Relationship between surface concentration of l-leucine and bulk powder properties in spray dried formulations

Mangal, Sharad; Meiser, Felix; Tan, Guojin; Gengenbach, Thomas R.; Denman, John A.; Rowles, Matthew R.; Larson, Ian; Morton, David Alexander Vodden

doi:10.1016/j.ejpb.2015.04.035

Cited by 83 publications

(51 citation statements)

References 28 publications

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“…1b and c) rather than the spray dried L-leucine (47). Previous studies have shown that L-leucine could alter the morphology of some spray-dried particles due to enrichment of L-leucine on the particle surface (56). Our SEM data showed that L-leucine had no apparent effects on the morphology of spray-dried azithromycin particles.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have shown that L-leucine can act as the force control agent to reduce the cohesion and improve the aerosolization upon co-spraying (61,62). The capability of L-leucine to reduce cohesion is believed to be associated with its enrichment on the particle surface, which allows it to produce rougher particles with lower surface energy (56). Our results showed that L-leucine did not enrich on the surfaces of the composite formulations and have no significant impact in aerosolization.…”

Section: Resultsmentioning

confidence: 99%

“…It is believed that the addition of L-leucine increases the surface roughness and reduces surface energy of the spray-dried particles as consequences of L-leucine enrichment on the particle surface (56,67–69). However, in this study, co-spray drying with L-leucine had no significant effects on the FPF of azithromycin.…”

Section: Discussionmentioning

confidence: 99%

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Physico-Chemical Properties, Aerosolization and Dissolution of Co-Spray Dried Azithromycin Particles with L-Leucine for Inhalation

Mangal

Nie

et al. 2018

Pharm Res

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Purpose Inhalation therapy is popular to treat lower respiratory tract infections. Azithromycin is effective against some bacteria that cause respiratory tract infections; but it has poor water solubility that may limit its efficacy when administrated as inhalation therapy. In this study, dry powder inhaler formulations were developed by co-spray drying azithromycin with L-leucine with a purpose to improve dissolution. Methods The produced powder formulations were characterized regarding particle size, morphology, surface composition and in-vitro aerosolization performance. Effects of L-leucine on the solubility and in-vitro dissolution of azithromycin were also evaluated. Results The spray dried azithromycin alone formulation exhibited a satisfactory aerosol performance with a fine particle fraction (FPF) of 62.5 ± 4.1%. Addition of L-leucine in the formulation resulted in no significant change in particle morphology and FPF, which can be attributed to enrichment of azithromycin on the surfaces of composite particles. Importantly, compared with the spray-dried amorphous azithromycin alone powder, the co-spray dried powder formulations of azithromycin and L-leucine demonstrated a substantially enhanced in-vitro dissolution rate. Such enhanced dissolution of azithromycin could be attributed to the formation of composite system and the acidic microenvironment around azithromycin molecules created by the dissolution of acidic L-leucine in the co-spray dried powder. Fourier transform infrared spectroscopic data showed intermolecular interactions between azithromycin and L-leucine in the co-spray dried formulations. Conclusions We developed the dry powder formulations with satisfactory aerosol performance and enhanced dissolution for a poorly water soluble weak base, azithromycin, by co-spray drying with an amino acid, L-leucine.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Physico-Chemical Properties, Aerosolization and Dissolution of Co-Spray Dried Azithromycin Particles with L-Leucine for Inhalation

Mangal

Nie

et al. 2018

Pharm Res

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“…The spray-dried powders modified by HIS and LEU had EDs of 92.8 ± 0.7% and 98.0 ± 0.7% respectively, suggesting LEU was more effective than HIS in improving the flowability of spray-dried powders. Many reports have demonstrated that the use of LEU, either through coating on the particle surface, adding to the solution for spray-dried powders, or physically mixing with drug particles, can dramatically improve the flowability of drug particles [12,[15][16][17]. Additionally, our previous paper has demonstrated that other amino acids such as arginine, phenylalanine and threonine can also improve the flowability of spray-dried powders [11].…”

