Muhammad Tayyab Ansari

Preparation and characterization of hybrid pH-sensitive hydrogels of chitosan-co-acrylic acid for controlled release of verapamil

In the present work crosslinked hydrogels based on chitosan (CS) and acrylic acid (AA) were prepared by free radical polymerization with various feed compositions using N,N methylenebisacrylamide (MBA) as crosslinking agent. Benzoyl peroxide was used as catalyst. Fourier transform infrared spectra (FTIR) confirmed the formation of the crosslinked hydrogels. This hydrogel is formed due to electrostatic interaction between cationic groups in CS and anionic groups in AA. Prepared hydrogels were used for dynamic and equilibrium swelling studies. For swelling behavior, effect of pH, polymeric and monomeric compositions and degree of crosslinking were investigated. Swelling studies were performed in USP phosphate buffer solutions of varying pH 1.2, 5.5, 6.5 and 7.5. Results showed that swelling increased by increasing AA contents in structure of hydrogels in solutions of higher pH values. This is due to the presence of more carboxylic groups available for ionization. On the other hand by increasing the chitosan content swelling increased in a solution of acidic pH, but this swelling was not significant and it is due to ionization of amine groups present in the structure of hydrogel. Swelling decreased with increase in crosslinking ratio owing to tighter hydrogel structure. Porosity and sol-gel fraction were also measured. With increase in CS and AA contents porosity and gel fraction increased, whereas by increasing MBA content porosity decreased and gel fraction increased. Furthermore, diffusion coefficient (D) and the network parameters i.e., the average molecular weight between crosslinks (Mc), polymer volume fraction in swollen state (V2s), number of repeating units between crosslinks (Mr) and crosslinking density (q) were calculated using Flory-Rehner theory. Selected samples were loaded with a model drug verapamil. Release of verapamil depends on the ratios of CS/AA, degree of crosslinking and pH of the medium. The release mechanisms were studied by fitting experimental data to model equations and calculating the corresponding parameters. The result showed that the kinetics of drug release from the hydrogels in both pH 1.2 and 7.5 buffer solutions was mainly non-Fickian diffusion.

Malaria and artemisinin derivatives: an updated review.

Malaria is the worlds most prevalent disease that affects 515-600 million people each year and about 40% of the worlds population live at risk for this infection. The prevalence of morbidity and mortality from drug resistant malaria (Plasmodium falciparum) is increasing in most of the developing countries, which is also a global threat because international travel is common now and imported malaria is increasingly a serious problem. Since rapid schizonticidal action of naturally occurring endoperoxides pharmacophore present in artemisinin against drug-resistant malaria has been documented, researchers have focused more on artemisinin analogs than any other antimalarials. In this review, drugs of choice about malaria i.e. artemisinin and its analogus/derivatives (arteether, artemether, artemiside, artemisinin, artemisone, artesunate, dihydroartemisinin) have been discussed in detail e.g. bioavailability, formulation development, stability, combination therapy, additional benefits, drug resistance and toxicity have been reviewed.

Dihydroartemisinin-cyclodextrin complexation: Solubility and stability

Dihydroartemisinin (DHA) is a major metabolite of artemisinin and its derivatives, including arteether, artemether, and artesunate. To improve the solubility and stability of poorly soluble DHA, we prepared inclusion complexes with hydroxypropyl-β-cyclodextrin (HPβCD) and recrystalized DHA to study its thermal stability. The complexes were characterized by differential scanning calorimetery (DSC), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction patterns (XRD), thermal stability, phase, and equilibrium solubility studies. Pure DHA was crystalline and remained crystalline after recrystallization, but its unit cell dimensions changed as exhibited by XRD. DHA-HPβCD complexes showed a phase transitions towards amorphous in DSC thermograms, FTIR spectra, and XRD patterns. The phase solubility profiles of complexes prepared in water, acetate buffer, and phosphate buffers were classified as AL-type, indicating the formation of a 1:1 stoichiometric inclusion complex. The equilibrium solubility of DHA was enhanced as a function of HPβCD concentration. DHA-HPβCD complexes showed an 89-fold increase in solubility compared to DHA. Solubilities of complexes containing 275.1 mM HPβCD in water, acetate buffer (pH 3.0), and phosphate buffer (pH 3.0 and 7.4) were 10.04, 7.96, 6.30, and 11.61 mg/ml, respectively. Hydrogen bonding was found between DHA and HPβCD, and it was stronger in complexes prepared in water than in buffers. However, the ÄH values were higher in buffer than water. DHA-HPβCD complexes prepared using commercial (untreated) or recrystallized DHA (no detectable impurity) showed a 40% increase in thermal stability (50°C) and a 29-fold decrease in hydrolysis rates compared with DHA. The rank order of stability constants (Ks) was: water, acetate buffer (pH 3.0), phosphate buffer (pH 3.0), and phosphate buffer (pH 7.4). Thus, HPβCD complexation with recrystalized DHA increases DHA solubility and stability.

