Crisaborole-Enthused Glycerosomal Gel for an Augmented Skin Permeation.

BACKGROUND: Crisaborole (CB), a boron-based compound, is the first topical PDE4 inhibitor to be approved by the US Food and Drug Administration (2016) for the treatment of Atopic Dermatitis. It is marketed as a 2% ointment (Eucrisa, Pfizer). However, CB is insoluble in water; therfore, CB glycersomes were formulated to enhance its permeation flux across the skin. OBJECTIVE: We developed a glycerosomal gel of CB and compared its in vitro release and permeation flux with the 2% conventional ointment. METHODS: Glycerosomes were prepared using a thin film hydration method employing CB, soya phosphatidylcholine, and cholesterol. The formed film was further hydrated employing a mixture of phosphate buffer pH 7.4 /glycerin solution containing varying percentages (20,30, 40, and 50 %) of glycerol. The glycerosomes obtained were characterized by their size, polydispersity index (PDI), and Zeta potential. The entrapment efficiency of the optimized formulation (F 1) was determined. The in vitro release of F1 was compared with its 2% conventional ointment. F1 was further incorporated into carbopol 934 P gel. The gel was characterized by pH, viscosity, spreadability, and drug content. The permeability flux of the glycerosomal gel was compared with its 2% conventional ointment. RESULTS: The optimized CB glycerosomes had a vesicle size of 137.5 ± 50.58 nm, PDI 0.342, and zeta potential -65.4 ± 6.75 mV. CB glycerosomal gel demonstrated a 2.13-fold enhancement in the permeation flux. CONCLUSION: It can thereby be concluded that glycerosomes can be an effective delivery system to enhance the penetration of CB across the skin.

Crisaborole loaded nanoemulgel for the mitigation of atopic dermatitis in mice model.

OBJECTIVE: The present work aims to formulate nanoemulgel of crisaborole (CB) and evaluate its effectiveness against 2,4-Di-nitrochlorobenzene induced (DNCB) atopic dermatitis (AD) in mice. SIGNIFICANCE: AD is a chronic inflammation of the skin affecting the quality of life. CB is a topical PDE4 inhibitor marketed as a 2% ointment. It, however, possesses poor aqueous solubility. An o/w nanoemulsion shall exhibit an enhanced therapeutic effect owing to the increased solubility of CB and an augmented skin penetration. The addition of a gelling agent to form a nanoemulgel further provides ease of application to the patients. METHODS: Nanoemulsion was prepared by aqueous titration method using caproyl PGMC, cremophore EL and propylene glycol as the oil, surfactant, and cosurfactant respectively. The formulations were characterized by their size, zeta potential and polydispersity index (PDI). 1% Carbopol 934 was used as the gelling agent to formulate nanoemulgel comprising of optimized nanoemulsion (NE 9). Ex vivo skin permeation of the CB nanoemulgel was compared with the CB ointment. Its therapeutic effect was evaluated in Balb/c mice. RESULTS: NE 9 comprised of 7.49% oil, 37.45% Smix (1:3) and water 55.06%. Its particle size, PDI and zeta potential were 15.45 ± 5.265 nm, 0.098 and -17.9 ± 8.00 mV respectively. The nanoemulgel exhibited a 3-fold higher permeation flux as compared to the ointment. In vivo studies demonstrated that the nanoemulgel provided better therapeutic effect than the ointment. CONCLUSION: We can thereby conclude that nanoemulgel formulation can be a successful drug delivery strategy for enhancing the therapeutic effect of CB.

Glibenclamide-malonic acid cocrystal with an enhanced solubility and bioavailability.

