HFA-134a Propellant Research Articles

Gold Nanoparticles: Tunable Characteristics and Potential for Nasal Drug Delivery.

A general procedure to prepare gold nanourchins (GNUs) via a seed-mediated method was followed using dopamine hydrochloride as a reducing agent and silver nitrate salt (AgNO3) as a shape-directing agent. The novelty of this study comes from the successful incorporation of the prepared gold urchins as an aqueous suspension in a nasal pressurized metered dose inhaler (pMDI) formulation and the investigation of their potential for olfactory targeting for direct nose-to-brain drug delivery (NTBDD). The developed pMDI formulation was composed of 0.025% w/w GNUs, 2% w/w Milli-Q water, and 2% w/w EtOH, with the balance of the formulation being HFA134a propellant. Particle integrity and aerosolization performance were examined using an aerosol exposure system, whereas the nasal deposition profile was tested in a sectioned anatomical replica of human nasal airways. The compatibility of the gold dispersion with the nasal epithelial cell line RPMI 2650 was also investigated in this study. Colloidal gold was found to be stable following six-month storage at 4 °C and during the lyophilization process utilizing a pectin matrix for complete re-dispersibility in water. The GNUs were intact and discrete following atomization via a pMDI, and 13% of the delivered particles were detected beyond the nasal valve, the narrowest region in the nasal cavity, out of which 5.6% was recovered from the olfactory region. Moreover, the formulation was found to be compatible with the human nasal epithelium cell line RPMI 2650 and excellent cell viability was observed. The formulated GNU-HFA-based pMDI is a promising approach for intranasal drug delivery, including deposition in the olfactory region, which could be employed for NTBDD applications.

Molecular Dynamic Simulation Approach to Predict the Compatibility of Formulation Components of Salbutamol Sulfate Metered Dose Inhaler Free off Ethanol

More than 50 years since the first introduction of metered dose inhaler (MDI) by Riker laboratories 1956. The major development in MDI manufacturing was the transformation from chloroflouro carbon (CFC) to hydroflouro alkane (HFA) which required a new engineering design to the MDI components and reformulation of existing MDI to fit the new propellant. Evolution of MDI formulation was challenging due to the low solubility profile of most excipients in HFA propellants and the limitation of generally recognized as safe (GRAS) excipients that could be delivered to the lung. The main purpose of this study was to develop a new salbutamol sulfate (SS) MDI using PEG400(1%) w/w as suitable alternative co-solvents to ethanol (10%)w/w. PVP-k30(0.001-0.0001%) w/w and Brij72(0.001-0.005-0.01%) were used separately as suggested stabilizer. In silico molecular dynamic (MD) simulation was carried out to investigate the compatibility of new excipients with SS and PEG400 before adding the HFA134a. Differential scanning calorimeter(DSC) was also run to evaluate the compatibility between formulations components that passed the visual observation test. Content per actuation was also used to estimate the developing formulation at accelerated stability conditions (40°C/75%RH).(N=10). MD simulation results demonstrated the compatibility of PVP-k30(0.0001%) w/w with other formulation's components before adding HFA134a propellant(small or negative value for and ). MD simulation results were also confirmed by DSC thermograms which indicate the compatibility between PVP-k30 based formulation due to a small change in endothermic maximum melting point compared with Brij 72 based formulation.Content per actuation of PVP-k30(0.0001%)w/w based formulation passed the accelerated stability test and there is a significant effect of stabilizer type and concentration on the emitted dose (p-value >0.05). This work confirms that MD simulations could save time and reduce the cost of experiments during the early stage of reformulation process of MDI.

