Textural, viscoelastic and mucoadhesive properties of pharmaceutical gels composed of cellulose polymers

This study examined the mechanical/textural, viscoeiastic and mucoadhesive properties of a range of aqueous gels composed of either hydroxyethylcellulose (HEC) or sodium carboxymethylcellulose (Na CMC). The mechanical/textural properties of each formulation were determined using texture profile analysis. The viscoelastic properties of each formulation were examined over a defined frequency range (0.01-1.0 Hz) using oscillatory rheometry in conjunction with stainless steel parallel plate geometry. The mucoadhesive properties of the gels were evaluated by measuring the tensile force required to overcome the gel/mucin adhesive interaction. Both gel hardness and compressibility, properties that affect the ease of product removal from a container and spreadability, increased as a function of increasing polymer concentrations. This is attributed to the effects of HEC and Na CMC on gel viscosity. Gel adhesiveness, a property related to bioadhesion, also increased as a function of polymer concentration and is attributed to the reported adhesive nature of these polymers. Increasing frequency of oscillation increased the storage and loss moduli yet decreased bath the dynamic viscosity of each gel type and also the loss tangent of HEC (but not Na CMC) gels. Therefore, following exposure to the range of oscillatory stresses that may be expected in vivo, HEC gels will be more susceptible than Na CMC gels to alterations in these rheological properties. Consequently, it would be expected that the clinical performance of HEC gels will be modified to a greater extent than Na CMC gels. In general, HEC gels exhibited a greater elastic nature than Na CMC gels over the frequency range employed for oscillation The storage and loss moduli and dynamic viscosity of both gel types increased, yet the loss tangent of both gel types decreased as a function of increasing polymer concentration. Gel mucoadhesive strength was dependent on both the time of contact of the formulation with mucin and also on polymer concentration. In conclusion, this study has characterised a number of gels containing either HEC or Na CMC in terms of their mechanical/textural, viscoelastic and mucoadhesive properties. Due to its relevance to the clinical performance, it is suggested that the information derived from these methods may be usefully combined to provide a more rational basis for the selection of polymers and their formulation as topical drug delivery systems. (C) 1997 Elsevier Science B.V.

The potential of electron beam radiation for simultaneous surface modification and bioresorption control of PLLA

Bioresorbable polymers have been widely investigated as materials exhibiting significant potential for successful application in the fields of tissue engineering and drug delivery. Further to the ability to control degradation, surface engineering of polymers has been highlighted as a key method central to their development. Previous work has demonstrated the ability of electron beam (e-beam) technology to control the degradation profiles and bioresorption of a number of commercially relevant bioresorbable polymers (poly-l-lactic acid (PLLA), Llactide/DL-lactide co-polymer (PLDL) and poly(lactic-co-glycolic acid (PLGA)). This work investigates the further potential of ebeam technology to impart added biofunctionality through the manipulation of polymer (PLLA) surface properties. PLLA samples were subjected to e-beam treatments in air, with varying beam energies and doses. Surface characterization was then performed using contact angle analysis, X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, and atomic force microscopy. Results demonstrated a significant increase in surface wettability post e-beam treatment. In correlation with this, XPS data showed the introduction of oxygen-containing functional groups to the surface of PLLA. Raman spectroscopy indicated chain scission in the near surface region of PLLA (as predicted). However, e-beam effects on surface properties were not shown to be dependent on beam energy or dose. E-beam irradiation did not seem to affect the surface roughness of PLLA as a direct consequence of the treatment.

Pharmacological Activity of Ibuprofen Release from Measoporous Silica

Novel drug delivery systems (DDS) to improve the pharmacokinetic profile of hydrophobic drugs following oral administration are an area of keen interest in drug research. An ideal DDS should not adversely affect drug activity, be capable of delivering a therapeutic dose of drug, and allow homogenous drug loading and drug release. Mesoporous silica has been proposed for this application, with ibuprofen employed as the model drug. It was hypothesised that mesoporous silica MCM-41 is capable of delivering a pharmacologically therapeutic dose of ibuprofen. Ibuprofen-loaded MCM-41 can be prepared reproducibly at a drug to carrier ratio of 30% (wt/wt). The release profile was seen to be 90% within 2 h. Initial assessment of COX-1 inhibitory activity suggests the absence of adverse effects attributable to drug-carrier interaction. The results of this study provide further evidence in support of the proposed use of mesoporous silica in drug delivery.

Pharmacokinetics and efficacy of a vaginally administered maraviroc gel in rhesus macaques

Objectives: To investigate the pharmacokinetics (PK) of maraviroc, a CCR5-targeted HIV-1 entry inhibitor, in rhesus macaques following vaginal administration of various maraviroc-loaded aqueous hydroxyethylcellulose (HEC) gels, and to correlate the PK data with efficacy in a single high-dose vaginal SHIV-162P3 challenge model.

