Characterization of the suspension stability of pharmaceuticals using a shadowgraphic imaging method.

A new shadowgraphic imaging method and an associated instrument for analyzing the physical stability of pharmaceutical suspensions are introduced in this paper. The new suspension tester consists mainly of a high-resolution camera that takes sequential shadowgraphic images of emulsions or suspensions and a 2D collimated LED for simultaneous whole-sample illumination in bright field. A built-in ultrasonic bath provides controlled initial agitation to the samples of interest. Sequential images acquired by the experimental setup were used to derive normalized transmission profiles from which an instability index was developed for quantitative stability comparison between samples. Instrument performance was verified by measuring the stability of a series of oil-in-water emulsions prepared with surfactant mixtures of different ratios. The new instrument correctly determined the required hydrophilic-lipophilic balance for sunflower oil to be 7.0. The stability of a pressurized suspension of spray dried lipid (DSPC) particles was monitored for 5 days after propellant filling. Although stable for the first 24 h, the lipid suspension was found to decrease in stability from day 1 to day 4. Morphological and spectroscopic analysis revealed that the suspended DSPC particles had reformed into large thin sheets of lipid, thereby causing the gradual stability decrease during the aging study. The effects of initial agitation on the stability of suspensions were demonstrated by agitating a suspension of micronized fluticasone propionate in propellant using a wrist action shaker and an ultrasonic bath respectively. A significant improvement of suspension stability was achieved by replacing the wrist action shaker method with ultrasonic agitation. Simultaneous illumination of the complete suspension, a high image acquisition rate, and controlled initial agitation are features that make this new suspension tester a suitable and more reliable instrument for investigating the stability of pressurized pharmaceutical suspensions.

Beclomethasone dipropionate hydrofluoroalkane for the treatment of allergic rhinitis.

Allergic rhinitis (AR) is a common respiratory disease, and its prevalence is increasing all over the world, both in adults and in children. Patients experience symptoms that may negatively impact on physical, social and psychological well-being. Hence, if left untreated, allergic rhinitis may significantly affect quality of life. Under current guidelines, intranasal corticosteroids are considered the most effective drugs and they are recommended as first-line therapy. Among the several corticosteroid intranasal sprays available, beclomethasone dipropionate is one of the most prescribed. Recently, new intranasal hydrofluoroalkane-propelled formulations with little or no impact on the ozone layer have been developed for the treatment of AR. The use of these devices might improve patients' adherence to treatment, avoiding some of the most common side effects associated with aqueous formulations. This review provides the most recent evidence for the efficacy and safety of beclomethasone dipropionate hydrofluoroalkane nasal aerosol in the treatment of allergic rhinitis.

A novel bottom-up process to produce nanoparticles containing protein and peptide for suspension in hydrofluoroalkane propellants.

To overcome the disadvantages of microemulsion and nanoprecipitation methods to produce protein-containing nanoparticles, a novel bottom-up process was developed to produce nanoparticles containing the model protein lysozyme. The nanoparticles were generated by freeze-drying a solution of lysozyme, lecithin and lactose in tert-butyl alcohol (TBA)/water co-solvent system and washing off excess lecithin in lyophilizate by centrifugation. Formulation parameters such as lecithin concentration in organic phase, water content in TBA/water co-solvent, and lactose concentration in water were optimized so as to obtain desired nanoparticles with retention of the bioactivity of lysozyme. Based on the results, 24.0% (w/v) of lecithin, 37.5% (v/v) of water content, and 0.56% (w/v) of lactose concentration were selected to generate spherical nanoparticles with approximately 200 nm in mean size, 0.1 in polydispersity index (PI), and 99% retained bioactivity of lysozyme. These nanoparticles rinsed with ethanol containing dipalmitoylphosphatidylcholine (DPPC), Span 85 or oleic acid (3%, w/v) could readily be dispersed in HFA 134a to form a stable suspension with good redispersibility and 98% retained bioactivity of lysozyme. The study indicates there is a potential to produce pressed metered dose inhaler (pMDI) formulations containing therapeutic protein and peptide nanoparticles.

