Protective effect of sodium stearate on the moisture-induced deterioration of hygroscopic spray-dried powders.

Amorphous powders are thermodynamically unstable, significantly impacting the processing, storage and performance of a product. Therefore, stabilization of the amorphous contents is in demand. In this study, disodium cromoglycate (DSCG) powder was chosen as a model drug because it is amorphous and highly hygroscopic after spray drying. Sodium stearate (NaSt) was co-spray dried with DSCG at various concentrations (10, 50 and 90% w/w) to investigate its effect against moisture-induced deterioration on the in vitro aerosolization performance of DSCG. Particle size distribution and morphology were measured by laser diffraction and scanning electron microscopy (SEM). Physicochemical properties of the powders were analysed by X-ray powder diffraction (XRPD) and dynamic vapour sorption (DVS). Particle surface chemistry was analysed by the time-of-flight secondary ion mass spectrometry (ToF-SIMS). In vitro dissolution behaviours of the spray-dried (SD) powders were tested by the Franz cell apparatus. In vitro aerosolization performance of SD formulations stored at different relative humidity (RH) was evaluated by a multi-stage liquid impinger (MSLI), using an Osmohaler® at 100 L/min. Results showed that adding NaSt in the formulation not only increased the aerosolization performance of DSCG significantly, but also effectively reduced the deleterious impact of moisture. No significant difference was found in the fine particle fraction (FPF) of formulations containing NaSt before and after storage at both 60% and 75% RH for one week. However, after one month storage at 75% RH, SD formulation containing 10% NaSt showed a reduction in FPF, while formulations containing 50% or 90% NaSt showed no change. The underlying mechanism was that NaSt increased the crystallinity of the powders and its presence on the particle surface reduced particle aggregations and cohesiveness. However, NaSt at high concentration could reduce dissolution rate, which needs to be taken into consideration.

Pharmacokinetics of Cromolyn and Ibuprofen in Healthy Elderly Volunteers.

BACKGROUND AND OBJECTIVES: The combination of cromolyn and ibuprofen is being investigated as a treatment for early Alzheimer's disease (AD). This study investigated the pharmacokinetics, safety, and tolerability of cromolyn and ibuprofen co-administration in healthy elderly adult volunteers. METHODS: In this open-labeled study, 26 subjects, aged 55-75 years, received co-administration of inhaled cromolyn (single dose 17.1 mg; double dose 34.2 mg total) and oral ibuprofen (single dose 10 mg; double dose 20 mg total). Blood sampling was performed for 6 h after co-administration in all subjects; cerebrospinal fluid (CSF) was collected in three to four subjects per cohort for 4 h following co-administration. Safety parameters, including adverse events (AEs), were monitored throughout the study. RESULTS: For cromolyn, the mean (±SD) maximum observed concentration (C max) in plasma was 46.69 ± 32.97 and 96.75 ± 46.22 ng/ml after single- and double-dose inhalation, respectively [time to C max (t max) ~22 min for each; terminal elimination half-life (t ½) ~1.8 h for each]. For ibuprofen, the plasma C max was 1090.98 ± 474.64 ng/ml and 2062.96 ± 655.13 ng/ml after single- and double-dose oral administration, respectively (t max ~1.6-1.8 h; t ½ ~1.9 h for each). For cromolyn, the CSF C max was 0.24 ± 0.08 ng/ml at 3.72 ± 0.70 h after single-dose administration and 0.34 ± 0.17 ng/ml at 3.45 ± 0.95 h after double-dose administration, and for ibuprofen, the CSF C max was 3.94 ± 1.29 ng/ml at 2.55 ± 0.96 h after single-dose administration and 8.93 ± 3.29 ng/ml at 3.15 ± 1.05 h after double-dose administration. Three (12%) subjects reported mild or moderate AEs which were unlikely to be related to study drug. CONCLUSIONS: The combination of cromolyn and ibuprofen was safe and well tolerated. The concentrations of cromolyn and ibuprofen observed in the CSF are considered sufficient to titrate the estimated daily amyloid production and the associated inflammatory response in patients with AD.

Highly water-soluble mast cell stabiliser-encapsulated solid lipid nanoparticles with enhanced oral bioavailability.

