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Particulate drug-containing products and method of manufacture

a technology of powder and drug, applied in the field of powder products, can solve the problems of not producing powders with sufficiently good flowability or dispersibility characteristics to be advantageous for pulmonary delivery, and the presence of water in the cosolvent system can often be highly detrimental to the flowability and/or dispersibility characteristics of manufactured powder, so as to improve the characteristics of pulmonary delivery applications, reduce the effect of toxicity and high dispersibility

Inactive Publication Date: 2007-05-24
ENDO PHARMA COLORADO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a method for manufacturing drug-containing powders with improved characteristics for pulmonary delivery applications. The method involves precipitating drug-containing particles using a cosolvent system including two or more mutually soluble organic solvents. The resulting powders have good flowability and dispersability, and can be efficiently aerosolized in inhalers. The method also allows for the modification of the geometry of the precipitation chamber to control the tap density of the powders. The powders can be in the form of large particles that are effectively broken into smaller particles during aerosolization. Overall, the invention provides a more efficient and effective way to manufacture drug-containing powders for pulmonary delivery.

Problems solved by technology

It has been found that prior supercritical anti-solvent techniques that describe use of a single solvent system for drug manufacture, typically either DMSO or DMFA as the sole solvent, do not produce powders with sufficiently good flowability or dispersability characteristics to be advantageous for pulmonary delivery.
Although at first blush it might seem that the presence of some water in the cosolvent system would stabilize the drug during processing, it has been found that the presence of water in the cosolvent system can often be highly detrimental to flowability and / or dispersability characteristics of the manufactured powder.

Method used

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  • Particulate drug-containing products and method of manufacture
  • Particulate drug-containing products and method of manufacture
  • Particulate drug-containing products and method of manufacture

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0106] This example demonstrates manufacture of single-component powders including substantially only insulin according to the manufacture method of the present invention using a feed solution including a cosolvent system.

[0107] Feed solutions are prepared including insulin dissolved in a variety of cosolvent systems at a concentration of about 1-2 mg / mL. The feed solution is contacted in countercurrent flow with supercritical compressed carbon dioxide as an anti-solvent flowing through a precipitation chamber at a temperature of about 37±2° C. and a pressure of about 83.6±1.4 atm to precipitate insulin from the feed solution. The precipitation chamber is a stainless steel chamber about 20 cm long and having a square cross-section of about 2 cm by 2 cm. The compressed carbon dioxide is delivered to the chamber via a pressure regulator and is introduced into the top of the chamber. The feed solution is delivered to the chamber via a syringe pump and is introduced into the flowing ca...

example 2

[0112] This example demonstrates the manufacture of multi-component particles including insulin and a biocompatible polymer according to the manufacture method of the present invention using a feed solution including a cosolvent system.

[0113] Feed solutions are prepared including various molecular weight poly(L-lactic acid) and human insulin in different solvent systems. Tests 14 and 15 are comparative test using a single solvent (DMSO), while tests 16-37 use various cosolvent systems with either DMSO or methanol as the first organic solvent and methylene chloride as the second organic solvent. Insulin loading is varied from 7% to 50% by weight (based on weight of insulin relative to total weight of insulin medium plus polymer). Each feed solution is prepared in 50 mL batches generally by the following procedure: DMSO or methanol is acidified with concentrated HCl to provide the desired level of acidification and the insulin is then dissolved into the resulting acidified solvent wi...

example 3

[0117] This example demonstrates sustained release of insulin in animal studies by pulmonary delivery using multi-component particles including insulin and a biocompatible polymer.

[0118] A powder of substantially pure insulin, of the type as prepared in Test 2 shown in Example 1, and a powder of multi-component particles, of the type as prepared in Test 33 of Example 2 (including 12% by weight insulin and 88% by weight of 100 k Da L-PLA), are administered intratracheally to male rabbits. Blood samples are taken prior to administration and periodically over a 24 hour period following administration and analyzed for insulin concentration.

[0119] Male rabbits weighing about 3 Kg are treated and / or anesthetized with atropine (subcutaneous), acepromazine (intramuscular) and halothane (inhalation). Intratrachael insulin placement is accomplished using a pediatric bronchoscope. An aqueous suspension of the powder (11.16 mg powder / mL of saline) is administered with a syringe and catheter p...

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Abstract

Provided is a compressed anti-solvent technique for manufacture of drug-containing powders for pulmonary delivery. The drug is processed in a cosolvent system including two or more mutually soluble organic solvents. Also provided are powders manufacturable by the manufacture method, including powders of substantially pure drug and powders including a biocompatible polymer for pulmonary sustained drug release applications. Also provided are packaged products including drug-containing powder in a container that is receivable by and operable with a dry powder inhaler to produce an aerosol including dispersed drug-containing particles when the inhaler is actuated.

Description

CROSS-REFERENCE TO RELATED APPLICATION [0001] This application is a divisional of U.S. patent application Ser. No. 10 / 717,429, which is a divisional of U.S. patent application Ser. No. 09 / 740,573 filed Dec. 18, 2000, now issued as U.S. Pat. No. 6,669,960, which is a continuation-in-part of U.S. patent application Ser. No. 09 / 604,786 filed Jun. 26, 2000, now abandoned, which is a continuation-in-part of U.S. patent application Ser. No. 09 / 469,733, filed Dec. 21, 1999, now issued as U.S. Pat. No. 6,761,909, and the contents, and each portion thereof, of each of the aforementioned patent applications is incorporated herein as if set forth herein in full.FIELD OF THE INVENTION [0002] The invention involves particulate products including an active drug useful for pulmonary delivery applications, manufacture of particles of the product using compressed anti-solvent precipitation, and inhalers actuatable to aerosolize the product and produce aerosols including the active drug. In one aspec...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/14B29B9/00A61K9/16A61K38/00A61K48/00
CPCA61K9/0075A61K9/14A61K9/1617A61K9/1647A61K9/1694A61K38/00A61K48/00
Inventor ETTER, JEFFREY B.
Owner ENDO PHARMA COLORADO