Physicochemical characterization of artemether solid dispersions with hydrophilic carriers by freeze dried and melt methods

Solid dispersions of artemether (ARM), a poorly soluble drug, were prepared using polyvinylpyrrolidone (PVPK25, MW 25000) and polyethyleneglycol (PEG4000, MW 4000) as excipients. These dispersions were studied by physical mixture, freeze-drying, and melting methods. They were characterized by X-ray diffraction pattern, fourier transform infrared spectrophotometry, differential scanning calorimetery, and dissolution studies. X-ray diffraction pattern revealed the complete crystalline nature of artemether, whereas physical mixtures, melt mixtures (MM), and freeze-dried solid dispersions (FDSD) of ARM-PVP and ARM-PEG showed reduced peak intensities with increased PVP/PEG content. PEG showed lower decreases in intensity than PVP preparations. Differential scanning calorimetery also confirmed this finding by showing either a small or absent endotherm. Red shifts in O-H stretching vibrations of ARM were higher in the MM of ARM-PVP than its FDSD as exhibited by fourier transform infrared spectrophotometry. The carbonyl peak of PEG was blue shifted in MM and FDSD, whereas the C=O peak of PVP was red shifted in FDSD and MM, indicating different H-bonding by PEG and PVP with ARM. The rate of dissolution (phosphate buffer at pH 4.5) was improved up to 4-fold in MM and FDSD compared to artemether, and up to 50% compared to physical mixtures. The preparation of solid dispersions influenced the rate of dissolution at various drug-carrier ratios, i.e., the dissolution order of 1:1–1:4 ratio was MM > FDSD; FDSD > MM at 1:6–1:8 ratios of both ARM-PVP and ARM-PEG; and FDSD of ARM-PEG > FDSD of ARM-PVP > MM of ARM-PEG > MM of ARM-PVP at a 1:10 ratio.

Solid dispersions of dihydroartemisinin in polyvinylpyrrolidone

In the present study the physicochemical characteristics of dihydroartemisinin, polyvinylpyrrolidone and their solid dispersions were evaluated at various proportions of drug and polyvinylpyrrolidone. These properties were investigated with X-ray diffraction, fourier transform infrared spectrophotometry, differential scanning calorimetry, equilibrium solubility at twenty five and thirty seven degree centigrade. X-ray diffraction analysis detected that dihydroartemisinin became more amorphous as drug carrier ratio was enhanced in solid dispersions. Fourier transform infrared spectra suggested that there was a hydrogen bonding interaction between dihydroartemisinin and polyvinylpyrrolidone in all solid dispersions. These interactions reflected the changes in crystalline structures of dihydroartemisinin. The thermal behavior of dihydroartemisinin was unusual as it exhibited melting exotherm instead of endotherm. In solid dispersions containing varying contents of polyvinylpyrrolidone, enthalpy change and peak area were enhanced while melting onset temperature decreased with increase in polyvinylpyrrolidone proportion. This was attributed to a solid-state interaction. Equilibrium solubility of dihydroartemisinin increased sixty-fold due to induction of polyvinylpyrrolidone. When this solubility was compared among thirty-seven and twenty five degree centigrade in solid dispersions, it was up to seven times more at higher temperature. Physicochemical characteristics of solid dispersions containing drug carrier ratio of one: nine prepared in acetonitrile, ethanol, methanol and tetrahydrofuran showed differences which indicated that properties of medium i.e. dielectric constant, dipole moment and structure, influenced the amount of amorphousness and related properties of dihydroartemisinin.

