Engineered Nano-carrier systems for the oral targeted delivery of follicle stimulating Hormone: Development, characterization, and, assessment of in vitro and in vivo performance and targetability.

Follicle stimulating hormone (FSH) is widely used for the treatment of female infertility, where the level of FSH is suboptimal due to which arrest in follicular development and anovulation takes place. Currently, only parenteral formulations are available for FSH in the market. Due to the drawbacks of parenteral administration and the high market shares of FSH, there is a need for easily accessible oral formulation. Therefore, enteric coated capsules filled with FSH loaded nanostructured lipid carriers (NLCs) or liposomes were prepared. Preliminary studies such as circular dichroism, SDS-PAGE, FTIR and ELISA were conducted to analyze FSH. Prepared formulations were optimized with respect to the size, polydispersity index, zeta potential, and entrapment efficiency using the design of experiments. Optimized formulations were subjected to particle counts and distribution analysis, TEM analysis, in vitro drug release, dissolution of enteric coated capsules, cell line studies, everted sac rat's intestinal uptake study, pharmacokinetics, pharmacodynamics, and stability studies. In the case of liposomes, RGD conjugation was done by carbodiimide chemistry and conjugation was confirmed by FTIR, 1HNMR and Raman spectroscopy. The prepared formulations were discrete and spherical. The release of FSH from enteric coated capsules was slow and sustained. The increased permeability of nano-formulations was observed in Caco-2 monoculture as well as in Caco-2 and Raji-B co-culture models. NLCs and liposomes showed an improvement in oral bioavailability and efficacy of FSH in rats. This may be due to mainly chylomicron-assisted lymphatic uptake of NLCs; whereas, in the case of liposomes, RGD-based targeting of ß1 integrins of M cells on Peyer's patches may be the main reason for the better effect by FSH. FSH was found to be stable chemically and conformationally. Overall, the study reveals the successful development and evaluation of FSH loaded NLCs and liposomes.

Organophosphorus pesticide quinalphos (Ekalux 25 E.C.) reduces sperm functional competence and decreases the fertilisation potential in Swiss albino mice.

Quinalphos (QP) is one of the most commonly used organophosphate pesticide for agriculture. In this study, adult Swiss albino male mice were orally administered with 0.25, 0.5 and 1.0 mg/kg of QP (Ekalux 25 E.C.) for ten consecutive days and the reproductive function was assessed at 35 and 70 days after QP treatment. At highest dose (1.0 mg/kg), QP exposure resulted in significant decrease in motility and increase in sperm head defects and DNA damage. Pharmacokinetic data showed a threefold increase in concentration of QP in the testis as compared to serum. QP was detectable in testes even after 24 hr of administration indicating slow clearance from tissue. In addition, high oestradiol, low testosterone level with a parallel increase in aromatase and cytochrome P450 transcript levels was observed. Significant decrease in fertilisation, lower blastocyst rate and poor blastocyst quality was observed when spermatozoa collected from QP exposed mice were subjected to in vitro fertilisation. In conclusion, exposure of QP to male mice decreases the sperm functional competence and fertilising ability, which appears to be mediated through elevated oxidative stress and altered steroidogenesis in testes.

Hot liquid extrusion assisted drug-cyclodextrin complexation: a novel continuous manufacturing method for solubility and bioavailability enhancement of drugs.

In this study, drug-cyclodextrin (CD) complexes were prepared using hot liquid extrusion (HLE) process with an aim to improve solubility and bioavailability of carbamazepine. Saturation solubility studies of CBZ in water and different pH media showed a pH-independent solubility. Phase solubility studies of CBZ at different molar concentrations of beta-cyclodextrin (ß-CD) and hydroxypropyl beta-cyclodextrin (HP-ß-CD) indicated AL-type solubility profile with stability constants of 574 M-1 and 899 M-1 for ß-CD and HP-ß-CD. Drug-ß-CD and drug-HP-ß-CD complexes were prepared using HLE process and conventional methods (such as physical mixture, kneading method, and solvent evaporation) as well. Optimized complexes prepared using HLE viz. CBP-4 and CHP-2 showed a solubility of 4.27 ± 0.09 mg/mL and 6.39 ± 0.09 mg/mL as compared to plain CBZ (0.140 ± 0.007 mg/mL). Formation of drug-CD inclusion complexes was confirmed using DSC, FTIR, and XRD studies. Drug release studies indicated highest release of CBZ from CHP-2 (98.69 ± 2.96%) compared to CBP-4 (82.64 ± 2.45%) and plain drug (13.47 ± 0.54%). Complexes prepared using kneading showed significantly lesser drug release (KMB 75.52 ± 2.68% and KMH 85.59 ± 2.80%) as that of CHP-2 and CBP-4. Pre-clinical pharmacokinetic studies in Wistar rats indicated a significant increase in Cmax, Tmax, AUC, and mean residence time for CHP-2 compared to KMH and plain CBZ. All these results suggest that HLE is an effective method to increase the solubility of poorly water-soluble drugs. Graphical Abstract.

Active Targeting of Drugs and Bioactive Molecules via Oral Administration by Ligand-Conjugated Lipidic Nanocarriers: Recent Advances.

The oral route is the most widely accepted and commonly used route for administration. However, this route may not be suitable for certain drug candidates which suffer from the problem of low aqueous solubility and gastrointestinal absorption and extensive first-pass effect. Nanotechnology-based approaches can be taken up as remedies to overcome the disadvantages associated with the oral route. Among the various nanocarriers, lipidic nanocarriers are widely used for oral delivery of bioactive molecules owing to their several advantages. Active targeting of bioactive molecules via lipidic nanocarriers has also been widely attempted to improve oral bioavailability and to avoid first-pass effect. This active targeting approach involves the use of ligands grafted or conjugated onto a nanocarrier that is specific to the receptors. Active targeting increases the therapeutic efficacy as well as reduces the toxic side effects of the drug or bioactive molecules. This review mainly focuses on the challenges involved in the oral delivery of drugs and its approaches to overcome the challenges using nanotechnology, specifically focusing on lipidic nanocarriers like liposomes, solid lipid nanoparticles, and nanostructured lipid carriers and active targeting of drug molecules by making use of ligand-conjugated lipidic nanocarriers.

Targeting the intestinal lymphatic system: a versatile path for enhanced oral bioavailability of drugs.

INTRODUCTION: The major challenge of first pass metabolism in oral drug delivery can be surmounted by directing delivery toward intestinal lymphatic system (ILS). ILS circumvents the liver and transports drug directly into systemic circulation via thoracic duct. Lipid and polymeric nanoparticles are transported into ILS through lacteal and Peyer's patches. Moreover, surface modification of nanoparticles with ligand which is specific for Peyer's patches enhances the uptake of drugs into ILS. Bioavailability enhancement by lymphatic uptake is an advantageous approach adopted by scientists today. Therefore, it is important to understand clear insight of ILS in targeted drug delivery and challenges involved in it. AREAS COVERED: Current review includes an overview of ILS, factors governing lymphatic transport of nanoparticles and absorption mechanism of lipid and polymeric nanoparticles into ILS. Various ligands used to target Peyer's patch and their conjugation strategies to nanoparticles are explained in detail. In vitro and in vivo models used to assess intestinal lymphatic transport of molecules are discussed further. EXPERT OPINION: Although ILS offers a versatile pathway for nanotechnology based targeted drug delivery, extensive investigations on validation of the lymphatic transport models and on the strategies for gastric protection of targeted nanocarriers have to be perceived in for excellent performance of ILS in oral drug delivery.