Inhalable antifibrotic compounds

Development of a formulation method and formulation of antifibrotic small molecule tilorone as inhalable dry powder

Ville Vartiainen

Research output: ThesisDoctoral ThesisCollection of Articles

Abstract

The purpose of this work was to develop a formulation method to produce high quality inhalable dry powder, to formulate an anti-fibrotic small molecule tilorone to a respirable form, and to assess its anti-fibrotic potential in pulmonary administration. The aerosol flow reactor method was used to produce carrier-free formulations of water soluble and insoluble drugs as well as combination powders with drugs of opposing solubilities. L-leucine, L-valine and L-phenylalanine were studied for coating and encapsulation of drug particles. L-valine and L-phenylalanine were found unsuitable for formulation of inhalable dry powder, but the studies confirmed L-leucine’s high potential as an excipient. The produced formulations were tested for their aerosolization properties, cytocombatibility and drug permeation properties. All leucine coated powders showed good aerosolization performance. They were shown to perform flow rate independently in terms of emitted dose and fine particle fraction. In addition the doses were shown to be repeatable with coefficient of variance of the emitted dose being ≤ 0.11 for every formulation at least with one of the tested inhalers. The fine particle fractions were 28-49% when mannitol was used as matrix former and 54-70% when cyclodextrin was used instead. Water insoluble beclomethasone dipropionate in combination powder was found to have significantly faster permeation through a lung cell monolayer when compared to physical mixture of the formulation components. Similar difference was not seen with water soluble salbutamol sulphate. The effect was not observed with cyclodextrine based formulations of prednisolone and fludrocortisone-21-acetate.The anti-fibrotic water soluble small molecule tilorone was formulated and its anti-fibrotic potential was studied in vivo. The produced formulation showed flow rate independent emission and fine particle fraction when emitted from Easyhaler® at flow rates of 40 and 55 Lmin-1. The emitted doses were 3.0 mg for both flow rates with fine particle fractions being 28% and 30% for 40 and 55 Lmin-1 respectively. The formulation was shown to retain its biological activity in vitro after the processing despite high reactor temperatures. Tilorone was studied in pulmonary administration in a silica model of pulmonary fibrosis in mice. It produced significant reduction in histological scoring of fibrosis when compared to the vehicle group. The effectiveness of tilorone in pulmonary administration could likely be increased with more refined dosing. In this thesis we have shown that the aerosol flow reactor method is a versatile mean for formulating both water soluble and insoluble drugs. We have shown that tilorone can be formulated as inhalable dry powder andhas high potential in treatment of fibrotic lung diseases.
Original languageEnglish
Supervisors/Advisors
  • Myllärniemi, Marjukka, Supervisor
  • Raula, Janne, Supervisor, External person
Award date28 Sep 2018
Place of PublicationHelsinki
Publisher
Print ISBNs978-951-51-4419-5
Electronic ISBNs978-951-51-4420-1
Publication statusPublished - 2018
MoE publication typeG5 Doctoral dissertation (article)

Fields of Science

  • Pulmonary Fibrosis
  • +drug therapy
  • Pneumonia
  • Idiopathic Pulmonary Fibrosis
  • Lung Diseases, Interstitial
  • Tilorone
  • +administration & dosage
  • +pharmacology
  • +pharmacokinetics
  • Dry Powder Inhalers
  • Drug Compounding
  • Mannitol
  • Leucine
  • Valine
  • Phenylalanine
  • Lung
  • Excipients
  • Cyclodextrins
  • Beclomethasone
  • Prednisolone
  • Solubility
  • Drug Combinations
  • Mice
  • 3121 Internal medicine

