Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2001-07-13
2004-12-21
Davis, Brian (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S109000, C514S002600, C514S282000, C514S610000, C424S617000, C424S718000
Reexamination Certificate
active
06833478
ABSTRACT:
TECHNICAL FIELD
This invention relates generally to methods and compositions for increasing the solubility of biologically active agents in lipophilic media. More particularly, the invention relates to the use of N,N-dinitramide salts as solubilizing agents for ionizable biologically active agents, particularly biologically active agents that when ionized are positively charged. The invention finds utility in a variety of fields, including pharmaceuticals and drug delivery, medical imaging and diagnostics, agrochemical manufacture, and dietary supplement formulation.
BACKGROUND
Many hydrophobic compounds are not only poorly soluble or even insoluble in water, but are also insoluble or only slightly soluble in lipophilic media. It is very difficult to manufacture useful products with such compounds because their insolubility limits the ability to chemically transform and/or formulate the compounds in any sort of composition. This is particularly problematic with hydrophobic pharmacologically active agents, which if insoluble in both aqueous and lipophilic media have very low oral bioavailability. Furthermore, for those drugs that are intended to be delivered to the brain, and thus be transported across the “blood-brain barrier” as will be described below, an insufficient amount of the drug penetrates the blood brain barrier and enters the central nervous system.
For treating pathologic processes inside the central nervous system (CNS), therapeutic benefit derives from availability of the agent inside the CNS. Undesired effects can result from effects of the agent anywhere in the body of the treated organism. The blood-brain barrier, regulates the exchange of materials between the bloodstream and the CNS, and may present a formidable barrier to drug transport into the CNS, thus affecting the effective dose of an agent or precluding its use by systemic administration altogether. As physical breach of the meninges is known to be medically undesirable, the inability of a pharmacologic agent to penetrate the blood-brain barrier can preclude its use altogether or limit its use to only life threatening situations.
The physiological basis for the blood-brain barrier are the brain capillaries, which are comprised of a lining of endothelial cells (Goldstein et al. (1986)
Scientific American
255:74-83 (1986); Pardridge (1986)
Endocrin. Rev.
7:314-330). The endothelial cells lining the capillaries of the blood-brain barrier are different from those lining capillaries of other tissues. Specifically, they form complex tight junctions, which prevent passage of molecules and ions between cells. The blood-brain barrier is formed by these high-resistance, tight intercellular junctions along with the endothelial cells themselves. The integrated structure forms a continuous wall against the passive movement of many molecules from the blood to the brain. The capillary endothelial cells forming the blood-brain barrier are also different in that they have few pinocytotic vesicles, which allow somewhat unselective transport across the capillary wall in other tissues. Continuous gaps or channels running through the cells, which would allow unrestrained passage of moieties, are also absent in blood-brain barrier capillary lining.
The structure of the blood-brain barrier may be subdivided into two components: the endothelial or capillary barrier and the ependymalbarrier (Banks et al (1991)
Pharm. Res.
8:1345-1350). The nature of the mechanism of the penetration of substances through the blood-brain barrier has not been fully explained, but many regulators of brain function, such as cytokines, transferrin, enkephalins and endorphins, are believed capable of traversing the blood-brain barrier from the blood vessels into the brain (Raeissi et al (1989)
J. Pharm. Phy.
41:848-852; Zlokovich et al. (1989)
Peptides
10:249-254; and Zlokovich, B. (1990)
J. Control. Rel.
13:185-201). However, many substances that can affect the CNS including adenosine, &bgr;-endorphin and synthetic analogs of endogenous peptides and some excitatory and inhibitor amino acids and trophic factors, penetrate the blood-brain barrier poorly or not at all (Houghten et al (1980)
Proc. Natl. Acad. Sci. USA
77:4588-4591; Levin et al. (1987)
Biochem. Biophys. Res. Commun.
147:1226-123; Sakane et al. (1989)
Int. J. Pharm.
57:77-83). Currently, drugs with little or no blood-brain barrier penetration can only be administered by direct CNS infusion or by implantation of controlled-release polymers (see, e.g., U.S. Pat. No. 4,883,666 to Sabel et al.). Thus, many potentially potent drugs are not clinically useful inside the CNS because of inability to cross the blood-brain barrier in amounts capable of yielding therapeutic levels in the CNS at below toxic systemic doses.
Many pharmacologic agents exert desirable therapeutic effects inside the CNS at attainable systemic levels, but can be employed with only limited therapeutic scope because of severe side effects to peripheral organs and/or the peripheral nervous system. Thus, a need generally exists to reduce the side effects of drugs directed to the CNS by reducing side effects on peripheral organs and tissues by increasing the action inside the blood-brain barrier.
One approach has been to alter the permeability of the blood-brain barrier itself. For instance, some osmotic agents administered peripherally, as by intravenous or intramuscular injection, result in the breach of the blood-brain barrier. Further, some drugs acting on the CNS can alter the permeability properties of the blood-brain barrier for other substances. Cholinomimetic arecolines, for example, have been reported to induce alterations of drug penetration through the blood-brain barrier (Saija et al. (1990)
J. Pharm. Pha.
42:135-138). Other drugs that may be administered to change the blood-brain barrier permeability are disclosed in U.S. Pat. Nos. 5,059,415 and 5,124,146 to Neuwelt. Bradykinin is one specific drug with such effects (see U.S. Pat. No. 5,112,596 to Malfroy-Camine). Another method involves administration of permeabilizer peptides such as A-7 or conformational analogs thereof (see Kozarich et al., International Patent Publication No. WO 92/18529). Tomasz et al. (International Patent Publication No. WO 91/16064) administer parenteral injections of purified cell walls or cell wall fragments of eubacteria such as
Streptococcus pneumoniae
to open the blood-brain barrier, a relatively invasive method.
U.S. Pat. No. 5,260,210 to Rubin et al. discloses a method of increasing the permeability of the blood-brain barrier by administering an agent to reduce or inhibit intracellular cyclic AMP concentrations or to increase cyclic GMP concentrations. One disadvantage of wholesale alteration of blood-brain barrier permeability is the resulting lack of selectivity. Thus, any method of changing the permeability of the blood-brain barrier itself is compromised by the possible entry of unwanted molecules from which the brain is normally protected by the blood-brain barrier. Such methods are thus impracticable due to unpredictable and uncontrollable consequences.
Another approach has been the modification of drug molecules themselves. The properties of the molecule, such as size and pK
a
, are important to the drug's ability to penetrate the blood-brain barrier. For example, macromolecules, including folded proteins, do not pass the blood-brain barrier at all. One way of modifying a molecule so as to render it capable of traversing the blood brain barrier involves isolating the active moiety of a macromolecule, i.e., that portion of the molecule responsible for the biologically desirable result, and using only that active moiety. Because size is one of the factors affecting ability of a molecule to traverse the blood-brain barrier, reduced size is employed to enhance the kinetics of penetration of the blood-brain barrier, and consequently increase the likelihood that the smaller molecule may traverse the blood-brain barrier in therapeutically significant amounts. Other modifications to macromolecules to enh
Bomberger David C.
Bottaro Jeffrey C.
Penwell Paul E.
Petrie Mark A.
Davis Brian
Reed Diane E.
Reed & Eberle LLP
SRI - International
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