Biomedical subjects

Gary P Martin

Publications and source records attributed to Gary P Martin.

At least 19 recordsLinked to original sources

PubMed2007

Variability in human skin permeability in vitro: comparing penetrants with different physicochemical properties.

Appreciating and compensating for the inherent variability associated with percutaneous absorption is essential in optimizing (trans)dermal therapy. In this study, the variability in human skin permeability associated with model penetrants of differing lipophilicity (caffeine (CF), methyl paraben (MP), and butyl paraben (BP)) was examined in a standardized intra-laboratory study (Franz cell experiments) using epidermal tissue from various donors. Experimentally derived permeability coefficients (K(P)) were also compared to that derived from two skin permeation models namely, Potts & Guy and Robinson (revised) models in order to further validate the Franz diffusion method employed and also elucidate the potential permeation pathway(s) employed by the model penetrants. Intra-subject variability associated with skin permeation of the model penetrants was generally found to be lower than inter-subject variability. Experimental K(P) values were found to be the same order of magnitude as predicted by the mathematical models. Calculated residual variance suggested the Potts and Guy's model to be relatively accurate in predicting skin permeability of the two parabens whilst the Robinson (revised) model was more effective for CF. The high variability in CF permeation compared to the parabens may suggest the in vitro skin permeation of solutes becomes more sensitive to intra- and/or inter-subject variation in skin lipid content, appendageal density, and imperfections (pores, cracks) as the hydrophilic nature of the solute increases. Such variability in skin permeability suggests a difference in CF permeation kinetics relative to the parabens. As such when performing in vitro drug permeation studies, it is essential that the variability in the absorption of the model permeants, according to their physicochemical properties, is considered when they are used to normalize or standardize any resulting data.

Caffeine↗

PubMed2006

Influence of realistic inspiratory flow profiles on fine particle fractions of dry powder aerosol formulations.

PURPOSE: The purpose of the study was to determine how air flow profiles affect fine particle fractions (FPF) (<5 microm) from dry powder aerosol formulations and whether laser diffraction (LD) could be used to measure FPF of aerosols generated by variable flows. MATERIALS AND METHODS: Carrier-based formulations containing 1.5% w/w micronized salbutamol base blended with the 63-90 microm fraction of alpha-lactose monohydrate or sorbitol or maltose were aerosolised from a model glass device using either a constant flow rate or a predetermined flow profile. The FPFs of the same aerosolised particles were first measured by LD and then by a liquid impinger. Volunteer inhalation airflow profiles and 3-phase (acceleration, constant flow rate and deceleration) square wave airflow profiles were generated using the Electronic Lung and an Inhalation Profile Recorder. Similar experiments were conducted for a carrier-free formulation from the Bricanyl Turbohaler. RESULTS: Salbutamol FPFs of all carrier-based formulations were found to increase by increasing the initial flow increase rate (FIR) from 200 to 600 l min(-1) s(-1) although they could be placed in an increasing order of maltose blend < sorbitol blend < lactose blend. A significant linear correlation was found between FPFs measured by LD and by inertial impaction (R (2) = 0.95, p < 0.01, ANOVA). For the Bricanyl Turbohaler, increasing FIR from 120 to 600 l min(-1) s(-1) for a constant peak flow rate (PFR) of 60 l min(-1) increased the mean Terbutaline FPF from 18.2% to 45.5%. For the volunteer inhalation profiles, a higher FIR tended to be associated with higher PFR, leading to a marked increase in drug FPF due to the combined effect of FIR and PFR. CONCLUSION: Drug FPF from either carrier-free or carrier-based formulations is determined by both FIR and PFR. LD is a viable technique to measure the performance of dry powder aerosol formulations at realistic inspiratory flow profiles.

Administration, Inhalation↗

PubMed2006

Humidity-induced changes of the aerodynamic properties of dry powder aerosol formulations containing different carriers.

