Kerr H. Matthews

Characterisation of freeze-dried wafers and solvent evaporated films as potential drug delivery systems to mucosal surfaces.

Freeze-dried (lyophilised) wafers and solvent cast films from sodium alginate (ALG) and sodium carboxymethylcellulose (CMC) have been developed as potential drug delivery systems for mucosal surfaces including wounds. The wafers (ALG, CMC) and films (CMC) were prepared by freeze-drying and drying in air (solvent evaporation) respectively, aqueous gels of the polymers containing paracetamol as a model drug. Microscopic architecture was examined using scanning electron microscopy, hydration characteristics with confocal laser scanning microscopy and dynamic vapour sorption. Texture analysis was employed to investigate mechanical characteristics of the wafers during compression. Differential scanning calorimetry was used to investigate polymorphic changes of paracetamol occurring during formulation of the wafers and films. The porous freeze-dried wafers exhibited higher drug loading and water absorption capacity than the corresponding solvent evaporated films. Moisture absorption, ease of hydration and mechanical behaviour were affected by the polymer and drug concentration. Two polymorphs of paracetamol were observed in the wafers and films, due to partial conversion of the original monoclinic to the orthorhombic polymorph during the formulation process. The results showed the potential of employing the freeze-dried wafers and solvent evaporated films in diverse mucosal applications due to their ease of hydration and based on different physical mechanical properties exhibited by both type of formulations.

Development and mechanical characterization of solvent-cast polymeric films as potential drug delivery systems to mucosal surfaces

Solvent-cast films from three polymers, carboxymethylcellulose (CMC), sodium alginate (SA), and xanthan gum, were prepared by drying the polymeric gels in air. Three methods, (a) passive hydration, (b) vortex hydration with heating, and (c) cold hydration, were investigated to determine the most effective means of preparing gels for each of the three polymers. Different drying conditions [relative humidity – RH (6–52%) and temperature (3–45°C)] were investigated to determine the effect of drying rate on the films prepared by drying the polymeric gels. The tensile properties of the CMC films were determined by stretching dumbbell-shaped films to breaking point, using a Texture Analyser. Glycerol was used as a plasticizer, and its effects on the drying rate, physical appearance, and tensile properties of the resulting films were investigated. Vortex hydration with heating was the method of choice for preparing gels of SA and CMC, and cold hydration for xanthan gels. Drying rates increased with low glycerol content, high temperature, and low relative humidity. The residual water content of the films increased with increasing glycerol content and high relative humidity and decreased at higher temperatures. Generally, temperature affected the drying rate to a greater extent than relative humidity. Glycerol significantly affected the toughness (increased) and rigidity (decreased) of CMC films. CMC films prepared at 45°C and 6% RH produced suitable films at the fastest rate while films containing equal quantities of glycerol and CMC possessed an ideal balance between flexibility and rigidity.

Thermoreversible polymer gel electrolytes

Abstract Thermoreversible polymer gel electrolytes with ionic conductivities in the region of 10−3 S cm−1 (even at −20°C) have been prepared from a variety of commercially available polymers and organic solvents by gel casting from high-temperature solutions at polymer/solvent ratios down to 10 90 . Lithium trifluoromethanesulfonate has been incorporated as the ionic species necessary for conduction. A typical gel has polymer/solvent in mass ratio 40 60 and has salt incorporated to give an active O/Li ratio of 12 1 . In general, the dynamic modulus (G′) of these gels is in excess of 105 Pa at low strain, but decreases rapidly with increasing strain amplitude despite remaining approximately constant with strain rate. This drop in modulus, which is attributed to breakdown of the gel network, is completely recoverable. In particular, one polymer, poly(vinylidene fluoride), was studied in detail. Gels made from this polymer formed self-supporting transparent films. The incorporation of lithium trifluoromethanesulfonate changed the crystal structure and decreased the solvent evaporation rate, at elevated temperatures, of poly(vinylidene fluoride) gels made with tetraethylene glycol dimethyl ether. Ionic conductivities of liquid electrolytes (dimethylformamide with lithium trifluoromethanesulfonate) and corresponding gels (dimethylformamide, lithium trifluoromethanesulfonate and poly(vinylidene fluoride)) suggest that there is no interaction between salt and polymer in these gels, although this is still under investigation.

