined nationally in some countries, with some similarities to those in the UK and Ireland. However, some training programmes remain heterogeneous with regional variation, including those in many European countries. Some countries outline minimum operative case requirement (range 60-1600), mandatory courses, or operative, academic or management competencies. The length of postgraduate training ranges from 4 to 10 years. The maximum hours worked per week ranges from 38 to 88 h, but with no limit in some countries. Conclusion: Countries have specific and often differing requirements of their medical profession. Equivalence in training is granted on political agreements, not healthcare need or competencies acquired during training.

Antecedentes: Existen muchas diferencias entre los programas de formación quirúrgica de posgrado del mundo. El objetivo de este estudio fue proporcionar una visión general de los requisitos formativos en cirugía general en 23 países diferentes. Métodos: En cada uno de los países participantes, un colaborador recopiló datos de la página web del organismo oficial encargado de la formación, si era posible. La información incluyó: gestión, formación, competencias académicas y operatorias, cursos obligatorios, años de formación de postgrado (que incluía el período de internado), regulaciones sobre las horas de trabajo, proceso de selección para la formación y existencia de un examen final. Resultados: Se incluyeron los datos de Australia, Bélgica, Canadá, Colombia, Dinamarca, Alemania, Grecia, Guatemala, India, Irlanda, Italia, Kuwait, Países Bajos, Nueva Zelanda, Rusia, Arabia Saudita, Sudáfrica, Corea del Sur, Suecia, Suiza, Reino Unido, Estados Unidos de América y Zambia. En algunos países existen los marcos normativos para definir los resultados del programa de formación, con ciertas semejanzas a los del Reino Unido e Irlanda. Sin embargo, algunos programas de formación, incluso en muchos países europeos, son muy heterogéneos con variaciones regionales. Pocos países describen el número mínimo de procedimientos quirúrgicos (rango 60 a 1.600), los cursos obligatorios o competencias quirúrgicas, académicos o de gestión exigidos. La duración de la formación postgraduada osciló de los 4 a los 10 años. El número de horas trabajadas máximas por semana oscilaron entre 38 y 88, sin límite en algunos países. Conclusión: Cada país tiene unos requisitos específicos, a menudo diferentes, para la formación de sus médicos. La convalidación se otorga por acuerdos políticos, más que por las necesidades médicas o por las competencias adquiridas durante la formación.

Formulation of monolayered films with drug and polymers of opposing solubilities.

The aim of this study was to prepare and characterise monolayered multipolymeric films (MMFs) comprising of a hydrophilic drug (Propranolol HCl) (PHCl) and polymers of opposing solubilities. Films were prepared by emulsification and casted by a new approach using a silicone-molded tray with individual wells. MMFs comprising of PHCl with Eudragit 100 (EUD100) and Chitosan (CHT), i.e. films with drug and polymers of opposing solubilities were successfully prepared (PHCl:EUD100:CHT; 1:10:0.5) and demonstrated uniform and reproducible drug content (100.71+/-2.66%), thickness (0.442+/-0.030 mm), mucoadhesivity (401.40+/-30.73 mN) and a controlled drug release profile. Drug release followed Higuchi's square-root model. Maximum swelling of the films occurred after 1h and 28.26% of the films eroded during the 8-h test period. Mechanical testing revealed that the MMFs displayed a greater abrasion resistance, were more elastic and also required more energy to break, rendering them tougher and more suitable for buccal delivery than the monopolymeric PHCl:EUD100 film. The inclusion of CHT to the film led to a more porous surface morphology. The surface pH of the films remained constant at neutral pH. This study confirmed the potential of the above MMFs as a promising candidate for buccal delivery of PHCl.

The in vivo effects of Tulbhagia violacea on blood pressure in a salt-sensitive rat model.

