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Stable, aerosolizable suspensions of proteins in ethanol

a stable suspension and protein technology, applied in the direction of aerosol delivery, peptide/protein ingredients, spray delivery, etc., can solve the problems of reduced biological potency, reduced biological potency, and reduced shelf life of formulations, and achieve the effect of promoting the formation of protein crystals

Inactive Publication Date: 2002-08-01
VENTAIRA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0013] According to the present invention, one method for stabilizing a protein in ethanol includes the step of making a suspension of a protein in ethanol by means of over-saturating ethanol with the protein, thereby promoting the formation of crystals of the protein. In an alternative method, protein crystals are added to ethanol at a high concentration to form a suspension, whereby the protein remains crystallized and does not dissolve.

Problems solved by technology

Biological molecules such as proteins are frequently difficult to formulate in certain solvents or solvent systems (e.g., mixtures of water and organic solvents) because organic solvents tend to compromise the stability of the protein in solution.
Proteins dissolved or suspended in liquid solvent systems typically suffer from chemical or physical degradation, thereby resulting in a formulation with little or no shelf-life.
Furthermore, insulin aggregation leads to significant reductions in biological potency and obstruction of delivery routes, thereby creating serious complications for drug delivery systems and diminishing the patient's abilities to control their blood glucose levels."
While being effective at stabilizing certain biomolecules under certain conditions, the related art deals primarily with dry power or other solid systems, and do not offer methods or compositions for stabilizing biomolecules in liquid solvent systems suitable for use in electrostatic or electrohydrodynamic aerosol devices and systems.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0036] Lyophilized human insulin, supplied from Roche Biochemical Co., was used. To obtain the desired pH, 100 mg of insulin was first dissolved in 2.667 ml of 10 mM PBS buffer, pH 7.4 (Supplied from Sigma, P 3813); 356 ul of this dissolved insulin was aliquoted into 15 ml polypropylene conical tubes, which were later used for the 20 mg / ml suspension samples. To make the insulin suspension samples at a concentration of 1.5 mg / ml, 26.67ul of the dissolved insulin was aliquoted into 15 ml polypropylene conical tubes. The conical tubes were then sealed with punctured parafilm, and frozen overnight at .about.-15.degree. C. to -20.degree. C. The following day the frozen insulin samples were lyophilized to a fine, free-flowing powder using a bench top Labconco Freeze Dry System with Stoppering Tray. This process was started two or three days prior to the start of the experiment. The 100% ethanolic insulin samples were prepared in duplicates. For each sample, there were four (4) time-point...

example 2

[0038] A. Deoxyribonuclease I (DNase I), Grade II from Bovine Pancreas, supplied from Roche Molecular Biochemicals, was used. Protease Inhibitor, Sigma P 2714, was prepared by dissolving 1 vial with 100 ml of MilliQ water. CaCl.sub.2, supplied by Sigma, was made into a 7.5 mg / ml stock solution, using MilliQ water. Three (3) mg of DNase I was weighed into glass, type 1 reaction vials. Four time-points were prepared for each sample. The samples were prepared in duplicates at either 10 mg / ml or 30 mg / ml. For the DNase I samples at 10 mg / ml insulin 300 ul of 200 proof ethanol was added to the reaction vial. The 30 mg / ml DNase I samples were suspended with 100 ul of 200 proof ethanol, supplied from Spectrum Chemicals. For Day 0 the 10 mg / ml samples were diluted with 9.7 ml of Buffer A, while the 30 mg / ml samples were diluted with 9.9 ml of Buffer A. Buffer A consists of the following chemicals at the specified concentrations, 24 mM Hepes (Sigma H 3375), 2.4 mM MgCl.sub.2 (Sigma M 2670), ...

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Abstract

Stable suspensions of a biologically active protein are disclosed that are suited for aerosol delivery to the lungs of a patient in need of treatment, which comprise particles of biologically active protein suspended in ethanol. In a preferred embodiment, the invention describes a stable suspension of insulin useful for aerosol delivery to the lungs of a patient in need of treatment comprising particles of a pharmaceutically effective amount of insulin suspended in ethanol. A method of delivering a therapeutically effective amount of a protein to the respiratory tract of a patient is described which comprises producing an aerosol of a stable liquid suspension of a protein using an electrohydrodynamic spraying means wherein the liquid suspension comprises particles of the protein suspended in ethanol. The stable ethanol suspensions of the invention may optionally contain up to about 20% (V / V) of a pharmaceutically acceptable formulation additive such as glycerol, propylene glycol and polyethylene glycol as well as minor amounts (from about 0.05% to about 5.0% W / V) of a pharmaceutically acceptable excipient.

Description

[0001] The present application claims the benefit of U.S. Provisional Application No. 60 / 250,491 [Attorney Docket No. 22112(1)P], filed Dec. 1, 2000.BACKGROUND OF INVENTION[0002] This invention relates generally to aerosolizable stable suspensions of proteins in ethanol. The suspensions of the invention are particularly suited for inhalation delivery using electrostatic or electrohydrodynamic aerosol devices to produce the aerosol.[0003] Pulmonary delivery of therapeutic agents by means of inhaled aerosols is an area of increasing importance in the biotechnology and pharmaceutical industries. Electrostatic or electrohydrodynamic devices which are capable of generating inhalable aerosols with certain preferred properties frequently require liquid formulations containing one or more aqueous solvents such as water, an organic solvent such as an alcohol, or a mixture of an aqueous and an organic solvent.[0004] Biological molecules such as proteins are frequently difficult to formulate i...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/12A61K9/00A61K9/10A61K9/72A61K38/00A61K38/22A61K38/28A61K38/43A61K38/46A61K47/10A61K47/26A61P5/50A61P11/00
CPCA61K9/0073A61K9/0078A61K38/28A61K47/10A61K47/26A61P5/50A61P11/00
Inventor COWAN, SIU MAN L.
Owner VENTAIRA PHARMA
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