Development of novel gastroretentive salbutamol sulfate-loaded sodium alginate-pectin bubble beads prepared by co-axial needle air-injection method and in vivo clinical evaluation by ultrasound studies.

In the present study, the salbutamol sulfate-loaded sodium alginate-pectin (SS-loaded SA-PEC) bubble beads have been optimized and evaluated for drug loading, in vitro drug release, in vivo floating behavior in the stomach, etc. Nine batches (F1-F9) of bubble beads with different SA and PEC contents were prepared by novel co-axial needle air-injection method and related to their percent drug loading efficiency (%DLE) and percent drug release at 4 h (%R4h) as response factors. The multivariate analysis has shown the effect of SA/PEC ratio, total polymer content, as well as their interaction on %DLE and %R4h. In the quantitative modeling, the satisfactory adjustment of the linear models (along with interaction terms) with the experimental data for both %DLE and %R4h has confirmed the findings of the multivariate analysis. The optimized SS-loaded SA-PEC bubble beads based on 2D (contours), 3D, desirability, and overlay plots has exhibited %DLE of 87.35 ±â€¯2.48% (n = 3 and error = 2.94%) and %R4h of 85.79 ±â€¯2.98% (n = 3 and error = 0.25%). The in vitro drug release studies have shown almost complete (≥85%) SS release from all the batches within 4-6 h in simulated gastric fluid (SGF) pH 1.2. The in vivo clinical findings by ultrasound studies have shown excellent floatation (>6 h) behavior of bubble beads in the upper gastrointestinal tract (GIT) and efficient stomach-specific gastroretention.

Interaction of Formulation and Device Factors Determine the In Vitro Performance of Salbutamol Sulphate Dry Powders for Inhalation.

A variety of capsule-based dry powder inhalers were used to evaluate formulation-device interaction. The in vitro deposition of salbutamol sulphate (SS) was compared directly to published data for salmeterol xinafoate (SX). A 3(2) factorial design was used to assess the effect of SS formulations with three blends of different grade coarse lactose supplemented with different levels of fine lactose. These formulations were tested for homogeneity and evaluated for their in vitro deposition using Aeroliser, Handihaler and Rotahaler devices. The performance of the SS-lactose formulations differed across the grade of lactose and amount of fine lactose used compared to the same powder compositions blended with SX. SX had a greater fine particle fraction than SS for most of the comparable formulations, probably because of the different cohesiveness of the drugs. A head-to-head comparison of 'matched' SX and SS formulations when aerosolised from the same three devices demonstrated that formulation-device interactions are as critical in determining the in vitro deposition of drug-lactose blends as the identity of the active pharmaceutical ingredient. This work has revealed the limitations of the interpretative value of published in vitro performance data generated with a single device (even at equivalent aerosolisation force), when designing formulations for a different device.

Triggering effect of N-acetylglucosamine on retarded drug release from a lectin-anchored chitosan nanoparticles-in-microparticles system.

The aim of this study was to investigate the use of N-acetylglucosamine (NAG) to accelerate drug release from a lectin-modified carrier. A wheat germ agglutinin (WGA)-anchored salmeterol xinafoate (SalX)-loaded nanoparticles-in-microparticles system (NiMS) was prepared with an ionotropic gelation technique combined with a spray drying method. The formulated microparticles were spherical, with diameters ranging mainly from 2 to 8 µm; the drug entrapment efficiency was >70% (w/w), and the loading capacity was approximately 8% (w/w). Drug release from WGA-SalX-NiMS, within the first 4h, was approximately 30% less than that from SalX-NiMS, indicating an effect of lectin-modification to retard drug release from the NiMS. Due to "sugar-lectin" interactions, drug release from WGA-SalX-NiMS was substantially increased after the addition of NAG to the release medium. However, no significant influence of NAG was observed on the drug release profile of SalX-NiMS without WGA anchorage. The characteristics of NAG-WGA interaction may provide valuable insights into the "triggering-effects" of specific sugars on drug release from lectin-anchored carriers. These results suggest that it is possible to control drug release from a lectin-anchored drug delivery system using a specific sugar, and that the designed novel WGA-SalX-NiMS may be a suitable formulation for chronotherapy of asthma.

Characterization and biological activity of Solidago canadensis complex.