Split-face comparison study of cryogen spray cooling versus pneumatic skin flattening in skin tightening treatments using a long-pulsed Nd:YAG laser.

BACKGROUND: Nd:YAG pulsed lasers are used for non-ablative skin tightening treatment. A common drawback of this procedure is pain, which is often intolerable. Pneumatic skin flattening (PSF) is a new technology which alleviates pain in laser treatments. The purpose of this study is to assess the clinical efficacy and pain reduction in Nd:YAG laser skin tightening treatments with PSF compared to Nd:YAG laser skin tightening treatments with cryogen spray cooling (CSC). METHODS: Eleven patients were treated on the face with an Nd:YAG laser operated at an energy setting of 30 J/cm(2) and a pulse duration of 50 ms. Half of the face was treated with the Nd:YAG using CSC and the other side was treated with the Nd:YAG using PSF. A comparison of pain elicited from each treatment was done by comparing each patient's VAS pain scoring of the two sides. RESULTS: Treatment efficacy with CSC and with PSF was identical. The study confirmed significant pain reduction with PSF (p < 0.01). The average pain scores for PSF and CSC were 2.4 and 6.9, respectively. Mild ecchymosis was observed in two patients on the PSF side. CONCLUSION: Nd:YAG laser skin tightening treatments with PSF are less painful than Nd:YAG laser skin tightening treatments with CSC; the PSF treatments can be done with minimum side effects.

An in vitro evaluation of the efficiency of an air-abrasion system using helium as a propellant.

OBJECTIVES: Helium is currently used as a propellant gas for air-abrasion with manufacturer claims that this affords greater cutting efficiency compared to the use of air as a propellant. Higher cutting rates, when desired, can reduce operative times. This study set out to investigate these claims by comparing the rate at which helium propelled air-abrasion cut a standard enamel analogue, Macor, versus that of standard air propelled air-abrasion at different propellant pressures. METHODS: An enamel substitute, Macor, was used as the substrate in order to enable a greater control of physical variables. Powder flow rate, air abrasion nozzle distance and angle to the enamel substitute were constant throughout the experiments. The cutting efficiency of air and helium with propellant pressures of 20, 40, 60, 80 and 100PSI were dynamically investigated, attempting to replicate clinical use. RESULTS: Helium air-abrasion was significantly more efficient in cutting the enamel analogue at all pressures, with a 40% increase for 100PSI propellant pressure. SIGNIFICANCE: This finding suggests that air-abrasion units using helium as a propellant will be able to cut enamel more quickly in the clinical setting.

Novel propellant-driven inhalation formulations: engineering polar drug particles with surface-trapped hydrofluoroalkane-philes.

Challenges in reformulating pressurized metered-dose inhalers (pMDIs) with hydrofluoroalkane (HFA) propellants, and the potential of inhalation formulations for the delivery of drugs to and through the lungs have encouraged the development of novel suspension-based pMDI formulations. In this work we propose a new methodology for engineering polar drug particles with enhanced stability and aerosol characteristics in propellant HFAs. The approach consists in 'trapping' HFA-philic moieties at the surface of particles, which are formed using a modified emulsification-diffusion method. The trapped moieties act as stabilizing agents, thus preventing flocculation of the otherwise unstable colloidal drug particles. This approach has advantages compared to surfactant-stabilized colloids in that no free stabilizers remain in solution (reduced toxicity), and the challenges associated with the synthesis of well-balanced amphiphiles are circumvented. The methodology was tested by trapping polyethylene glycol (PEG) at the surface of particles of a model polar drug-salbutamol sulfate. Colloidal probe microscopy is used to quantitatively demonstrate the trapping of the HFA-phile at the surface, and the ability of PEG in screening particle-particle cohesive interactions. Both physical stability and the corresponding aerosol characteristics are significantly improved compared to those of a commercial formulation. The fine particle fraction of PEG-coated salbutamol sulfate was observed to be 42% higher than that of Ventolin HFA. The formation of stable dispersions of terbutaline hemisulfate using the same approach, suggests this to be a generally applicable methodology to polar drugs.

