Interactions Between Biological Products and Product Packaging and Potential Approaches to Overcome Them.

Biological products such as protein-based biopharmaceuticals are playing an important role in the healthcare and pharmaceutical industry. The interaction between biological products and packaging materials has become the focus of many studies since it can reduce the effectiveness of biological products. These interactions are heavily influenced by the surface properties and physicochemical nature of the therapeutic agents and the packaging materials. Therefore, it is critical to understand the interactions between packaging materials and biological products in order to design biocompatible packaging materials and develop approaches to minimize adverse interactions. We describe the interactions that occur when using several common packaging materials, including glass and polymer. We discuss the interaction between these materials and biological products such as blood, blood derivatives, recombinant proteins, monoclonal antibodies, and gene therapeutics. We also summarize approaches for overcoming these interactions. Understanding the interactions between biological materials and packaging materials is critical for the development of novel packaging materials that improve the safety of pharmaceutical products.

Influence of process and formulation parameters on dissolution and stability characteristics of Kollidon® VA 64 hot-melt extrudates.

The objective of the present study was to investigate the effects of processing variables and formulation factors on the characteristics of hot-melt extrudates containing a copolymer (Kollidon® VA 64). Nifedipine was used as a model drug in all of the extrudates. Differential scanning calorimetry (DSC) was utilized on the physical mixtures and melts of varying drug-polymer concentrations to study their miscibility. The drug-polymer binary mixtures were studied for powder flow, drug release, and physical and chemical stabilities. The effects of moisture absorption on the content uniformity of the extrudates were also studied. Processing the materials at lower barrel temperatures (115-135°C) and higher screw speeds (50-100 rpm) exhibited higher post-processing drug content (~99-100%). DSC and X-ray diffraction studies confirmed that melt extrusion of drug-polymer mixtures led to the formation of solid dispersions. Interestingly, the extrusion process also enhanced the powder flow characteristics, which occurred irrespective of the drug load (up to 40% w/w). Moreover, the content uniformity of the extrudates, unlike the physical mixtures, was not sensitive to the amount of moisture absorbed. The extrusion conditions did not influence drug release from the extrudates; however, release was greatly affected by the drug loading. Additionally, the drug release from the physical mixture of nifedipine-Kollidon® VA 64 was significantly different when compared to the corresponding extrudates (f2 = 36.70). The extrudates exhibited both physical and chemical stabilities throughout the period of study. Overall, hot-melt extrusion technology in combination with Kollidon® VA 64 produced extrudates capable of higher drug loading, with enhanced flow characteristics, and excellent stability.

Development of taste masked caffeine citrate formulations utilizing hot melt extrusion technology and in vitro-in vivo evaluations.

The objective of this study was to develop caffeine citrate orally disintegrating tablet (ODT) formulations utilizing hot-melt extrusion technology and evaluate the ability of the formulation composition to mask the unpleasant bitter taste of the drug using in vitro and in vivo methods. Ethylcellulose, along with a suitable plasticizer, was used as a polymeric carrier. Pore forming agents were incorporated into the extruded matrix to enhance drug release. A modified screw configuration was applied to improve the extrusion processability and to preserve the crystallinity of the API. The milled extrudates were subjected to dissolution testing in an artificial salivary fluid and investigations using e-tongue, to assess the extent of masking of bitter taste of the API. There was an insignificant amount of drug released from the formulation in the salivary medium while over 80% of drug released within 30 min in 0.1N HCl. ODTs were also developed with the extrudate mixed with mannitol and crospovidone. The quality properties such as friability and disintegration time of the ODTs met the USP specifications. The lead extrudate formulations and the ODTs prepared using this formulation were subjected to human gustatory evaluation. The formulations were found to mask the unpleasant taste of caffeine citrate significantly.

Influence of cations on activated-sludge effluent quality.

