Johan Carlfors

Rheological evaluation of poloxamer as an in situ gel for ophthalmic use

The contact time of a vehicle on the cornea is of utmost importance for ocular drug delivery. In the present study rheological measurements were performed to study the gel and the sol-gel transition of an in situ gel, Poloxamer 407. The rheological measurements and a small in vivo study of ocular residence times in humans were used to evaluate poloxamer as an ocular vehicle. An increasing concentration of poloxamer resulted in a slightly increasing elasticity of the gels and a decreasing sol-gel transition temperature. The contact time increased with increasing concentration of poloxamer which could be explained and correlated with the rheology of poloxamer solutions/gels mixed with simulated tear fluid. The maximum contact time for the preparations studied was about 1 h. The poloxamer system did not seem to be promising as an ophthalmic in situ gel due to the strong concentration dependence of the sol-gel transition temperature combined with the dilution that occurs in the eye.

Rheological evaluation of Gelrite® in situ gels for ophthalmic use

One of the reasons for the relatively low bioavailability of conventional eye drops is their short precorneal contact times. In situ gels are promising ocular drug delivery systems since they are conveniently dropped into the eye as a liquid whereafter they undergo a transition into a gel. Due to their elastic properties hydrogels resist ocular drainage leading to longer contact times. In this paper the rheology of Gelrite in situ gels was studied. A complementary in vivo study for determining precorneal contact times in humans and in rabbits was performed. The elastic moduli of the gels increased with increasing concentration of electrolytes. At physiological concentration of the electrolytes, the elasticity of the gels was independent of Gelrite concentration. The human contact times increased up to 20 h with decreasing osmolality of the formulations. The results indicate that a high rate of the sol/gel transition results in long contact times.

A new method for preparing biodegradable microparticles and entrapment of hydrocortisone in dl-PLG microparticles using supercritical fluids

An improved process for the production of polymeric microparticles, based on solution-enhanced dispersion by supercritical fluids (SEDS) using a combination of supercritical N(2) and CO(2), was evaluated. The biodegradable polymers, poly(D,L-lactide-co-glycolide): copolymer composition 50:50 (DL-PLG), poly(L-lactide) (L-PLA), poly(D,L-lactide) (DL-PLA) and polycaprolactone, were used for preparation of microparticles by a modified SEDS process. Solutions of the polymers in organic solvents were dispersed and the solvent was extracted with supercritical CO(2) and N(2). The morphology, the size distributions and degree of hydrocortisone entrapment were determined. The combination of supercritical N(2) and CO(2) led to a more efficient dispersion of the polymer solutions than CO(2) alone. This resulted in a reduction of particle size of the microparticles produced from all of the amorphous polymers. Discrete spherical microparticles with a mean volumetric diameter of less than 10 microm were produced from DL-PLG, DL-PLA and L-PLA. Hydrocortisone was successfully entrapped within the DL-PLG microparticles. The modified SEDS process improved the dispersion of amorphous polymer solutions resulting in formation of small spherical microparticles. The SEDS process can be used for incorporation of drugs into the DL-PLG microparticles.

Preparation of Biodegradable Microparticles Using Solution-Enhanced Dispersion by Supercritical Fluids (SEDS)

AbstractPurpose. We have evaluated a new process, involving solution-enhanced dispersion by supercritical fluids (SEDS), for the production of polymeric microparticles. Methods. The biodegradable polymers, Poly (DL-lactide-co-glycolide) : copolymer composition 50:50 (DL-PLG), Poly (L-lactide) (L-PLA), Poly (DL-lactide) (DL-PLA) and Polycaprolactone (PCL), were used for preparation of microparticles using SEDS. Solutions of the polymers in organic solvents were dispersed and sprayed with supercritical CO2. Extraction of the organic solvents resulted in the formation of solid microparticles. The amounts of highly toxic solvents such as dichloromethane (MC) were reduced in the process. Results. Microparticles were obtained from all polymers. The mean particle size and shape varied with the polymer used. The morphology of the particles was strongly affected by the choice of polymer solvent. Discrete spherical microparticles of DL-PLG were produced with a mean volumetric diameter of 130 μm. The microparticles of the L-PLA were almost spherical, and their size increased from 0.5 to 5 μm as the density of supercritical CO2 decreased. PCL formed microparticles with diameters of 30−210 μm and showed a strong tendency to form films at high pressure. Conclusions. The SEDS process appears a promising method for production of microparticles from biodegradable polymers without the use of toxic solvents.

Effect of preparative parameters on the characteristics of poly (D,L-lactide-co-glycolide) microspheres made by the double emulsion method

The mechanism for drug-release from poly(d,lt.-lactide-co-glycolide) (PLG) microspheres is generally a combination of the diffusion of the drug and the degradation rate of the polymer. The degradation rate is controlled by the molecular weight and the copolymer composition of PLG. The porosity, of the microspheres, which is dependent on the preparation method used, will also influence the drug-release rate. PLG microspheres containing mannitol4C were prepared by a small-scale w/o/w double emulsion method. As the PLG concentration in the middle phase was increased from 4.3 (w/w) to 43%, the entrapment efficiency of mannitol4C rose from 1 to 25%C and the diameter of the microspheres increased from 4.5 to 29 μm while the release rate of mannitol14C decreased. By increasing the volume of the internal aqueous phase the release rate of mannitol14C was increased. When using phosphatidylcholine (PC) as a stabiliser the size of the microspheres decreased from 23 to 16 υm. The presence of PC during preparation lowered the entrapment efficiency of mannitol14C. The results were related to the dynamics of the double emulsion and the porosity of the microspheres.