OBJECTIVE: The objective of the work is to enhance the solubility, dissolution, and pharmacokinetic properties of glibenclamide (GLB) via cocrystallization technique. SIGNIFICANCE: Glibenclamide is an oral hypoglycemic agent used for treating non-insulin-dependent (type II) diabetes mellitus. It exhibits poor aqueous solubility and oral bioavailability, thereby compromising its therapeutic effect. Therefore, utilizing cocrystal approach for enhancing the solubility will modulate the physicochemical properties of GLB without altering its molecular structure. METHODS: Cocrystal was prepared by solution crystallization method using coformer malonic acid. The cocrystal was characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared (FT-IR) studies. The prepared cocrystal was subjected to solubility, in vitro dissolution, and pharmacokinetic studies. RESULTS: The DSC endotherms, PXRD patterns, and the FT-IR spectra of the cocrystal established the formation of a cocrystal. The formation of eutectic mixture was refuted upon comparing the DSC endotherm and PXRD pattern of the cocrystal with that of the physical mixture. GLB showed a twofold enhancement in solubility and a significant improvement in the rate of dissolution (p < 0.05, independent t-test) after cocrystallization. The pharmacokinetic parameters on male Sprague Drawly rats showed 1.45 enhancement in AUC0-24 and 1.36-fold enhancement in the Cmax of GLB as compared to the pure drug. CONCLUSION: These findings demonstrate that cocrystallization technique was able to tailor the solubility and dissolution profile of GLB leading to an enhanced pharmacokinetic property.

Novel Aceclofenac Cocrystals with l-Cystine: Virtual Coformer Screening, Mechanochemical Synthesis, and Physicochemical Investigations.

AIM: Current work focuses on the improvement of the solubility and dissolution of ACF by the cocrystal approach. BACKGROUND: Aceclofenac (ACF) is one of the commonly used Nonsteroidal Anti-Inflammatory Drug (NSAID) representing a variety of therapeutic applications including management of pain, inflammation, rheumatoid arthritis, and osteoarthritis, etc. But very low solubility and dissolution rate of ACF compromise its therapeutic utility. Now a day's cocrystallization technique has emerged as a novel technique for modulation of the said problems. OBJECTIVE: The Specific objectives of this research work were mechanochemical synthesis, characterization, and performance evaluation of aceclofenac cocrystal. METHODS: ACF was screened with various pharmaceutically acceptable coformers (Selected from GRAS and EAFUS list) using MOPAC software and physical screening method to find out novel cocrystals of ACF with enhanced solubility and dissolution rate. Novel cocrystals (multi-component crystalline solid) of ACF with l-cystine were prepared by a neat grinding method and by liquid assisted grinding method. The synthesized cocrystals (ACF-l-CYS NG and ACF-l-CYS LAG) were characterized carefully by Differential Scanning Calorimetry (DSC), Infrared Spectroscopy (IR), and Powder XRay Diffraction (PXRD) to verify the formation of the cocrystals. Pharmaceutically significant properties such as powder dissolution rate, solubility, and stability of the prepared cocrystals were evaluated. RESULTS: Compared to pure ACF, the prepared cocrystals showed superior solubility and dissolution rate. The prepared cocrystals were found to be stable and non-hygroscopic under study conditions. CONCLUSION: The cocrystallization technique was successfully utilized to increase the solubility and dissolution rate of aceclofenac.

Furosemide - Soluplus® Solid Dispersion: Development and Characterization.

BACKGROUND: Recent patents reveal that Soluplus® has proved to be a promising excipient that modulates dissolution characteristics of many active pharmaceutical ingredients (WO2016161995A1, WO2016169534A1 and WO2016165676A1). OBJECTIVE: Current article investigates stable solid solution of furosemide with Soluplus® to enhance the dissolution properties of the drug. METHOD: Drug to carrier ratios to prepare solid dispersion were selected based on the phase solubility study. Solid dispersions of furosemide with Soluplus® were prepared by solvent evaporation and fusion methods. Physicochemical parameters were characterized using Fourier transform infra-red spectrophotometer, thermo- gravimetric analyzer, differential thermal analyzer, and scanning electron microscopy. Drug release from the formulations was compared using USP type II (paddle type) dissolution apparatus containing 900 mL of phosphate buffer (pH - 6.8) maintained at 37±0.5°C at a paddle rotation speed of 50rpm. RESULTS: Fourier transform infra-red spectroscopy confirmed absence of any chemical interaction while thermo-gravimetry and differential thermal analysis showed evidences of formation of a solid solution of furosemide. No furosemide crystals were observed under scanning electron microscope in case of solid dispersion. Dissolution data indicated that furosemide dissolution was enhanced to a great extent and drug to carrier ratio of 1:10 was found to be most suitable. CONCLUSION: Solid dispersions prepared by fusion method exhibited faster drug release compared to those prepared by solvent evaporation.