Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
1989-03-13
2004-07-06
Wang, Andrew (Department: 1639)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C424S812000, C264S004100
Reexamination Certificate
active
06759057
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is directed to the treatment of disease states, such as inflammation, pain and fever, using compositions comprising a non-steroidal anti-inflammatory drug which may be encapsulated in a liposome. More particularly, the invention describes methods for reducing toxic side effects related to non-steroidal anti-inflammatory drugs by administering these drugs in liposomes, wherein the composition also includes a glycolipid.
A number of non-steroidal anti-inflammatory drugs (“NSAIDs”) for the effective treatment of inflammatory illnesses, for example, rheumatoid arthritis, have been known. Examples of such drugs include salicylic acid acetate, indomethacin, and piroxicam. Since the inflammations for which one would be using such substances are chronic, the treatment will usually extend over a long period of time. Gastrointestinal irritation, including bleeding and ulcers, is a side effect commonly associated with NSAIDs. The present combination of an NSAID with a liposome permits efficacy of anti-inflammatory therapy of that of free drug alone, while preventing or ameliorating the gastrointestinal irritation or ulcers.
Liposomes are completely closed bilayer membranes containing an entrapped aqueous volume. Liposomes may be unilamellar vesicles (possessing a single membrane bilayer) or multilamellar vesicles (onion-like structures characterized by multiple membrane bilayers, each separated from the next by an aqueous layer). The structure of the resulting membrane bilayer is such that the hydrophobic (non-polar) “tails” of the lipid orient toward the center of the bilayer while the hydrophilic (polar) “heads” orient towards the aqueous phase.
The original liposome preparation of Bangham et. al. (
J. Mol. Biol
., 13, 238-252 1965) involves suspending phospholipids in an organic solvent which is then evaporated to dryness leaving a phospholipid film on the reaction vessel. Then an appropriate amount of aqueous phase is added, the mixture is allowed to “swell”, and the resulting liposomes which consist of multilamellar vesicles (MLVs) are dispersed by mechanical means. This technique provides the basis for the development of the small sonicated unilamellar vesicles described by Papahadjopoulos et al. (
Biochim. Biophys. Acta.
135, 624-638 1967), and large unilamellar vesicles.
Other techniques that are used to prepare vesicles include those that form reverse-phase evaporation vesicles (REV), Papahadjopoulos et al., U.S. Pat. No. 4,235,871, stable plurilamellar vesicles (SPLV), Lenk et al., U.S. Pat. No. 4,522,803 incorporated herein by reference, monophasic vesicles (MPV), Fountain et al., U.S. Pat. No. 4,588,578 and incorporated herein by reference, freeze and thaw multilamellar vesicles (FATMLV), Bally et al., U.S. application Ser. No. 752,423, filed Jul. 5, 1985, and U.S. patent application Ser. No. 800,545, filed Nov. 21, 1985, both of which are incorporated herein by reference.
In a liposome-drug delivery system, the medicament is entrapped in the liposome and then administered to the patient to be treated. For example, see Rahman et al., U.S. Pat. No. 3,993,754; Sears, U.S. Pat. No. 4,145,410; Papahadjopoulos et al., U.S. Pat. No. 4,235,871; Schneider, U.S. Pat. No. 4,224,179, Lenk, et al., U.S. Pat. No. 4,522,803, and Fountain, et al., U.S. Pat. No. 4,588,578.
References citing the use of phospholipids to treat gastrointestinal ulceration have appeared in the literature; this effect due to the purported ability of the lipid to restore the stomach's natural protective barrier to irritants. For example, Dial et al.,
Gastroenterology
, 87, 379-385 (1984), suggested the anti-ulcer activity of bovine milk was due to its concentration of dipalmitoyl phosphatidylcholine. Other studies cite lysolecithin (Clemencon et al.,
Scad. J. Gastroenterol
. Suppl., 19, 116-120, 1984) and lipids isolated from both the fruits of the
Melia azedarach
plant, and the mussel
Perna canaliculus
(Al-Khatib,
Jpn. J. Pharmacol
., 36, 527-533, 1984, and Rainsford et al.,
Arzneim.-Forsch
., 30, 2128-2132, 1980, respectively), as ulceroprotective agents in rats.
