Development of a self-microemulsifying drug delivery system to deliver delamanid via a pressurized metered dose inhaler for treatment of multi-drug resistant pulmonary tuberculosis.

Tuberculosis (TB) is a serious health issue that contributes to millions of deaths throughout the world and increases the threat of serious pulmonary infections in patients with respiratory illness. Delamanid is a novel drug approved in 2014 to deal with multi-drug resistant TB (MDR-TB). Despite its high efficiency in TB treatment, delamanid poses delivery challenges due to poor water solubility leading to inadequate absorption upon oral administration. This study involves the development of novel formulation-based pressurized metered dose inhalers (pMDIs) containing self-microemulsifying mixtures of delamanid for efficient delivery to the lungs. To identify the appropriate self-microemulsifying formulations, ternary diagrams were plotted using different combinations of surfactant to co-surfactant ratios (1:1, 2:1, and 3:1). The combinations used Cremophor RH40, Poly Ethylene Glycol 400 (PEG 400), and peppermint oil, and those that showed the maximum microemulsion region and rapid and stable emulsification were selected for further characterization. The diluted self-microemulsifying mixtures underwent evaluation of dose uniformity, droplet size, zeta potential, and transmission electron microscopy. The selected formulations exhibited uniform delivery of the dose throughout the canister life, along with droplet sizes and zeta potentials that ranged from 24.74 to 88.99 nm and - 19.27 to - 10.00 mV, respectively. The aerosol performance of each self-microemulsifying drug delivery system (SMEDDS)-pMDI was assessed using the Next Generation Impactor, which indicated their capability to deliver the drug to the deeper areas of the lungs. In vitro cytotoxicity testing on A549 and NCI-H358 cells revealed no significant signs of toxicity up to a concentration of 1.56 µg/mL. The antimycobacterial activity of the formulations was evaluated against Mycobacterium bovis using flow cytometry analysis, which showed complete inhibition by day 5 with a minimum bactericidal concentration of 0.313 µg/mL. Moreover, the cellular uptake studies showed efficient delivery of the formulations inside macrophage cells, which indicated the potential for intracellular antimycobacterial activity. These findings demonstrated the potential of the Delamanid-SMEDDS-pMDI for efficient pulmonary delivery of delamanid to improve its effectiveness in the treatment of multi-drug resistant pulmonary TB.

A Self-Emulsified Adjuvant System Containing the Immune Potentiator Alpha Tocopherol Induces Higher Neutralizing Antibody Responses than a Squalene-Only Emulsion When Evaluated with a Recombinant Cytomegalovirus (CMV) Pentamer Antigen in Mice.

The development of new vaccine adjuvants represents a key approach to improvingi the immune responses to recombinant vaccine antigens. Emulsion adjuvants, such as AS03 and MF59, in combination with influenza vaccines, have allowed antigen dose sparing, greater breadth of responses and fewer immunizations. It has been demonstrated previously that emulsion adjuvants can be prepared using a simple, low-shear process of self-emulsification (SE). The role of alpha tocopherol as an immune potentiator in emulsion adjuvants is clear from the success of AS03 in pandemic responses, both to influenza and COVID-19. Although it was a significant formulation challenge to include alpha tocopherol in an emulsion prepared by a low-shear process, the resultant self-emulsifying adjuvant system (SE-AS) showed a comparable effect to the established AS03 when used with a quadrivalent influenza vaccine (QIV). In this paper, we first optimized the SE-AS with alpha tocopherol to create SE-AS44, which allowed the emulsion to be sterile-filtered. Then, we compared the in vitro cell activation cytokine profile of SE-AS44 with the self-emulsifying adjuvant 160 (SEA160), a squalene-only adjuvant. In addition, we evaluated SE-AS44 and SEA160 competitively, in combination with a recombinant cytomegalovirus (CMV) pentamer antigen mouse.

Formulation Design, Optimization and In Vivo Evaluations of an α-Tocopherol-Containing Self-Emulsified Adjuvant System using Inactivated Influenza Vaccine.