Antihaemorrhagic potentials of Fagonia cretica against Naja naja karachiensis (black Pakistan cobra) venom

Plants have been extensively used as a remedy for the treatment of snake bites. The aim of this study was to determine the antivenom potentials of methanolic extract from the aerial parts (leaves and twigs) of Fagonia cretica L. on a haemorrhage induced by venom from Naja naja karachiensis. The haemorrhagic response of venom was dose dependent from 0.1 to 4.0 µg per 1.5 µL phosphate buffer saline (PBS) on vitelline veins of fertilised hens’ eggs in their shells. The extract effectively eliminated and neutralised, in a dose-dependent manner, the haemorrhagic activity of snake venom. The minimum effective neutralising dose of F. cretica extract was found to be 15 µg per 1.5 µL PBS. The extract possesses potentials as haemorrhagic inhibitor against snake venom compared to the standard antiserum and various plants reported in the literature. This study also provides a scientific base for the use of F. cretica in traditional medicine for the treatment of snake bite.

Preparation and Characterization of Solid Dispersions of Artemether by Freeze-Dried Method

Solid dispersions of artemether and polyethylene glycol 6000 (PEG6000) were prepared in ratio 12 : 88 (group-1). Self-emulsified solid dispersions of artemether were prepared by using polyethylene glycol 6000, Cremophor-A25, olive oil, Transcutol, and hydroxypropyl methylcellulose (HPMC) in ratio 12 : 75 : 5 : 4 : 2 : 2, respectively (group-2). In third group, only Cremophor-A25 was replaced with Poloxamer 188 compared to group-2. The solid dispersions and self-emulsified solid dispersions were prepared by physical and freeze dried methods, respectively. All samples were characterized by X-ray diffraction, attenuated total reflectance Fourier transform infrared spectroscopy, differential scanning calorimeter, scanning electron microscopy, and solubility, dissolution, and stability studies. X-ray diffraction pattern revealed artemether complete crystalline, whereas physical mixture and freeze-dried mixture of all three groups showed reduced peak intensities. In attenuated total reflectance Fourier transform infrared spectroscopy spectra, C–H stretching vibrations of artemether were masked in all prepared samples, while C–H stretching vibrations were representative of polyethylene glycol 6000, Cremophor-A25, and Poloxamer 188. Differential scanning calorimetry showed decreased melting endotherm and increased enthalpy change (ΔH) in both physical mixture and freeze-dried mixtures of all groups. Scanning electron microscopy of freeze-dried mixtures of all samples showed glassy appearance, size reduction, and embedment, while their physical mixture showed size reduction and embedment of artemether by excipients. In group-1, solubility was improved up to 15 times, whereas group-2 showed up to 121 times increase but, in group-3, when Poloxamer 188 was used instead of Cremophor-A25, solubility of freeze-dried mixtures was increased up to 135 times. In fasted state simulated gastric fluid at pH 1.6, the dissolution of physical mixture was increased up to 12 times and freeze-dried mixtures up to 15 times. The stability of artemether was substantially enhanced in freeze-dried mixtures by using polyethylene glycol 6000, Cremophor-A25, and Poloxamer 188 of self-emulsified solid dispersions of artemether in Hanks balanced salt solution at pH 7.4.

The evaluation of coated granules to mask the bitter taste of dihydroartemisinin

O objetivo deste estudo foi o de mascarar o gosto amargo caracteristico da diidroartemisinina (DHA) pelo uso de diferentes materiais de revestimento. Experimento-1 e experimento-2 foram realizados para preparar grânulos de DHA. Os grânulos produzidos pelo experimento-1 mostraram-se irregulares e menores se comparados aos obtidos pelo experimento-2, que foram mais regulares e maiores. Os grânulos obtidos em ambos os experimentos foram, entao, revestidos por dois metodos distintos de revestimento, designados como A e B, dependendo do material de revestimento empregado. Os grânulos do experimento-2 mostraram melhor propriedade de fluxo que os obtidos no experimento-1. Estudos de dissolucao in vitro em tampao fosfato pH 6,8 revelaram que grânulos do experimento-2B liberaram apenas 34% ± 3 da DHA em dois minutos se comparado com experimento-1A (57% ± 2), experimento-1B (48% ± 2) e experimento-2A (53% ± 7). A Analise Sensorial quanto ao sabor (Pleasant Taste Perception - PTP) tambem confirmou a eficacia do experimento-2B (P <0,05) em mascarar o gosto amargo da DHA. Microscopia Eletronica de Varredura (SEM) revelou a superficie mais regular e lisa dos grânulos obtidos pelo experimento-2B. Alem disso, Analise Termogravimetrica e Analise Termica Diferencial (TG-DTA) confirmaram que nao ha nenhuma interacao entre os materiais e a DHA pura. DHA mostrou seus picos caracteristicos na Difracao de Raios X (XRD) em padroes que tambem foram proeminentes em todas as amostras. Em conclusao, os grânulos obtidos pelo experimento-2B exibiram diminuicao consideravel no gosto amargo da DHA, o que era o proposito deste estudo.

