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Pulmonary delivery of 17-hydroxyprogesterone caproate (17-HPC)

A technology of 17-HPC and progesterone, which is applied in powder delivery, aerosol delivery, nebulizer for treatment, etc., can solve the problem of not improving enzyme activity

Active Publication Date: 2014-02-12
SHENZHEN EVERGREEN THERAPEUTICS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Steroid treatment increases cytosolic MAPK tyrosine phosphorylation but not enzymatic activity

Method used

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  • Pulmonary delivery of 17-hydroxyprogesterone caproate (17-HPC)
  • Pulmonary delivery of 17-hydroxyprogesterone caproate (17-HPC)
  • Pulmonary delivery of 17-hydroxyprogesterone caproate (17-HPC)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0131] Example 1. Addition of IL-2 and IL-4 reduces steroid sensitivity or induces steroid resistance in male smokers

[0132] IL-2 / 4-induced steroid resistance in PBMCs, a well-known research model, was used to evaluate potential modulators of steroid resistance and sensitivity. PBMCs were collected from healthy smokers. Corticosteroid insensitivity or tolerance was induced by addition of IL-2 and IL-4 in peripheral blood mononuclear cells (PBMC) from healthy male smokers (n=11). PBMC (10 6 cells / ml) were cultured in 96-well plates for 48 hours, and then exposed to serial dilutions of dexamethasone (10 -10 M, 10 -8 M to 10 -6 M) for 1 hour, then at 37°C, 5% CO 2 Stimulated with PHA (15 μg / ml) for 24 hours. IL-2 levels were quantified using ELISA. The percent inhibition of PHA-induced IL-2 production was calculated, % inhibition = 1 - (IL-2 with dexamethasone / IL-2 without dexamethasone).

[0133] figure 2 The results in showed that the addition of IL-2 and IL-4 sig...

Embodiment 2

[0134] Example 2. Progestins increase corticosteroid sensitivity or reverse corticosteroid resistance in male smokers.

[0135] Corticosteroid insensitivity or tolerance can be reversed pharmacologically. We investigated the role of progestogens, currently of unknown function, in reversing steroid resistance and tested the progestogenic drug 17α-hydroxyprogesterone caproate in peripheral blood mononuclear cells (PBMCs) from healthy male smokers. Effects of ketone (17HPC), medroxyprogesterone acetate (MPA) and natural progesterone (P4) on enhancing glucocorticoid sensitivity.

[0136] PBMC (10 6 cells / ml) were cultured in 96-well plates for 48 hours, followed by 17HPC (10 -10 M, 10-7 M and 10 -5 M or P4 or MPA (10 -10 M, 10 -8 M and 10 -5 M) Stimulate for 12 hours, and then in 37 ℃, 5% CO 2 , with or without low-dose and high-dose dexamethasone (10 -10 M and 10 -6 M) exposure for 1 hour followed by 24 hours exposure to PHA (15 μg / ml) (n=11 for the combination of 17HP...

Embodiment 3

[0140] Example 3. 17HPC reverses corticosteroid tolerance in male smokers

[0141] PBMC (10 6 cells / ml) were cultured in 96-well plates for 48 hours, followed by 17HPC (10 -10 M, 10 -7 M and 10 -5 M) Stimulate for 12 hours, and then in 37 ℃, 5% CO 2 , with or without three doses of dexamethasone (10 -10 M, 10 -8 M and 10 -6 M) exposure for 1 hour followed by 24 hours exposure to PHA (15 μg / ml). IL-2 levels were quantified using ELISA.

[0142] Figure 5 It was shown that addition of IL-2 and IL-4 significantly reduced steroid sensitivity at all three dexamethasone concentrations. Increased dexamethasone inhibition of PHA-induced IL-2 release was obtained by adding 17HPC. In a dose-response plot, 17HPC reversed glucocorticoid insensitivity. Thus, 17HPC restored corticosteroid sensitivity. For example, in the presence of dexamethasone 10 -10 M but without 17HPC, the PHA-induced IL-2 level was 2364pg / ml, vs. -10 M, 10 -7 M and 10 -5 After M, significantly increa...

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Abstract

The invention relates to 17-HPC pulmonary formulations for administration by inhalation comprising 17-HPC and a pharmaceutically acceptable excipient. Particle size reduction of 17-HPC is required for the pulmonary delivery, and can be achieved with a surfactant or water without the surfactant. Preferred pulmonary formulations include a powder blend comprising a therapeutically effective amount of at least one steroid hormone (progestogen) as a glucocorticoid sensitizer, and at least one pharmaceutically acceptable excipient, wherein the at least one steroid hormone (progestogen) has a particle size distribution profile ranging from about one nanometer to about ten microns in the powder blend.

Description

[0001] Cross References to Related Applications [0002] This application is a currently pending Continuation-In-Part application of U.S. Patent Application No. 13 / 021,950, filed February 7, 2011, and claims PCT International Patent Application No. The benefit of PCT / US11 / 23917 and US Provisional Patent Application No. 61 / 302,325, filed February 8, 2010, the entire contents of which are incorporated herein by reference. field of invention [0003] Glucocorticoid insensitivity is a difficult problem to manage in diseases / conditions treated with glucocorticoids because of the lack of effective treatments. The invention particularly relates to inhalation formulations comprising progestins such as 17α-hydroxyprogesterone caproate (17-HPC); and for administration of progestins as glucocorticoid sensitizers to restore corticosteroid sensitivity or to reverse glucocorticoid Methods and kits for hormone insensitivity or for enhancing glucocorticoid sensitivity to treat one or more di...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/57A61K31/573A61K9/14A61K47/26A61M11/00A61P11/00A61P29/00A61P37/00
CPCA61K9/12A61K31/56A61K9/0075A61K31/57A61P11/00A61P19/02A61P25/00A61P29/00A61P31/04A61P33/00A61P37/00A61P37/08
Inventor 李长青杜涛
Owner SHENZHEN EVERGREEN THERAPEUTICS CO LTD
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