Gaurav Mittal

Nano-salbutamol dry powder inhalation: a new approach for treating broncho-constrictive conditions.

Nanoparticle DPI is known to have deeper lung penetration but its clinical utility as a potentially better treatment option needs to be evaluated in the light of higher expected mucociliary movement of the nanoparticles compared to micronized DPI. The objective of this study was to make nano-salbutamol sulphate (SBS) DPI, radiolabel it with Tc-99m using a novel surface labeling methodology, characterize the formulation and assess its in vitro and in vivo deposition in healthy human volunteers to estimate its bioavailability in the target area. Nano-SBS with a mean particle of 60.71+/-35.99 nm was produced using liquid anti-solvent precipitation method. The drug particles were spherical, pure and crystalline. Anderson cascade impaction showed that blend formulations of Nano-SBS exhibited significantly higher respirable fraction of 45.2% compared to the known behavior of micronized salbutamol sulphate blends. Though the particle size tended to increase due to solid phase interaction after blending with lactose, there was definitive correlation between the radiolabeled and non-radiolabeled forms. In 10 healthy volunteers, lower oropharyngeal depositions (25.3+/-4.5%) were observed with nano-SBS formulation compared to micronized SBS formulation (58.4+/-6.1%). Furthermore, Nano-SBS formulations showed nearly 2.3-fold increase in total lung deposition compared to micronized SBS. The in vivo deposition data and the ratio of peripheral to central lung deposition (P/C) of 1.12+/-0.4 indicate that Nano-SBS is evenly distributed within different lung regions. As demonstrated for SBS, nano-sizing may enhance regional deposition and thus provide an attractive particle engineering option for the development of blend formulations for inhalation delivery.

Role of Polymeric Biomaterials as Wound Healing Agents

In uncontrolled hemorrhage, the main cause of death on the battlefield and in accidents, half of the deaths are caused by severe blood loss. Polymeric biomaterials have great potential in the control of severe hemorrhage from trauma, which is the second leading cause of death in the civilian community following central nervous system injuries. The intent of this article is to provide a review on currently available biopolymers used as wound dressing agents and to describe their best use as it relates to the condition and type of the wound (acute, chronic, superficial, and full thickness) and the phases of the wound healing process. These biopolymers are beneficial in tissue engineering as scaffolds, hydrogels, and films. Different types of wound dressings based on biopolymers are available in the market, with various physical, chemical, and biological properties. The use of biopolymers as a hemostatic agent depends on its biocompatibility, biodegradability, nonimmunogenicity, and optimal mechanical property. This review summarizes different biopolymers, their physiological characters, and their use as wound healing agents along with biomedical applications.

Impact of polymeric nanoparticles on oral pharmacokinetics: A dose-dependent case study with estradiol

The present study reports the significance of polymeric nanoparticles in oral drug delivery from pharmacokinetic perspective. Impact of different dose polymeric nanoparticulate formulations on various pharmacokinetic parameters has been reported. All nano-formulations were found to have significant effect on important pharmacokinetic parameters like C(max), T(max), AUC, absolute bioavailability, absorption rate constant (K(a)), elimination rate constant (K(el)), elimination half life (t(1/2)), mean residence time (MRT) and mean absorption time (MAT). Further, drug in polymeric nanoparticles exhibited the flip-flop pharmacokinetics suggesting its slow and sustained release from the polymeric matrix. Together, polymeric nanoparticles hold promise for the oral delivery of molecules having pharmacokinetic hurdles in their delivery approach.

Clinical and bioavailability studies of sublingually administered atropine sulfate

INTRODUCTION The increased use of organophosphorus (OP) pesticides and the ever increasing possibility of terror groups using nerve agents underscore a need to develop effective and safe antidotes against OP poisoning. The objectives of the present study were to develop a novel atropine sulfate (AS) sublingual injection formulation, to create its bioavailability data in humans and to evaluate its suitability for field use with a view to obtain early therapeutic drug concentration in comparison to the conventional intramuscular route that provides a therapeutic peak of 6 to 8 ng/mL in blood at 30 minutes. METHODS Two milligrams per 0.1 mL of AS was sublingually injected in 6 volunteers, and bioavailability and atropinization signs (blood pressure, pupil diameter, and heart rate) were noted. RESULTS Human bioavailability curve was created, which was equivalent to 2 mg IM injection in amplitude within 10 minutes and describing a better curve thereafter. Peak plasma concentration of AS occurred at 15 minutes and was 21 ng/mL. Increase in heart rate became extremely significant at 5 minutes (P < .0001) with maximum increase of 62% + or - 6% at 10 minutes after administration. Pupil diameter showed maximal increase of 58% + or - 21% at 15 minutes (P < .01). CONCLUSIONS Sublingual AS appears to have several advantages over conventional IM route including better bioavailability, rapid onset of action, and early atropinization. It is a safe and efficacious procedure with the potential to become an alternative to conventional IM injection, particularly in case of chemical terrorism scenario where hundreds of victims may require immediate atropinization simultaneously.

