Biodegradable polymeric nanoparticles based drug delivery systems

Nanoemulsions fabricated from food-grade ingredients are being increasingly utilized in the food industry to encapsulate, protect, and deliver lipophilic functional components, such as biologically-active lipids (e.g., ω-3 fatty acids, conjugated linoleic acid) and oil-soluble flavors, vitamins, preservatives, and nutraceuticals. The small size of the particles in nanoemulsions (r<100 nm) means that they have a number of potential advantages over conventional emulsions-higher stability to droplet aggregation and gravitational separation, high optical clarity, ability to modulate product texture, and, increased bioavailability of lipophilic components. On the other hand, there may also be some risks associated with the oral ingestion of nanoemulsions, such as their ability to change the biological fate of bioactive components within the gastrointestinal tract and the potential toxicity of some of the components used in their fabrication. This review article provides an overview of the current status of nanoemulsion formulation, fabrication, properties, applications, biological fate, and potential toxicity with emphasis on systems suitable for utilization within the food and beverage industry.

Food-grade nanoemulsions: formulation, fabrication, properties, performance, biological fate, and potential toxicity.

Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.

Strategies to Address Low Drug Solubility in Discovery and Development

Solubility, the phenomenon of dissolution of solute in solvent to give a homogenous system, is one of the important parameters to achieve desired concentration of drug in systemic circulation for desired (anticipated) pharmacological response. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as for the generic development. More than 40% NCEs (new chemical entities) developed in pharmaceutical industry are practically insoluble in water. Solubility is a major challenge for formulation scientist. Any drug to be absorbed must be present in the form of solution at the site of absorption. Various techniques are used for the enhancement of the solubility of poorly soluble drugs which include physical and chemical modifications of drug and other methods like particle size reduction, crystal engineering, salt formation, solid dispersion, use of surfactant, complexation, and so forth. Selection of solubility improving method depends on drug property, site of absorption, and required dosage form characteristics.

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Drug Solubility: Importance and Enhancement Techniques

Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: basic approaches and practical applications.

Development and bioavailability assessment of ramipril nanoemulsion formulation.

Ramipril 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 345 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

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

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

Ritonavir is an antiretroviral drug characterized by low solubility and high permeability which corresponds to BCS class II drug. The purpose of the study was to develop solid dispersion by different methods and investigate them for in vitro and in vivo performance for enhancing dissolution and bioavailability, respectively. Since the drug possesses food-related absorption, the effect of biorelevant media (FaSSIF and FeSSIF state) on dissolution behavior was also studied. The solid dispersion was prepared using Gelucire as carrier in 1:4 ratio by different methods and were characterized for differential scanning calorimetry (DSC), X-ray diffractometry, scanning electron microscopy, and FT-IR. Oral bioavailability of 10 mg of ritonavir in solid dispersion prepared by solvent evaporation (SE1) and melt method (MM1) was compared with pure drug after oral administration of solid dispersion and pure drug to Albino Wistar rats of either sex. The results suggested formation of eutectic solid dispersion. In vitro dissolution studies was performed in 0.1 N HCl and biorelevant media showed enhanced dissolution rate as compared to pure drug in both FeSSIF media and 0.1 N HCl. The apparent rate of absorption of ritonavir from SE1 (Cmax 20221.37 ng/ml, tmax 0.5 h) was higher than that of MM1 (Cmax 2,462.2, tmax 1 h) and pure drug (Cmax 1,354.8 ng/ml, tmax 0.5 h). On the basis of the result obtained, it was concluded that solid dispersion is a good approach to enhance solubility and bioavailability of poorly water-soluble ritonavir.

Solid Dispersion as an Approach for Bioavailability Enhancement of Poorly Water-Soluble Drug Ritonavir

Silymarin, a flavonolignan derived from Silybum marianum, possesses diverse pharmacological activities, including hepatoprotective, antioxidant, anti-inflammatory, anticancer, and cardioprotective. Although clinical trials have shown silymarin is safe at high doses (>1500 mg/day) in humans, the pharmacokinetic studies over the past three decades related to absorption, distribution, metabolism, and excretion of silymarin have revealed poor absorption, rapid metabolism, and ultimately poor oral bioavailability. For optimum silymarin bioavailability, issues of solubility, permeability, metabolism, and excretion must be addressed. An array of methods have been described in recent years that can improve its bioavailability, including complexation with β-cyclodextrins, solid dispersion method, formation of microparticles and nanoparticles, self-microemulsifying drug delivery systems, micelles, liposomes, and phytosomes. This article critically reviews the recent published literature on various techniques for increasing the bioavailability of silymarin.

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Mushir Ali

Papers

Development and bioavailability assessment of ramipril nanoemulsion formulation.

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

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

Solid Dispersion as an Approach for Bioavailability Enhancement of Poorly Water-Soluble Drug Ritonavir

Reassessing bioavailability of silymarin.