Protein Adsorption and Excipient Effects on Kinetic Stability of Silicone Oil Emulsions

Effects of added excipients on emulsion stability in the absence of protein. Increases in transmission are reflective of decreases in light scattering due to emulsion creaming. Circles denote excipient-free formulations; squares denote formulations containing 0.03% polysorbate 20; triangles denote formulations containing 150 mM NaCl; Xs denote formulations containing 500 mM sucrose.

The effect of silicone oil on the stability of therapeutic protein formulations is of concern in the biopharmaceutical industry as more proteins are stored and delivered in prefilled syringes. Prefilled syringes provide convenience for medical professionals and patients, but prolonged exposure of proteins to silicone oil within prefilled syringes may be problematic.

In this study, we characterize systems of silicone oil-in-aqueous buffer emulsions and model proteins in formulations containing surfactant, sodium chloride, or sucrose. For each of the formulations studied, silicone oil-induced loss of soluble protein, likely through protein adsorption onto the silicone oil droplet surface. Excipient addition affected both protein adsorption and emulsion stability. Addition of surfactant stabilized emulsions but decreased protein adsorption to silicone oil microdroplets.

In contrast, addition of sodium chloride increased protein adsorption and decreased emulsion stability. Silicone oil droplets with adsorbed lysozyme rapidly agglomerated and creamed out of suspension. This decrease in the kinetic stability of the emulsion is ascribed to surface charge neutralization and a bridging flocculation phenomenon and illustrates the need to investigate not only the effects of silicone oil on protein stability, but also the effects of protein formulation variables on emulsion stability. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1721-1733, 2010

Ludwig DB, Carpenter JF, Hamel JB, Randolph TW. Protein adsorption and excipient effects on kinetic stability of silicone oil emulsions. J Pharm Sci. 2010; 99:1721-1733. Correspondence to Theodore W. Randolph, University of Colorado, Center for Pharmaceutical Biotechnology, at theodore.randolph@colorado.edu or (303) 492-8592.

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Brain Delivery of Proteins by the Intranasal Route of Administration

Intranasally administered liposomal Alexa 488-OVAL (2 µg/µL, 25 µL) is taken up by cells in the substantia nigra by six hours after administration (80×). Scale bars = 10 µm.

The goal of this research was to evaluate the effectiveness of cationic liposomes for intranasal administration of proteins to the brain. Cationic liposomes were loaded with a model protein, ovalbumin (OVAL), and a 50 µg dose was administered intranasally to rats. In qualitative studies, liposomes were loaded with Alexa 488-OVAL and delivery was assessed by fluorescence microscopy.

By six and 24 hours after administration, Alexa 488-OVAL deposits were widely distributed throughout brain, with apparent cellular uptake in midbrain by six hours after administration. In quantitative studies, liposomes were loaded with 111In-OVAL, and distribution to brain and peripheral tissues was monitored by gamma counting at one, four, six, and 24 hours after administration. The highest brain concentrations were achieved at the shortest time point, one hour, for both liposomal and aqueous OVAL. However, the liposomes yielded higher 111In-OVAL concentrations in brain than 111In-OVAL in PBS.

Moreover, a 2 µg/µL form of liposomal OVAL yielded a higher percentage of dose in brain, and a lower percentage in stomach and intestines, than twice the volume of a 1 µg/µL preparation. Cationic liposomes may provide a novel, noninvasive strategy for delivery of neuroactive proteins to the brain for treatment of central nervous system disorders.

Migliore MM, Vyas TK, Campbell RB, Amiji MM, Waszczak BL. Brain delivery of proteins by the intranasal route of administration: A comparison of cationic liposomes versus aqueous solution formulations. J Pharm Sci. 2010; 99: 1745-1761. Correspondence to Barbara L. Waszczak, Department of Pharmaceutical Sciences, Northeastern University, at b.waszczak@neu.edu or (617) 373-3312.

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Development of Patch and Spray Formulations for Enhancing Topical Delivery

Effect of pH on (a) SMH concentrations in aqueous phase (black diamonds) and n-octanol phase (open squares) and (b) apparent partition coefficients of SMH.

The purpose of this work was to investigate feasibility of a promising topical drug delivery system for sinomenine hydrochloride (SMH), extracted from the Chinese medicinal plant sinomenine acutum and currently used for the treatment of rheumatoid arthritis. It was found that SMH was a weak base (pKa, 7.98 ± 0.04) with pH-dependent solubility and partition coefficient.

The result of in vitro permeation studies demonstrated that the permeation enhancer azone was the most effective. In contrast, spray had higher accumulative permeated amounts of SMH than patch, but permeated duration of spray was shorter than that of patch. The efficacy on Freund’s complete adjuvant-induced arthritis suggested that there was near arthritis index for SMH spray with medium dose (i.e., 15 mg/rat) and oral solution at a dose of 12 mg/rat, indicating that topical SMH delivery system could achieve the similar anti-inflammatory efficacy with oral administration.

Pharmacokinetic parameters including Cmax and AUC for both topical preparations were lower than those for oral preparation, which hinted that systemic side effects could be ignored. Therefore, the spray and patch were promising formulations for successful topical delivery of SMH through the skin instead of oral administration with side effects.

Li X, Li X, Zhou Y, Liu Y, et al. Development of patch and spray formulations for enhancing topical delivery of sinomenine hydrochloride. J Pharm Sci. 2010; 99:1790-1799. Correspondence to Yan Liu, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, at yanliu@bjmu.edu.cn or 86-10-82801508.

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Formulation Design and Photochemical Studies on Nanocrystal Solid Dispersion

Nanoemulsion formulation of curcumin. Transmission electron microscopic image of a nanoemulsion of curcumin suspended in water. Scale bar = 100 nm.

Considerable interest has been focused on curcumin due to its use to treat a wide variety of disorders. However, the therapeutic potential of curcumin could often be limited by its poor solubility, bioavailability, and photostability.

To overcome these drawbacks, efficacious formulations of curcumin, including nanocrystal solid dispersion (CSD-Cur), amorphous solid dispersion (ASD-Cur), and nanoemulsion (NE-Cur), were designed with the aim of improving physicochemical and pharmacokinetic properties. Physicochemical properties of the prepared formulations were characterized by scanning/transmission electron microscope for morphological analysis, laser diffraction, and dynamic light scattering for particle size analysis, and polarized light microscope, powder X-ray diffraction and differential scanning calorimetry for crystallinity assessment.

In dissolution tests, all curcumin formulations exhibited marked improvement in the dissolution behavior when compared with crystalline curcumin. Significant improvement in pharmacokinetic behavior was observed in the newly developed formulations, as evidenced by 12- (ASD-Cur), 16- (CSD-Cur), and nine-fold (NE-Cur) increase of oral bioavailability. Upon photochemical characterization, curcumin was found to be photoreactive and photodegradable in the solution state, possibly via type two photochemical reaction, whereas high photochemical stability was seen in the solid formulations, especially CSD-Cur.

On the basis of these observations, taken together with dissolution and pharmacokinetic behaviors, CSD strategy would be efficacious to enhance bioavailability of curcumin with high photochemical stability.