Cromolyn sodium (CS), a mast cell stabiliser, is widely employed for the prevention and treatment of allergic conditions. However, high hydrophilicity and poor oral permeability hinder its oral clinical translation. Here, solid lipid nanoparticles (SLNs) have been developed for the purpose of oral bioavailability enhancement. The CS-SLNs were engineered by double emulsification method (W1/O/W2) and optimised by using Box-Behnken experimental design. The surface and solid-state characterisations revealed the presence of CS in an amorphous form without any interactions inside the spherical-shaped SLNs. The in-vitro release study showed an extended release up to 24 hr by diffusion controlled process. Ex-vivo and in-vivo intestinal permeation study showed ∼2.96-fold increase in permeability of CS by presentation as SLNs (p < 0.05). Further, in-vivo pharmacokinetic study exhibited ∼2.86-fold enhancements in oral bioavailability of CS by encapsulating inside SLNs, which clearly indicate that SLNs can serve as the potential therapeutic carrier system for oral delivery of CS.

Cromolyn as surface active drug (surfadrug): Effect of the self-association on diffusion and percutaneous permeation.

Cromolyn sodium, or disodium cromoglycate (CS), is a surface active drug: a pharmacologically active compound with an amphiphilic nature. At certain conditions it is able to self-associate in several kind of supramolecular aggregates. Since CS could play the role of both carrier and drug, bypassing the use of additional excipients and increasing the system biocompatibility, the effects of cromolyn self-aggregates on diffusion and percutaneous permeation across rabbit ear skin were investigated. Niosomes (vesicular systems, 0.5wt% of CS), monomeric and isotropic solutions (0.5 and 5wt% of CS), nematic (15wt% of CS) and hexagonal phases (30wt% of CS) were selected as supramolecular systems and tested as transdermal delivery systems. Results demonstrated that CS was able to form vesicular structures of about 500nm of diameter and this formulation gave the higher percutaneous permeation profile (systemic action), while isotropic solution and liquid crystals mesophases acted as slower release reservoir of drug on the skin surface (local action), as confirmed by diffusion coefficients. Diffusion rates through a synthetic membrane were dependent both on CS concentration present into the formulations and on its structural organization: maximum diffusion was noticed with isotropic solution, a lower amount of diffused cromolyn sodium was achieved by hexagonal phase. Consequently, CS appears as a versatile surfadrug as, depending on the disease degree, it is possible to modulate its permeation profile by choosing the most appropriate formulation.

Modification of disodium cromoglycate passage across lung epithelium in vitro via incorporation into polymeric microparticles.

Two microparticle systems containing disodium cromoglycate (DSCG) alone or with polyvinyl alcohol (DSCG/PVA) were produced via spray drying and compared in terms of their physicochemical characteristics, aerosol performance and drug uptake across a pulmonary epithelial cell line (Calu-3), cultured under air interface conditions. The particle size distribution of DSCG and DSCG/PVA were similar, of spherical geometry, amorphous and suitable for inhalation purposes. Aerosolisation studies using a modified twin-stage impinger showed the DSCG/PVA to have greater aerosol performance than that of DSCG alone. Aerosol particles of DSCG and DSCG/PVA were deposited onto the surface of the Calu-3 air interface epithelium monolayer and the drug uptake from apical to basal directions measured over time. Drug uptake was measured across a range of doses to allow comparison of equivalent drug and powder mass deposition. Analysis of the data indicated that the percentage cumulative drug uptake was independent of the mass of powder deposited, but dependent on the formulation. Specifically, with the formulation containing DSCG, the diffusion rate was observed to change with respect to time (indicative of a concentration-dependent diffusion process), whilst DSCG/PVA showed a time-independent drug uptake (suggesting a zero-order depot release).

Have inadequate delivery systems hampered the clinical success of inhaled disodium cromoglycate? Time for reconsideration.