In vitro drug release studies of polymeric freeze-dried wafers and solvent-cast films using paracetamol as a model soluble drug

Drug dissolution and release characteristics from freeze-dried wafers and solvent-cast films prepared from sodium carboxymethylcellulose (CMC) have been investigated to determine the mechanisms of drug release from the two systems. The formulations were prepared by freeze-drying (wafers) or drying in air (films), the hydrated gel of the polymer containing paracetamol as a model soluble drug. Scanning electron microscopy (SEM) was used to examine differences between the physical structure of the wafers and films. Dissolution studies were performed using an exchange cell and drug release was measured by UV spectroscopy at 242 nm. The effects of drug loading, polymer content and amount of glycerol (films) on the release characteristics of paracetamol were investigated. The release profiles of paracetamol from the wafers and films were also compared. A digital camera was used to observe the times to complete hydration and dissolution of the wafers containing different amounts of CMC and how that impacts on drug release rates. Both formulations showed sustained type drug release that was modelled by the Korsmeyer-Peppas equation. Changes in the concentration of drug and glycerol (films) did not significantly alter the rate of drug release while increasing polymer content significantly decreased the rate of drug release from both formulations. The results show that the rate of paracetamol release was faster from the wafers than the corresponding films due to differences in their physical structures. The wafers which formed a porous network, hydrated faster than the more dense and continuous, (non-porous) sheet-like structure of the films.

Gel formulations for treatment of the ophthalmic complications in cystinosis.

Nephropathic cystinosis is a rare autosomal recessive disease characterised by raised lysosomal levels of cystine in the cells of all organs. It is treated by regular administration of the aminothiol, cysteamine. Corneal crystal deposition is one of the most troublesome complications affecting patients and requires the hourly administration of cysteamine eye drops. In an attempt to reduce this frequency and improve the treatment, the preparation and evaluation of cysteamine containing Carbomer gel is reported. The results demonstrated that a weak gel network was formed at low shear-stress, the bioadhesion of the gel was increased with inclusion of a cysteamine derivative (e.g. mean force of 0.067N compared to 0.107N with compound included) and first-order release from the gel was observed. In conclusion these results offer the possibility to formulate cysteamine in an ocular applicable gel formulation.

Formulation, stability and thermal analysis of lyophilised wound healing wafers containing an insoluble MMP-3 inhibitor and a non-ionic surfactant

Lyophilised wafers are being developed as topical drug delivery systems for the treatment of chronic wounds. This study describes the formulation of xanthan wafers containing a selective, insoluble MMP-3 inhibitor (UK-370,106) and a non-ionic surfactant, designed to release accurate doses of UK-370,106 directly to a suppurating wound bed. Stability of UK-370,106 in the wafer compared to a non-lyophilised gel suspension was investigated using a combination of light scattering, thermal and microscopic techniques. Particle size distributions in UK-370,106-loaded wafers were constant throughout an accelerated stability study (12 weeks, 40 degrees C) while the mean particle size in a non-lyophilised suspension increased by 15 microm in the same period. Thermal analysis of UK-370,106-loaded wafers highlighted an unexpected interaction between the drug and the surfactant that was further investigated using simple mixtures of each component. It was concluded that an in situ solvate of UK-370,106 and the non-ionic surfactant can form and that this may have implications towards the stability of UK-370,106 during the formulation process. Further concerns regarding high water contents (14%) in the wafer and its effect on product stability were unfounded and it was concluded that these novel delivery systems provided a viable alternative to gel suspensions.

