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Pulmonary delivery of polyene antifungal agents

a technology of antifungal agents and polyene, which is applied in the direction of pharmaceutical delivery mechanism, organic active ingredient delivery, aerosol delivery, etc., can solve the problems of drug degradation, difficult formulation of compounds outside of dry mixing, and technical challenges, and achieve excellent aerosol characteristics, good chemical and physical stability, and efficient administration

Inactive Publication Date: 2009-03-26
NEKTAR THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010]In an effort to address these problems, the present invention provides methods for spray drying polyene antifungal agents that result in the formation of chemically stable yet highly dispersible powders. That is to say, the antifungal powders of the invention have excellent aerosol characteristics, such that they are reproducibly prepared and can be efficiently administered by inhalation to the lung, while exhibiting good chemical and physical stability.
[0018]In yet another embodiment of this aspect of the invention, the spray dried powder is exposed to moisture prior to packaging (i.e., either during or post spray drying) to decrease or maintain the aerodynamic diameter of the particles preferably below about 5 microns.

Problems solved by technology

Thus, formulation of these compounds outside of dry mixing is extremely difficult.
Although the solubility of the polyene, amphotericin, can be increased under extreme conditions of pH, such conditions typically lead to significant levels of degradation of drug and are usually considered undesirable for the formation of powders for direct administration to the lung.
Thus, the inventors were faced with the challenge of trying to find conditions for spray drying the highly insoluble drug, amphotericin, that (i) did not promote high levels of degradation of drug, (ii) were economically practical, and (iii) resulted in the formation of aerosolizable particles suitable for inhalation.
While finding a solution to one of these problems was rather straightforward, arriving at a spray drying method in which all of these factors were balanced to produce a chemically stable and highly dispersible powder was a technical challenge.

Method used

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  • Pulmonary delivery of polyene antifungal agents
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Examples

Experimental program
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Effect test

example 1

Inhaleable Amphotericin B Dry Powder Formulations

[0129]A. Finding a Suitable Solvent for Spray Drying

[0130]The solubility of amphotericin and excipients / additives of interest was determined in various solvents in an attempt to find a solvent system suitable for spray drying (i.e., having a sufficiently high vapor pressure) and capable of dissolving both amphotericin and any added excipients at an extent greater than about 10 mg / mL solvent. Although active agents can be spray-dried as suspensions, having the formulation components dissolved in solution provides resulting particles having a homogeneous composition (i.e., when comparing one particle to another particle)—that is to say, each particle in the composition has approximately the same composition and distribution of formulation components.

[0131]Amphotericin B is difficult to spray dry due to its poor solubility in water at any pH where it is likely to have reasonable stability (amphotericin is insoluble in water at pH 6 to 7)...

example 2

Inhaleable Amphotericin B Dry Powder Formulations Containing Deoxycholate

[0138]A. Preparing Dry Powders

[0139]Sodium deoxycholate was dissolved in water. Amphotericin was added to the sodium deoxycholate solution, and sonicated. 6 molar sodium hydroxide was slowly added to the mixture while stirring and / or sonicating, until the amphotericin was dissolved. The pH of the resulting solution was adjusted (acidified) to 7.0-7.5, while stirring, with 1.2 normal hydrochloric acid. The solution was protected from light. The aim was to utilize the most neutral solution possible that resulted in complete solubilization, to minimize or essentially eliminate any chemical destabilization of the components in the solution. The resulting solution was then spray dried as detailed in Example 1.

[0140]The characteristics of each of the formulations prepared and the characteristics of the resulting powders are provided in Table 3 below.

TABLE 3Amphotericin B / Sodium Deoxycholate Powder Preparation:Formul...

example 3

Inhaleable Dry Powder Formulations of Nystatin

[0142]The solubility of nystatin and leucine in various solvents was explored to identify a solvent for preparing a spray-dried powder of the invention; solubility results are provided in Example 1 above.

[0143]Dry powders were prepared as described in Example 1 above using acidified methanol as the solvent. The characteristics of the resulting powders are summarized below.

TABLE 4Inhaleable Formulations of Nystatin: Composition Characteristics%DrugpH ofResidual% ED ±FormulationLot No.SolutionSolventRSDMMADMorphologyNystatin1696-HS-403.01.674 ± 41.6Dimpledspheres75% Nystatin +1696-HS-423.91.879 ± 31.5Highly dimpled25% L-spheresLeucineMMDDrug Formulation% μmNystatin840.875% Nystatin (w / w)880.625% L-Leucine(w / w)

[0144]Spray drying neat nystatin dissolved in acidified methanol yielded a powder with a good emitted dose of greater than 70% and a superior MMAD of 1.6 microns. The addition of 25% leucine to the formulation resulted in a nominal im...

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Abstract

The present invention provides spray-dried polyene compositions for oral inhalation to the lung. The polyene antifungal compositions demonstrate superior aerosol properties, do not exhibit appreciable degradation of the polyene upon spray-drying, and are useful in the treatment and prophylaxis of both pulmonary and systemic fungal infections.

Description

[0001]This application claims the benefit of priority of U.S. Provisional Patent Application Ser. No. 60 / 257,613, the contents of which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION[0002]The present invention relates to spray-dried polyene compositions, and to methods for making and administering such compositions. In particular, the invention is directed to polyene powder compositions which possess a number of notable features, making them advantageous for oral inhalation to the lung for the treatment and / or prophylaxis of pulmonary and systemic fungal infections. The polyene is surprisingly stable (i.e., exhibits minimal chemical degradation) upon spray-drying, and the resulting powder possesses superior aerosol properties (low MMAD, excellent dispersibility), even in the absence of stabilizing carriers or excipients.BACKGROUND OF THE INVENTION[0003]Pulmonary fungal infections, which are associated with significant levels of morbidity and mortality, re...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/72A61K9/14A61P31/10A61K9/12A61K9/00A61K9/16A61K31/00A61K31/7048A61K47/04A61K47/12A61K47/18
CPCA61K9/1688A61K9/0075A61P31/10A61K9/14
Inventor WEICKERT, MICHAELGORDON, MARC S.KUMAR, SANDEEPYANG, BINGSARWAR, RAZAQ
Owner NEKTAR THERAPEUTICS INC
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