Effect of Amino Acids on the Dispersion of Disodium Cromoglycate Powders

Chew, Nora Y.K.; Shekunov, Boris Y.; Tong, Henry H.Y.; Chow, Albert H.L.; Savage, Charles R.; Wu, James Yuliang; Chan, Hak‐Kim

doi:10.1002/jps.20426

Cited by 151 publications

(87 citation statements)

References 17 publications

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“…Among the common amino acids, L-leucine was found to be the most surface active (17). L-leucine is a natural antiadherent amino acid that is commonly employed in dry powder inhaler (DPI) formulations to improve the dispersibility of drug particles like disodium cromoglycate (18), ß-estradiol (19) and tobramycin sulfate (20). Indeed, the deposition of spray dried powders intended for pulmonary gene therapy was significantly increased by the incorporation of L-leucine (21).…”

Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: The Influence of Sodium Hyaluronate, l-Leucine and Sodium Taurocholate on the Nebulization of Aqueous Betamethasone-17-Valerate Suspensions

Tadros

2008

AAPS PharmSciTech

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Abstract. The purpose of this research was to evaluate the variables that are suggested to influence the adsorption of the hydrophilic hyaluronic acid (HA) onto the surface of the hydrophobic betamethasone-17-valerate (BV) particles in order to formulate a nebulizable suspension. The adsorption of HA from aqueous solutions (0.04% to 0.16%, w/v) to a fixed BV concentration (0.04%, w/v) under different experimental conditions, was investigated. The method of preparation of HA-BV suspensions involved suspending BV particles either in the hydrated HA solution (method 1) or in water followed by addition of solid HA (method 2). Other variables like the time required for the adsorption to complete and temperature at which adsorption is carried out were studied. The nebulization of the suspensions was tested via an air jet nebulizer connected to a twin stage impinger. In order to improve the nebulization behavior of the optimized suspension, L-leucine or sodium taurocholate was incorporated in increasing concentrations (0.01-0.04%, w/v). The optimized suspension, having a nebulization efficiency of 33.75%, was achieved following the adsorption of HA (0.1%, w/v) onto BV particles adopting method 2 of preparation and extending for three days at 4°C. Incorporation of either l-leucine or sodium taurocholate significantly decreased the aggregate size of the optimized suspension and consequently caused significant increases in the nebulization efficiency to reach 46.87% and 56.25%, respectively.

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Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: The Influence of Sodium Hyaluronate, l-Leucine and Sodium Taurocholate on the Nebulization of Aqueous Betamethasone-17-Valerate Suspensions

Tadros

2008

AAPS PharmSciTech

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“…L-leucine, trileucine and phenylalanine [45,46]. These carrier/ excipients help to reduce the interparticulate forces between drug molecules, alter density of particles, improve surface activity and subsequently reduce the dependence of FPF on flow rate and inhaler type hence improving aerosolization [46].…”

Section: Introductionmentioning

confidence: 99%

Engineering hydrophobically modified chitosan for enhancing the dispersion of respirable microparticles of levofloxacin

Merchant

Taylor

Stapleton

et al. 2014

European Journal of Pharmaceutics and Biopharmaceutics

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a b s t r a c tThe potential of amphiphilic chitosan formed by grafting octanoyl chains on the chitosan backbone for pulmonary delivery of levofloxacin has been studied. The success of polymer synthesis was confirmed using FT-IR and NMR, whilst antimicrobial activity was assessed against Pseudomonas aeruginosa. Highly dispersible dry powders for delivery as aerosols were prepared with different amounts of chitosan and octanoyl chitosan to study the effect of hydrophobic modification and varying concentration of polymer on aerosolization of drug. Powders were prepared by spray-drying from an aqueous solution containing levofloxacin and chitosan/amphiphilic octanoyl chitosan. L-leucine was also used to assess its effect on aerosolization. Following spray-drying, the resultant powders were characterized using scanning electron microscopy, laser diffraction, dynamic light scattering, HPLC, differential scanning calorimetry, thermogravimetric analysis and X-ray powder diffraction. The in vitro aerosolization profile was determined using a Next Generation Impactor, whilst in vitro antimicrobial assessment was performed using MIC assay. Microparticles of chitosan have the property of mucoadhesion leading to potential increased residence time in the pulmonary mucus, making it important to test the toxicity of these formulations. In-vitro cytotoxicity evaluation using MTT assay was performed on A549 cell line to determine the toxicity of formulations and hence feasibility of use. The MTT assay confirmed that the polymers and the formulations were non-cytotoxic. Hydrophobically modifying chitosan showed significantly lower MIC (4-fold) than the commercial chitosan against P. aeruginosa. The powders generated were of suitable aerodynamic size for inhalation having a mass median aerodynamic diameter less than 4.5 lm for formulations containing octanoyl chitosan. These highly dispersible powders have minimal moisture adsorption and hence an emitted dose of more than 90% and a fine particle fraction (FPF) of 52%. Powders with non-modified chitosan showed lower dispersibility, with an emitted dose of 72% and FPF of 20%, as a result of high moisture adsorption onto the chitosan matrix leading to cohesiveness and subsequently decreased dispersibility.