IMPORTANCE OF THE FIELD: Disodium cromoglycate (DSCG) fits with the perception of a safe drug, but conclusions from questionable meta-analyses reduced its use. In addition, drug delivery aspects, such as hygroscopicity and the poor performance of delivery systems, were not considered to be important determinants of therapeutic failures. AREAS COVERED IN THIS REVIEW: Drug delivery aspects and parameters affecting lung deposition and distribution, important parameters for therapeutic efficacy, are addressed. In addition, the distribution and ratio of mast cell tryptase and chymase-positive phenotypes in the lungs and their role in the prostaglandin and leukotriene pathway are discussed. WHAT THE READER WILL GAIN: Information on why in vitro data are an excellent tool to understand better therapeutic failures associated with the moisture sensitivity of DSCG and the difficulty in handling and operating DSCG delivery systems in a therapeutically reliable way. TAKE HOME MESSAGE: Pharmacological efficacy of DSCG has been demonstrated in animals and humans. If the drug is delivered to the site of inflammation in an effective dose, a reliable therapeutic effect can be expected. DSCG has extra properties and potential unspecific antiviral properties and may offer new therapeutic treatment aspects for asthma and viral-induced bronchiolitis in early childhood.

Effect of dodecylmaltoside (DDM) on uptake of BCS III compounds, tiludronate and cromolyn, in Caco-2 cells and rat intestine model.

The efficacy of n-lauryl-beta-D-maltopyranoside, (dodecylmaltoside, DDM) as a permeability-enhancer for tiludronate and cromolyn (BCS Class III, water-soluble compounds with oral bioavailability < 5%) was evaluated in Caco-2 cell monolayers and rat intestinal sacs. In Caco-2 cells samples were collected over a 5-h period and transepithelial resistance (TEER) was measured concurrently. In rat intestinal sacs, samples of the test compounds and marker (Lucifer Yellow) were collected over a 40 min period; accumulation in the serosal fluid and intestinal tissue was measured. At lower concentration DDM had no effect on cromolyn permeability and a marginal increase was observed at higher concentration. Tiludronate permeability in the presence of DDM showed greater enhancement as compared to cromolyn. At higher concentration DDM appeared to cause permanent damage to the cell monolayer (irreversible change in TEER). In the intestinal tissue, DDM caused increased tissue accumulation of test compounds. This indicated that transport was not restricted to the paracellular route and damage to the intestinal tissue could not be ruled out. Based on the results obtained in this study it can be concluded that at concentrations that are non-toxic DDM appears to have a limited use to improve the oral absorption of cromolyn and tiludronate.

[HPLC-MS/MS method for determination of sodium cromoglycate concentration in human plasma and its pharmacokinetics].

The study established an HPLC-MS/MS method for determining the concentrations of sodium cromoglycate in human plasma and evaluated the pharmacokinetics of nasal drops and nasal spray. A C18 column was used to separate sodium cromoglycate in plasma with a mobile phase of a mixture of ammonium-methanol (involves 50% acetonitrile) (15:85) at a flow rate of 0.4 mL x min(-1). Electronic spray ionization (ESI) and multiple-reaction monitoring (MRM) were used for the determination of sodium cromoglycate in human plasma. The linear range of the standard curve of sodium cromoglycate was from 0.3 to 20 ng x mL(-1), and the minimum concentration of detection was 0.3 ng x mL(-1). The extraction recovery was more than 94.1%, intra-day and inter-day RSD were less than 14.3%. After a single dose of sodium cromoglycate, the main pharmacokinetic parameters of nasal spray and nasal drops were as follows, T(1/2)(1.82 +/- 0.54) h, (1.59 +/- 0.52) h; Tmax (0.47 +/- 0.12) h, (0.44 +/- 0.15) h; Cmax, (9.79 +/- 4.66) ng x mL(-1), (10.88 +/- 4.05) ng x mL(-1); AUC(0-5 h)(11.52 +/- 3.46) ng x mL(-1) x h x h, (12.63 +/- 4.23) ng x mL(-1) x h, Fr(93.6 +/- 13.8)%. The method is sensitive, rapid and accurate. It is suitable for therapeutic drug monitoring and human pharmacokinetic study of sodium cromoglycate.

Determination of sodium cromoglycate in human plasma by liquid chromatography with tandem mass.