Acute, repeated inhalation toxicity, respiratory system irritation, and mutagenicity studies of 1,1,2,2-tetrafluoroethane (HFC-134) as the impurity in the pharmaceutical propellant 1,1,1,2-tetrafluoroethane (HFA-134a)

HFC-134 is the main impurity of HFA-134a. In order to verify the rationality of HFC-134 limits in HFA-134a and ensure the safety of HFA-134a as propellant in pharmaceutical metered-dose inhalers, acute inhalation toxicity, seven-day repeat dose inhalation irritation study, 21-day repeat dose inhalation toxicity study and reverse mutation assay of HFC-134 were tested to evaluate its inhalation safety. In acute inhalation studies, Sprague-Dawley rats were exposed nose-only to HFC-134 at levels of 100 000, 200 000, 400 000, 600 000, and 800 000 ppm for 4 h. Based on the mortality incidence, the calculated four-hour LC50 value for HFC-134 is 532 069 ppm for males and 502 058 ppm for females and acute inhalation toxicity is manifested as the lung lobes turn dark red. Exposures to 836 ± 67 ppm for 4 hours/day 7 days/week continuously did not induce local irritation of the respiratory system in Sprague-Dawley rats. Sprague-Dawley rats were exposed nose-only to HFC-134 at levels of 0 (control), 203 929 ppm and 394 871 ppm 2 h/day for 21 consecutive days, no significant treatment-related adverse effects was noted. Results from Ames studies demonstrated that HFC-134 was not mutagenic. Although HFC-134 has a very low acute inhalation toxicity, considering that its acute inhalation toxicity is higher than that of HFA-134a, and due to the high frequency of use of MDI by asthma patients, acceptance criteria of HFC-134 as the impurity in aerosol propellant HFA-134a should be lower than 8-h TWA WEEL value of 1000 ppm to ensure the safety of the MDI.

Formulation development and in-vitro evaluation of montelukast sodium pressurized metered dose inhaler

Montelukast is used as alternative treatment for asthma. However, some adverse drug reactions have been reported for the oral dosage form of montelukast. To counter this issue, the drug was formulated into a pressurized metered-dose inhaler (pMDI), which delivered montelukast directly to the lower regions of the lungs. Montelukast sodium, mixed with either HFA 134a propellant or a mixed propellant (HFA-134a and HFA227), was formulated into a pMDI with other excipients. The canister was prepared using a pressurized filling method, followed by disk sampling to assess content per spray and content uniformity. The effects of ethanol and polyethylene glycol (PEG) 400 on the fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) of the formulation were evaluated. In vitro cytotoxicity of the developed montelukast pMDIs was tested in lung airway cell lines. Their effects on the levels of inflammatory nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β), generated from NR8383 alveolar macrophage (AM) cells, were also evaluated. All selected formulations had a FPF >46%, whereas the formulation containing 20% v/v ethanol and 1% v/v PEG 400 showed the highest FPF. The MMADs of all formulations were within 1–5 μm. The montelukast pMDI formulations were found to be non-toxic to lung airway cell lines and did not induce inflammatory NO, TNF-α, or IL-1β production in NR8383 cells.

Drug distribution transients in solution and suspension-based pressurised metered dose inhaler sprays

This paper presents in situ time-resolved drug mass fraction measurements in pressurised metered dose inhaler (PMDI) sprays, using a novel combination of synchrotron X-ray fluorescence and scattering. Equivalent suspension and solution formulations of ipratropium bromide in HFA-134a propellant were considered. Measurements were made both inside the expansion chamber behind the nozzle orifice, and in the first few millimeters of the spray where droplet and particle formation occur. We observed a consistent spike in drug mass fraction at the beginning of the spray when the first fluid exits the nozzle orifice. Approximately 20% of the total delivered dose exits the nozzle in the first 0.1 s of the spray. The drug mass fraction in the droplets immediately upon exiting the nozzle peaked at approximately 50% of the canister mass fraction, asymptoting to approximately 20% of the canister concentration. The effect is due to a change in the drug mass fraction inside the droplets, rather than changes in droplet size or distribution. The transient was found to originate inside the expansion chamber. We propose that this effect may be a major contributor to low delivery efficiency in PMDIs, and have important implications for oropharyngeal deposition and inhalation technique. This highlights the importance of expansion chamber and nozzle design on the structure of PMDI sprays, and indicates areas of focus that may lead to improvement in drug delivery outcomes.

