The %DE values were computed at two times, showing the early and late phase of dissolution study for comparative analysis of all the formulations. The %DE values in the initial time period of dissolution study, i.e., %DE10 min, provide comparative information for very fast releasing formulations, whereas %DE30 min provides relative information about both fast and slow releasing formulations. The value of %DE10 min for pure gliclazide (9.16%) was enhanced in PMs (21.94%) as well as in SDs (49.87%). The value of %DE30 min for the pure drug increased to 45.11% in PMs and up to 73.20% in SDs (Table II).
The obtained values of mean dissolution time (MDT) for pure gliclazide, PMs, and SDs are presented in Table II. The MDT of gliclazide was 12.5 min and it decreased to 7.09 min in SD with PVP K90 at 1:5 (gliclazide/PVP K90) ratio, whereas in case of PMs, MDT decreased to 9.43 min.
The results of the dissolution study indicate an improvement of dissolution rate of gliclazide in solid dispersion. The rate of dissolution increases as the concentration of PVP K90 increases in SDs. The improvement of dissolution rate is possibly caused by several factors. Such factors are: (a) the strong hydrophilic character of PVP K90, which improves the water penetration and the wettability of the hydrophobic gliclazide; (b) the optimal dispersion of gliclazide to PVP K90; (c) the absence of crystals (amorphous dispersions) corresponds to lower energy required for dissolution; and (d) the intermolecular hydrogen bonds and the molecular dispersion of gliclazide on PVP leads to partial miscibility, improving the hydrophilic characteristics of the drug substance via interactions within the polymer (22). The improvement of dissolution rate of gliclazide in PMs is due to increased wettability of the drug powder (23).
Rilpivirine having lowest water solubility indicates class II drugs of BCS. These classes of drugs could potentially exhibit dissolution rate limited absorption. The objective of the present study is to improve the solubility and dissolution of Rilpivirine through inclusion complexation with βCD and HPβCD. Solid binary systems of Rilpivirine with βCD and HPβCD were prepared by solvent evaporation and kneading methods at 1:1 and 1:2 M ratios. The prepared solid binary systems were studied in solution state by phase solubility, in vitro dissolution rate and solid state by FTIR and XRD. The dissolution parameters were studied by using dissolution software PCP Disso V3. The drug content was uniform in all the solid binary systems with low SD and CV values. The apparent stability constant indicates there is a 1:1 stochiometric complex with βCD and HPβCD. The formation of inclusion complexes with βCD and HPβCD in the solid state were confirmed by FTIR, XRD. The dissolution data clearly suggest drug release was method dependent and type of cyclodextrin. The dissolution of solid binary systems obeyed first-order kinetics and model fitted with Hixon crowel. A true inclusion complex of Rilpivirine was observed with βCD and HPβCD. Dissolution properties of solid binary systems were superior then rilpivirine alone and its corresponding physical mixtures. Overall dissolution rate was solvent evaporation > kneaded binary systems > physical mixture > pure drug. One-way ANOVA results suggest the DE30 and DE60 values were significantly higher (P
The aim of the present study was to formulate EFV-containing SNEDDS which may enhance the bioavailability of EFV. The Labrafil M 2125 CS, Tween 80, and Transcutol®P isotropic mixture was utilized, and its effects on various physicochemical properties were evaluated. The in vitro and in vivo drug release kinetic study was performed to determine the improvement in dissolution rate and bioavailability of SNEDDS. Moreover, the SNEDDS was investigated for vitrification if any during its 3-month storage.
The solubility of EFV in various oils, surfactants, and co-surfactants was accomplished by adding an excess amount of EFV in a 2-mL microtube (Tarson-500020) containing 1 mL vehicle. Mixture was vortexed and kept for 24 h at 25°C in a shaking water bath to facilitate the solubilization. The samples were centrifuged (Allegra 64 R, Beckman Coulter, USA) at 4000 rpm for 15 min, and the supernatant was removed. The amount of dissolved drug was determined at 248 nm using a UV-visible spectrophotometer (Jasco, V-530, Japan).
To determine the concentration range of components for the existing boundary of SNEDDS and to identify the better self-emulsifying region, pseudo-ternary phase diagrams were constructed (23). Ternary phase diagram was plotted using PCP-Disso software (V3; Poona College of Pharmacy, Pune, India). The oil, surfactant, and co-surfactant concentration was varied from 10 to 80% (v/v). These mixtures were diluted dropwise with double-distilled water, to formulate emulsion under moderate agitation.
EFV (150 mg) was dissolved in 1-mL mixture of oil, surfactant, and co-surfactant. All components were mixed on a magnetic stirrer at 50°C and then subjected to vortex. These batches were further screened on the basis of solubility of EFV, particle size of droplets, and phase separation (Table I).
