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Inhalable spray-dried formulation of D-LAK antimicrobial peptides targeting tuberculosis.
Int J Pharm. 2015 Aug 01; 491(1-2):367-74.IJ

Abstract

Tuberculosis (TB) is a global disease that is becoming more difficult to treat due to the emergence of multidrug resistant (MDR) Mycobacterium tuberculosis. Inhalable antimicrobial peptides (AMPs) are potentially useful alternative anti-TB agents because they can overcome resistance against classical antibiotics, reduce systemic adverse effects, and achieve local targeting. The aims of the current study were to produce inhalable dry powders containing d-enantiomeric AMPs (D-LAK120-HP13 and D-LAK120-A) and evaluate their solid state properties, aerosol performance, and structural conformation. These two peptides were spray dried with mannitol as a bulking agent at three mass ratios (peptide:mannitol 1:99, 1:49, and 1:24) from aqueous solutions. The resultant particles were spherical, with those containing D-LAK120-HP13 being more corrugated than those with D-LAK120-A. The median volumetric diameter of the particles was approximately 3μm. The residual water content of all powders were <3% w/w and crystalline, due to the low hygroscopicity and crystallinity of mannitol, respectively. The mannitol changed from a mixture of alpha- and beta-forms to delta form with an increasing proportion of AMP in the formulation. The emitted fraction and fine particle fraction of the powders when dispersed from an Osmohaler(®) at 90L/min were about 80% and 50-60% of the loaded dose, respectively, indicating good aerosol performance. Circular dichroism data showed that D-LAK120-HP13 dissolved in Tris buffer at pH 7.15 was of a disordered conformation. In contrast, D-LAK120-A showed greater α-helical conformation. Since the conformations of the AMPs were comparable to the controls (unprocessed peptides), the spray drying process did not substantially affect their secondary structures. In conclusion, spray dried powders containing d-enantiomeric AMPs with preserved secondary molecular structures and good aerosol performance could be successfully produced. They may potentially be used for treating MDR-TB when delivered by inhalation.

Authors+Show Affiliations

Department of Pharmacology & Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, 21 Sassoon Road, Hong Kong.School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N A1X, United Kingdom.Department of Pharmacology & Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, 21 Sassoon Road, Hong Kong.Department of Pharmacology & Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, 21 Sassoon Road, Hong Kong.Department of Pharmacology & Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, 21 Sassoon Road, Hong Kong.Department of Biomolecular Sciences, University of Urbino, Piazza Rinascimento, 6, Urbino 61029, Italy.Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom.Department of Pharmacology & Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, 21 Sassoon Road, Hong Kong. Electronic address: jkwlam@hku.hk.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26151107

Citation

Kwok, Philip Chi Lip, et al. "Inhalable Spray-dried Formulation of D-LAK Antimicrobial Peptides Targeting Tuberculosis." International Journal of Pharmaceutics, vol. 491, no. 1-2, 2015, pp. 367-74.
Kwok PC, Grabarek A, Chow MY, et al. Inhalable spray-dried formulation of D-LAK antimicrobial peptides targeting tuberculosis. Int J Pharm. 2015;491(1-2):367-74.
Kwok, P. C., Grabarek, A., Chow, M. Y., Lan, Y., Li, J. C., Casettari, L., Mason, A. J., & Lam, J. K. (2015). Inhalable spray-dried formulation of D-LAK antimicrobial peptides targeting tuberculosis. International Journal of Pharmaceutics, 491(1-2), 367-74. https://doi.org/10.1016/j.ijpharm.2015.07.001
Kwok PC, et al. Inhalable Spray-dried Formulation of D-LAK Antimicrobial Peptides Targeting Tuberculosis. Int J Pharm. 2015 Aug 1;491(1-2):367-74. PubMed PMID: 26151107.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhalable spray-dried formulation of D-LAK antimicrobial peptides targeting tuberculosis. AU - Kwok,Philip Chi Lip, AU - Grabarek,Adam, AU - Chow,Michael Y T, AU - Lan,Yun, AU - Li,Johnny C W, AU - Casettari,Luca, AU - Mason,A James, AU - Lam,Jenny K W, Y1 - 2015/07/04/ PY - 2015/03/30/received PY - 2015/05/29/revised PY - 2015/07/01/accepted PY - 2015/7/8/entrez PY - 2015/7/8/pubmed PY - 2016/5/18/medline KW - Antimicrobial peptides KW - Dry powder inhaler KW - Inhalation KW - Pulmonary delivery KW - Spray drying KW - Tuberculosis SP - 367 EP - 74 JF - International journal of pharmaceutics JO - Int J Pharm VL - 491 IS - 1-2 N2 - Tuberculosis (TB) is a global disease that is becoming more difficult to treat due to the emergence of multidrug resistant (MDR) Mycobacterium tuberculosis. Inhalable antimicrobial peptides (AMPs) are potentially useful alternative anti-TB agents because they can overcome resistance against classical antibiotics, reduce systemic adverse effects, and achieve local targeting. The aims of the current study were to produce inhalable dry powders containing d-enantiomeric AMPs (D-LAK120-HP13 and D-LAK120-A) and evaluate their solid state properties, aerosol performance, and structural conformation. These two peptides were spray dried with mannitol as a bulking agent at three mass ratios (peptide:mannitol 1:99, 1:49, and 1:24) from aqueous solutions. The resultant particles were spherical, with those containing D-LAK120-HP13 being more corrugated than those with D-LAK120-A. The median volumetric diameter of the particles was approximately 3μm. The residual water content of all powders were <3% w/w and crystalline, due to the low hygroscopicity and crystallinity of mannitol, respectively. The mannitol changed from a mixture of alpha- and beta-forms to delta form with an increasing proportion of AMP in the formulation. The emitted fraction and fine particle fraction of the powders when dispersed from an Osmohaler(®) at 90L/min were about 80% and 50-60% of the loaded dose, respectively, indicating good aerosol performance. Circular dichroism data showed that D-LAK120-HP13 dissolved in Tris buffer at pH 7.15 was of a disordered conformation. In contrast, D-LAK120-A showed greater α-helical conformation. Since the conformations of the AMPs were comparable to the controls (unprocessed peptides), the spray drying process did not substantially affect their secondary structures. In conclusion, spray dried powders containing d-enantiomeric AMPs with preserved secondary molecular structures and good aerosol performance could be successfully produced. They may potentially be used for treating MDR-TB when delivered by inhalation. SN - 1873-3476 UR - https://www.unboundmedicine.com/medline/citation/26151107/Inhalable_spray_dried_formulation_of_D_LAK_antimicrobial_peptides_targeting_tuberculosis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-5173(15)30020-X DB - PRIME DP - Unbound Medicine ER -