Electro-powder

Details Electro-powder Electro-powder

2000-08-11

2004-02-24

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S490000, C424S491000, C424S497000, C424S498000, C264S004000, C264S004100, C264S004320, C264S004330

Reexamination Certificate

active

06696090

ABSTRACT:

TECHNICAL FIELD
The present invention relates to powders with electrostatic properties as well as a process and a method for preparation of such an electro-powder as a s medical powder and more particularly to preparations of chemical and biological substances forming an electro-powder suitable for electrostatic charging and dosing for functionality in an inhaler device.
GENERAL BACKGROUND
Today high quality dosing is one of the most difficult factors slowing down the growth of the inhaler market. This is specially the case for systemic delivery by inhalation through a dry powder inhaler (DPI) which represents a market segment making it possible to compete with the injection needle for many types of drugs, i.e. insulin, pain management etc. Systemic delivery refers to the delivery of an active substance to be carried to a deep area of the lung. U.S. Pat. No. 5,997,848 discloses a systemic delivery of insulin to a mammalian host being accomplished by inhalation of a dry powder of insulin. An insulin dose 0.5 to 15 mg is dispersed into a high velocity air or gas stream to form a dry insulin aerosol in a holding chamber from which the created aerosol is inhaled. The volume of the chamber has to be sufficiently large to capture a desired dose and may optionally have baffles and/or one-way valves for promoting containment. Such a device is often referred to as a spacer. The device for instance has a drawback in that there are difficulties to control the amount of medicine emitted to the lung as an uncontrolled amount of powder will stick to the walls of the spacer.
A dry powder inhaler, DPI is intended for administration of powder into the deep or upper lung airways by oral inhalation. With deep lung should be understood the peripheral lung and alveoli, where direct transport of active substance to the blood can take place. Particle sizes, to reach into the deep lung, should be in the range 0.5-3 &mgr;m and for a local lung delivery in the range 3-5 &mgr;m, as measured with a laser diffraction instrument, e.g. a Malvern Mastersizer for physical size classification or an Andersen Impactor for an aerodynamic size classification according to US Food and Drug Administration (FDA) current guidelines.
Powders for inhalers have a tendency of agglomerating, in other word to clod or to form small or larger lumps, which then have to be de-agglomerated. De-agglomeration is defined as breaking up agglomerated powder by introducing electrical, mechanical, or aerodynamic energy. Usually de-agglomeration is performed as a step one during dosing and as a final step two during the patient's inspiration through the DPI.
Technologies to de-agglomerate today include advanced mechanical and aerodynamic systems and combinations between electrical and mechanical filling systems that can be seen in for instance in U.S. Pat. No. 5,826,633. Further there are systems disclosed for dispersing aerosolized doses of medicaments, e.g. U.S. Pat. No. 5,775,320, U.S. Pat. No. 5,785,049, and U.S. Pat. No. 5,740,794. Furthermore, in our International Publications WO 00/0636 and WO 00/6235 principles for de-agglomeration and classification are disclosed.
As already noted for an optimal amount of substance to reach the alveoli, an administered powder dose should preferably have a grain size between 0.5 and 3 &mgr;m. Besides, the inspiration must take place in a calm way to decrease air speed and thereby reduce deposition in the upper respiratory tracts.
Mainly particles larger than 5 &mgr;m will be deposited in the upper airways by impaction and particles less than 0.5 &mgr;m will not sediment before exhaling and therefore not being efficient for delivery to upper or deep lung.
It is also common to utilize carriers i.e. Lactose having a larger grain size onto which the fine power is distributed. Upon inspiration the large size grains will then stick in the oral cavity while the fine particle fraction, this is powder smaller than 5 &mgr;m, will be let free and proceed to the lung. For instance U.S. Pat. No. 5,642,727 discloses a tribo-inhaler having a container portion for electrostatically retaining a predefined dose of medicament powder. The container portion contains a plurality of polymeric beads that have diameters of approximately 50 to 200 microns. Each of the polymeric beads has a specific quantity of dry powder medicament electrostatically adhered to its surface.
To achieve a high quality dose, a so-called spacer is often used to achieve the small grains evenly distributed in a container from which the inhalation can take place. In principal a dosing device or an inhaler is connected to a spacer forming a container having a relatively large volume and into this container a powder or an aerosol is injected, which partly is distributed in the air space and partly sticks to the walls. Upon inhalation from the spacer the fine powder floating free in the air will effectively reach the alveoli of the lung. This method in principle has two drawbacks, firstly difficulties to control the amount of medicine emitted to the lung as an uncontrolled amount of powder sticks to the walls of the spacer and secondly difficulties in handling the relatively space demanding apparatus. The uncontrolled sticking to the walls is highly dependent on the electrostatic charge of the medical powder.
Today dosing into cavities for inhalation through a dry powder inhaler (DPI) is performed by using mechanical, fluidization and electrical technologies in combinations to fill cavities with powder intended for inhalation by patients. One example of this technique is the already mentioned U.S. Pat. No. 5,826,633 in which a combination of fluidization and mechanical forces is used to fill a cavity with a metered dose.
This type of technique will give a dose that will need a lot of energy to de-agglomerate before inhalation into the deep lung. This is performed using a mechanical pump that is actuated before inhalation and a high-pressurized air stream is shot down into the powder for de-agglomeration into a cylindrical spacer. Inhalation efficiency for this type of system is normally not more than 20% of metered dose.
One major problem with some of the technique described above is to also obtain a low relative standard deviation (RSD) between doses with this type of technique due to lack of in-line control possibilities in production making it hard to be in compliance with regulatory demands.
Different commercial manufacturing equipment are today present on the market, i.e. equipment used to produce micronized powders working with specialized nozzles for creating liquid or semisolid aerosols, which are dried to powders. The equipment can also be used for coating-techniques and Cryo-techniques to produce low-density powders. Fluid Jet Mill equipment is used to produce micronized powders by working with high-pressurized gases, normally air or nitrogen. Also solvents defined as liquids are used to dissolve or disperse active substances and excipients, e.g. alcohols, before sprayed into the manufacturing equipment or other gases such as carbon dioxide, chlorofluorocarbons or eqivalent, perfluorocarbons, air or other suitable inert gas for the manufacturing equipment can be used. Such equipment also can be used for purposes of coating, drying and Cryo-techniques, one at a time or in combinations, where Cryo-techniques is a method in which super cold media, i.e. liquid nitrogen or carbon dioxide, is used for cooling down the manufacturing equipment and the preparation below 0° C. Blending is defined as a homogeneous mixture of at least one active substance and one or many excipients regardless of amounts and particle sizes, and can be used alone or in combinations with spray drying and Fluid Jet Milling to prepare an electro-powder. By the term excipient is meant a chemical or biological substance introduced together with a pharmaceutical active substance to, for instance, improve the performance of the preparation or is an compound intended to act as an inactive surface and/or volume suitable for the active substance normally being a mix prefera

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