Cite this

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title = "Inhalable antifibrotic compounds: Development of a formulation method and formulation of antifibrotic small molecule tilorone as inhalable dry powder",
abstract = "The purpose of this work was to develop a formulation method to produce high quality inhalable dry powder, to formulate an anti-fibrotic small molecule tilorone to a respirable form, and to assess its anti-fibrotic potential in pulmonary administration. The aerosol flow reactor method was used to produce carrier-free formulations of water soluble and insoluble drugs as well as combination powders with drugs of opposing solubilities. L-leucine, L-valine and L-phenylalanine were studied for coating and encapsulation of drug particles. L-valine and L-phenylalanine were found unsuitable for formulation of inhalable dry powder, but the studies confirmed L-leucine’s high potential as an excipient. The produced formulations were tested for their aerosolization properties, cytocombatibility and drug permeation properties. All leucine coated powders showed good aerosolization performance. They were shown to perform flow rate independently in terms of emitted dose and fine particle fraction. In addition the doses were shown to be repeatable with coefficient of variance of the emitted dose being ≤ 0.11 for every formulation at least with one of the tested inhalers. The fine particle fractions were 28-49{\%} when mannitol was used as matrix former and 54-70{\%} when cyclodextrin was used instead. Water insoluble beclomethasone dipropionate in combination powder was found to have significantly faster permeation through a lung cell monolayer when compared to physical mixture of the formulation components. Similar difference was not seen with water soluble salbutamol sulphate. The effect was not observed with cyclodextrine based formulations of prednisolone and fludrocortisone-21-acetate.The anti-fibrotic water soluble small molecule tilorone was formulated and its anti-fibrotic potential was studied in vivo. The produced formulation showed flow rate independent emission and fine particle fraction when emitted from Easyhaler{\circledR} at flow rates of 40 and 55 Lmin-1. The emitted doses were 3.0 mg for both flow rates with fine particle fractions being 28{\%} and 30{\%} for 40 and 55 Lmin-1 respectively. The formulation was shown to retain its biological activity in vitro after the processing despite high reactor temperatures. Tilorone was studied in pulmonary administration in a silica model of pulmonary fibrosis in mice. It produced significant reduction in histological scoring of fibrosis when compared to the vehicle group. The effectiveness of tilorone in pulmonary administration could likely be increased with more refined dosing. In this thesis we have shown that the aerosol flow reactor method is a versatile mean for formulating both water soluble and insoluble drugs. We have shown that tilorone can be formulated as inhalable dry powder andhas high potential in treatment of fibrotic lung diseases.",
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author = "Ville Vartiainen",
note = "M1 - 80 s. + liitteet",
year = "2018",
language = "English",
isbn = "978-951-51-4419-5",
publisher = "[V. Vartiainen]",
address = "Finland",

}

Inhalable antifibrotic compounds : Development of a formulation method and formulation of antifibrotic small molecule tilorone as inhalable dry powder. / Vartiainen, Ville.

Helsinki : [V. Vartiainen], 2018. 80 p.

Research output: ThesisDoctoral ThesisCollection of Articles

TY - THES

T1 - Inhalable antifibrotic compounds

T2 - Development of a formulation method and formulation of antifibrotic small molecule tilorone as inhalable dry powder

AU - Vartiainen, Ville

N1 - M1 - 80 s. + liitteet

PY - 2018

Y1 - 2018

N2 - The purpose of this work was to develop a formulation method to produce high quality inhalable dry powder, to formulate an anti-fibrotic small molecule tilorone to a respirable form, and to assess its anti-fibrotic potential in pulmonary administration. The aerosol flow reactor method was used to produce carrier-free formulations of water soluble and insoluble drugs as well as combination powders with drugs of opposing solubilities. L-leucine, L-valine and L-phenylalanine were studied for coating and encapsulation of drug particles. L-valine and L-phenylalanine were found unsuitable for formulation of inhalable dry powder, but the studies confirmed L-leucine’s high potential as an excipient. The produced formulations were tested for their aerosolization properties, cytocombatibility and drug permeation properties. All leucine coated powders showed good aerosolization performance. They were shown to perform flow rate independently in terms of emitted dose and fine particle fraction. In addition the doses were shown to be repeatable with coefficient of variance of the emitted dose being ≤ 0.11 for every formulation at least with one of the tested inhalers. The fine particle fractions were 28-49% when mannitol was used as matrix former and 54-70% when cyclodextrin was used instead. Water insoluble beclomethasone dipropionate in combination powder was found to have significantly faster permeation through a lung cell monolayer when compared to physical mixture of the formulation components. Similar difference was not seen with water soluble salbutamol sulphate. The effect was not observed with cyclodextrine based formulations of prednisolone and fludrocortisone-21-acetate.The anti-fibrotic water soluble small molecule tilorone was formulated and its anti-fibrotic potential was studied in vivo. The produced formulation showed flow rate independent emission and fine particle fraction when emitted from Easyhaler® at flow rates of 40 and 55 Lmin-1. The emitted doses were 3.0 mg for both flow rates with fine particle fractions being 28% and 30% for 40 and 55 Lmin-1 respectively. The formulation was shown to retain its biological activity in vitro after the processing despite high reactor temperatures. Tilorone was studied in pulmonary administration in a silica model of pulmonary fibrosis in mice. It produced significant reduction in histological scoring of fibrosis when compared to the vehicle group. The effectiveness of tilorone in pulmonary administration could likely be increased with more refined dosing. In this thesis we have shown that the aerosol flow reactor method is a versatile mean for formulating both water soluble and insoluble drugs. We have shown that tilorone can be formulated as inhalable dry powder andhas high potential in treatment of fibrotic lung diseases.