Effect of ambient humidity on light transmittance through skin phantoms during cryogen spray cooling.

Cryogen spray cooling (CSC) is a technique employed to reduce the risk of epidermal damage during dermatologic laser surgery. However, while CSC protects the epidermis from non-specific thermal damage, it might reduce the effective fluence reaching the target chromophore due to scattering of light by the spray droplets and subsequent water condensation/freezing on the skin surface. The objective of this work was to study the effect of ambient humidity (omega) on light transmittance during CSC. An integrating sphere was employed to measure the dynamics of light transmittance through a deformable agar phantom during CSC. The study included two representative CSC spurt patterns studied using four omega: 57, 40, 20 and 12%. Results show that during CSC, as omega increased, light transmittance decreased. For the highest humidity level (57%) studied, light transmittance reached a minimum of 55% approximately 30 ms after spurt termination. In a controlled environment with omega = 12%, light transmittance reached a minimum of 87% approximately 30 ms after spurt termination. The reduced light transmittance immediately after spurt termination was most likely because of scattering of light caused by condensation of water vapour due to aggressive cooling of ambient air in the wake of the cryogen spurt.

Epidermal and vascular damage analysis of in vivo human skin in response to 595 nm pulsed laser irradiation.

BACKGROUND AND OBJECTIVES: Laser irradiation is the current modality for treatment of cutaneous hypervascular malformations such as port wine stains and telangiectasia. Although cryogen spray cooling (CSC) is used to protect the epidermis from non-specific laser-induced thermal damage in moderately-pigmented skin types, individuals with high melanin content are still at risk for epidermal damage using the current laser irradiation and CSC parameters. The objective of this study was to investigate the influence of the spray Weber number (1,100 or 5,100) on epidermal protection and examine vascular coagulation in response to pulsed dye laser irradiation. STUDY DESIGN/MATERIALS AND METHODS: Normal, in vivo human skin from eight subjects of Fitzpatrick skin types I-V were precooled with either low or high Weber number cryogen sprays and subsequently irradiated with a pulsed dye laser at 595 nm. Analysis of gross purpura, morphological vascular damage, and apoptosis of the vascular walls were performed. RESULTS: Results demonstrated a high Weber number spray of 5,100 decreased the level of epidermal damage in darker and moderate pigmented individuals compared to a Weber number spray of 1,100. This study also established a positive correlation between gross purpura and the level of vessel wall apoptosis. CONCLUSIONS: This study has demonstrated that CSC with a high Weber number spray can decrease nonspecific thermal damage to the epidermis in response to laser irradiation in vivo. We have also established a positive correlation between gross purpura and the level of vessel wall apoptosis. Lasers Surg. Med. (c) 2005 Wiley-Liss, Inc.

Comparison of the systemic pharmacodynamic effects and pharmacokinetics of salmeterol delivered by CFC propellant and non-CFC propellant metered dose inhalers in healthy subjects.

This was a randomised, double-blind, placebo-controlled, cross-over study comparing the systemic pharmacodynamic effects (heart rate and serum potassium) and pharmacokinetics of salmeterol delivered by the non-CFC hydrofluoralkane (HFA) propellant 134a and the CFC propellant (propellant 11/12) metered dose inhalers (MDI) in healthy subjects. At the therapeutic dose (50 microg), salmeterol-mediated systemic pharmacodynamics were equivalent for the HFA and CFC MDIs. Higher doses of salmeterol (150 and 300 microg) produced dose-related beta-agonist pharmacodynamic effects irrespective of the propellant. However, these effects were lower with salmeterol HFA MDI than with the salmeterol CFC MDI at all dose levels. Overall, salmeterol Cmax and AUC(0-t) values were lower for salmeterol HFA compared with salmeterol CFC MDI. At the highest dose (300 microg), where a full pharmacokinetic profile was obtained, exposure to salmeterol delivered by the HFA MDI compared with the salmeterol CFC MDI was 27% and 30% lower for Cmax and AUC(0-t), respectively. Maximum plasma concentrations were generally seen in the first plasma samples taken 5 min after the start of dosing. Salmeterol HFA was well-tolerated. At supratherapeutic doses, adverse events were typical for high-dose salmeterol with fewer adverse events occurring with the HFA compared with the CFC formulation. These data indicate that the salmeterol HFA MDI would not be associated with a significantly different pharmacodynamic, safety and tolerability profile compared with the salmeterol CFC MDI.

