Development, characterisation and evaluation of supersaturated triglyceride free drug delivery (s-TFDDS) of lornoxicam.

The present work was aimed at formulating a supersaturated triglyceride free drug delivery system (s-TFDDS) of lornoxicam and evaluating its in vitro and in vivo potential. s-TFDDS contain the drug above its saturation solubility and consists of a hydrophilic surfactant, a hydrophobic surfactant, solubiliser and pH modifier. D-optimal mixture experimental design was applied to optimise s-TFDDS. Three formulation variables, X 1 (Tween 20®), the surfactant X 2 (Capryl PGMC®) and X 3 (Transcutol P), were included in the design. The systems were assessed for light transmittance and solubility of lornoxicam. The values of optimised formulation components (X 1, X 2 and X 3) were 60.0, 10.0 and 30.0 %, respectively. The combination of components was optimised for maximum solubilisation capacity of lornoxicam by combined effect of pH and temperature. The optimised liquid preconcentrate was evaluated for particle size (small-angle neutron scattering study), robustness to precipitation, effect of polymer on precipitation inhibition and by in vitro dissolution. The liquid preconcentrate was adsorbed on solid carrier (Neusilin US2, Sylysia 320) and characterised by in vitro dissolution, X-ray diffraction, differential scanning calorimetry and scanning electron microscopy study. An increase in dissolution (DE15min, 100 %) in simulated gastric fluid at pH 1.2 was achieved without precipitation of lornoxicam. Spectral characterisation reveals no sign of lornoxicam precipitation on solid carriers. Comparative pharmacodynamic evaluation was investigated in terms of anti-inflammatory efficacy using a rat paw oedema model in rats. The s-TFDDS formulation showed the maximum percent inhibition of oedema as compared with plain and micronised lornoxicam.

Polymeric nanoparticle formulation of octapeptide (NP-OP): in vitro release and in vivo effect in common marmosets, Callithrix jacchus Linn.

Octapeptide (OP)/FSH-Receptor Binding Inhibitor-8 (FRBI-8), is a synthetic peptide corresponding to N-terminal sequence of purified fraction of Follicle Stimulating Hormone Binding-Inhibitor (FSHBI), isolated earlier from human ovarian follicular-fluid. In order to avoid the repeated drug-administration, OP-loaded, polymeric polylactide (PLA) nanoparticle formulation (NP-OP), was developed using multiple-emulsion technique. This yielded an average particle size of 120 nm with 70% encapsulation-efficiency. In vitro release profile of NP-OP showed sustained release of OP for 21 days. In vivo anti-fertility studies were conducted in marmosets. Results indicated that control animals conceived in the same cycle while two of three treated animals failed to conceive in treatment cycle. The in vivo studies thus corroborate with in vitro release of OP, demonstrating its anti-fertility activity in 66% of animals.

Physicochemical, in silico and in vivo evaluation of a danazol-beta-cyclodextrin complex.

Inclusion complexation of danazol with beta-cyclodextrin (BCD) in aqueous solution, in solid state and in silico state was investigated to examine the interactions of danazol with BCD. The study also explored the potential application of danazol-beta-cyclodextrin complex as an oral antiovulatory agent. Phase solubility analysis suggested formation of first-order soluble complex with stability constant 972.03 M(-1) while Job's plot affirmed 1:1 stoichiometry. Solution state complexation in water was studied by ultra violet absorption, circular dichroism and nuclear magnetic resonance ((1)H NMR) spectroscopy. The solid state complexes were evaluated by differential scanning calorimetry, powder X-ray diffractometry, fourier transform infrared spectroscopy and scanning electron microscopy. Thermodynamic studies in water indicated exothermic nature of inclusion complexation. Molecular modeling was used to help establish the mode of interaction of BCD with danazol. (1)H NMR analysis suggested that the protons of steroidal skeleton of danazol are preferably involved in the complexation with BCD, which was confirmed by molecular dynamic simulations. An inclusion complex model has been established for explaining the observed enhancement of solubility of danazol in water by BCD. Moreover, in mouse model, danazol-beta-cyclodextrin complex at 51.2mg/kg (equivalent to 400mg human dose) showed 100% anovulation when given orally.

Nanotechnology and pharmaceutical inhalation aerosols.