Development of atropine sulphate nasal drops and its pharmacokinetic and safety evaluation in healthy human volunteers

INTRODUCTION The increased use of organophosphate (OP) insecticides and the ever increasing possibility of terror groups using nerve agents underscore the need to develop effective and safe antidotes against OP poisoning. While intramuscular administration of nerve gas antidotes like atropine sulphate has certain lacunae, intravenous route is neither practical nor feasible in the field conditions for mass casualties. The objective was to develop a novel atropine sulphate nasal drop formulation, evaluate and characterize it using scintigraphy and to carry out safety-efficacy study in human volunteers with a view to obtain early pharmacological effects in comparison to the existing options, particularly the conventional intramuscular route. METHODS Permeability studies were done using atropine sulphate solution containing variable amount of chitosan. Radiometric method was developed for scintigraphy studies while standard spectroscopy was used for the quantification of atropine sulphate in fluids. Concentration of atropine sulphate in nasal drops to produce therapeutic concentration in blood was calculated. Six volunteers (age range 18-53 years) were administered the formulation delivering 6mg of atropine sulphate each. Bioavailability and atropinization were noted serially. RESULTS Based on the results of in vitro, human scintigraphy and analytical data, 1% atropine sulphate-0.5% chitosan was chosen as the final nasal formulation. Human bioavailability curve was created which showed that the therapeutic concentration of the drug in blood was reached within 5min with nasal drops suggesting that drug delivery through the nasal route is significantly better than the intramuscular route. Unpaired t-test between the means of baseline value of heart rate and that of each time interval showed that increase in heart rate of all the volunteers became significant at 15min (P<0.01) and extremely significant at 30min (P<0.001). Correlation was evident from 5min (c>0.7). Pupil diameter showed maximal increase at 30min (P<0.01). CONCLUSIONS This novel product, 1% atropine sulphate-0.5% chitosan nasal drops might be a safe and efficacious emergency treatment of organophosphorous poisoning with several advantages over the present management, including early atropinization and capability of mass treatment in least amount of time.

Inhalation of alendronate nanoparticles as dry powder inhaler for the treatment of osteoporosis

The precipitation technique was used to prepare non-polymeric alendronate nanoparticles. The influence of various formulation parameters on the average particle size was investigated and the effect of various stabilizers (PVA, tween, chitosan, alginate, PEG, HPMC, poloxomers) was evaluated. The selection of surfactant was a key factor to produce particles with desired properties. Poloxomer F68 was found best in achieving the minimum particle size and providing physical stability to the drug. On basis of preliminary trials, a central composite design was employed to study the effect of independent variables, drug concentration (X1), antisolvent volume (X2), stirring speed (X3), and stabilizer concentration (X4) on the average particle size. The drug and stabilizer concentrations exhibited a more significant effect on a dependent variable. The particle size varied from 62 to 803.3 nm depending upon the significant terms. The validation of optimization study, performed using six confirmatory runs, indicated very high degree of prognostic ability of response surface methodology, with mean percentage error (±SD) as −2.32 ± 2.47. The minimum particle size (44.11 nm) was predicted at 10 mg/ml drug concentration, 20 ml antisolvent volume, 925 rpm stirring speed, and 8.5% stabilizer concentration with 98.16% experimental validity. Respirable fraction for optimized nanosized alendronate (43.85% ± 0.52%) was significantly higher when compared with commercial alendronate (17.6 ± 0.32). Mass median aerodynamic diameter of designed particles was 3.45 µm with geometric standard deviation of 2.10.

