Antitumor activity of tumor necrosis factor-alpha conjugated with polyvinylpyrrolidone on solid tumors in mice.
We attempted the development of a novel polymer conjugation to further improve the therapeutic potency of antitumor cytokines compared with PEGylation for clinical application. Compared with native tumor necrosis factor (TNF)-alpha in vitro, specific bioactivities of polyvinyl-pyrrolidone (PVP)-modified TNF-alphas (PVP-TNF-alphas) were decreased by increasing the degree of PVP attachment. PVP-TNF-alpha fraction 3, Mr 101,000, had the most effective antitumor activity of the various PVP-TNF-alphas in vivo. PVP-TNF-alpha fraction 3 had >200-fold higher antitumor effect than native TNF-alpha, and the antitumor activity of PVP-TNF-alpha fraction 3 was >2-fold higher than that of MPEG-TNF-alpha (Mr 108,000), which had the highest antitumor activity among the polyethylene glycol (PEG)-conjugated TNF-alphas. Additionally, a high dose of native TNF-alpha induced toxic side effects such as body weight reduction, piloerection. and tissue inflammation, whereas no side effects were observed after i.v. administration of PVP-TNF-alpha fraction 3. The plasma half-life of PVP-TNF-alpha fraction 3 (360 min) was about 80- and 3-fold longer than those of native TNF-alpha (4.6 mm) and MPEG-TNF-alpha (122 min), respectively. The mechanism of increased antitumor effect in vivo caused the prolongation of plasma half-life and increase in stability. These results suggested that PVP is a useful polymeric modifier for bioconjugation of TNF-alpha to increase its antitumor potency, and multifunctionally bioconjugated TNF-alpha may be a potentiated antitumor agent for clinical use. (+info)
Influence of hydrogel bases on liberation rate and structural viscosity of potential drug XX Z.
Influences of cellulose derivatives (with and without additives of humectants) on two parameters, namely the liberation of the potential local anaesthetic XX Z and the structural viscosity of preparations were compared. The aim was to select a suitable base for topic application of the substance XX Z, chemically pyrrolidinoethylester of 3-heptyloxyphenylcarbamic acid. The rate of release of the substance XX Z from 2.5% methylcellulose base was higher then from 2% hydroxyethylcellulose base, and in both cases it was reduced after addition of humectants. It is concluded that among bases with additives of humectants is, for topic applications, more suitable the hydroxyethylcellulose base then methylcellulose base. (+info)
Another feature of TURP syndrome: hyperglycaemia and lactic acidosis caused by massive absorption of sorbitol.
Endoscopic transurethral resection of the prostate (TURP) can be complicated by absorption of a large volume of irrigation fluid. The clinical features of this complication are referred as the TURP syndrome. We report a case where hyperglycaemia and lactic acidosis complicated the TURP syndrome caused by the massive absorption (approximately 15 litres) of a sorbitol- mannitol irrigation solution. The proposed mechanism is a type B lactic acidosis related to the metabolism of sorbitol. (+info)
A new drug delivery system using plasma-irradiated pharmaceutical aids. VIII. Delayed-release of theophylline from double-compressed tablet composed of eudragit as wall material.
The rapid release from a double-compressed tablet containing theophylline as a core drug with the pH-dependent water-soluble polymers, Eudragit L100, S100 or L100-55 used as a wall material was suppressed by argon plasma-irradiation due to an effect of inter-segmental cross-link reactions on the decrease in the surface polymer solubility of outer layer. In addition, the rapid theophylline release from the double-compressed tablet of Eudragit L100-55 with a lower glass transition temperature (Tg) has converted into the delayed-release system under a set of plasma operational conditions due to an additional effect of plasma heat flux on softening of Eudragit L100-55 surface resulting in the formation of the film-like surface with a particle-particle interlinking of the outer layer. (+info)
Evaluation of the disintegration time of rapidly disintegrating tablets via a novel method utilizing a CCD camera.
