Fabrication of moxifloxacin HCl-loaded biodegradable chitosan nanoparticles for potential antibacterial and accelerated cutaneous wound healing efficacy.

AIM: This work aims to formulate topical hybrid gel containing chitosan-coated moxifloxacin (MXF) HCl nanoparticles (NPs) with enhanced antibacterial and healing activity. METHODS: MXF HCl NPs prepared by the ionic gelation method were loaded onto a hybrid chitosan carbomer gel. Size analysis of the prepared NPs was performed using SEM and Zeta-sizer. Further characterisation was done using Fourier transforms infra-red spectroscopy (FTIR), X-ray diffraction (XRD), and Thermogravimetric analysis (TGA). Prepared gel was evaluated for its in vitro drug release, biocompatibility, antibacterial activity, and stability studies under storage conditions. In-vivo wound healing was measured by observing percentage reduction in wound. RESULTS: NPs have 359 ± 79 nm mean particle size, 31.01 mV zeta potential with 0.008 polydispersity index (PD1), 63.5% drug entrapment and 83 ± 3.5% drug release at pH 5.5. Hybrid chitosan carbomer gel showed good biocompatibility, antibacterial, in-vivo wound healing properties and stable properties. CONCLUSIONS: NP-loaded hybrid gel can be an effective treatment for acute and challenged topical wounds.

Formulation and characterization of orodispersible film containing diltiazem hydrochloride with taste masked effects.

Orodispersible film (ODF) is a better alternate to oral disintegrating tablets owing to its ease in application and subsequent patient compliance. This study investigates an improvement in physico-mechanical properties and palatability of Diltiazem Hydrochloride (DTZ) by formulating ODF employing solvent casting method. DTZ, used in the treatment of angina and hypertension, undergoes extensive presystemic metabolism and gives an incomplete bioavailability of 35-40%. DTZ also manifests a very bitter taste and after taste. DTZ was formulated into films using different polymer concentrations of Hydroxypropyl methylcellulose ethocel5 and Carboxymethyl cellulose and plasticizer levels of Propylene glycol and Glycerin to screen appropriate polymer-plasticizer combination. Optimized film disintegrated in 10.0±1.53 sec and appeared to be clear and smooth and almost 100% of the drug release was achieved within 4min from the ODF. Film revealed a good mechanical strength with folding endurance of >260, tensile strength of 1.36±0.11 N/mm2 and % elongation of 15.47±0.47%. FTIR and DSC showed compatibility between the drug and polymer. Film demonstrated a slightly sweet taste and after taste as well as an acceptability by the human volunteers. In conclusion DTZ was successfully formulated into film with improved physical properties and taste and could be beneficial to patients with cardiovascular disorders.

Amelioration of physicochemical, pharmaceutical, and pharmacokinetic properties of lornoxicam by cocrystallization with a novel coformer.

OBJECTIVE: The present study was aimed to prepare and characterize new cocrystals of lornoxicam (LORX), a BCS class II drug employing 1,3-dimethyl urea (DMU) as a coformer to improve physicochemical, pharmaceutical, and pharmacokinetic performance. METHODS: A screening study was conducted by employing three techniques viz. neat grinding, liquid-assisted grinding (LAG), and solvent evaporation (SE) using different drug-coformer molar ratios (1:1, 1:2, and 1:3). Samples were characterized by DSC, PXRD, ATR-FTIR, SEM, intrinsic dissolution rate (IDR) studies, compressional studies, and pharmacokinetic studies. In vitro dissolution and stability studies (25 °C/60%RH and 40 °C/75%RH for three months) were carried out for cocrystal tablets. RESULTS: LAG and SE were found successful in ratio 1:3 and IDR showed approximately 28- and 19-fold increase, respectively in 0.1 N HCl (pH 1.2) and buffer (pH 7.4) as compared to pure LORX. The cocrystal exhibited good tabletability and was ∼2.5 times that of LORX at 6000 Psi. Dissolution profiles of tablets of cocrystal increased (56% and 100% at pH 1.2 and 7.4, respectively in contrast to those of physical mixture (PhyMix) (∼35% and ∼10%) and pure LORX (∼17% and ∼7%) within 60 min. The Cmax and AUC0-∞ for the selected cocrystal were significantly increased (p < 0.05) which was 2.4 and 2.5 times, respectively, that of LORX in a single dose oral pharmacokinetic study executed in rabbits. Tablets of cocrystal were found stable at both conditions. CONCLUSION: The study indicates that cocrystallization with DMU can concomitantly improve tabletability, dissolution rate, and in vivo performance of dissolution limited drug LORX.

