Formulation development and evaluation of the anti-malaria properties of sustained release artesunate-loaded solid lipid microparticles based on phytolipids.

UNLABELLED: CONTEXTS: Artemisinins and its derivatives are considered the basis in the treatment of Plasmodium falciparum malaria due to their high potency and rapid action. However, they have short half life, low solubility, and poor oral bioavailability, hence the need to formulate sustained release lipid particulate dosage form of these drugs. OBJECTIVES: To formulate and evaluate artesunate-loaded solid lipid microparticles (SLMs) based on structured lipid matrices consisting of soybean oil and dika wax. MATERIALS AND METHODS: The lipid matrices were characterized by differential scanning calorimetry (DSC), small-angle X-ray diffraction (SAXD), and wide-angle X-ray diffraction (WAXD). The SLMs were prepared by hot melt-homogenization. Time-dependent particle size analysis, time-dependent pH stability studies, encapsulation efficiency (EE%), and in vitro drug release were carried out on the SLMs. In vivo anti-malarial studies were performed using a modified Peter's 4-day suppressive protocol using Plasmodium berghei infected mice. RESULTS AND DISCUSSION: Thermograms of the lipid matrices showed modifications in the microstructure of dika wax as a result of inclusion of soybean oil. SAXD and WAXD diffractograms showed that the lipid matrices were found to be non-lamellar. Particle size of SLM increased with time, while the pH was almost constant. The SLMs had maximum EE% of 80.6% and sustained the release of artesunate more than the reference tablet. In vivo pharmacodynamic studies showed that the SLMs had significant (p < 0.05) reduction in parasitaemia compared with reference tablet. CONCLUSION: Artesunate-loaded SLMs could be used once daily in the treatment of malaria.

Preliminary evaluation of the immunoenhancement potential of Newcastle disease vaccine formulated as a cationic liposome.

This study evaluates the enhancement of immune response of birds to Newcastle disease (ND) vaccine encapsulated in 1,2-dioleoyl-3-trimethylammonium propane (DOTAP)-based liposomes. The vesicles of the liposomal ND vaccine were physically characterized for shape, particle size and zeta potential. The results of the analyses showed that vesicles of the liposomal ND vaccine were spherical and tightly packed. The mean size distribution was below 100 nm. The mean zeta potential was 24 mV. Sixty experimental birds were then divided into an unvaccinated group, a liposomal ND vaccine group and a live La Sota(®) vaccine group. Both the liposomal ND vaccine and live La Sota(®) vaccine groups were vaccinated orally at 3 and 6 weeks of age. The mean antibody titres, total and differential white blood cell count, and blood chemistry, respectively, were assessed. Ten birds from each group were challenged by oral administration of 0.2 ml virulent Herts 33 strain at 9 weeks of age. The log(2) mean antibody titre induced by the liposomal ND vaccine after secondary immunization of the birds was 9.60±0.95 while that of the live La Sota( (®) ) vaccine was 6.00±0.63. Nine of the 10 challenged birds in the unvaccinated group died while none died from the liposomal ND vaccine group or the live La Sota(®) vaccine group. After the boost vaccination, the chickens vaccinated with the liposomal ND vaccine had a higher mean antibody titre, indicating that encapsulating ND vaccine in DOTAP-based liposome induced significantly higher immunity than the live La Sota(®) vaccine.

Antagonistic antimalarial properties of pawpaw leaf aqueous extract in combination with artesunic acid in Plasmodium berghei-infected mice.