Polyphenolic-polysaccharide-protein complex has been isolated from flowers of Solidago canadensis L. by hot alkaline extraction procedure. Compositional analyses of S canadensis complex revealed the presence of carbohydrates (43 wt%), protein (27 wt%), phenolics (12 wt%), uronic acids (10 wt%) and inorganic material (8 wt%). The carbohydrate part was rich in neutral sugars (81 wt%) while uronids were determined in lower amount (19 wt%). Monosaccharide analysis of carbohydrate part revealed the presence of five main sugar components, i.e. rhamnose (~23 wt%), arabinose (~20 wt%), uronic acids (~19 wt%), galactose (~17 wt%) and glucose (~14 wt%), and indicated thus the presence of rhamnogalacturonan and arabinogalactan in S. canadensis complex. HPLC analysis of complex showed one single peak of molecule mass at 11.2 kDa. Antitussive activity tests, performed in three doses of Solidago complex, showed the reduction of the number of cough efforts in the dose-dependent manner. Higher doses (50 and 75 mg/kg b.w.) were shown to be by 15 and 20% more effective than that of lower one (25mg/kg b.w.). However, the antitussive effect of the highest dose (75 mg/kg b.w.) was by 10% lower in comparison with that of codeine, the strongest antitussive agent. Besides, the highest dose of the complex (75 mg/kg b.w.) significantly decreased values of specific airways resistance and their effect remained longer as that of salbutamol, a representative of classic antiasthmatic drugs.

Molecular simulation study of the effect of various additives on salbutamol sulfate crystal habit.

The effects of polyvinylpyrrolidone (PVP), hydroxypropyl methyl cellulose (HPMC), and lecithin additives on salbutamol sulfate (SS) crystal growth are studied using molecular dynamics (MD) simulation, to provide an insight into the interaction between the additives and SS crystal faces at the atomistic level. The interaction energy between additives and crystal faces is presented. The intermolecular contacts between the additives and the crystal faces are analyzed by calculating the average number of contacts between O atoms of the additives and the H atoms of the first layer of the SS crystal. The mobility of each additive on SS crystal faces is also reported by determining the mean square displacement. Our results suggest that PVP is the most effective among the three additives for the inhibition of SS crystal growth. The methodology used in this study could be a powerful tool for selection of habit-modifying additives in other crystallization systems.

A comparative study of different release apparatus in generating in vitro-in vivo correlations for extended release formulations.

The importance of hydrodynamics in the development of in vitro-in vivo correlations (IVIVCs) for a BCS Class II compound housed in a hydrophilic matrix formulation and for a BCS Class I compound housed in an osmotic pump formulation was assessed. In vitro release data were collected in media simulating the fasted state conditions in the stomach, small intestine and the ascending colon using the USP II, the USP III and the USP IV release apparatuses. Using the data collected with the USP II apparatus, the plasma profiles were simulated and compared with human plasma profiles obtained after administration of the same dosage forms to healthy fasted volunteers. Data obtained with the USP III and USP IV apparatuses were directly correlated with the deconvoluted human plasma profiles. In vitro hydrodynamics affected the release profile from the hydrophilic matrix. For both formulations, based on the values of the difference factor, all three apparatuses were equally useful in predicting the actual in vivo profile on an average basis. Although some hydrodynamic variability is likely with low solubility drugs in hydrophilic matrices, the hydrodynamics of USP II, III and IV may all be adequate as a starting point for generating IVIVCs for monolithic dosage forms in the fasted state.

Albuterol metered dose inhaler performance under hyperbaric pressures.

The weight change per actuation and aerosol particle size and number delivered by albuterol metered dose inhalers (MDIs) were measured in a multiplace hyperbaric chamber at pressures ranging from one atmosphere absolute (1 ATA, 0 feet of seawater, fsw, 101 kPa) to three ATA (66 fsw, 304 kPa). Weight change per actuation by CFC (chlorofluorocarbon) and long canister HFA (hydrofluoroalkane) powered MDIs was 13 +/- 1% and 12 +/- 1% less, respectively, at 3 ATA compared to 1 ATA. However, weight change per actuation by short canister HFA MDIs was not significantly changed with pressure. The geometric mean diameters of nano particles from the CFC and short canister HFA MDIs decreased from 50 nm at 0 fsw to 32 nm at 66 fsw whereas the long canister HFA aerosol diameters were not affected. The numbers of nanometer size particles delivered at 66 fsw were only 4-7% of those delivered at 0 fsw for the CFC and long canister HFA MDIs whereas for the short canister MDIs it was 26%. We conclude that the weight change per actuation of albuterol and the sizes and numbers of aerosol particles emitted from albuterol MDIs actuated in a hyperbaric environment vary by canister type.