Section: In-vitro Aerosolization and Depositionmentioning

confidence: 93%

The influence of amino acids on aztreonam spray-dried powders for inhalation

Yang

Qu³

et al. 2015

Asian Journal of Pharmaceutical Sciences

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Available online A B S T R A C TThe dry powder inhalation of antibiotics for the treatment of lung infections has attracted drastically increasing attention as it offers rapid local therapy at lower doses and minimal side effects. In this study, aztreonam (AZT) was used as the model antibiotic and spraydried to prepare powders for inhalation. Amino acids of glycine (GLY), histidine (HIS) and leucine (LEU) were used as excipients to modify the spray-dried particles. It was demonstrated that the GLY-AZT spray-dried powders formed huge agglomerates with the size of 144.51 μm, which made it very difficult to be delivered to the lungs (FPF: 0.29% w/w only).In comparison with the AZT spray-dried powders, HIS-modified spray-dried powders showed increased compressibility, indicating larger distance and less cohesion between particles; while the LEU-modified spray-dried particles showed a hollow structure with significantly decreased densities. The fine particle fraction for HIS-and LEU-modified powders was 51.4% w/w and 61.7% w/w, respectively, and both were significantly increased (one-way ANOVA, Duncan's test, P < 0.05) compared to that of AZT spray-dried powders (45.4% w/w), showing a great potential to be applied in clinic. © 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of Shenyang Pharmaceutical University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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“…L-leucine, in combination with the other BCAAs, has also been reported to be prescribed for patients with hepatic encephalopathy (Freund et al, 1982;Gluud et al, 2013Gluud et al, , 2015. In addition, L-leucine is used in the condiment industry and as a lubricant in the pharmaceutical industry (Leuchtenberger, 2008;Mangal et al, 2015;Platell et al, 2000). Moreover, the pentanol isomers, such as 3-methyl-1-butanol, manufactured from the L-leucine precursor 2-ketoisocaproate have a potential application as biofuels Li et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Metabolic engineering of Corynebacterium glutamicum to enhance L-leucine production

Huang¹,

Liang²,

Wu³

et al. 2017

Afr. J. Biotechnol.

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This work aimed to develop an efficient L-leucine industrial production strain of Corynebacterium glutamicum by using metabolic engineering. A recombinant C. glutamicum strain was constructed by expressing a feedback-resistant leuA-encoded 2-isopropylmalate synthase (IPMS) that carries three amino acid exchanges (R529H, G532D and L535V) from the mutant strain C. glutamicum ML1-9 which was obtained by screening for structural analogues. In order to improve the expression of IPMS, a strong promoter (tac promoter) was used to ensure efficient expression of the rate-limiting enzyme. In addition, reasonable metabolic modifications on the central carbon metabolic pathway and competitive metabolic pathways to optimize the L-leucine biosynthesis pathway by redistribution of various types of precursors and repression of negative regulation were used aimed for increased L-leucine production. The modifications involved (1) deletion of the gene encoding the repressor LtbR to increase expression of leuBCD, (2) deletion of the gene encoding the AlaT to decrease the concentration of extracellular L-alanine, and increased availability of pyruvate for L-leucine formation, (3) deletion of the gene encoding the threonine dehydratase to abolish L-isoleucine synthesis and to eliminate the intermediate precursor of L-isoleucine biosynthesis competing with L-leucine biosynthesis, (4) inactivation of the pantothenate synthetase to increase α-ketoisovalerate formation, and to enable its further conversion to L-leucine, and (5) inactivation of lactate dehydrogenase to decrease lactate production and its pyruvate consumption, concomitant to decreased glucose consumption rates and prevention of lactic acid to restrict cell growth. The production performance of the engineered strain MDLeu-19/pZ8-1leuA r was characterized with cultivations in a bioreactor. Under fed-batch conditions in a 50-L automated fermentor, the best producer strain accumulated 38.1 g L -1 of L-leucine; the molar product yield being 0.42 mol L-leucine per mole of glucose (glucose conversion rate attained 26.4%). Moreover, during large-scale fermentation using a 150-m 3 fermentor, this strain produced more than 37.5 g L -1 L-leucine and the glucose conversion rate was 25.8%, making this process potentially viable for industrial production.

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Relationship between surface concentration of l-leucine and bulk powder properties in spray dried formulations

Cited by 83 publications

References 28 publications

Physico-Chemical Properties, Aerosolization and Dissolution of Co-Spray Dried Azithromycin Particles with L-Leucine for Inhalation

Physico-Chemical Properties, Aerosolization and Dissolution of Co-Spray Dried Azithromycin Particles with L-Leucine for Inhalation

The influence of amino acids on aztreonam spray-dried powders for inhalation

Metabolic engineering of Corynebacterium glutamicum to enhance L-leucine production

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