Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
2000-07-25
2002-07-23
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C424S450000, C424S489000, C424S490000, C264S004100, C264S004300
Reexamination Certificate
active
06423338
ABSTRACT:
BACKGROUND OF THE INVENTION
It is known that water insoluble drugs can be rendered injectable by formulating them into aqueous suspensions of phospholipid-coated microcrystals. Haynes, U.S. Pat. No. 5,091,188 and U.S. Pat. No. 5,091,187, disclosed a method of coating pharmaceutical compounds with a phospholipid layer that makes water insoluble drugs able to be contained within an aqueous medium, and therefore suitable for injection in a mammal.
Baurain et al., U.S. Pat. No. 4,973,467 describes the preparation of microcrystals of ginkolide B, kadsurenone, amphotericin B, and nystatin. Baurain et al. prepared microcrystals by the common method of forming a lipid film in a flask by dissolving the lipids to be used in organic solvent, evaporating the solvent, and then sonicating in the presence of the active compound to produce microcrystals sized between 0.1 &mgr;m and 2 &mgr;m.
Animal husbandry operations which manage large numbers of animals have been unable to realize the benefits of the prior technology because it has not been successfully applied on a large scale. The procedures disclosed by Haynes and others have had limited commercial practicability since the methods involve the use of sonication or other processes which are inappropriate or impractical for producing commercially advantageous quantities of product.
The present invention provides a method suitable for economically producing yields of up to thousands of liters of pharmaceutical compositions for the sustained release of a pharmacologically active compound. The method can be applied with a commercial scale homogenizer, or any instrument or technique which provides the necessary forces to effectively coat the pharmacologically active compound with the lipid suspension.
Furthermore, the compositions of the prior art have relied on commonly available forms of phospholipid mixtures which are highly purified and prohibitively expensive for use on a commercial scale. The present invention discloses a method for isolating a composition of lipids from egg yolk which results in a suspension of lipids which can be economically produced, and can be used to coat a pharmacologically active compound to produce the microcrystals of the present invention. These microcrystals exhibit several beneficial characteristics, including a longer sustained release time and the ability to sharply decrease the toxicity of drug compounds. These microcrystals may be formed into an injectable suspension for subcutaneous injection into a mammal. The suspension may be syringeable and therefore suitable for subcutaneous injection.
One skilled in the art will realize that the microcrystals of this invention can be administered to the mammal in a variety of other ways including, but not limited to, skin patches, ocular inserts, shooting through the skin at high velocity with a medical “air gun,” suppositories, or simply providing the compounds in a mammal's food and water.
It has been previously thought that it is desirable to produce a composition of microcrystals having homogeneous microcrystals of a very small size. Previously, it has been believed that it is desirable to produce microcrystals below 1 &mgr;m, or at least below 2 &mgr;m or 3 &mgr;m. The present invention discloses that unexpected benefits, including benefits in timed release delivery, can be realized by producing a composition which contains microcrystals of varying sizes. The present invention discloses compositions wherein at least 50 percent of the microcrytals are from about 0.5 &mgr;m to about 3.0 &mgr;m in diameter, at least ten percent of the microcrystals are from about 3.0 &mgr;m to about 10 &mgr;m in diameter, and the compositions contain microcrystals which are greater than about 10 &mgr;m in diameter. In a preferred embodiment, at least about 50 percent of the microcrystals will be from about 0.5 &mgr;m to about 3 &mgr;m in diameter, from about thirty to about forty percent of the microcrystals will be from about 3 &mgr;m to about 10 &mgr;m in diameter, and the composition contains microcrystals which are greater than about 10 &mgr;m in diameter. We have found that by utilizing microcrystals of these varying sizes sustained release times of as long as 10-12 days can be obtained. The person of skill in the art will readily realize that even presently known lipid compositions may be put into the novel compositions claimed herein to realize these benefits. The invention teaches novel compositions which are mixtures of microcrystals of varying sizes as disclosed herein.
The present invention also discloses methods for treating infections in mammals. In preferred embodiments, methods are provided for treating respiratory diseases in mammals, in particular, infections of the respiratory tract. In particularly preferred embodiments, methods are provided for treating bovine respiratory disease (commonly known as “shipping fever”), kennel cough in dogs, and Potomac fever in horses. In another particularly preferred embodiment, methods are provided for treating infections of the respiratory tract in cats.
Prior methods of treating infections in animals have centered on the regular and repeated administration of antibiotics to the mammal until the infection was eradicated, sometimes by incorporating the drug into the animal's food or water, by oral administration in a paste or with a balling gun, or by repeated injections. Therapeutic regimens often failed due to a failure on the part of the animal owner to follow the prescribed regimen. The present invention provides a method of treating infections which requires only a single administration of the microcrystal compositions of the present invention. The microcrystal composition may be an injectable syringeable suspension. The administration can be delivered by an animal care professional and does not require further participation by the owner for a successful result of the therapy, thereby eliminating issues of therapy noncompliance by the owner as a reason for failure of the therapy. The present methods are applicable to a variety of mammals including, but not limited to, bovines, equines, porcines, canines, and felines. The person of skill in the art will readily realize that the methods herein disclosed will find applicability to a wide variety of mammals.
The person of skill in the art will also readily realize that the compositions and techniques described herein can be applied to a wide variety of pharmacologically active compounds. Various antibiotics, anesthetics, anti-inflammatory agents, and anti-protozoan agents may all be incorporated into a microcrystal suspension, as may other chemical compounds of varied uses which will be apparent to those of skill in the art.
We have also observed that pharmacologically active compounds which are coated with the phospholipid composition of the present invention are able to attach to blood cells. In this case the pharmacologically active compound is found associated with the blood cells in blood analysis assays. This characteristic of the microcrystals of the present invention serves to facilitate the delivery of pharmacologically active compound to the body tissues.
SUMMARY OF INVENTION
The present invention realizes a substantial advance in the field of microcrystal technology by providing novel lipid compositions for coating microcrystals of useful drugs. These novel compositions result in pharmaceutical suspensions containing phospholipid coated microcrystals which offer significantly longer sustained release times than those of the prior art. These compositions offer the additional and important benefit of sharply reducing the toxicity of many useful pharmaceutical compounds which are underutilized due to concerns about their toxicity.
The present invention also provides new methods for manufacturing suspensions of microcrystals which contain pharmaceutically active compounds encapsulated in a phospholipid layer on a commercial scale. The suspensions may be made suitable for injection. Various water insoluble and pharmaceutically active compounds may be produc
Campbell William R.
Hepler Douglas I.
Larson Kenneth A.
Foley & Lardner
IDEXX Pharmaceuticals, Inc.
Kishore Gollamudi S.
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