Gary P. Martin

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.

Drug delivery to the respiratory tract using dry powder inhalers

Abstract The inhalation of aerosolised drug has become a well established treatment modality in conditions such as asthma. The pressurised metered-dose inhaler (MDI) is still the most commonly prescribed inhalation system, despite a number of associated disadvantages. The requirement to replace the ozone-depleting chlorofluoro-carbon propellants, present as an integral part of all MDIs, has led to the pharmaceutical industry re-evaluating the potential of dry powder inhalers (DPIs). However, the efficiency of delivery is currently not high, with in some cases only approx. 10% of the inhaled dose of the drug reaching the alveoli. The site of deposition and the deposition patterns of the inhaled aerosol from DPIs is influenced by two major interdependent factors: (a) the patient (anatomical and physiological aspects of the respiratory tract as well as mode of inhalation) and (b) the physical properties of the aerosol cloud (attributable either to the dry powder formulation or the design of the DPI devices). More recently, as engineers have contributed to the design of DPI devices encouraging results have been obtained in clinical trials performed to compare the efficacy and acceptability of DPI with other drug delivery systems. Undoubtedly more cross-disciplinary collaboration of this kind will lead to further improvements in drug delivery from such formulations and may ultimately provide a feasible means of presenting drugs of peptide origin to the body for systemic therapeutic action.

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.

The influence of carrier morphology on drug delivery by dry powder inhalers

Alpha-lactose monohydrate was prepared to have different morphological features but with similar particle size. The crystal shape and surface smoothness of lactose were quantified by a number of shape descriptors and these were supported qualitatively by the visual examination of scanning electron (SE) micrographs of the crystals. All batches of lactose were subjected to a similar history of processing before blending separately with micronised salbutamol sulphate (SS) in a ratio of 67.5:1, w/w, using similar procedures. In vitro deposition of SS from these formulations was investigated after aerosolisation of the formulations at 60 l min(-1) via the Rotahaler and the Cyclohaler into a twin stage liquid impinger. The formulations prepared using the different batches of lactose produced different deposition profiles of SS. The fine particle (< 6.4 microm) fraction (FPF) of aerosolised SS varied from 12.6 +/- 2.4 to 25.6 +/- 1.5% after aerosolisation from the Cyclohaler whilst it changed from 15.0 +/- 2.2 to 24.4 +/- 0.8% after aerosolisation from the Rotahaler. The fine particle dose (FPD) and dispersibility of SS followed a similar trend to the change in the FPF of the drug. No significant difference (ANOVA P > 0.05) was observed for the deposition profiles of SS after aerosolisation from the Rotahaler and the Cyclohaler. The FPF and dispersibility of SS increased with either the surface smoothness (P < 0.01) or elongation ratio (P < 0.01) of lactose crystals. The t-ratio values of FPF and dispersibility of SS generated by changes in the surface smoothness were similar to those resulting from changes in elongation ratio. Increasing either the surface smoothness or the elongation ratio of lactose crystals will increase the potentially respirable fraction of SS from dry powder formulations for inhalation.

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.

THE INFLUENCE OF CARRIER AND DRUG MORPHOLOGY ON DRUG DELIVERY FROM DRY POWDER FORMULATIONS

Lactose was crystallised either from neutralised Carbopol 934 gel or from water-ethanol solution without stirring, with a view to obtaining lactose alpha-monohydrate of favourable shape and smooth surface, suitable for use as carriers in formulations for dry powder inhalers (DPIs). Crystallisation of salbutamol sulphate was carried out in the presence of water, lecithin and ethanol to form salbutamol crystals with defined shape and smooth surface. The crystals formed were needle-shaped, with a length of less than 6 microm and a width between 0.5 and 1 microm. DSC and TGA showed that lactose crystals produced from Carbopol gel or from water-ethanol solution existed as alpha-lactose monohydrate. The DSC thermograms of micronised and crystallised salbutamol sulphate showed two similar endothermic transitions at 200 and 290 degrees C, respectively. The first transition was initially thought to correspond to the melting of salbutamol sulphate. However, the shape of the particles as observed by optical microscopy was not altered after heating the sample to 250 degrees C, suggesting that no transition from solid to liquid state occurred at 200 degrees C. This was confirmed by observations made using hot stage microscopy. The two endothermic transitions are suggested to correspond to the decomposition of the salbutamol sulphate molecule. The elongation ratio of the commercial lactose crystals, lactose crystallised from Carbopol and from water-ethanol were 1.69+/-0.05, 2.01+/-0.13 and 6.25+/-0.17, respectively. As the elongation ratio increased the flow properties of the carrier were affected detrimentally and this consequently reduced the content uniformity of salbutamol sulphate and drug emission from the inhaler device. Whereas, increasing the elongation ratio of the carrier or drug improved the deposition profiles of salbutamol sulphate, suggesting that the more elongated particles would be more aerodynamic and favour deep lung penetration.