BACKGROUND & OBJECTIVES: Artemisinins, the main stay in the treatment of malaria are used in combinations with other antimalarials to forestall resistance, as artemisinin-combination therapies (ACTs). However, ACTs are expensive and some of the non-artemisinin components are not well-tolerated by patients. There are several folkloric and scientific proofs of the efficacy of herbal remedies for malaria. Mature leaves of Carica papaya is widely used to treat malaria in several African countries. An ACT involving a medicinal herb extract or its active constituent(s) will provide an indigenous alternative/herbal ACT. METHODS: Mature fresh leaves of Carica papaya were grounded and macerated in cold distilled water for 24 h and the extract (PCE) was stored in the refrigerator for seven days. Fresh extracts were made as needed. The antiplasmodial activity of PCE and/or artesunic acid were determined by using the Peter's 4-day suppressive test in Plasmodium berghei-infected mice. The ED50 and ED90 were calculated from the dose-response relationships. RESULTS: The combination of 50 mg/kg of PCE and 15 mg/kg of artesunic acid produced a significant reduction of parasitemia (81.25%), compared to 50 mg/kg PCE alone (37.7%). The mean survival time of the combinations of PCE and 15 mg/kg of artesunic acid, and PCE alone followed a dose-dependent manner. The ED50 of PCE showed that it has a very good activity. The isobolar equivalent (IE) calculated from the ED90 of PCE in combination with artesunic acid showed that the interaction was antagonistic. INTERPRETATION & CONCLUSION: Although pawpaw alone was found to have a very good activity, its combination with artesunic acid is antagonistic. Combinations of artemisinins and pawpaw show little promise for combination therapy development.

Formulation and evaluation of niosomes.

Span 20-based niosome was prepared by lipid film hydration technique and loaded with Newcastle disease vaccine. Three batches with Span 20, cholesterol and dicetyl phosphate in micro molar ratios of 10:10:1; 15:15:1 and 20:20:1 were prepared and evaluated for encapsulation efficiency using haemagglutination test. The morphology of the vesicles was studied by means of transmission electron microscopy. Particle size, zeta potential and polydispersity index were determined by photon correlation spectroscopy using a nanosizer. Adjuvanticity was assessed using haemagglutination inhibition test. The vesicles of Span 20-based niosomes were distinct, near spherical large unilamellar vesicles. The vesicles were of varied sizes (<1000 nm) with the entrapped Newcastle disease vaccine in the core of the vaccine. The zeta potential had a peak at -50 mV. The polydispersity index was 0.68. Haemagglutination inhibition test showed a 71% increment in immune response over that of the marketed La Sota(®) vaccine which had a 60% increment in immune response. The niosomal vaccine did not alter but rather enhanced the immunogenicity of the Newcastle disease vaccine.

Preparation and evaluation of mucin-gelatin mucoadhesive microspheres for rectal delivery of ceftriaxone sodium.

Soluble mucin (S-mucin) processed from the small intestines (ileal region) of freshly slaughtered pigs via homogenization, dialysis, centrifugation and lyophilization and its admixtures with type A gelatin were dispersed in an aqueous medium and used to formulate ceftriaxone sodium-loaded mucoadhesive microspheres by the emulsification cross-linking method using arachis oil as the continuous phase. The release profile of ceftriaxone sodium from the microspheres was evaluated in both simulated gastric fluid (SGF) without pepsin (pH 1.2) and simulated intestinal fluid (SIF) without pancreatin (pH 7.4). The microspheres were further evaluated as possible novel delivery system for rectal delivery of ceftriaxone sodium in rats. Release of ceftriaxone sodium from the microspheres in both release media was found to occur predominantly by diffusion following non-Fickian transport mechanism and was higher and more rapid in SIF than in SGF. The results obtained from this study may indicate that ceftriaxone sodium could be successfully delivered rectally when embedded in microspheres formulated with either type A gelatin alone or its admixtures with porcine mucin; hence providing a therapeutically viable alternative route for the delivery of this acid-labile third generation cephalosporin.

Thermodynamic considerations of the interaction between caffeine and paracetamol in aqueous solutions.

Caffeine interacts physically with paracetamol thus producing changes in some physicochemical properties of paracetamol. There is evidence that the interaction may be in the form of a 1:1 association complex. Complexation of caffeine and paracetamol leads to increases in the aqueous solubility of the later. Thermodynamic influences play significant roles in the stabilization of the formed complex.