AIM OF THE STUDY: The in vivo effects of Tulbhagia violacea on systemic arterial blood pressure and on the renin-angiotensin system in a Dahl salt-sensitive rat model were investigated. MATERIALS AND METHODS: Animals were treated for 14 days intraperitoneally as follows: Tulbhagia violacea (Tvl) (50mg/kg b.w.), captopril (Cap) (10mg/kg b.w.) or DMSO (Con). Baseline blood pressures were recorded prior to the commencement of the study and biweekly during the experimental period. Urine volume and sodium concentration were measured during the experimental period. On day 15, animals were anaesthetized (sodium thiopentane, 50mg/kg, i.p.), blood samples for aldosterone levels were taken and the kidneys removed for determining AT1a mRNA expression. RESULTS: Cap and Tvl groups showed significantly reduced AT1a mRNA expressions by 3.11- and 5.03-fold, respectively, when compared to the Con group (p<0.05). When compared to baseline blood pressures (day 0); Cap and Tvl showed reductions in systolic blood pressure (SBP) of 7.76+/-0.41% and 9.12+/-0.31%, respectively (mean% decrease from day 0 to day 14). In contrast, in the Con group the systolic blood pressure increased from day 0 to day 14 by 4.66+/-0.56%. Blood pressure changes in all treated groups differed from Con significantly. Systolic blood pressure decreased with the decrease in AT1a mRNA expressions in these groups. When comparing day 0 to day 14, urine output increased in the Cap and Tvl groups. In the Con group, urinary volume was reduced by day 14 as compared to day 0. Urinary sodium excretion was increased in the treated groups by day 14. CONCLUSION: It can be concluded that Tulbhagia violacea reduces systemic arterial blood pressure in the Dahl rat by decreasing renal AT1 receptor gene expression and hence modulating sodium and water homeostasis.

Investigating a new approach to film casting for enhanced drug content uniformity in polymeric films.

Films prepared by conventional casting onto trays such as teflon-coated perspex trays (TCPTs) suffer from poor drug content uniformity. The aim of this study was to prepare a silicone-molded tray (SMT) with individual wells for film casting and to evaluate it in terms of enhancing drug content uniformity. Films were prepared by solvent evaporation or emulsification and cast onto TCPT and SMT. Preparation of films by the SMT method was superior in terms of meeting drug content uniformity requirements. As compared with the TCPT method, the SMT casting method also reduced the variability in mucoadhesivity, drug release, and film thickness. Reproducibility of the SMT method was demonstrated in terms of drug content, mucoadhesion, and drug release.

Investigation of the binding free energies of FDA approved drugs against subtype B and C-SA HIV PR: ONIOM approach.

Human immune virus subtype C is the most widely spread HIV subtype in Sub-Sahara Africa and South Africa. A profound structural insight on finding potential lead compounds is therefore necessary for drug discovery. The focus of this study is to rationalize the nine Food and Drugs Administration (FDA) HIV antiviral drugs complexed to subtype B and C-SA PR using ONIOM approach. To achieve this, an integrated two-layered ONIOM model was used to optimize the geometrics of the FDA approved HIV-1 PR inhibitors for subtype B. In our hybrid ONIOM model, the HIV-1 PR inhibitors as well as the ASP 25/25' catalytic active residues were treated at high level quantum mechanics (QM) theory using B3LYP/6-31G(d), and the remaining HIV PR residues were considered using the AMBER force field. The experimental binding energies of the PR inhibitors were compared to the ONIOM calculated results. The theoretical binding free energies (?Gbind) for subtype B follow a similar trend to the experimental results, with one exemption. The computational model was less suitable for C-SA PR. Analysis of the results provided valuable information about the shortcomings of this approach. Future studies will focus on the improvement of the computational model by considering explicit water molecules in the active pocket. We believe that this approach has the potential to provide much improved binding energies for complex enzyme drug interactions.

Statistical optimisation of the mucoadhesivity and characterisation of multipolymeric propranolol matrices for buccal therapy.

A Box-Behnken experimental design was employed to optimise a polymeric blend for the preparation of propranolol HCl matrices with maximum mucoadhesivity and was thereafter modified for achieving controlled drug release. The quantitative effects of the polymers used i.e. poly(acrylic acid) (PAA) and poly(vinyl pyrrolidone) (PVP) on mucoadhesion could be predicted using polynomial equations. A formulation of 20% PAA, 20% CMC and 20% PVP was identified for maximising mucoadhesivity and obtaining a controlled drug release profile. Reproducibility of the optimal formulation in terms of mucoadhesivity and controlled drug release was confirmed. The optimal formulation was characterised in terms of mucoadhesivity, release kinetics, swelling/erosion, hydration dynamics and surface pH. From the model fitting analyses, drug release was found to be diffusion, polymeric relaxation and erosion based with the former two being more dominant over erosion. This was in agreement with the erosion and swelling studies which showed swelling and erosion occurring in the tablet matrix. Textural profiling showed initial rapid hydration, which could be beneficial for enhanced mucoadhesivity. Surface pH of the multipolymeric matrices was similar to salivary pH and did not show extremes in changes over the test period. The optimal preparation of multipolymeric propranolol matrices identified in this study shows potential for buccal administration.

Synthesis of a novel PEG-block-poly(aspartic acid-stat-phenylalanine) copolymer shows potential for formation of a micellar drug carrier.