Successful treatment of hypersensitivity pneumonitis caused by Grifola frondosa (Maitake) mushroom using a HFA-BDP extra-fine aerosol.

We successfully treated a patient with occupational hypersensitivity pneumonitis (HP) caused by Grifola frondosa (Maitake) mushroom spore with an extra-fine aerosol corticosteroid; beclomethasone dipropionate (BDP) dissolved in hydrofluoroalkane-134a (HFA). A 49-year-old woman developed respiratory symptoms 3 months after beginning work on a mushroom farm. She was diagnosed as HP based on radiological and serological findings. Oral prednisolone therapy improved her HP and she returned to the same farm. Her HP relapsed after 5 months, and daily 400 microg of HFA-BDP was administered with gradual improvement. An extra-fine particle inhaled corticosteroid might reach appropriate alveoli to be effective therapy for mild HP.

Flunisolide HFA for the treatment of asthma: an old friend reformulated.

The environmental mandate to eliminate the production of ozone-depleting products including chlorofluorocarbon (CFC) propellants has encouraged much needed research into improving modes of delivery of inhaled corticosteroids and enhancing drug deposition. Consequently, flunisolide CFC, an inhaled corticosteroid with a proven track record in the treatment of asthma, has been reformulated using a hydrofluoroalkane (HFA) as a propellant and is now awaiting FDA approval. Flunisolide HFA is a solution aerosol, unlike flunisolide CFC which is a suspension aerosol. As a solution aerosol, flunisolide HFA has a smaller mean particle size than flunisolide CFC. In addition, the built-in spacer included in the flunisolide HFA inhaler acts to reduce ex-actuator particle size; the smaller particle size of flunisolide HFA results in an improved deposition profile. Flunisolide HFA has substantially more lung deposition and much less oropharyngeal deposition than flunisolide CFC. Limited information is currently available on the clinical performance of flunisolide HFA. A single dose-response study has been performed in adults and in children comparing multiple doses of flunisolide HFA and flunisolide CFC. These studies indicate that flunisolide HFA is effective in controlling asthma. No unusual safety concerns have been noted, although further studies are needed to determine the long-term systemic effects of flunisolide HFA.

Characterization of the mechanism of interaction in ibuprofen-Eudragit RL100 coevaporates.

The present study is a preliminary exploration of the affinity between a carboxylic model drug, the nonsteroidal antiinflammatory agent ibuprofen (IBU) and Eudragit RL100 (RL) polymer. Due to the presence of a variable amount of quaternary ammonium groups in this matrix, physical and chemical interaction with the carboxylic drug can occur, which reinforces its scant mechanical dispersion in the polymer network and can ultimately affect its release profile in vitro and in vivo. To study these aspects, IBU was mixed at increasing weight ratios and in different chemical forms (free acid, sodium salt, and n-butyl ester), to investigate further the role of the carboxylic group in the interaction with the RL polymer. Therefore, IBU-RL solid dispersions (coevaporates) were obtained and fully characterized in the solid state through spectroscopic, calorimetric, and x-ray diffractometric analyses. The in vitro release pattern of the drug, in the different chemical states, was studied for the coevaporates, compared with drug-RL physical mixtures, along with drug adsorption profiles from aqueous solutions on the surface of the polymer granules.

Methodology for characterizing heat removal mechanism in human skin during cryogen spray cooling.