Methods: Maraviroc concentrations in vaginal fluid (Weck-Cel® sponge), vaginal tissue (punch biopsy) and plasma were assessed over 72 h following single dose vaginal application of various maraviroc-loaded HEC gels. The range of maraviroc gel concentrations was sufficiently broad (0.003 – 3.3% w/w) such that test gels included both fully solubilised and predominantly dispersed formulations. The efficacy of the HEC gels against a single high dose vaginal SHIV-162P3 challenge was also measured, and correlated with the PK concentrations.

Results: Maraviroc concentrations in vaginal fluid (range 104 – 107 ng/mL), vaginal tissue (100-1200 ng/g) and plasma (< 102 ng/mL) were highly dependent on maraviroc gel loading, irrespective of the form of the maraviroc component within the gel (solubilised vs. dispersed). Fluid and plasma concentrations were generally highest 0.5 or 2 h after gel application, before declining steadily out to 72 h. Maraviroc concentrations in the various biological compartments correlated strongly with the extent of protection against vaginal SHIV-162P3 challenge. Complete protection was achieved with a 3.3% w/w maraviroc gel.

Conclusions: A high degree of correlation between PK and efficacy was observed. Based on the data obtained with the 3.3% w/w maraviroc gel, maintenance of vaginal fluid and tissue levels in the order of 107 ng/mL and 103 ng/g, respectively, are required for complete protection with this compound.

Platinum-catalysed intravaginal rings

The present invention provides improved intravaginal drug delivery devices, i.e., intravaginal rings, useful for the prophylactic administration of an antimicrobial compound, e.g., Dapivirine, to a human. The intravaginal rings of the invention address previous stability issues by utilizing a platinum catalyst (e.g., in the form of a platinum-siloxane complex) for the cross-linking reaction. The vaginal rings surprisingly achieve relatively high and steady release rates in vivo with a matrix ring containing a relatively small loading dose. While the matrix rings of the present invention have in vivo the steady release rates associated with reservoir rings, they are easier and less expensive to manufacture. The present invention also provides methods of blocking DNA polymerization by an HIV reverse transcriptase enzyme, methods of preventing HIV infection in a female human, methods of treating HIV infection in a female human, and methods of preparing platinum-catalyzed intravaginal rings.

Pharmaceutical applications of dynamic mechanical thermal analysis

The successful development of polymeric drug delivery and biomedical devices requires a comprehensive understanding of the viscoleastic properties of polymers as these have been shown to directly affect clinical efficacy. Dynamic mechanical thermal analysis (DMTA) is an accessible and versatile analytical technique in which an oscillating stress or strain is applied to a sample as a function of oscillatory frequency and temperature. Through cyclic application of a non-destructive stress or strain, a comprehensive understanding of the viscoelastic properties of polymers may be obtained. In this review, we provide a concise overview of the theory of DMTA and the basic instrumental/operating principles. Moreover, the application of DMTA for the characterization of solid pharmaceutical and biomedical systems has been discussed in detail. In particular we have described the potential of DMTA to measure and understand relaxation transitions and miscibility in binary and higher-order systems and describe the more recent applications of the technique for this purpose. © 2011 Elsevier B.V.

Hot-melt extrusion technology and pharmaceutical application

The use of hot-melt extrusion (HME) within the pharmaceutical industry is steadily increasing, due to its proven ability to efficiently manufacture novel products. The process has been utilized readily in the plastics industry for over a century and has been used to manufacture medical devices for several decades. The development of novel drugs with poor solubility and bioavailability brought the application of HME into the realm of drug-delivery systems. This has specifically been shown in the development of drug-delivery systems of both solid dosage forms and transdermal patches. HME involves the application of heat, pressure and agitation through an extrusion channel to mix materials together, and subsequently forcing them out through a die. Twin-screw extruders are most popular in solid dosage form development as it imparts both dispersive and distributive mixing. It blends materials while also imparting high shear to break-up particles and disperse them. HME extrusion has been shown to molecularly disperse poorly soluble drugs in a polymer carrier, increasing dissolution rates and bioavailability. The most common difficulty encountered in producing such dispersions is stabilization of amorphous drugs, which prevents them from recrystallization during storage. Pharmaceutical industrial suppliers, of both materials and equipment, have increased their development of equipment and chemicals for specific use with HME. Clearly, HME has been identified as an important and significant process to further enhance drug solubility and solid-dispersion production. © 2012 Future Science Ltd.

The mechanical and rheological characterisation of implantable medical devices formulated from binary mixtures of cellulose derivatives

This study highlights the potential associated with utilising multi-component polymeric gels to formulate materials that possess unique rheological and mechanical properties. The synergistic effect* and interaction between hydroxyethylcellulose (HEC) and sodium carboxymethylcellulose (NaCMC), polymers which are commonly employed as drug delivery platforms for implantable medical devices (1), have been determined using dynamic, continuous shear and texture profile analysis. * The difference between the actual response of a binary mixture and the sum of the two components comprising the mixture Increases in polymer concentration resulted in an increase in G', G? and ?' whereas tan d decreased. Similarly, significant increases were also apparent in continuous shear and texture analysis. All binary mixtures showed positive synergy values which may suggest associative interaction between the two components.