This paper presents the findings of two related studies. The aim of the first was to study any changes in the aerodynamic properties of salbutamol base powder formulations when different sugars were used as the carriers, after storage at an elevated humidity (75% RH), and whether any such changes (if any) were related to the physical properties of the carriers. The aim of the second was to investigate whether "ageing", i.e. storage of the carrier, drug and blends under desiccation for more than 2 years, affected the aerodynamic properties of salbutamol sulphate powder formulations. Different formulations were prepared, each containing 1.5% (w/w) micronised salbutamol base or sulphate blended with the sieved fraction (63-90 microm) of one of the following sugars: alpha lactose monohydrate, sorbitol, maltose and dextrose. The salbutamol base blends were then stored unprotected at 75% RH (ambient temperature) and salbutamol fine particle fractions (FPFs) were measured by laser diffraction (LD) (% < 5.2 microm) and a multistage liquid impinger (MSLI) (% < 5.3 microm), following aerosolisation at 100 l min(-1) from a model glass inhaler, after storage of each formulation at the elevated conditions for 0, 1 and 6 days. Particle morphology and equilibrium moisture content (EMC) of each formulation prior to and after storage were also evaluated. However, the salbutamol sulphate blends containing either "fresh" or "aged" components were only characterized using LD at 60 l min(-1). Prior to exposure to 75% RH, the lactose blend was found to give the highest FPF of salbutamol (30% by LD and 37% by MSLI), followed by the sorbitol blend (17% by LD and 29% by MSLI), then by the dextrose blend (15% by LD and 25% by MSLI) and finally by the maltose blend (13% by LD and 13% by MSLI). Exposure to 75% RH for 6 days resulted in a small reduction of salbutamol FPF from the lactose blend but drastic diminution of salbutamol FPFs from other blends. After exposure to the high RH, the lactose blend adsorbed ca. 0.4% whilst each of the other sugars took up larger quantities of water (15-40%) and underwent a marked change in the surface texture of the particles. "Ageing" of the carriers and/or formulations did not seem to alter the aerodynamic properties of the drug. "Ageing" of micronised salbutamol sulphate prior to blending, however, was found to improve the FPF of drug. LD was capable of detecting subtle differences between the various formulations and generated FPF results that correlated with those measured by MSLI.

Administration, Inhalation↗

PubMed2006

Correlation between inertial impaction and laser diffraction sizing data for aerosolized carrier-based dry powder formulations.

PURPOSE: The purpose of the study was to determine whether the drug fine particle fraction (FPF) from different dry powder aerosol formulations measured by laser diffraction at a range of flow rates correlated with that measured by inertial impaction. MATERIALS AND METHODS: Ten binary formulations were prepared containing 1.5% w/w salbutamol base or sulphate, blended with the sieved (63-90 microm) fraction of different sugars (regular lactose, spray-dried lactose, sorbitol, dextrose or maltose). A further six ternary formulations were prepared containing 1.5% w/w salbutamol sulphate, 97% coarse lactose (63-90 microm) and 1.5% micronised or intermediate-sized lactose (1-50 microm). The FPF particles (< 5 microm) of these formulations were measured by laser diffraction and inertial impaction at flow rates between 28.3 and 100 l min(-1). RESULTS: When only the particles with diameter < 60 microm obtained by laser diffraction were considered the FPF (< 5 microm) could be determined and this enabled the aerosolisation of all 16 blends to be feasibly compared at flow rates ranging from 28.3 to 100 l min(-1). A significant linear correlation was found between the fine fractions measured by laser diffraction and the salbutamol fine fractions determined by inertial impaction (r2 = 0.934). Such correlation was also confirmed for formulations containing added fine lactose. CONCLUSION: Particle size measured by laser diffraction under the employed conditions reflected the aerodynamic properties of the drug. Laser diffraction can be used as on-, in- and/or at-line measurements and controls for dry powder aerosol formulations.

Adrenergic beta-Agonists↗

PubMed2006

Characterisation of a carrier-free dry powder aerosol formulation using inertial impaction and laser diffraction.

