In VitroIn Vivo Studies

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The influence of three different enzymes (amylase, pepsin, and esterase) on the stability of polybutylcyanoacrylate nanoparticles was studied as an in vitro investigation using side-by-side diffusion cells [928]. In vitro resistance of tumor cells to doxorubicin was fully circumvented by using doxorubicin-loaded nanospheres, consisting of biodegradable polyisohexylcyanoacrylate polymers of 300 nm diameter and containing 2.83 mg of doxorubicin per 31.5 mg of polymer [929]. The in vitro release kinetic pattern of indomethacin from poly(D,L-lactide) nanocapsules was studied [930]. In vivo evaluation of polyisobutylcyanoacry-late microparticles containing fluorouracil was performed [931]. Effect on cerebral blood-flow, jejunal absorption, and pharmacological activity and pharmacokinetic evaluation of orally administered indomethacin-loaded poly-isobutylcyanoacrylate and poly(D,L-lactide) nanocapsules were investigated [932, 933]. The biliary clearance and enterohepatic circulation of indomethacin in the rabbit was examined [934]. Nanocapsules were used as carriers for oral peptide delivery [935].

Preparation methods of cyanoacrylic nanocapsules or nanoparticles containing phthalocyanines and naphthalocya-nines were described [936]. Nanocapsules were obtained by interfacial polymerization in an oil-in-water emulsion. Drug encapsulation efficiency depended on drug concentration, ethanol concentration, and phthalocyanine sulfonation degree and reached 100% in some cases.

Polylactic acid nanocapsules of clofibride containing soybean oil or medium-chain triglycerides as the oil core were prepared [937]. The in vitro drug release kinetic profiles were determined and compared to those of a clofibride submicron emulsion using two different kinetic techniques: the bulk equilibrium reverse dialysis sac technique and the centrifugal ultrafiltration technique.

The physical and chemical properties of tramcinolone acetonide nanocapsules, prepared by interfacial polymerization of isobutyl-2-cyanoacrylate at the oil/water interface, were studied [938]. The joint effect of monomer and oil in organic phase on the size and encapsulation efficiency was analyzed. Polymer coating around the oil droplets caused an important variation in droplet size and encapsulation efficiently. The release of drug from the nanocapsules was investigated in vitro.

A pharmaceutical form of atovaquone was developed and its activity against Toxoplasma gondii was studied in vitro and in vivo [939]. Nanocapsules were chosen as the oral dosage form of administration. The in vitro activity of atovaquone-loaded nanocapsules against tachyzoites of T.gondii (RH stain) was comparable to its suspension form. In vivo studies were carried out in murine models of acute and chronic toxoplasmosis. The sensibility of T.gondii to atovaquone was different according to the strains and the fact that the activity of atovaquone in the treatment of toxoplasmosis was enhanced when administered in nonoparticular form.

6.3.8. Reviews

The nanoparticles are colloidal polymeric drug carriers that hold promise for peroral drug delivery. The peroral administration of nanoparticles was reviewed [940]. Nanoparticles were retained in the gut of rats and mice in small quantities for substantial time periods (up to 6 days). They were taken up in particulate form in the intestine and appeared in the lymph nodes, blood, liver, spleen, and sites of inflammation in the body. Three possibilities in the mechanism of uptake were discussed: (1) intracellular uptake; (2) intercel-lular/paracellular uptake; and (3) uptake via the M-cells and Peyer's patches in the gut. The uptake was size-dependent; smaller particles were taken up to a higher degree than larger particles. Binding to nanoparticles enhanced the peroral bioavailability of a number of drugs, and a significantly enhanced and prolonged pharmacological activity by binding to nanoparticles was reported for insulin and hydrocortisone.

Nanoparticles and microparticles for the delivery of polypeptides and proteins [941, 942], and for ocular delivery [943] were reviewed. The main objective for these systems was to improve the classical aqueous eyedrop formulations that have major disadvantages like rapid elimination of drugs from the precorneal area. Consequently, colloidal carrier suspensions were designed to combine ophthalmic prolonged action with ease in application of liquid eyedrops. The review summarized the manufacturing methods and the materials used for these delivery systems with respect to ophthalmic purposes. The distribution and penetration pathways of the particulate delivery systems were described. The applications of drug-loaded particles were presented with focus on ophthalmic diseases like glaucoma, inflammations, or infections of the eye. Accordingly, particulate carriers, outlined in the review, included systems loaded with pilo-carpine, ^-blockers, hydrocortisone, amikacin, and miscellaneous drugs.

