scholarly journals Inhalable Dry Powder of Bedaquiline for Pulmonary Tuberculosis: In Vitro Physicochemical Characterization, Antimicrobial Activity and Safety Studies

Pharmaceutics ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 502 ◽  
Author(s):  
Mohammad A. M. Momin ◽  
Bhamini Rangnekar ◽  
Shubhra Sinha ◽  
Chen-Yi Cheung ◽  
Gregory M. Cook ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Mycobacterium Tuberculosis ◽  
Side Effects ◽  
Pulmonary Tuberculosis ◽  
Fine Particle ◽  
Fine Particle Fraction ◽  
Particle Fraction ◽  
Powder Particles ◽  
Inhalable Dry Powder

Bedaquiline is a newly developed anti-tuberculosis drug, conditionally approved by the United States Food and Drug Administration (USFDA) for treating drug-resistant tuberculosis in adults. Oral delivery of bedaquiline causes severe side effects such as increased hepatic aminotransferase levels and cardiac arrhythmias (prolongation of QT-interval). This study aimed to develop inhalable dry powder particles of bedaquiline with high aerosolization efficiency to reduce the side-effects of oral bedaquiline. Bedaquiline (with or without l-leucine) powders were prepared using a Buchi Mini Spray-dryer. The powders were characterized for physicochemical properties and for their in vitro aerosolization efficiency using a next-generation impactor (NGI). The formulation with maximum aerosolization efficiency was investigated for physicochemical and aerosolization stability after one-month storage at 20 ± 2 °C/30 ± 2% relative humidity (RH) and 25 ± 2 °C/75% RH in an open Petri dish. The cytotoxicity of the powders on A549 and Calu-3 cell-lines was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The powders were also evaluated for antimicrobial activity against Mycobacterium tuberculosis. The aerodynamic diameter of the l-leucine-containing powder was 2.4 µm, and the powder was amorphous in nature. The aerosolization efficiency (fine-particle fraction) of l-leucine-containing powder (fine-particle fraction (FPF): 74.4%) was higher than the bedaquiline-only powder (FPF: 31.3%). l-leucine containing powder particles were plate-shaped with rough surfaces, but the bedaquiline-only powder was spherical and smooth. The optimized powder was stable at both storage conditions during one-month storage and non-toxic (up to 50 µg/mL) to the respiratory cell-lines. Bedaquiline powders were effective against Mycobacterium tuberculosis and had a minimal inhibitory concentration (MIC) value of 0.1 µg/mL. Improved aerosolization may help to combat pulmonary tuberculosis by potentially reducing the side-effects of oral bedaquiline. Further research is required to understand the safety of the optimized inhalable powder in animal models.

scholarly journals Aerosolization Performance of Jet Nebulizers and Biopharmaceutical Aspects

Pharmaceutics ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 406 ◽  
Author(s):  
Greta Adorni ◽  
Gerrit Seifert ◽  
Francesca Buttini ◽  
Gaia Colombo ◽  
Luciano A. Stecanella ◽  
...  
Keyword(s):  
Fine Particle ◽  
Drug Product ◽  
Patient Characteristics ◽  
Relevant Information ◽  
Fine Particle Fraction ◽  
Particle Fraction ◽  
Dose Delivery ◽  
Aerosol Emission ◽  
Jet Nebulizers

In this work, 13 jet nebulizers, some of which in different configurations, were investigated in order to identify the biopharmaceutical constraints related to the quality attributes of the medicinal products, which affect their safety, efficiency, compliance, and effectiveness. The aerosolization parameters, including the aerosol output, aerosol output rate, mass median aerodynamic diameter, and fine particle fraction, were determined according to the European Standard EN 13544-1, using sodium fluoride as a reference formulation. A comparison between the aerosol output nebulization time and the fine particle fraction displayed a correlation between the aerosol quality and the nebulization rate. Indeed, the quality of the nebulization significantly increased when the rate of aerosol emission was reduced. Moreover, the performance of the nebulizers was analyzed in terms of respirable delivered dose and respirable dose delivery rate, which characterize nebulization as the rate and amount of respirable product that could be deposited into the lungs. Depending on which of these two latter parameters was used, the nebulizers showed different performances. The differences, in terms of the rate and amount of delivered aerosol, could provide relevant information for the appropriate choice of nebulizer as a function of drug product, therapy, and patient characteristics.