Incorporation of protein in PLG-microspheres with retention of bioactivity

The enzyme urease was incorporated into poly(lactide-co-glycolide) microspheres using a double emulsion solvent removal technique. Ethyl acetate was used as organic solvent since it is less toxic than the more commonly used methylene chloride. The effect of the two solvents on urease was compared. Although this preparation technique is well established, it is often associated with reduced bioactivity and low entrapment efficiency of proteins. In order to retain a high degree of bioactivity, the well known protein stabilisers: sucrose, trehalose and poloxamer 407, were added to the urease in the preparation. The bioactivity of the entrapped urease was reduced more by methylene chloride than by ethyl acetate. The gelled form of poloxamer was shown to highly favour the retention of bioactivity, demonstrated by an increase of 41% compared to preparations without poloxamer. Moreover, the presence of poloxamer strongly increased the in vitro release rate of urease from the microspheres. The entrapment efficiency was increased by 44% using the sugars in the preparation. These results clearly show the great potential of small quantities of additive in the formulation to control the properties of the microspheres. The amount and type of additive could be adjusted according to the therapeutic application of the preparation.

Biological activity of lysozyme after entrapment in poly (d,l-lactide-co-glycolide)-microspheres

AbstractPurpose. The purpose of this study was to investigate the process of preparing microspheres for maximising entrapment efficiency (EE) and retained biological activity (RBA) of peptides and proteins. Methods. A controlled-release formulation based on poly(d,l-lactide-co-glycolide) was designed and produced using a small-scale double emulsion method. These PLG microspheres contained a model peptide, lysozyme. The retained bioactivity of the incorporated lysozyme was determined by bacterial assay. The size distributions and the morphology of the microspheres were characterized. Results. The RBA and EE improved when the PLG concentration in the organic phase of the emulsion was increased. A high lysozyme concentration in the inner water phase of the emulsion resulted in decreased EE and an increase in the proportion of fragmented particles. The RBA of lysozyme in the microspheres varied between 30 and 80% with changes to the process. Conclusions. The study shows that the RBA of lysozyme in PLG microspheres is strongly dependent on the experimental conditions for preparing the microspheres. Measurement of the EE alone, without the RBA is insufficient to evaluate the efficacy of the designed delivery system.

Supercritical fluids crystallization of budesonide and flunisolide

AbstractPurpose: Budesonide and flunisolide anhydrate were crystallized using the solution enhanced dispersion by supercritical fluids (SEDS) technique. The aim was to investigate the possibility of preparing different pure polymorphs. Methods: 0.25% w/v solutions of each drug were prepared from acetone and methanol. Operating conditions were 40-80°C and 80-200 bars. The flow rate of drug solution was 0.3 mL/min and that of CO2 was 9-25 mL/min. Sample characterizations included differential scanning calorimetry, X-ray powder diffraction, variable temperature X-ray diffraction, scanning electron microscopy, and solubility studies. Results: The particle morphology of budesonide was dependent on the nature of the solvent. SEDS processing of flunisolide with acetone at 100 bars resulted in the formation of polymorphic mixtures at 80°C and a new polymorph III at 60 C and 40°C. With methanol at 100 bars another new polymorph IV was formed with different particle morphology at 80°C and a polymorphic mixture at 60°C. Conclusion: Using the SEDS, microparticles of crystalline budesonide were prepared and new polymorphs of flunisolide were produced. Particle characteristics were controlled by the temperature, pressure and relative flow rates of drug solution and CO2.

Substrate binding to cyclodextrins in aqueous solution: A multicomponent self-diffusion study

It is demonstrated that substrate binding to α- and β-cyclodextrins (CD) in solution can conveniently and directly be monitored from multicomponent self-diffusion data on these solutions, using the Fourier Transform NMR pulsed-gradient spin-echo technique. Included are aromatics and a series of alcohols ranging from methanol to octanol. Experimentally it was found thatn-alcohols associate more strongly with α-CD than with β-CD. As the bulkiness of the alcohol increased, binding to β-CD was enhanced while the reverse effect was observed in the case of α-CD. For both cyclodextrins it was found thatn-alcohol complexation in the homologous series was attributable to an increment in standard free energy of complexation of ∼ −3.0 kJ/mol for each −CH2− group, suggesting that the binding mechanism is of a hydrophobic nature.

Preparation of biodegradable poly(lactic-co-glycolic) acid microspheres and their in vitro release of timolol maleate

Abstract Poly(lactic-co-glycolic) acid, PLG, 50:50 microspheres containing homogeneously dispersed timolol maleate were prepared in an oil-in-oil solvent evaporation method. By varying the PLG concentration in the microsphere preparation, different particle sizes were obtained. A constant drug loading of about 2% (w/w) independently of PLG and timolol maleate concentration was obtained. As the drug loading was low and the particles exhibited a slow release of drug, it is suggested that the release of drug was due to polymer degradation rather than to pore diffusion. Timolol release was initiated with a small burst. After a lag time, a second period of extensive and rapid release of drug was observed. This secondary burst was accompanied by the collapse of the polymer matrix. The release from microspheres with polyethylene glycol (PEG) incorporated showed no secondary burst. After the secondary burst there was very little, if any, further release of drug. The presence of detergent in the release medium resulted in a smooth and relatively fast release rate from the particles. In this case no secondary burst was detected.