Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-03-03
2001-08-07
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S502000, C514S169000, C514S458000, C514S725000
Reexamination Certificate
active
06270806
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to nanoparticulate formulations of a drug having at least one polyethylene glycol (PEG)-derivatized phospholipid, PEG-derivatized cholesterol, PEG-derivatized cholesterol derivative, PEG-derivatized vitamin A, or PEG-derivatized vitamin E adsorbed on the surface of the drug as a surface stabilizer, and methods of making and using such compositions.
BACKGROUND OF THE INVENTION
Nanoparticulate compositions, first described in U.S. Pat. No. 5,145,684 (“the '684 patent”), are particles consisting of a poorly soluble therapeutic or diagnostic agent having adsorbed onto the surface thereof a non-crosslinked surface stabilizer. The '684 patent describes the use of a variety of surface stabilizers for nanoparticulate compositions. The use of a PEG-derivatized phospholipid, PEG-derivatized cholesterol, PEG-derivatized cholesterol derivative, PEG-derivatized vitamin A, or PEG-derivatized vitamin E as a surface stabilizer for nanoparticulate compositions, or any other component of such compositions, is not described by the '684 patent.
The '684 patent describes a method of screening drugs to identify useful surface stabilizers that enable the production of a nanoparticulate composition. Not all surface stabilizers will function to produce a stable, non-agglomerated nanoparticulate composition for all drugs. Moreover, known surface stabilizers may be unable to produce a stable, non-agglomerated nanoparticulate composition for certain drugs. Thus, there is a need in the art to identify new surface stabilizers useful in making nanoparticulate compositions. Additionally, such new surface stabilizers may have superior properties over prior known surface stabilizers.
A. Lipids in Nanoparticulate Compositions
A lipid is an inclusive term for fats and fat-derived materials. It includes all substances which are (i) relatively insoluble in water but soluble in organic solvents (benzene, chloroform, acetone, ether, etc.); (ii) related either actually or potentially to fatty acid esters, fatty alcohols, sterols, waxes, etc.; and (iii) utilizable by the animal organism. Because lipids are relatively insoluble in water, but soluble in organic solvents, lipids are often referred to as “fat soluble,” denoting substances extracted from animal or vegetable cells by nonpolar or “fat” solvents. Exemplary lipids include phospholipids (such as phosphatidylcholine, phosphatidylethanolamine, and cephalin), fats, fatty acids, glycerides and glycerol ethers, sphingolipids, alcohols and waxes, terpenes, steroids, and “fat soluble” vitamins A or E, which are non-cholesterol based poorly water soluble vitamins.
Stedman's Medical Dictionary,
25
th
Edition, pp. 884 (Williams & Wilkins, Baltimore, Md., 1990);
Hawley's Condensed Chemical Dictionary,
11
th
Edition, pp. 704 (Van Nostrand Reinhold Co., New York, 1987).
A number of U.S. patents teach the use of a charged phospholipid, such as dimyristoyl phophatidyl glycerol, as an auxiliary surface stabilizer for nanoparticulate compositions. See e.g., U.S. Pat. No. 5,834,025 for “Reduction of Intravenously Administered Nanoparticulate-Formulation-Induced Adverse Physiological Reactions”; U.S. Pat. No. 5,747,001 for “Aerosols Containing Beclomethasone Nanoparticle Dispersions”; and U.S. Pat. No. 5,718,919 for “Nanoparticles Containing the R(−)Enantiomer of Ibuprofen.”
Other U.S. patents describe the use of a charged phospholipid, such as diacylphosphatidyl glycerol or dimyristoyl phosphatidyl glycerol, as a cloud point modifier for the surface stabilizer of a nanoparticulate composition to prevent particle aggregation during steam heat autoclaving. See e.g., U.S. Pat. No. 5,670,136 for “2,4,6-triiodo-5-substituted-amino-isophthalate Esters Useful as X-ray Contrast Agents for Medical Diagnostics Imaging”; U.S. Pat. No. 5,668,196 for 3-amido-triiodophenyl Esters as X-ray Contrast Agents”; U.S. Pat. No. 5,643,552 for “Nanoparticulate Diagnostic Mixed Carbonic Anhydrides as X-ray Contrast Agents for Blood Pool and Lymphatic System Imaging”; U.S. Pat. No. 5,470,583 for “Method of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation”; and U.S. Pat. No. 5,336,507 for “Use of Charged Phospholipids to Reduce Nanoparticle Aggregation.” None of these patents refer to the use of a PEG-derivatized phospholipid, PEG-derivatized cholesterol, PEG-derivatized cholesterol derivative, PEG-derivatized vitamin A, or PEG-derivatized vitamin E in nanoparticulate compositions, either as a surface stabilizer, cloud point modifier, or as any other constituent of a nanoparticulate composition.