Optimization of the Fine Particle Fraction of a Lyophilized Lysozyme Formulation for Dry Powder Inhalation

2013 ◽  
Vol 30 (6) ◽  
pp. 1698-1713 ◽  
Author(s):  
Sarah Claus ◽  
Claudius Weiler ◽  
Joerg Schiewe ◽  
Wolfgang Friess
Keyword(s):  
Fine Particle ◽  
Fine Particle Fraction ◽  
Particle Fraction ◽  
Dry Powder Inhalation ◽  
Dry Powder

scholarly journals Formulation and evaluation of CFC free inhalers for beclomethasone dipropionate

2013 ◽  
Vol 49 (2) ◽  
pp. 221-231 ◽  
Author(s):  
Gopala Krishna Murthy Talasila ◽  
Bala Vishnu Priya Mukkala ◽  
Satyanarayana Vattikuri
Keyword(s):  
Quality Control ◽  
Fine Particle ◽  
Beclomethasone Dipropionate ◽  
Dry Powder Inhalers ◽  
Fine Particle Fraction ◽  
Particle Fraction ◽  
Metered Dose Inhalers ◽  
Spray Pattern ◽  
Metered Dose ◽  
Emitted Dose

Beclomethasone dipropionate CFC free inhalation formulations were developed with a view to treat asthma prophylactically. Dry powder inhalers (DPI) for beclomethasone dipropionate were prepared with different grades of lactose monohydrate. The influence of carrier and overages on performance of DPI was studied. Metered dose inhalers (MDI) with HFA based propellants were formulated with various doses, overages and different concentrations of alcohol. Formulated DPI and MDI were evaluated for various official and unofficial quality control tests. The influence of over doses on valve delivery, effect of overages on emitted dose and influence of alcohol on spray pattern from MDI were studied. The better fine particle fraction and emitted dose were obtained from the DPI formulated with 10:90 ratio of fine lactose: coarse lactose and with 20% w/w overages. The studies on MDI revealed that the 15% of overdoses are required for effective valve delivery and 20% overages are required for 100% drug delivery. 5-10%v/v alcohol was found to be preferable to get optimum emitted dose and fine particle fraction.

scholarly journals Dissociating antibacterial from ototoxic effects of gentamicin C-subtypes

2020 ◽  
Vol 117 (51) ◽  
pp. 32423-32432
Author(s):  
Mary E. O’Sullivan ◽  
Yohan Song ◽  
Robert Greenhouse ◽  
Randy Lin ◽  
Adela Perez ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Side Effects ◽  
Hair Cell ◽  
Aminoglycoside Antibiotic ◽  
Antimicrobial Activities ◽  
Proof Of Concept ◽  
Cell Toxicity ◽  
Structure Activity ◽  
Future Drug

Gentamicin is a potent broad-spectrum aminoglycoside antibiotic whose use is hampered by ototoxic side-effects. Hospital gentamicin is a mixture of five gentamicin C-subtypes and several impurities of various ranges of nonexact concentrations. We developed a purification strategy enabling assaying of individual C-subtypes and impurities for ototoxicity and antimicrobial activity. We found that C-subtypes displayed broad and potent in vitro antimicrobial activities comparable to the hospital gentamicin mixture. In contrast, they showed different degrees of ototoxicity in cochlear explants, with gentamicin C2b being the least and gentamicin C2 the most ototoxic. Structure–activity relationships identified sites in the C4′-C6′ region on ring I that reduced ototoxicity while preserving antimicrobial activity, thus identifying targets for future drug design and mechanisms for hair cell toxicity. Structure–activity relationship data suggested and electrophysiological data showed that the C-subtypes both bind and permeate the hair cell mechanotransducer channel, with the stronger the binding the less ototoxic the compound. Finally, both individual and reformulated mixtures of C-subtypes demonstrated decreased ototoxicity while maintaining antimicrobial activity, thereby serving as a proof-of-concept of drug reformulation to minimizing ototoxicity of gentamicin in patients.

scholarly journals Synthesis of Some New Pyrimidine-Azitidinone Analogues and Their Antioxidant,In VitroAntimicrobial, and Antitubercular Activities