Many kinds of rapidly disintegrating or oral disintegrating tablets (RDT) have been developed to improve the ease of tablet administration, especially for elderly and pediatric patients. In these cases, knowledge regarding disintegration behavior appears important with respect to the development of such a novel tablet. Ordinary disintegration testing, such as the Japanese Pharmacopoeia (JP) method, faces limitations with respect to the evaluation of rapid disintegration due to strong agitation. Therefore, we have developed a novel apparatus and method to determine the dissolution of the RDT. The novel device consists of a disintegrating bath and CCD camera interfaced with a personal computer equipped with motion capture and image analysis software. A newly developed RDT containing various types of binder was evaluated with this protocol. In this method, disintegration occurs in a mildly agitated medium, which allows differentiation of minor distinctions among RDTs of different formulations. Simultaneously, we were also able to detect qualitative information, i.e., morphological changes in the tablet during disintegration. This method is useful for the evaluation of the disintegration of RDT during pharmaceutical development, and also for quality control during production. (+info)
Release from or through a wax matrix system. IV. Generalized expression of the release process for a reservoir device tablet.
Generalization of the release process through the wax matrix layer was examined by use of a reservoir device tablet. The wax matrix layer of the reservoir device tablet was prepared from a physical mixture of lactose and hydrogenated castor oil to simplify the release properties. Release through the wax matrix layer showed zero-order kinetics in a steady state after a given lag time, and could be divided into two stages. The first stage was the formation process of water channel by dissolving the soluble component in the wax matrix layer. The lag time obtained by applying the square root law equation was well connected with the amount of the matrix layer and mixed weight ratio of components in this layer. The second stage was the zero-order release process of drug in the reservoir through the wax matrix layer, because the effective surface area was fixed. The release rate constants were connected with thickness of the matrix layer and permeability coefficient, and the permeability coefficients were connected with the diffusion coefficient of drug and porosity. Hence the release rate constant could be connected with the amount of matrix layer and the mixed weight ratio of components in the matrix layer. It was therefore suggested that the release process could be generalized using the amount of matrix layer and the mixed weight ratio of components in the matrix layer. (+info)
Physicochemical properties of PEG-grafted liposomes.
Egg phosphatidylcholine (EggPC) or dimyristoylphosphatidylcholine (DMPC) liposomes containing polyethylene glycol (PEG)-lipids covering a range of 0-30 mol% have been prepared by Extrusion method. The physicochemical properties including size evolution and calcein permeation were evaluated to investigate the effect of PEG-lipids on bilayer structure. The results from quasielasetic light scattering (QELS), freeze-fracture microscopy, and gel exclusion chromatography revealed that presence of low concentration of PEG-lipid results in decreasing of vesicle size and further increase in the PEG-lipid concentrations lead to a transition from the lamellar membranes to micelles. The permeability for calcein increased with increase in concentration of distearoylphosphatidylethanolamine (DSPE)-PEG. On the other hand, the permeability decreased with low amount of cholesterol-PEG (blow 20% cholesterol-PEG) and increased with high amount of it. The maximum concentration of PEG-lipid that may be incorporated without alteration of the liposome structure depends on the composition of the bilayer. The concentration of DSPE-PEG2000 incorporated into vesicles without damaging vesicle structures were <20 mol% for EggPC and <10% for DMPC. (+info)
Comparison of the formulation requirements of dosator and dosing disc automatic capsule filling machines.
The overall objective of this study was to provide 'semi-quantitative' or 'rigorous' definitions of the fluidity, lubricity and compactibility requirements of formulation for representative dosator and dosing disc capsule filling machines. To that end, model formulations were developed for those properties using Carr's compressibility index, ejection force, and plug breaking force at a specified compression force to gauge fluidity, lubricity, and compactibility, respectively. These formulations were each encapsulated on an Hofliger-Karg GKF-400 dosing disc machine and a Zanasi LZ-64 dosator machine. Each machine was instrumented to measure plug compression and ejection forces. The encapsulation process was evaluated for %CV of fill-weight, ejection force, plug breaking force and the dissolution of marker drugs incorporated in the formulations. The f2 metric was used to compare dissolution profiles. The results suggest: (1) formulations should meet different flow criteria for successful encapsulation on the two machines, (2) a relatively lower level of lubricant may be sufficient for the dosing disc machine, (3) a higher degree of formulation compactibility is needed for the dosator machine, and (4) transferring formulations between these machine types (same class, different subclass per FDA's SUPAC-IR/MR Manufacturing Equipment Addendum) could be challenging. In certain cases dissolution profiles for the same formulation filled on the two machines with equivalent compression force were different based on f2 < 50. Overall, the results of this study suggest a range of formulation characteristics appropriate for transferring formulations between these two types of machines. (+info)