Interaction kinetics of salmeterol with egg phosphatidylcholine liposomes by surface plasmon resonance.

Surface plasmon resonance (SPR) Biacore and equilibrium dialysis were applied to investigate the membrane affinities of salmeterol and propranolol and the kinetic interactions of salmeterol with egg phosphatidylcholine liposomes. The two methods revealed similar affinity values; however, they were dependent on the investigated drug concentrations. The kinetic experiments with salmeterol were optimized to obtain pseudo-first-order kinetics that were independent of the drug concentration. The adsorption and desorption phases followed biexponential functions up to pH 8.8 and mono or biexponential functions at higher pH values (i.e., between the two pK(a) values). The apparent rate constants of the faster phases of the biexponential functions were beyond the time resolution of the instrument in most measurements. The apparent rate constants of the slower phases ranged from 0.01 to 0.03 s(-1) and were pH independent between pH 5.0 and pH 8.0. The rates of the monoexponential kinetics were between 0.08 and 0.12 s(-1). We conclude that the biexponential kinetics at physiological pH reflect the partitioning into the outer lipid leaflet and "flip-flop," respectively, of the cationic species.

The role of force control agents in high-dose dry powder inhaler formulations.

The aim of this study was to determine the aerosolisation and aerodynamic properties of model inhalation particles (salbutamol sulphate and budesonide) upon coprocessing with force control agents (FCAs)-leucine, lecithin and magnesium stearate. Coprocessing of the drug particles with FCAs (5%, w/w) was conducted using mechanofusion-a novel dry mechanical fusion process. The influence of mechanofused FCAs on the entrainment and deaggregation behaviour of the drug-only formulations was investigated using a next generation impactor (NGI) and an in-line Spraytec laser diffraction particle sizer. In vitro measurements of salbutamol sulphate coprocessed with FCAs indicated a significant (p < 0.001) improvement of the fine particle fraction (FPF). The coprocessing of salbutamol sulphate with magnesium stearate produced the highest FPF, with an increase from 29.18% to 79.42% of the emitted dose. Coprocessing of budesonide particles only led to a small increase in fine particle delivery but a greater reduction in device retention. Aerosolisation analysis of the aerosolised powders indicated more effective aerosolisation and a considerable time reduction in powder bed fluidisation and entrainment upon coprocessing of the APIs with FCAs. From these data, it can be postulated that processing of drug actives with FCAs using mechanofusion is an effective means of improving the deagglomeration and aerosolisation properties of cohesive powders in DPI systems.

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.

The discovery of indole-derived long acting beta2-adrenoceptor agonists for the treatment of asthma and COPD.

The design and profile of a series of indole containing long acting beta(2)-adrenoceptor agonists is described. Evaluation of these analogues using an in vitro guinea pig trachea tissue model demonstrates that analogues within this series have salmeterol-like duration of action with potential for long duration of action in humans.

Physicochemical compatibility of fluticasone-17- propionate nebulizer suspension with ipratropium and albuterol nebulizer solutions.

The objective of this in-vitro study was to determine whether mixtures of three nebulizable drugs are physicochemically compatible. Drug combinations were prepared by mixing the content of one respule Flutide forte "ready to use" (fluticasone propionate) with 2 milliliter Atrovent LS (ipratropium bromide) and 0.5 milliliter Sultanol inhalation solution (albuterol sulfate). Test suspensions were stored at room temperature and exposed to normal laboratory light for 5 hours. Concentrations of fluticasone- 17-propionate, ipratropium bromide, and albuterol sulfate were determined by using stability-indicating high-performance liquid chromatography assays with ultraviolet detection. Physical compatibility was determined by measuring pH and osmolality. Main outcome measures were the drug concentrations of the active components of the mixtures. All drug concentrations retained nearly 100% of the initial drug concentrations after mixing and storage in glass containers at room temperature. Osmolality and pH of the mixtures exhibited no significant changes and no visible changes of the mixtures were detectable over the inspection period. Mixtures of fluticasone propionate, ipratropium bromide, and albuterol sulfate inhalation drug products were shown to be physicochemically compatible over a period of 5 hrs. In order to avoid contamination and microbiological instability, mixing should only take place immediately before administration. Further investigations are needed to determine whether or not drug delivery is affected by mixing the nebulizer suspensions and to ensure that simultaneous nebulization is recommendable.