Formulation and Evaluation of a Clove Oil-Encapsulated Nanofiber Formulation for Effective Wound-Healing.

Wound-healing is complicated process that is affected by many factors, especially bacterial infiltration at the site and not only the need for the regeneration of damaged tissues but also the requirement for antibacterial, anti-inflammatory, and analgesic activity at the injured site. The objective of the present study was to develop and evaluate the natural essential oil-containing nanofiber (NF) mat with enhanced antibacterial activity, regenerative, non-cytotoxic, and wound-healing potential. Clove essential oil (CEO) encapsulated in chitosan and poly-ethylene oxide (PEO) polymers to form NFs and their morphology was analyzed using scanning electron microscopy (SEM) that confirmed the finest NFs prepared with a diameter of 154 ± 35 nm. The successful incorporation of CEO was characterized by Fourier transform infra-red spectroscopy (FTIR) and X-ray diffractometry (XRD). The 87.6 ± 13.1% encapsulation efficiency and 8.9 ± 0.98% loading of CEO was observed. A total of 79% release of CEO was observed in acidic pH 5.5 with 117% high degree of swelling. The prepared NF mat showed good antibacterial activity against Staphylococcus aureus and Escherichia coli and non-cytotoxic behavior against human fibroblast cell lines and showed good wound-healing potential.

Physicomechanical, stability, and pharmacokinetic evaluation of aceclofenac dimethyl urea cocrystals.

Poor physicomechanical properties and limited aqueous solubility restrict the bioavailability of aceclofenac when given orally. To improve its above properties, aceclofenac (ACE) was cocrystallized with dimethyl urea (DMU) in 1:2 molar ratio by dry and solvent assisted grinding. The cocrystals were characterized by ATR-FTIR, DSC, and PXRD, and their surface morphology was studied by SEM. There was enhancement in intrinsic dissolution rate (IDR) (~eight- and ~fivefold in cocrystals prepared by solvent assisted grinding (SAG) and solid state grinding (SSG), respectively, in 0.1 N HCl, pH 1.2) and similarly (~3.42-fold and ~1.20-fold in phosphate buffer, pH 7.4) as compared to pure drug. Additionally, mechanical properties were assessed by tabletability curves. The tensile strength of ACE was < 1 MPa in contrast to the cocrystal tensile strength (3.5 MPa) which was ~1.98 times higher at 6000 psi. The tablet formulation of cocrystal by direct compression displayed enhanced dissolution profile (~36% in 0.1 N HCl, pH 1.2, and ~100% in phosphate buffer, pH 7.4) in comparison to physical mixture (~ 30% and ~ 80%) and ACE (~18% and ~50%) after 60 min, respectively. Stability studies of cocrystal tablets for 3 months indicated a stable formulation. Pharmacokinetic studies were performed by using rabbit model. The AUC0-∞ (37.87±1.3 µgh/ml) and Cmax (6.94±2.94 µg/ml) of the selected cocrystal C1 prepared by SAG were significantly enhanced (p < 0.05) and were ~3.43 and ~1.63-fold higher than that of ACE. In conclusion, new cocrystal of ACE-DMU was successfully prepared with improved tabletability, in vitro and in vivo properties.