Investigation of swelling and network parameters of poly(ethylene glycol)-crosslinked poly(methyl vinyl ether-co-maleic acid) hydrogels

The influence of poly(ethylene glycol) (PEG) plasticiser content and molecular weight on the physicochemical properties of films cast from aqueous blends of poly(methyl vinyl ether-co-maleic acid) was investigated using thermal analysis, swelling studies, scanning electron microscopy (SEM) and attenuated total reflectance (ATR)-Fourier transform infrared (FTIR) spectroscopy. FTIR spectroscopy revealed a shift of the C{double bond, long}O peak from 1708 to 1731 cm, indicating that an esterification reaction had occurred upon heating, thus producing crosslinked films. Higher molecular weight PEGs (10,000 and 1000 Da, respectively), having greater chain length, producing hydrogel networks with lower crosslink densities and higher average molecular weight between two consecutive crosslinks. Accordingly, such materials exhibited higher swelling rates. Hydrogels crosslinked with a low molecular weight PEG (PEG 200) showed rigid networks with high crosslink densities and, therefore, lower swelling rates. Polymer:plasticizer ratio alteration did not yield any discernable patterns, regardless of the method of analysis. The polymer-water interaction parameter (?) increased with increases in the crosslink density. SEM studies showed that porosity of the crosslinked films increased with increasing PEG MW, confirming what had been observed with swelling studies and thermal analysis, that the crosslink density must be decreased as the M of the crosslinker is increased. Hydrogels containing PMVE/MA/PEG 10,000 could be used for rapid delivery of drug, due to their low crosslink density. Moderately crosslinked PMVE/MA/PEG 1000 hydrogels or highly crosslinked PMVE/MA/PEG 200 systems could then be used in controlling the drug delivery rates. We are currently evaluating these systems, both alone and in combination, for use in sustained release drug delivery devices. © 2008 Elsevier Ltd. All rights reserved.

Preliminary clinical assessment of polyvinyl alcohol-tetrahydroxyborate hydrogels as potential topical formulations for local anesthesia of lacerations

The aim of this study was to assess a novel semisolid material as a potential topical drug delivery system for acute laceration. The objectives were to correlate physical characterization data using rheologic studies and to compare with clinical assessment of performance in an emergency department (ED).

Hydrogel-forming microneedle arrays exhibit antimicrobial properties:potential for enhanced patient safety

We describe, for the first time, the microbial characterisation of hydrogel-forming polymeric microneedle arrays and the potential for passage of microorganisms into skin following microneedle penetration. Uniquely, we also present insights into the storage stability of these hydroscopic formulations, from physical and microbiological viewpoints, and examine clinical performance and safety in human volunteers. Experiments employing excised porcine skin and radiolabelled microorganisms showed that microorganisms can penetrate skin beyond the stratum corneum following microneedle puncture. Indeed, the numbers of microorganisms crossing the stratum corneum following microneedle puncture were greater than 105 cfu in each case. However, no microorganisms crossed the epidermal skin. When using a 21G hypodermic needle, more than 104 microorganisms penetrated into the viable tissue and 106 cfu of Candida albicans and Staphylococcus epidermidis completely crossed the epidermal skin in 24 h. The hydrogel-forming materials contained no microorganisms following de-moulding and exhibited no microbial growth during storage, while also maintaining their mechanical strength, apart from when stored at relative humidities of 86%. No microbial penetration through the swelling microneedles was detectable, while human volunteer studies confirmed that skin or systemic infection is highly unlikely when polymeric microneedles are used for transdermal drug delivery. Since no pharmacopoeial standards currently exist for microneedle-based products, the exact requirements for a proprietary product based on hydrogel-forming microneedles are at present unclear. However, we are currently working towards a comprehensive specification set for this microneedle system that may inform future developments in this regard.

Flux of ionic dyes across microneedle-treated skin:effect of molecular characteristics

Drug flux across microneedle (MN)-treated skin is influenced by the characteristics of the MN array, formed microconduits and physicochemical properties of the drug molecules in addition to the overall diffusional resistance of microconduits and viable tissue. Relative implication of these factors has not been fully explored. In the present study, the in vitro permeation of a series of six structurally related ionic xanthene dyes with different molecular weights (MW) and chemical substituents, across polymer MN-pretreated porcine skin was investigated in relation of their molecular characteristics. Dyes equilibrium solubility, partition coefficient in both n-octanol or porcine skin/aqueous system, and dissociation constants were determined. Results indicated that for rhodamine dyes, skin permeation of the zwitterionic form which predominates at physiological pH, was significantly reduced by an increase in MW, the skin thickness and by the presence of the chemically reactive isothiocyanate substituent. These factors were generally shown to override the aqueous solubility, an important determinant of drug diffusion in an aqueous milieu. The data obtained provided more insight into the mechanism of drug permeation across MN-treated skin, which is of importance to both the design of MN-based transdermal drug delivery systems and of relevance to skin permeation research.