Shaila Lewis

In situ forming polymeric drug delivery systems.

In situ forming polymeric formulations are drug delivery systems that are in sol form before administration in the body, but once administered, undergo gelation in situ, to form a gel. The formation of gels depends on factors like temperature modulation, pH change, presence of ions and ultra violet irradiation, from which the drug gets released in a sustained and controlled manner. Various polymers that are used for the formulation of in situ gels include gellan gum, alginic acid, xyloglucan, pectin, chitosan, poly(DL-lactic acid), poly(DL-lactide-co-glycolide) and poly-caprolactone. The choice of solvents like water, dimethylsulphoxide, N-methyl pyrrolidone, triacetin and 2-pyrrolidone for these formulations depends on the solubility of polymer used. Mainly in situ gels are administered by oral, ocular, rectal, vaginal, injectable and intraperitoneal routes. The in situ gel forming polymeric formulations offer several advantages like sustained and prolonged action in comparison to conventional drug delivery systems. The article presents a detailed review of these types of polymeric systems, their evaluation, advancements and their commercial formulations. From a manufacturing point of view, the production of such devices is less complex and thus lowers the investment and manufacturing cost.

Design and evaluation of matrix type and membrane controlled transdermal delivery systems of nicotine suitable for use in smoking cessation

The availability of nicotine-replacement therapies is very low in India, as there are only a few importers. Currently, negligible forms of transdermal patches are available, they are expensive, and not easily accessible to the common man. In this study, an attempt was made to develop transdermal patches of nicotine, which are cost effective and conducive to the Indian market. Two types of patches, monolayered and bilayered, were prepared. The monolayered patch bore a rate- controlling membrane, whereas the bilayered, served as matrix type. The physical charecteristics of the patches were evaluated by standard techniques. The drug content was found to be uniform in the patches. In vitro release studies of transdermal patches showed a biphasic release pattern, with diffusion as the dominating mechanism of drug release for the matrix type, while the membrane-controlled released nicotine, gradually over the 24 h study.

Enhanced ex vivo intestinal absorption of olmesartan medoxomil nanosuspension: Preparation by combinative technology

The purpose of this study was to develop nanosuspension based on combinative technology to enhance the intestinal absorption of Olmesartan medoxomil (OLM), a potent antihypertensive agent with limited oral bioavailability. Two combinative approaches were employed and then characterized. In vitro intestinal absorption of OLM nanosuspension and plain OLM was studied using non-everted rat intestinal sac model. Optimal OLM nanosuspension was prepared by a combination of ball milling and probe sonication using stabilizer, Poloxamer 407. The formula exhibited particle size of 469.9 nm and zeta potential of −19.1 mV, which was subjected to ex vivo studies. The flux and apparent permeability coefficient in intestine from OLM nanosuspension was higher than the plain drug, thereby suggesting better drug delivery.

Nanostructured lipid carriers for the topical delivery of tretinoin

Cosmetic skin care products currently in the market demonstrate an increasing trend toward antiaging products. Selection of the right formulation approach is the key to successful consumer acceptance. Nanostructured lipid carriers (NLCs) for dermal application can render added benefits to the formulation. Tretinoin a derivative of vitamin A, is a retinoid with anti-aging and anti-acne potential. The present study was aimed at formulating NLCs of tretinoin for reducing the skin irritation potential, increasing the drug loading capacity and prolonging the duration of action. The NLCs were optimized using the response surface methodology based on the particle size. Preliminary study, suggested the use of stearic acid, oleic acid, Tween 80 and Span 60 as solid lipid, liquid lipid and surfactants respectively formed a stable dispersion. NLCs of tretinoin were prepared by hot melt microemulsion and hot melt probe sonication methods. The properties of the optimized NLCs such as morphology, size, Zeta potential, stability and in vitro drug release were investigated. Tretinoin loaded NLCs in carbopol gel showed a sustained release pattern with isopropyl alcohol as the receptor fluid compared to the marketed gel using Franz diffusion cells. Eight prepared gel formulations tested were found to follow the Higuchi model of drug release. Stability studies indicated that the formulations stored at refrigeration and room temperature showed no noticeable differences in the drug content and release profiles in vitro, after a period of 4 weeks. In vivo skin irritation test on male Wister rats indicated no irritation or erythema after application of the NLCs loaded gel repeated for a period of 7 days compared to the application of marketed tretinoin gel which showed irritation and slight erythema within 3 days. The results showed that the irritation potential of tretinoin was reduced, the drug loading was increased and the drug release was prolonged by the incorporation into the NLCs.