In-vitro and in-vivo respiratory deposition of a developed metered dose inhaler formulation of an anti-migraine drug

Enhancement of zolmitriptan bioavailability through development of micronized zolmitriptan pressurized metered dose inhaler (MDI) as an alternative to its traditional drug delivery systems. A reversed phase HPLC method for zolmitriptan determination was developed and evaluated. Micronized zolmitriptan MDI formulations were prepared using two different propellants. The prepared formulations were evaluated for mean shot weight, drug content, and leakage rate in addition to in-vitro deposition using next generation impactor where mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD), fine particle dose, fine particle fraction (FPF), emitted dose (ED), and dispersibility were determined. The selected formulation was evaluated for in-vivo bronchial absorption in rats. The physicochemical characters of the prepared formulations were found to be dependent mainly on the vapor pressure of the used propellant. MDI formulation prepared with HFA 134a propellant was found to have the lowest MMAD (3.47 ± 0.65) with GSD of 2.3 ± 0.4. It also had the highest FPF (41.9), ED (89.26 ± 2.35) with dispersibility of 46.9%. This formulation, when applied to rats, resulted in faster Tmax (27 ± 5 min) with higher Cmax (1236 ± 116 ng/mL) and AUC(0-12) (3375 ± 482 ng/mL·h) over the oral tablet. Its relative bioavailability was 72.7% which was 1.25 times higher than the oral tablet relative bioavailability. Zolmitriptan MDI formulation was developed using micronized zolmitriptan powder without further modification or particle engineering. The developed formulation using HFA 134a propellant could be favorable alternative, with enhanced bioavailability, to zolmitriptan oral tablet for acute migraine treatment.

AN ATOMIZER TO GENERATE MONODISPERSE DROPLETS FROM HIGH VAPOR PRESSURE LIQUIDS

This work describes an atomizer capable of generating monodisperse droplets of high vapor pressure liquids such as HFA227ea and HFA134a. This atomizer is expected to be a useful tool in future fundamental explorations of the mechanics of these highly dynamic aerosols. Hydrofluoroalkanes (HFAs) are the most common propellants in metered dose inhalers (MDIs), which are themselves the most common delivery method for pulmonary disease medications. As a result of the high vapor pressure of these fluids, generation of monodisperse droplets and their study are not possible with previously existing monodisperse atomizers due to fluid flashing when exposed to ambient conditions. The new atomizer uses a piezoelectric transducer to disintegrate the propellant jet, a cooling circuit with a low-temperature limit of −30°C to reduce propellant vapor pressure, and a high-pressure feed system (up to 2.7 MPa) to keep the propellant in the liquid phase, thereby avoiding flash atomization. In the current setup, the diameter of the generated droplets was monitored with a laser scattering system (using Fraunhofer diffraction theory) to optimize the operating parameters of the setup (for example, the actuation frequency and amplitude of the piezoelectric transducer). This monitoring system allowed for the measurement of droplet geometric diameter, spacing, and velocity. The capabilities of the atomizer for generating monodisperse droplets are demonstrated by a case study in which monodisperse dry particles of beclomethasone dipropionate (BDP) are generated using a solution of BDP, ethanol co-solvent, and HFA134a propellant.

The effect of actuator nozzle designs on the electrostatic charge generated in pressurised metered dose inhaler aerosols.