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Mallikarjunaswamy Chandrashekaraiah ◽  
Mallesha Lingappa ◽  
Vathsala Deepu Channe Gowda ◽  
Doddamedur Giddegowda Bhadregowda
Keyword(s):  
Antimicrobial Activity ◽  
Mycobacterium Tuberculosis ◽  
Schiff Base ◽  
Aromatic Amines ◽  
Dimethyl Formamide ◽  
Chloroacetyl Chloride ◽  
Antituberculosis Activity ◽  
Sodium Sulphide ◽  
Molecular Studies

A series of 1-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenyl)-3-chloro-4-(2-mercaptoquinolin-3-yl)azetidin-2-one (7a-j) have been synthesized from the condensation of aromatic amines withN-phenylacetamide. The thione nucleus formed from 2-chloroquionoline-3-carbadehyde using sodium sulphide in dimethyl formamide (DMF) was followed by the reaction with pyrimidine amine to form the Schiff base intermediates. Attempt has been made to derive final azetidinone analogues from Schiff bases by using chloroacetyl chloride. The newly synthesized analogues were examined for the antimicrobial activity against some bacterial and fungal strains andin vitroantituberculosis activity against mycobacterium tuberculosis. These observations provide some predictions to design further antibacterial and antituberculosis active compounds prior to their synthesis according to molecular studies.

scholarly journals The protective action of piperlongumine against mycobacterial pulmonary tuberculosis in its mitigation of inflammation and macrophage infiltration in male BALB/c mice

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Nihong Lu ◽  
Yongrui Yang ◽  
Xiaofei Li ◽  
Jie Li ◽  
Jie Cheng ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Pulmonary Tuberculosis ◽  
Protective Action ◽  
Granulomatous Inflammation ◽  
Mycobacterial Infection ◽  
Immunomodulatory Activity ◽  
Lymphocyte Function ◽  
Inflammatory Reactions ◽  
Lectin Receptor

Abstract Introduction Piperlongumine (PL) is a bioactive alkaloid and medicinal compound of piperamide isolated from the long pepper (Piper longum Linn). It has demonstrated bactericidal action against Mycobacterium tuberculosis (MTB), the cause of pulmonary tuberculosis; nevertheless, immunomodulatory activity had not been identified for it in MTB-triggered granulomatous inflammation. This study investigated if piperlongumine could inhibit such inflammation. Material and Methods Mycobacterium tuberculosis strain H37Rv was subjected to a broth microdilution assay. Piperlongumine at 5, 15, and 25 μg/mL, 0.2% dimethyl sulphoxide as control or 4 μM of dexamethasone were tested in vitro on MH-S murine alveolar macrophages. BALB/c mice were orally administered PL at 50, 100 and 150 mg/kg b.w. after trehalose-6,6-dimycolate (TDM) stimulation. Chemokine and cytokine concentrations were determined in lung supernatants. Flow cytometry and Western blot analysis were performed to determine phosphorylated spleen tyrosine kinase (Syk), c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) pathways. Results Piperlongumine inhibited inflammatory mediators and adherence of lymphocyte function-associated antigen 1 to MH-S cells following TDM activation. It also improved macrophage clearance of MTB. In TDM-stimulated MH-S cells, PL significantly influenced the macrophage inducible Ca2+-dependent lectin receptor (Mincle)-Syk-ERK signalling pathway. Oral dosing of PL effectively suppressed the development of pulmonary granulomas and inflammatory reactions in the TDM-elicited mouse granuloma model. Conclusion PL as an inhibitor of MTB-triggered granulomatous inflammation may be an effective complementary treatment for mycobacterial infection.

scholarly journals Providing calves different feed source early in life would not affect feed sorting and rumen fermentation for a long term

2020 ◽  
Author(s):  
Jianxin Xiao ◽  
Muhammad Zahoor Khan ◽  
Gibson Maswayi Alugongo ◽  
Wei Wang ◽  
Yajing Wang ◽  
...  
Keyword(s):  
Fine Particle ◽  
Volatile Fatty Acids ◽  
Rumen Fluid ◽  
Rumen Fermentation ◽  
Fine Particle Fraction ◽  
Particle Fraction ◽  
Calf Health ◽  
Rumen Ph ◽  
Short Period

