Injectable Drug Delivery System Research Articles

Injectable Supramolecular Hydrogels Self-Assembled by Polymers and Cyclodextrins for Controlled Drug Delivery

Of many polymeric biomaterials, hydrogels are of special importance because of their favorable biocompatibility and pertinence in delivering delicate bioactive agents such as proteins. Physical hydrogels have attracted much attention for controlled drug delivery because of the mild and aqueous conditions involved in trapping bioactive agents. This paper reviews our recent progress on developing a new class of physical hydrogels based on the supramolecular self-assembly between cyclodextrins and bioabsorbable poly(ethylene oxide) (PEO) or its copolymers. Being thixotropic, the hydrogels can be injected through needles and applied as injectable drug delivery systems. The properties of the hydrogels also can be fine-tuned with triblock copolymers where PEO segments flank hydrophobic or biodegradable segments in the middle.

Synthesis and Properties of Novel Poly(Hexyl-Substituted Lactides) for Pharmaceutical Applications

Monohexyl-substituted lactide (mHLA) was synthesized by reaction of 2-hydroxyoctanoic acid with 2-bromopropionyl bromide, and polymerized with tin(II) 2-ethylhexanoate (Sn(Oct)2) or 4-dimethylaminopyridine (DMAP) in the presence of benzyl alcohol by ring-opening polymerization (ROP). Poly(monohexyl-substituted lactide) (PmHLA) of predictable molecular weights and narrow polydispersities were obtained in convenient bulk conditions at 100 °C within short polymerization times. The polymerizations were well controlled, showing a 'living' character for targeted degrees of polymerization up to DP = 60 as evidenced by molecular weight versus conversion studies and 1H NMR end group analysis. The hexyl groups have a strong impact on the glass transition temperature (Tg), which is low for PmHLA compared to standard poly(D,L-lactide) (PLA). Tg and zero shear viscosities at 25 °C can be controlled by the polymer molecular weight, ranging from ?22 °C for Mn = 2800 g/mol to ?10 °C for Mn = 9100 g/mol and 140 to 4850 Pa.s, respectively. These data are in correspondence with the Fox and Flory equations. The degradation mechanism of the PmHLA polymer in phosphate buffer pH 7.4 at 37 °C was shown to be similar to that of the standard PLA ('bulk erosion' type), with a slightly higher degradation rate, leading to the non-toxic degradation products lactic acid and 2-hydroxyoctanoic acid. PmHLA has the great potential as an alternative to conventional PLA/PLGA for drug delivery systems. By the hexyl-substitution the biodegradable PLA-ester backbone is conserved but the hydrophobicity is increased in comparison to standard PLA, while a viscous polymer is obtained. This leads to advantageous injectable solvent-free drug delivery systems, in which drugs can easily be incorporated by simple mixing.

Injectable intrathecal delivery system for localized administration of EGF and FGF-2 to the injured rat spinal cord

The administration of growth factors (GFs) for treatment of experimental spinal cord injury (SCI) has shown limited benefits. One reason may be the mode of delivery to the injury site. We have developed a minimally invasive and safe drug delivery system (DDS) consisting of a highly concentrated collagen solution that can be injected intrathecally at the site of injury providing localized delivery of GFs. Using the injectable DDS, epidermal growth factor (EGF) and basic fibroblast growth factor (FGF-2) were co-delivered in the subarachnoid space of Sprague-Dawley rats. The in vivo distribution of EGF and FGF-2 in both injured and uninjured animals was monitored by immunohistochemistry. Although significant differences in the distribution of EGF and FGF-2 in the spinal cord were evident, localized delivery of the GFs resulted in significantly less cavitation at the lesion epicenter and for at least 720 mum caudal to it compared to control animals without the DDS. There was also significantly more white matter sparing at the lesion epicenter in animals receiving the GFs compared to control animals. Moreover, at 14 days post-injection, delivery of the GFs resulted in significantly greater ependymal cell proliferation in the central canal immediately rostral and caudal to the lesion edge compared to controls. These results demonstrate that the injectable DDS provides a new paradigm for localized delivery of bioactive therapeutic agents to the injured spinal cord.