PURPOSE: The purpose of the study was to examine the suitability of using laser diffraction to measure the fine particle fraction (FPF) of drugs emitted from carrier-free dry powder aerosol formulations. MATERIALS AND METHODS: Particle size distribution of terbutaline sulphate from Bricanyl Turbohaler, which contained loose agglomerates of drug particles only, was measured separately by laser diffraction apparatus equipped with a metal throat and a twin-stage, multi-stage liquid impingers, or Andersen cascade impactor at flow rates ranging from 28.3 to 100 l min(-1). In-line measurements were then conducted which allowed the same aerosolised particles to be measured first by laser diffraction then captured by an impactor or impinger for subsequent chemical analysis. RESULTS: A significant linear correlation (p < 0.001, R2 = 0.96, ANOVA) existed between the results obtained from two techniques when measurements were conducted independently. There was little difference in FPFs measured by inertial impaction and laser diffraction at the same flow rate. When in-line measurements were conducted, the FPFs measured by inertial impaction were approximately 0.7-0.9 times the aerosol FPFs measured by laser diffraction. This linear relationship was statistically significant and had a statistically insignificant y-intercept, regardless of inhaler batches, impinger types and measuring position of the laser beam. CONCLUSION: Laser diffraction could prove to be a reliable technique for development, evaluation and quality control of carrier-free, dry powder aerosol formulations.

Aerosols↗

PubMed2006

Development of a laser diffraction method for the determination of the particle size of aerosolised powder formulations.

Impactor data are an essential component of marketing authorisation for new dry powder aerosol formulations. However such data are time-consuming to obtain and therefore impede the rapid screening of pilot formulations. In this phase of development it would be of considerable benefit to employ a technique where data acquisition was more rapid, such as laser diffraction, to predict the fine particle fraction. It was the aim of this study to investigate whether this is a feasible premise. Five different formulations were prepared, each containing 1.5% (w/w) micronised salbutamol base (volume median diameter: 2.42 microm) blended with the sieved fraction (63-90 microm) of one of the following sugars: regular crystalline lactose, spray dried lactose "Zeparox", sorbitol, maltose and dextrose monohydrate. A Perspex box was constructed to contain particles released from a glass inhaler and allow the particles to be measured by laser diffraction at different flow rates. After being validated using monodisperse aerosols, this assembly was then employed to measure the particle size distributions of each powder formulation and its respective sugar carrier at flow rates ranging from 28.3 to 100 l min(-1). Aerodynamic particle size distribution of salbutamol base from each formulation was also measured after aerosolisation at 28.3 l min(-1) from the glass inhaler into an Andersen cascade impactor. The flight of monodisperse particles with diameters (2-6 microm) in the desired size range of dry powders for inhalation could be contained and the size distribution determined by laser diffraction using the assembly at all flow rates investigated. Treatment of the particle size distributions measured by laser diffraction, i.e. examining only the aerosol particles with diameter <60 microm, highlighted the fine fraction (<5 microm) and enabled the aerosolisation of different blends to be feasibly compared at a range of different flow rates. The blends containing the following excipients could be placed in the following order of increasing fine fraction: spray-dried lactose<dextrose<<maltose<lactose<sorbitol. At 28.3 l min(-1) a significant linear correlation was found between the fine fractions measured by laser diffraction and the salbutamol fine fractions determined by inertial impaction (R(2)=87.4%, p=0.02, ANOVA). Therefore, the laser diffraction technique could prove to be an important tool for particle size characterisation of dry powder aerosol formulations.

Aerosols↗

PubMed2006

Culture of Calu-3 cells at the air interface provides a representative model of the airway epithelial barrier.

PURPOSE: The aim of this study was to compare the effect of liquid-covered culture (LCC) and air-interfaced culture (AIC) on Calu-3 cell layer morphology and permeability, thus assessing the fitness of these culture systems as models of airway epithelium barrier function. METHODS: Cell layers were grown on 0.33 cm2 Transwell polyester cell culture supports. Cell layers grown using LCC and AIC were evaluated by using light and electron microscopy, transepithelial electrical resistance (TER), and permeability to the transepithelial flux of fluorescein sodium (flu-Na), and by varying molecular weight dextrans labeled with fluorescein isothiocyanate (FITC-dex). The tight junction protein, zona occludens protein-1 (ZO-1), was visualized by confocal microscopy and apical glycoprotein secretions were identified by using alcian blue. RESULTS: Cells grown via AIC produced a more columnar epithelium with a more rugged apical topography and greater glycoprotein secretion compared to cells grown via LCC. Apical protrusions appearing to be cilia-like structures were observed on occasional cells using AIC, but typical airway ciliated cell phenotypes were not produced under either condition. Secretory granules were observed in cells cultured under both conditions. Cells cultured using LCC exhibited higher levels of ZO-1 protein than the AIC counterpart. The maximal TER of cells using LCC, 1,086 +/- 113 ohms cm2 at 11-16 days, was significantly greater than the TER of cells cultured using AIC, 306 +/- 53 ohms cm2 at 11-13 days. Apparent permeability (P(app)) values for the transport of flu-Na using LCC and AIC were 1.48 +/- 0.19x10(-7) and 3.36 +/- 0.47x10(-7) cm s(-1), respectively. Transport rates of flu-Na and FITC-dex were inversely proportional to molecular weight, and were significantly lower (p < 0.05) in cell layers grown using LCC than AIC. Renkin analysis fitted the data to single pore populations of radii 7.7 and 11.0 nm for LCC and AIC, respectively. CONCLUSION: Distinct differences in morphology and permeability result when Calu-3 cells are grown using AIC or LCC. Cells cultured using AIC generate a model more morphologically representative of the airway epithelium than cells cultured using LCC.

