Showing papers on "Drug carrier published in 1990"

New methods of drug delivery.

Abstract: Conventional forms of drug administration generally rely on pills, eye drops, ointments, and intravenous solutions. Recently, a number of novel drug delivery approaches have been developed. These approaches include drug modification by chemical means, drug entrapment in small vesicles that are injected into the bloodstream, and drug entrapment within pumps or polymeric materials that are placed in desired bodily compartments (for example, the eye or beneath the skin). These techniques have already led to delivery systems that improve human health, and continued research may revolutionize the way many drugs are delivered.

Characterization and Anticancer Activity of the Micelle-forming Polymeric Anticancer Drug Adriamycin-conjugated Poly(ethylene glycol)-Poly(aspartic acid) Block Copolymer

Abstract: Adriamycin (ADR), an anthracycline anticancer drug, was bound to the poly(aspartic acid) chain of poly(ethylene glycol)-poly(aspartic acid) block copolymer by amide bond formation between an amino group of Adriamycin and the carboxyl groups of the poly(aspartic acid) chain The polymeric drug thus obtained was observed to form a micelle structure possessing diameter of approximately 50 nm, with a narrow distribution, in phosphate-buffered saline and to show excellent water solubility despite a large amount of ADR introduction Further, it was able to be stored in lyophilized form without losing its water solubility in the redissolving procedure Increased stability of the bound Adriamycin molecules in phosphate-buffered saline and elimination of binding affinity for bovine serum albumin due to the micelle formation were further advantages of this polymeric drug In vivo high anticancer activity of this micelle-forming polymeric drug against P 388 mouse leukemia was obtained with less body weight loss than that seen with free ADR, due to low toxicity as compared with free ADR

Preparation, characterization, and properties of polylactide (PLA)–poly(ethylene glycol) (PEG) copolymers: A potential drug carrier

Abstract: Polylactide (PLA)-poly(ethylene glycol) (PEG) copolymers were synthesized from polyethylene glycol and D,L-lactide using low toxic stannous octoate as catalyst at 180°C by bulk polymerization. The copolymers were characterized by GPC, IR, and 13C-NMR. A full assignment NMR spectrum is presented. The physical, drug release, and biodegradable properties in vitro of PLA–PEG copolymers were investigated. The result indicates that the rates of drug release and biodegradation could be tailored by adjusting polymer composition. This amorphous material might be used as a drug carrier in medical applications.

Efficiency of cytoplasmic delivery by pH-sensitive liposomes to cells in culture.

Abstract: The intracellular processing of pH-sensitive liposomes composed of cholesterylhemisuccinate (CHEMS) and dioleoylphosphatidylethanolamine (DOPE) by eukaryotic cell lines has been compared to non-pH-sensitive liposomes made of CHEMS and dioleoylphosphatidylcholine (DOPC). The pH-sensitive liposomes can deliver encapsulated fluorescent molecules [calcein, fluoresceinated dextran, fluoresceinated polypeptide, and diphtheria toxin A chain (DTA)] into the cytoplasm. Cytoplasmic delivery can be blocked in the presence of ammonium chloride or EDTA, indicating that the process requires a low-pH environment and the presence of divalent cations. Inhibition of cellular protein synthesis by DTA delivery from the pH-sensitive liposome is orders of magnitude greater than from the non-pH-sensitive liposome composition. The delivery of DTA into the cytoplasm by pH-sensitive liposomes is at least 0.01% of cell-associated liposomal DTA. There is no significant difference in the degradation rate of bovine serum albumin (BSA) or the rate of acidification of pH-sensitive dye, 8-hydroxy-l,3,6-pyrene-trisulfonate (HPTS), when delivered to cells in pH-sensitive and non-pH-sensitive liposomes. Thus the efficiency of cytoplasmic delivery is less than 10% of the cell-associated liposome contents, which is the smallest difference that can be detected by these two assays. Based upon the various assays used to measure liposome content disposition in the cell, we conclude that the efficiency of cytoplasmic delivery by the CHEMS/DOPE liposomes is greater than 0.01% and less than 10% of the cell-associated liposomal contents.