To investigate the influence of different actuator nozzle designs on aerosol electrostatic charges and aerosol performances for pressurised metered dose inhalers (pMDIs). Four actuator nozzle designs (flat, curved flat, cone and curved cone) were manufactured using insulating thermoplastics (PET and PTFE) and conducting metal (aluminium) materials. Aerosol electrostatic profiles of solution pMDI formulations containing propellant HFA 134a with different ethanol concentration and/or model drug beclomethasone dipropionate (BDP) were studied using a modified electrical low-pressure impactor (ELPI) for all actuator designs and materials. The mass of the deposited drug was analysed using high performance liquid chromatography (HPLC). Both curved nozzle designs for insulating PET and PTFE actuators significantly influenced aerosol electrostatics and aerosol performance compared with conducting aluminium actuator, where reversed charge polarity and higher throat deposition were observed with pMDI formulation containing BDP. Results are likely due to the changes in plume geometry caused by the curved edge nozzle designs and the bipolar charging nature of insulating materials. This study demonstrated that actuator nozzle designs could significantly influence the electrostatic charges profiles and aerosol drug deposition pattern of pMDI aerosols, especially when using insulating thermoplastic materials where bipolar charging is more dominant.

Formulation and evaluation of novel reverse microemulsions containing salmon calcitonin in hydrofluoroalkane propellants

To develop reverse microemulsion as a potential strategy for pulmonary delivery of salmon calcitonin (sCT) in HFA134a propellant of pressurized metered dose inhalers (pMDIs), pluronic P85 (P85) was chosen as the most appropriate surfactant to form microemulsions containing sCT. Formulation parameters, including the surfactant and ethanol content, water content, and sCT loading, were optimized to obtain two desired pMDI formulations A and B with clear and transparent appearance, Tyndall effect, good physical stability and aerosolization properties. Aerosolization properties of the optimized pMDIs were assessed by next generation impactor (NGI) and twin-stage impactor (TSI), and the dose of sCT in each stage was assayed by HPLC. The fine particle fraction (FPF) of formulations A and B were both at the range of approximately 28.0-36.0%. Cytotoxicity studies indicated the cell viability determined by MTT assay only slightly dropped when the A549 cells were exposed to the pMDI formulations. Pharmacological study performed on the male Wistar rats showed the intratracheal administration of the microemulsion pMDIs containing sCT exhibited similar but prolonged hypocalcemic activity compared with the intravenous injection of sCT solution. Therefore, such reverse microemulsions are potential for pulmonary delivery of therapeutic peptides using HFA-pMDIs.

The Influence of Actuator Materials and Nozzle Designs on Electrostatic Charge of Pressurised Metered Dose Inhaler (pMDI) Formulations

To investigate the influence of different actuator materials and nozzle designs on the electrostatic charge properties of a series of solution metered dose inhaler (pMDI) aerosols. Actuators were manufactured with flat and cone nozzle designs using five different materials from the triboelectric series (Nylon, Polyethylene terephthalate, Polyethylene-High density, Polypropylene copolymer and Polytetrafluoroethylene). The electrostatic charge profiles of pMDI containing beclomethasone dipropionate (BDP) as model drug in HFA-134a propellant, with different concentrations of ethanol were studied. Electrostatic measurements were taken using a modified electrical low-pressure impactor (ELPI) and the deposited drug mass assayed chemically using HPLC. The charge profiles of HFA 134a alone have shown strong electronegativity with all actuator materials and nozzle designs, at an average of -1531.34 pC ± 377.34. The presence of co-solvent ethanol significantly reduced the negative charge magnitude. BDP reduced the suppressing effect of ethanol on the negative charging of the propellant. For all tested formulations, the flat nozzle design showed no significant differences in net charge between different actuator materials, whereas the charge profiles of cone designs followed the triboelectric series. The electrostatic charging profiles from a solution pMDI containing BDP and ethanol can be significantly influenced by the actuator material, nozzle design and formulation components. Ethanol concentration appears to have the most significant impact. Furthermore, BDP interactions with ethanol and HFA have an influence on the electrostatic charge of aerosols. By choosing different combinations of actuator materials and orifice design, the fine particle fractions of formulations can be altered.

