Development of lipid-based nanoparticles for enhancing the oral bioavailability of paclitaxel.

The current research work investigates the potential of solid lipid nanoparticles (SLNs) in improving the oral bioavailability of paclitaxel. Paclitaxel-loaded SLNs (PTX-SLNs) were prepared by modified solvent injection method using stearylamine as lipid, soya lecithin and poloxamer 188 as emulsifiers. SLNs were characterized in terms of surface morphology, size and size distribution, surface chemistry and encapsulation efficiency. Pharmacokinetics and bioavailability studies were conducted in male Swiss albino mice after oral administration of PTX-SLNs. SLNs exhibited spherical shape with smooth surface as analyzed by transmission electron microscopy (TEM). The mean particle size of SLNs was 96 ± 4.4 nm with a low polydispersity index of 0.162 ± 0.04 and zeta potential of 39.1 ± 0.8 mV. The drug entrapment efficiency was found to be 75.42 ± 1.5% with a loading capacity of 31.5 ± 2.1% (w/w). Paclitaxel showed a slow and sustained in vitro release profile and followed Higuchi kinetic equations. After oral administration of the PTX-SLNs, drug exposure in plasma and tissues was ten- and twofold higher, respectively, when compared with free paclitaxel solution. PTX-SLNs produced a high mean C (max) (10,274 ng/ml) compared with that of free paclitaxel solution (3,087 ng/ml). The absorbed drug was found to be distributed in liver, lungs, kidneys, spleen, and brain. The results suggested that PTX-SLNs dispersed in an aqueous environment are promising novel formulations that enhanced the oral bioavailability of hydrophobic drugs, like paclitaxel and were quite safe for oral delivery of paclitaxel as observed by in vivo toxicity studies.

Melatonin-Caffeine Combination Modulates Gamma Radiation-induced Sperm Malformations in C57BL/6 Male Mice at Sublethal Dose of Gamma Radiation.

AIMS: The aim of this study was to assess the protective effect of the melatonin-caffeine combination against γ radiation-induced alterations in the morphological characteristics of sperms. SETTINGS AND DESIGN: C57BL/6 male mice (n = 30) were randomly divided into five groups: control, radiation (2 Gy), melatonin (100 mg/kg body wt.) + radiation (2 Gy), caffeine (30 mg/kg body wt.) + radiation (2 Gy), melatonin-caffeine (100-30 mg/kg body wt.) + radiation (2 Gy). MATERIALS AND METHODS: All the mice were sacrificed 24 h postirradiation, and cauda epididymis was collected. In this study, sperm concentration along with any abnormality in their morphology (amorphous heads, pinheads, hookless, coiled tails, midpiece defect, and tail-less) was observed in the control and treatment group of animals. RESULTS: Radiation exposure (2 Gy) considerably decreases the sperm count when compared with the control group. However, pretreatment with melatonin and melatonin-caffeine combination before gamma irradiation increased the sperm count (P < 0.05), but with caffeine alone could not produce a significant difference. The higher rate of abnormal sperms was observed in the γ-irradiated mice when compared with the control group (P < 0.05). Besides, the numbers of sperm that are hookless and coiled tails were significantly increased after irradiation. Melatonin significantly reduced the number of sperm with amorphous heads and coiled tails. Melatonin-caffeine combination further reduced sperm malformations when compared with the melatonin + 2 Gy radiation and caffeine + 2 Gy radiation group. CONCLUSIONS: This study suggests that caffeine exerts a protective effect when given in combination with melatonin against gamma irradiation in sperms of C57BL/6 mice and could be a potent combination for the development of radioprotector.

Critical evaluation of permeation enhancers for oral mucosal drug delivery.

