Mushir Ali

Formulation development and optimization using nanoemulsion technique: a technical note.

Summary and ConclusionRamipril nanoemulsion formulations were successfully prepared by the spontaneous emulsification method (titration method). Sefsol 218 was selected as the oil phase for the development of the formulation on the basis of the solubility studies. The differences in the droplet size between the formulations selected from the phase diagram was not statistically significant, although the polydispersity was at a minimum for the formulation containing 20% oil, 27% Smix, and 53% vol/vol aqueous phase. The droplet size was found to be 34.5 nm. Therefore, nanoemulsion, a multipurpose technology, can be exploited in drug delivery for poorly soluble drugs. Nanoemulsions have a higher solubilization capacity than simple micellar solutions, and their thermodynamic stability offers advantages over unstable dispersions, such as emulsions and suspensions, because they can be manufactured with little energy input (heat or mixing) and have a long shelf life. This technical note explains the basis for calculation and construction of pseudoternary phase diagrams and, most important, explains selection of the formulations from the phase diagrams to avoid metastable formulations having minimum surfactant concentration in the least possible time.

Study of surfactant combinations and development of a novel nanoemulsion for minimising variations in bioavailability of ezetimibe

The present study aimed at developing an optimal nanoemulsion of ezetimibe and evaluating its stability, pharmacodynamic and pharmacokinetic potential. Solubility of ezetimibe was determined in various vehicles. Surfactants and cosurfactants were grouped in two different combinations to construct pseudoternary phase diagrams. Formulations were selected from the o/w nanoemulsion region and were subjected to various thermodynamic stability and dispersibility tests. Optimized formulations were characterized for their percentage transmittance, refractive index, viscosity, droplet size and zeta potential. Release rate of optimized formulations was determined using an in vitro dissolution test. The formulation used for assessment of lipid lowering potential and bioavailability contained Capryol 90 (10%, v/v), Tween 20 (33.33%, v/v), PEG 400 (16.67%, v/v), double distilled water (40%, v/v). The release of drug from the nanoemulsion formulations was extremely significant (p<0.001) in comparison to the drug suspension. More than 60% of the drug was released in the initial 1h of the dissolution study in comparison to the drug suspension. The value of total cholesterol in the group administered with the formulation PF1 was highly significant (p<0.001) with respect to the group administered with the suspension of the drug. The plasma concentration time profile of ezetimibe from nanoemulsion represented greater improvement of drug absorption than the marketed formulation and simple drug suspension. The shelf life of the nanoemulsion was found to be 5.94 years at room temperature. The present study established nanoemulsion formulation to be one of the possible alternatives to traditional oral formulations of ezetimibe to improve its bioavailability.

Improved immune response from biodegradable polymer particles entrapping tetanus toxoid by use of different immunization protocol and adjuvants

Poly lactide-co-glycolide (PLGA) and polylactide (PLA) particles entrapping immunoreactive tetanus toxoid (TT) were prepared using the solvent evaporation method. The effect of different formulation parameters such as polymer hydrophobicity, particle size and use of additional adjuvants on the generation of immune responses in experimental animals was evaluated. Immune responses from hydrophobic polymer particles were better than those from hydrophilic polymer. Immunization with physical mixtures of different size particles resulted in further improvement in anti-TT antibody titers in Wistar rats. Physical mixture of nano and microparticles resulted in early as well as high antibody titers in experimental animals. Immunization with polymer particles encapsulating stabilized TT elicited anti-TT antibody titers, which persisted for more than 5 months and were higher than those obtained with saline TT. However, antibody responses generated by single point immunization of either particles or physical mixture of particles were lower than the conventional two doses of alum-adsorbed TT. Immunization with nanoparticles along with alum resulted in very high and early immune response: high anti-TT antibody titers were detected as early as 15 days post-immunization. Use of a squalene emulsion along with the particles during immunization enhanced the level of anti-TT antibody titers considerably. Single point immunization with admixtures of PLA microparticles and alum resulted in antibody response very close to that achieved by two injections of alum-adsorbed TT; the antibody titers were more than 50 microg/ml over a period of 6 months. These results indicated that the judicious choice of polymer and particles size, protecting the immunoreactivity of the entrapped antigen and the appropriate design of immunization protocol along with suitable adjuvant can lead to the generation of long lasting immune response from single dose vaccine formulation using polymer particles.

Nanocarrier for the enhanced bioavailability of a cardiovascular agent: in vitro, pharmacodynamic, pharmacokinetic and stability assessment.