Sildenafil citrate monohydrate–cyclodextrin nanosuspension complexes for use in metered-dose inhalers

Sildenafil is a selective phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction and pulmonary hypertension. Sildenafil citrate monohydrate was complexed with α-, hydroxypropyl-β- and γ-cyclodextrin (α-CD, HP-β-CD and γ-CD, respectively) to enhance its water solubility. The complexes of sildenafil citrate monohydrate with all types of CDs were characterized by phase solubility diagrams, (1)H and (13)C NMR, and dielectric constants. Sildenafil citrate monohydrate complexed with CDs was developed as nanosuspensions for use in a pressurized metered-dose inhaler (pMDI). Sildenafil citrate monohydrate pMDI formulations were prepared by a bottom-up process using dried ethanol as a solvent and HFA-134a as an antisolvent and propellant in order to form nanosuspensions. A 3×3 factorial design was applied for the contents of the dried ethanol and HFA-134a propellant. The phase solubility profiles of the sildenafil and cyclodextrins were described as AL type with a mole ratio 1:1. The piperazine moiety of sildenafil formed an inclusion in the cavity of the CDs. The particle diameters of the sildenafil citrate monohydrate suspensions in pMDIs were all within a nanosuspension size range. An assay of the sildenafil content showed that the formation of complexes with CDs was close to 100%. In the case of the formulations with CDs, the emitted doses varied within 97.4±10.8%, the fine particle fractions (FPFs) were in a range of 45-81%, the fine particle dose (FPD) was 12.6±2.0 μg and the mass median aerodynamic diameters (MMADs) were 1.86±0.41 μm. In contrast, the formulations without CDs produced a low emitted dose of sildenafil (<60%). Therefore, only sildenafil citrate monohydrate pMDI formulations containing CDs were suitable for use as aerosols.

In Vitro Investigation of the Effect of Ambient Humidity on Regional Delivered Dose with Solution and Suspension MDIs

Existing literature has shown that high relative humidity (RH) affects in vitro aerosol drug delivery of nebulizer and pressurized metered dose inhaler (pMDI) formulations. The aim of this study is to investigate in vitro mouth-throat deposition and lung delivery of selected solution and suspension pMDI formulations, under a range of RH, temperature, and flow rate conditions. The Alberta Idealized Throat was connected to a collection filter and placed in an environmental control chamber. The formulations selected were beclomethasone dipropionate (BDP) in 13% w/w ethanol/1.3% w/w glycerol and HFA-134a propellant solution ("BDP HFA134a"), BDP in 13% w/w ethanol and HFA-227 propellant solution ("BDP HFA227"), and Flixotide Evohaler (fluticasone propionate 250 μg/dose in HFA-134a suspension). Each of these pMDI formulations was dispersed into the mouth-throat and filter assembly in triplicate, according to an experimental matrix consisting of the following conditions: air flow rates of 28.3, 60, and 90 L/min; 0%, 35%, and 80% RH; operating temperatures of 20°C and 40°C. There was a general increase in mouth-throat deposition and corresponding decrease in filter deposition (representing lung dose fraction), with increasing RH for both BDP HFA134a and Flixotide pMDIs. Increasing temperature from 20°C to 40°C resulted in decreased mouth-throat deposition and increased lung dose fraction for the solution pMDIs, but generally no effect for the suspension pMDI. Not only is the dose delivery of pMDI formulations affected by environmental conditions (in some cases causing up to 50% reduction in lung delivery), but solution and suspension formulations also behave differently in response to these conditions. These results have implications during dosage form design, testing, and for usage patient use.