BACKGROUND: Drug delivery via oral mucosa is an alternative method of systemic administration for various classes of therapeutic agents. Among the oral mucosae, buccal and sublingual mucosae are the primary focus for drug delivery. Buccal delivery offers a clear advantage over the peroral route by avoidance of intestinal and hepatic first-pass metabolism. However, despite offering the possibility of improved systemic drug delivery, buccal administration has been utilized for relatively few pharmaceutical products so far. One of the major limitations associated with buccal delivery is low permeation of therapeutic agents across the mucosa. Various substances have been explored as permeation enhancers to increase the flux/absorption of drugs through the mucosa, but irritation, membrane damage, and toxicity are always associated with them and limit their use. A clinically accepted permeation enhancer must increase membrane permeability without causing toxicity and permanent membrane damage. To date, the information available on oral mucosal permeation enhancement is much less than transdermal enhancement, though oral mucosa is more resistant to damage than other mucosal membranes. This article reviews the various categories of permeation enhancers for oral mucosal drug delivery, their mechanism of action, their usefulness, and the limitations associated with their use. CONCLUSION: To optimize the concentration of enhancer to limit its toxicity while facilitating an enhancing effect reproducibly will be a big challenge for future developments. Advances in permeability modulation and formulation with appropriate enhancers can provide for effective and feasible buccal drug delivery for many drugs, which otherwise have to be injected or ingested with water.

A Comparative Study of Chitosan Gel and Soframycin in the Management of Wounds.

Wounds and related injuries remain a major cause of death and disability. Healing of wound is a complex, highly regulated process that includes cellular, molecular, biochemical, and physiological events that permit living organisms to repair accidental lesions. Therefore, dealing with wounds has always been a subject of concern to the world, and demand for products in wound management had increased to $9.3 trillion worldwide in the health care industry, affecting economic growth. The present work aimed to assess the wound healing effect of chitosan, and a comparative profile with soframycin is established in experimental animals. Enormous research reports, the wound healing properties of chitosan, but the protective mechanism implicated in wound healing activity of chitosan is unknown. In addition to this, we evaluated the anatomical, macroscopical, and histopathological alterations in wounds of experimental rats. Collagenase activity was performed to determine the granulation tissue formation and epithelialization of wounds treated with untainted chitosan. Wounds treated with glycerated chitosan gel, that is, GCG-3 (high degree of deacetylation), showed faster healing with highest percentage of contraction as compared with the soframycin-treated group. The healing of wounds was found to be 85% in GCG-3 on the sixth day of treatment, showing significant (P < .001) improvement in epithelial tissue. The collagenase activity in GCG-3 was 192 unit/mg of protein. Wound reepithelialization was found to be to 94 ± 4% in case of the GCG-3-treated group and 87 ± 5% in the soframycin-treated group. Higher degree of deacetylation in the chitosan, GCG-3, warrants its use in the treatment and management of dermal wounds.

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.

Development and in-vitro evaluation of transdermal matrix films of metoprolol tartrate.

The transdermal matrix films of metoprolol tartrate (MT) were prepared by casting on mercury substrate employing different ratios of polymers, ethyl cellulose (EC) and polyvinyl pyrrolidone (PVP), using dibutyl phthalate (DBT) as a plasticizer. Four formulations were prepared. Formulations MF-1, MF-2, MF-3 and MF-4 were composed of EC and PVP in the following ratios: 4.5:0.5, 4:1, 3:2 and 2:3 respectively. The formulations were subjected to various physical characterization studies namely, thickness, weight variation, drug content, moisture uptake, in vitro drug release and in vitro skin permeation. The in vitro permeation studies were carried out across excised porcine ear skin using Franz diffusion cell. Cumulative amounts of the drug released in 24 hours from the four formulations were 69.58%, 96.13%, 98.85% and 99.60%, respectively. Corresponding values for the cumulated amounts of drug permeated across the porcine skin for the above matrix films were 124.38, 153.22, 156.46 and 163.25 mug/cm(2) respectively. By fitting the data into zero order, first order and Higuchi model, it was concluded that drug release from matrix films followed Higuchi model (r(2)=0.9147-0.9823), and the mechanism of release was diffusion mediated. Based on the physical evaluation, in vitro drug release & permeation characteristics, it was concluded that for potential therapeutic use, monolithic drug matrix films MF-3, composed of EC: PVP (3:2), may be suitable for the development of a transdermal drug delivery system of MT.