Cryogen spray cooling (CSC) reduces epidermal damage during laser treatment of various dermatoses. The goal of this study was to determine the heat removal mechanism in skin and quantify the amount in response to CSC. Thermocouples were imbedded in four model substrates with a range of thermal diffusivities, greater than three orders of magnitude in difference, to measure the temperature profiles in response to CSC and sapphire contact cooling, which removes heat completely by conduction. An algorithm solving an inverse heat conduction problem was subsequently used to quantify the amount of heat removal from the substrates using the measured temperatures. The interface thermal conductance and internal temperatures within the substrates were computed by a finite difference algorithm that solved the heat conduction equation. Results verify a marked increase in heat removal and interface thermal conductance with increasing thermal diffusivity. By estimation from the model substrate results, heat removal and interface thermal conductance values for skin were obtained. Data demonstrate that during CSC, evaporation is the dominant heat transfer mechanism in materials with higher thermal diffusivities; however, conductive cooling dominates in substrates with lower thermal diffusivities such as skin.

Albuterol HFA is as effective as albuterol CFC in preventing exercise-induced bronchoconstriction.

BACKGROUND: Secondary to the phase-out of chlorofluorocarbons (CFCs), the albuterol (Ventolin, GlaxoSmithKline, Uxbridge, Middlesex, United Kingdom) pressurized metered-dose inhaler (MDI) has been formulated in a non-ozone-depleting propellant, hydrofluoroalkane (HFA) 134a. OBJECTIVE: To compare the efficacy of albuterol HFA to albuterol CFC and placebo HFA in protecting patients from exercise-induced bronchospasm (EIB). METHODS: Randomized, double-blind, placebo-controlled, three-way crossover study in patients with documented EIB. Patients (n = 24) aged 18 to 45 years old received albuterol HFA or albuterol CFC, (total dose of 180 microg ex-actuator), or placebo HFA via an MDI, 30 minutes before a standardized exercise challenge. Serial forced expiratory volume in 1 second (FEV1) measurements were made 5 minutes before exercise and 5, 10, 15, 20, 25, 30, and 60 minutes postexercise. The primary outcome measure was the maximum percentage fall in FEV1 over the 60 minutes after exercise. RESULTS: The adjusted mean maximum percentage falls in FEV1 postexercise for albuterol HFA and CFC groups were 15.4% and 14.9%, respectively. The two formulations were comparable with a treatment difference of -0.5% (P = 0.848; 95% confidence interval, -5.3 to 4.4%). When compared with the fall in FEV1 for placebo (33.7%), both active treatments demonstrated a significantly smaller fall in FEV1 postexercise (P < 0.001). Safety profiles were similar among the three treatment groups. CONCLUSIONS: The results provide assurance to prescribers that the formulation of albuterol in the non-ozone-depleting propellant HFA 134a has not affected its efficacy in the treatment of EIB in asthmatic patients. Single doses of albuterol HFA and CFC from an MDI are comparable in terms of efficacy and safety on a microgram per microgram basis.

A comparison of the efficacy and tolerability of single doses of HFA 134a albuterol and CFC albuterol in mild-to-moderate asthmatic patients.

BACKGROUND: After the signing of the Montreal Protocol in 1987, new propellants for use in pressurized metered-dose inhalers that are non-ozone-depleting have been developed. OBJECTIVE: This study was designed to compare the efficacy and tolerability of single doses of albuterol/HFA 134a with albuterol/CFC and to demonstrate a dose-response among the different doses of both formulations. METHODS: A single-center, randomized, double-blind, placebo-controlled, cross-over study. Sixty-three adolescent and adult asthmatic patients were randomized to receive at separate treatment visits single doses via a pressurized metered-dose inhaler of either placebo/hydrofluoroalkane (HFA) 134a; 100 microg, 200 microg, or 400 microg albuterol/HFA 134a; 100 microg or 200 microg albuterol/chlorofluorocarbon (CFC). Triplicate measurements of forced expiratory volume in 1 second (FEV1) were made immediately before dosing and 15 minutes, 30 minutes, 1, 2, 3, 4, 5, and 6 hours postdose. The primary efficacy variables were area under the entire 6-hour FEV1 curve, relative to baseline subtracted from the area above baseline (AUC(0-6)) and peak effect (derived from serial FEV1 measurements). RESULTS: Analysis of AUC(0-6) and peak effect showed that all doses of albuterol had a significantly greater effect than placebo (HFA 134a propellant). Comparisons of the two formulations at 100 microg and 200 microg showed no difference in AUC(0-6) (100 microg, -0.23 Lhr, P = 0.114 and 200 microg -0.08 Lhr, P = 0.590) or in peak effect, percentage of baseline (100 microg, -1.3%, P = 0.354 and 200 microg, 0.17%, P = 0.902). There were no differences seen among formulations in the incidence of adverse events or with any of the other safety parameters, including electrocardiograms, vital signs, clinical laboratory assessments, and asthma exacerbations. CONCLUSIONS: The study demonstrated comparability in terms of efficacy and safety between albuterol/HFA 134a and albuterol/CFC.