Laboratory experiments and field tests were conducted to determine the effect of inorganic cations on effluent from activated-sludge systems. Laboratory experiments showed that monovalent cations tend to increase the concentration of solution biological polymers (biopolymers), whereas divalent cations tend to retain the biopolymers in the floc. Biopolymers in solution affect effluent chemical oxygen demand (COD). Coagulation tests were performed on the effluent with ferric chloride. Ferric hydroxide can coagulate protein through possible adsorptive interactions and may be responsible for some biopolymer retention in the flocs. In the field study, it was found that sodium ions in the influent wastewater caused an increase in proteins and polysaccharides in solution, thereby increasing the effluent COD concentration of the treated municipal wastewater. The attachment or release of these microbially derived organic biopolymers and recalcitrant influent substrate may depend on the monovalent-to-divalent cation ratio and the concentration of iron. Modeling of effluent organics in the activated-sludge process can be enhanced through incorporation of concepts that take into account the partitioning (between floc and solution) of microbial biopolymers and influent recalcitrant substrate.

Cytoplasmic remodeling of erythrocyte raft lipids during infection by the human malaria parasite Plasmodium falciparum.

Studies of detergent-resistant membrane (DRM) rafts in mature erythrocytes have facilitated identification of proteins that regulate formation of endovacuolar structures such as the parasitophorous vacuolar membrane (PVM) induced by the malaria parasite Plasmodium falciparum. However, analyses of raft lipids have remained elusive because detergents interfere with lipid detection. Here, we use primaquine to perturb the erythrocyte membrane and induce detergent-free buoyant vesicles, which are enriched in cholesterol and major raft proteins flotillin and stomatin and contain low levels of cytoskeleton, all characteristics of raft microdomains. Lipid mass spectrometry revealed that phosphatidylethanolamine and phosphatidylglycerol are depleted in endovesicles while phosphoinositides are highly enriched, suggesting raft-based endovesiculation can be achieved by simple (non-receptor-mediated) mechanical perturbation of the erythrocyte plasma membrane and results in sorting of inner leaflet phospholipids. Live-cell imaging of lipid-specific protein probes showed that phosphatidylinositol (4,5) bisphosphate (PIP(2)) is highly concentrated in primaquine-induced vesicles, confirming that it is an erythrocyte raft lipid. However, the malarial PVM lacks PIP(2), although another raft lipid, phosphatidylserine, is readily detected. Thus, different remodeling/sorting of cytoplasmic raft phospholipids may occur in distinct endovacuoles. Importantly, erythrocyte raft lipids recruited to the invasion junction by mechanical stimulation may be remodeled by the malaria parasite to establish blood-stage infection.

Formulation and evaluation of controlled-release transdermal patches of theophylline-salbutamol sulfate.

Transdermal formulations containing theophylline and salbutamol sulfate (SS) were formulated using hydroxypropylmethylcellulose. Theophylline was loaded by adsorption with the aid of the coadsorbate sodium chloride. The formulations were subjected to in vitro release studies, and the dose of salbutamol and theophylline was optimized to yield the desired flux. The films were uniform and 93 +/- 5.4 microm thick. The in vitro fluxes of theophylline and salbutamol sulfate from the formulation were 1.22 +/- 0.4 mg/h/cm2 and 13.36 +/- 1.02 microg/h/cm2, respectively. The formulation was subjected to pharmacodynamic studies in guinea pigs. The preconvulsive time (PCT) of guinea pigs increased significantly after 4 h, and the same was observed even after 24 h Pharmacokinetic studies were carried out in healthy human volunteers. Theophylline was analyzed in saliva, and salbutamol was analyzed in the blood plasma. The Tmax of the drugs was 3 h, and appreciable concentrations of the drugs above their MEC could be analyzed even after 12 h. The elimination half-life of the drugs was significantly prolonged compared to that for tablets. There were no signs of erythema or edema in the volunteers during observation for a period of 7 days.

Cross-linked polymers in the red cell membranes of a patient with Hb-Koln disease.

Membranes isolated from the red cells of a Hb-Koln patient were shown to contain appreciable amounts of N epsilon-(gamma-glutamyl)lysine, the characteristic product of the post-translational cross-linking of proteins by transglutaminase. Such an apparently irreversible fusion of membrane proteins may contribute to the membrane defect in Hb-Koln disease.