The effect of reduction of propellant mass fraction on the injection profile of metered dose inhalers

In order to provide an improved understanding of the flow in pressurized-metered dose inhalers (pMDIs), especially monitoring the output temperature and mass flow rate to obtain maximum atomization efficiency from the available energy, a numerical model for a two phases, multi-component compressible flow in a pressurized-metered dose inhaler is presented and validated. It is suitable for testing with various formulations and different geometries for a range of pMDI devices. We validated the model against available data in the literature for a single component HFA 134a propellant, and then investigated the response of the model to other formulations containing non-volatile components. Further validation is obtained by an experiment using the dual beam method which acquired the actuation flow properties such as spray velocity and duration. The deviation of the numerical predictions for the peak exit velocity against the experimental results is 5.3% and that for effective spray duration 5.0%. From the numerical and experimental results, it is found that for the formulations with the mass fraction of HFA 134a > 80%, the effective spray duration of the pMDI is around 0.1 s. Furthermore the droplet peak exit velocity at the axial station x = 25 mm from the actuation nozzle decreases from 20 to 15 m/s with the reduction of the propellant (HFA 134a) from 95%. Formulations with the mass fraction of HFA 134a below 80% produce poor quality spray which is indicated from the unsteady peak exit velocity, changeable spray number density in each experimental test, and numerical simulations also confirmed the non-viability of this condition.

Anti-cancer effect of celecoxib and aerosolized docetaxel against human non-small cell lung cancer cell line, A549

Direct delivery of chemotherapeutic agents to the lung can increase both the drug concentration and exposure period to lung tumours. The objective of this study was to formulate docetaxel (DOC) into a metered dose inhaler (MDI), assess its aerodynamic characteristics and to evaluate the effect of celecoxib (CXB), a cyclooxygenase-2 (COX-2) inhibitor, on the in-vitro cytotoxicity and apoptotic response of aerosolized DOC against human lung adenocarcinoma cell line A549. A stable solution-type MDI formulation was developed with 0.25% DOC and 15% w/w ethyl alcohol using HFA 134a propellant. The formulation was evaluated for medication delivery, mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD), percent throat deposition, respirable mass and respirable fraction. A six-stage viable impactor was used to assess the in-vitro cytotoxicity of DOC-MDI alone or in combination with CXB. Induction of apoptosis in A549 cells by DOC (non-aerosolized and aerosolized) in combination with CXB was evaluated by established techniques, such as caspase-3 estimation and terminal deoxynucleotidyl transferase-mediated nick end labelling (TUNEL) staining. The influence of different treatments on the expression of COX-2 and peroxisome proliferator-activated receptor-gamma(PPAR-gamma) in A549 cells was studied by RT-PCR. The DOC-MDI formulation had a MMAD of 1.58 microm, (GSD = 3.2) and a medication delivery of 80 microg/shot. DOC-MDI (one shot) in combination with CXB (10 microg mL(-1)) had a cell kill of more than 80% as determined by in-vitro cytotoxicity assay. The specific caspase-3 activity in A549 cells treated with DOC (0.01 microg mL(-1)) and CXB (10.0 microg mL(-1)) combination was 4 times higher than CXB and untreated control group, respectively. Further, TUNEL staining showed significant apoptosis of A549 cells treated with aerosolized DOC alone or in combination with CXB when compared with CXB and untreated cells. The RT-PCR experiments showed similar expression of COX-2 in both control and treated groups. PPAR-gamma expression was increased in the combination treatment (0.01 microg mL(-1) DOC and 10 microg mL(-1) CXB) as compared with control (untreated), DOC (0.01 microg mL(-1)) and CXB (10 microg mL(-1)) treatments. Our results indicate the potential of inhalation delivery of DOC in the treatment of lung cancer.

Albuterol HFA for the management of obstructive airway disease

Albuterol (salbutamol outside the USA) is used to acutely relieve symptoms related to airway obstruction and prevent exercise-induced bronchospasm. Albuterol is most commonly administered by metered-dose inhaler (MDI). MDIs had used chlorofluorocarbon (CFC) propellants, but CFCs accumulate in the stratosphere and contribute to ozone catabolism. Loss of the ‘ozone layer’, which filters UVB rays, has public health concerns. Albuterol has been reformulated in MDIs using hydrofluoroalkane (HFA) propellants, which do not affect the ozone layer. Albuterol HFA MDIs deliver the same amount of drug per puff with similar particle size distributions as albuterol CFC MDIs, resulting in comparable bronchodilator efficacy of the two products. The highly favorable safety profile of albuterol has not been altered with reformulation. The propellant HFA-134a appears to be devoid of safety concerns.