A sensitive and selective liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the determination of sodium cromoglycate (SCG) in human plasma after a nasal dose of 10.4 mg sodium cromoglycate nasal spray, using pravastatin sodium as the internal standard. The method was validated over a linear range of 0.300-20.0 ng/mL. SCG and I.S. were extracted from 1.0 mL of heparinized plasma by C(18) solid-phase extraction cartridges using methanol as eluting solvent. The dried residue was reconstituted with 100 microL of mobile phase, and 10 microL was injected onto the LC-MS/MS system. Chromatographic separation was achieved on a C(18) column (250 x 4.6 mm i.d., 5 microm particle size) with a mobile phase of methanol-acetonitrile-water (containing 2 mmol/L ammonium acetate; 42.5:42.5:15, v/v/v) at a flow rate of 0.4 mL/min. The analytes were detected with a triple quad LC-MS/MS using ESI with positive ionization. Ions monitored in the multiple reaction monitoring mode were m/z 469.0 (precursor ion) to m/z 245.0 (product ion) for SCG and m/z 447.2 (precursor ion) to m/z327.1 (product ion) for pravastatin sodium (internal standard) The average recovery of SCG from human plasma was 94.88% and the lower limit of quantitation was 0.3 ng/mL. Results from a 3-day validation study demonstrated excellent precision and accuracy across the calibration range of 0.3-20 ng/mL. The method was successfully applied to the pharmacokinetic study of SCG in healthy Chinese volunteers.

Gamma scintigraphy for testing bioequivalence: a case study on two cromolyn sodium nasal spray preparations.

The present work was carried out to study the deposition patterns and clearance of technetium-99m (99mTc) DTPA labeled cromolyn sodium (CS) solutions when administered from two different CS nasal products using gamma scintigraphy. Five healthy volunteers received a single dose with complete crossover design involving treatment A (test formulation) and treatment B (reference formulation). The deposition patterns as well as the changes in distribution of the radiolabeled CS solutions due to the mucociliary transport were monitored by gamma scintigraphy. Primary deposition of the aforementioned nasal solutions occurred in the anterior portion of the nose. After migration into the posterior nasal cavity, the solutions were rapidly cleared by ciliary action into the nasopharynx where it was swallowed. The test product of cromolyn sodium was shown to be equivalent to the reference product with regard to nasal deposition and clearance. The results from this study indicate that external gamma scintigraphy can be used to demonstrate the equivalence of nasal sprays that are intended for local therapeutic action where the drug is not systemically absorbed into the blood circulation. Furthermore, a non-invasive imaging method such as rhinoscintigraphy may prove to be a useful technique to be utilized during the regulatory approval process for local-acting nasal products, and may facilitate the early introduction of these products to the market.

Lung deposition after inhalation with various nebulisers in preterm infants.

AIM: To compare pulmonary deposition after inhalation with three different nebulisers in preterm infants under conditions relevant to practice. METHODS: The relative lung deposition (bioavailability) was estimated by inhalation of the marker substance, sodium cromoglycate (SCG), and measurement of urinary excretion of SCG. Seventeen spontaneously breathing preterm infants received 20 mg of SCG as nebuliser solution by means of (a) an LC Star jet nebuliser; (b) an LS 290 ultrasonic nebuliser; and (c) a Projet ultrasonic nebuliser in a randomised three-period, crossover design. Serial urine samples were collected until about 12 hours after inhalations, and the excreted SCG was determined by high-performance liquid chromatography. RESULTS: The mean (SD) total amounts of SCG excreted in urine measured after inhalation with the LC Star nebuliser (0.089 (0.036) mg) were significantly higher than those obtained with the LS 290 (0.055 (0.019) mg) or the Projet nebuliser (0.046 (0.025) mg). The average pulmonary deposition after inhalation using the LC Star, LS 290 and Projet devices was estimated as 0.89%, 0.55% and 0.46% of the nominal dose, respectively. CONCLUSION: Inhalation with the LC Star jet nebuliser producing the greatest proportion of droplets <2 mum yielded a higher lung deposition in preterm infants than the LS 290 and Projet ultrasonic nebulisers.

Mechanistic understanding of oral drug absorption enhancement of cromolyn sodium by an amino acid derivative.