Physicochemical compatibility of nebulizable drug mixtures containing dornase alfa and ipratropium and/or albuterol.

Patients suffering from cystic fibrosis (CF) often need to inhale multiple doses of different nebulizable drugs per day. Patients attempt to shorten the time consuming administration procedure by mixing drug solutions/suspensions for simultaneous inhalation. The objective of this experimental study was to determine whether mixtures of Pulmozyme inhalation solution with Atrovent or Sultano are physicochemically compatible. Drug combinations were prepared in accordance with the product information and clinical practice by mixing the content of one respule Pulmozyme with 2 mL Atrovent LS and 0.5 mL Sultanol Inhalationslösung (inhalation solution) or with one respule of either Atrovent 500 microg/2 mL Fertiginhalat (unit dose formulation) or Sultanol forte Fertiginhalat. Test solutions were stored at room temperature and exposed to light. Dornase alfa activity was determined by a kinetic colorimetric DNase activity assay. Ipratropium bromide and albuterol concentrations were investigated by a stability-indicating HPLC assay with ultraviolet detection. Physical compatibility was determined by visual inspection and measurements of pH and osmolality. Ipratropium bromide and albuterol concentrations were not affected by mixing the drug products. Dornase alfa activity is affected by benzalkonium chloride, used as excipient in Atrovent"LS and Sultanol'Inhalationsl6öung, and disodium edetate used as an excipient in AtroventfLS. Patients should be advised not to mix Pulmozymelwith Atrovent1LS and/or Sultanol"Inhalationsldöung, because of the incompatibility reaction. Mixtures of Pulmozyme with Atrovent 500 microg/2 mL Fertiginhalat or Sultanol forte Fertiginhalat can be designated as compatible for a limited period of time.

Single-isomer R-salbutamol is not superior to racemate regarding protection for bronchial hyperresponsiveness.

Bronchial hyper-reactivity (BHR) has been suggested to follow cessation of regular medication with racemic salbutamol. This study aimed at investigating the effects from medication with R,S- and R-salbutamol on bronchial response to provocation with isocapnic hyperventilation of cold air (IHCA). Twenty-six patients with mild to moderate asthma were enrolled in a double-blind, randomised, cross-over study. Bronchial response to provocation was measured before and after 1 week's medication. Doses of 0.63 mg R-salbutamol or 1.25 mg R/S-salbutamol were inhaled three times daily during medication-weeks and a wash-out week intervened. Tests were performed 6 h after the last dose of test drug. Impulse oscillometry and forced expiratory volume during one second were methods used to identify bronchial response to provocation. Two patients withdrew from the investigation due to side-effects, one from R- the other from R,S-salbutamol. Comparable resting bronchial conditions were indicated by differences in baseline lung function values of <2% between study days. No statistically significant medication-dependent differences in BHR could be demonstrated between treatment groups. However, 15 patients exhibited higher (P = 0.03) post-treatment BHR after pure R-salbutamol than after R,S-salbutamol. Furthermore, plasma concentrations of R-salbutamol tended to be lower (P = 0.08) after medication with R- than after R,S-salbutamol despite equal doses of R-salbutamol given during the two separate treatment periods. We also found that considerable amounts of S-salbutamol were retrieved in plasma after medication with pure R-salbutamol. We conclude that we were unable to demonstrate favourable effects of R-salbutamol over R,S-salbutamol regarding response to provocation with IHCA after regular medication of 1 week's duration.

Evaluation of SCF-engineered particle-based lactose blends in passive dry powder inhalers.