Effect of dika fat content of a barrier film coating on the kinetics of drug release from swelling polymeric systems.

Reservoir drug release systems were produced by coating drug loaded Carbopol 934P disks with polymer films containing Eudragit RL and dika fat at varying proportions. Uncoated disks produced maximal drug release after 5 hrs at pH 1.2 or 13 hrs at pH 6.8. Under these conditions, drug release occurred mainly by gel erosion and/or Fickian diffusion. Coating the disks with films of the polymer blends, predictably, led to more controlled drug release rates. But the ratio of the polymers in the coatings was found to be the modifying factor in the drug release mechanism. Systems containing less than 50% dika fat in the film coatings had a predominantly zero order release mechanism.

Use of dika fat in the formulation of sustained release frusemide encapsulated granules.

Sustained release frusemide granules were formulated with Dika fat, a vegetable oil extracted from the kernels of Irvingia gabonesis Var excelcia. Granules containing 60% w/w, of Dika fat and 200% w/w frusemide and lactose were prepared using the fusion method. Prepared granules (passed through 0.600 micron stainless steel sieve) were encapsulated such that each capsule contained frusemide granules equivalent to 75mg of the pure drug. Granules of same size fraction containing 10% w/w maize starch, or alginic acid and 60, 20, and 10% w/w of Dika fat, frusemide and lactose respectively were similarly prepared and encapsulated. Dissolution profiles of the encapsulated granules were assessed in 0.1 sodium hydroxide, simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) without enzymes. Results obtained indicated sustained release of frusemide in the presence of Dika fat. The presence of maize starch modulated the release of frusemide while the presence of alginic acid could not show significant (P < 0.05) enhancement on frusemide release. Dissolution of frusemide was greatest in 0.1N NaOH and least in SGF. Drug release from the matrices was of mixed order with diffusion controlled mechanism and leaching process occurring together to a greater extent.

Solubility and stability of indomethacin in sodium acetate solution. A consideration of hydrotropic mechanism.

The effect of sodium acetate on the aqueous solubility of indomethacin was studied. Increases in solubility were associated with the presence of sodium acetate in the dissolution medium. The mechanism of solubilisation was considered in relation to the possible effects of highly water-soluble substances on the structure of water. Thermodynamic conditions associated with the interactions were found to be favourable to the proposed mechanism. However, indomethacin was hydrolytically unstable in the solubilised state.

Effect of ascorbic acid on the binding of cloxacillin sodium to bovine serum albumin.

Using dynamic and equilibrium dialysis methods, it has been demonstrated that ascorbic acid (CAS 50-81-7) inhibits the binding of cloxacillin sodium (CAS 7081-44-9) to bovine serum albumin (BSA) in vitro. Normally, ascorbic acid has a lower number of binding sites and a much lower binding constant for BSA than cloxacillin sodium. There is an indication that ascorbic acid inhibits the binding of cloxacillin to BSA through a noncompetitive mechanism. The probable interactions leading to the non-competitive inhibition were suggested.

Determination of the synergy of antibiotic combinations by an overlay inoculum susceptibility disc method.

A method involving an overlay inoculum agar and antibiotic susceptibility discs in the determination of synergy of gentamicin and disc antibiotics against clinical isolates of Pseudomonas aeruginosa has been described. Gentamicin combinations with carbenicillin showed synergism against all test isolates. Combinations containing fosfomycin had indifferent effects. Netilmicin, ceftriaxone and ampicillin, respectively, produced interisolate variations in the synergy of their combinations with gentamicin. In all cases synergy was determined on the basis of correlations between inhibition zone diameter (IZD) increments and fractional inhibitory concentration (FIC) indices. An IZD increment of 19% or more predominantly corresponded with synergy. Cases showing less than 19% increase in IZD produced additive effects, while cases showing no variations in IZD had indifferent effects.