Injectable Delivery System Research Articles

Liposomal sustained-release delivery systems for intravenous injection. II. Design of liposome carriers and blood disposition of lipophilic mitomycin C prodrug-bearing liposomes.

Various types of unilamellar liposomes possessing a narrow size distribution were prepared by controlled dialysis and their blood clearance was studied in mice and rats to assess their suitability as drug carriers for intravenously injectable liposomal sustained-release delivery systems. Also, the utility of these liposomal carrier systems combined with lipophilic prodrugs of mitomycin C (MMC) was evaluated. The fate of the liposomes was monitored uisng N-4-nitrobenzo-2-oxa-1, 3-diazole-dipalmitoylphosphatidylethanolamine (NBD-PE), a liposomal membrane marker. The effect of vesicle size on the blood clearance was investigated for neutral liposomes. Small-sized (S-) liposomes (90±15 nm) were cleared slowly compared with medium-sized (M-) liposomes (181±31 nm) and large-sized liposomes (281±38 nm). Surface charge was also an important determinant of the disposition of small-sized liposomes. S-Liposomes were retained in the circulation longer than positively (S+-) and negatively (S--) charged liposomes. The integrity of S-liposomes in the circulation was examined by simultaneous determination of NBD-PE and carboxyfluorescein (CF) entrapped in the liposomal membrane and liposomal aqueous phase, respectively. CF administered in the liposome-encapsulated form was cleared slowly in a fashion similar to NBD-PE, while free CF, administered as an aqueous solution, was rapidly removed from the circulation. These results reveal that S-liposomes show the best pharmacokinetic properties as a carrier vehicle for intravenously injectable sustained-release delivery systems. S-Liposomes loaded with the lipophilic MMC prodrug, N-(cholesteryloxycarbonyl)glycyl MMC or cholesteryloxyacetyl MMC, successfully gave sustained blood levels of the parent drug following intravenous injection. Thus, the potential utility of MMC prodrug-bearing S-liposomes as an intravenously injectable MMC sustained-release dosage form was demonstrated.

Liposomal sustained-release delivery systems for intravenous injection. III. Antitumor activity of lipophilic mitomycin C prodrug-bearing liposomes.

An intravenously injectable sustained-release delivery system for mitomycin C (MMC) was prepared by formulating a lipophilic MMC prodrug, N-(cholesteryloxycarbonyl)glycyl MMC (COCG-MMC), in unilamellar liposomes, and its blood disposition and antitumor activity were investigated in mice. Liposomes composed of egg phosphatidylcholine, egg sphingomyelin and COCG-MMC in a molar ratio of 7 : 3 : X (X=0-2.7) were prepared by the combination of controlled dialysis or sonication and sequential extrusion. All the preparations prepared by controlled dialysis showed a fairly narrow size distribution. After intavenous injection of COCG-MMC-bearing liposomes at a dose of 20 μmol/kg as a prodrug, the blood levels of regenerated MMC were maintained for the first 7 h in the range of 1.16 to 0.48 μM. In contrast, when an equimolar amount of MMC was given in an aqueous solution, MMC was rapidly cleared with little remaining in the circulation after 2 h. COCG-MMC exhibited significant cytotoxicity against P 388 leukemia in vitro and its activity was approximately one-third that of the parent drug. Prodrug-bearing liposomes inhibited the growth of subcutaneously-implanted Colon 26 adenocarcinoma and human mammary carcinoma MX-1 xenograft. Compared with MMC aqueous solution, prodrug-bearing liposomes showed reduced antitumor activity and reduced toxicity. In each tumor system, the body weight change differences (test minus controls), indices of host toxicity, at the ID50's (the doses which inhibit tumor growth to 50% of controls) showed no significant difference between these dosage forms. The results indicate that COCG-MMC-bearing liposomes successully maintain blood MMC levels over a prolonged period of time, but their therapeutic efficacy is almost equal to that of MMC aqueous solution.

Perspectives on root canal obturation with thermoplasticized injectable gutta-percha.

Summary. Perspectives on the clinical usage of a thermoplastic injection delivery system for guttapercha are presented. Areas which have been identified as problems in the clinical use of the technique and management of the system are highlighted. succinct guidelines for effective usage are presented along with cases typifying clinical achievement.