PURPOSE: Examine the oral absorption enhancement mechanism of cromolyn sodium by sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) by evaluating the effect of SNAC on cromolyn sodium lipophilicity and changes in Caco-2 cell membrane fluidity. MATERIALS AND METHODS: Standard Shake-flask method was used to evaluate the effect of SNAC on the lipophilicity of cromolyn sodium. The measurements were carried out in three partitioning solvents with varying hydrogen-bonding properties. Steady state fluorescence emission anisotropy technique was used to evaluate the effect of SNAC with/without cromolyn sodium on Caco-2 cell membrane fluidity. RESULTS: The lipophilicity measurements showed that SNAC had no influence on the lipophilicity of cromolyn sodium in the three partitioning solvent systems. The findings of the steady-state fluorescence anisotropy showed that SNAC increases the membrane fluidity of the Caco-2 cells in a concentration dependent manner. The increase in fluidity with SNAC was seen in the presence and absence of cromolyn sodium and the presence of cromolyn sodium did not augment the effect of SNAC on membrane fluidity. CONCLUSIONS: The increase in membrane fluidity by SNAC plays a pivotal role in the permeation enhancement mechanism of cromolyn sodium. Therefore, the increase in permeation is a result of changing Caco-2 cell membrane fluidity resulting in change in membrane integrity and not due to an increase in the lipophilicity of cromolyn sodium through its interaction with SNAC.

Promising ternary dry powder inhaler formulations of cromolyn sodium: formulation and in vitro-in vivo evaluation.

Glucose monohydrate and sorbitol were evaluated as alternative carriers to á-lactose monohydrate in dry powder inhalations. Cromolyn sodium (CS) - carrier binary formulae were prepared and tested in vitro by aerosolization via a twin stage impinger using three types of inhaler devices; Spinhaler, Aerolizer and Handihaler. Glucose monohydrate and sorbitol-containing formulae that were inhaled via a Handihaler showed significantly higher drug fine particle fractions (P<0.001) than that of the same formulae aerosolized via other devices. Upon storage of the prepared formulae under uncontrolled humidity, that may be encountered during storage and use, marked reductions in these fractions were observed. Incorporation of an optimum Aerosil 200 concentration, as a ternary component, minimized this effect. A urinary excretion pharmacokinetic method was used to evaluate the bioavailability of the selected ternary formulae, inhaled via a Handihaler, relative to the marketed Intal Spincaps, inhaled via a Spinhaler. It was found that the relative bioavailability percentages of the developed formulae were more than twice that of the marketed one suggesting possible future utilization of these more effective ternrry formulae using the more efficient Handihaler inhaler device.

The interaction and compatibility between a soft contact lens and an ophthalmic drug.

PURPOSE: To investigate the interaction and compatibility between a soft contact lens (SCL) and an ophthalmic drug. METHODS: Samples were prepared with the nonionic SCL (groups I and II), the anionic SCL (group IV), and the zwitter ionic SCL (group IV). Chlorpheniramine maleate and sodium cromoglycate were used to measure the drug uptake into the SCL. RESULTS: The results showed the largest drug uptake into the anionic SCL accompanied with dimensional changes and lower drug uptakes into the nonionic and the zwitter ionic SCL with dimensional stability. The cell permeability of the substances when instilled in the eye over the SCL was also measured. The zwitter ionic SCL allowed cell permeability comparable to that by oral administration. CONCLUSIONS: These results indicated the possibility for the zwitter ionic SCL as a lens to be worn concomitantly with ophthalmic drug instillation.

Lung deposition after electronically breath-controlled inhalation and manually triggered conventional inhalation in cystic fibrosis patients.