The role of fine particle lactose on the dispersion and deaggregation of salbutamol sulphate in an air stream in vitro

Abstract Sieved (63–90 μ m) lactose (L) particles supported on a 63- μ m sieve was subjected to a compressed airstream with a flow rate of 160 l/min in order to remove existing fine particles. Fractions of the air-treated L were then blended separately with either 1.5%, w/w micronised L (5.0 μ m) or magnesium stearate (7.6 μ m, MS) and the blends were further sieved gently using a 45- μ m sieve to remove any freely dispersed fine L. Other fractions of the air-treated L were also blended with different quantities of intermediate sized lactose (15.9 μ m, IML) to obtain final concentrations of IML between 1.5 and 9% w/w. The various batches of L were then mixed separately with salbutamol sulphate (SS, 5.8 μ m) in a ratio of 67.5:1 (w/w). The particle size and shape of L were characterised by laser diffraction, a time-of-flight technique and scanning electron microscopy. The in vitro deposition of SS was measured using a twin impinger after aerosolisation at 60 l/min via a Rotahaler®. Air treatment of the coarse L was found to reduce significantly (ANOVA, p μ m sieve removed the majority of freely dispersed fine L thereby reducing significantly ( p 60% increase in FPF of SS whilst increasing the concentration of the added IML from 1.5 to 9% produced an approximate 50% further increase in the drug FPF.

The controlled delivery of drugs to the lung

Inhalation of aerosolised drugs has become a well established modality in the treatment of localised disease states within the lung. However, most medications in aerosol form require inhalation daily at least 3-4 times because of the relatively short duration of resultant clinical effects. Some studies have been conducted with a view to sustaining release of drugs in the lung so as to prolong drug action, reduce side effects and improve patient compliance. Liposomes have been shown to have the potential to produce controlled delivery to the lung, since they can be prepared with phospholipids endogenous to the lung as surfactants. Up to now, many drugs have been incorporated into liposomes and tested in both human subjects and animal models as pulmonary delivery systems. Other biodegradable microspheres (MS) such as albumin MS and poly(lactide and/or glycolide) copolymer MS are also being investigated. In contrast to liposomes, these MS may be more physico-chemically stable both in vitro and in vivo. Thus, drugs entrapped in biodegradable MS may have a slower release rate and a longer duration of action than those incorporated in liposomes. The prodrug approach has been successful in producing long-lasting bronchodilators whilst conjugation of drugs to macromolecules provides a possible mechanism for controlled release of drugs for either localised or systemic actions. Sustained release in the lung can also be achieved by reducing the aqueous solubility of the drug or co-precipitating relatively insoluble materials with aqueous soluble drugs. In contrast, inclusion of drugs in cyclodextrins is unable to sustain drug release in the lung, which may be due to the premature breakdown of drug-cyclodextrin conjugates in vivo. Many interdependent factors, involving the lung, carrier, drug and device have been shown to influence the overall disposition of drugs in the respiratory tract after inhalation. Current studies on pulmonary delivery systems have many limitations, mainly due to the lack of suitable animal models and the chronic side effects of drug carriers have yet to be established. Thus, more inter-disciplinary collaboration is essential for the development of effective controlled drug delivery systems intended for administration to the lung.

Particulate interactions in dry powder formulations for inhalation

Particulate interactions in dry powder formulations for inhalation , Particulate interactions in dry powder formulations for inhalation , مرکز فناوری اطلاعات و اطلاع رسانی کشاورزی

Direct effect of bile salts and phospholipids on the physical properties of mucus.

Reflux of duodenal contents into the stomach has been implicated in the disruption of mucosal defence and the subsequent occurrence of gastric ulcer. The change produced in the rheological properties following the addition of bile salts and phospholipids to mucus samples was used to assess resultant structural changes. Sodium deoxycholate, sodium taurodeoxycholate, sodium glycocholate, and lysophosphatidylcholine decreased both viscosity and elasticity, indicating that structural breakdown had occurred, whereas phosphatidylcholine could not be shown to have any effect. It is therefore suggested that some of the ulcerogenic activity of naturally occurring surfactants may be associated with their ability directly to reduce mucus consistency.