Lipid Cubic Systems for Sustained and Controlled Delivery of Antihistamine Drugs.

Antihistamines are capable of blocking mediator responses in allergic reactions including allergic rhinitis and dermatological reactions. By incorporating various H1 receptor antagonists into a lipid cubic phase network, these active ingredients can be delivered locally over an extended period of time owing to the mucoadhesive nature of the system. Local delivery can avoid inducing unwanted side effects, often observed after systematic delivery. Lipid-based antihistamine delivery systems are shown here to exhibit prolonged release capabilities. In vitro drug dissolution studies investigated the extent and release rate of two model first-generation and two model second-generation H1 antagonist antihistamine drugs from two monoacyglycerol-derived lipid models. To optimize the formulation approach, the systems were characterized macroscopically and microscopically by small-angle X-ray scattering and polarized light to ascertain the mesophase accessed upon an incorporation of antihistamines of varying solubilities and size. The impact of encapsulating the antihistamine molecules on the degree of mucoadhesivity of the lipid cubic systems was investigated using multiparametric surface plasmon resonance. With the ultimate goal of developing therapies for the treatment of allergic reactions, the ability of the formulations to inhibit mediator release utilizing RBL-2H3 mast cells with the propensity to release histamine upon induction was explored, demonstrating no interference from the lipid excipient on the effectiveness of the antihistamine molecules.

Balanced lipase interactions for degradation-controlled paclitaxel release from lipid cubic phase formulations.

Lipid cubic phase (LCP) formulations enhance the intestinal solubility and bioavailability of hydrophobic drugs by reducing precipitation and facilitating their mass transport to the intestinal surface for absorption. LCPs with an ester linkage connecting the acyl chain to the glycerol backbone (monoacylglycerols), are susceptible to chemical digestion by several lipolytic enzymes including lipases, accelerating the release of hydrophobic agents from the lipid bilayers of the matrix. Unlike regular enzymes that transform soluble substrates, lipolytic enzymes act at the interface of water and insoluble lipid. Therefore, compounds that bind to this interface can enhance or inhibit the activity of enzymes to varying extent. Here, we explore how the lipolysis rate can be tuned by the interfacial interaction of porcine pancreatic lipase with monoolein LCPs containing a known lipase inhibitor, tetrahydrolipstatin. Release of the Biopharmaceutical Classification System (BCS) class IV drug, paclitaxel, from the inhibitor-modified LCP was examined in the presence of lipase and its effectors colipase and calcium. By combining experimental dynamic digestion studies, thermodynamic measurements and molecular dynamics simulations of the competitive inhibition of lipase by tetrahydrolipstatin, we reveal the role and mode of action of lipase effectors in creating a precisely-balanced degradation-controlled LCP release system for the poorly soluble paclitaxel drug.

Long acting injectables for therapeutic proteins.

Biotherapeutic development presents a myriad of challenges in relation to delivery, in particular for protein therapeutics. Protein delivery is complicated due to hydrophilicity, size, rate of degradation in vivo, low permeation through biological barriers, pH and temperature sensitivity, as well as the need to conserve its quaternary structure to retain function. To preserve therapeutic levels in vivo, proteins require frequent administration due to their short half-lives. Formulation strategies combining proteins with lipid carriers for parenteral administration show potential for improving bioavailability, while preserving protein activity and bypassing the mucosal barriers of the body. Encapsulating protein in long acting injectable delivery systems can improve therapeutic indices by prolonging and controlling protein release and reducing the need for repeat interventions. Two lyotropic crystal forming lipids, monoolein and phytantriol, have been formulated to produce lipidic cubic phases and assessed for their use as long acting protein eluting injectables. Three soluble proteins, cytochrome c, glyceraldehyde-3-phosphate dehydrogenase and aldehyde dehydrogenase and one membrane protein, cytochrome c oxidase, were incorporated into bulk cubic phase formulations of each lipid system to comparatively assess protein release kinetics. The activity of the soluble proteins was measured upon release from a phytantriol bulk cubic phase and phytantriol cubosomes, produced using a liquid precursor method.

Stent conditioned media for in vitro evaluation of hydrophobic stent coatings.

In vitro cell studies of hydrophobic drugs face difficulties associated with their low aqueous solubility. To study poorly soluble drugs in bio-relevant media, solubilizing agents are frequently used to make stock solutions before final reconstitution in media. This results in drug concentrations that are not representative of in vivo conditions and may pose adverse effects on cells' biological functions. This is especially true of typical hydrophobic stent coatings intended for vascular applications, where poor in vitro to in vivo correlation exists. To this end, a method for preparation of hydrophobic drug suspensions in bio-relevant media via stent conditioned media using paclitaxel (PTX) as a model drug is proposed. Since the drug is present as a suspension, this media was validated for its content uniformity and potency to induce formation of micronuclei, typical of cells undergoing prolonged mitotic arrest. Further, PTX uptake by endothelial cells was quantified and showed that the PTX stent conditioned media (at a theoretical concentration of 100 µM) suppressed cellular growth equivalent to the 0.1 µM DMSO dissolved PTX.

Modulating the release of pharmaceuticals from lipid cubic phases using a lipase inhibitor.

Lipid cubic phase formulations have gained recognition as potential controlled delivery systems for a range of active pharmaceutical and biological agents on account of their desirable physiochemical properties and ability to encapsulate both hydrophobic and hydrophilic molecules. The most widely studied lipid cubic systems are those of the monoacylglycerol lipid family. These formulations are susceptible to lipolysis by a variety of enzymes, including lipases and esterases, which attack the ester bond present on the lipid chain bridging the oleic acid component to the glycerol backbone. The release of poorly soluble molecules residing in the lipid membrane portions of the phase is limited by the breakdown of the matrix; thus, presenting a potential means for further controlling and sustaining the release of therapeutic agents by targeting the matrix stability and its rate of degradation. The aims of the present study were twofold: to evaluate an approach to regulate the rate of degradation of lipid cubic phase drug delivery systems by targeting the enzyme interactions responsible for their demise; and to study the subsequent drug release profiles from bulk lipid cubic gels using model drugs of contrasting hydrophobicity. Here, hybrid materials consisting of cubic phases with monoacylglycerol lipids of different chain lengths formulated with a potent lipase inhibitor tetrahydrolipstatin were designed. Modulation of the release of a hydrophobic model pharmaceutical, a clofazimine salt, was obtained by exploiting the matrices' enzyme-driven digestion. A stable cubic phase is described, displaying controlled degradation with at least a 4-fold improvement compared to the blank systems shown in inhibitor-containing cubic systems. Sustained release of the model hydrophobic pharmaceutical was studied over 30 days to highlight the advantage of incorporating an inhibitor into the cubic network to achieve tunable lipid release systems. This is done without negatively affecting the structure of the matrix itself, as shown by comprehensive small-angle x-ray scattering experiments.