A New Degradable Controlled Release Device for Treatment of Periodontal Disease: In Vitro Release Study

Abstract: The substantivity of a drug in the periodontal pocket is an important factor determining its effect on the subgingival flora. Therefore, one of the predominant factors in the development of a sustained release delivery device is the ability to control the rate of release of the drug. Previous studies have demonstrated the advantages of the local sustained release of chlorhexidine from nondegradable devices in the treatment of periodontal diseases. The aim of this study was to develop a degradable sustained release device composed of a cross-linked protein containing chlorhexidine as the therapeutic agent. The in vitro release profile of chlorhexidine from the degradable films was altered by the amount of chlorhexidine incorporated into the film, by the cross-link density of the polymer, and by the chlorhexidine salt used. The chlorhexidine in the final pharmaceutical preparation did not lose its antibacterial activity as was shown in an in vitro antibacterial test. This work demonstrates that the release of chlorhexidine from a degradable delivery system and the degradation of the matrix can be controlled by variation in the formulation. This presents a new dental drug delivery system that can be used as an adjunct in the treatment of periodontal diseases in the future. These studies enable us to choose the pharmaceutical formulations for clinical trials to be conducted testing the efficacy of this treatment modality.

Nebulization of liposomes. I. Effects of lipid composition.

Abstract: A series of multilamellar liposome dispersions was prepared from lipids of soy phosphatidylcholine or hydrogenated soy phosphatidylcholine containing from 0 to 30 mol% of either cholesterol, stearylamine, or dipalmitoyl phosphatidylglycerol. The liposome dispersions were aerosolized with a Collison nebulizer for 80 min at an output flow rate of 4.7 liters of air/min. The effects of nebulization on the vesicles were determined by monitoring the release of encapsulated 5,6-carboxylfluorescein (CF) from dispersions containing approximately 200 micrograms of total CF, of which 93.1 +/- 2.4% (N = 18) was initially encapsulated. In all experiments CF was released from the liposomes while being aerosolized, and this ranged from a mean of 12.7 +/- 3.8 to 60.9 +/- 1.9% of the encapsulated CF, depending upon the lipid composition. The lipid concentration in the dispersions did not affect the rate or percentage release of CF over a range of approximately 0.5 to 50 mg per nebulized dispersion. If liposomes are to be used as drug carriers in an inhalation aerosol a lipid composition should be employed which will minimize the release of encapsulated drug caused by nebulization.

Hepatic tissue distribution of doxorubicin-loaded nanoparticles after i.v. administration in reticulosarcoma M 5076 metastasis-bearing mice.

Abstract: In our previous studies, doxorubicin-loaded polyisohexylcyanoacrylate nanoparticles have been proven to increase dramatically the antitumoral activity of the cytotoxic agent in metastasis-bearing mice. The experimental model consisted of metastases induced by i.v. inoculation of reticulosarcoma M 5076 cell suspension to C57BL/6 mice. The improved efficacy of the drug was noted in terms of either metastasis count or survival. Therefore, tissue-distribution studies of this drug delivery system within the metastatic liver after i.v. administration were undertaken to gain more insight into the mechanism of action. Doxorubicin measurements in healthy hepatic or neoplastic tissue were carried out together with histological examinations using transmission electron microscopy. These results demonstrated the hepatic tissue to be an efficient reservoir of the drug when it was injected associated with nanoparticles. Accumulation of biodegradable nanoparticles with associated doxorubicin in Kupffer cells created a gradient of drug concentration for a massive and prolonged diffusion of the free drug towards the neoplastic tissue.

Optimization of topical therapy: partitioning of drugs into stratum corneum.

