Formulation and Stability Study of Eslicarbazepine Acetate Oral Suspensions for Extemporaneous Compounding

Eslicarbazepine acetate is an anticonvulsant drug with a recent U.S. Food and Drug Administration approval for expanded use in children and adolescents. Currently, eslicarbazepine acetate is only available in the U.S. as 200-mg to 800-mg strength tablets (Aptiom), which are not easy to administer for pediatric patients. This study was initiated to develop an oral suspension formulation for extemporaneous compounding by pharmacists and to generate stability data for storage recommendations. Nine suspension formulations of eslicarbazepine acetate were prepared from Aptiom tablets and commercially available liquid vehicles using the standard mortar/pestle method. The vehicles varied mainly in their solvents, viscosities, and sweeteners. The formulations were evaluated for ease of preparation, physical properties, and initial potency. Two lead formulations were selected for a two-month stability study at room temperature or under refrigeration (2°C to 8°C). The stability samples were withdrawn at pre-determined time points and analyzed by visual inspection, pH measurement, and a stability-indicating high-performance liquid chromatographic assay. The majority of the 9 formulations were found to be easy to prepare and administer at a concentration of 40-mg/mL eslicarbazepine acetate. Particle settling was observed in several formulations over time, but they were re-suspended satisfactorily upon shaking. Two suspensions in 50:50 v/v mixtures of Ora-Sweet or Ora-Sweet SF with Ora-Plus were selected as the lead formulations for the two-month stability study. At the initiation of the study, all samples appeared as white and smooth suspensions with pH ranging from 4.39 to 4.46. The high-performance liquid chromatographic results confirmed that the initial samples contained 100.4% to 102.2% of the label claim strength. Over two months of storage at room temperature or refrigeration, there were no significant changes in visual appearance, re-suspendability, pH, or potency for any samples. No new degradation peaks were observed in any highperformance liquid chromatograms. Based on the study results, two eslicarbazepine acetate suspensions are recommended for extemporaneous compounding from Aptiom tablets. The formulations consist of 40 mg/mL eslicarbazepine acetate in 50:50 v/v Ora-Sweet:Ora-Plus or Ora-Sweet SF:Ora-Plus. Once prepared, these suspensions can be stored at room temperature or under refrigeration for up to two months

Emerging technologies for the non-invasive characterization of physical-mechanical properties of tablets

The density, porosity, breaking force, viscoelastic properties, and the presence or absence of any structural defects or irregularities are important physical-mechanical quality attributes of popular solid dosage forms like tablets. The irregularities associated with these attributes may influence the drug product functionality. Thus, an accurate and efficient characterization of these properties is critical for successful development and manufacturing of a robust tablets. These properties are mainly analyzed and monitored with traditional pharmacopeial and non-pharmacopeial methods. Such methods are associated with several challenges such as lack of spatial resolution, efficiency, or sample-sparing attributes. Recent advances in technology, design, instrumentation, and software have led to the emergence of newer techniques for non-invasive characterization of physical-mechanical properties of tablets. These techniques include near infrared spectroscopy, Raman spectroscopy, X-ray microtomography, nuclear magnetic resonance (NMR) imaging, terahertz pulsed imaging, laser-induced breakdown spectroscopy, and various acoustic- and thermal-based techniques. Such state-of-the-art techniques are currently applied at various stages of development and manufacturing of tablets at industrial scale. Each technique has specific advantages or challenges with respect to operational efficiency and cost, compared to traditional analytical methods. Currently, most of these techniques are used as secondary analytical tools to support the traditional methods in characterizing or monitoring tablet quality attributes. Therefore, further development in the instrumentation and software, and studies on the applications are necessary for their adoption in routine analysis and monitoring of tablet physical-mechanical properties

Formulation and characterization of an apigenin-phospholipid phytosome (APLC) for improved solubility, in vivo bioavailability, and antioxidant potential

The apigenin-phospholipid phytosome (APLC) was developed to improve the aqueous solubility, dissolution, in vivo bioavailability, and antioxidant activity of apigenin. The APLC synthesis was guided by a full factorial design strategy, incorporating specific formulation and process variables to deliver an optimized product. The design-optimized formulation was assayed for aqueous solubility, in vitro dissolution, pharmacokinetics, and antioxidant activity. The pharmacological evaluation was carried out by assessing its effects on carbon tetrachloride-induced elevation of liver function marker enzymes in a rat model. The antioxidant activity was assessed by studying its effects on the liver antioxidant marker enzymes. The developed model was validated using the design-optimized levels of formulation and process variables. The physical-chemical characterization confirmed the formation of phytosomes. The optimized formulation demonstrated over 36-fold higher aqueous solubility of apigenin, compared to that of pure apigenin. The formulation also exhibited a significantly higher rate and extent of apigenin release in dissolution studies. The pharmacokinetic analysis revealed a significant enhancement in the oral bioavailability of apigenin from the prepared formulation, compared to pure apigenin. The liver function tests indicated that the prepared phytosome showed a significantly improved restoration of all carbon tetrachloride-elevated rat liver function marker enzymes. The prepared formulation also exhibited antioxidant potential by significantly increasing the levels of glutathione, superoxide dismutase, catalase, and decreasing the levels of lipid peroxidase. The study shows that phospholipid-based phytosome is a promising and viable strategy for improving the delivery of apigenin and similar phytoconstituents with low aqueous solubility

