Marc B. Brown

Dermal and Transdermal Drug Delivery Systems: Current and Future Prospects

The protective function of human skin imposes physicochemical limitations to the type of permeant that can traverse the barrier. For a drug to be delivered passively via the skin it needs to have adequate lipophilicity and also a molecular weight <500 Da. These requirements have limited the number of commercially available products based on transdermal or dermal delivery. Various strategies have emerged over recent years to optimize delivery and these can be categorized into passive and active methods. The passive approach entails the optimization of formulation or drug carrying vehicle to increase skin permeability. Passive methods, however do not greatly improve the permeation of drugs with molecular weights >500 Da. In contrast active methods that normally involve physical or mechanical methods of enhancing delivery have been shown to be generally superior. Improved delivery has been shown for drugs of differing lipophilicity and molecular weight including proteins, peptides, and oligonucletides using electrical methods (iontophoresis, electroporation), mechanical (abrasion, ablation, perforation), and other energy-related techniques such as ultrasound and needless injection. However, for these novel delivery methods to succeed and compete with those already on the market, the prime issues that require consideration include device design and safety, efficacy, ease of handling, and cost-effectiveness. This article provides a detailed review of the next generation of active delivery technologies.

Preparation and evaluation of the in vitro drug release properties and mucoadhesion of novel microspheres of hyaluronic acid and chitosan.

Rapid mucociliary clearance of intranasally administered drugs is often a key factor in determining the bioavailability of such therapeutic agents. The use of mucoadhesive microparticles provide a potential strategy for improving retention of drugs within the nasal cavity, and thereby improve the resultant pharmacokinetic profile. This study describes the comparison of a number of novel, potentially mucoadhesive microspheres, prepared by solvent evaporation, composed of hyaluronic acid (HA), chitosan glutamate (CH) and a combination of the two with microcapsules of HA and gelatin prepared by complex coacervation. The microspheres had a mean particle size of 19.91+/-1.57 microm (HA), 28.60+/-1.34 microm (HA/CH), 29.47+/-3.58 microm (CH). The incorporation of a model drug, gentamicin sulphate (%) was 46.90+/-0.53 (HA), 28.04+/-1.21 (HA/CH) and 13.32+/-1.04 (CH). The in vitro release profiles of microsphere formulations prepared by solvent evaporation were determined. The release of gentamicin from HA and HA/CH was 50% longer than CH and was best modelled as a release from a matrix. The degree of mucoadhesion of each formulation was investigated by determining the mucociliary transport rate (MTR) of the microparticles across an isolated frog palate. Acacia/gelatin microcapsules were used as a positive control. The rank order of mucoadhesion for the microspheres and the microparticles was HA=HA/CH>CH>HA/gelatin>CHins. The entrapment of gentamicin did not affect the mucoadhesive properties (P>0.05, Mann--Whitney U-test). The combination of HA with chitosan may afford additional advantages in combining the mucoadhesive potential of HA with the penetration enhancing effect of chitosan.

Advances in oral transmucosal drug delivery

The successful delivery of drugs across the oral mucosa represents a continuing challenge, as well as a great opportunity. Oral transmucosal delivery, especially buccal and sublingual delivery, has progressed far beyond the use of traditional dosage forms with novel approaches emerging continuously. This review highlights the physiological challenges as well as the advances and opportunities for buccal/sublingual drug delivery. Particular attention is given to new approaches which can extend dosage form retention time or can be engineered to deliver complex molecules such as proteins and peptides. The review will also discuss the physiology and local environment of the oral cavity in vivo and how this relates to the performance of transmucosal delivery systems.