Pharmaceutical inhalation aerosols have been playing a crucial role in the health and well being of millions of people throughout the world for many years. The technology's continual advancement, the ease of use and the more desirable pulmonary-rather-than-needle delivery for systemic drugs has increased the attraction for the pharmaceutical aerosol in recent years. But administration of drugs by the pulmonary route is technically challenging because oral deposition can be high, and variations in inhalation technique can affect the quantity of drug delivered to the lungs. Recent advances in nanotechnology, particularly drug delivery field have encouraged formulation scientists to expand their reach in solving tricky problems related to drug delivery. Moreover, application of nanotechnology to aerosol science has opened up a new category of pharmaceutical aerosols (collectively known as nanoenabled-aerosols) with added advantages and effectiveness. In this review, some of the latest approaches of nano-enabled aerosol drug delivery system (including nano-suspension, trojan particles, bioadhesive nanoparticles and smart particle aerosols) that can be employed successfully to overcome problems of conventional aerosol systems have been introduced.

Nasal drug delivery of sumatriptan succinate.

The purpose of this work was to increase the nasal absorption of sumatriptan succinate by using bile salts. A rat in situ nasal perfusion technique was used to examine the rate and extent of absorption of sumatriptan succinate. In vitro enzymatic drug degradation studies were carried out with rat nasal washings. Various experimental conditions such as nasal perfusion rate, pH of the perfusion medium and concentrations of absorption enhancers such as sodium deoxycholate, sodium caprate, sodium tauroglycocholate and EDTA were optimized. In vivo studies were carried out for the optimized formulation in rabbits and the pharmacokinetics parameters of nasal solution were compared with marketed nasal solutions. Nasal absorption of sumatriptan succinate was pH dependent. It was found maximum at pH 5.5 and decreased at higher pH values. In in vitro enzymatic degradation studies, no measurable degradation was observed during the first week. The extent of drug absorption was increased by absorption enhancers. Sodium deoxycholate appeared to be more effective for enhancing the nasal absorption of sumatriptan succinate than the other absorption enhancers. The order of increasing absorption of sumatriptan succinate caused by theenhancers was sodium deoxycholate > sodium caprate > sodium tauroglycocholate > EDTA.

Electron beam irradiation: a novel technology for the development of transdermal system of isosorbide dinitrate.

The development of a transdermal delivery system for isosorbide dinitrate (ISDN) using electron beam irradiation was studied. The solid state stability of the drug to irradiation was assessed. The drug was dissolved in 2-ethylhexylacrylate (EHA)-acrylic acid (AA) system and this solution was directly irradiated on a backing membrane (Scotchpak1006) at different doses to get transdermal patches. The developed systems were evaluated for residual monomer content, equilibrium weight swelling ratios (EWSR), differential scanning calorimetry (DSC), weight uniformity, thickness uniformity, drug content and content uniformity, peel strength, in vitro release, skin permeation kinetics and skin irritation potential. The developed system possessed excellent adhesive properties. Increase in the irradiation doses did not have a significant effect on the peel strength values. The systems exhibited promising skin permeation kinetics and no skin irritating potential, both of which are important properties for transdermal drug delivery. The ISDN-EHA-AA system developed at an irradiation dose of 50 kGy showed a higher skin permeation profile as compared to an internationally marketed transdermal matrix system of ISDN.

Eudragits: role as crystallization inhibitors in drug-in-adhesive transdermal systems of estradiol.

A transdermal steroidal delivery system usually contains a high concentration of drug to obtain high drug fluxes. The present investigation involved the development of drug-in-adhesive transdermal systems of estradiol using synthesized acrylate copolymer (EA) of 2-ethylhexyl acrylate and acrylic acid. The effect of several variables such as varying drug polymer ratios, effect of Eudragit RL PO and Eudragit E PO and effect of drying temperatures on prevention of drug crystallization in the formulation matrix was investigated. The systems free from drug crystals were evaluated and compared with a marketed formulation with respect to its skin permeation profile. The optimized formulation was also subjected to accelerated stability testing. Eudragit RL PO and Eudragit E PO were found to be effective as crystallization inhibitors in the transdermal matrix systems tested. Formulations fabricated with Eudragit E PO gave transparent systems with good film properties and a higher skin permeation profile as compared to that of the marketed system. Higher temperature and humidity conditions facilitated the formation of drug crystals, whereas no crystals were observed in the formulation matrix at 23+/-0.5 degrees C and at 30+/-1 degrees C for the period of 6 months studied.