Drug-Phospholipid Complex-loaded Matrix Film Formulation for the Enhanced Transdermal Delivery of Quercetin

A novel quercetin-phospholipid-complex(QPLC)-loaded matrix film for improved transdermal delivery of quercetin was developed. The QPLC formulation, prepared using a solvent-evaporation method, was optimized using a central-composite design. The optimized QPLC formulation was characterized by particle size and zeta potential analysis, thermal analysis, Fourier transform infrared spectroscopy (FTIR), and proton nuclear magnetic resonance spectroscopy (1H-NMR). QPLC formulation was functionally evaluated for solubility and in vitro dissolution of quercetin. Matrix films of pure quercetin (Q-MF)or QPLC QPLC-MF) were prepared using a solvent casting method. The prepared Q-MF and QPLC-MF were characterized for weight uniformity, folding endurance, moisture content, and moisture uptake. The films were also functionally characterized for in vitro diffusion of quercetin through a dialysis membrane and ex vivo permeability of quercetin across rat skin. Finally, the anti-inflammatory activity of the films was evaluated on carrageenan-induced paw edema in Wistar albino rats. The experimental design identified the optimal formulation and process variables for the preparation of QPLC. The validation of the obtained model using these values confirmed the suitability and robustness of the model. The physical-chemical characterization of the prepared QPLC supported the formation of a stable complex. The solubility analysis of QPLC showed a 22-fold increase in quercetin aqueous solubility, compared to pure quercetin. The dissolution results exhibited a significantly higher rate and extent of quercetin dissolution from QPLC compared to that of pure quercetin. The permeability of quercetin from Q-MF and QPLC-MF across rat skin mirrored those obtained from the dissolution studies. Topical application of QPLC-MF exhibited a significant (p\u3c0.05) inhibition of carrageenan-induced paw edema in rats compared to that of Q-MF. This study provides a promising combination approach, i.e., phospholipid-based complexation and transdermal film formulation for improved transdermal delivery of quercetin and similar pharmacologically active phytoconstituents

Kaempferol-Phospholipid Complex: Formulation, and Evaluation of Improved Solubility, In Vivo Bioavailability, and Antioxidant Potential of Kaempferol

The current work describes the formulation and evaluation of a phospholipid complex of kaempferol toenhance the latter’s aqueous solubility, in vitro dissolution rate, in vivo antioxidant and hepatoprotectiveactivities, and oral bioavailability. The kaempferol-phospholipid complex was synthesized using a freeze-drying method with the formulation being optimized using a full factorial design (32) approach. The resultsinclude the validation of the mathematical model in order to ascertain the role of specific formulation andprocess variables that contribute favorably to the formulation’s development. The final product wascharacterized and confirmed by Differential Scanning Calorimetry (DSC), Fourier Transform InfraredSpectroscopy (FTIR), Proton Nuclear Magnetic Resonance Spectroscopy (1H-NMR), and Powder X-rayDiffraction (PXRD) analysis. The aqueous solubility and the in vitro dissolution rate were enhanced comparedto that of pure kaempferol. The in vivo antioxidant properties of the kaempferol-phospholipid complex wereevaluated by measuring its impact on carbon tetrachloride (CCl4)-intoxicated rats. The optimizedphospholipid complex improved the liver function test parameters to a significant level by restoration of allelevated liver marker enzymes in CCl4-intoxicated rats. The complex also enhanced the in vivo antioxidantpotential by increasing levels of GSH (reduced glutathione), SOD (superoxide dismutase), catalase anddecreasing lipid peroxidation, compared to that of pure kaempferol. The final optimized phospholipidcomplex also demonstrated a significant improvement in oral bioavailability demonstrated by improvementsto key pharmacokinetic parameters, compared to that of pure kaempferol

The enhancement of the aqueous solubility of ritonavir via formulation of a drug-phospholipid complex

Objective: To evaluate the enhancement of aqueous solubility of a poorly water soluble drug ritonavir by forming its complex with a phospholipid (Phospholipon®90H)

