Engineered particles and methods of use

a technology of microstructures and particles, applied in the direction of aerosol delivery, spray delivery, antinoxious agents, etc., can solve the problems of increasing the flowability of the resulting powder, lowering the shear force, etc., to improve the flowability and dispersibility, improve the delivery of agents, and reduce the attractive force

Inactive Publication Date: 2005-04-07
NOVARTIS FARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

These and other objects are provided for by the invention disclosed and claimed herein. To that end, the methods and associated compositions of the present invention provide, in a broad aspect, for the improved delivery of agents to a desired site. More particularly, the present invention may provide for the delivery of bioactive agents to selected physiological target sites using perforated microstructure powders. In preferred embodiments, the bioactive agents are in a form for administration to at least a portion of the pulmonary air passages of a patient in need thereof. To that end, the present invention provides for the formation and use of perforated microstructures and delivery systems comprising such powders, as well as individual components thereof The disclosed powders may further be dispersed in selected suspension media to provide stabilized dispersions. Unlike prior art powders or dispersions for drug delivery, the present invention preferably employs novel techniques to reduce attractive forces between the particles. As such, the disclosed powders exhibit improved flowability and dispersibilty while the disclosed dispersions exhibit reduced degradation by flocculation, sedimentation or creaming. Moreover, the stabilized preparations of the present invention preferably comprise a suspension medium (e.g. a fluorochemical) that further serves to reduce the rate of degradation with respect to the incorporated bioactive agent. Accordingly, the dispersions or powders of the present invention may be used in conjunction with metered dose inhalers, dry powder inhalers, atomizers, nebulizers or liquid dose instillation (LDI) techniques to provide for effective drug delivery.

Problems solved by technology

More particularly, the use of relatively low density perforated (or porous) microstructures or microparticulates significantly reduces attractive forces between the particles thereby lowering the shear forces and increasing the flowability of the resulting powders.

Method used

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  • Engineered particles and methods of use
  • Engineered particles and methods of use

Examples

Experimental program
Comparison scheme
Effect test

example iv

illustrates that the physical characteristics of the blowing agent (i.e., boiling point) greatly influences the ability to provide perforated microparticles. A particular advantage of the present invention is the ability to alter the microstructure morphology and porosity by modifying the conditions and nature of the blowing agent.

V

Preparation of Spray Dried Albuterol Sulfate Particles Using Various Blowing Agents

Approximately 185 ml of the following solutions were prepared for spray drying:

49% w / w Hydrogenated Phosphatidylcholine, E100-3 (Lipoid KG, Ludwigshafen, Germany)

50% w / w Albuterol Sulfate (Accurate Chemical, Westbury, N.Y.)

1% w / w Poloxamer 188, NF grade (Mount Olive, N.J.)

Deionized water.

Blowing Agents:

Perfluorodecalin, FDC (Air products, Allenton Pa.)

Perfluorooctylbromide, Perflubron (Atochem, Paris)

Perfluorobutylethane F4H2 (F-Tech, Japan)

Perfluorotributylamine FTBA (3M, St. Paul, Minn.)

Albuterol sulfate powder was prepared by spray-drying technique...

example v

further demonstrates the wide variety of blowing agents that may be used to provide perforated microparticles. A particular advantage of the present invention is the ability to alter the microstructure morphology and porosity by manipulating the formulation and spray drying conditions. Furthermore, Example V demonstrates the particle diversity achieved by the present invention and the ability to effectively incorporate a wide variety of pharmaceutical agents therein.

VI

Preparation of Hollow Porous PVA Particles by Spray Drying a Water-in-oil Emulsion

100 ml of the following solutions were prepared for spray drying:

80% w / w Bis-(2-ethylhexyl) Sulfosuccinic Sodium Salt, (Aerosol OT, Kodak, Rochester, N.Y.)

20% w / w Polyvinyl Alcohol, average molecular weight=30,000-70,000 (Sigma Chemicals, St. Louis, Mo.)

Carbon Tetrachloride (Aldrich Chemicals, Milwaukee, Wis.)

Deionized water.

Aerosol OT / polyvinyl alcohol particles were prepared by spray-drying technique using a B-191 Mini Spra...

example vi

further demonstrates the variety of emulsion systems (here, reverse water-in-oil), formulations and conditions that may be used to provide perforated microparticles. A particular advantage of the present invention is the ability to alter formulations and / or conditions to produce compositions having a microstructure with selected porosity. This principle is further illustrated in the following example.

VII

Preparation of Hollow Porous Polycaprolactone Particles by Spray Drying a Water-in-Oil Emulsion

100 mls of the following solutions were prepared for spray drying:

80% w / w Sorbitan Monostearate, Span 60 (Aldrich Chemicals, Milwaukee, Wis.)

20% w / w Polycaprolactone, average molecular weight=65,000 (Aldrich Chemicals, Milwaukee, Wis.)

Carbon Tetrachloride (Aldrich Chemicals, Milwaukee, Wis.)

Deionized water.

Span 60 / polycaprolactone particles were prepared by spray-drying technique by using a B-191 Mini Spray-Drier (Büchi, Flawil, Switzerland) under the following conditions:

Asp...

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Abstract

Engineered particles are provided may be used for the delivery of a bioactive agent to the respiratory tract of a patient. The particles may be used in the form of dry powders or in the form of stabilized dispersions comprising a nonaqueous continuous phase. In particularly preferred embodiments the particles may be used in conjunction with an inhalation device such as a dry powder inhaler, metered dose inhaler or a nebulizer.

Description

FIELD OF THE INVENTION The present invention relates to formulations and methods for the production of perforated microstructures which comprise an active agent. In particularly preferred embodiments, the active agent will comprise a bioactive agent. The perforated microstructures will preferably be used in conjunction with inhalation devices such as a metered dose inhaler, dry powder inhaler or nebulizer for both topical and systemic delivery via pulmonary or nasal routes. BACKGROUND OF THE INVENTION Targeted drug delivery means are particularly desirable where toxicity or bioavailability of the pharmaceutical compound is an issue. Specific drug delivery methods and compositions that effectively deposit the compound at the site of action potentially serve to minimize toxic side effects, lower dosing requirements and decrease therapeutic costs. In this regard, the development of such systems for pulmonary drug delivery has long been a goal of the pharmaceutical industry. The thre...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/12A61K9/16A61K9/22A61K9/00A61K9/51A61K9/72A61K45/00A61K47/24A61K49/04A61P11/00A61P39/00
CPCA61K9/0073Y10S514/937A61K9/0078A61K9/008A61K9/1611A61K9/1617A61K9/1635A61K9/1641A61K9/1652A61K9/1694A61K31/685Y10S977/906Y10S977/904Y10S977/926A61K9/0075A61P11/00A61P39/00Y02A50/30
Inventor TARARA, THOMAS E.WEERS, JEFFRY G.KABALNOV, ALEXEYSCHUTT, ERNEST G.DELLAMARY, LUIS A.
Owner NOVARTIS FARMA
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