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 with Lactobacillus 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).

Diffuse reflectance near infrared-chemometric methods development and validation of amoxicillin capsule formulations.

OBJECTIVE: The aim of present study was to establish near infrared-chemometric methods that could be effectively used for quality profiling through identification and quantification of amoxicillin (AMOX) in formulated capsule which were similar to commercial products. In order to evaluate a large number of market products easily and quickly, these methods were modeled. MATERIALS AND METHODS: Thermo Scientific Antaris II near infrared analyzer with TQ Analyst Chemometric Software were used for the development and validation of the identification and quantification models. Several AMOX formulations were composed with four excipients microcrystalline cellulose, magnesium stearate, croscarmellose sodium and colloidal silicon dioxide. Development includes quadratic mixture formulation design, near infrared spectrum acquisition, spectral pretreatment and outlier detection. According to prescribed guidelines by International Conference on Harmonization (ICH) and European Medicine Agency (EMA) developed methods were validated in terms of specificity, accuracy, precision, linearity, and robustness. RESULTS: On diffuse reflectance mode, an identification model based on discriminant analysis was successfully processed with 76 formulations; and same samples were also used for quantitative analysis using partial least square algorithm with four latent variables and 0.9937 correlation of coefficient followed by 2.17% root mean square error of calibration (RMSEC), 2.38% root mean square error of prediction (RMSEP), 2.43% root mean square error of cross-validation (RMSECV). CONCLUSION: Proposed model established a good relationship between the spectral information and AMOX identity as well as content. Resulted values show the performance of the proposed models which offers alternate choice for AMOX capsule evaluation, relative to that of well-established high-performance liquid chromatography method. Ultimately three commercial products were successfully evaluated using developed methods.

Revisiting the nanoformulation design approach for effective delivery of topotecan in its stable form: an appraisal of its in vitro Behavior and tumor amelioration potential.

Topotecan (TPT) is indicated against a variety of solid tumors, but has restricted clinical use owing to associated pharmaceutical caveats. This study is focused at formulating a successful TPT PLGA nanosystem which ameliorates the rapid conversion of active lactone form of drug to its inactive carboxylate form and consequently improvises its efficacy. TPT PLGA nanoparticles were formulated by a double emulsion-solvent evaporation technique with sequential optimization to obtain desired particle size, PDI, zeta potential, and entrapment efficiency. Stability of TPT was ensured by maintaining an acidic pH in the drug-containing phase and the system was evaluated for in vitro-in vivo performance including cytotoxic potency. The optimized nanosystem had a particle size of 187.33 ± 7.50 nm, a PDI of 0.179 ± 0.05, and an entrapment efficiency of 56 ± 1.2%. Low pH in the interior of nanoparticles stabilized the drug to remain in its active lactone form and revealed a biphasic release pattern till 15 d. Additionally, an in vitro cytotoxicity testing as well as in vivo antitumor efficacy demonstrated a significant potential of higher proliferation inhibition as compared with neat drug (TPT). Thus, the investigation summarized an innovative simple tool for developing stable TPT NPs for effective delivery for treating solid tumors.

Feasibility of Assam Bora rice starch as a compression coat of 5-fluorouracil core tablet for colorectal cancer.

The colon and rectum are the parts of digestive system of human beings. Cancer affecting either of these organs may be called colorectal cancers. Conventional cancer chemotherapy is not very effective for treatment of colorectal cancer, as the drug molecule does not reach the target site at therapeutic concentration, on the other side they produces sever systemic toxic effect. Aim of this study was to develop a novel colon targeted Assam Bora rice starch compression coated tablet for site specific delivery of 5-FU to the colon without the drug being released in stomach or small intestine. Core tablet of 5-FU was prepared using microcrystalline cellulose (MCC) and spray dried lactose by direct compression method. The in vitro drug release study in different physiological environment confirmed insignificant release of 5-FU in physiological condition of stomach and small intestine further fast and major drug release in caecal content. In vivo drug absorption of optimized formulation was performed in order to establish its targeting potential in colon. It is concluded from the present study that Assam Bora rice starch can be used as a drug carrier for an effective colon targeted delivery system for drugs effective against the large intestine resident disease condition.