A novel functionalised copolymer with three polymeric components, poly(ethylene glycol)-block-poly(aspartic acid-stat-phenylalanine), PEG-P(asp-phe), was synthesised and investigated for its potential to form micelles via ionic interactions with a model water-soluble drug, diminazene aceturate. Drug-free solutions of structurally related PEG-P(asp-phe) 5:6:4 and PEG-P(asp-phe) 5:4:6 copolymers indicated polymeric aggregation into micellar-type constructs. The size of PEG-P(asp-phe) 5:6:4 micelles was found to be pH and drug content-dependent. The drug-loaded systems existed as discreet units and were fairly uniform in size and shape. More drug could be included in the PEG-P(asp-phe) 5:6:4 micelles as compared to if only interaction with carboxyl groups from aspartic acid units was responsible for micelle formation, indicating the augmentative role of phenylalanine moieties in drug-incorporation. The slower in vitro drug release from PEG-P(asp-phe) 5:6:4 micelles as compared to PEG-Pasp (AB) micelles indicated the role of the phenylalanine moiety in controlling drug release. This study, therefore, confirmed the potential of a novel tri-component copolymer structure, PEG-P(asp-phe), for the formation of polyionic micelles for drug delivery.

Optimisation and characterisation of bioadhesive controlled release tetracycline microspheres.

A Box-Behnken experimental design was employed to statistically optimise the formulation parameters of a tetracycline microsphere preparation for maximum bioadhesivity and controlled drug release. The quantitative effect of the formulation parameters at different levels on bioadhesion and drug release could be predicted using polynomial equations. A formulation comprising of 3% (w/w) chitosan, 10% (w/w) tetracycline HCl and 9% (w/v) tripolyphosphate was identified for maximising bioadhesivity and obtaining controlled drug release. The optimal microsphere preparation was subsequently characterised in terms of hydration dynamics, release kinetics, antimicrobial activity, thermal properties, morphology and surface pH. Kinetic models revealed that drug release followed Fickian diffusion while textural analysis showed minimal hydration over the test period. Antimicrobial studies showed that the drug concentrations in the in vitro release samples were above the minimum concentration of drug required for inhibition of Staphylococcus aureus growth. Thermal analyses showed a possible interaction between the drug and polymer. Scanning electron microscopy confirmed the integrity of the microspheres and identified the morphological changes following drug release. Surface pH of the microspheres was similar to salivary pH and did not show extremes in changes over the test period.

Climate change is catchy--but when will it really hurt?

Concern and general awareness about the impacts of climate change in all sectors of the social-ecological-economic system is growing as a result of improved climate science products and information, as well as increased media coverage of the apparent manifestations of the phenomenon in our society. However, scales of climate variability and change, in space and time, are often confused and so attribution of impacts on various sectors, including the health sector, can be misunderstood and misrepresented. In this review, we assess the mechanistic links between climate and infectious diseases in particular, and consider how this relationship varies, and may vary according to different time scales, especially for aetiologically climate-linked diseases. While climate varies in the medium (inter-annual) time frame, this variability itself may be oscillating and/or trending on cyclical and long-term (climate change) scales because of regional and global scale climate phenomena such as the El-Nino southern oscillation coupled with global-warming drivers of climate change. As several studies have shown, quantifying and modelling these linkages and associations at appropriate time and space scales is both necessary and increasingly feasible with improved climate science products and better epidemiological data. The application of this approach is considered for South Africa, and the need for a more concerted effort in this regard is supported.

Drug-polyionic block copolymer interactions for micelle formation: physicochemical characterisation.

While covalent attachment of small drug molecules to AB copolymers for the formation of polymeric micelles for drug delivery has been investigated, few studies have focused on non-covalent interactions. The aim of this study was therefore to explore the potential of non-covalent interactions between an AB copolymer, Poly(aspartic acid)-poly(ethylene glycol) (Pasp-PEG), with anionic pendant groups and diminazene aceturate, a small molecular weight cationic drug. Micelles were prepared by mixing solutions of Pasp-PEG and diminazene in 25 mM Tris-HCl buffer. At all Pasp-PEG concentrations studied, the micelles appeared to be water soluble with a unimodal size distribution and ranged in size from approximately 22 to 60 nm. The polyionic micelles also displayed similar and small absolute zeta potential values at various drug:monomer molar ratios which confirmed stabilisation by the PEG corona. The scattering intensity was maximal and remained unchanged, while particle size increased slightly at pH range from 3.4 to 7.2. At this pH range both the polymer and drug would be ionised and ionic interactions possible to drive micellar formation. An increase in size and scattering intensity with addition of NaCl to the micelles was attributed to dehydration of the PEG corona which may have led to aggregation of the micelles. The absence of micellar dissociation upon addition of salt was attributed to the dominance of hydrogen bonding between Pasp and diminazene aceturate, as assessed by isothermal titration microcalorimetry. Morphological evaluation of these constructs showed them to be discrete and fairly uniform in size and shape. This study was therefore successful in confirming the potential of non-covalent interactions using an AB copolymer to form polyionic micelles for drug delivery.