α-Tocopherol has been used as an immune supplement in humans, as an emulsion adjuvant component in several veterinary vaccines as well as an immunomodulatory component of AS03, an emulsion adjuvant that was used in an H1N1 pandemic vaccine (Pandemrix). AS03 is manufactured using microfluidization and high-pressure homogenization. Such high energy and complex manufacturing processes make it difficult and expensive to produce emulsion adjuvants on a large scale, especially in developing countries. In this study we have explored simpler, comparatively inexpensive methods, to formulate emulsion adjuvants containing α-tocopherol, that have the potential to be made in any well-established scale-up facility. This might facilitate producing and stock-piling adjuvant doses and therefore aide in pandemic preparedness. We used design of experiment as a tool to explore incorporating α-tocopherol into self-emulsified systems containing squalene oil and polysorbate 80. We created novel self-emulsified adjuvant systems (SE-AS) and evaluated their potency in vivo in BALB/c mice with inactivated quadrivalent influenza vaccine (QIV) and tested the cellular and humoral immune responses against the four vaccine strains.

Self-nanoemulsifying drug delivery system of docosahexanoic acid: development, in vitro, in vivo characterization.

CONTEXT: Docosahexanoic acid (DHA) is an essential omega-3 fatty acid for normal brain development and its use has increased considerably in recent years. OBJECTIVE: The aim of this study is to develop and evaluate self-nanoemulsifying drug delivery systems (SNEDDS) of DHA for improved palatability, dispersibility and bioavailability. METHODS: The SNEDDS were prepared and evaluated for miscibility, employing different combinations of olive oil and soyabean oil as oil phase, Span 80, Span 20, soya phosphatidylcholine, Labrafil M 1944 CS as surfactants while Tween 80, PEG 400, Cremophor RH40 and propylene glycol as cosurfactants. Thermodynamically stable SNEDDS were characterized for dispersibility, self-emulsification time, droplet size, zeta potential along with sensory analysis. The optimized formulation was subjected to ex vivo and in vivo evaluation such as intestinal permeability, memory performance test, brain concentration and histopathology studies. RESULTS: The optimized SNEDDS formulation showed emulsification time of 27 ± 4.7 s with droplet size of 17.6 ± 3.5 nm and zeta potential of -37.6 ± 0.5 mV. Intestinal absorption study depicted 18.3%, 21.5%, 41.5%, 98.7% absorption of DHA with SNEDDS-based formulation in comparison to 8.2%, 15.1%, 28.8%, 46.1% absorption of DHA with oil-based marketed formulation after 0.5, 1, 2 and 4 h. DHA concentration in brain homogenate was found to be increased to 2.6-fold in comparison to DHA-marketed formulation. This could be ascribed to enhanced dispersibility and bioavailability of DHA from nanosized formulation. CONCLUSION: The developed formulation led to enhanced dispersibility and bioavailability of DHA due to the formation of nanodroplets.

Evaluation of the versatile character of a nanoemulsion formulation.

The formulate-ability of six model active pharmaceutical ingredients (API), with different physico-chemical profiles, in a nanoemulsion designed to be intraveinously administrable was explored. Nanoemulsions were spontaneously generated at room temperature by pouring a phosphate buffer in an anhydrous mixture containing pharmaceutically acceptable triglycerides and non-ionic surfactants. After determination of the apparent solubility of each API in excipients and characterization of mixtures by DSC, API-loaded nanoemulsions were formulated and characterized in terms of granulometric properties, surface potential, drug recovery efficiency, pH, osmolarity, in vitro drug release, and stability. Except ciprofloxacin, a BCS class IV drug, all studied APIs were soluble in at least one excipient used, i.e. Labrasol. At 2 wt% API, all drug-loaded nanoemulsions present properties compatible with i.v. administration. The formulation should permit to increase apparent solubility of poorly water-soluble APIs, and also to prolong delivery of hydrophobic as well of more hydrophilic compounds. Herein, the relative affinity of the API for nanodroplets and the release medium would directly influence drug release profiles. Nanoemulsions were stable for 7 days. They could also been extemporaneously reconstituted before use. Such a versatile nanoemulsion would provide a valuable option as formulation strategy for improvement of drug properties.