Stability indicating HPTLC method for the simultaneous determination of pseudoephedrine and cetirizine in pharmaceutical formulations.

The combination of pseudoephedrine and cetirizine is widely used in the treatment of allergic rhinitis. A rapid, selective and stability indicating high performance thin layer chromatographic method was developed and validated for their simultaneous estimation in pharmaceutical dosage forms. The method employed TLC aluminium plates precoated with silica gel 60F-254 as the stationary phase. The solvent system consisted of ethyl acetate-methanol-ammonia (7:1.5:1, v/v/v). This system was found to give compact spots for both pseudoephedrine (Rf value of 0.69+/-0.01) and cetirizine (Rf value of 0.38+/-0.01). Also the degraded products were well separated from the pure drugs. Spectrodensitometric scanning-integration was performed at a wavelength of 240 nm. The polynomial regression data for the calibration plots showed good linear relationship with r(2)=0.9947 in the concentration range of 10-26 microg for pseudeophedrine and 200-1200 ng for cetirizine with r(2)=0.9973. The method was validated for precision, accuracy, ruggedness and recovery. The minimum detectable amounts were found to be 2 microg and 500 pg for pseudoephedrine and cetirizine, respectively. The limits of quantitation were found to be 6 microg for pseudoephedrine and 800 pg for cetirizine. Both the drugs do not undergo degradation under acidic and basic conditions. The samples degraded with hydrogen peroxide showed additional peaks at Rf values of 0.75 and 0.28 for pseudoephedrine and cetirizine, respectively. This indicates that both the drugs are susceptible to oxidation. Statistical analysis proves that the method is reproducible and selective for the simultaneous estimation of pseudoephedrine and cetirizine. As the method could effectively separate the drugs from their degradation products, it can be employed as a stability indicating one.

Oxidative degradation study of nitrendipine using stability indicating, HPLC, HPTLC and spectrophotometric method.

The objective of this study is to develop validated stability indicating HPLC (A), HPTLC (B) and spectrophotometric (C) method for the estimation of nitrendipine. The stability indicating capability of the assays is proved using forced degradation, by exposing drug solution to sunlight, acidic and alkaline medium. The chromatogram and UV spectrum showed nitrendipine well resolved from the degradation product. Degradation of drug is found faster in acidic (0.1 N hydrochloric acid) medium as compared to alkaline (0.1 N sodium hydroxide) medium at 100 degrees C. Also, photodegradation is studied, with special emphasis on the effect of solvents like methanol (1), chloroform (2), dichloromethane (3), acetone (4) and ethyl acetate (5), on the rate of photodegradation. The degradation of title compound followed first order kinetics in all cases. Estimation of the drug is carried out by the stability indicating methods mentioned, using one point standardization within the linearity range of interest. The methods are compared in respect of performance precision and accuracy. Major route of degradation in all cases is found to be oxidation and degradation product is confirmed as dehydronitrendipine by the use of relevant UV, IR and 1H NMR spectrometry.

HPTLC method to study skin permeation of acylovir.

A new simple, rapid and selective high performance thin layer chromatography (HPTLC) method is developed for the quantitation of acyclovir during in vitro skin permeation studies. Separation of guinea pig skin proteins and acyclovir was achieved by employing a mobile phase consisting of chloroform-methanol-ammonia (15:9:4, v/v/v) on precoated silica gel 60F254 aluminum plates. Densitometnic analysis was carried out at 255 nm. The limit of detection and quantification were 30 and 50 ng, respectively. The calibration curve was linear in the range of 10-20 microg/ml (r = 0.9965). The relative standard deviation for a sample of concentration 100 microg/ml were 1.15 and 2.85 for system and method precision, respectively. Intraday and interday variation studies gave an average 0.763 and 0.463% relative standard deviation for the three levels tested. Average recoveries of 101.8 and 100.1% were recorded for two marketed preparations studied. The method was employed to optimize topical liposomal gel formulation of acyclovir on basis of maximum skin permeation.

Stability indicating HPTLC method for the estimation of estradiol.