Abstract: To optimize a topical formulation for therapeutic effect generally implies that the flux of drug into the skin be maximized. This requirement means that the product of drug concentration in the vehicle (C v) and drug partition coefficient (PC) between stratum corneum (SC) and vehicle be as large as possible. While C v is a formulation variable which can be easily manipulated up to the drug's saturation solubility, PC is a parameter that is difficult to predict a priori. However, there is no question that an ability to evaluate PC would greatly facilitate the efficient screening of drugs and formulations. We have measured the SC/water and SC/isopropylmyristate (a model lipophilic vehicle) PCs of seven drugs: acitretin, progesterone, testosterone, diazepam, estradiol, hydrocortisone, and caffeine. SC/ water PCs were determined as a function of the following variables: (i) initial drug concentration in the vehicle, (ii) length of equilibrium, (iii) SC source and preparation technique, and (iv) SC delipidization. The data obtained were reproducible and physicochemically consistent, and they show that useful partitioning information from both aqueous and nonaqueous vehicles can be obtained with the biological tissue of greatest relevance. The SC/water PCs of the steroids were in reasonable agreement with previous measurements. A facile approach to an integral determinant of formulation optimization is suggested, therefore, by these observations.

Polymeric temperature sensitive drug carrier

Abstract: The drug carrier of this invention provides a temperature-sensitive polymer chemically bonded to a drug. The drug carrier is capable of releasing a drug continuously in the body. The drug carrier is a liquid when administered and becomes solid in the body, in which state it is capable of releasing a drug continuously. The drug carrier has a lower LCST than human body temperature.

Direct cerebrospinal fluid delivery of an antiretroviral agent using multivesicular liposomes

Abstract: The use of multivesicular liposomes for administration of antiviral agents into cerebrospinal fluid was explored in a Sprague-Dawley rat model. DDC (2',3'-dideoxycytidine) was encapsulated into multivesicular liposomes made from dioleoyl lecithin, dipalmitoyl phosphatidylglycerol, cholesterol, and triolein. The half-lives of drug leakage in human plasma and in 0.9% NaCl were 15 and 47 h, respectively. After intraventricular injection with a stereotaxic apparatus, DDC levels within the central nervous system decreased exponentially, with a half-life of 1.1 h for the unencapsulated DDC and 23 h for the liposome-encapsulated DDC. There were no abnormalities observed in the behavior of the rats. Encapsulation of a more hydrophilic antiviral agent is expected to increase the half-life even further. The results of this study offer the possibility of a practical intrathecal drug delivery for drugs that do not cross the blood-brain barrier.

Utility of 2-Hydroxypropyl-β-cyclodextrin in an Intramuscular Injectable Preparation of Nimodipine

Abstract: Possible utility of hydroxyalkylated beta-cyclodextrin (beta-CyD) derivatives as parenteral drug carriers was investigated, using nimodipine, a dihydropyridine derivative with calcium antagonistic action, as a model drug. The aqueous solubility of nimodipine increased linearly with increase in the concentration of hydroxyalkylated beta-CyDs, showing an AL-type phase solubility diagram. The stability constant of nimodipine--hydroxyalkylated beta-CyD complexes was in the order of 2,3-dihydroxypropyl-beta-CyD less than beta-CyD less than 2-hydroxyethyl-beta-CyD less than 3-hydroxypropyl-beta-CyD less than 2-hydroxypropyl-beta-CyD, and the solubilizing ability of the beta-CyDs was also in that order. The results of powder X-ray diffractometry and thermal analysis suggested 1:3 (guest:host) complex formation of nimodipine with 2-hydroxypropyl-beta-CyD in the solid state. The dissolution rate of nimodipine-2-hydroxypropyl-beta-CyD complex was much faster than that of the drug alone. Nimodipine-2-hydroxypropyl-beta-CyD complex gave higher plasma levels of the drug after intramuscular administration to rabbits, i.e., the area under the plasma concentration--time curve and the maximum plasma concentration of the complex were about 2.5 times higher than those of the drug alone. The muscular damage after the injection of nimodipine was reduced by the administration of the complexed form.

