DRUG DELIVERY

Lipogelosome and niogelosome drug formulations can offer controlled/sustained release and site-specific delivery.

ALL IMAGES COURTESY OF BY YEKTA OZER, PHD

Liposomes, Niosomes Could Improve Drug Delivery

They can prolong the time a drug spends at the target site

L iposomes and niosomes, which deliver drugs for the diagnosis or treatment of diseases, have been a popular scientific area in recent years. Phospholipids and nonionic surfactants are the main ingredients of liposomes and niosomes, respectively. The combination of liposomes or niosomes with gel-form lipogelosome or niogelosome complexes has generated a great deal of interest in the scientific community over the last decade.

The main obstacle to using liposomes is that they are rapidly cleared by macrophage cells in the circulatory system. Although there are several alternatives-such as steric stabilization or targeting to the tissue or organs to increase the residence time of liposomes in the circulatory system-this is still a problem.

Furthermore, the release of a drug might be more effective when it is applied locally than when it takes the systemic route. Researchers have shown by using a chemotherapeutic agent that release time can be longer when the agent is injected into the tumor after entrapment in gel.

In several studies, liposomes and polymeric materials have been combined in order to prolong the residence time of a drug at the target site. In this type of system, liposomes have been dispersed in the gel. The function of the polymer is to provide a matrix for the entrapment of liposomes, while the function of the liposome is to provide a reservoir for the controlled release of the drug.

Due to their phospholipids and surfactants, liposomes and niogelosomes contain lipidic ingredients. They are prepared with the dispersion of this lipidic phase in the polymer. For the formulation of lipogelosome and niogelosome combinations, several matrix materials-chitosan, collagen, alginate, alginate-polylysine, carboxy vinyl acid copolymers, poloxamer 407, and gelatin-were used. Reportedly, the type and the concentration of gel-forming agents have the most effect on the rheological properties and physical stability of the formulation.

Research has shown that liposomes are compatible with high molecular weight polymers like carbopols, which form during the cross-linking of methyl cellulose and acrylic acid with polyalkenyl ether. Carbopols are often preferred due to their ability to increase the residence time of the formulation at the application site, as well as for their bio-adhesive and viscosity enhancement properties. When carbopols come into contact with water, they have the ability to swell and form dispersions if they are in free acidic forms. When they react with bases, they form high viscosity gels at low concentrations. The rheological properties depend on the type and amount of the organic or inorganic bases reacted. It has been reported that the maximum viscosity can be obtained around the neutral pHs.

The compound's effect on the carboxylic group's ionization or the hydration stages of macromolecules (like electrolytes, alcohols, and polyalcohols) has been reported to play an important role in the viscosity of gels.

Still Some Difficulties

Although the entrapment of liposomes in gel and the evaluation of lipogelosome release profiles seem simple, there are still some difficulties that arise in promoting the liposome-gel combination. The most important of these is the tendency of polymers to interact with the liposomal surface. In order to prevent this interaction, specific functional groups can be added to the liposomal surface or the gel. For example, liposomes coated with polyethylene glycol (PEG) have been used to decrease the liposome/matrix polymer interaction. According to reports, the availability of PEG chains on the liposomal surface stabilizes the membrane by creating a polymeric barrier, blocking the interaction between the matrix polymer and the lipid.

Liposome-gel complexes (lipogelosomes) are, reportedly, the most preferable systems for prevention of bacterial adhesion to catheters, prolongation of antigen release for the enhancement of immunization, hormone transport, drug delivery system development for topical use, and prolongation of drug delivery to cell cultures.

The first lipogelosome drug delivery system was designed in our department and involved buccal application of dexamethasone sodium phosphate (DSP) lipogelosomes for the treatment of aphtous stomatitis in rats and human volunteers. DSP lipogelosomes successfully treated recurrent aphtous stomatitis when compared histopathologically to the commercial DSP ointment.

Because of problems in ocular drug delivery, researchers have developed new drug delivery systems that have depot effect and provide slow release. Previously, many studies have shown liposomes to be promising systems for ocular drug delivery. It has been shown, for example, that the pre-corneal residence time of ophthalmic solutions can be increased by viscosity enhancers. Given these results, researchers thought that an increase in the pre-corneal residence times might be valid for the vesicular systems; they dispersed tropicamide liposomes in polycarbofil gels and applied them topically to rabbits. When tropicamide lipogelosomes were compared with neutral liposomes, the residence time and effect of the drug substance were found to be considerably higher due to increased viscosity.

Lipogelosome and niogelosome formulations are promising drug delivery systems. The advantages for patients are easy application, controlled/sustained release, and site-specific delivery for drug substances.

Other researchers prepared lipogelosome formulations by dispersing liposomes in poloxamer 407 copolymer. After characterization studies, these preparations were found to have temperature sensitive and controlled release properties and are, therefore, very promising for ocular drug delivery.

In another study, topical lipogelo-some complexes were prepared with diclofenac sodium liposomes in Carbopol 934 gels. Lipogelosomes, lotion, and a commercial product (Voltaren Emulgel, Novartis) were compared; the former was found to be the most convenient for topical application.

Effect on NSAIDs

The chemical structure of ibuprofen. Lipogelosome formulation increased the epidural absorption of ibuprofen in vitro.

When non-steroidal anti-inflammatory drugs (NSAIDs) are applied topically in inflammatory arthritis, drug concentration in synovial liquid increases in comparison to the plasma drug concentration. According to researchers, if the drug is entrapped in a niosome drug delivery system, the active drug released from topically applied niosomes prevents the systemic effect to a great extent. This occurs because the drug directly penetrates the joint. In this research, an NSAID-nimesulide-was dispersed in Carbopol 940 gel; this niogelosome complex was topically applied to rats and compared with control gel formulation. According to the results, niogelosome complexes maintained the anti-inflammatory effect, increased the therapeutic index, and increased the concentration of the drug at the site of action, thus decreasing the side effects.

Other researchers have studied lipogelosomes and niogelosomes containing diclofenac sodium (DFNa) for the treatment of rheumatoid arthritis in rabbits. Depending on the scinti-graphic images, lipogelosomes were found to be the optimum formulation when compared with the commercial product. By applying this optimum lipogelosome formulation in lower doses intra-articularly, researchers found they could administer lower doses less frequently and still decrease rheumatoid arthritis inflammation.

The use of liposomal systems in the treatment of dermatological diseases has led researchers to believe they are good candidates for vaginal applications. The main problem with topical or vaginal liposomes is their liquidity and flowability. When researchers employed polyacrilate gels in order to facilitate liposomal stability, they observed an increase in vaginal drug delivery.

In addition, these systems have exhibited controlled or sustained release properties. Methyl nicotine (MN) absorption by the skin was investigated when applied MN liposomes were dispersed in Carbopol 934 P gel as lipogelosomes. The results led researchers to conclude that MN permeability is in proportion to the phospholipid's concentration, but not with the liposomal vesicle size and viscosity. In this research, MN change is not an important factor for dermal absorption.

For the treatment of aches and pains, ibuprofen lipogelosomes have been used via an epidural route. Because it is less toxic and has weak immunogenicity, poloxamer 407 was employed. Lipogelosome formulation increased the epidural absorption of ibuprofen in vitro.

Lipogelosome and niogelosome formulations are promising drug delivery systems. The advantages for patients are easy application, controlled/sustained release, and site-specific delivery for drug substances.