A modified prescription‐event monitoring study to assess the introduction of Flixotide EvohalerTM into general practice in England: an example of pharmacovigilance planning and risk monitoring

A modified prescription-event monitoring (PEM) study was conducted to examine the safety of the introduction of the metered dose inhaler (MDI) Flixotide Evohaler (fluticasone with the propellant HFA 134a). Patients were identified from the first NHS prescriptions dispensed in England for Flixotide Evohaler. Postal questionnaires were sent to the prescribing doctor, requesting information including: demographic characteristics, severity of indication, concomitant medication, event data 3 months prior to and 3 months after the first prescription, and any reasons for stopping Flixotide. Pregnancies, deaths and selected events were followed up. Incidence density ratios (IDRs) were calculated to compare event rates 3 months before and 3 months after the introduction of Flixotide Evohaler. The cohort comprised 13 413 patients that were prescribed Flixotide Evohaler. The response rate was 64.0%. When the pre- and post-exposure periods were compared fewer patients had events in the post-exposure period, and there was no significant difference in the length of courses of oral steroid use. Eighteen patients experienced an event within 1 hour of using Flixotide Evohaler; these were minor with the exception of one case of angioneurotic facial oedema. Six of these events were assessed as possibly related to Flixotide Evohaler. During the study period there were an additional 13 patients with events assessed as possibly related to Flixotide Evohaler, including two reports of allergic reactions. The results suggest that the transition to Flixotide Evohaler was generally well tolerated. The modified methodology has contributed to the risk management of the introduction of this product.

A comparison of two methods to determine the solubility of compounds in aerosol propellants

A new on-line reverse phase HPLC method for determining the solubility of compounds in propellant based metered dose inhaler (MDI) formulations was compared with a conventional method. The new method employs a direct injection from a MDI vial into the needle injector port of a manual injector. To evaluate the two methods, beclomethasone dipropionate (BDP), 5,5-diphenyl hydantoin and 3,3′-diindolylmethane, were used as model compounds in propellant HFA-134a. Comparison was performed by analyzing known and unknown concentrations of BDP in various combinations of HFA-134a and ethanol. In addition, the solubility of 5,5-diphenyl hydantoin and 3,3′-diindolylmethane were determined in HFA-134a using both the new and the conventional methods. The two methods were found to be in good agreement with each other, with the new direct injection technique offering enhanced precision and accuracy along with considerable reduction in analysis time.

Beclomethasone dipropionate crystallized from HFA-134a and ethanol

Beclomethasone dipropionate (BDP) is a long-acting inhaled corticosteroid, used for the treatment of asthma, and as an inhalation therapy with HFA-134a. The sample studied by X-ray crystallography was grown in a mixture of the aerosol propellant HFA-134a, C2H2F4, and 200-proof ethanol. The formula of the crystalline material is C28H37ClO7·2C2H6O·C2H2F4. In the crystal structure, disordered solvent occupies a channel which is perpendicular to the BDP mol­ecules. The latter are are stacked together by hydrogen bonding.

