J. L. Grossiord

A Review of Poloxamer 407 Pharmaceutical and Pharmacological Characteristics

AbstractPoloxamer 407 copolymer (ethylene oxide and propylene oxide blocks) shows thermoreversible properties, which is of the utmost interest in optimising drug formulation (fluid state at room temperature facilitating administration and gel state above sol–gel transition temperature at body temperature promoting prolonged release of pharmacological agents). Pharmaceutical evaluation consists in determining the rheological behaviour (flow curve or oscillatory studies), sol–gel transition temperature, in vitro drug release using either synthetic or physiological membrane and (bio)adhesion characteristics. Poloxamer 407 formulations led to enhanced solubilisation of poorly water-soluble drugs and prolonged release profile for many galenic applications (e.g., oral, rectal, topical, ophthalmic, nasal and injectable preparations) but did not clearly show any relevant advantages when used alone. Combination with other excipients like Poloxamer 188 or mucoadhesive polymers promotes Poloxamer 407 action by optimising sol–gel transition temperature or increasing bioadhesive properties. Inclusion of liposomes or micro(nano)particles in Poloxamer 407 formulations offers interesting prospects, as well. Besides these promising data, Poloxamer 407 has been held responsible for lipidic profile alteration and possible renal toxicity, which compromises its development for parenteral applications. In addition, new findings have demonstrated immuno-modulation and cytotoxicity-promoting properties of Poloxamer 407 revealing significant pharmacological interest and, hence, human trials are in progress to specify these potential applications.

W/O/W multiple emulsions of insulin containing a protease inhibitor and an absorption enhancer: biological activity after oral administration to normal and diabetic rats

Abstract In this work, the biological effects of w/o/w multiple emulsions of medium-chain triglycerides containing sodium insulin alone or with a protease inhibitor, or with an absorption enhancer, or with a protease inhibitor and an absorption enhancer, were compared to a w/o/w multiple emulsion containing zinc insulin. The release mechanism of all multiple emulsions was the swelling–breakdown phenomenon after dilution of the emulsions under hypo-osmotic conditions. The biological effects after oral administration to normal and diabetics rats showed a larger decrease of glycemia with the multiple emulsions containing sodium insulin than with the multiple emulsion containing zinc insulin. However, there was no significant difference between the hypoglycemic effects induced by the emulsions containing sodium insulin. These results suggest that the aggregation state of insulin molecules might be the major factor responsible for increasing the extent of intestinal insulin absorption. Thus, the nature of the insulin plays a fundamental role and, at the concentration used in this work, the addition of sodium taurocholate was not able to modify its aggregation state in aqueous solution, as confirmed by circular dichroism studies.

Characterization of a new ocular delivery system based on a dispersion of liposomes in a thermosensitive gel

Abstract This paper describes a novel approach for designing an ocular delivery system based on the dispersion of liposomes into a thermosensitive gel made of a copolymer of ethylene oxide and propylene oxide (poloxamer 407). At high copolymer concentrations (20–30%), and from a temperature of approximately 20°C, poloxamer 407 passes from a solution to a gel. In order to stabilize liposomes in the gel, PEG2000-DSPE was introduced in their composition. Adsorption studies investigated by size and ζ-potential measurements have shown that the adsorption was higher for positively charged or neutral non-sterically stabilized liposomes. Poloxamer 407 adsorbed to a lower extent with negatively charged or PEG-DSPE containing liposomes. Furthermore, using a fluorescent aqueous marker, it was shown that liposome permeability was dramatically reduced in the presence of poloxamer 407 when PEG-DSPE was incorporated into the liposomes. This data suggests that poloxamer 407 could adsorb, at different extents, to all types of vesicles but that bilayer destabilization by the copolymer was reduced when liposomes were sterically stabilized. This was explained by the poor accessibility of the poloxamer to the phospholipidic which is the possible consequence of the steric repulsion effect induced by polyethylene glycol. Finally, it was shown that the thermosensitivity of poloxamer 407 was maintained after introducing the liposomes into the gel. In conclusion, a new system based on a dispersion of peggylated liposomes into thermosensitive poloxamer 407 is proposed, offering new potentialities for delivery of drugs.

Rheological study of a thermoreversible morphine gel

AbstractThe rheological behavior of a poloxamer 20% thermoreversible gel with morphine or without was studied. Its behavior was newtonian below the transition temperature and became non newtonian above this temperature. The non newtonian part was best fitted with the Herschel-Bulkley equation in comparison with the Casson equation. The sol-gel transition was associated with a drastic increment of the apparent viscosity and a brutal modification of the Herschel-Bulkley equation parameters. Likewise, the oscillatory parameters (the lag phase, the storage modulus and the loss modulus) revealed the great influence of the temperature on the viscoelastic properties of the sample. Different rheological methods have been described in order to determine the transition temperature usable for the control of preparations. The temperature interval corresponding to the sol-gel transition ranged between 22-25°C for the solution with morphine and between 23-26°C for the solution without. Thereby, the addition of morphine...

Influence of methyl-β-cyclodextrin and liposomes on rheological properties of Carbopol® 974P NF gels

The influence of positively-charged and sterically stabilized liposomes and/or methyl-beta-cyclodextrin on rheological properties of Carbopol 974P NF hydrogels was investigated. All formulations have displayed a shear-thinning behavior of Carbopol gels, and the rate stress as a function of the shear rate was fitted using the Cross equation. An important loss of viscosity was observed when 1.5% Carbopol gels were formed in Hepes/NaCl buffer or in a 5% aqueous solution of methyl-beta-cyclodextrin. Nevertheless, when methyl-beta-cyclodextrin was dissolved in buffer at 5% there was no additional effect on gel viscosity reduction. The incorporation of positively-charged and sterically stabilized liposomes at 2 mM of lipid concentration had no incidence on rheological properties of the Carbopol gels, whereas gel viscosity was significantly increased in the presence of positively-charged liposomes at 10 mM of lipid concentration. Finally, the viscosity of hydrogels containing both liposomes and methyl-beta-cyclodextrin tended to be close to control gels, remaining high and relevant for a topical delivery.

