Robert Gurny

Mechanisms of solute release from porous hydrophilic polymers

Abstract Porous hydrophilic discs were prepared from two grades of poly(vinyl alcohol) of varying degree of hydrolysis. The influence of the molecular size of the tracer used (potassium chloride, phenylpropanolamine hydrochloride and bovine serum albumin), that of the addition of a second water-soluble polymer poly(N-vinyl-2-pyrrolidone) and poly(ethylene glycol)) and the effect of the tracer/excipient ratio on the release profile were examined. Finally the role of the dynamic swelling and the dissolution of the polymer matrix on the release mechanism are discussed.

Structure and interactions in covalently and ionically crosslinked chitosan hydrogels for biomedical applications.

This review presents a critical analysis of covalently and ionically crosslinked chitosan hydrogels and related networks for medical or pharmaceutical applications. The structural basis of these hydrogels is discussed with reference to the specific chemical interactions, which dictate gel formation. The synthesis and chemistry of these hydrogels is discussed using specific pharmaceutical examples. Covalent crosslinking leads to formation of hydrogels with a permanent network structure, since irreversible chemical links are formed. This type of linkage allows absorption of water and/or bioactive compounds without dissolution and permits drug release by diffusion. pH-controlled drug delivery is made possible by the addition of another polymer. Ionically crosslinked hydrogels are generally considered as biocompatible and well-tolerated. Their non-permanent network is formed by reversible links. Ionically crosslinked chitosan hydrogels exhibit a higher swelling sensitivity to pH changes compared to covalently crosslinked chitosan hydrogels. This extends their potential application, since dissolution can occur in extreme acidic or basic pH conditions.

Structure and interactions in chitosan hydrogels formed by complexation or aggregation for biomedical applications

The aim of this review was to provide a detailed overview of physical chitosan hydrogels and related networks formed by aggregation or complexation, which are intended for biomedical applications. The structural basis of these systems is discussed with particular emphasis on the network-forming interactions, the principles governing their formation and their physicochemical properties. An earlier review discussing crosslinked chitosan hydrogels highlighted the potential negative influence on biocompatibility of covalent crosslinkers and emphasised the need for alternative hydrogel systems. A possible means to avoid the use of covalent crosslinkers is to prepare physical chitosan hydrogels by direct interactions between polymeric chains, i.e. by complexation, e.g. polyelectrolyte complexes (PEC) and chitosan/poly (vinyl alcohol) (PVA) complexes, or by aggregation, e.g. grafted chitosan hydrogels. PEC exhibit a higher swelling sensitivity towards pH changes compared to covalently crosslinked chitosan hydrogels, which extends their potential application. Certain complexed polymers, such as glycosaminoglycans, can exhibit interesting intrinsic properties. Since PEC are formed by non-permanent networks, dissolution can occur. Chitosan/PVA complexes represent an interesting alternative for preparing biocompatible drug delivery systems if pH-controlled release is n/ot required. Grafted chitosan hydrogels are more complex to prepare and do not always improve biocompatibility compared to covalently crosslinked hydrogels, but can enhance certain intrinsic properties of chitosan such as bacteriostatic and wound-healing activity.

State of the art in the delivery of photosensitizers for photodynamic therapy

In photodynamic therapy, one of the problems limiting the use of many photosensitizers (PS) is the difficulty in preparing pharmaceutical formulations that enable their parenteral administration. Due to their low water solubility, the hydrophobic PS cannot be simply injected intravenously. Different strategies, including polymer-PS conjugation or encapsulation of the drug in colloidal carriers such as oil-dispersions, liposomes and polymeric particles, have been investigated. Although these colloidal carriers tend to accumulate selectively in tumour tissues, they are rapidly taken up by the mononuclear phagocytic system. In order to reduce this undesirable uptake by phagocytic cells, long-circulating carriers that consist of surface modified carriers have been developed. Moreover, considerable effort has been directed towards using other types of carriers to improve tumour targeting and to minimize the side effects. One of the approaches is to entrap PS into the lipophilic core of low-density lipoproteins (LDL) without altering their biological properties. The LDL receptor pathway is an important factor in the selective accumulation of PS in tumour tissue owing to the increased number of LDL receptors on the proliferating cell surface. Specific targeting can also be achieved by binding of monoclonal antibodies or specific tumour-seeking molecules to PS or by the coating of PS loaded carriers.

Chitosan: A Unique Polysaccharide for Drug Delivery

The aim of this review is to give an insight into the many potential applications of chitosan as a pharmaceutical drug carrier. The first part of this review concerns the principal uses of chitosan as an excipient in oral formulations (particularly as a direct tableting agent) and as a vehicle for parenteral drug delivery devices. The use of chitosan to manufacture sustained-release systems deliverable by other routes (nasal, ophthalmic, transdermal, and implantable devices) is discussed in the second part.