Anthracycline Antibiotics with High Liposome Entrapment: Structural Features and Biological Activity

Abstract: We evaluated the entrapment of 21 different water-insoluble aglycones or anthracycline antibiotics in multilamellar liposomes composed of dimyristoyl phosphatidyl choline and dimyristoyl phosphatidyl glycerol at a 7:3 molar ratio. The drug:lipid weight ratio was 1:15 to 1:50. The different analogues tested were modified at position 4 in the aglycone portion (4-demethoxy) and/or positions 2' (halo), 3' (hydroxy, acetoxy), or 4' (epi, acetoxy) in the sugar portion. The entrapment efficiency was assessed by measuring the amount of free drug remaining in the supernatant after centrifugation of the liposomes and by direct examination of the pellets by fluorescent microscopy. Optimal entrapment (greater than 98%) was observed with only four compounds: 4-demethoxyadriamycinone; 2'-iododaunorubicin; 4-demethoxydaunorubicin; and 2'-iodo-3'-hydroxy-4'-epi-4-demethoxydoxorubicin (Compound 22). All other compounds showed significant drug precipitation outside the multilamellar vesicles when observed by fluorescent microscopy. Compound 22, entrapped in liposomes, was evaluated in vivo against i.p. L-1210 leukemia by the i.p. route, and liver metastases of M5076 reticulosarcoma by the i.v. route. In both models, liposome-entrapped Compound 22 was more active than doxorubicin at the optimal dose [median survival (given in percentage) of treated to control animals was for L-1210, greater than 600 versus 212; for M5076, 200 versus 133]. 4-Demethoxy and 2'-iodo are structural modifications that markedly enhance the affinity of anthracycline antibiotics for lipid bilayers without compromising biological activity. These findings will serve as a guideline to obtain liposome-anthracycline preparations, with optimal formulation characteristics, enhanced tumor-targeting properties, and non-cross-resistance with doxorubicin.

The future of liposomal drug delivery.

Abstract: Liposomes are microvesicles composed of continuous bilayers of phospholipid surrounding an aqueous phase. They have been extensively used to deliver antibiotics, antifungal agents, and antiviral compounds for the treatment of animal model infections. Three rationales have been invoked to justify their use as carriers of anti-infectious agents: (i) passive targeting of compounds to the mononuclear phagocytic system for enhanced effects at this site; (ii) targeted drug delivery; and (iii) site-avoidance delivery, wherein the rate of transfer of drug to the toxic site(s) is reduced but not the drug transfer rate to the active site. All strategies result in an increase in the therapeutic index of the drug; however, to obtain optimal drug therapy the characteristics for a particular drug for site-specific delivery differ from those of site-avoidance delivery. Future developments that will permit a larger variety of agents to be delivered in liposomes include the development of fusogenic liposomes and of liposomes that avoid the reticuloendothelial system.

Review : Biodegradable Microcapsular Drug Delivery Systems: Manufacturing Methodology, Release Control and Targeting Prospects

Abstract: An overview of the subject of biodegradable microcapsular drug delivery systems is presented from a polymer chemist's viewpoint. Various polymerization and microencapsulation techniques (including emulsion polymerization, interfacial polycondensation, suspension crosslinking, coacer vation/phase separation and solvent evaporation/extraction) suitable for the preparation of biodegradable microcapsules based on proteins, polysaccharides, polyesters, polyamides, or cyanoacrylates are described. Drug release from biodegradable microcapsules is discussed, and examples are presented to illus trate how the rate of drug release can be controlled by adjusting parameters such as microcapsule size, porosity, and crosslinking. Prospects of site-specific chemotherapy by means of passive and active targeting of microcapsular drug carriers are also analyzed.

6-O-carboxymethyl-chitin(CM-chitin) as a drug carrier.

Abstract: Gel was prepared from 6-O-carboxymethyl-chitin (CM-chitin) by the addition of iron(III) chloride under mild conditions without any organic solvent. The optimal conditions for the gel formation were 15 to 30 mM iron(III) chloride and 0.5 to 0.8 degree of substitution in CM-chitin. The amounts of bovine serum albumin (BSA) and the anticancer drug doxorubicin (DOX) incorporated into CM-chitin gels were more than 80% and 30%, respectively under the conditions described above. The release of BSA or DOX from the gesl was observed to be increased by lysozyme digestion in a time-dependent manner. This result indicates that CM-chitin might prove useful as a carrier gel for the sustained release of drugs and cytokines, including vaccines.