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

Curcumin (diferuloylmethane) is a yellow pigment present in the spice turmeric (Curcuma longa) that has been associated with antioxidant, anti-inflammatory, anticancer, antiviral, and antibacterial activities as indicated by over 6,000 citations. In addition, over one hundred clinical studies have been carried out with curcumin. One of the major problems with curcumin is perceived to be the bioavailability. How curcumin should be delivered in vivo, how bioavailable is it, how well curcumin is absorbed and how it is metabolized, is the focus of this review. Various formulations of curcumin that are currently available are also discussed.

http://www.e-crt.org/upload/pdf/crt-46-2.pdf

Recent developments in delivery, bioavailability, absorption and metabolism of curcumin: The golden pigment from golden spice

Physical and chemical stability of drug nanoparticles

Nanocrystals: Industrially feasible multifunctional formulation technology for poorly soluble actives

State of the art of nanocrystals--special features, production, nanotoxicology aspects and intracellular delivery

Development of an oral rutin nanocrystal formulation.

Curcumin (CUR) has various pharmacological effects, but its extensive first-pass metabolism and short elimination half-life limit its bioavailability. Therefore, transdermal application has become a potential alternative to delivery CUR. To increase CUR solubility for the development of a transparent homogenous gel and also enhance the permeation rate of CUR into the skin, β-cyclodextrin–curcumin nanoparticle complex (BCD–CUR-N) was developed. CUR encapsulation efficiency was increased by raising the percentage of CUR to BCD up to 20%. The mean particle size of the best CUR loading formula was 156 nm. All evaluation data using infrared spectroscopy, Raman spectroscopy, powder X-ray diffractometry, differential thermal analysis and scanning electron microscopy confirmed the successful formation of the inclusion complex. BCD–CUR-N increased the CUR dissolution rate of 10-fold (p < 0.01). In addition, the improvement of CUR permeability acrossed skin model tissue was observed in gel containing the BCD–CUR-N and was about 1.8-fold when compared with the free CUR gel (p < 0.01). Overall, CUR in the form of the BCD–CUR-N improved the solubility further on the penetration of CUR.

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Molecular Inclusion Complex of Curcumin–β-Cyclodextrin Nanoparticle to Enhance Curcumin Skin Permeability from Hydrophilic Matrix Gel

Kinetic solubility and dissolution velocity of rutin nanocrystals.

The aim of this work is to develop a curcumin nanoemulsion for transdermal delivery. The incorporation of curcumin inside a nanoglobul should improve curcumin stability and permeability. A nanoemulsion was prepared by the self-nanoemulsification method, using an oil phase of glyceryl monooleate, Cremophor RH40 and polyethylene glycol 400. Evaluation of the nanoemulsion included analysis of particle size, polydispersity index, zeta potential, physical stability, Raman spectrum and morphology. In addition, the physical performance of the nanoemulsion in Viscolam AT 100P gel was studied. A modified vertical diffusion cell and shed snake skin of Python reticulatus were used to study the in vitro permeation of curcumin. A spontaneously formed stable nanoemulsion has a loading capacity of 350 mg curcumin/10 g of oil phase. The mean droplet diameter, polydispersity index and zeta potential of optimized nanoemulsion were 85.0 ± 1.5 nm, 0.18 ± 0.0 and −5.9 ± 0.3 mV, respectively. Curcumin in a nanoemulsion...

Curcumin nanoemulsion for transdermal application: formulation and evaluation.

Toxoplasmic encephalitis (TE) is the most common clinical manifestation of reactivated infection with Toxoplasma gondii in immunocompromised patients that is lethal if untreated. The combination of pyrimethamine plus sulfadiazine or clindamycin is the standard therapy for the treatment of TE, but these combinations are associated with hematologic toxicity and/or life-threatening allergic reactions. Therefore, alternative treatment options are needed. Atovaquone is safe and highly effective against T. gondii in vitro, but the oral micronized solution shows poor bioavailability. We synthesized atovaquone nanosuspensions (ANSs) coated with poloxamer 188 (P188) and sodium dodecyl sulfate (SDS) to improve oral bioavailability and passage through the blood-brain barrier (BBB). Coating of ANSs with SDS resulted in enhanced oral bioavailability and enhanced brain uptake of atovaquone compared to Wellvone(®) in murine models of acute and reactivated toxoplasmosis as measured by high performance liquid chromatography (HPLC). Parasite loads and inflammatory changes in brains of mice treated with SDS-coated ANS were significantly reduced compared to untreated controls and to Wellvone(®)-treated mice. In conclusion, nanosuspensions coated with SDS may ultimately lead to improvements in the treatment of TE and other cerebral diseases.

SDS-coated atovaquone nanosuspensions show improved therapeutic efficacy against experimental acquired and reactivated toxoplasmosis by improving passage of gastrointestinal and blood-brain barriers.

Rachmat Mauludin

Papers

Development of an oral rutin nanocrystal formulation.

Molecular Inclusion Complex of Curcumin–β-Cyclodextrin Nanoparticle to Enhance Curcumin Skin Permeability from Hydrophilic Matrix Gel

Kinetic solubility and dissolution velocity of rutin nanocrystals.

Curcumin nanoemulsion for transdermal application: formulation and evaluation.

SDS-coated atovaquone nanosuspensions show improved therapeutic efficacy against experimental acquired and reactivated toxoplasmosis by improving passage of gastrointestinal and blood-brain barriers.