Hyaluronic acid : a unique topical vehicle for the localized delivery of drugs to the skin

Hyaluronic acid (HA) is a naturally occurring polyanionic, polysaccharide that consists of N‐acetyl‐d‐glucosamine and β‐glucoronic acid. It is present in the intercellular matrix of most vertebrate connective tissues especially skin where it has a protective, structure stabilizing and shock‐absorbing role. The unique viscoelastic nature of HA along with its biocompatibility and non‐immunogenicity has led to its use in a number of clinical applications, which include: the supplementation of joint fluid in arthritis; as a surgical aid in eye surgery; and to facilitate the healing and regeneration of surgical wounds. More recently, HA has been investigated as a drug delivery agent for various routes of administration, including ophthalmic, nasal, pulmonary, parenteral and topical. In fact, regulatory approval in the USA, Canada and Europe was granted recently for 3% diclofenac in 2.5% HA gel, Solaraze®, for the topical treatment of actinic keratoses, which is the third most common skin complaint in the USA. The gel is well tolerated, safe and efficacious and provides an attractive, cost‐effective alternative to cryoablation, curettage or dermabrasion, or treatment with 5‐fluorouracil. The purpose of this review is to describe briefly the physical, chemical and biological properties of HA together with some details of its medical and pharmaceutical uses with emphasis on this more recent topical application.

Hyaluronan: Pharmaceutical Characterization and Drug Delivery

Hyaluronic acid (HA), is a polyanionic polysaccharide that consists of N-acetyl-D-glucosamine and β-glucoronic acid. It is most frequently referred to as hyaluronan because it exists in vivo as a polyanion and not in the protonated acid form. HA is distributed widely in vertebrates and presents as a component of the cell coat of many strains of bacteria. Initially the main functions of HA were believed to be mechanical as it has a protective, structure stabilizing and shock-absorbing role in the body. However, more recently the role of HA in the mediation of physiological functions via interaction with binding proteins and cell surface receptors including morphogenesis, regeneration, wound healing, and tumor invasion, as well as in the dynamic regulation of such interactions on cell signaling and behavior has been documented. The unique viscoelastic nature of hyaluronan along with its biocompatibility and nonimmunogenicity has led to its use in a number of cosmetic, medical, and pharmaceutical applications. More recently, HA has been investigated as a drug delivery agent for ophthalmic, nasal, pulmonary, parenteral, and dermal routes. The purpose of our review is to describe the physical, chemical, and biological properties of native HA together with how it can be produced and assayed along with a detailed analysis of its medical and pharmaceutical applications.

Potency of Δ9–THC and Other Cannabinoids in Cannabis in England in 2005: Implications for Psychoactivity and Pharmacology*

Abstract:  Gas chromatography was used to study the cannabinoid content (“potency”) of illicit cannabis seized by police in England in 2004/5. Of the four hundred and fifty two samples, indoor‐grown unpollinated female cannabis (“sinsemilla”) was the most frequent form, followed by resin (hashish) and imported outdoor‐grown herbal cannabis (marijuana). The content of the psychoactive cannabinoid Δ9‐tetrahydrocannabinol (THC) varied widely. The median THC content of herbal cannabis and resin was 2.1% and 3.5%, respectively. The median 13.9% THC content of sinsemilla was significantly higher than that recorded in the UK in 1996/8. In sinsemilla and imported herbal cannabis, the content of the antipsychotic cannabinoid cannabidiol (CBD) was extremely low. In resin, however, the average CBD content exceeded that of THC, and the relative proportions of the two cannabinoids varied widely between samples. The increases in average THC content and relative popularity of sinsemilla cannabis, combined with the absence of the anti‐psychotic cannabinoid CBD, suggest that the current trends in cannabis use pose an increasing risk to those users susceptible to the harmful psychological effects associated with high doses of THC.

Effects of Sucrose and Trehalose on the Preservation of the Native Structure of Spray-Dried Lysozyme

AbstractPurpose. To investigate the effects of sucrose, trehalose, sucrose/dextran mixtures, and sucrose/trehalose mixtures on the preservation of the native structure of spray-dried lysozyme in the solid state. Methods. The intensity of the α-helical band and the melting enthalpies (ΔHm ) of spray-dried lysozyme in the dried form and in aqueous solution were obtained using second derivative FTIR and differential scanning calorimetry (DSC) respectively. Results. The intensity of the Δ-helical band and the ΔH m of spray-dried lysozyme obtained were linearly correlated and both suggest that the stabilization of lysozyme in the dried form was excipient concentration-dependent with a close to maximum stabilization being conferred by sucrose or trehalose at a mass ratio 1–2 (sugar:enzyme). Sucrose appeared to be more effective than trehalose on a weight by weight basis whilst stabilizing effects of dextran/sucrose or trehalose/sucrose mixtures were found to be additive. Conclusion. Dehydration during spray drying was considered the main stress to the denaturation of lysozyme. A major effect of the sugars in protecting lysozyme against dehydration was attributable to hydrogen bonding between the sugar and protein molecules, which lead to an increase in the change in the negative value of the free energy between native and denatured states.