AB - The purpose of this work was to develop a formulation method to produce high quality inhalable dry powder, to formulate an anti-fibrotic small molecule tilorone to a respirable form, and to assess its anti-fibrotic potential in pulmonary administration. The aerosol flow reactor method was used to produce carrier-free formulations of water soluble and insoluble drugs as well as combination powders with drugs of opposing solubilities. L-leucine, L-valine and L-phenylalanine were studied for coating and encapsulation of drug particles. L-valine and L-phenylalanine were found unsuitable for formulation of inhalable dry powder, but the studies confirmed L-leucine’s high potential as an excipient. The produced formulations were tested for their aerosolization properties, cytocombatibility and drug permeation properties. All leucine coated powders showed good aerosolization performance. They were shown to perform flow rate independently in terms of emitted dose and fine particle fraction. In addition the doses were shown to be repeatable with coefficient of variance of the emitted dose being ≤ 0.11 for every formulation at least with one of the tested inhalers. The fine particle fractions were 28-49% when mannitol was used as matrix former and 54-70% when cyclodextrin was used instead. Water insoluble beclomethasone dipropionate in combination powder was found to have significantly faster permeation through a lung cell monolayer when compared to physical mixture of the formulation components. Similar difference was not seen with water soluble salbutamol sulphate. The effect was not observed with cyclodextrine based formulations of prednisolone and fludrocortisone-21-acetate.The anti-fibrotic water soluble small molecule tilorone was formulated and its anti-fibrotic potential was studied in vivo. The produced formulation showed flow rate independent emission and fine particle fraction when emitted from Easyhaler® at flow rates of 40 and 55 Lmin-1. The emitted doses were 3.0 mg for both flow rates with fine particle fractions being 28% and 30% for 40 and 55 Lmin-1 respectively. The formulation was shown to retain its biological activity in vitro after the processing despite high reactor temperatures. Tilorone was studied in pulmonary administration in a silica model of pulmonary fibrosis in mice. It produced significant reduction in histological scoring of fibrosis when compared to the vehicle group. The effectiveness of tilorone in pulmonary administration could likely be increased with more refined dosing. In this thesis we have shown that the aerosol flow reactor method is a versatile mean for formulating both water soluble and insoluble drugs. We have shown that tilorone can be formulated as inhalable dry powder andhas high potential in treatment of fibrotic lung diseases.

KW - Pulmonary Fibrosis

KW - +drug therapy

KW - Pneumonia

KW - Idiopathic Pulmonary Fibrosis

KW - Lung Diseases, Interstitial

KW - Tilorone

KW - +administration & dosage

KW - +pharmacology

KW - +pharmacokinetics

KW - Dry Powder Inhalers

KW - Drug Compounding

KW - Mannitol

KW - Leucine

KW - Valine

KW - Phenylalanine

KW - Lung

KW - Excipients

KW - Cyclodextrins

KW - Beclomethasone

KW - Prednisolone

KW - Solubility

KW - Drug Combinations

KW - Mice

KW - 3121 Internal medicine

M3 - Doctoral Thesis

SN - 978-951-51-4419-5

PB - [V. Vartiainen]

CY - Helsinki

ER -