Improving the Solubility and Bioavailability of Dihydroartemisinin by Solid Dispersions and Inclusion Complexes

Dihydroartemisinin (DHA) is a poorly water-soluble drug that displays low bioavailability after oral administration. Attempts have been made to improve the solubility of DHA. Yet, no information is available concerning improved bioavailability. This study aimed to improve the water solubility of DHA by two systems: solid dispersions with polyvinylpyrrolidone (PVPK30, PVPK25, PVPK15) and inclusion complexes with hydroxypropyl-β-cyclodextrin (HPβCD), as well as improving the bioavailability of both systems. The phase transition of DHA with hydrophilic polymers was evaluated by X-ray diffraction (XRD) and differential scanning calorimetery (DSC). DHA became amorphous in DHA-HPβCD complexes and showed more amorphous behavior in XRD analyses with rise in molecular weight of PVP. Melting onset temperature of DHA decreased, while DSC thermograms revealed the peak area and enhanced enthalpy change (DH) in solid dispersions as well as inclusion complexes. DHA solubility was enhanced 84-fold in DHA-HPβCD complexes and 50-times in DHA-PVPK30. The improved solubility using the four polymers was in the following order: HPβCD > PVPK30 > PVPK25 > PVPK15. Values of area under curve (AUC) and half life (t1/2) of DHA-PVPK30 were highest followed by DHA-HPβCD, DHA-PVPK15 and DHA-PVPK25. Vd/f of DHA-PVPK30 was 7-fold. DHA-HPβCD, DHA-PVPK15 and DHA-PVPK25 showed significantly different pharmacokinetic parameters compared with DHA solutions. The 95% confidence interval was meaningful in AUC and t1/2. Pharmacokinetic parameters revealed that all four-test preparations were significantly more bioavailable than DHA alone.

Permeation Kinetics Studies of Physical Mixtures of Artemisinin in Polyvinylpyrrolidone

Artemisinin (ART), the parent compound of a novel family of antimalarial drugs, was used as a model drug that is lipophilic and has low bioavailability (32%) after oral delivery. The primary objective was to study the effect of polyvinylpyrrolidone (PVP) on the permeation enhancement and solubility of physical mixtures (PM) of ART in PVP–K30 in various solvent systems (i.e., distilled water, phosphate buffered saline [PBS], and methanol). PMs of drug–PVP in 1:0.5, 1:1, 1:2, 1:4, and 1:9 ratios were prepared by simple mixing in a mortar and pestle. Fourier transform infrared (FTIR) spectrophotometry and X-ray powder diffraction (XRPD) were applied to characterize the PMs. The solubility of ART was investigated at 37 ± 0 .5 ° C in three solvents. Permeation of ART-saturated solutions across a silicone membrane in Franz diffusion cells was studied using Fick’s law of diffusion. FTIR and XRPD studies have shown some interactions, and there was a phase change of artemisinin from crystalline to amorphous form as the concentration of PVP–K30 in PM ratios increased. Solubility order increased with an increase in PVP– K30 concentration for the water–PBS solvent system, while in methanol, it was erratic. Flux rate and permeability coefficient were enhanced with an increase in PVP–K30 concentration. In less permeable solvents like water and PBS, the enhancement ratio was high, while the enhancement ratio was low in a highly permeable solvent like methanol. In conclusion, with an increase in concentration of PVP, the permeation rate and solubility of ART increased.