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“…Hydrophobic amino acids such as L-leucine (Leu) or L-phenylalanine have been reported to improve the dispersibility of small particles prepared with the spray-drying method. 19,20) The particle design described above is one of the critical factors to determine the effectiveness of inhalation therapy. Inhalation devices and inhalation patterns of patients are other important factors.…”

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confidence: 99%

“…They also reported that Leu and Phe were the best two to maximize the inhalation performance of disodium cromoglycate. 19) Li et al prepared several admixtures of amino acids and lactose to enhance the aerosolization of spray-dried powders for pulmonary gene therapy. 20) They did not try Leu but reported 1 : 10 admixture of arginine or 1 : 5 admixture of Phe with lactose showed the highest inhalation performance.…”

mentioning

confidence: 99%

Development of Spray-Freeze-Dried Powders for Inhalation with High Inhalation Performance and Antihygroscopic Property

2016

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Spray-freeze-drying (SFD) is a unique powderization technique to produce highly porous dry powders with a low density. The characteristic morphology can markedly contribute to the superior inhalation performances of SFD powders. Due to the increased specific surface area of the powders, however, moisture adsorption may readily occur, subsequently leading to losses of their inhalation potentials. In this study, hydrophobic amino acids were newly applied as pharmaceutical excipients to obtain SFD powders with both a favorable inhalation performance and antihygroscopic property. SFD powders composed of several hydrophobic amino acids were prepared. The morphology, particle size distribution, and crystallinity of the prepared powders were evaluated by scanning electron micrography, laser diffraction, and X-ray powder diffraction, respectively. The inhalation characteristics of the SFD powders were examined using a twin-stage liquid impinger equipped with an inspiratory pattern simulator and devices. To investigate their antihygroscopicity, moreover, the SFD powders were stored under a humidified condition to assess the morphology, crystallinity, and inhalation performance as described above. It was demonstrated that a SFD powder composed of L-leucine, L-isoleucine, or L-phenylalanine showed a superior inhalation performance, which was sufficiently maintained after storage under the humidified condition, strongly indicating their antihygroscopicity. These results indicated that the hygroscopicity of SFD powders can be effectively improved by the application of hydrophobic amino acids as excipients. Key words dry powder inhaler (DPI); spray-freeze-drying (SFD); hydrophobic amino acid; inhalation performance; antihygroscopic propertyInhalants that can deliver a drug deep into the lungs directly and noninvasively have attracted attention as dosage forms for the therapy of not only local diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis but also systemic diseases such as diabetes. [1][2][3] There are three kinds of inhalant on the market: pressurized metered-dose inhalers (pMDIs), inhalation solutions, and dry powder inhalers (DPIs). DPIs have many advantages compared to the other two forms: (1) no propellant or battery is required, (2) the device is small, and (3) powders are dispersed on inhalation by a patient, minimizing the mismatch between the timing of inhalation and drug dispersal. 4,5) The powders for DPIs should have an appropriate mass median aerodynamic diameter (MMAD) suitable for inhalation and small adhesion cohesiveness. The commonly recognized optimum MMAD is in the range of 1-6 µm.4) However, the adhesion cohesiveness of such small particles is usually high, and they easily aggregate to form large particles that are not suitable for inhalation. 6) To solve this problem, the small particles of an active ingredient are generally mixed with large inert carrier particles (50-100 µm) such as lactose monohydrate to prevent the small particles of an active ingredient from unde...

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Effect of Amino Acids on the Dispersion of Disodium Cromoglycate Powders

Cited by 151 publications

References 17 publications

RETRACTED ARTICLE: The Influence of Sodium Hyaluronate, l-Leucine and Sodium Taurocholate on the Nebulization of Aqueous Betamethasone-17-Valerate Suspensions

RETRACTED ARTICLE: The Influence of Sodium Hyaluronate, l-Leucine and Sodium Taurocholate on the Nebulization of Aqueous Betamethasone-17-Valerate Suspensions

Engineering hydrophobically modified chitosan for enhancing the dispersion of respirable microparticles of levofloxacin

Development of Spray-Freeze-Dried Powders for Inhalation with High Inhalation Performance and Antihygroscopic Property

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