Preparation and Characterization of pH-Independent Sustained-Release Tablets Containing Hot Melt Extruded Solid Dispersions of Clarithromycin : Tablets Containing Solid Dispersions of Clarithromycin.

The limited solubility of clarithromycin (CAM), coupled with low bioavailability and rapid elimination, are major shortcomings, needed to be addressed to achieve optimum therapeutic goals. Therefore, sustained-release (SR) tablets containing solid dispersion (SD) granules of CAM were prepared in this study. Initially, SD granules of CAM were prepared by hot melt extrusion (HME) technique using Kollidon VA64 as a hydrophilic carrier. The saturation solubility of SD showed almost 4.5-fold increase as compared to pure CAM in pH 6.8 medium. In vitro drug dissolution data indicated a substantial increase in the dissolution of SD as compared to that of pure CAM. The thermal stability of drug, carrier, and SD at elevated HME temperatures was evident from the results of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). Powder X-ray diffraction (PXRD) data and scanning electron microscope (SEM) images revealed a decrease in the crystallinity and the uniform dispersion of drug, respectively. Moreover, Fourier transformed infrared spectroscopy (FT-IR) data confirmed the formation of hydrogen bond between the carbonyl group of drug and the hydroxyl group of carrier. SD loaded sustained-release (SD-SR) matrix tablets were prepared with hydrophobic polymers (Eudragit RS100 and Eudragit RL100). The pH-independent swelling and permeability of both polymers were responsible for the sustained drug release from SD-SR tablets. Pharmacokinetic (PK) studies suggested a 3.4-fold increase in the relative bioavailability of SD-SR tablets as compared to that of pure CAM.

Microneedle based transcutaneous delivery of low molecular weight heparin.

This study aimed to fabricate and characterize polymeric microneedle patches for rapid and non-invasive administration of enoxaparin across skin layers. The patches comprising of PVA, sorbitol and enoxaparin sodium were prepared by employing micromolding technique. Formulated patches were characterized physicochemically by folding endurance, dimensional analysis and swelling study, morphologically by optical and scanning electron microscopy and thermally by thermogravimetric analysis. Moreover, performance efficiency of prepared polymeric device was analyzed by in-vitro drug release study and piercing ability. Prepared patches showed appropriate dimensions and folding endurance (i.e., ~1100) indicating satisfactory integrity of polymeric device. Patches exhibited appropriately distanced needles with pointed tips in optical and scanning electron microscopy analysis. Thermogravimetric analysis proved thermal stability of formulation ingredients and prepared patches. Swelling percentage was >110 % suggesting that prepared formulation would allow penetration of physiological fluids in its polymeric network. Maximum (~89%) drug was released within ~2 hours during in-vitro release study. In-vitro piercing ability experiments suggested that prepared patches successfully breached skin barrier stratum corneum. It is concluded that prepared microneedle device can serve as a potential alternative of currently employed invasive parenteral route for rapid and efficient administration of enoxaparin sodium in the systemic circulation.

Solubility and dissolution rate enhancement of ibuprofen by cyclodextrin based carbonate nanosponges.

In the present study nanotechnology approach, i.e., a cyclodextrin (CD) based carbonate nanosponge was used to improve the solubility and dissolution of ibuprofen. Solvent and ultrasound assisted methods were used to prepare nanosponges using two CDs (ß-CD and 2-hydroxypropyl-ß-CD (2HP-ß-CD)) and a cross-linker (CL) diphenyl carbonate (DPC) in varying molar ratios. Nanosponges were investigated for their solubilizing efficiency and phase solubility studies. Structural analysis by Fourier transform infrared (FTIR) and powder X-ray diffraction (PXRD), thermo-analytical characterization by differential scanning calorimetry (DCS), morphology by scanning electron microscopy (SEM). In-vitro drug release followed by in-vivo analgesic and anti-inflammatory studies were performed. 2HP-ß-CD based nanosponges (molar ratio 0.01:0.04) prepared by ultrasound assisted method showed the highest solubilizing efficiency (i.e., 4.28 folds). Stability constant values showed that all complexes were stable. Inclusion complexes of drug was confirmed by PXRD and DSC. SEM images showed porous structures confirming the formation of cross-linked network. Particle size was in the range of 296.8±64 to 611.7±32nm. In-vitro release studies showed enhanced dissolution profile from nanosponge formulation (~94% from I11) as compared to the pure drug (~45% Ibuprofen) in 120min. Significant (p<0.05) extent of pain inhibition and anti-inflammatory activity was observed for nanosponge formulation when compared with the pure drug. CD based carbonate nanosponges with better solubility, enhanced release profile, improved analgesic and anti-inflammatory activity were successfully formulated for ibuprofen.