Poly( d,l-lactide-ran- ε-caprolactone)-poly(ethylene glycol)-poly( d,l-lactide-ran- ε-caprolactone) as parenteral drug-delivery systems

P(DLAX-ran-CLY)n-b-PEG-b-P(DLAX-ran-CLY)ns (P(DLAX-ran-CLY)m: Poly(d,l-lactide-ran-epsilon-caprolactone), PEG: Poly(ethylene glycol), X: d,l-lactyl unit ratio, Y: epsilon-caproyl unit ratio, m : molecular weight of P(DLAX-ran-CLY)), were investigated as the novel parenteral drug-delivery system. The thermal behavior in the DSC characterization and variable viscosity with temperature suggest their potential usuage as a injectable drug-delivery system. The variation of tri-block structure affects the drug release behavior by changing the morphology and also by changing the interaction between the polymer matrix and the hydrophilic drug.

The effect of Pluronic on the protein release kinetics of an injectable drug delivery system

A new class of injectable controlled release depots has been prepared by incorporating materials that preferentially segregate during phase inversion. These consist of blends of poly(ethylene oxide) (PEO)/poly(propylene oxide) (PPO)/poly(ethylene oxide) (PEO) triblock copolymers (Pluronics) with poly(D,L-lactide) (PDLA)/1-methyl-2-pyrrolidinone (NMP) solutions. The effects of preferential segregation on the phase inversion dynamics and in vitro protein release kinetics were examined using dark ground imaging, high performance liquid chromatography (HPLC), scanning electron microscopy (SEM), and confocal microscopy. Variations in Pluronic concentration and molecular weight had an insignificant effect on the internal depot morphologies, however, increasing the concentration and molecular weight did result in increased phase separation rates and, surprisingly, a decrease in the magnitude of the protein burst, though the release profiles still retained a typical burst-type shape. Additionally, increasing the Pluronic concentration beyond a critical point resulted in a transition from a burst-type profile to an extended-release profile. An interpretation of these results in terms of a qualitative model for the protein release mechanism is also given.

Role of crystallization in the phase inversion dynamics and protein release kinetics of injectable drug delivery systems

The role of polymer crystallization in the phase inversion dynamics and in vitro protein release kinetics of semi-crystalline poly (epsilon-caprolactone) and amorphous poly (D,L-lactide) (PDLA) blend solutions has been examined using high performance liquid chromatography (HPLC), scanning electron microscopy (SEM), and differential scanning calorimetry (DSC) techniques. Varying the degree of crystallizability of the solutions led to the emergence of two general classes of depots. Depots with a high degree of crystallinity are characterized by porous morphologies indicative of solid-liquid (s--l) de-mixing and delayed burst release profiles. Alternatively, depots with a low degree of crystallinity are characterized by dense morphologies formed by mild liquid-liquid (l--l) phase separation and slow, uniform protein release rates. An interpretation of these results in terms of a qualitative model for the protein release mechanism is also given.

The Evaluation of the Efficacy of the Egg PC/HA/water Drug Delivery System

Background: Local anesthetics have been widely used to control postoperative pain and chronic pain. However, their usage in controlling long-lasting pain has been limited due to a relatively short duration of action. Many attempts have been made to develop a controlled release drug delivery system to provide long-lasting anesthesia. The goal of this study was to evaluate the histocompatibility and effectiveness of a new injectable lipid gel type drug delivery system (PHW, egg phosphatidylcholine/hyaluronic acid/water) using bupivacaine. Methods: Eighty-four male Sprague-Dawley rats were divided into 3 groups; 44 in the bupivacaine group, 20 in the PHW-bupivacaine (PHW-B) group, and 20 in the PHW group; and each drug mixture was injected in a 0.1 ml solution near the sciatic notch. Motor block was assessed by direct observation of motor skills to splay toes. Sensory block was assessed by measuring withdrawal response latencies to radiant heat using an analgesiameter. Gross and microscopic examinations on the sciatic nerve and surrounding muscle were performed for 3weeks after the injection. Results: Nerve block was significantly prolonged in the PHW-B group (190.0 ± 42.8 min) compared to the plain bupivacaine group (99.0 ± 30.5 min). There was no sign of nerve block in the PHW group. We observed moderate perimuscular inflammation in the PHW and PHW-B groups for the first 3 days. After 3 days, we did not observe inflammation of muscles and there was no sign of perineural inflammation. Conclusions: In conclusion, the histocompatibility of a bupivacaine incorporated PHW drug delivery system was satisfactory and the controlled releasing property of this drug delivery system was evaluated as effective. (Korean J Anesthesiol 2001; 40: 413∼419) ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ

Controlled release injectable liposomal gel of ibuprofen for epidural analgesia

The epidural administration is used commonly in the treatment of pain. Nonsteroidal anti-inflammatory drugs, especially ibuprofen, would have potential in epidural use. Like many epidurally useful drugs it, however, has a short duration of action, which is a limiting factor. To improve epidural pain treatment, a long-acting, single-dose gel injection is being developed. In the present study, the possibility of using liposomal systems to control the release and dural permeation of ibuprofen was investigated in vitro. Liposomal solutions of ibuprofen.Na (20 mg/ml) were prepared by high-pressure homogenization from egg phosphatidylcholine. The liposomal gel consisted of poloxamer 407 and the liposomal solution. No signs in the 1H-NMR spectroscopy of line broadenings or chemical shifts were observed. The liposomal formulations were reproducible and stable. Ibuprofen release in phosphate buffer, pH 7.4, at 37 degrees C from the liposomal solution and the liposomal gel were prolonged significantly compared with their respective solution and gel controls. The liposomal gel controlled ibuprofen release and dural permeation in vitro and showed a permeation pattern favourable for maintaining constant drug levels. The liposomal poloxamer gel represents a new formulation approach to increase the local epidural availability of ibuprofen. It appeared to be a promising injectable controlled-release drug delivery system.

New biodegradable polymers for injectable drug delivery systems

Many biodegradable polymers were used for drug delivery and some are successful for human application. There remains fabrication problems, such as difficult processability and limited organic solvent and irreproducible drug release kinetics. New star-shaped block copolymers, of which the typical molecular architecture is presented, results from their distinct solution properties, thermal properties and morphology. Their unique physical properties are due to the three-dimensional, hyperbranched molecular architecture and influence microsphere fabrication, drug release and degradation profiles. We recently synthesized thermosensitive biodegradable hydrogel consisting of polyethylene oxide and poly(L-lactic acid). Aqueous solution of these copolymers with proper combination of molecular weights exhibit temperature-dependent reversible sol-gel transition. Desired molecular arrangements provide unique behavior that sol (at low temperature) form gel (at body temperature). The use of these two biodegradable polymers have great advantages for sustained injectable drug delivery systems. The formulation is simple, which is totally free of organic solvent. In sol or aqueous solution state of this polymer solubilized hydrophobic drugs prior to form gel matrix.

Influence of irradiation sterilization on a semi-solid poly(ortho ester)

Viscous poly(ortho ester) (POE), a promising polymer for controlled release is being investigated as an injectable drug delivery system for peptides, for antiproliferative agents after glaucoma filtering surgery and for antibiotics in the treatment of periodontitis. Due to the chemical lability of POE, the strategies for obtaining a sterile product are limited to aseptic processing and terminal sterilization using high energy radiation. In the first part of the present investigation, we used electron-paramagnetic-resonance (EPR) spectroscopy to evaluate radical formation and radical-induced polymer degradation after irradiation treatment. Due to the viscous nature of POE, radicals were only found at low temperatures or by using the method of ‘spin-trapping’. Several radical species could be distinguished by a variation of the microwave power and the differences of the thermal stability of the radicals. The incorporation of 5-fluorouracil accelerates the degradation of the polymer. In the second part, we have compared the effects of the two commonly applied methods for irradiation sterilization (i.e. gamma and beta rays) on POE and on POE with incorporated 5-fluorouracil and compared these methods to aseptically prepared devices. In addition, we have checked the possibility of preventing radical-induced degradation using two different protecting agents: α-tocopherol at a concentration of 0.1% (w/w) and sterilization under nitrogen monoxide. The weight and number average molecular weight of POE decreased drastically after irradiation treatment and subsequent to irradiation, an accelerated degradation was observed. Generally it was found that higher molecular weight polymers are more affected and that gamma irradiation leads to more degradation than beta treatment. Also, the addition of protecting agents did not significantly prevent polymer degradation. Therefore, we have concluded that irradiation sterilization of POE is not a viable process and aseptic preparation is preferred. Without sterilization POE is stable for about 1 year when kept as monodoses at low temperatures.

