Preclinical formulations: insight, strategies, and practical considerations.

A lot of resources and efforts have been directed to synthesizing potentially useful new chemical entities (NCEs) by pharmaceutical scientists globally. Detailed physicochemical characterization of NCEs in an industrial setup begins almost simultaneously with preclinical testing. Most NCEs possess poor water solubility posing bioavailability issues during initial preclinical screening, sometimes resulting in dropping out of an NCE with promising therapeutic activity. Selection of right formulation approach for an NCE, based on its physicochemical properties, can aid in improving its solubility-related absorption and bioavailability issues. The review focuses on preclinical formulations stressing upon different preclinical formulation strategies and deciphers the understanding of formulation approaches that could be employed. It also provides detailed information related to a vast pool of excipients available today, which is of immense help in designing preclinical formulations. Few examples mentioned, throw light on key aspects of preclinical formulation development. The review will serve as an important guide for selecting the right strategy to improve bioavailability of NCEs for academic as well as industrial formulation scientists.

An Overview of Recent Patents and Future Perspective Based on Cyclodextrin Complexation.

The majority of drugs taken orally have limited aqueous solubility and dissolution rate. Cyclodextrin (CD) and its derivatives are used as pharmaceutical adjuvants, contributing to the development of safe and high bioavailability formulations. CDs have a unique structure with a variety of physicochemical features that aid pharmaceutical scientists in solving drug delivery issues for poorly water-soluble drugs (PWS). This article covers information about cyclodextrin and its various derivatives, its different manufacturing process, physicochemical properties, advantages, and recent advancements. There are various advantages of CD-based inclusion complexes, such as enhancement of solubility, bioavailability, and stability and reduction of irritation caused by the drug. Moreover, they are used as odor and taste enhancers and also prevent incompatibility by physically isolating the incompatible drug components in drug formulation. CD and its derivatives are extensively employed as solubilizers in the manufacturing of parenteral and oral dosage forms. Inclusion complexes formed by CDs with appropriately sized guest molecules improve drug water solubility, physical-chemical stability, and bioavailability. Simultaneously CDs prevent the drugs from degradation like oxidation, hydrolysis, and photodegradation and extend the shelf life of the drug. The manuscript also highlights patents and exclusive branded formulations of modified CDs. It also discusses the different examples of chemically modified CDs, i.e., captisol, sulfobutyl ether-ß-CD, hydroxy propyl betadex, randomly methylated ß-CD, methyl ß-CD, and hydoxy propyl γ-CD, all are used in the various dosage forms.

An Overview on Recent Patents and Technologies on Solid Dispersion.

The oral bioavailability enhancement of poorly water-soluble medicaments is still one of the most complicated aspects of the formulation development. Various approaches are currently available for solubility and rate of dissolution enhancement such as salt formation, solubilization and reduction of particle size, each with its own limitations and advantages. Solid dispersion is one of the most suitable approaches for the formulation development of poorly water-soluble drugs. The popularity of solid dispersion is evident from the increasing number of patent applications and patents granted in this field during recent years. This article reviews the various approaches for the preparation of solid dispersion such as a solvent melting, hot-melt extrusion method, solvent evaporation method, cryogenic processing approaches etc. from the perspective of patents filed or granted for these techniques. Some of the aspects taken into account before the preparation of solid dispersions are carrier selection and physicchemical testing along with an insight into the molecular arrangement of medicaments in solid dispersion. The manuscript further highlights various commercial patented technology platforms such as Solumertm, Hovione and Kinetisol which are based on the concept of solid dispersions.

Importance of the liposomal cationic lipid content and type in tumor vascular targeting: physicochemical characterization and in vitro studies using human primary and transformed endothelial cells.

Using cationic liposomes to deliver cytotoxic molecules to the tumor microvasculature is currently being developed for the treatment of cancer and other angiogenesis-related diseases. To improve on their beneficial properties, the authors have examined whether the particular cationic lipid type and lipid content employed are important factors influencing cellular interactions and formulation effects. The authors prepared different PEG (polyethylene glycol)-modified cationic liposomes (PCLs) with varying percent cationic lipid content and lipid type, and evaluated liposome size, surface charge (zeta) potential, and cellular properties in vitro. The cell lines used were human umbilical vein (HUVEC), lung microvascular (HMVEC-L and HPVE-26), coronary microvascular (HMVEC-C), dermal microvascular (HMVEC-D), and immortalized dermal microvascular (HMEC-1) endothelial cells. In vitro experiments consisted of cellular uptake and cytotoxicity studies, fluorescence-activated cell sorting (FACS) analysis, fluorescence, and transmission electron microscopic analysis. Liposome size and zeta potential analysis of five different PCLs revealed significant differences in their physicochemical properties. Some cationic lipids formed relatively toxic liposomes compared to others. The efficiency of loading chemotherapeutic drugs (doxorubicin hydrochloride, etoposide), affinity of PCLs for endothelial cells, and formulation effects varied according to cationic lipid content and the lipid type. Cellular uptake was observed in lung, dermal, and coronary endothelial cells. Heparan sulfate proteoglycans were found present on HMEC-1 cells, which may have enabled PCL uptake. In conclusion, physicochemical properties of cationic liposomes and their ability to interact with endothelial cells are important factors to consider during the early stages of formulation development for the treatment of cancer and other angiogenesis-dependent diseases.