Comparison of the in vitro release characteristics of mucosal freeze-dried wafers and solvent-cast films containing an insoluble drug.

Drug release characteristics of freeze-dried wafers and solvent-cast films prepared from sodium carboxymethylcellulose have been investigated and compared. In vitro drug dissolution studies were performed using an exchange cell and drug release was measured by UV spectroscopy at 272 nm using distilled water. The dissolution profiles of hydrochlorothiazide from the wafers and films were compared by determining the rates of drug release, estimated from the % release versus time profiles and calculating their difference (f1) and similarity (f2) factors. The effects of drug loading, polymer content and amount of glycerol (GLY) (films) on the drug release characteristics of both formulations were investigated. Both the wafers and films showed sustained type release profiles that were best explained by the Korsmeyer–Peppas equation. Changes in the concentration of drug and GLY (films) did not significantly alter the release profiles whilst increasing polymer content significantly decreased the rate of drug release from both formulations. The rate of release was faster from the wafers than the corresponding films which could be attributed to differences in the physical microstructure. The results show the potential of employing both formulations in various mucosal drug delivery applications.

The hen's egg chorioallantoic membrane (HET-CAM) test to predict the ophthalmic irritation potential of a cysteamine-containing gel: Quantification using Photoshop® and ImageJ.

A modified hens egg chorioallantoic membrane (HET-CAM) test has been developed, combining ImageJ analysis with Adobe(®) Photoshop(®). The irritation potential of an ophthalmic medicine can be quantified using this method, by monitoring damage to blood vessels. The evaluation of cysteamine containing hyaluronate gel is reported. The results demonstrated that the novel gel formulation is non-irritant to the ocular tissues, in line with saline solution (negative control). In conclusion, the modification of the established HET-CAM test can quantify the damage to minute blood vessels. These results offer the possibility to formulate cysteamine in an ocular applicable gel formulation.

Synthesis and properties of phospholipid polyurethanes with poly(isoprene) soft segment

Polyrethanes, based on 2-[bis(2-hydroxyethyl)methylammoni]ethylstearylphosphate, alone or together with 1,4-butanediol as the chain extender, poly(isoprene) diol and 4,4′-methylenediphenyl diisocyanate, were prepared. These segmented phospholipid polyurethanes were characterized by IR, elemental analyses, and gel permeation chromatography. The polyurethane, with both phospholipid diol and 1,4-butanediol as the chain extender, was further investigated by differential scanning calorimetry, x-ray diffraction, scanning electron microscopy, plasma contact and clotting time. An x-ray diffraction measurement for the polymer shows a intense scattering at 79.3 A corresponding to the length of soft segments, which is hydrophobic poly(isoprene), and a weak diffuse scattering at 5.1 A corresponding to the distance between the hydrophobic poly (isoprene) layers. The hemocompatibilities of the polymer were evaluated by platelet rich plasma contacting studies and by scanning electron microscopy using medical grade poly(vinyl chloride) as control. The hot-pressed films of the polymer exhibit a favorable surface in terms of platelet adhesion, and the morphology of adhered platelets undergoes to a relatively lower degree of variation compared to poly(vinyl chloride). Moreover, the clotting time of the polymer in contact with human platelet rich plasma was 220, 100, and 86 s for the phospholipid-based polyurethane, poly(vinyl chloride), and glass, respectively.

Drug delivery dressings

Abstract: This chapter concerns the targeted and sustained topical delivery of therapeutic agents to chronic wounds using natural and synthetic polymer carriers. It outlines the role of drug delivery dressings in wound management and focuses on the delivery of antimicrobials and growth factors to facilitate the healing process. Using the established dressing categories of hydrocolloids, hydrogels, collagen and alginates, it reviews recent research, limiting discussion to combinations of polymer and therapeutic agent. Traditional dressings composed of cotton wool, lint, natural or synthetic bandages and gauzes are only discussed in terms of secondary dressings for the primary dressings of interest.