O/W Lipid Emulsions for Parenteral Drug Delivery. III. Lipophilicity Necessary for Incorporation in Oil Particles Even After Intravenous Injection

The potential usefulness of oil-in-water (O/W) lipid emulsions as injectable drug delivery systems was examined. Plasma concentrations of oil particles after intravenous injection of a standard lipid emulsion composed of soybean oil and egg yolk phosphatides were monitored based on the plasma concentrations of phospholipids and triglycerides, and the light scattering intensity of the plasma. Their time profiles were similar to each other, and the oil particle size decreased time-dependently. Pretreatment with dextran sulfate, a known reticuloendothelial system (RES) suppressor, resulted in marked reduction of the plasma clearance of the oil particles and of the time-dependent alteration of oil particle size, suggesting that oil particles were trapped by RES. The lipophilicity of the drug needed for its incorporation in the oil particles even after intravenous injection was found to be clog P > 8, where clog P is the calculated logarithm of the partition coefficient between n-octanol and water. In the case of Sudan II (clog P = 5.4), the release from the oil particles was very quick after intravenous injection, resulting in slight alteration in biodistribution when compared with its micellar solution. In contrast, menatetrenone (clog P = 9.5) was selectively delivered to the liver, lungs and spleen, being consistent with the oil particles taken up by RES.

Phase Inversion Dynamics of PLGA Solutions Related to Drug Delivery

AbstractDark ground optical microscopy, electron microscopy, and protein release rate studies have been used to quantify the effects of formulation changes on the phase inversion dynamics and in vitro drug release properties of an injectable PLGA-based drug delivery system. Gel growth rates and water influx rates are determined from plots of the square of the respective front with time. Results show that additives that increase the solution gelation rate and produce finger-like void morphologies result in higher initial release rates. Conversely, additives that slow the rate of gelation dramatically reduce the initial drug release rate and lead to a more dense sponge-like morphology.

Biodegradable block copolymers as injectable drug-delivery systems.

Polymers that display a physicochemical response to stimuli are widely explored as potential drug-delivery systems. Stimuli studied to date include chemical substances and changes in temperature, pH and electric field. Homopolymers or copolymers of N-isopropylacrylamide and poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (known as poloxamers) are typical examples of thermosensitive polymers, but their use in drug delivery is problematic because they are toxic and non-biodegradable. Biodegradable polymers used for drug delivery to date have mostly been in the form of injectable microspheres or implant systems, which require complicated fabrication processes using organic solvents. Such systems have the disadvantage that the use of organic solvents can cause denaturation when protein drugs are to be encapsulated. Furthermore, the solid form requires surgical insertion, which often results in tissue irritation and damage. Here we report the synthesis of a thermosensitive, biodegradable hydrogel consisting of blocks of poly(ethylene oxide) and poly(L-lactic acid). Aqueous solutions of these copolymers exhibit temperature-dependent reversible gel-sol transitions. The hydrogel can be loaded with bioactive molecules in an aqueous phase at an elevated temperature (around 45 degrees C), where they form a sol. In this form, the polymer is injectable. On subcutaneous injection and subsequent rapid cooling to body temperature, the loaded copolymer forms a gel that can act as a sustained-release matrix for drugs.

Preparation and Characterization of Agarose Hydrogel Nanoparticles for Protein and Peptide Drug Delivery

ABSTRACTThe purpose of this work was to develop and characterize a protein and peptide injectable drug delivery system in agarose hydrogel nanoparticles. The nanoparticles were prepared by using a new emulsion-converted-to-suspension in situ method. This is an emulsifier-free method that has advantages for protein and peptide drug encapsulations. Ovalbumin, used as a model protein drug, was successfully encapsulated into nearly spherical agarose hydrogel nanoparticles under mild conditions. The nanoparticles possessed a log-normal size distribution with an average size of 504 nm. They imbibed a large amount of water (66.85% to 84.33%) and the water content was a function of temperature; the water content increased with increase in temperature. Release studies of the ovalbumin from the agarose hydrogel nanoparticles revealed a diffusion-controlled release mechanism with a temperature dependence; the ovalbumin release rate was higher at 37°C than that at room temperature. The great biocompatibility of agarose hydrogel, plus the mild conditions for drug encapsulation, make the agarose hydrogel nanoparticles a potential system for protein and peptide drug delivery.

Rifampicin carrying poly (D,L-lactide)/poly(ethylene glycol) microspheres: loading and release.