The applications of electron microscopic techniques to the characterization and evaluation of drug delivery systems were reviewed [944]. Various EM related techniques such as TEM, SEM, SEM with energy dispersive X-ray microanal-ysis, and freeze-fracture electron microscopy were extensively used for this purpose. Microcapsules, microspheres, nanocapsules, liposomes, polymeric carriers, and other drug delivery systems were characterized using EM related techniques for their surface topography, size and shape analysis, biodegradation, in vitro-in vivo evaluation, and drug excipient interactions and characterization. EM methods are very useful in understanding the mechanism of drug carrier formation, drug release in in vitro-in vivo situations, and drug carrier-body fluid interactions, and in studying ultrastructural disposition of drug carriers in body compartments.

A review focused on the gastrointestinal bioadhesion of micro- and nanoparticles [945]. Bioadhesion was obtained by the building of either nonspecific interactions with the mucosal surface, which were driven by the physicochemi-cal properties of the particles and the surfaces, or specific interactions when a ligand attached to the particle was used for the recognition and attachment to a specific site at the mucosal surface. The relative merits of those systems were discussed. Their fate in the gastrointestinal tract, including three different pathways, (i) bioadhesion, (ii) translocation through the mucosa, and (iii) transit and direct fecal elimination, was presented.

The techniques available to prepare biodegradable nano-particles (nanospheres and nanocapsules) from preformed polymers were reviewed [946]. Four techniques were discussed in terms of their technological advantages and drawbacks: emulsification evaporation, solvent displacement, salting-out, and emulsification diffusion. The proposed mechanism of nanoparticle formation for each technique was described from a physicochemical perspective. The effects of preparative variables on nanoparticle size and drug-entrapment efficiency were discussed.

Microparticulate delivery systems, potential drug/vaccine carriers for poorly bioavailable drugs and vaccines via mucosal (particularly oral) routes, were reviewed [947]. A variety of therapeutic moieties, including peptides and proteins, show enhanced oral uptake when entrapped within various types of microparticulate system constructs, and this approach was used successfully for the oral, nasal, and rectal delivery of a variety of vaccines. As drug-delivery technology becomes more sophisticated and our understanding of the uptake and immunological mechanisms of mucosal sites becomes more defined, many further microparticulate constructs would emerge and demonstrate their potential.

The contribution of Francis Puisieux and his group to one of the greatest challenges in pharmaceutical science, namely, the development of an oral dosage form for insulin, was reviewed [948]. This review traced their work with liposomes, multiple emulsions, and nanoparticles as insulin vehicles for oral delivery.

Steroid receptors and immunophilin relationships in hormone-dependent cancers, use of long-circulation anti-steroid hormone and/or immunosuppressant carriers as a promising therapeutic approach, were reviewed [949]. General aspects of nanocapsules used in drug delivery systems were reviewed from both a physicochemical and a therapeutic point of view [950]. The preparation methods, ways to characterize this o/w system (size, surface, density, release, stability), and the influence of encapsulation within nanocapsules on the biological activity of numerous drugs were described. Among the indications for the therapeutic use nanocapsules, one can cite solubilization of poorly water-soluble drugs, protection of drugs from inactivation in the gastrointestinal tract, protection of mucosa from the toxicity of drugs, increased permeation of drugs through mucosal surfaces, and prolongation of the blood circulation of injected drugs.

The use of colloidal carriers made of hydrophilic polysac-charides (i.e. chitosan) arose as a promising alternative for improving the transport of such macromolecules across biological surfaces. The approaches aiming to associate macromolecules to chitosan in the form of colloidal structures were reviewed and the evidence of their efficacy in improving the transport of the associated molecule through mucosae and epithelia was analyzed [951]. Chitosan was shown to form colloidal particles and entrap macro-molecules through a number of mechanisms, including ionic cross-linking, desolvation, or ionic complexation, though some of these systems were realized only in conjunction with DNA molecules. An alternative involving the chemical modification of chitosan was useful for the association of macromolecules to self-assemblies and vesicles. The in vivo efficacy of these chitosan-based colloidal carriers was reported for two different applications: while DNA-chitosan hybrid nanospheres were found to be acceptable transfec-tion carriers, ionically cross-linked chitosan nanoparticles appeared to be efficient vehicles for the transport of pep-tides across the nasal mucosa.