A new HFA-134a propellant in the administration of inhaled BDP via the Jet ® spacer: controlled clinical trial vs the conventional CFC

This study was carried out with the aim of demonstrating the efficacy and tolerability of beclomethasone dipropionate (BDP) aerosol spray 500μg b.i.d. via a spacer device (Jet ®, Chiesi Farmaceutici S.p.A.) using a new HFA-134a formulation or chlorofluorocarbon (CFC) propellant. After having completed a 2-week run-in period, 154 adult patients (77 in each group) with mild-to-moderate persistent asthma were randomised into two groups to receive the study treatment for a duration of 12 weeks in a double-blind, multinational, multicentre, parallel-group design. Morning and evening peak expiratory flow rate (PEFR), use of rescue salbutamol, number of day- and night–time asthma attacks, number of night-time awakenings due to asthma and clinical symptoms were recorded daily by patients on diary cards. Pulmonary function tests (FEV 1, FVC, PEFR, FEF 25–75%, MEF 50 and FEF 25) and vital signs were measured at the clinic at study entry, at the start of treatment and every 2 weeks thereafter. Morning serum cortisol (8.00–10.00 a.m.) was measured at the start and at the end of the treatment period. Adverse events were recorded throughout the total study period. Significant improvements over baseline were reported in both groups in terms of lung function, symptoms and use of rescue inhaled salbutamol. Equivalence between groups was demonstrated for the primary end-point morning PEFR, as well as for evening PEFR and FEV 1. No statistically significant differences in the comparisons between groups, except for FEF 25 ( P=0.044), were observed in any of the other efficacy variables. Adverse events were reported in 31% of patients in the BDP–HFA group and in 32% in the CFC group. Adverse drug reactions were 4 and 2 in the two groups, respectively. No drug-related serious adverse events were reported in either of the groups. No signs of relevant adrenal suppression were observed in both groups: 2 patients in each group had final values below the normal range. In conclusion, the BDP–HFA-134a formulation proved to be equivalent in efficacy and comparable in safety to the standard BDP–CFC product over 12 weeks in adult patients with mild-to-moderate persistent asthma.

Assessment of Efficacy and Systemic Safety of a New Chlorofluorocarbon-Free Formulation of Inhaled Beclomethasone Dipropionate in Asthmatic Children

This study was undertaken with the objective to demonstrate clinical equivalence of a standard 400 μg/d dose of inhaled beclomethasone dipropionate (BDP) given via a new HFA-134a propellant (Chiesi Farmaceutici S.p.A., Parma, Italy), in two dose-units of 50 μg and 100 μg or with the conventional chlorofluorocarbon (CFC) (Becotide™, 50 μg unit dose, Allen & Hanburys, U.K.). A total of 218 children, ages 6-16, with mild to moderate persistent asthma in a stable phase, entered a 2-week run-in period and were then assigned to a 12-week treatment with one of the three treatment tests, following a double-blind, double-dummy (100 μg-dose strength as open arm), multicenter, parallel groups design. Two hundred seven patients entered the intent-to-treat (ITT) analysis and 181 completed the study period. The following efficacy variables were daily recorded by children on a diary card: morning and evening PEFR, number of daytime and nighttime asthma attacks, number of nocturnal awakenings because of asthma, symptoms' scores and intake of salbutamol. Pulmonary function tests (forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC], peak expiratory flow rate [PEFR], forced expiratory flow between 25%-75% of vital capacity [FEV25-75], midexpiratory flow [MEF50], forced expiratory flow at 25% of vital capacity [FEF25] were measured at the clinic visits at -2, 0, 2, 4, 8 and 12 weeks of treatment. A blood sample for the measurement of morning cortisol was taken between 8:00 AM and 10:00 AM at the start and at the end of the treatment. Equivalence between the three treatment groups was demonstrated for the primary outcome measure morning PEFR as well as for the evening PEFR. No significant differences among the groups were observed for the other efficacy variables, except for FEV1 and FVC (significantly higher increase in the two HFA groups than in the CFC group) and for the intake of salbutamol (non-significantly higher decrease of consumption in the CFC group). The three treatments also gave comparable results in terms of adverse drug reactions and of mean values of morning serum cortisol. No signs of marked cortisol decrease were reported in any of the three groups. The results of the present study therefore show that the new HFA-134a propellant can represent an alternative to the traditional CFCs in the delivery of 400 μg/d BDP in mild to moderate asthmatic children.