Design, evaluation and pharmacokinetic study of mucoadhesive buccal tablets of nicotine for smoking cessation

Mucoadhesive tablets for buccal administration of nicotine were prepared as an alternative to the available nicotine dosage forms. Three types of tablets were developed each containing two mucoadhesive components (HPMC, K4M and sodium alginate), (HPMC, K4M and carbopol) (Chitosan and sodium alginate). For each of these types, batches were produced changing the quantity of polymers resulting in nine different formulations. The tablets were evaluated for release pattern, and mucoadhesive performance. Pharmacokinetic studies were conducted in smokers. A peak plasma concentration of 16.78±2.27 ng was obtained in two hours, which suggests potential clinical utility in nicotine replacement therapy.

Subacute Toxicity Profile of Lacidipine Nanoformulation in Wistar Rats

The present study was aimed at investigating the safety of Lacidipine (LCDP) loaded nanostructured lipid carriers (NLCs) in Wistar rats. NLCs were formulated using ultrasound dispersion technique. Animals were orally treated once daily with NLCs containing 0.140 mg, 0.350 mg, and 0.875 mg of LCDP as low, medium, and high dose per kg body weight, respectively, during 28 days along with blank formulation and pure LCDP. Control rats were fed with water. Animals were observed throughout experiment period and their body weight was recorded once weekly. Overnight fasted rats were sacrificed on the 29th day. Study revealed no signs or symptoms of toxicity or morbidity. No significant changes in the body weight were observed between treated and control group. Significant increase in left testis weight and liver weight was observed in male and female rats, respectively. Haematological estimation revealed significant decrease in haemoglobin count in male rats while female rats showed significant increase in granulocyte count. All the serum clinical parameters were within the normal range and no gross histopathological changes were observed. No delayed effect was noted in satellite group. The results indicate that developed LCDP loaded NLCs are safe when administered orally in rats.

Development and Validation of a Stability-Indicating RP-HPLC Method by a Statistical Optimization Process for the Quantification of Asenapine Maleate in Lipidic Nanoformulations

A stability-indicating RP-HPLC method was developed for quantification of asenapine maleate (ASPM) in lipid nanoformulations. The proposed method was used to assess intrinsic stability of ASPM by conducting force degradation study. The results indicated no considerable degradation of ASPM on subjecting it to hydrolytic, oxidative, thermal and photolytic stresses. The method was validated according to ICH Q2(R1) guidelines by employing Full factorial design using Design-Expert(®) software. ASPM was precisely and accurately quantified in nanoparticles by separating it on Hyperclone BDS C18 using 80-20% v/v mixture of potassium phosphate solution containing 0.1% v/v triethylamine and acetonitrile. The effect of flow rate, pH, acetonitrile content and column temperature was assessed on method responses. The current method was linear in the range of 0.1-20 µg/mL with limit of detection (LOD) and limit of quantification (LOQ) of 29 and 89 ng/mL, respectively. The method was precise and accurate in the determination of ASPM with peak area RSD and recovery of <1.0% and 97-101% in bulk drug solution and of <1.0% and 92-104% in nanoformulations, respectively. Analysis of variance indicated the significance (P < 0.0001) of a statistical model in validating the method with respect to change in independent chromatographic factors. The developed method was successfully employed in determining ASPM content in bulk and lipid nanoformulations.