The progress in the development of biodegradable nanoparticulate systems, including nanospheres, emulsions, and liposomes, was reviewed [952]. The major purpose of lymphatic targeting was to provide an effective anticancer chemotherapy to prevent the metastasis of tumor cells by accumulating the drug in the regional lymph node via subcutaneous administration. The objectives of lymph targeting involved the localization of diagnostic agents to the regional lymph node to visualize the lymphatic vessels before surgery, and the improvement of peroral bioavailability of macromolecular drugs, like polypeptides or proteins. The in vivo study proved that polyisobutylcyanoacrylate nano-capsules showed enhanced accumulation of drug in the lymph node, compared with other carriers such as emulsions and liposomes.

Cyclosporin eyedrops allow local immunoregulation without systemic side effects and are an alternate to local steroids. Specific problems of product setup and clinical studies were reviewed [953]. The main problems in eye-drop preparation are sterility, pH, particles, and lipophilic properties. Numerous excipients were tested including oil solvents, alphacyclodextrin, collagen shields, liposomes, and polyester nanocapsules, but documentation on stability of the molecule was inadequate.

Acrylic nanoparticles for ocular drug delivery were developed [954]. The efficacy of ophthalmic drug delivery systems was governed by their ability to increase the ocular residence time. Several attempts were made to minimize the rapid and extensive precorneal loss of the administered drug. Besides the application of eyedrops with an enhanced viscosity, ocular inserts or soft contact lenses, and colloidal drug carriers, such as nanoparticles or nanocapsules as well as micro-spheres, were evaluated as ophthalmic delivery systems. In general, acrylic acid derivatives like polyalkyl cyanoacrylates and polyalkyl methacrylates were used for the preparation of drug carrier particles in the size range between 200 and 500 nm. That reviewed summarized the preparation methods of acrylic nanoparticles and their application in several in vitro and in vivo systems. The pharmacokinetic and phar-macodynamic effects after the application of drug-loaded nanoparticles to rabbit eyes were compared to conventional eyedrop preparations.

The nano/microparticles as drug delivery devices were reviewed [955]. The principal studies where peptide-loaded particles were administered by the oral route were reviewed [956]. The preparation methods and in vitro trials were presented and in vivo results were discussed with emphasis placed on the peptide blood levels reached or on the biological effects observed.

The advantages and disadvantages of the nanocapsules used in the drug delivery are as follows: There are many similarities between liposomes and nanoparticles. They are similar in size and thus are often used for similar purposes, and both have many advantages and disadvantages. Liposomes have the advantage of primarily consisting of lecithin and cholesterol, which are materials that occur naturally in the human body. Lecithin and cholesterol are also present in the body in large amounts and thus demand good bioac-ceptability. Nanoparticles or nanocapsules have the advantage of being more stable. Many types of drug targeting depend on good stability. A better penetration of the particles inside the body following administration, as well as longer shelf storage life, has several benefits of the good stability of nanoparticles. Artificial or natural polymers are the primary constituents of nanoparticles. Polymers are usually restricted by their bioacceptability. The bioacceptability is affected by the polymer and the supplementary components, as well as by particle size. A reduction in the particle size of the polymeric particles has many advantages: (1) Intravenous injection can be allowed if there is a decrease in the particle size. (2) Intramuscular and subcutaneous distribution require small particle size. (3) Irritant reactions at

Figure 26. Water-soluble polyelectrolyte nanocapsules prepared by use of vesicular polymerisation, which undergo a reversible swelling process on changing pH and/or salt concentration, mimicking certain biological processes. After [1035], M. Sauer and W. Meier, Chem. Commun. 1, 55 (2001). © 2001, Royal Society of Chemistry.

the injection site are minimized by using small particle size. (4) Cancerogenic effects depend on particle size. Choosing the appropriate polymer, particle size, and method of production would depend on three major aspects: bioac-ceptability of the polymer, physicochemical properties of the drug, and the type of therapy the drug should have. Recent advances and many other studies on drug delivery and controlled release are found in the literature [957-1034]. Figure 26 shows water-soluble polyelectrolyte nanocapsules prepared by use of vesicular polymerization, which undergo a reversible swelling process on changing pH and/or salt concentration, mimicking certain biological processes [1035].

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