Enhancing the Oral Absorption of Kinase Inhibitors Using Lipophilic Salts and Lipid-Based Formulations.

The absolute bioavailability of many small molecule kinase inhibitors (smKIs) is low. The reasons for low bioavailability are multifaceted and include constraints due to first pass metabolism and poor absorption. For smKIs where absorption limits oral bioavailability, low aqueous solubility and high lipophilicity, often in combination with high-dose requirements have been implicated in low and variable absorption, food-effects, and absorption-related drug-drug interactions. The current study has evaluated whether preparation of smKIs as lipophilic salts/ionic liquids in combination with coadministration with lipid-based formulations is able to enhance absorption for examples of this compound class. Lipophilic (docusate) salt forms of erlotinib, gefitinib, ceritinib, and cabozantinib (as example smKIs demonstrating low aqueous solubility and high lipophilicity) were prepared and isolated as workable powder solids. In each case, the lipophilic salt exhibited high and significantly enhanced solubility in lipidic excipients (>100 mg/g) when compared to the free base or commercial salt form. Isolation as the lipophilic salt facilitated smKI loading in model lipid-based formulations at high concentration, increased in vitro solubilization at gastric and intestinal pH and in some cases increased oral absorption (∼2-fold for cabozantinib formulations in rats). Application of a lipophilic salt approach can therefore facilitate the use of lipid-based formulations for examples of the smKI compound class where low solubility limits absorption and is a risk factor for increased variability due to food-effects.

pH-driven colloidal transformations based on the vasoactive drug nicergoline.

The structure of colloidal self-assembled drug delivery systems can be influenced by intermolecular interactions between drug and amphiphilic molecules, and is important to understand in the context of designing improved delivery systems. Controlling these structures can enable controlled or targeted release systems for poorly water-soluble drugs. Here we present the interaction of the hydrophobic vasoactive drug nicergoline with the internal structure of nanostructured emulsion particles based on the monoglyceride-water system. Addition of this drug leads to modification of the internal bicontinuous cubic structure to generate highly pH-responsive systems. The colloidal structures were characterized with small-angle X-ray scattering and visualized using cryogenic transmission electron microscopy. Reversible transformations to inverse micelles at high pH, vesicles at low pH, and the modification of the spacing of the bicontinuous cubic structure at intermediate pH were observed, and enabled the in situ determination of an apparent pKa for the drug in this system--a difficult task using solution-based approaches. The characterization of this phase behavior is also highly interesting for the design of pH-responsive controlled release systems for poorly water-soluble drug molecules.

Antimicrobial Activity from Colistin-Heparin Lamellar-Phase Complexes for the Coating of Biomedical Devices.

Infections arising in hospitalized patients, particularly those who have undergone surgery and are reliant on receiving treatment through biomedical devices, continue to be a rising concern. It is well-known that aqueous mixtures of oppositely charged surfactant and polymer molecules can self-assemble to form liquid crystalline structures, primarily via electrostatically driven interactions that have demonstrated great potential as tailored-release nanomaterials. Colistin is a re-emerging antibiotic used against multidrug-resistant Gram-negative bacteria. Its amphiphilic structure allows it to form micellar aggregates in solution. Thus, the aim of this study was to determine whether structured complexes form between colistin and negatively charged biopolymers, such as the highly sulfated anticoagulant, heparin. Cross-polarized light microscopy and synchrotron small-angle X-ray scattering were employed to visualize the appearance of birefringent structures and identify liquid crystalline structures, respectively, formed across the interface between solutions of colistin and heparin. A lamellar phase with a lattice parameter of ∼40 Šwas formed upon contact between the oppositely charged solutions of colistin and heparin. In addition, in vitro release studies showed a slow release of colistin from the lamellar-phase gel complexes into the bulk media, and disk diffusion bioassays revealed antimicrobial activity against Pseudomonas aeruginosa. This system provides a novel, cost-effective, and simple approach to reducing the risk of infections by potentially applying the formulation as a coating for biomedical implants or tubing.

Confectionery-based dose forms.

Conventional dosage forms such as tablets, capsules and syrups are prescribed in the normal course of practice. However, concerns about patient preferences and market demands have given rise to the exploration of novel unconventional dosage forms. Among these, confectionery-based dose forms have strong potential to overcome compliance problems. This report will review the availability of these unconventional dose forms used in treating the oral cavity and for systemic drug delivery, with a focus on medicated chewing gums, medicated lollipops, and oral bioadhesive devices. The aim is to stimulate increased interest in the opportunities for innovative new products that are available to formulators in this field, particularly for atypical patient populations.

Controlling the Mesostructure Formation within the Shell of Novel Cubic/Hexagonal Phase Cetyltrimethylammonium Bromide-Poly(acrylamide-acrylic acid) Capsules for pH Stimulated Release.