The present work aimed to investigate whether lung deposition can be improved by using a device that optimizes the breathing pattern through electronic control. The relative lung deposition was estimated by inhalation of the marker substance, sodium cromoglycate (SCG), and measurement of urinary excretion of SCG. Thirteen cystic fibrosis (CF) patients (aged 8-20 years) received 20 mg of SCG as nebulizer solution by means of (a) conventional inhalation (Parimaster + Pari LC Star nebulizer, manual interrupter) and (b) electronically breath-controlled inhalation (AKITA + Pari LC Star nebulizer). Inhalations were trained and supervised by a physiotherapist. Patients were asked to provide answers to a questionnaire about the convenience of electronically breath-controlled inhalation. Urine was collected in five fractions until 12 h p.a., and the excreted SCG was determined by means of high-performance liquid chromatography (HPLC). Following breath-controlled inhalation, the amount of SCG excreted in urine was significantly greater than after conventional inhalation (2.22 +/- 0.61 mg vs. 1.63 +/- 0.59 mg, p < 0.001). The absorption half-life for SCG following breath-controlled inhalation was significantly shorter when compared with conventional inhalation (78 +/- 23 min vs. 107 +/- 29 min; p < 0.01), suggestive of a more peripheral deposition for the former. Ninety-two percent of the patients judged that the electronically breath-controlled inhalation was good or very good. In conclusion, inhalation with an electronically optimized breathing pattern yields a greater and more peripheral lung deposition of SCG compared with the manually triggered conventional nebulizer technique in CF patients with several years of aerosol inhalation experience.

The effect of vehicle on physical properties and aerosolisation behaviour of disodium cromoglycate microparticles spray dried alone or with L-leucine.

The aim of this study was to improve the aerosolisation behaviour of disodium cromogycate (DSCG), using spray drying technique. The effect of vehicle on the drug particle properties was investigated. L-leucine was selected as a natural antiadherent amino acid to improve the deagglomeration of DSCG particles. Spray dried samples of DSCG alone or with L-leucine were prepared from water and ethanol under the same conditions. The powder properties of the samples were examined by laser diffraction, helium densitometer, X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis. The in vitro deposition was determined, using an Andersen cascade impactor with a Spinhaler at a flow rate of 60 l/min. An amorphous form of the drug was obtained when water was used. However, crystal transformation of original DSCG in the presence of ethanol during spray drying resulted in production of elongated particles. These particles exhibited improved aerodynamic properties, compared to the amorphous and commercial materials. Significant differences in fine particle fraction were observed using the two vehicles. Co-spray drying of DSCG and L-leucine improved the deposition profiles of the drug. These results indicated that the change in crystal structure of DSCG during spray drying process was susceptible to the nature of the vehicle. A crystalline form of DSCG with good aerodynamic properties was achieved during spray drying process. In addition, the processing of DSCG with L-leucine in a single step using ethanol resulted in an improvement in dispersion properties of the drug particles.

Does wearing a noseclip during inhalation improve lung deposition?

Using nebulization, only a small proportion of the dose reaches the lungs, while the remainder is swallowed, exhaled into the atmosphere, or remains in the nebulizer. It was the purpose of this study to investigate whether wearing a noseclip during inhalation can improve lung deposition. Relative lung deposition was compared by inhalation of the marker substance, sodium cromoglycate (SCG), and measurement of urinary excretion of SCG. The SCG absorption half-life allows one to differentiate indirectly between a more or less peripheral deposition. Ten CF patients (9-18 years old) inhaled, under routine conditions, a solution containing 20 mg of SCG in a randomized crossover design through a mouthpiece, without and with a noseclip being worn. Following inhalation without and with a noseclip, no statistically significant difference was seen in the amount of SCG excreted in urine (0.9 +/- 0.4 mg vs. 1.0 +/- 0.5 mg; p = 0.402) and absorption half-life (93 +/- 25 min vs. 113 +/- 36 min; p = 0.083). In conclusion, wearing a noseclip during inhalation under conditions relevant to practice does not increase the amount deposited into the lungs of CF patients and, also, there has been no indication of a more peripheral lung deposition.

Self-association of cromolyn sodium in aqueous solution characterized by nuclear magnetic resonance spectroscopy.