Infrared imaging of 2-D temperature distribution during cryogen spray cooling.

Cryogen spray cooling (CSC) is used in conjunction with pulsed laser irradiation for treatment of dermatologic indications. The main goal of this study was to determine the radial temperature distribution created by CSC and evaluate the importance of radial temperature gradients upon the subsequent analysis of tissue cooling throughout the skin. Since direct measurement of surface temperatures during CSC are hindered by the formation of a liquid cryogen layer, temperature distributions were estimated using a thin, black aluminum sheet. An infrared focal plane array camera was used to determine the 2-D backside temperature distribution during a cryogen spurt, which preliminary measurements have shown is a good indicator of the front-side temperature distribution. The measured temperature distribution was approximately gaussian in shape. Next, the transient temperature distributions in skin were calculated for two cases: 1) the standard 1-D solution which assumes a uniform cooling temperature distribution, and 2) a 2-D solution using a nonuniform surface cooling temperature distribution based upon the back-side infrared temperature measurements. At the end of a 100-ms cryogen spurt, calculations showed that, for the two cases, large discrepancies in temperatures at the surface and at a 60-micron depth were found at radii greater than 2.5 mm. These results suggest that it is necessary to consider radial temperature gradients during cryogen spray cooling of tissue.

Flunisolide HFA.

Flunisolide is a synthetic corticosteroid approved for the treatment of persistent asthma and delivered by means of a metered-dose inhaler (MDI). A new formulation of flunisolide, using hydrofluoroalkane (HFA) as a propellant, has been developed to comply with the mandated worldwide phase-out of ozone-depleting chlorofluorocarbon (CFC) propellants. Aerosol particle size in the new flunisolide HFA solution is smaller than the flunisolide CFC suspension (1.2 vs 3.8 microm mass median aerodynamic diameter). Aerosol particle size is a key element in determining lung deposition and the regional distribution of inhaled medication within the lung. In addition, the flunisolide HFA MDI has been redesigned to include a built-in spacer. These features have improved distal lung deposition. Flunisolide HFA, at one-third the dosage (170 and 340 microg twice daily), had similar efficacy to flunisolide CFC (500 and 1000 microg twice daily) and significantly greater efficacy than placebo in a randomized, double-blind, placebo-controlled, 12-week study in patients with mild to moderate asthma. Flunisolide HFA was well tolerated in all trials. A long-term study found no suppression of adrenal function and minimal systemic effects were observed both in adults and children.

A comparative study of human skin thermal response to sapphire contact and cryogen spray cooling.

Surface cooling, in conjunction with various thermally mediated therapeutic procedures, can provide a means to protect superficial tissues from injury while achieving destruction of deeper targeted structures. We have investigated the thermal response of in-vivo human skin to: 1) contact cooling with a sapphire window (6-12 degrees C); and 2) spray cooling with a freon substitute cryogen [tetrafluoroethane; boiling point approximately -26 degrees C at 1 atmospheric pressure (atm)]. Measurements utilizing infrared radiometry show surface temperature reductions from 30 degrees C to 14-19 degrees C are obtained within approximately 1 s in response to sapphire contact cooling. Surface temperature reductions to values between 5 degrees C and -9 degrees C are obtained in response to 20-100-ms cryogen spurts. Computational results, based on fitting the measured radiometric surface temperature to estimate heat transfer parameters, show: 1) temperature reductions remain localized to approximately 200 microns of superficial tissue; and 2) values of heat flux and total energy removed per unit skin surface area at least doubled when using cryogen spray cooling.