B. PEG-derivatized Lipids in Pharmaceutical Compositions
Liposomes, or vesicles composed of single or multiple phospholipid bilayers, have been investigated as possible carriers for drugs. Unmodified liposomes tend to be taken up in the liver and spleen. For drugs targeted to these areas, unmodified liposomes are useful drug adjuvants. However, often the liver and spleen are not the target areas for drug delivery. This affinity for the liver and spleen limits the effectiveness of liposome-encapsulated drugs and complicates dosing. Kimelberg et al., “Properties and Biological Effects of Liposomes and Their Uses in Pharmacology and Toxicology,”
CRC Crit. Rev. Toxicol.,
6:25-79 (1978); and Allen et al., “Stealth® Liposomes: An Improved Sustained Release System For 1-beta-D-arabinofuranosyl-cytosine,”
Cancer Res.,
521:2431-2439 (1992). To avoid these problems, researchers have studied various ways of modifying the liposome structure to prolong circulation time. Allen,
Cancer Res.,
521:2431-2439 (1992).
It was discovered that one useful type of modified lipid contains polyethylene glycol (PEG). In its most common form PEG, also known as poly(ethylene oxide) (PEO), is a linear polymer terminated at each end with hydroxyl groups:
HO—CH
2
CH
2
O—(CH
2
CH
2
O)
n
—CH
2
CH
2
—OH
This polymer can be represented as HO-PEG-OH, where it is understood that the −PEG-symbol represents the following structural unit:
—CH
2
CH
2
O—(CH
2
CH
2
O)
n
—CH
2
CH
2
—
PEG is particularly useful because of its ease of preparation, relatively low cost, controllability of the molecular weight, and the ability to link to lipid by various methods. PEG is believed to act by forming a hydrophilic coat and by causing steric hindrance at the liposome surface, thus reducing liposome-serum protein interaction and liposome-RES (reticuloendothelial system) cells interaction. Yuda et al., “Prolongation of Liposome Circulation Time by Various Derivatives of Polyethyleneglycols,”
Biol. Pharm. Bull.,
19:1347-1351, 1347-1348 (1996).
PEG-derivatized lipids are described in, for example, U.S. Pat. No. 5,672,662 (“the '662 Patent”) for “Poly(Ethylene Glycol) and Related Polymers Monosubstituted with Propionic or Butanoic Acids and Functional Derivatives Thereof for Biotechnical Applications,” and Yuda et al. (1996).
1. PEG-Derivatized Lipid Drug Carriers Result in Increased In Vivo Circulation Times of the Administered Drug
PEG derivatized lipids or liposomes are referred to as “sterically stabilized” lipids or liposomes (S-lipids or S-liposomes). Allen, “Long-circulating (sterically stabilized) liposomes for targeted drug delivery,”
TiPS,
15:215-220 (1994). PEG attracts water to the lipid surface, thus forming a hydrophilic surface on the lipid. The hydrophilic surface inhibits opsonization of the lipid by plasma proteins, leading to increased survival times of PEG-lipid in the circulation. Opsonization refers to uptake by the cells of the mononuclear phagocyte system (MPS), located primarily in the liver and spleen. Because PEG-derivatized lipids evade the cells of the MPS, they are often called Stealth® lipid or liposomes. Lasic D., “Liposomes,”
Am. Scientist,
80:20-31 (1992); Papahadjopoulos et al., “Sterically Stabilized Liposomes; Pronounced Improvements in Blood Clearance, Tissue Distribution, and Therapeutic Index of Encapsulated Drugs Against Implanted Tumors,”
PNAS, U.S.A.,
88:11460-11464
Gottardy Greta A.
Liversidge Elaine
Elan Pharma International Limited
Foley & Lardner
Kishore Gollamudi S.
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