The objective of this study was to assess the performance of SCF-engineered budesonide and albuterol sulfate powder blends in passive dry powder inhalers (DPI) relative to micronized drug blends. A number of lactose grades for inhalation were screened and the appropriate carrier and drug-to-lactose blending ratio were selected based on drug content and emitted dose uniformity. Aerosol performance was characterized by Andersen cascade impaction. Blend formulations of SEDS (solution enhanced dispersion by supercritical fluids) budesonide and albuterol exhibited a significant drug content uniformity (7-9% RSD) improvement over micronized drug blends (16-20% RSD). Further, the SEDS formulations demonstrated higher emitted dose and reduced emitted dose variability (10-12% RSD) compared to micronized powders (21-25% RSD) in the Turbospin, albeit without significant enhancement of the fine particle fraction. In contrast, SEDS powders exhibited increased fine particle fractions over micronized blends in the Clickhaler; improvements were more pronounced with albuterol sulfate. The performance enhancements observed with the SEDS powders are attributed to their increased surface smoothness and reduced surface energy that are presumed to minimize irreversible drug-carrier particle interactions, thus resulting in more efficient drug detachment from the carrier particle surface during aerosolization. As demonstrated for budesonide and albuterol, SEDS may enhance performance of lactose blends and thus provide an attractive particle engineering option for the development of blend formulations for inhalation delivery.

Bronchial hyperresponsiveness induced by chronic treatment with albuterol: Role of sensory nerves.

BACKGROUND: It has recently been suggested that regular treatment with racemic beta(2)-adrenoceptor agonists might result in bronchial hyperresponsiveness (BHR) to a range of spasmogens, and this might be due to adverse effects of the distomer. OBJECTIVE: We sought to determine whether BHR induced by means of continuous exposure to racemic and S-albuterol was mediated by sensory nerves. METHODS: Naive or ovalbumin-sensitized guinea pigs were treated for 10 days with RS-, R-, or S-albuterol (1 mg.kg(-1).d(-1)) through subcutaneously implanted minipumps. Lung function was then determined in response to a number of spasmogens and assessed on the basis of an increase in total airway resistance. A separate group of animals were chronically treated with capsaicin (80 mg/kg) before the albuterol treatment. RESULTS: Treatment with RS- or S-albuterol increased airway responsiveness to bradykinin, leukotriene C(4), and capsaicin in naive guinea pigs (P <.05) and to histamine and ovalbumin in immunized guinea pigs (P <.05). Chronic treatment with capsaicin prevented the development of RS- and S-albuterol-induced BHR in these models. The bronchodilator efficacy of acute intravenously administered RS-albuterol was unaffected in RS-, R-, or S-albuterol-treated guinea pigs compared with in vehicle-treated animals. CONCLUSION: We have provided evidence demonstrating that continuous exposure to RS- and S-albuterol increases bronchial responsiveness to a range of stimuli, an effect not attributed to beta-adrenoceptor occupancy or desensitization. Furthermore, capsaicin-sensitive sensory nerves mediate the development of BHR, at least in part.

Respiratory deposition patterns of salbutamol pMDI with CFC and HFA-134a formulations in a human airway replica.

This paper describes a technique that uses a well-defined human airway replica and gamma counting as a standard method for evaluating and comparing the performance of medical inhalers and spacers. High-fidelity replicas reproduced as needed from master casts made from human cadavers include the oropharyngeal cavity, larynx, trachea, and five to nine generations of bronchi. Deposition in the small airways and alveoli region of the cast is simulated by material that passes through the upstream airways and is collected on foam filters. Deposition patterns in the respiratory tract replica were obtained by using radiolabel in the medical inhaler and by gamma scintigraphy. This technique was used to determine respiratory deposition patterns of salbutamol in a pressurized metered dose inhaler (pMDI) with chlorofluorocarbon (CFC, in-house formulation) and HFA-134 formulations (Proventil hydrofluoroalkane [HFA]). At an inspiration flow of 30 L/min, patterns in the salbutamol/CFC formula showed a high deposition in the oropharyngeal airway (78%) and a 16% deposition in the lung, similar to in vivo measurements reported in the literature. However, the salbutamol/HFA formula showed lower oral deposition (56%) but higher lung deposition (24%). The difference in the oral deposition patterns may be attributed to lower initial spray velocity, initial droplet evaporation rate, and possibly initial droplet sizes of Proventil HFA. The small orifice diameter (0.25 mm) of the Proventil HFA actuator produced a softer plume with a smaller impact force, resulting in lower oropharyngeal deposition. Cascade impactor measurements showed similar aerodynamic particle size distribution of the CFC and HFA formulations. We also showed that using spacers in the Proventil HFA resulted in a lower oropharyngeal deposition and higher lung deposition, indicating beneficial effects. Comparison of oropharyngeal deposition and those predicted by artificial throats used in the impactor measurements showed that, in general, the artificial throat predicted a lower deposition.