In-Silico Assisted Development of Supersaturable Preconcentrated Isotropic Mixture of Atazanavir for Augmenting Biopharmaceutical Performance in Presence of H2-Receptor Antagonist

The therapeutic potential of atazanavir (BCS Class II drug), a highly selective inhibitor of human immunodeficiency virus (HIV-1) has been largely limited due to its low intrinsic solubility at elevated pH resulting in low oral bioavailability. Thus, the current work describes the systematic development, optimization and evaluation of HPMC-AS based supersaturable preconcentrate isotropic mixture (SP-IM) containing long chain triglyceride to improve intestinal lymphatic transport and augment oral bioavailability of atazanavir (ATZ). A D-optimal mixture design was employed for optimization of plain IM containing Corn Oil, Oleic acid, Tween 80 and Propylene Glycol, evaluating CQAs like particle size, PDI, self-emulsification time, % transmittance and drug content. In-silico analysis and in-vitro supersaturation test facilitated the selection of HPMC-AS as a best suited polymeric precipitation inhibitor (PPI) for formulating ATZ loaded SP-IM (ATZ-SP-IM). In-vitro dissolution data indicated that ATZ-SP-IM exhibits superior performance in 0.025N HCl and pH 6.8 over pure drug. Ex-vivo permeation and in-vivo pharmacokinetic study of ATZ-SP-IM corroborated enhanced permeation (2.03 fold) and improved drug absorption via lymphatic transport in wistar rats. Further, the pharmacokinetic performance of ATZ-SP-IM was not affected in presence of H2 receptor antagonist. Therefore, the results showed that ATZ-SP-IM can significantly improve the biopharmaceutical attributes of ATZ so as to lay a foundation of further research on the new dosage form of ATZ.

Therapeutic Management of Breast Cancer Related Upper Limb Lymphedema

Lymphedema represents a chronic condition with impaired lymphatic transport, having primary and secondary etiologies. The most common type of secondary lymphedema in western countries is represented by breast cancer related upper limb lymphedema. This condition, once installed, determines limb structure changes, progressive functional impairment, specific complications, consequently impacting the quality of patient’s life. An accurate diagnosis is mandatory, using both clinical and imagistic methods with clear definition disease extent as per standardized staging systems, in order to further provide an adequate therapeutic strategy. The main therapeutic goal in patients with lymphedema is represented by limb volume reduction with subsequent symptoms relief, improving quality of life and avoiding complications such as recurrent infections. Through this paper, we aim to present a comprehensive overview of current therapeutic options of breast cancer upper limb related lymphedema. Therapeutic approach comprises of non-surgical (conservative) therapy, which is mandatory as initial therapy and surgical procedures for selected cases. Most patients with lymphedema benefit from conservative treatment alone. In non-responsive cases, in patients with progressive disease, in late stage complicated lymphedema, and also recently added as prophylactic strategy, surgical treatment, trough recent developed techniques, offer very good results in long-term control of disease. Surgical options are classified firstly in physiologic procedures that aim to create new lymphatic channels, promote physiologic drainage of the lymph and should be considered early in the course of the disease, and secondly ablative procedures that reduce through liposuction or various excision techniques the volume of the affected limb. Both types of techniques can be combined to ensure the best functional outcome of the patient.

Lipid-Based Nanocarrier System for the Effective Delivery of Nutraceuticals

Nutraceuticals possess several health benefits and functions; however, most nutraceuticals are prone to degradation in the gastrointestinal environment and have poor bioavailability. Application of a novel carrier system is of increasing importance to overcome obstacles and provide efficient applicability. Lipid-based nanocarriers provide a large surface-to-mass ratio, enhanced intestinal absorption by solubilization in the intestinal milieu, intestinal lymphatic transport, and altering enterocyte-based transport. A critical overview of the current limitation, preparation, and application of lipid-based nanocarriers (liposomes and niosomes) and lipid nanoparticles (SLNs and NLCs) is discussed. Physical and gastrointestinal stability and bioavailability of nanoencapsulated nutraceuticals are considered as well.

Pharmaceutical Applications of Vitamin E TPGS

D-tocopheryl polyethylene glycol succinate (Vitamin E TPGS) has been approved as a safe pharmaceutical adjuvant by FDA, and several drug delivery systems (DDS) based on TPGS have been developed. TPGS properties as a P-gp inhibitor, solubilizer/absorption and permeation enhancer in drug delivery and TPGS-related formulations such as nanocrystals, nanosuspensions, tablets/solid dispersions, vaccine system adjuvant, nutritional supplement, film plasticizer, anticancer reagent, and so on, are discussed in this review. Consequenly, TPGS can inhibit ATP-dependent P-glycoprotein activity and act as a potent excipient that promotes the efficiency of delivery and the therapeutic effect of drugs. Inhibition of P-gp occurs through mitochondria-dependent inhibition of the P-gp pump. Many of the latest studies address the use of TPGS for many poorly water-soluble or permeable drugs in the manufacture of nanodrugs or other formulations. In addition, it has been reported that TPGS shows a robust improvement in chylomicron secretion at low concentrations and improves intestinal lymphatic transport, which would also boost the potential of drug absorption. It also indicates that there are still many problems facing clinical translation of TPGS-based nanomedicines, requiring a more deep evaluation of TPGS properties and a future-based delivery method.

Inclusion of Medium-Chain Triglyceride in Lipid-Based Formulation of Cannabidiol Facilitates Micellar Solubilization In Vitro, but In Vivo Performance Remains Superior with Pure Sesame Oil Vehicle

Oral sesame oil-based formulation facilitates the delivery of poorly water-soluble drug cannabidiol (CBD) to the lymphatic system and blood circulation. However, this natural oil-based formulation also leads to considerable variability in absorption of CBD. In this work, the performance of lipid-based formulations with the addition of medium-chain triglyceride (MCT) or surfactants to the sesame oil vehicle has been tested in vitro and in vivo using CBD as a model drug. The in vitro lipolysis has shown that addition of the MCT leads to a higher distribution of CBD into the micellar phase. Further addition of surfactants to MCT-containing formulations did not improve distribution of the drug into the micellar phase. In vivo, formulations containing MCT led to lower or similar concentrations of CBD in serum, lymph and MLNs, but with reduced variability. MCT improves the emulsification and micellar solubilization of CBD, but surfactants did not facilitate further the rate and extent of lipolysis. Even though addition of MCT reduces the variability, the in vivo performance for the extent of both lymphatic transport and systemic bioavailability remains superior with a pure natural oil vehicle.