PLGA nanoparticles prepared by nanoprecipitation: drug loading and release studies of a water soluble drug.

The nanoprecipitation technique for preparation of nanoparticles suffers the drawback of poor incorporation of water soluble drugs. The aim of this study was therefore to assess various formulation parameters to enhance the incorporation of a water soluble drug (procaine hydrochloride) into poly(dl-lactide-co-glycolide) (PLGA) nanoparticles prepared by this technique. Approaches investigated for drug incorporation efficiency enhancement included the influence of aqueous phase pH, replacement of procaine hydrochloride with procaine dihydrate and the inclusion of excipients: poly(dl-lactide) (PLA) oligomers, poly(methyl methacrylate-co-methacrylic acid) (PMMA-MA) or fatty acids into the formulation. The nanoparticles produced were submicron size (<210 nm) and of low polydispersity. It was found that an aqueous phase pH of 9.3, replacement of procaine hydrochloride with procaine dihydrate and the incorporation of PMMA-MA, lauric and caprylic acid into the formulation could enhance drug incorporation efficiency without the size, morphology and nanoparticle recovery being adversely influenced. For instance changing the aqueous phase pH from 5.8 to 9.3 increased nanoparticle recovery from 65.1 to 93.4%, drug content from 0.3 to 1.3% w/w and drug entrapment from 11.0 to 58.2%. However, the presence of high ratios of lauric acid and procaine dihydrate in the formulation adversely affected the morphology and size of the nanoparticles. Also, PLA oligomers were not considered a feasible approach since it decreased drug entrapment from 11.0 to 8.4% and nanoparticle recovery from 65.1 to 19.6%. Drug release from nanoparticles appears to consist of two components with an initial rapid release followed by a slower exponential stage. This study has demonstrated that formulation variables can be exploited in order to enhance the incorporation of a water soluble drug into PLGA nanoparticles by the nanoprecipitation technique.

Defining the drug incorporation properties of PLA-PEG nanoparticles.

The drug incorporation and physicochemical properties of PLA-PEG micellar like nanoparticles were examined in this study using a model water soluble drug, procaine hydrochloride. Procaine hydrochloride was incorporated into nanoparticles made from a series of PLA-PEG copolymers with a fixed PEG block (5 kDa) and a varying PLA segment (3-110 kDa). The diameter of the PLA-nanoparticles increased from 27.7 to 174.6 nm, with an increase in the PLA molecular weight. However, drug incorporation efficiency remained similar throughout the series. Incorporation of drug into the smaller PLA-PEG nanoparticles made from 3:5, 15:5 and 30:5 copolymers did not influence the particle size, while an increase was observed for the larger systems comprising 75:5 and 110:5 copolymers. An increase in drug content for PLA-PEG 30:5 nanoparticles was achieved by increasing the theoretical loading (quantity of initially present drug). The size of these nanoparticles remained unchanged with the increasing drug content, supporting the proposed micellar type structure of the PLA-PEG 30:5 nanoparticles. The morphology of these systems remained unchanged both at low and high theoretical drug loadings. Formulation variables, such as an increase in the aqueous phase pH, replacement with the base form of the drug and inclusion of lauric acid in the formulation did not improve the incorporation efficiency of drug into PLA-PEG 30:5 nanoparticles. While poly(aspartic acid) as a complexation agent did not improve the drug incorporation efficiency of procaine hydrochloride, it did so for another water soluble drug diminazene aceturate. This may be attributed to a stronger interaction of diminazene aceturate with poly(aspartic acid) relative to procaine hydrochloride, as confirmed by thermodynamic analysis of isothermal titration calorimetric data. The drug incorporation and physicochemical characterisation data obtained in this study may be relevant in optimising the drug incorporation and delivery properties of these potential drug targeting carriers.

Drug release modulation from cross-linked calcium alginate microdiscs, 1: evaluation of the concentration dependency of sodium alginate on drug entrapment capacity, morphology, and dissolution rate.