The goals of the current study were to develop and characterize a nanoemulsion of ezetimibe, evaluate its stability, lipid lowering and pharmacokinetic profile. Solubility of the drug was estimated in various oils and surfactants. Existence of nanoemulsion region was confirmed by plotting phase diagrams. Various thermodynamic stability and dispersibility tests were performed on the formulations chosen from phase diagram. Percentage transmittance, refractive index, viscosity, droplet size and zeta potential of the optimized formulations were determined. Dialysis bag method was employed to study the release rate. The formulation selected for bioavailability estimation contained Capryol 90 (10%, v/v), Crempophor EL (11.25%, v/v), Transcutol(®) P (33.75%, v/v), and double distilled water (45%, v/v). The release rate from the nanoemulsion was highly significant (p<0.001) in contrast to the drug suspension. The level of total cholesterol in the group receiving nanoemulsion CF1 was found to be highly significant (p<0.001) in comparison to the group receiving drug suspension. Bioavailability studies in rats revealed superior absorption of ezetimibe from nanoemulsion as compared to the marketed formulation and drug suspension. The shelf life of the nanoemulsion was estimated to be 18.53 months. The present study corroborated nanoemulsion to be a promising choice to improve the bioavailability of ezetimibe.

Characterization of 5-fluorouracil microspheres for colonic delivery

The purpose of this investigation was to prepare and evaluate the colon-specific microspheres of 5-fluorouracil for the treatment of colon cancer. Core microspheres of alginate were prepared by the modified emulsification method in liquid paraffin and by cross-linking with calcium chloride. The core microspheres were coated with Eudragit S-100 by the solvent evaporation technique to prevent drug release in the stomach and small intestine. The microspheres were characterized by shape, size, surface morphology, size distribution, incorporation efficiency, and in vitro drug release studies. The outer surfaces of the core and coated microspheres, which were spherical in shape, were rough and smooth, respectively. The size of the core microspheres ranged from 22 to 55 μm, and the size of the coated microspheres ranged from 103 to 185 μm. The core microspheres sustained the drug release for 10 hours. The release studies of coated microspheres were performed in a pH progression medium mimicking the conditions of the gastrointestinal tract. Release was sustained for up to 20 hours in formulations with core microspheres to a Eudragit S-100 coat ratio of 1∶7, and there were no changes in the size, shape, drug content, differential scanning calorimetry thermogram, and in vitro drug release after storage at 40°C/75% relative humidity for 6 months.

Potential of Nanoparticulate Drug Delivery Systems by Intranasal Administration

Due to number of problems related with oral, parenteral, rectal and other routes of drug administration, the interest of pharmaceutical scientists has increased towards exploring the possibilities of intranasal delivery of various drugs. Nasal drug delivery system is commonly known for the treatment of local ailments like cold, cough, rhinitis, etc. Efforts have been made to deliver various drugs, especially peptides and proteins, through nasal route for systemic use; utilizing the principles and concepts of various nanoparticulate drug delivery systems using various polymers and absorption promoters. The incorporation of drugs into nanoparticles might be a promising approach, since colloidal formulations have been shown to protect them from the degrading milieu in the nasal cavity and facilitate their transport across the mucosal barriers. The use of nanoparticles for vaccine delivery provides beneficial effect, by achieving good immune responses. This could be due to the fact that small particles can be transported preferentially by the lymphoid tissue of the nasal cavity (NALT). The brain gets benefited through the intranasal delivery as direct olfactory transport bypasses the blood brain barrier and nanoparticles are taken up and conveyed along cell processes of olfactory neurons through the cribriform plate to synaptic junctions with neurons of the olfactory bulb. The intranasal delivery is aimed at optimizing drug bioavailability for systemic drugs, as absorption decreases with increasing molecular weight, and for drugs, which are susceptible to enzymatic degradation such as proteins and polypeptides. This review discusses the potential benefits of using nanoparticles for nasal delivery of drugs and vaccines for brain, systemic and topical delivery. The article aims at giving an insight into nasal cavity, consideration of factors affecting and strategies to improve drug absorption through nasal route, pharmaceutical dosage forms and delivery systems with examples of some patents for intranasal delivery, its advantages and limitations.

Chemical permeation enhancers for transbuccal drug delivery

Importance of the field: The buccal drug delivery system has been accepted as a potential non-invasive route of drug administration, with the advantages of avoidance of the first-pass metabolism, sustained therapeutic action and better patient compliance. However, transmucosal delivery of drugs by means of the buccal route is still very challenging. The main obstacles derive from the limited absorption area and from the barrier properties of the mucosa that have to be overcome for successful delivery drug molecules to the systemic circulation by this route. Areas covered in this review: One long-standing approach for improving buccal drug delivery uses buccal absorption promoters, also called permeation enhancers. This requisite has fostered the study of permeation enhancers that will safely alter the permeability restrictions of the buccal mucosa. This review includes various classes of transmucosal chemical permeation enhancers and their mechanism of action. As enhancers influence drug delivery, further exploration of these compounds is required to understand their modifying action on the properties of buccal mucosa. What the reader will gain: This review will help the readers in the selection of a suitable enhancer(s) for improving the buccal drug delivery for future endeavor. Take home message: The authors imagine new buccal formulations bearing permeation enhancer(s) being commercialized in the coming years.