Bronchi↗

PubMed2006

Stabilisation of deoxyribonuclease in hydrofluoroalkanes using miscible vinyl polymers.

A mix of biocompatible macromolecules (poly(vinyl alcohol) (PVA) and poly(vinyl pyrrolidone) (PVP)) has been shown previously to enhance the physical stability of non-aqueous pharmaceutical suspensions. The aim of this work was to assess the feasibility of employing such a combination to facilitate the formulation of deoxyribonuclease I (DNase I) in a metered dose inhaler (MDI) using hydrofluoroalkane (HFA) propellants. DNase I was combined with the selected excipients and formed into an inhalable microparticle by spray-drying. When spray-dried alone DNase I lost almost 40% of its original biological activity, but stabilising DNase I with trehalose and PVA (DTPVA) retained 85% biological activity and trehalose, PVA and PVP (DTPVAPVP) retained 100%. Suspending the DTPVAPVP microparticles within a HFA pMDI for 24 weeks led to no further reduction in the biological activity of DNase I and the formulation delivered almost 60% of the dose expelled to the second stage of a twin-stage impinger. The solubility of PVP in HFA propellants suggests that the enhanced physical stability observed with PVA and PVP may partially be as a result of steric stabilisation. However, the large zeta potential associated with the suspensions suggested that charge stabilisation may also influence the pMDI physical stability.

Algorithms↗

PubMed2006

Composite membrane of bacterially-derived cellulose and molecularly imprinted polymer for use as a transdermal enantioselective controlled-release system of racemic propranolol.

A composite membrane for transdermal delivery of S-propranolol enantiomer was developed based on the controlled pore functionalization of bacterial cellulose membranes using a molecularly imprinted polymer (MIP) layer synthesis. The reactive pore-filling of an asymmetric porous cellulose membrane with a MIP thin-layer was effected using a silanized coupler as an additional anchor for the MIP. MIP thin-layers with specific binding sites for S-propranolol were synthesized by copolymerization of methacrylic acid with a cross-linker, ethylene glycol dimethacrylate in the presence of S-propranolol as the template molecule and the latter was subsequently extracted. Selective transport of S-propranolol through the MIP composite membrane was obtained, although this was determined mostly by the parent cellulose membrane with some ancillary contributory effect from the MIP layer. In addition, an enantioselectivity in the transport of propranolol prodrug enantiomers was found, suggesting that the shape and functional groups orientation, which are similar to that of the print molecule were essential for enantiomeric recognition of the MIP composite membrane. The enantioselectivity of S-MIP membranes was also shown when the release of propranolol enantiomers was studied in vitro using rat skin, with racemic propranolol contained in the donor compartment. The composite membrane of bacterially-derived cellulose and molecularly imprinted polymer may have great potential for use as a transdermal enantioselective controlled-release system for racemic propranolol.

Administration, Cutaneous↗

PubMed2006

Temperature sensitive dopamine-imprinted (N,N-methylene-bis-acrylamide cross-linked) polymer and its potential application to the selective extraction of adrenergic drugs from urine.