Development of polysaccharide based colon targeted drug delivery system: design and evaluation of Assam Bora rice starch based matrix tablet.

The aim of this study was to develop a novel colon targeted matrix tablet containing Metronidazole (MTZ) as model drug. Matrix tablets were prepared using Assam Bora rice starch, which is essentially a natural polymer, by wet granulation technique. The granules prepared were subjected to evaluation for angle of repose, bulk density, compressibility index, Hausner's ratio, total porosity, and drug content. The developed tablets were also analysed for thickness, diameter, weight variation tests, tablet crushing strength, friability, and in vitro release studies. The granules displayed satisfactory flow properties, compressibility, Hausner's ratio and drug content. Almost all the tablet formulations showed acceptable pharmacotechnical properties and complied with the in-house developed specifications for the tested parameters. Drug release study confirmed to the initial fast release in the acidic environment of surface adhered drug followed by slow release in alkaline media subsequently leading to fast and major drug release in the caecal content. Furthermore, the release of drug was unaffected by the hostile environment of GIT which can be ascribed to microbial degradation, promptly followed by enzymatic degradation. Curve fitting proved that the drug release from the tablets followed the Higuchi model. In vitro bacterial inhibition studies illustrated that the released drugs were able to diffuse through agar medium, inhibiting MTZ sensitive Bacteroides fragilis. The selected MTZ matrix tablets (F1-F6) had zones of inhibition paralleling those of the marketed formulation.

Cancer targeted metallic nanoparticle: targeting overview, recent advancement and toxicity concern.

The targeted delivery of theranostic agents to the cancer cells is one of the major challenges and an active field of research in the development of cancer chemotherapeutic approaches. Theranostic metallic nanoparticles (TMNPs) have garnered increasing attention in recent years as a novel tool for theranostic application such as imaging, diagnosis, and therapeutic delivery of active agents to tumour specific cells. This paper attempts to unveil the multidimensional theranostic aspects of multifunctional metallic nanoparticles (MNPs)including passive and active targeting (HER2, Folate, Angiogenesis etc.) as well as the RES escaping approach. Special attention is given to the theranostic application of MNPs in oncology. Patents issued by the US office in this nanotechnological arena are also included emphasising the importance of MNPs in current cancer treatment/imaging research scenario. Keeping in mind the blooming research in clinical application directed nanotechnology; toxicity concerns related with MNPs are. also discussed, in element.

Metallic nanoparticles: technology overview & drug delivery applications in oncology.

IMPORTANCE OF THE FIELD: The targeted delivery of therapeutic agents to tumour cells is a challenge because most of the chemotherapeutic agents distribute to the whole body, which results in general toxicity and poor acceptance by patients and sometimes discontinuation of the treatment. Metallic nanoparticles have been used for a huge number of applications in various areas of medical treatment. Metallic nanoparticles are emerging as new carrier and contrast agents in cancer treatment. These metallic nanoparticles have been used for imaging of tumour cells by means of active and passive targeting. Recent advances have opened the way to site-specific targeting and drug delivery by these nanoparticles. AREAS COVERED IN THIS REVIEW: This review summarizes the mechanisms of passive and active targeted drug delivery by metallic nanoparticles and their potential use in cancer theranostics. WHAT THE READER WILL GAIN: The reader will gain information on the development of tumour cells, advantages of modern methods of cancer treatment over the traditional method, targeted delivery of anticancer agents using nanoparticles, influence of nanotechnology on the quality and expectancy of life, and challenges, implications and future prospects of metallic nanoparticles as probes in cancer treatment. TAKE HOME MESSAGE: The development of metallic nanoparticles is rapid and multidirectional, and the improved practical potential of metallic nanoparticle highlights their potency as new tools for future cancer therapeutics modalities.

