Process and formulation variables of pregabalin microspheres prepared by w/o/o double emulsion solvent diffusion method and their clinical application by animal modeling studies

Abstract

Pregabalin is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. In conventional therapy recommended dose for pregabalin is 75 mg twice daily or 50 mg three times a day, with maximum dosage of 600 mg/d. To achieve maximum therapeutic effect with a low risk of adverse effects and to reduce often drug dosing, modified release preparations; such as microspheres might be helpful. However, most of the microencapsulation techniques have been used for lipophilic drugs, since hydrophilic drugs like pregabalin, showed low-loading efficiency and rapid dissolution of compounds into the aqueous continous phase. The purpose of this study was to improve loading efficiency of a water-soluble drug and modulate release profiles, and to test the efficiency of the prepared microspheres with the help of animal modeling studies. Pregabalin is a water soluble drug, and it was encapsulated within anionic acrylic resin (Eudragit S 100) microspheres by water in oil in oil (w/o/o) double emulsion solvent diffusion method. Dichloromethane and corn oil were chosen primary and secondary oil phases, respectively. The presence of internal water phase was necessary to form stable emulsion droplets and it accelerated the hardening of microspheres. Tween 80 and Span 80 were used as surfactants to stabilize the water and corn oil phases, respectively. The optimum concentration of Tween 80 was 0.25% (v/v) and Span 80 was 0.02% (v/v). The volume of the continous phase was affected the size of the microspheres. As the volume of the continous phase increased, the size of microspheres decreased. All microsphere formulations were evaluated with the help of in vitro characterization parameters. Microsphere formulations (P1-P5) exhibited entrapment efficiency ranged between 57.00 ± 0.72 and 69.70 ± 0.49%; yield ranged between 80.95 ± 1.21 and 93.05 ± 1.42%; and mean particle size were between 136.09 ± 2.57 and 279.09 ± 1.97 µm. Pregabalin microspheres having better results among all formulations (Table 3) were chosen for further studies such as differential scanning calorimetry, Fourier transform infrared analysis and dissolution studies. In the last step, the best pregabalin microsphere formulation (P3) was chosen for in vivo animal studies. The pregabalin-loaded microspheres (P3) and conventional pregabalin capsules were applied orally in rats for three days, resulted in clinical improvement of cold allodynia, an indicator of peripheral neuropathy. This result when evaluated together with the serum pregabalin levels and in vitro release studies suggests that the pregabalin microspheres prepared with w/o/o double emulsion solvent diffusion method can be an alternative form for neuropathic pain therapy. Conclusively, a drug delivery system successfully developed that showed modified release up to 10 h and could be potentially useful to overcome the frequent dosing problems associated with pregabalin conventional dosage form.

Development and characterization of polymeric-based nanoparticles for sustained release of amoxicillin – an antimicrobial drug

“…According to this, it was observed that increasing concentration of span 80 from 1% to 4% caused the decrease of particles size from 558.3 ± 31.39 to 397 ± 22.73 nm. Similarly, Jose et al [33] and Aydogan et al [34] have reported that higher span 80 concentration caused the smaller particle size when they prepared diltiazem-loaded microspheres and pregabalin-loaded microspheres, respectively. Relatedly, Huang et al [35] reported that this surfactant agent (span 80) diminished particle size by reducing surface tension between liquid paraffin and organic phase in 5-fluorouracil-loaded microparticles.…”

“…In fact, span 80 tends to reduce surface tension between the two phases, thereby preventing coalescence of particles by forming a thin layer around the droplets while stabilizing the emulsion. When the amount of span 80 in formulation falls below a certain concentration, droplets tend to aggregate because of insufficiency of surface tension reducing effect of surfactant agent and thus particle size is increased [33][34][35][36]. Figure 2 shows SEM microphotograph of AMO-loaded nanoparticles.…”

Formulation and in vitro evaluation of ketoprofen fast-dissolving tablets

“…FTIR spectra of Ketoprofen, Eudragit EPO, Ketoprofen:Eudragit EPO physical mixture (drug:polymer ratio; 1:2) and Ketoprofen:Eudragit EPO taste-masked granules (drug:polymer ratio; 1:2) were obtained by KBr disc method 9 (1:100 physical mixture; Shimadzu 8400S) in the range of 400-500 cm À1 .…”

Development and Characterization of Thermosensitive intranasal Gel Containing Paliperidone Loaded Microspheres

“…Tween 80 being a surfactant played an important role in determining the size of microsphere and percentage yield of the microsphere which in turn controls the drug release. 23 Different amounts of ethyl cellulose and surfactant were used in a 3^2 factorial design to identity a combination that would give a programmed release of 8 hours, small particle size and high percentage yield (Table 1). Multiple linear regression analysis was performed to equate the multiple factors with each response and mathematical models were generated.…”