Pulmonary delivery of spherical insulin microparticles

A technology of insulin and spherical particles, which can be used in drug combination, drug delivery, pharmaceutical formulation, etc., to solve the problems of poor patient compliance and shortness of breath.

Inactive Publication Date: 2010-08-11
BAXTER INT INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These complications with previously suggested methods of pulmonary insulin delivery caused shortness of breath, coughing, and thus poor patient compliance

Method used

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  • Pulmonary delivery of spherical insulin microparticles
  • Pulmonary delivery of spherical insulin microparticles
  • Pulmonary delivery of spherical insulin microparticles

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0214] General method for preparing small spherical particles of insulin

[0215] A solution buffered at pH 5.65 (0.033M sodium acetate buffer) containing 16.67% PEG 3350 was prepared. A concentrated slurry of crystalline insulin zinc was added to the solution with stirring. The concentration of insulin in the final solution was 0.83 mg / mL. The solution was heated to about 85 to 90°C. Insulin crystals dissolve completely within 5 minutes in this temperature range. When the temperature of the solution is lowered at a controlled rate, small spherical particles of insulin begin to form around about 60°C. Yield increased with increasing PEG concentration. The process yielded small spherical particles with various size distributions, with an average size of 1.4 μm.

[0216] The resulting insulin spheroids were separated from PEG by washing the spheres by diafiltration under conditions in which the spheroids do not dissolve. Use containing Zn 2+ aqueous solution, the insulin ...

Embodiment 2

[0217] Example 2: A non-stirring batch process for the manufacture of small spherical insulin particles

[0218] Suspend 20.2 mg of crystalline insulin zinc in 1 mL of deionized water at room temperature. Add 50 microliters of 0.5N HCl to the insulin. Add 1 mL of deionized water to form a 10 mg / mL solution of crystalline insulin zinc. 12.5 g polyethylene glycol 3350 (Sigma) and 12.5 g polyvinylpyrrolidone (Sigma) were dissolved in 50 mL of 100 mM sodium acetate buffer, pH 5.7. Adjust the volume of the polymer solution to 100 mL with sodium acetate buffer. To the 800 µl polymer solution in a microcentrifuge tube, add 400 µl 10 mg / mL insulin solution. When mixed, the insulin / polymer solution became cloudy. A control was prepared using water instead of the polymer solution. Heat the microcentrifuge tube in a water bath at 90 °C for 30 min without mixing or agitation, then remove and place on ice for 10 min. The insulin / polymer solution was clear after removal from the 90°C ...

Embodiment 3

[0219] Example 3: Continuous flow-through process for the manufacture of small spherical insulin particles

[0220] Weigh out 36.5 mg of insulin and suspend in 3 mL of deionized water. Add 30 µL of 1N HCl to dissolve the insulin. Adjust the final volume of the solution to 3.65 mL with deionized water. 7.3 mL of PEG / PVP solution (25% PEG / PVP, pH 5.6 in 100 mM NaOAc buffer) was then added to the insulin solution to give a final total volume of 10.95 mL of insulin solution. The solution was then vortexed, resulting in a homogeneous suspension of insulin and PEG / PVP.

[0221] Pass the insulin suspension through Tubing (TFE 1 / 32 inch inner diameter elastic tubing) was connected to a BioRad peristaltic pump running at 0.4 mL / min. The tubing from the pump was submerged in a water bath maintained at 90°C before being inserted into a collection tube soaked in ice. When the temperature of the insulin solution was lowered from about 90°C in a water bath to about 4°C in a collection...

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Abstract

Compositions of spherical insulin particles having improved pulmonary application potentials and methods of forming and using these compositions are disclosed in the present application. In one clinical trial with 30 healthy male human subjects, no coughing was observed upon a single pulmonary administration of the spherical insulin particles at an insulin dose of 6.5 mg, nor during the 10-hour post dosing period.

Description

technical field [0001] This application relates to pulmonary delivery of insulin by using small spherical insulin particles. Background technique [0002] In the past, several techniques have been used to produce biopolymer nanoparticles and microparticles. Conventional techniques including spray drying and milling to form particles can be used to produce particles with a size of 5 μm or less. [0003] Particles produced by standard production methods often have a broad particle size distribution, lack uniformity, do not provide adequate release kinetics, and are difficult and expensive to produce. Typically, the polymers used to make these microspheres are primarily dissolved in organic solvents, requiring the use of specialized facilities designed to handle organic solvents. Organic solvents can denature proteins or peptides contained in microspheres, can also be toxic to the environment, present an inflammatory hazard, and can be toxic when administered to humans or ani...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/72A61K38/28
CPCA61K38/28A61K9/0075A61P11/00A61P5/48
Inventor 拉里·R·布朗约翰·K·麦克吉亨秦元西朱莉娅·拉什巴-施特普特伦斯·L·斯克特
Owner BAXTER INT INC
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