Stability indicating HPTLC method for determination of terbutaline sulfate in bulk and from submicronized dry powder inhalers.

A stability-indicating high-performance thin-layer chromatographic (HPTLC) method has been developed for the determination of terbutaline sulfate (TBS) as a bulk drug and in pharmaceutical formulations (submicronized dry powder inhalers). The separation was achieved on TLC aluminum plates precoated with silica gel 60F-254 using chloroform-methanol (9.0:1.0 v/v) as mobile phase. The densitometric analysis was carried out at 366 nm wavelength. Compact spots appeared at R(f) = 0.34 +/- 0.02. For the proposed procedure, linearity (r(2) = 0.9956 +/- 0.0015), limit of quantification (28.35 ng spot(-1)), limit of detection (9.41 ng spot(-1)), recovery (97.06-99.56%), and precision (< or = 1.86) were found to be satisfactory. TBS was subjected to acid and alkali hydrolyses, oxidation and photodegradation treatments. The degraded products were well separated from the pure drug. Statistical analysis reveals that the developed method has potential for routine analysis and stability testing of terbutaline sulfate in pharmaceutical drug delivery systems.

An HPTLC method for the determination of minocycline in human plasma, saliva, and gingival fluid after single step liquid extraction.

A rapid, sensitive and specific high-performance thin-layer chromatographic (HPTLC) method was developed and validated for determination of minocycline in human plasma, saliva, and gingival fluid samples. Densitometric analysis of minocycline was carried out at 345 nm after single step extraction with methanol. The method uses TLC aluminium plates pre-coated with silica gel 60F-254 as a stationary phase and methanol-acetonitrile-isopropyl alcohol-water (5:4:0.5:0.5, v/v/v/v) as mobile phase. In all the three matrices, the calibration curve was linear (r(2) >/= 0.9958) in the tested range of 100 - 1200 ng spot(-1) with a limit of quantification of 15.4 ng spot(-1). Drug recovery from plasma, saliva and gingival fluid averaged 97.7%. Intra- and inter-day accuracies, determined at three different concentrations, were 95.08 to 100.6% and the corresponding precision (% CV) values were < 4.61%. In all the three matrices, rapid degradation of drug occurred and the half-life of drug ranged from 9.9 to 16.1 h at 4 degrees C and from 6.3 to 11.5 h at 20 degrees C. Frozen at -20 degrees C, this drug was stable for at least 2 months and can tolerate two freeze-thaw cycles without losses higher than 10%. The method's ability to quantify minocycline with precision, accuracy and sensitivity makes it useful in pharmacokinetic studies.

Validated stability-indicating densitometric thin-layer chromatography: application to stress degradation studies of minocycline.

A simple, stability-indicating high-performance thin-layer liquid chromatographic (HPTLC) method for analysis of minocycline was developed and validated. The densitometric analysis was carried out at 345 nm using methanol-acetonitrile-isopropyl alcohol-water (5:4:0.5:0.5, v/v/v/v) as mobile phase. The method employed TLC aluminium plates pre-coated with silica gel 60F-254 as the stationary phase. To achieve good result, plates were sprayed with a 10% (w/v) solution of disodium ethylene diaminetetraacetic acid (EDTA), the pH of which was adjusted to 9.0. Compact spots of minocycline were found at R(f) = 0.30+/-0.02. For proposed procedure, linearity (r = 0.9997), limit of detection (3.7 ng spot(-1)), recovery (99.23-100.16%), and precision (% R.S.D. < or = 0.364) was found to be satisfactory. The drug undergoes acidic and basic degradation, oxidation and photodegradation. All the peaks of degradation products were well resolved from the pure drug with significantly different R(f) values. The acidic and alkaline degradation kinetics of minocycline, evaluated using this method, is found to be of first order.