Development of paracetamol-caffeine co-crystals to improve compressional, formulation and in vivo performance.

Paracetamol, a frequently used antipyretic and analgesic drug, has poor compression moldability owing to its low plasticity. In this study, new co-crystals of paracetamol (PCM) with caffeine (as a co-former) were prepared and delineated. Co-crystals exhibited improved compaction and mechanical behavior. A screening study was performed by utilizing a number of methods namely dry grinding, liquid assisted grinding (LAG), solvent evaporation (SE), and anti-solvent addition using various weight ratios of starting materials. LAG and SE were found successful in the screening study. Powders at 1:1 and 2:1 weight ratio of PCM/CAF by LAG and SE, respectively, resulted in the formation of co-crystals. Samples were characterized by PXRD, DSC, and ATR-FTIR techniques. Compressional properties of PCM and developed co-crystals were analyzed by in-die heckle model. Mean yield pressure (Py), an inverse measure of plasticity, obtained from the heckle plots decreased significantly (p < .05) for co-crystals than pure drug. Intrinsic dissolution profile of co-crystals showed up to 2.84-fold faster dissolution than PCM and physical mixtures in phosphate buffer pH 6.8 at 37 °C. In addition, co-crystals formulated into tablets by direct compression method showed better mechanical properties like hardness and tensile strength. In vitro dissolution studies on tablets also showed enhanced dissolution profiles (∼90-97%) in comparison to the tablets of PCM prepared by direct compression (∼55%) and wet granulation (∼85%) methods. In a single dose sheep model study, co-crystals showed up to twofold increase in AUC and Cmax. A significant (p < .05) decrease in clearance as compared to pure drug was also recorded. In conclusion, new co-crystals of PCM were successfully prepared with improved tabletability in vitro and in vivo profile. Enhancement in AUC and Cmax of PCM by co-crystallization might suggest the dose reduction and avoidance of side effects.

Simultaneously Improving Mechanical, Formulation, and In Vivo Performance of Naproxen by Co-Crystallization.

Naproxen (NAP), an anti-inflammatory drug belonging to class II of Biopharmaceutic Classification System, has low aqueous solubility and dissolution rate which limit its oral bioavailability. The focus of this investigation was to assess the impact of co-crystallization in improving the physico-mechanical and in vivo performance of NAP. NAP was co-crystallized using nicotinamide as a co-former employing liquid-assisted grinding method and characterized by intrinsic dissolution rate, DSC, and PXRD. Prepared co-crystal exhibited improved physicochemical and mechanical properties. Mechanical behavior of NAP and developed co-crystal was analyzed by drawing tabletability curves. Over the entire range of used compaction pressure, NAP showed poor tensile strength (< 2 MPa) which resulted in lamination and capping in some tablets. In contrast, tensile strength of co-crystal gradually increased with pressure and was ~ 1.80 times that of NAP at 5000 psi. Intrinsic dissolution profile of co-crystal showed a more than five and twofold faster dissolution than NAP in 0.1 M HCl and phosphate buffer pH 7.4 at 37°C. In addition, formulation of co-crystal powder into tablets by direct compression demonstrated enhanced dissolution profiles (~ 43% in 0.1 M HCl and ~ 92% in phosphate buffer pH 7.4) in comparison to a marketed product, Neoprox (~ 25 and ~ 80%) after 60 min. In a single dose oral exposure study conducted in sheep, co-crystal showed more than 1.5-fold increase in AUC and Cmax. In conclusion, co-crystals of NAP illustrated better tabletability, in vitro and in vivo performance.