Physostigmine emulsion: a new injectable controlled release delivery system

Physostigmine salicylate was incorporated in a soybean injectable emulsion in an attempt to control the drug release from the emulsion. In vitro examination of the physicochemical properties of the emulsions revealed that a mixture of an anionic (phospholipid) and non-ionic surfactant (Pluronic) was required to prepare stable physostigmine emulsions. Variation in concentration of either the anionic or non-ionic emulsifier decreased the mean droplet size while the zeta potential did not show any clear correlation with increasing phospholipid concentration but decreased, reached a plateau and fell again with increasing Pluronic concentration. In the presence of physostigmine salicylate. instability was introduced which changed the profile of zeta potential dependency on phospholipids and Pluronic concentrations. Zeta potential increased with physostigmine concentration as a result of increasing ionization of various polar groups at the oil-water droplet interface. Moreover, physostigmine incorporated in the emulsion was protected from its aqueous decomposition and remained intact. Stable physostigmine emulsions preserved over long periods of time were obtained using appropriate experimental conditions probably as a result of optimization of effects due to surface potential increase, droplet size reduction and formation of a resistant close-packed interfacial mixed film. which confers steric stabilization to the dispersed droplets.

Preparation and evaluation in vitro and in vivo of fibrinogen microspheres containing adriamycin.

Fibrinogen microspheres containing adriamycin were prepared and eveluated as a novel drug delivery system. The shape of the microspheres was invariably spherical. The average diameters were 2.4 and 1.7 μm, and the drug contents in the microspheres were 10.2 and 9.9%, for the microspheres prepared at 110 and 140°C, respectively. Release of the drug from fibrinogen microspheres was slow, and the drug release continued over. 7 d. These results indicated that drug-loaded fibrinogen microspheres could provide a sustained release property in vitro.The antitumor activity of fibrinogen microspheres containing adriamycin was evaluated against Ehrlich ascites carcinoma in mice on the basis of animal survival data. Tumor cell injections were performed on day 0 and microsphere injections on day 1, both intraperitoneally. A prolongation of the life span of tumor-bearing mice following injection of therapeutic microspheres was noted, and the microspheres containing adriamycin were therapeutically more active than adriamycin alone. The high chemotherapeutic efficiency of fibrinogen-adriamycin microspheres was striking at high doses, which would be toxic in the case of the drug alone.These results indicated that fibrinogen microspheres containing adriamycin may be effective in cancer chemotherapy. Microspheres composed of fibrinogen show good biocompatibility and could be useful as a novel drug carrier in injectable delivery systems for anticancer agents.

Fibrinogen microspheres as novel drug delivery systems for antitumor drugs.

Fibrinogen microspheres containing 5-fluorouracil (5-FU) were prepared and evaluated as a novel drug delivery system. The shape of the microspheres was invariably spherical. The average diameters were 3.9 and 1.1 μm and the drug contents in the microspheres were 16.1 and 6.1%, for the microspheres prepared at 90 and 160°C, respectively. Release of the drug from fibrinogen microspheres was slow after the initial burst, and the drug release continued over 5d. These results indicated that the drug-loaded fibrinogen microspheres could be prepared providing a sustained release property in vitro. The antitumor activity of fibrinogen microspheres containing 5-FU was evaluated against Ehrlich ascites carcinoma in mice. The mean survival time of the group receiving the microspheres was larger than that of the control group, though essentially the same as that of the free 5-FU-treated group. Fibrinogen microspheres show good biocompatibility and should be useful as a novel drug carrier in injectable delivery systems for antitumor drugs.

Antitumor effect of fibrinogen microparticles containing adriamycin on Ehrlich ascites carcinoma in mice.

The antitumor activity of fibrinogen microparticles containing adriamycin against Ehrlich ascites carcinoma in mice was evaluated on the basis of animal survival data. Tumor cell injections were performed on day 0 and microparticle injections on day 1, both intraperitoneally. A prolongation of the life span of tumor-bearing mice following injection of therapeutic microparticles was noted, and the microparticles containing adriamycin were therapeutically more effective than adriamycin alone. The high chemotherapeutic efficiency of fibrinogen-adriamycin microparticles was striking at high doses which would be toxic in the case of the drug alone. These results indicated that fibrinogen microparticles containing adriamycin may be effective in cancer chemotherapy. Microparticles composed of fibrinogen could be a novel drug carrier for use in injectable delivery systems for anticancer agents.

An injectable biodegradable controlled release delivery system for LHRH analogues

An injectable biodegradable controlled release delivery system for LHRH analogues

A jacket for stimulating and recording from monkeys

A jacket is described which allows for attaching surface electrodes to the hands of relatively unrestrained monkeys. It may also be used for chronic electrical recording and injection delivery systems in monkeys where restraining chairs are objectionable and more freedom and movement is desired.

Automatic titrimetry: A simple apparatus for recording full scale potentiometric titrations

AbstractA simple apparatus is described for the recording of full scale potentiometric titrations. It consists of three essential parts: (1) an injection delivery system which delivers titrant at a definite rate; (2) a system indicating pH or e.m.f. change produced by the titrant and (3) a recorder. Examples are given of the use of the apparatus in conventional potentiometric titrations.