A temperature sensitive dopamine-imprinted polymer was prepared in 80% aqueous methanol solution by free-radical cross-linking co-polymerisation of methacrylic acid and acrylamide at 60 degrees C in the presence of N,N-methylene-bis-acrylamide as the cross-linker and dopamine hydrochloride as template molecule. The resulting molecularly imprinted polymer (MIP) formed temperature responsive materials, which could be used for the selective separation of appropriate dopamine and adrenergic compounds from a liquid matrix at ambient temperatures. The thermoresponsive MIP exhibited a swelling-deswelling transition in 80% aqueous methanol solution at about 35 degrees C. The capacity of the thermoresponsive MIP to recognise the template molecule when present in aqueous methanol solution changed with temperature, with the highest selectivity found at 35 degrees C. Additionally, binding parameters obtained from Scatchard analyses indicate that increasing temperature resulted in an increased affinity and binding capacity of specific binding sites, but had less effect on non-selective binding sites. Subsequently, the thermoresponsive MIP was tested for its application as a sorbent material, utilisable in the selective solid-phase extraction (SPE) of dopamine and other adrenergic compounds (epinephrine, isoproterenol, salbutamol and serotonin) from urine samples. It was shown that the compounds that were structurally related to dopamine could be removed by elution, while dopamine and serotonin, the analytes of interest, remained strongly adsorbed to the adsorbent during SPE applications. The thermoresponsive MIP displayed different efficiency in clean-up and enrichments using the SPE protocol at different temperatures.

Acrylamides↗

PubMed2006

Manipulation of beclomethasone-hydrofluoroalkane interactions using biocompatible macromolecules.

The aim of this work was to physically stabilise beclomethasone dipropionate (BDP) microparticles within a hydrofluoroalkane (HFA) propellant using biocompatible polymers in order to allow the efficient delivery of the steroid to the airways from a pressurised metered dose inhaler (pMDI). BDP microparticles were coated with a number of different "amphiphilic" macromolecular excipients by spray-drying an aqueous BDP suspension in which the excipients were dissolved. The physical stability of the coated BDP microparticles was assessed both indirectly using a twin-stage impinger (TSI) and directly using "in-situ" laser diffraction particle size analysis in a range of nonpolar solvents. The solubility of the formulation excipients within a number of the nonpolar vehicles was determined using an internally manufactured filtration rig and the influence of zeta potential within the microparticle suspensions measured in a series surrogate nonpolar systems. The size of the pure BDP microparticles increased significantly (p < 0.05, ANOVA) from 3.13 +/- 0.15 microm to 9.86 +/- 0.50 microm upon suspension within a nonpolar HFA solvent. However, the addition of poly(vinyl alcohol) (PVA) and poly(vinyl pyrrolidone) (PVP) to the BDP microparticles dramatically reduce this aggregation leading to the production of physically stable suspensions with excellent aerosolisation properties (Stage 2 deposition >40% in the twin-stage impinger). It is postulated that the enhanced physical stability observed when PVA and PVP are coated onto BDP microparticles is partially as a result of steric stabilisation in HFA solvents. However, the large zeta potential associated with the nonpolar microparticle suspensions suggest that charge stabilisation may also influence the physical stability within these systems.

Aerosol Propellants↗

PubMed2005

The microsponge delivery system of benzoyl peroxide: preparation, characterization and release studies.

Benzoyl peroxide (BPO) is commonly used in topical formulations for the treatment of acne and athletes foot. Skin irritation is a common side effect, and it has been shown that controlled release of BPO from a delivery system to the skin could reduce the side effect while reducing percutaneous absorption. Therefore, the aim of the present study was to produce ethylcellulose microparticles containing BPO which were able to control the release of BPO to the skin. In order to optimize the microparticle formulation, factors affecting the physical properties of microparticles were also investigated. Benzoyl peroxide microparticles were prepared using an emulsion solvent diffusion method by adding an organic internal phase containing benzoyl peroxide, ethyl cellulose and dichloromethane into a stirred aqueous phase containing polyvinyl alcohol. Drug content, particle size analysis and loading yield were determined in the prepared microparticles. BPO microparticles were then incorporated into standard vehicles for release studies. Scanning electron microscopy was used to study the shape and morphology of the microsponges. The micrograph of microsponges showed that they were spherical in shape and contained pores. These pores resulted from the diffusion of solvent from the surface of the microparticles and thus the particles were designated as microsponges. It was shown that the drug:polymer ratio, stirring rate, volume of dispersed phase influenced the particle size and drug release behavior of the formed microsponges and that the presence of emulsifier was essential for microsponge formation. The results showed that, generally, an increase in the ratio of drug:polymer resulted in a reduction in the release rate of BPO from microsponges which was attributed to a decreased internal porosity of the microsponges.