Acute and sub acute toxicity and efficacy studies of Hippophae rhamnoides based herbal antioxidant supplement

Objectives: Present study was carried out to evaluate acute and subacute toxicity and efficacy of Seabuckthorn (Hippophae rhamnoides) based herbal antioxidant supplement (HAOS). Materials and Methods: In vivo toxicity studies were performed in male balb ‘C’ mice by oral administration. Acute toxicity study was done at doses ranging from 2000 to 10 000 mg/ kg while in subacute studies, HAOS was given at doses of 2000, 4000, and 8000 mg/kg body weight. Animals were observed for any toxic sign and symptoms periodically. At completion of study animals were sacrificed; their hematological, biochemical parameters were analyzed and histopathology of vital organs was done. In vivo efficacy studies in human volunteers were done and the levels of vitamin A and Vitamin C in blood samples were analyzed in comparison to a similar commercially available formulation. Results: No mortality and any clinical signs of toxicity were found in HAOS administered group of animals. There were no significant alterations in hematological and biochemical parameters. Histopathological analysis of vital organs showed normal architecture in all the HAOS administered groups. Human studies showed an increase of 32% and 172% in Vitamin A and Vitamin C levels respectively in term of bioavailability. Conclusion: The data obtained indicate no toxicity of this antioxidant supplement up to the highest dose studied. Efficacy in terms of increased bioavailability of vitamin A and C in human volunteers indicates the clinical usefulness of the supplement.

Evidencing the Modulation of P-glycoprotein at Blood-Ocular Barriers using Gamma Scintigraphy

Purpose: To evaluate the effect of P-glycoprotein modulation at blood-ocular barriers using gamma scintigraphy. Methods: Ofloxacin, a fluoroquinolone, was selected as a substrate to study the drug efflux transporter (P-glycoprotein) modulation after labeling with Technetium (99mTc) in rabbits. New Zealand albino rabbits were randomized into two groups of 4 each. Group I received labeled ofloxacin intravitreally (100 μ Ci) and Group II animals were given verapamil intravitreally 15 min before the labeled ofloxacin. Static imaging was done at predetermined time, and dynamic images were also taken after 30 min of intravitreal injection. Results: The radio-chemical purity of labeled ofloxacin was found to be 90–95% with the labeling efficiency of 90%. The static anterior planar images of verapamil pre-treated group showed marginal increase in the uptake of labeled ofloxacin, and dynamic images showed less systemic pool as compared to its control. Conclusion: This study further confirms the findings of our laboratory regarding the involvement of P-glycoprotein in the intraocular disposition of susceptible drugs.

Development, characterisation and pharmacoscintigraphic evaluation of nano-fluticasone propionate dry powder inhalation as potential antidote against inhaled toxic gases

Acute lung injuries caused due to inhalation of toxic irritant gases such as ammonia, chlorine, hot smoke and burning plastic fumes predominantly affect the airways, causing tracheitis, bronchitis, and other inflammatory responses. The purpose was to develop and characterise nanoparticle based fluticasone propionate (FP) DPI formulation and assess its in vitro and in vivo pulmonary deposition using pharmacoscintigraphy. FP nanoparticles were prepared by nanoprecipitation method. Optimisation was carried out with the help of Box–Behnken statistical design. Nanoparticles were characterised with the help of SEM, FT-IR, DSC and XRD. Anderson cascade impaction showed that nano-FP exhibited significantly higher respirable fraction of 60.3 ± 2.41 as compared to 16.4 ± 0.66 for micronised form. Ventilation lung scintigraphy in human volunteers confirmed significant increase in drug delivery till alveolar region with nano-FP in comparison to micronised drug. Results indicate that the developed formulation may have a potential prophylactic/therapeutic role against toxic, irritant gas inhalation.

Edetate calcium disodium nanoparticle dry powder inhalation: A novel approach against heavy metal decorporation

Objective was to develop and characterize nano-edetate calcium disodium (Ca-Na(2)EDTA) dry powder inhaler (DPI), and assess its in vitro and in vivo deposition using pharmacoscintigraphy techniques. Factors influencing nanoparticle formation including concentration of drug, polymer solution and stirring rate were determined. Optimized formulation was characterized with the help of SEM, TEM and Malvern Zetasizer studies. Any change in physical characteristics after nanosizing was determined by FT-IR, XRD and DSC studies. Anderson cascade impaction showed that nano Ca-Na(2)EDTA exhibited significantly higher respirable fraction of 67.35±2.27% and 66.40±2.87% by scintigraphic and spectroscopic analysis respectively, as compared to 10.08±1.17% and 9.36±1.02% respectively for micronized form. Ventilation lung scintigraphy done in 12 volunteers showed significant increase in drug delivery till alveolar region with nano Ca-Na(2)EDTA. The developed formulation may have a role in neutralizing heavy metal toxicity through inhalation route, including radio-metal contamination.