The Q 0 to Q 240 values of capsules containing optimized SNEDDS formulation and EFV are represented in Table V. The 1% sodium lauryl sulphate (SLS) solution was used as a dissolution medium. Figure 6 indicates dissolution profile of optimized SNEDDS formulation and EFV. Optimized SNEDDS exhibits a constantly superior drug dissolution rate compared to that of EFV. Within the period of 30 min, only 35% EFV was dissolved form EFV sample. Conversely, a capsule containing optimized SNEDDS exhibits more than 50% of drug release. The total drug released from EFV was only 53.79% in 3 h, while percentage drug release (Q 120) from optimized SNEDDS was 98.39%. In the present study, SNEDDS exhibits a faster and almost complete dissolution profile compared to the pure drug in 2 h. SNEDDS dissolution behavior was attributed to oil/surfactant ratios and the properties of the surfactant phase. Emulsification time of formulations was increased as oil content was increased. But this may lead to poor self-nano-emulsifying systems due to larger oil droplets (27). Labrafil M 2125 CS is a moderate chain length linoleoyl macrogol glyceride. In comparison to long-chain triglycerides oils, moderate chain length oils are easy to nano-emulsify. Transcutol®P, i.e., amphiphilic solubilizers, is often used in the SNEDDS formulation to improve drug loading and time required for self-nano-emulsification (28). In addition, the presence of Tween 80 as co-surfactants helps build a flexible interracial film, reduces the interfacial tension, and improves the fluidity of the interface (29).
The mean EFV plasma concentration-time profile after oral administration of EFV suspended in water and optimized SNEDDS batch are shown in Fig. 7. The summary of pharmacokinetics of neat efavirenz and SNEDDS is given in Table II. The total plasma concentrations of optimized SNEDDS were found to be superior to EFV. Initial plasma concentrations of animals receiving optimized SNEDDS are significantly higher than those animals receiving EFV. The optimized SNEDDS exhibits noticeably higher AUC and C max than EFV. The AUC of EFV from optimized SNEDDS clearly indicates a threefold higher increment than that of EFV. Yet, the t max value of both optimized SNEDDS and EFV did not differ. Present results indicate that it is possible to improve the bioavailability of EFV if given in the form of SNEDDS. These results were steady with the results from the in vitro dissolution study, indicating that the differences in EFV absorption is primarily accredited to the dissolution profile of EFV. Surfactants help to improve permeability of drugs by maculating tight junctions among the cells and distribute the drug across the cell membrane (30). Oils with medium-chain mono- and di-glycerides, i.e., Labrafil M 2125 CS, have superior solubilization potential for hydrophobic drugs and permeation-enhancing properties (28). Improved bioavailability of EFV was due to medium-chain mono- and di-glycerides. In the current study, better performance of SNEDDS was explained by various factors like (i) improved surface area of droplets, (ii) superior solubilization potential for hydrophobic drugs due to Labrafil M 2125 CS, and (iii) result of surfactant on mucosal permeability.
A stable SNEDDS formulation of EFV was formulated successfully. SNEDDS containing EFV showed an appreciable improvement in in vitro and in vivo drug release. Chemical nature and concentration of oil, surfactant, and co-surfactant exhibit prominent effect on emulsifying potential, solubility, and dissolution behavior of EFV. The superior physicochemical properties were shown by SNEDDS due to unique mixture of Labrafil M 2125 CS, Tween 80, and Transcutol®P. It helps to enhance the solubility, stability, dissolution behavior, and bioavailability of EFV. Current results demonstrate SNEDDS as an opportunity to formulate a potential drug delivery system for improving solubility, stability, dissolution rate, and oral bioavailability of various BCS class II candidates.
Prochlorperazine maleate is a phenothiazine antipsychotic used in the treatment of nausea, vomiting and vertigo. Its antiemetic effects are attributed to dopamine blockade in the chemoreceptor trigger zone. For treatment of nausea and vomiting, 5 or 10 mg thrice or four times daily dose of prochlorperazine maleate is given orally. It has mean absolute bioavailability of 12.5% due to extensive metabolism, principally in liver. It has biological half life of 6 to 8 hrs. Due to solubility of drug in acidic pH, drug is absorbed in stomach; therefore the drug should be retained in the stomach for longer period of time to achieve the desired effect. Due to short biological half life, drugs usually require multiple dosing to achieve and maintain therapeutic level. Literature survey had indicated that, work has been carried out on mouth dissolving tablet, sustained release matrix tablet and transdermal patch for prochlorperazine maleate [7-9]. Prochlorperazine maleate was chosen as drug candidate for the present research work since it possesses all the ideal characteristics that a drug must have in formulating gastro retentive floating drug delivery system. The properties include, low molecular weight (606.10), low absolute bioavailability (12.5%) and short biological half life (6 to 8 hrs) [10-12]. 2b1af7f3a8