Abstract This study aimed to investigate the short and long-term effect of early in life exposure to different feed sources on feed sorting and rumen fermentation of calves. Forty newborn female Holstein calves were randomly divided based on supplementation of concentrate (CON) or hay (HAY) only during the milk-feeding stage (d 1 to 56). After that, all calves were offered a total mixed ration (TMR) containing 43% of forage and 57% of concentrate until the end of the experiment (d 57 to 196). Calves were weighed immediately after birth and raised in individual hutches until d 70. The calves were then transferred to a heifer barn, housed within treatment in pairs (2 calves/pen). Rectal temperature, feed intake, body weight, body structural measurement, fecal and cough score were recorded ranges from day 1 to 196. Fresh and orts feed were sampled daily at the first two weeks (d 57-70) once TMR was offered and at the last week of the experiment (d 190 to 196) for analysis of feed sorting. Rumen fluid samples were collected at ranges from d 14-190 for detecting rumen pH and volatile fatty acids (VFA) concentrations. Our findings showed that early feed exposure did not influence calf health and growth performance but affected feed sorting in a short period. Upon transition to the same mixed diet, differences were found between treatments in the sorting of the different particle fractions. At week 9 and 10, calves early exposed to concentrates began to sort for fine particle fraction (primarily concentrate in this fraction), and against the long particle fraction (solely forage in this fraction), whereas calves early fed hay sorted for the long particle fraction, and against the fine particle fraction. However, no carryover effect was found, the differences between treatments fade away when detecting feed sorting at the last week, all calves sorted for short and fine particle fractions, and sort against long and medium particle fractions. Although the pattern of feed sorting initially differed between treatments, the rumen pH and VFA concentration were not altered once all calves transitioned to a TMR. These results suggested that the feed familiarity established early in life would not affect diet selection and rumen fermentation in heifer later in life, the dietary experience after transition to same TMR would eventually override the effect of early feed experience.

scholarly journals Providing calves different feed source early in life would not affect feed sorting and rumen fermentation for a long term

2020 ◽  
Author(s):  
Jianxin Xiao ◽  
Muhammad Zahoor Khan ◽  
Gibson Maswayi Alugongo ◽  
Wei Wang ◽  
Yajing Wang ◽  
...  
Keyword(s):  
Fine Particle ◽  
Volatile Fatty Acids ◽  
Rumen Fluid ◽  
Rumen Fermentation ◽  
Fine Particle Fraction ◽  
Particle Fraction ◽  
Calf Health ◽  
Rumen Ph ◽  
Short Period

Abstract This study aimed to investigate the short and long-term effect of early in life exposure to different feed sources on feed sorting and rumen fermentation of calves. Forty newborn female Holstein calves were randomly divided based on supplementation of concentrate (CON) or hay (HAY) only during the milk-feeding stage (d 1 to 56). After that, all calves were offered a total mixed ration (TMR) containing 43 % of forage and 57 % of concentrate until the end of the experiment (d 57 to 196). Rectal temperature, feed intake, body weight, body structural measurement, fecal and cough score were recorded ranges from day 1 to 196. Fresh and orts feed were sampled daily at the first two weeks (d 57-70) once TMR was offered and at the last week of the experiment (d 190 to 196) for analysis of feed sorting. Rumen fluid samples were collected at ranges from d 14-190 for detecting rumen pH and volatile fatty acids (VFA) concentrations. Our findings showed that early feed exposure did not influence calf health and growth performance but affected feed sorting in a short period. Upon transition to the same mixed diet, differences were found between treatments in the sorting of the different particle fractions. At week 9 and 10, calves early exposed to concentrates began to sort for fine particle fraction, and against the long particle fraction, whereas calves early fed hay sorted for the long particle fraction, and against the fine particle fraction. However, no carryover effect was found, the differences between treatments fade away when detecting feed sorting at the last week, all calves sorted for short and fine particle fractions, and sort against long and medium particle fractions. Although the pattern of feed sorting initially differed between treatments, the rumen pH and VFA concentration were not altered once all calves transitioned to a TMR. These results suggested that the feed familiarity established early in life would not affect diet selection and rumen fermentation in heifer later in life, the dietary experience after transition to same TMR would eventually override the effect of early feed experience.

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