The aim of this study is to prepare rifampicin-loaded poly (D,L-lactide)/poly(ethylene golycol) (PDLLA/ PEG) copolymer microspheres as an injectable drug delivery system. PDLLA homopolymers with three different molecular weights (9,760, 14,540, and 23,050 daltons) were synthesized and then transesterified with PEG (with a molecular weight of approximately 3,300-4,000 daltons). By changing the ratio of PEG to PDLLA, block copolymers with different chain structures were synthesized. PDLLA and PDLLA/PEG microspheres in the size range of 2-10 microns were prepared by a modified solvent evaporation technique with the use of methylene chloride as the solvent and methyl cellulose as the emulsifier within the aqueous dispersion medium. Rifampicin was loaded within the microspheres during particle formation. Effects of the solvent/polymer and drug/polymer ratios, PDLLA molecular weight, and PEG content on drug loading and release were investigated. High drug loadings up to 100 mg rifampicin/g polymer were achieved. Both size and drug loadings were decreased by an increase in the solvent/polymer ratio and PEG content and by a decrease in the drug/polymer ratio and PDLLA molecular weight. High release rates were observed in the first 5 days after which constant and slow release rates were noted. Drug release was decreased by a decrease in the solvent/polymer ratio and PEG content and by an increase in the drug/polymer ratio and PDLLA molecular weight.

Intratumoral radioimmunotherapy of a human colon cancer xenograft using a sustained-release gel

Low tumor uptake and normal tissue toxicity limit the efficacy of RIT for the treatment of solid tumors. In this study, an intratumoral injectable gel drug delivery system for local administration of RIT was evaluated using the LS174T human colon cancer xenograft model in SCID mice. The injectable gel is a collagen-based drug delivery system designed for intratumoral (i.t.) administration, which has previously been shown to enhance drug retention at the injection site and reduce systemic drug exposure. We compared the local (tumor) retention and biodistribution of 111In-labeled NR-LU-10 monoclonal antibody given i.t. in the injectable gel versus simple aqueous solution. 111In gel given i.t. and 111In-NR-LU-10 given intraperitoneally (i.p.) were used as controls. The results showed that tumors treated with 111In-NR-LU-10 gel maintained the highest levels of radioactivity for up to 96 h. At 48 h after the administration of 111In-NR-LU-10 gel i.t., 111In-NR-LU-10 solution i.t., 111In gel i.t., or 111In-NR-LU-10 i.p., the level of radioactivity remaining in each gram of tumor was 98, 49, 45, and 16% of the injected dose, respectively. It was estimated that if 100 microCi of 90Y-NR-LU-10 were administered similarly, tumor treated with 90Y-NR-LU-10 gel i.t. would receive a dose of 90.0 Gy, whereas normal tissues in the same animal would receive a dose of approximately 2.43 Gy. In contrast, if 90Y-NR-LU-10 were delivered i.p., a comparable tumor would receive a dose of 16.8 Gy and corresponding normal tissues would receive 3.36 Gy. Consistent with these estimates, enhanced antitumor efficacy was observed when 90Y-NR-LU-10 gel was administered i.t. Tumor growth delay time was 6.9-fold (P < 0.01) longer in these animals (14.4 days) than in animals treated with 90Y-NR-LU-10 i.p. (2.1 days). Systemic toxicity was also significantly reduced in gel-treated animals as monitored by loss of body weight. This study demonstrated that intratumoral delivery of 90Y-NR-LU-10 gel markedly increased the retention of the radioisotope in tumors, enhanced the antitumor efficacy, and reduced systemic toxicity compared to systemic administration of the radiolabeled antibody. This injectable gel drug delivery system may allow for improvement in the therapeutic index for RIT.