In vivo evaluation of novel hyaluronan/chitosan microparticulate delivery systems for the nasal delivery of gentamicin in rabbits

Biodegradable microparticles containing gentamicin were prepared using chitosan hydroglutamate (CH), hyaluronic acid (HA) and a combination of both polymers by a solvent evaporation method. These formulations were administered nasally via an insufflator. Gentamicin was also administered nasally into rabbits as a solution and powder (a physical mixture of gentamicin and lactose), intravenously (IV) and intramuscularly (IM). The resultant serum levels of gentamicin were determined by Fluorescence Polarisation Immunoassay (FPIA). The bioavailability of gentamicin was poor when administered as a nasal solution (1.1%) and dry powder (2.1%) when compared with IV. However, the microparticulate systems composed of CH and HA/CH considerably enhanced the bioavailability of gentamicin (31.4 and 42.9%, respectively,) with HA microparticles inducing a less significant enhancement (23.3%). Previous in vitro dissolution and frog palate studies indicated that these microparticulate formulations were all mucoadhesive and demonstrated prolonged drug release. Such findings were translated into an increase in the bioavailability of gentamicin when compared with a simple nasal solution in vivo. When HA and CH were combined in the HA/CH formulation, the polymers appeared to improve the absorption of incorporated gentamicin synergistically in comparison to the individual polymers, suggesting a promising nasal delivery system.

In vivo and in vitro characterization of novel microparticulates based on hyaluronan and chitosan hydroglutamate

This study examined the application of previously characterized microparticles composed of hyaluronan (HA) and chitosan hydroglutamate (CH) as well as novel microparticles consisting of both polymers (HA/CH) to improve the nasal delivery of a model drug. The rabbit bioavailabilities of gentamicin incorporated in HA, CH, and HA/CH microparticles were increased 23-, 31-, and 42-fold, respectively, compared with the control intranasal solution of gentamicin, indicating that all test microparticles were retained for longer periods on the nasal mucosa of the rabbits as supported by previous in vitro dissolution as well as frog palate mucoadhesion studies, thereby improving drug absorption. The higher bioavailabilities of CH-based formulations (CH and HA/CH) suggest the penetration-enhancing effects of CH may also be partially responsible for the improvement. A model was developed, based on a glass impinger device, to deliver dry powder formulations reproducibly onto the surface of cultured cell monolayers. In vitro permeability and fluorescence microscopy studies on the tight junctions of the 16HBE14o- cell lines further confirmed the ability of CH-based formulations to enhance penetration. Furthermore, the in vitro absorption profile from cell culture studies was consistent with those determined from in vivo studies. The complementary effect from the mucoadhesive nature of HA coupled with the penetration-enhancing effects of CH makes the novel HA/CH formulation a promising nasal delivery system.

Protective mechanism of stabilizing excipients against dehydration in the freeze-drying of proteins.

AbstractPurpose. To investigate the influence of type and amount of excipient on the preservation of the native structure and the biologic activity of freeze-dried lysozyme and catalase. Methods. The secondary structure of protein in the dried form and in aqueous solution was obtained using second derivative infrared spectroscopy and circular dichroism spectra respectively whilst the activity was determined using bioassay. Results. Small molecular excipients (glycerol, sorbitol, 1,6-anhydroglucose, sucrose, and trehalose) were found to stabilize the activity and/or the native structure of freeze-dried lysozyme and catalase, despite the processing temperatures being above Tg′ of excipient-protein mixtures. The preservation of catalase activity required excipient to be present at a lower excipient to enzyme mass ratio than that necessary to preserve native structure in the dried form. Combining dextran with sucrose synergistically protected the native structure of catalase but preserved the activity in an additive manner. Conclusion. The results indicate that the stabilization of catalase and lysozyme by excipients during dehydration was mainly due to water substitution rather than the formation of glass; the latter appearing not to be a prerequisite during freeze-drying.