The self-assembly of ordered structures in mixtures of oppositely charged surfactant and polymer systems has been exploited in various cleaning and pharmaceutical applications and continue to attract much interest since their discovery in the late twentieth century. The ability to control the electrostatic and hydrophobic interactions that dictate the formation of liquid crystalline phases in these systems is advantageous in manipulation of structure and rendering them responsive to external stimuli. Nanostructured capsules comprised of the cationic surfactant, cetyltrimethylammonium bromide (CTAB), and the diblock copolymer poly(acrylamide-acrylic acid) (PAAm-AA) were prepared to assess their potential as pH responsive nanomaterials. Crossed-polarizing light microscopy (CPLM) and small-angle X-ray scattering (SAXS) identified coexisting Pm3n cubic and hexagonal phases at the surfactant-polymer interface. The hydrophobic and electrostatic interactions between the oppositely charged components were studied by varying temperature and solution pH, respectively, and were found to influence the liquid crystalline nanostructure formed. The lattice parameter of the mesophases and the fraction of cubic phase in the system decreased upon heating. Acidic conditions resulted in the loss of the highly ordered structures due to protonation of the carboxylic acid group, and subsequent reduction of attractive forces previously present between the oppositely charged molecules. The rate of release of the model hydrophilic drug, Rhodamine B (RhB), from nanostructured macro-sized capsules significantly increased when the pH of the solution was adjusted from pH 7 to pH 2. This allowed for immediate release of the compound of interest "on demand", opening new options for structured materials with increased functionality over typical layer-by-layer capsules.

Formation of liquid-crystalline structures in the bile salt-chitosan system and triggered release from lamellar phase bile salt-chitosan capsules.

Nanostructured capsules comprised of the anionic bile salt, sodium taurodeoxycholate (STDC), and the biocompatible cationic polymer, chitosan, were prepared to assess their potential as novel tailored release nanomaterials. For comparison, a previously studied system, sodium dodecyl sulfate (SDS), and polydiallyldimethylammonium chloride (polyDADMAC) was also investigated. Crossed-polarizing light microscopy (CPLM) and small-angle X-ray scattering (SAXS) identified the presence of lamellar and hexagonal phase at the surfactant-polymer interface of the respective systems. The hydrophobic and electrostatic interactions between the oppositely charged components were studied by varying temperature and salt concentration, respectively, and were found to influence the liquid-crystalline nanostructure formed. The hexagonal phase persisted at high temperatures, however the lamellar phase structure was lost above ca. 45 °C. Both mesophases were found to dissociate upon addition of 4% NaCl solution. The rate of release of the model hydrophilic drug, Rhodamine B (RhB), from the lamellar phase significantly increased in response to changes in the solution conditions studied, suggesting that modulating the drug release from these bile salt-chitosan capsules is readily achieved. In contrast, release from the hexagonal phase capsules had no appreciable response to the stimuli applied. These findings provide a platform for these oppositely charged surfactant and polymer systems to function as stimuli-responsive or sustained-release drug delivery systems.

Novel spiropyran amphiphiles and their application as light-responsive liquid crystalline components.

Light-responsive materials formed by liquid crystalline lipids in water have potential application to drug delivery through inclusion of photochromic additives such as spiropyran. A series of novel analogues of spiropyran (SP) have been synthesized with an SP headgroup that possess a C8 (SP-OC), C12 (SP-L), and C16 (SP-P) tail to probe the influence of the length of the hydrophobic tail on their physicochemical properties and effect on behavior in liquid crystal matrices with a view to application as stimulus-responsive elements on ultraviolet irradiation. In addition, compounds possessing an oleyl (SP-OL) and phytanyl (SP-PHYT) tail, to mimic those of the "parent" reverse bicontinuous cubic (V2) phase forming lipids, glyceryl monooleate (GMO) and phytantriol, were also prepared. The photochromic compounds were characterized by their melting points and photophysical behavior in solution using techniques including hot stage microscopy (HSM), differential scanning calorimetry (DSC), and UV-visible spectroscopy. Their effect on the equilibrium nanostructure of bulk V2 phases and phase-switching kinetics after exposure to UV light was assessed using small-angle X-ray scattering (SAXS). The melting point of the SP derivatives decreased linearly with increasing chain length, which suggests that interactions between the head groups governed their melting point, rather than the van der Waals interactions between the tails. Changing the R group did not influence the equilibrium rate constants for the isomerization of SP. Phase transition temperatures of liquid crystalline (LC) matrices were influenced significantly by incorporation of the SP derivatives and were greatest when the photochromic compound possessed an intermediate tail length substituent compared to the short alkyl or bulkier moieties. The level of disruption of lipid packing, and hence phase structure, were dependent on the duration of UV exposure.