Benzoyl Peroxide↗

PubMed2005

The effects of polyvinyl alcohol on the in vitro stability and delivery of spray-dried protein particles from surfactant-free HFA 134a-based pressurised metered dose inhalers.

The objective of the present study was to investigate the physical stability of spray-dried proteins within surfactant-free hydrofluoroalkane (HFA) pressurised metered dose inhalers (pMDIs) during prolonged storage. Two model proteins (lysozyme and catalase) were spray-dried and stabilised in the presence of excipients, and subsequently suspended within HFA 134a. The pMDIs were stored valve-up for 6 months at room temperature (ca. 25 degrees C). Activities of the proteins were determined using biological assays and the fine particle fraction of the pMDIs was measured using a twin-stage impinger. The biological activities of catalase and lysozyme were found to be preserved in the presence of sugars and/or 80% hydrolysed polyvinyl alcohol (PVA) during spray drying. In addition, suspending the stabilised proteins within HFA for up to 6 months had little effect on their activity. The aerosolisation performance of lysozyme or catalase formulations containing either sucrose or trehalose as stabilisers appeared to deteriorate as a function of storage time. However, those formulations containing PVA were found to generate the greatest fine particle fraction, which in some cases was up to 50%, and to possess excellent physical stability during storage. The results indicated that the presence of PVA in the spray-dried stabilised protein particles could enhance the physical stability of particles, when suspended in the surfactant-free HFA MDI formulations, without affecting the protein stability upon prolonged storage.

Aerosol Propellants↗

PubMed2004

An investigation of calibration methods for solution calorimetry.

Solution calorimetry has been used in a number of varying applications within pharmaceutical research as a technique for the physical characterisation of pharmaceutical materials, such as quantifying small degrees of amorphous content, identifying polymorphs and investigating interactions between drugs and carbohydrates or proteins and carbohydrates. A calibration test procedure is necessary to validate the instrumentation; a few of the suggested calibration reactions are the enthalpies of solution associated with dissolving Tris in 0.1 M HCl or NaCl, KCl or propan-1-ol in water. In addition, there are a number of different methods available to determine enthalpies of solution from the experimental data provided by the calorimeter, for example, the Regnault-Pfaundler's method, a graphical extrapolation based on the Dickinson method, or a manual integration-based method. Thus, the aim of the study was to investigate how each of these methods influences the values for the enthalpy of solution. Experiments were performed according to the method outlined by Hogan and Buckton [Int. J. Pharm. 207 (2000) 57] using KCl (samples of 50, 100 and 200 mg), Tris and sucrose as calibrants. For all three materials the manual integration method was found to be the most consistent with the KCl in water (sample mass of 200 mg) being the most precise. Thus, this method is recommended for the validation of solution calorimeters.

Analysis of Variance↗

PubMed2004

Investigation of the stabilisation of freeze-dried lysozyme and the physical properties of the formulations.

The long-term stability of a protein formulation requires that the glass transition temperature (Tg) of the formulation should be maximised and the perturbation of the protein native structure in the dried form after processing minimised. In the present study, the stabilisation of lysozyme structure conferred by excipients was monitored using second derivative Fourier transform infrared spectroscopy and the physical properties of protein formulations were investigated using differential scanning calorimetry. The results showed that the preservation of protein native structure during freeze-drying and the Tg of freeze-dried formulations were excipient- and excipient to enzyme mass ratio-dependent. The freeze-dried lysozyme appeared to be less effectively stabilised compared with the spray-dried enzyme when the excipients and the excipient to enzyme mass ratios were the same. In terms of the preservation of the secondary structure of lysozyme, glycerol and sucrose seemed to be more efficient than trehalose, although the Tg of trehalose-containing formulations were found to be higher than the Tg of the equivalent sucrose-based ones. With adding either trehalose or dextran to sucrose-containing formulations, the stabilisation of lysozyme native structure could be as effective as with sucrose alone, whilst the Tg could be enhanced. The results in this study suggested that lysozyme, processed by freeze-drying, is stabilised primarily by the water substitution mechanism.

Chemistry, Pharmaceutical↗

PubMed2004

Effect of heat on the percutaneous absorption and skin retention of three model penetrants.