Calcium alginate microdiscs were prepared by the gelification technique using sodium alginate as the precursor hydrophilic polymer and calcium chloride aqueous solution (1% w/v) as the cross-linking agent. Indomethacin, the model drug, was simultaneously encapsulated in the cross-linked swellable calcium alginate matrix. It was found that as the sodium alginate concentration was increased in the cross-linking reaction, there was a marked increase in drug entrapment capacity of the calcium alginate microdiscs. The 1% w/v indomethacin-calcium alginate microdisc formulation maximally entrapped 43.84% drug, while the 4% w/v formulation retained 92.18% drug. In addition, indomethacin release in phosphate buffer, pH 6.2, was markedly decreased as the precursor polymeric concentration was increased. The t(80%) for the 1% w/v formulation was approximately 3 h, while this value was extrapolated to 13.5 h for the 4% w/v formulation. A 1:1 combination of the 2 and 3% w/v formulations of the indomethacin-calcium alginate microdiscs provided bimodal, biphasic drug release characteristics similar to Indocid-R capsules. With the aid of scanning electron microscopy, it was demonstrated that the microdisc diameter also increased as the polymer concentration was increased. For example, the 1 and 4% w/v formulations had mean diameters of 1.26 and 2.17 mm, respectively. The micrographs also elucidated typical pore formation on the surface of the indomethacin-calcium alginate micro-discs, which suggested that the drug release mechanism is governed by swelling/erosion as well as partial diffusion. Density and surface area measurements of the indomethacin-calcium alginate microdiscs revealed that both dimensional characteristics decreased with increasing sodium alginate concentrations. A change in the drug:polymer ratio (1:1, 1:2, 1:2.5, 1:3, and 1:4) also resulted in microdiscs with higher potencies and slower dissolution rates. The above 4% w/v microdisc formulation was similar to the formulation containing the 1:4 drug:polymer fraction, in that both formulations were prepared from a 4% w/v sodium alginate solution. However, changing the polymer fraction proved more effective in decreasing the release of indomethacin from the calcium alginate microdiscs.

Drug release modulation from cross-linked calcium alginate microdiscs, 2: swelling, compression, and stability of the hydrodynamically-sensitive calcium alginate matrix and the associated drug release mechanisms.

Cross-linking through ionotropic gelation of sodium alginate with calcium chloride was employed to encapsulate the model drug indomethacin into the swellable multiple-unit calcium alginate microdisc delivery system to control its release. The influence of dissolution variables/hydrodynamics on drug release behavior was evaluated in accordance with the standard USP23 apparatus I and II, as well as the unofficial rotating bottle method. Drug release rates from the different methods were shown to be inter-and intradependent on the agitation rate as a result of the swellable, erosion-sensitive nature of the calcium alginate matrix. Preliminary compression studies indicated that the decrease in drug release was due to the hindrance of microdisc swelling as a result of the formation of a more dense and compact matrix, as observed from scanning electron microscopy. Maximum degree of swelling of the calcium alginate microdiscs (83.35 +/- 0.98%) occurred in <6 h of exposure to phosphate buffer, pH 6.2. The drug-encapsulated microdiscs were filled into no. 2 gelatin capsules and subject to stability testing at room temperature (21 +/- 1 degrees C), 40 degrees C, 37 degrees C with 80% relative humidity and at low temperature (5 +/- 1 degrees C). An evaluation of the potency, moisture content, and drug release behavior over a 3-month period provided evidence of a stable drug delivery system under all storage conditions. Mathematical analysis of dissolution data confirmed that the mechanism of drug release from the swellable microdiscs was modulated by mixed swelling/erosion following intermediate zero/first-order diffusion processes.

Low molecular weight quaternised chitosan (I): synthesis and characterisation.

For a better understanding of the behaviour of macromolecules in vitro and in vivo, their structural and chemical properties that may be influential as experimental variables need to be characterised. N-Trimethyl chitosan chloride and N-triethyl chitosan chloride have been synthesised from chitosan to increase the solubility range of these polymers. However, little is known about the effect of the degree of quaternisation, molecular weight, viscosity and different substitution groups on the polymer's ability to enhance the transport of large hydrophilic compounds, such as peptide and protein drugs, across intestinal and nasal epithelia and on their toxicity profile. This study describes the synthesis of various quaternised chitosan polymers from low and medium molecular weight chitosan. These polymers were characterised to determine if any relationships between their degree of quaternisation, molecular weight and viscosity could be found which will determine their behaviour as absorption enhancers in future studies.