Glucosamine HCl-based solid dispersions to enhance the biopharmaceutical properties of acyclovir

The objective of the work presented here was to assess the feasibility of using glucosamine HCl as a solid-dispersion (SD) carrier to enhance the biopharmaceutical properties of a BCS class III/IV drug, acyclovir (ACV). The solid-dispersions of acyclovir and glucosamine HCl were prepared by an ethanol-based solvent evaporation method. The prepared formulations characterized by photomicroscopy, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transforms infrared spectrophotometry (FTIR), powder x-ray diffractometry (PXRD) and drug content analysis. The functional characterization of ACV-SD was performed by aqueous solubility evaluation, dissolution studies, fasted versus fed state dissolution comparison, ex vivo permeability, and stability studies. Photomicroscopy and SEM analysis showed different surface morphologies for pure ACV, glucosamine HCl and ACV-SD. The physical-chemical characterization studies supported the formation of ACV-SD. A 12-fold enhancement in the aqueous solubility of ACV was observed in the prepared solid dispersions, compared to pure ACV. Results from in vitro dissolution demonstrated a significant increase in the rate and extent of ACV dissolution from the prepared ACV-SD formulations, compared to pure ACV. The rate and extent of ACV permeability across everted rat intestinal membrane were also found to be significantly increased in the ACV-SD formulations. Under fed conditions, the rate and extent of the in vitro dissolution of ACV from the formulation was appreciably greater compared to fasted conditions. Overall, the results from the study suggest the feasibility of utilizing glucosamine HCl as a solid dispersion carrier/excipient for enhancement of biopharmaceutical properties of acyclovir, and similar drugs with low solubility/permeability characteristics

Design and evaluation of sustained-release matrix once daily formulation of stavudine

The aim of the present study was to formulate once daily sustained release matrix tablets of Stavudine to increase therapeutic efficacy, reduce frequency of administration and improve patient compliance. The sustained release tablets were prepared by direct compression and formulated using different drug: polymer ratios, formulations such as F1to F15. Hydrophilic polymers like Hydroxy propyl methyl cellulose (HPMC), Carboxymethyl cellulose (CMC) and Starch 1500 were used. Compatibility of the drug with various excipients was studied. The compressed tablets were evaluated and showed compliance with pharmacopoeial standards. Formulation containing Stavudine:HPMCK15: Na-CMC (1:2:0.5) with hardness 10-11kg/cm2 showed the desired release profile which matched the theoretical release profile. SEM studies of the formulations were carried out for the confirmation of mechanism of drug release. The in vitro drug release characteristics were studied in both simulated gastric and intestinal fluids for a period of 24 hr using USP Type 2 dissolution apparatus. Mathematical analysis of the release kinetics indicated a coupling of diffusion and erosion mechanisms. The study proves that the developed sustained release tablet is capable of releasing the drug in a sustained manner for 24 hr.Keywords: Sustained release; Matrix tablets; Hydroxy propyl methylcellulose; Stavudin

Design and evaluation of sustained-release matrix once daily formulation of stavudine

The aim of the present study was to formulate once daily sustained release matrix tablets of Stavudine to increase therapeutic efficacy, reduce frequency of administration and improve patient compliance. The sustained release tablets were prepared by direct compression and formulated using different drug: polymer ratios, formulations such as F1to F15. Hydrophilic polymers like Hydroxy propyl methyl cellulose (HPMC), Carboxymethyl cellulose (CMC) and Starch 1500 were used. Compatibility of the drug with various excipients was studied. The compressed tablets were evaluated and showed compliance with pharmacopoeial standards. Formulation containing Stavudine:HPMCK15: Na-CMC (1:2:0.5) with hardness 10-11kg/cm2 showed the desired release profile which matched the theoretical release profile. SEM studies of the formulations were carried out for the confirmation of mechanism of drug release. The in vitro drug release characteristics were studied in both simulated gastric and intestinal fluids for a period of 24 hr using USP Type 2 dissolution apparatus. Mathematical analysis of the release kinetics indicated a coupling of diffusion and erosion mechanisms. The study proves that the developed sustained release tablet is capable of releasing the drug in a sustained manner for 24 hr.Keywords: Sustained release; Matrix tablets; Hydroxy propyl methylcellulose; Stavudin

Formulation and Characterization of the Improved Solubility, In Vivo Bioavailability and Antioxidant Activity of Apigenin-Phospholipid Complex (APLC)

In the present study a phospholipid based complex of apigenin (APLC) was prepared with a goal of improving its aqueous solubility, dissolution, in vivobioavailability, and antioxidant activity