Formulation and Characterization of Curcumin Niosomes: Antioxidant and Cytotoxicity Studies.

Curcumin's applications in the treatment of conditions including osteoarthritis, dementia, malignancies of the pancreas, and malignancies of the intestines have drawn increasing attention. It has several wonderful qualities, including being an anti-inflammatory agent, an anti-mutagenic agent, and an antioxidant, and has substantially reduced inherent cytotoxicity outcomes. Although curcumin possesses multiple known curative properties, due to its limited bioavailability, it is necessary to develop efficient strategies to overcome these hurdles. To establish an effective administration method, various niosomal formulations were optimized using the Box-Behnken design and assessed in the current investigation. To examine the curcumin niosomes, zeta sizer, zeta potential, entrapment efficiency, SEM, antioxidant potential, cytotoxicity, and release studies were performed. The optimized curcumin niosomes exhibited an average particle size of 169.4 nm, a low PDI of 0.189, and high entrapment efficiency of 85.4%. The release profile showed 79.39% curcumin after 24 h and had significantly higher antioxidant potential as compared with that of free curcumin. The cytotoxicity results of curcumin niosomes presented increased mortality in human ovarian cancer A2780.

Design and Characterization of Agarose/HPMC Buccal Films Bearing Ondansetron HCl In Vitro and In Vivo: Enhancement Using Iontophoretic and Chemical Approaches.

The study was aimed at designing and characterizing the ondansetron hydrochloride (OND) bearing agarose (AG), and hydroxypropyl methyl cellulose (HPMC) mucoadhesive buccal films employing glycerol as a plasticizer. The buccal delivery of ondansetron hydrochloride was remarkably boosted by employing physical (iontophoresis) and chemical enhancement approaches (chemical penetration enhancers). To explore the influence of different formulation components, i.e., agarose, hydroxypropyl methyl cellulose (HPMC), and glycerol on various evaluating parameters, i.e., tensile strength, swelling index, ex vivo mucoadhesion time, and subsequently on in vitro drug release, a D-optimal design was opted. A buccal film bearing OND was mounted on bovine buccal mucosa for ex vivo permeation studies and impact of chemical and physical enhancement techniques on the permeation profile was also analysed. A linear release profile was revealed in in vitro drug release of OND over 60 minutes and outcomes ascertained the direct relationship between HPMC content and in vitro drug release and inverse relationship was depicted by AG content. The FTIR and DSC thermal analysis was executed to determine the physicochemical interactions and results exposed no chemical interactions between drug and polymers. The drug (OND) appeared as tiny crystals on smooth film surface during scanning electron microscopy (SEM) analysis. A notable enhancement in permeation flux, i.e., 761.02 µg/min of OND during ex vivo permeation studies was witnessed after the application of current (0.5-1 mA) without any time lag and with enhancement ratio of 3.107. A time lag of 15 minutes, 19 minutes, and 26 minutes with permeation flux of 475.34 µg/min, 399.35 µg/min, and 244.81 µg/min was observed after chemical enhancer pretreatment with propylene glycol, Tween 80, and passive, respectively. Rabbit was employed as the experimental animal for pharmacokinetic studies (in vivo) and cats for pharmacological activity (in vivo), and the results illustrated the enhanced bioavailablity (2.88 times) in the iontophoresis animal group when compared with the rabbits of control group. Likewise, a remarkable reduction in emesis events was recorded in cats of iontophoresis group. Conclusively, the histopathological examinations on excised buccal mucosa unveiled no severe necrotic or cytopathetic outcomes of current.