O/W Lipid Emulsions for Parenteral Drug Delivery. II. Effect of Composition on Pharmacokinetics of Incorporated Drug

The potential usefulness of O/W lipid emulsions as injectable drug delivery systems for lipophilic drugs was examined using a model lipophilic drug, sudan II (clogP = 5.4) in the normal rats. The standard lipid emulsion composed of soybean oil and egg yolk phosphatides increased the blood concentration of sudan II after i.v. injection when compared with its solubilized solution by plasma. However, it was still lower than that of the oil particles, and the distribution of sudan II to liver, lungs, adipose tissue, heart, and muscle was not altered, and only that to brain and kidneys was decreased. Herein, the effect of extensive alterations in the lipid emulsion composition on the blood concentration and organ distribution of sudan II was examined in comparison with the standard formulation. Addition of cholesterol, use of pure egg yolk phosphatidylcholine, use of phospholipids with saturated alkyl chain, use of saturated long chain triglycerides, and use of saturated medium chain triglycerides were tested. The oil particles of all tested lipid emulsions were still located in plasma space, and use of saturated medium chain triglycerides was the most effective way to increase blood concentration of sudan II, resulting in higher distribution to liver, lungs, spleen, and brain. This was caused by the increase of the steady-state partition of sudan II to the oil particles, and not by alteration of their organ distribution clearance.

Tissue compatibility of poly (hydroxypropyl glutamate)-prazosin conjugates

Biocompatibility of an injectable biodegradable drug delivery system for prazosin was investigated in Sprague-Dawley rats by histological studies after subcutaneous injection ofpoly(hydroxypropyl glutamate)-prazosin (PHPG-prazosin) conjugate particles. The studies showed that (1) the acute inflammatory response to this injectable biodegradable polymeric prodrug system was mild and of only short duration, (2) the chronic inflammation was minimal to zero, (3) the fibrous capsule could be seen starting from 7 days and became more prominent at longer time periods, (4) a collagen network was formed into the injection site after 21 days, (5) the macrophages and foreign giant cells reacted to the globules of conjugate particles, and (6) no adverse reactions were identified. Focal inflammation and the formation of the fibrous capsule around the injection site were the significant histological findings in the histopathological studies. Therefore, it is concluded that the biodegradable injectable PHPG-prazosin carbamate polymeric prodrug system is tissue biocompatible.

Acute histopathological response to a new biodegradable polypeptidic polymer for implantable drug delivery system.

This article deals with the in vivo evaluation of a new class of synthetic polypeptides, the poly[(tert-butyloxycarbonylmethyl) glutamates], POMEG, as an injectable or implantable drug delivery system. Three different polymers, varying in their degree of esterification, were extruded either with or without progesterone, and finally implanted in rats up to 14 days. Histologic evaluation of the implant sites show evidence of the good biocompatibility of these polymers. In addition, the description of their in vivo behavior, based on microscopic observation of the implanted POMEG rods, enables one to appreciate their potential as a drug delivery system for short- or long-term therapy.

Use of liposomes as injectable-drug delivery systems

The formation of liposomes and their application as delivery systems for injectable drugs are described. Liposomes are microscopic vesicles composed of one or more lipid membranes surrounding discrete aqueous compartments. These vesicles can encapsulate water-soluble drugs in their aqueous spaces and lipid-soluble drugs within the membrane itself. Liposomes release their contents by interacting with cells in one of four ways: adsorption, endocytosis, lipid exchange, or fusion. Liposome-entrapped drugs are distributed within the body much differently than free drugs; when administered intravenously to healthy animals and humans, most of the injected vesicles accumulate in the liver, spleen, lungs, bone marrow, and lymph nodes. Liposomes also accumulate preferentially at the sites of inflammation and infection and in some solid tumors; however, the reason for this accumulation is not clear. Four major factors influence liposomes' in vivo behavior and biodistribution: (1) liposomes tend to leak if cholesterol is not included in the vesicle membrane, (2) small liposomes are cleared more slowly than large liposomes, (3) the half-life of a liposome increases as the lipid dose increases, and (4) charged liposomal systems are cleared more rapidly than uncharged systems. The most advanced application of liposome-based therapy is in the treatment of systemic fungal infections, especially with amphotericin B. Liposomes are also under investigation for treatment of neoplastic disorders. Liposomes' uses in cancer therapy include encapsulation of known antineoplastic agents such as doxorubicin and methotrexate, delivery of immune modulators such as N-acetylmuramyl-L-alanine-D-isoglutamine, and encapsulation of new chemical entities that are synthesized with lipophilic segments tailored for insertion into lipid bilayers. Liposomal formulations of injectable antimicrobial agents and antineoplastic agents already are undergoing clinical testing, and most probably will receive approval for marketing in the early 1990s. Liposomal encapsulation of drugs represents a new drug delivery system that appears to offer important therapeutic advantages over existing methods of drug delivery.