The effect of heat on the transdermal delivery of model penetrants of differing lipophilicity through artificial membranes (non-rate limiting) and human epidermis was investigated in vitro. Saturated suspensions of the model penetrants; methyl paraben (MP), butyl paraben (BP) and caffeine (CF) in deionised water (vehicle) were used to attain maximal thermodynamic activity. Franz cell experiments were performed at temperatures ranging from 23 to 45 degrees C using the infinite dose method. Artificial membrane studies showed the penetrant diffusivity (diffusion coefficient) in the vehicle to be totally dependent on temperature and not changes in donor solubility. Epidermal flux and retention of all penetrants was found to be affected by temperature. The amount of penetrant retained in the epidermis was found to be in the order BP>CF>MP whilst the transdermal fluxes increased in the order MP>BP>CF with increasing receptor temperature. Estimated epidermal diffusivity of MP was found to be significantly affected by temperature (P< or =0.05) compared to BP and CF. Using Arrhenius plots, a lower activation energy was recorded for CF and may suggest a difference in permeation kinetics compared to the other penetrants.

Adjuvants, Pharmaceutic↗

PubMed2003

The human bronchial epithelial cell line 16HBE14o- as a model system of the airways for studying drug transport.

The 16HBE14o- cell line, which forms polarised cell layers in vitro, provides a promising opportunity to develop a convenient epithelial cell culture model in which respiratory drug transport can be evaluated in vitro. This study investigated the effect of cell seeding density, collagen substratum and time in culture on the development of barrier properties in this cell line, after which the permeability of the 16HBE14o- cell layers to a series of solutes was studied. Seeding cells at a density of 2.5 x 10(5) cells per cm(2) on a monofibrillar Vitrogen-100 collagen substratum, followed by culture at an air-liquid interface for 6 days resulted in cell layers with a transepithelial electrical resistance (TER) of 247+/-47 omegacm(2) and an apparent permeability coefficient of 2.5 x 10(-6)cms(-1) for mannitol. The permeability of the 16HBE14o- cells to hydrophilic molecules (logP<1.9) was of an order of magnitude greater than that of typical alveolar cell cultures, possibly reflecting barrier properties more representative of the airways. More lipophilic drugs showed higher permeabilities indicating a sigmoidal relationship between permeability and lipophilicity similar to that observed for solute transport across primary cultured epithelial cell layers. These results indicate that under appropriate culture conditions, 16HBE14o- cell layers provide a discriminatory barrier to solute transport.

Albuterol↗

PubMed2003

Characterisation and deposition studies of engineered lactose crystals with potential for use as a carrier for aerosolised salbutamol sulfate from dry powder inhalers.

Lactose particles with different elongation ratio, roundness, polymorphic form and crystallinity were prepared by a one-step crystallisation process using varying ratios of acetone/water. The crystals were characterised using image analysis optical microscopy, scanning electron microscopy, differential scanning calorimetry and X-ray powder diffraction. The elongation ratio was found to increase with increasing acetone ratio which therefore, appears to accelerate the growth in length rather than width and/or thickness. The crystallinity and polymorphic forms were also acetone-concentration dependent. For example, the crystals formed using 65-80% v/v acetone were almost all of the alpha-form whereas at 85% v/v a small amount of beta-form was precipitated, as detected by a peak at the reflection angle 2 theta=10.4 in the X-ray diffractogram. When 90% v/v acetone was incorporated a mixture of alpha- and beta-forms were produced in almost equal quantity, whereas, with 95% v/v acetone the beta-form predominated. At high acetone concentration (90 and 95% v/v), the crystallisation proceeded rapidly leading to the creation of some amorphous content. The 63-90-microm sieve cut of either commercial grade lactose (CL) or crystallised lactose was mixed with salbutamol sulfate and dispersibility was determined using the twin stage liquid impinger. All the formulations containing carrier particles generated by crystallization from solvent showed higher dispersibility and fine particle fraction (FPF) of the drug compared to the formulation made containing CL. The carrier that showed the highest elongation ratio (produced from an 85% acetone 15% water solution), when mixed with salbutamol sulfate produced the highest dispersibility (38.5%) and highest FPF (29.24%). These parameters were six times higher than the values obtained with the formulation containing CL.

Acetone↗