The major objective of this study was to investigate and characterize the solution properties of cromolyn sodium (in D(2)O or D(2)O/H(2)O phosphate buffer at pH 7.5) using nuclear magnetic resonance (NMR) spectroscopy. The self-association of cromolyn molecules was examined primarily via one-dimensional (1)H and (13)C, and two-dimensional homonuclear NOESY NMR. Significant spectral shifts were observed for a majority of cromolyn (1)H and (13)C resonances, and are attributed to inter-molecular ring-stacking association accompanied by intra-molecular conformational changes. The critical self-association concentration was determined to be 10 mg/mL at pH 7.5 and 25 degrees C by measuring the chemical shift of a specific cromolyn (1)H resonance. The observed magnitude and sign changes of NOESY correlations indicate the formation of cromolyn aggregates with restricted molecular mobility. Mesomorphic liquid crystal formation is suggested by uniformly pronounced line broadening in concentrated cromolyn solutions; the transition concentration was approximately 60 mg/mL at 25 degrees C, which is consistent with literature findings based on other techniques. A stronger tendency toward association was observed at lower temperature but aggregation appeared to be independent of pH. Lastly, it was concluded that self-association of cromolyn is promoted by the presence of monovalent cations as a result of reduced electrostatic repulsive forces.

Oral absorption enhancement of cromolyn sodium through noncovalent complexation.

PURPOSE: To determine the effect of Sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) on the permeation of cromolyn across Caco-2 cell monolayers and explore the molecular basis for the enhanced absorption. METHODS: Transport studies of cromolyn across Caco-2 cell monolayers were conducted in the presence of various SNAC concentrations. Permeation of cellular transport markers and lactate dehydrogenase (LDH) release were measured to evaluate cell integrity. Molecular interactions betweent the two compounds were investigated using isothermal titration calorimetry (ITC), nuclear magnetic resonance (NMR), and Fourier-transfrom infrared (FTIR) spectroscopies and molecular dynamics simulations. RESULTS: The absorption of cromolyn across Caco-2 monolayers was enhanced markedly by SNAC. SNAC did not cause significant LDH leakage and changes in the permeation of transport markers. ITC, spectroscopies, and molecular dynamic simulations indicated the existence of intermolecular interactions between cromolyn and SNAC that involve the 2-hydroxybenzamide moiety on SNAC and weaken the hydrogen bonding between cromolyn and surrounding water molecules. CONCLUSIONS: SNAC increases the permeability of Caco-2 monolayers to cromolyn without measurable cell damage. SNAC interacts with cromolyn mainly via ring stacking. One major mode of interaction appears to involve the insertion of the aromatic ring of SNAC between cromolyn's rings. Such interaction appears to reduce the hydration of cromolyn and thus optimize its hydrophobicity for oral absorption.

Lung deposition in cystic fibrosis patients using an ultrasonic or a jet nebulizer.

This study was conducted to compare pulmonary deposition following inhalation with an ultrasonic and a jet nebulizer in CF patients under conditions relevant to practice. The marker substance used to estimate the relative lung bioavailability was sodium cromoglycate (SCG), which is poorly absorbed from the gastrointestinal tract, but is completely absorbed from the lungs. Ten CF patients (aged 9-21 years) used an ultrasonic nebulizer (Multisonic compact 2.4 MHz) and a jet nebulizer (Parimaster, LC Plus Turbo) in a crossover design to inhale a solution containing 20 mg of SCG and a beta(2)-agonist. Urine was collected in five fractions until 12 h p. a., and the excreted SCG was determined by means of HPLC. Prior to each inhalation, the patients' pulmonary function was measured employing a Pneumoscope. Using the ultrasonic nebulizer, the amount of SCG excreted in urine was significantly greater than that after inhalation with the jet nebulizer (1.43 +/- 0.47 mg vs. 1.04 +/- 0.47 mg; p = 0.002), despite the larger residual volume in the ultrasonic nebulizer. The absorption half-life for SCG following ultrasonic nebulization was significantly shorter when compared with jet nebulization (84 +/- 14 min vs. 101 +/- 19 min; p = 0.005), being suggestive of a more peripheral deposition. Furthermore, an inverse relationship was found between absorption half-life and FEV(1) (% pred.) (r = -0.655, p = 0.04) or MMEF(75/25) (% pred.) (r = -0.844, p = 0.031), but only with the ultrasonic nebulizer. In conclusion, the ultrasonic nebulizer tested when used for inhalation in CF patients was found to be at least equivalent to the jet nebulizer.