Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Food or edible as carrier for pharmaceutical
Reexamination Certificate
1999-07-26
2002-05-14
Azpuru, Carlos A. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Food or edible as carrier for pharmaceutical
C424S434000, C424S499000, C424S500000
Reexamination Certificate
active
06387394
ABSTRACT:
BACKGROUND OF THE INVENTION
The advantages of controlled release products are well known in the pharmaceutical field and include the ability to maintain a desired blood level of a medicament over a comparatively longer period of time and increasing patient compliance by reducing the number of administrations necessary to achieve the same. These advantages have been attained by a wide variety of methods.
Many controlled release delivery systems have already been developed for absorption in the gastrointestinal tract and are commercially available. Likewise, controlled release transdermal formulations are well known in the art.
Another commonly utilized path for drug delivery is via oral inhalation therapy.
Inhalations are drugs or solutions or suspensions of one or more drugs capable of administration by the nasal or oral respiratory route for local or systemic effect. There are several different delivery devices which may be used to administer drugs to a patient via the inhalation route.
Nebulizers are suitable to administer inhalation solutions or suspensions only if they produce droplets sufficiently fine and uniform in size so that the mist reaches the bronchioles. Nebulized solutions may be breathed directly from the nebulizer or from a plastic face mask, tent, or intermittent positive breathing machine. Disadvantages of nebulized systems include “through-use” dose variability and drug stability problems.
Another group of products are known as inhalations or insufflations. The British Pharmacepoeia defines an inhalation as a liquid drug delivery system whereas an insufflation is a powder delivery system for the respiratory tract. One such inhalation device is the pressurized metered dose inhaler (PMDI). Devices of this type are intended for delivering metered doses of a drug to the respiratory tract and include suspensions or solutions in a liquefied gas propellent, along with materials such as co-solvents (e.g., alcohol) and surfactants (e.g. lecithin). A metered dose inhaler contains multiple doses, often in the range of one to two hundred doses. The dose delivered is generally in the rage of 25 to 100 microliters (&mgr;l) per actuation.
Powdered drugs may be administered by mechanical devices that require externally-produced pressure or, more usually, deep inhalation by the patient. The powdered drug is often contained in a capsule which is placed in a suitable device and pierced to allow the powder to exit to the outside environment when an appropriate pressure drop is created. In certain devices, the pressured drop is created by having a patient place the device in his or her mouth and inhaling. Inhalation produces conditions which act to draw the drug out of the capsule and into the respiratory tract of the patient. The device may also contain turbulence-increasing structures which aim to enhance de-agglomeration, thereby preventing larger powder particles from entering the respiratory tract.
Increasing attention is now being given in the art to dry powder inhalers.
For example, International Patent Application WO 94/04133 describes a powder composition for inhalation which contains a microfine drug such as a salbutamol sulfate and a carrier containing an anti-static agent. The carrier is calcium carbonate or a sugar, especially lactose. The amount of carrier is 95-99.99 weight percent. The compositions were said to be useful for delivery of the active agent to the lungs while providing reduced side effects such as nausea by maximizing its proportion of drug reaching the lungs.
U.S. Pat. No. 4,590,206 describes capsules, cartridges or aerosol containers containing spray-dried sodium cromoglycate in finely divided and un-agglomerated form. A substantial proportion of the individual drug particles have shapes which allow deep penetration into the lung and yet are free-flowing so as to allow capsule filling.
International Patent Application WO 93/25198 is directed to an ultrafine powder for inhalation. The powder comprises a drug and hydroxypropyl cellulose and/or hydroxypropylmethyl cellulose. More than 80 weight percent of the particles in the powder are said to have a particle diameter of 0.5-10 microns. The powder is said to be able to reach the lower windpipe and bronchi and is further said to have good deposit (storage) properties, and is further said to be capable of releasing a drug continuously.
Previously, a hetero-disperse polysaccharide excipient system and controlled release oral solid dosage forms were described in our U.S. Pat. Nos. 4,994,276, 5,128,143, and 5,135,757, all of which are hereby incorporated by reference. These systems are commercially available under the tradename TIMERx™ from TIMERx Technologies, Patterson, N.Y. and Edward Mendell Co., Inc., N.Y., which is the assignee of the present invention.
It would be considered most advantageous in the art to provide new dry powder inhalation formulations which are capable of providing a slow, continuous release of drug while also being biodegradable or expellable from the pulmonary or nasal tract, and in which the active ingredient would be relatively bioavailable.
OBJECTS AND SUMMARY OF THE INVENTION
It is an object of the present invention to provide new oral or nasal inhalation carriers for a wide variety of medicaments which provide a reproducible in-vivo effect when a desired unit dose of the carrier in combination with a medicament is administered to a human patient via an oral or nasal inhalation device.
It is a further object of the present invention to provide a dry powder for oral or nasal inhalation or insufflation which comprises a cohesive composite of carrier and medicament, which provides a controlled release of medicament from the carrier in-vivo.
It is a further object of the present invention to provide a controlled release formulation for oral or nasal inhalation which is enzymatically degradable or expellable when administered in-vivo.
It is a further object of the present invention to provide a controlled release formulation for oral inhalation which enables controlled drug delivery in the naso-pharyngeal, tracheo-bronchial and combined naso-pharyngeal-bronchial regions of the pulmonary tract.
It is a further object of the present invention to provide a dry powder for inhalation therapy which is bioadhesive and which provides a controlled release of medicament when administered in-vivo.
It is a further object of the invention to provide an oral inhalation formulation for controlled release of a medicament in the upper airways of the respiratory tract.
The above-mentioned objects and others are achieved by virtue of the present invention, which relates in part to controlled release particles of a cohesive composite of a medicament together with a pharmaceutically acceptable carrier. The cohesive composite particles comprising the dry powder formulations of the invention are non-segregating. The average particle size is from about 0.1 to about 10 microns in diameter for lung delivery. For nasal delivery, the average particle size is from about 10 to about 355 microns and preferably 10-125 microns.
The pharmaceutically acceptable carrier can comprise, for example, xanthan gum, locust bean gum, galactose, other saccharides, oigosaccharides and/or polysaccharides, starch, starch fragments, dextrins, British gum and mixtures thereof. Preferably, the pharmaceutically acceptable carrier is of natural origin.
The pharmaceutically acceptable carrier can further comprise an inert saccharide diluent selected from a monosaccharide or disaccharide.
The present invention is further related to a capsule, cartridge or aerosol container containing a cohesive composite of a medicament together with a pharmaceutically acceptable polysaccharide carrier of natural origin, wherein the average particle size is from about 0.1 to about 10 microns in diameter for lung delivery. For nasal delivery, the average particle size is from about 1 to about 355 microns, and preferably from about 10 to about 125 microns.
The present invention is further directed to a method for preparing a controlled release pharma
Baichwal Anand
Staniforth John N.
Azpuru Carlos A.
Davidson Davidson & Kappel LLC
Penwest Pharmaceuticals Co.
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