Elasticity and viscoelasticity of embolization microspheres.

The present study investigates the mechanical properties of three embolization microspheres (E-ms): tris-acryl gelatin microspheres (TG-ms), acrylamido polyvinyl alcohol microspheres (APVA-ms), and polyphosphazene-coated polymethylmethacrylate microspheres (PP-PMMA-ms). Compression and relaxation tests were performed on monolayers of particles and their Youngs moduli and relaxation half times (RHTs) were determined. The elasticity of E-ms was evaluated by applying Hertz theory with the assumptions of incompressibility and a Poissons ratio of 0.5. The Youngs moduli of TG-ms, APVA-ms, and PP-PMMA-ms were 39.6±5.05 kPa, 18.8±4.00 kPa, and 13.6±1.98 kPa, respectively. The RHTs of TG-ms, APVA-ms, and PP-PMMA-ms were 52.3±5.56 s, 59.1±8.16 s, and 31.0±7.01 s, respectively. TG-ms have a high rigidity and deform slightly under a sustained compression since they have a high elasticity. PP-PMMA-ms are soft and deform a lot under sustained compression. They are more viscous than the other two microspheres. APVA-ms have intermediate material properties, having the same low rigidity as PP-PMMA-ms and being more elastic than TG-ms.

Stability Study of W/O/W Viscosified Multiple Emulsions

Stable multiple emulsions with a small proportion of primary emulsion containing different viscosifying agents in the outer aqueous phase were formulated. The multiple systems were assessed by evaluating several parameters, such as the macroscopic aspect, droplet size, release rate, and accelerated stability under elevated temperatures. The effect of different viscosifying agents at different concentrations on the stability and the multiplicity of the multiple emulsions was examined. The viscosity increased by increasing the concentration of the viscosifying agents. It also appeared that the viscosifying agents increased the temperature stability of the multiple emulsions. As a result, the formulation viscosified with Klucel was more stable, while the one prepared with carbomer viscosified the outer phase at much lower concentrations with much better skin feel.

Properties of various thermoassociating polymers: pharmaceutical and cosmetic applications

This paper describes the main results obtained in our group on three thermoassociating polymers with interesting applications in the pharmaceutical and cosmetic fields. These three polymers are based on the poloxamer structure. The poloxamer macromolecules per se have interesting thermoassociating properties in aqueous solutions but they can also be integrated as sub-units in the design of more complex molecular architectures such as grafted poloxamers. The thermoassociating properties and the sol–gel transition of these three different systems were investigated in aqueous solutions mainly by rheology. The poloxamer gels were then assessed as in situ generated implants for the controlled release of vancomycin. They were also incorporated in more complex formulations containing liposomes to protect unstable actives such as antisense oligonucleotides. As regards the grafted poloxamers, a lower polymer concentration was required to induce the gelation. Moreover, the viscosity of these hydrogels remains high enough under shear rates that correspond to a topical application. These properties make them suitable for the formulation of multiple emulsions that can release an entrapped active molecule under shear when the formulation is topically applied.

Formulation of a charcoal suspension for intratumor injection. Part 1: Study of the nature, granulometry, and concentration.

AbstractPurpose. We developed a charcoal suspension formulation to be injected intratumorally so that human breast cancers can be tatooed prior to chemotherapy. This deposit is intended to guide the surgeon at the time of the biopsy and resection, especially when the tumor nodule is not visible. The stain should remain in the tumor as long as the patient is on chemotherapy and should be harmless. Methods. We studied on the effect on the nature of the charcoal, its granulometric profile, and its concentration. We then measured diffusion in vitro, in gel, and in vivo in experimental tumors. Results. The formulation selected was prepared with a peat charcoal suspension in water for parenteral injections, with 50% of the particles measuring on average between 2 and 5 μm. The finest particles (<2 μm) seem to produce the greatest in vitro diffusion and are more readily phagocyted by macrophages and thus eliminated from the tumor by those cells. Conclusions. This charcoal suspension has satisfactory formulation characteristics and diffuses the least, be it in vitro or in vivo, mainly due to the granulometric distribution of the suspension.

Beads made of alpha-cyclodextrin and vegetable oils: oil composition and physicochemical properties influence bead feasibility and properties

Beads made of alpha-cyclodextrin and soybean oil are an efficient system for the encapsulation of lipophilic drugs. In this work we investigated the impact of vegetable oil composition and physicochemical properties on bead feasibility and properties. Vegetable oils used in the formulation of dermatological medicines were selected. Beads were successfully formed using wheat germ and sweet almond oils. The oils which could be formulated as beads had low acid value and contained at least 99 % of triglycerides. Bead yield, crystalline organization and rheological behavior of these formulations were similar. Beads formed from soybean oil were larger than those from wheat germ and sweet almond oils due to some traces of triglyceride degradation products. Borage oil led only to a fluid mixture which did not evolve into beads. The acid value of this oil was high and total triglyceride content was 68 % demonstrating the presence of a significant amount of triglyceride degradation products. The rheological behavior and X-ray diffraction pattern of the borage oil-based formulation were different from the other oils. Beads can be successfully prepared with various vegetable oils without modifying the conditions optimized with soybean oil. However, triglyceride degradation products can either increase bead size or prevent their formation.