Estradiol (ESD) is widely used in post climacteric replacement therapy. Most of the methods used for quantitation are expensive and time consuming. A rapid, selective and precise stability indicating high performance thin layer chromatography method was developed and validated for the estimation of ESD in bulk and pharmaceutical dosage forms. The method employed TLC aluminium plate precoated with silica gel 60F254 as the stationary phase. The solvent system employed consisted of chloroform-acetone-isopropyl alcohol-glacial acetic acid (9:1:0.4:0.1, v/v/v/v). Such a complex system was essential to obtain a dense and compact spot of the drug at an Rf value of 0.40 +/- 0.02. The drug on intentional degradation gave two products with Rf values of 0.52 +/- 0.01 and 0.58 +/- 0.01 respectively. Spectrodensitometric scanning-integration was performed on a Camag system using a wavelength of 286 nm. The polynomial regression data for the calibration plots exhibited good linear relationship (r = 0.9947) over a concentration range of 1-8 microg. Recovery studies were also performed at three experimental levels. The recovery data reveals that the RSD for intra-day and inter-day analysis was found to be 1.27% and 1.75%, respectively. The proposed method was found to be stability indicating. Statistical analysis proves that the method is precise, accurate and reproducible, hence can be employed for the routine analysis of the drug.

Simultaneous determination of alpha, beta and gamma cyclodextrins by LC.

Cyclodextrins (CDs) can be synthesized from starch by cyclodextrin glycosyltransferase (CGTase). This enzyme produces alpha-, beta- and gamma-CDs in varying proportions. In the production of cyclodextrins, purity as well as yield are important factors. A precise and reproducible method was developed and validated for the simultaneous determination of alpha-, beta-, and gamma-CDs. Optimum separation between the three CDs was achieved using a Finepak amino column with a mobile phase consisting of acetonitrile-water (70:30, v/v) at a flow rate of 1 ml/min. Detection was carried out using a differential refractive index detector. The developed method gave good chromatographic resolution of the three components with retention times of 13.16, 16.83 and 21.74 min for alpha-, beta- and gamma-CDs, respectively. The polynomial regression data for the calibration plots exhibited good linear relationship (coefficient of correlation r = 0.9987 for alpha, r = 0.9986 for beta and r = 0.9998 for gamma-CDs) over a concentration range of 2-10 mg/ml. Statistical analysis proves that the proposed LC method is precise, reproducible and accurate for the estimation of alpha-, beta- and gamma-cyclodextrins. The method can be employed for determination of percent purity as well as estimation of process yields of the cyclodextrins during the enzymatic production.

Stability indicating HPTLC determination of piroxicam.

A rapid and sensitive HPTLC method was developed and validated for the estimation of Piroxicam (PM). Spectrodensitometric scanning-integration was performed at an absorbance wavelength of 360 nm. To justify the suitability, accuracy and precision of the proposed method, recovery studies were performed at three concentration levels. One of the degradation products of PM is 2-aminopyridine (2AP). It becomes imperative to separate this compound as it is a precursor during synthesis of the drug. A TLC aluminium plate precoated with silica gel 60F-254 was used as the stationary phase. The solvent system toluene-acetic acid (8:2 v/v) gave a dense and compact spot of PM with a Rf value of 0.58 +/- 0.01 which was well separated from 2AP (Rf 0.23 +/- 0.01). The polynomial regression data for the calibration plots exhibited good linear relationship (coefficient of correlation r = 0.9982) over a concentration range of 400-800 ng. Statistical analysis proves that the proposed method is accurate and reproducible. The method is stability indicating and being economical can be employed for the routine analysis in bulk drug as well as pharmaceutical formulations.

Inclusion complexation of nimesulide with beta-cyclodextrins.

Nimesulide (NM), a nonsteroidal anti-inflammatory drug (NSAID) has poor aqueous solubility. The present study describes the complexation of NM with beta-cyclodextrin (beta-CD) and its derivative hydroxypropyl beta-cyclodextrin (HP beta-CD). The complexation was studied by phase solubility method, Fourier transformed infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), and X-ray diffractometry (XRD). The complexes were prepared by a freeze-drying technique. The in vitro dissolution rate of drug-HP beta-CD complex was faster compared to the drug-beta-CD complex and drug alone.