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Alpha1-proteinase inhibitor for delaying the onset or progression of pulmonary exacerbations

A technology for exacerbation of symptoms and lungs, applied in the direction of peptide/protein components, medical preparations containing active ingredients, anti-inflammatory agents, etc., can solve problems such as aggravation of pulmonary symptoms, exacerbation, damage to lung tissue, etc.

Inactive Publication Date: 2014-06-25
GRIFOLS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, established pulmonary exacerbations may be difficult to eradicate with A1PI
In addition, repeated exacerbations damage lung tissue and may gradually reduce the subject's FEV 1

Method used

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  • Alpha1-proteinase inhibitor for delaying the onset or progression of pulmonary exacerbations
  • Alpha1-proteinase inhibitor for delaying the onset or progression of pulmonary exacerbations
  • Alpha1-proteinase inhibitor for delaying the onset or progression of pulmonary exacerbations

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0138] Purified α 1 -Protease inhibitor

[0139] Including the final hydrophobic interaction chromatography step for purification of α 1 - A non-limiting procedure for protease inhibitors, described in US Patent Application Publication No. US2011 / 0237781A1, which is hereby incorporated by reference. The flow diagram of this purification process is shown in figure 2 . A1PI purified using this method is referred to herein as "A1PI-HC". The upstream process used to prepare AlPI-HC was based on Cohn's plasma fractionation. The starting material for the purification process was Cohn Fraction IV-1 paste, which was suspended in buffer solution and mixed until homogeneous. Contaminating proteins were precipitated from the suspension by addition of 11.5% PEG3350 and then removed by centrifugation followed by depth filtration. Make the PEG supernatant / filtrate with polysorbate 20 ( 20) mixed with tri-n-butyl phosphate (TNBP) to inactivate enveloped viruses (enveloped viruses). ...

Embodiment 2

[0141] Preclinical studies performed with A1PI-HC

[0142] The preclinical toxicology of AlPI-HC was evaluated using acute and 28-day daily repeated-dose studies in which aerosolized AlPI was administered by inhalation. These studies were performed in two species: Sprague-Dawley rats (Rattus norvegicus) (Rattus norvegicus) and cynomolgus monkeys (Macaca fascicularis). Additionally, a 26-week chronic inhalation toxicity study was performed in rats with a 13-week interim sacrifice. The results from these studies are summarized in Table 2.

[0143]

[0144]

[0145] In all studies listed in Table 2, AlPI-HC was well tolerated and did not cause any significant toxicity at doses well in excess of what could be administered to subjects. In the above study, cynomolgus monkeys received approximately 38 mg / kg / day for up to 28 days, while rats received approximately 46 mg / kg / day for 26 weeks. As a non-limiting example of the methods described herein, a subject may typically rec...

Embodiment 3

[0147] Advances in inhalation delivery device technology

[0148] Despite all the advantages of aerosol applications, the development of routes of administration has been hampered by poor device efficiency and the lack of inhalation systems that can efficiently deliver larger proteins to the peripheral airways. Previous devices required excessively long inhalation times and delivered widely varying amounts of AlPI primarily to the central airways rather than the peripheral lungs. New advances in inhalation delivery technology have created devices that deliver more effectively and reproducibly to the lungs, such as AKITA 2 Nebulized inhaler system. Brand et al., Eur. Respir. J. 34(2):354-360 (2009).

[0149] Using AKITA 2 (State-of-the-art delivery device) A recent study of A1PI deposition characterized that in a single inhalation of 2mL (70mg of A1PI) 99m Tc-labeled Later, the uniformity of the deposition site of the drug in the lung. Brand et al., Eur. Respir. J. 34:35...

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Abstract

Alpha1-proteinase inhibitor for delaying the onset or progression of pulmonary exacerbations is provided. Described herein are methods for delaying the onset or diminishing the progression of pulmonary exacerbations by the administration of inhaled alpha1-proteinase inhibitor.

Description

technical field [0001] This article describes the administration of inhaled alpha 1 -Protease inhibitors to delay the onset of pulmonary exacerbations (pulmonary exacerbations) or to attenuate the progression of pulmonary exacerbations. Background technique [0002] alpha 1 - protease inhibitors (abbreviated herein as A1PI; especially also known as alpha-1 protease inhibitors, alpha-1PI, A 1 PI, α-1PI, α 1 PI, alpha-1 trypsin inhibitor, alpha-1 antitrypsin, alpha1AT, A1A and A1AT, AAT), are major serine protease inhibitors (serine protease inhibitors) in humans. AlPI is represented as a 418 amino acid protein, of which residues 1–24 are the signal peptide. The mature protein consisting of residues 25-418 is a single-chain glycoprotein with a molecular weight of approximately 51 kD. see figure 1 . Although A1PI does not contain any disulfide bonds, the protein is highly structured, with 80% of its amino acids residing in 8 well-defined α-helices or 3 larger β-sheets. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/00A61P11/00A61K9/72
CPCA61K38/00A61P1/14A61P11/00A61P11/06A61P11/08A61P11/10A61P11/14A61P29/00A61P31/06A61P43/00A61M15/002A61K38/55A61M15/0018A61K38/57A61K45/06A61M15/0085A61M16/14
Inventor 马克·福尔沙格罗伊斯·瓦尔特利普莱斯·加尔林豪斯威廉·巴尼特
Owner GRIFOLS
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