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Compositions of clofazimine, combinations comprising them, processes for their preparation, uses and methods comprising them

A technology of clofazimine and its composition, applied to the composition of clofazimine, can solve the problems of high mortality, poor diagnosis, limited treatment options, etc.

Pending Publication Date: 2021-05-14
MANNKIND CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Each of these species causes hundreds of thousands of infections each year, with an unacceptably high mortality rate due to poor diagnosis and limited treatment options

Method used

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  • Compositions of clofazimine, combinations comprising them, processes for their preparation, uses and methods comprising them
  • Compositions of clofazimine, combinations comprising them, processes for their preparation, uses and methods comprising them
  • Compositions of clofazimine, combinations comprising them, processes for their preparation, uses and methods comprising them

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0192] 200 mg of clofazimine (as triclinic form I), 90 mg of sodium chloride and 9.5 ml of water were mixed twice in an Ultra-Turrax homogenizer at a speed of 10000 rpm for 5 minutes each. 0.5 ml of polysorbate 80 (NOF Hx2) was added. Using an ultrasound probe (Branson Digital Sonifier TM 250D with Bandelin Sonoplus Probe MS73) to process the mixture seven times, 3 minutes each time, with an amplitude of 70%. The volume was adjusted to 10 ml with water. The suspension was filtered through VWR folded qualitative filter paper (303, particle retention 5-13 μm, size: 150 mm) to obtain the composition of Example 1. The median particle diameter of clofazimine in the composition of Example 1 was 3.9 μm, and the D90 was 6.7 μm. The concentration of clofazimine was determined by 280nm ultraviolet / visible spectrophotometry, calibrated with 1 mg / ml clofazimine stock solution (stock) diluted in mobile phase, and the measurement result was 7.16 mg / ml.

[0193] Compositions in Example ...

Embodiment 2

[0199] In 100 ml of water containing 0.5% polysorbate 80 (NOF Hx2) and 0.6% sodium chloride, 6 g of orthorhombic form III clofazimine was added, and pre-micronized using an Ultra-Turrax at 10,000 rpm for about 40 seconds. Preformulations were prepared by adding 0.6% sodium chloride in water to give a volume of 300ml. 300 ml of this suspension was added to the inlet of a homogenizer (M-110EH-30 Microfluidizer (Microfluidics, Westwood, MA, USA)) and pre-homogenized for 15 minutes by circulating the suspension through the H30Z chamber at 5000 psi. qualitative step. Subsequently, a second H10Z chamber was installed in series with the first chamber, and the suspension was further homogenized at 25,000 psi for 23 minutes. Particle size analysis using HORIBA LA 950 showed a median particle size of 0.83 μm and a D90 value of 1.17 μm. The 1 mg / ml clofazimine stock solution diluted in the mobile phase was used for calibration, and the concentration of clofazimine was determined to be ...

Embodiment 3

[0204] Suspensions of clofazimine (crystal-modified orthorhombic form III) in water, sodium chloride, and polysorbate 80 solutions were treated using an M-110EH-30 microfluidizer processor (chambers: H30Z and G10Z), The composition of Example 3 was produced in the H30Z-G10Z configuration at a pressure of 28250 psi for 30 minutes, resulting in clofazimine particles with a median particle size of 1.28 μm and a D90 of less than 2 μm.

[0205] Compositions in Example 3 are shown in Table 3

[0206]

[0207] table 3

[0208] Viscosity measurement

[0209] The viscosity of the composition of Example 3 was tested using a STRESSTECH rheometer in stress control mode. A double gap geometry is employed and the spindle rotates continuously to ensure that the particles remain suspended during the temperature point. Viscosities measured at 20°C, 25°C, and 30°C across stresses of 0.01, 0.05, and 0.1 Pa, respectively. Two separate loadings were performed to obtain the average viscosi...

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Abstract

The present invention relates to pharmaceutical compositions for inhalation comprising a therapeutically effective dose of clofazimine wherein the clofazimine is provided in the form of a suspension, and processes for their preparation. Furthermore, the present invention provides pharmaceutical combinations comprising clofazimine in the form of an aerosol for pulmonary inhalation. The combinations and compositions provided by the present invention may be used in the treatment and / or prophylaxis of pulmonary infections caused by mycobacteria and other gram-positive bacteria, and of pulmonary fungal infections.

Description

[0001] This application claims priority to U.S. Provisional Application No. 62 / 722,048, filed August 23, 2018, and this application also claims priority to U.S. Provisional Application No. 62 / 796,322, filed January 25, 2019, both of which Incorporated herein by reference. technical field [0002] The present invention relates to pharmaceutical compositions for inhalation containing a therapeutically effective dose of clofazimine, wherein said clofazimine is provided in the form of a suspension; their preparation; and their use and treatment methods . Furthermore, the present invention provides a pharmaceutical combination containing clofazimine in aerosol form for pulmonary inhalation. [0003] Combinations and compositions provided herein are useful for treating and / or preventing pulmonary fungal infections and pulmonary infections caused by mycobacteria and other Gram-positive bacteria. Background technique [0004] Clofazimine is a very hydrophobic methylenephenazine an...

Claims

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Application Information

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IPC IPC(8): A61K9/72A61K47/26A61K31/498
CPCA61K9/0078A61K31/47A61K31/498A61K31/7036A61K45/06A61K47/26A61K2300/00A61K47/02A61P31/10A61P11/00
Inventor 托马斯·霍夫曼斯蒂芬·厄弗凯文·斯泰普勒顿
Owner MANNKIND CORP
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