Development and evaluation of acid-buffering bioadhesive vaginal tablet for mixed vaginal infections

An acid-buffering bioadhesive vaginal tablet was developed for the treatment of genitourinary tract infections. From the bioadhesion experiment and release studies it was found that polycarbophil and sodium carboxymethylcellulose is a good combination for an acid-buffering bioadhesive vaginal tablet. Sodium monocitrate was used as a buffering agent to provide acidic pH (4.4), which is an attribute of a healthy vagina. The effervescent mixture (citric acid and sodium bicarbonate) along with a superdisintegrant (Ac-Di-sol) was used to enhance the swellability of the bioadhesive tablet. The drugs clotrimazole (antifungal) and metronidazole (antiprotozoal as well as an antibacterial) were used in the formulation along withLactobacillus acidophilus spores to treat mixed vaginal infections. From the ex vivo retention study it was found that the bioadhesive polymers hold the tablet for more than 24 hours inside the vaginal tube. The hardness of the acid-buffering bioadhesive vaginal tablet was optimized, at 4 to 5 kg hardness the swelling was found to be good and the cumulative release profile of the developed tablet was matched with a marketed conventional tablet (Infa-V). The in vitro spreadability of the swelled tablet was comparable to the marketed gel. In the in vitro antimicrobial study it was found that the acid-buffering bioadhesive tablet produces better antimicrobial action than marketed intravaginal drug delivery systems (Infa-V, Candid-V and Canesten 1).

Preparation, characterization, in vivo biodistribution and pharmacokinetic studies of donepezil-loaded PLGA nanoparticles for brain targeting

Abstract Objective: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder manifested by cognitive, memory deterioration and variety of neuropsychiatric symptoms. Donepezil is a reversible cholinesterase inhibitor used for the treatment of AD. The purpose of this work is to prepare a nanoparticulate drug delivery system of donepezil using poly(lactic-co-glycolic acid) (PLGA) for sustained release and efficient brain targeting. Materials and methods: PLGA nanoparticles (NPs) were prepared by the solvent emulsification diffusion–evaporation technique and characterized for particle size, particle-size distribution, zeta potential, entrapment efficiency, drug loading and interaction studies and in vivo studies using gamma scintigraphy techniques. Results and discussion: The size of drug-loaded NPs (drug polymer ratio 1:1) was found to be 89.67 ± 6.43 nm. The TEM and SEM images of the formulation suggested that particle size was within 20–100 nm and spherical in shape, smooth morphology and coating of Tween-80 on the NPs was clearly observed. The release behavior of donepezil exhibited a biphasic pattern characterized by an initial burst release followed by a slower and continuous sustained release. The biodistribution studies of donepezil-loaded PLGA NPs and drug solution via intravenous route revealed higher percentage of radioactivity per gram in the brain for the nanoparticulate formulation as compared with the drug solution (p < 0.05). Conclusion: The high concentrations of donepezil uptake in brain due to coated NPs may help in a significant improvement for treating AD. But further, more extensive clinical studies are needed to check and confirm the efficacy of the prepared drug delivery system.

Development and in vitro evaluation of an acid buffering bioadhesive vaginal gel for mixed vaginal infections.

Development and in vitro evaluation of an acid buffering bioadhesive vaginal gel for mixed vaginal infections An acid buffering bioadhesive vaginal (ABBV) gel was developed for the treatment of mixed vaginal infections. Different bioadhesive polymers were evaluated on the basis of their bioadhesive strength, stability and drug release properties. Bioadhesion and release studies showed that guar gum, xanthan gum and hydroxypropyl methylcelullose K4M formed a good combination of bioadhesive polymers to develop the ABBV gel. Monosodium citrate was used as an acid buffering agent to provide acidic pH (4.4). The drugs clotrimazole (antifungal) and metronidazole (antiprotozoal as well as antibacterial) were used in the formulation along with Lactobacillus spores to treat mixed vaginal infections. The ex vivo retention study showed that the bioadhesive polymers hold the gel for 12-13 hours inside the vaginal tube. Results of the in vitro antimicrobial study indicated that the ABBV gel had better antimicrobial action than the commercial intravaginal drug delivery systems and retention was prolonged in an ex vivo retention experiment. Razvoj i in vitro vrednovanje puferiranog bioadhezivnog vaginalnog gela za miješane vaginalne infekcije U radu je opisan razvoj puferiranog biodhezivnog vaginalnog (acid buffering bioadhesive vaginal, ABBV) gela za terapiju miješanih vaginalnih infekcija. Ispitani su različiti bioadhezivni polimeri - procijenjena su njihova bioadhezivna svojstva, stabilnost i sposobnost oslobađanja ljekovite tvari. Guar guma, ksantan guma i hidroksipropilmetilceluloza K4M tvore dobru kombinaciju za ABBV gel. Mononatrijev citrat upotrebljen je kao puferirajuća tvar koja omogućava blago kiseli pH (4,4), a kao ljekovite tvari upotrebljeni su klotrimazol (antimikotik) i metronidazol (antiprotozoik i antibakterijsko sredstvo), zajedno sa sporama Lactobacillus. Pripravci su upotrebljeni u terapiji miješanih vaginalnih infekcija. Pokusi ex vivo pokazali su da se bioadhezivni gel zadržava u vagini 12-13 sati. Rezultati in vitro ispitivanja ukazuju na to da ABBV gel ima bolje antibakterijsko djelovanje i dulje zadržavanje od intravaginalnog sustava koji je dostupan na tržištu.