Another study assessing membrane damage incurred by sodium dodecyl sulfate cites phosphatidylcholine (Martin et al.,
J. Pharm. Pharmacol
., 33, 754-759, 1981) as a protective agent against such damage. Finally, Lichtenberger et al. (
Science
, 219, 1327-1328, 1983) studied the ameliorative effects of a liposomal phospholipid suspension composed of 135 ug of dipalmitoyl phosphatidylcholine, and 15 ug each of phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, and sphingomyelin. They postulate the enhanced protection due to formation of an absorbed hydrophobic layer between the gastric epithelium and the luminal contents. Prostaglandins have been cited as protectants against gastric ulcerogenesis and bleeding in laboratory animals and man (Robert et al.,
Gastroenterology
, 77, 433, 1979, and Robert et al.,
Gastroenterology
, 55, 481, 1968), however Lichtenberger et al. (vide infra) determined that prostaglandin synthesis was not required for extrinsic phospholipid-induced gastric protection. However, when rats were dosed with Prostaglandin E
2
, rat stomach mucosa demonstrated a 2-6 fold increase in the major gastric surface protective surfactant with the greatest enhancements seen in concentrations of phosphatidylethanolamine and phosphatidylcholine.
In addition, Lichtenberger et al. European Pat. Appl. 92121, published Oct. 26, 1983, suggest phospholipid compositions for the treatment of ulcer. An application for similar compositions combined with a prostaglandin, for treatment of gastric and intestinal ulcers is Imagawa et al., European Pat. Appl. 150732, published Aug. 7, 1985. A further reference suggesting anti-ulcer compositions is Amen et al., U.S. Pat. No. 4,029,773, for a saccharose, amino acid and trigylceride mixture.
Ghyczy et al., U.S. Pat. No. 4,528,193, discloses compositions and methods of treating inflammation comprising phospholipids and non-steroidal anti-inflammatory drugs where the molar ratio is about 1:0.1 to 1:20. The mixture is prepared by co-solubilizing the drug and lipid in organic solvent, followed by removal of the solvent by distillation. Alternatively, the components are co-mixed in water. The solutions so obtained are then lyophilized.
A major plant galactolipid, digalactosyl diglyceride (DGDG) has been used to prepare liposomes. DGDG accounts for about 40% of the total lipid content of higher plant chloroplast and thylakoid membranes (Quinn et al.,
Prog. Biophys. Molec. Biol
., 34, 109-173, 1978). It has been used in studies where photosystems utilizing chlorophylls and cytochromes are reconstituted into liposomes (Sprague et al.,
J. Cell Biol
., 100, 552-557, 1985, and Morschel et al.,
J. Cell Biol
. 97, 301-310, 1983, respectively). Studies involving immunological activity of DGDG in liposomes as measured by complement dependent glucose release (Alving et al.,
Immunochemistry
, 11, 475-481, 1974) and the reactivity of sera from multiple sclerosis patients with DGDG liposomes and its ability to cause complement-mediated lysis of the liposomes (Boggs et al.,
J. Neurol. Sci
., 66, 339-348, 1984) have been performed. DGDG has been suggested as a minor liposome component for the purpose of delivering liposomal-encapsulated drugs to hepatocytes (Geho, U.S. Pat. No. 4,377,567).
There is an ongoing need for compositions which can buffer the unwanted gastrointestinal side effects of NSAIDs.
SUMMARY OF THE INVENTION
In view of the foregoing state of the art, it is an object of the present invention to provide compositions and methods of administration for non-steroidal anti-inflammatory drugs, which are less likely to produce ulcerogenic effects when used to treat chronic inflammatory diseases such as arthritis, or when used for their general analgesic and antipyretic effects.
Compositions are provided for non-steroidal anti-inflammatory drugs with a glycolipid. The glycolipid can be a glycosphingolipid or a galactolipid, such as digalactos
Cullis Pieter R.
Weiner Alan L.
Burns Doane Swecker & Mathis L.L.P.
The Liposome Company Inc.
Tran My Chau T
Wang Andrew
LandOfFree
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