Application of pectin‑zinc oxide hybrid nanocomposite in the delivery of a hydrophilic drug and a study of its isotherm, kinetics and release mechanism

Pectin-based gel and its nanocomposite with zinc oxide have been compared for their capacity to release Donepezil for the possible use as an implantable drug delivery platform for the treatment of Alzheimers disease. Adsorption capacities of the samples were determined as a function of pH, temperatures, concentrations of the drug, and the mass of the adsorbent. The nanocomposite exhibited significant adsorption compared to the parent gel. Adsorption data for the nanocomposite system fits well with Langmuir model and followed pseudo-first order kinetics, while that of the parent polymeric system followed pseudo-second-order kinetics. Donepezil adsorbed polymeric samples were prepared and evaluated for tensile strength, swelling index, folding endurance and characterized by FTIR, FESEM, EDS, XRD and TGA techniques. The desorption of zinc oxide was also monitored using the dynamic light scattering technique. The in vitro drug release study indicated desorption of Donepezil to the maximum extent of ~88% and 46% during 5 days period from the nanocomposite and the parent gel respectively. The developed systems showed negligible (<10%) percentage of hemolysis after incubation with sheep erythrocytes. In conclusion, the developed pectin-based nanocomposite can be explored as a potential platform for the development of implantable drug delivery systems for chronic diseases.

Aceclofenac ethosomes for enhanced transdermal delivery

The oral administration of aceclofenac has often resulted in side effects with chronic use. Using the transdermal route eliminates these side effects. Aceclofenac ethosomes were prepared and incorporated into a gel to enhance the skin permeability of aceclofenac. Ethosomal system comprised of phospholipids, ethanol, propylene glycol and lecithin. Different formulations were prepared with varying concentrations of lecithin and ethanol. The optical microscopy confirmed the formulation of multilamellar vesicles. The vesicle size of the ethosomes ranged between 0.696–1.140µm. Surface morphology was conducted by scanning electron microscopy. The entrapment efficiency was determined by centrifugation method. Effect of ethanol and lecithin concentration on entrapment of ethosomes was observed. Franz diffusion cell was used to evaluate the in vitro transdermal permeability of aceclofenac ethosomes. The studies were carried out using mouse skin as well as commercial sigma membrane. The in vitro drug permeation of the optimised formulation was compared with commercial conventional gel-Ziynac gel. The flux values of different ethosomal formulation were observed between 116.5µg/cm2/hr to 226.15µg/cm2 /hr. Formulation 5 showed maximum J value 226.1 as compared to marketed one 131.5µg/cm2 /hr. From the results of the present study it can be concluded that ethosomes improve the transdermal flux, prolong the release and represent an active carrier for sustained transdermal delivery.

In silico prediction coupled with in vitro experiments and absorption modeling to study the inclusion complex of telmisartan with modified beta-cyclodextrin

Telmisartan (TEL) is a poorly bioavailable antihypertensive drug candidate owing to its low solubility in all the biofluids. The present study is aimed to enhance the solubility of TEL by forming an inclusion complex with sulfobutylether beta-cyclodextrin (SBE-β-CD), discover its mode of inclusion and predict the bioavailability of the prepared complexes. The formation of the inclusion complex is explained based on the hydrogen bond propensities and molecular dynamics simulations. Freeze-drying method was employed for the preparation of inclusion complexes. These complexes were subsequently characterized by powder X-ray diffraction, differential scanning calorimetry, and Fourier transform-infrared spectroscopy. The spatial configuration of the drug inside the cyclodextrin cavity is probed using 1H and 13C NMR. The in silico docking results are in good agreement with the experimental data and reveal that the hydrogen bond is formed as a part of the guest molecule enters from the broader end of the ring and the protons at the interior portion of the molecule interact with the carboxylic acid (–COOH) group of TEL leading to the formation of a hydrogen bond. The phenyl moiety of TEL occupies the central core and forms multiple Van-der-Waals interactions with the glucopyranose units of the SBE-β-CD. The inclusion complex demonstrates significantly higher in vitro dissolution profile as compared with plain TEL. The GastroPlus™ simulation software generated parameters of inclusion complex in comparison to plain TEL show a seven fold increase in Cmax and 18 fold increase in bioavailability.