Poly(ortho esters): synthesis, characterization, properties and uses

Over the last 30 years, poly(ortho esters) have evolved through four families, designated as POE I, POE II, POE III and POE IV. Of these, only POE IV has been shown to have all the necessary attributes to allow commercialization, and such efforts are currently underway. Dominant among these attributes is synthesis versatility that allows the facile and reproducible production of polymers having the desired mechanical and thermal properties as well as desired erosion rates and drug release rates that can be varied from a few days to many months. Further, the polymer is stable at room temperature when stored under anhydrous conditions and undergoes an erosion process confined predominantly to the surface layers. Important consequences of surface erosion are controlled and concomitant drug release as well as the maintenance of an essentially neutral pH in the interior of the matrix because acidic hydrolysis products diffuse away from the device. Two physical forms of such polymers are under development. One form, solid materials, can be fabricated into shapes such as wafers, strands, or microspheres. The other form are injectable semi-solid materials that allow drug incorporation by a simple mixing at room temperature and without the use of solvents. GMP toxicology studies on one family of POE IV polymers has been concluded, an IND filed and Phase I clinical trials are in progress. Important applications under development are treatment of post-surgical pain, osteoarthritis and ophthalmic diseases as well as the delivery of proteins, including DNA. Block copolymers of poly(ortho ester) and poly(ethylene glycol) have been prepared and their use as a matrix for drug delivery and as micelles, primarily for tumor targeting, are being explored.

Topical use of chitosan in ophthalmology : tolerance assessment and evaluation of precorneal retention

The mucoadhesive polysaccharide chitosan was evaluated as a potential component in ophthalmic gels for enabling increased precorneal drug residence times. This cationic vehicle was expected to slow down drug elimination by the lacrymal flow both by increasing solution viscosity and by interacting with the negative charges of the mucus. The molecular weight (Mw) and concentration of polysaccharide were studied in four types of chitosan as parameters that might influence ocular tolerability and precorneal residence time of formulations containing tobramycin as therapeutic agent. An ocular irritation test, using confocal laser scanning ophthalmoscopy (CLSO) combined with corneal fluorescein staining, clearly demonstrated the excellent tolerance of chitosan after topical administration onto the corneal surface. Gamma scintigraphic data showed that the clearance of the formulations labelled with 99mTc-DTPA was significantly delayed in the presence of chitosan with respect to the commercial collyrium (Tobrex(R)), regardless of the concentration and of the molecular weight of chitosan in solution. At least a 3-fold increase of the corneal residence time was achieved in the presence of chitosan when compared to Tobrex(R).

Preparation and characterization of sterile and freeze-dried sub-200 nm nanoparticles

The feasibility of producing sterile and freeze-dried polyester nanoparticles was investigated. Various poly(D,L-lactide-co-glycolide) and poly(D,L-lactide) were selected as biodegradable polymers. Using the salting-out procedure, process parameters were optimized to obtain sub-200 nm particles. After purification, the nanoparticle suspensions containing different lyoprotectants were sterilized by filtration. Freeze-drying was performed using vials covered with 0.22 microm membrane filters in order to preserve the suspensions from bacterial contamination. Sterility was assessed on the final product according to pharmacopoeial requirements using the membrane filtration method. With all polymers tested, sub-200 nm particles could be obtained. Nanoparticles with a size as low as 102 nm were prepared with good reproducibility and narrow size distribution. Upon freeze-drying, it appeared that complete redispersion of all types of polyester nanoparticles could be obtained in presence of the lyoprotectants tested such as saccharides while aggregation was observed without lyoprotectant. Sterility testing showed no microbial contamination indicating that sterile nanoparticulate formulations have been achieved.

Biodegradable nanoparticles : From sustained release formulations to improved site specific drug delivery

Abstract Biodegradable poly( dl -lactic acid) nanoparticles (NP) produced by the salting-out process were evaluated in vitro and in vivo for their sustained release properties and their capacity to temporarily avoid the mononuclear phagocyte system (MPS). In vivo, NP loaded with neuroleptic compound savoxepine were able to provide sustained plasma levels after intramuscular and intravenous injection. Intramuscularly injected NP remained at the site of injection, whereas intravenously injected NP were located mostly in the MPS. The NP were successfully coated during the preparation procedure with PEG 6000 and PEG 20 000. In vitro, these coatings provided a protective barrier against extensive uptake by human monocytes, at least in plasma. Analysis of plasma proteins adsorbed on NP and in vitro experiments on isolated cells revealed some differences between the opsonization process of plain and coated NP. Plain and PEG 20000-coated NP loaded with photosensitizer hexafluoro zinc phthalocyanine were injected intravenously to mice bearing EMT-6 mouse mammary tumors. The protective coating produced a dramatic increase of the photosensitizer concentration in blood and tumor as well as a decrease in the MPS sequestration. These findings suggest that surface-modified NP should prove useful for the delivery of chemotherapeutic drugs to tumoral tissues.

Polymeric nano- and microparticles for the oral delivery of peptides and peptidomimetics

Due to recent advances, numerous bioactive peptides are now available in large quantities. Administering these substances by the oral route appears as a formidable challenge due to their insufficient stability in the gastrointestinal tract and their poor absorption pattern. Several approaches have been investigated to improve their oral bioavailability. Among them, the use of polymeric particulate delivery systems (microparticles and nanoparticles) represents a promising concept. Encapsulating or incorporating peptides in particles should at least protect these substances against degradation and, in some cases, also enhance their absorption. The aim of this paper is to review the principal studies where peptide-loaded particles were administered by the oral route. The preparation methods and in vitro trials are presented and in vivo results are discussed with emphasis placed on the peptide blood levels reached or on the biological effects observed. Whether or not intact particles can be taken up and translocated to the systemic circulation is not the aim of this review.