CA2106105C - Polymer-bound nitric oxide/nucleophile adduct compositions, pharmaceutical compositions incorporating same and methods of treating biological disorders using same - Google Patents

Polymer-bound nitric oxide/nucleophile adduct compositions, pharmaceutical compositions incorporating same and methods of treating biological disorders using same Download PDF

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CA2106105C
CA2106105C CA002106105A CA2106105A CA2106105C CA 2106105 C CA2106105 C CA 2106105C CA 002106105 A CA002106105 A CA 002106105A CA 2106105 A CA2106105 A CA 2106105A CA 2106105 C CA2106105 C CA 2106105C
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nitric oxide
group
branched chain
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pharmaceutically acceptable
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Larry K. Keefer
Joseph A. Hrabie
Joseph E. Saavedra
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US Department of Health and Human Services
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment
    • C08F8/30—Introducing nitrogen atoms or nitrogen-containing groups
    • C08F8/32—Introducing nitrogen atoms or nitrogen-containing groups by reaction with amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/593—Polyesters, e.g. PLGA or polylactide-co-glycolide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F112/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an aromatic carbocyclic ring
    • C08F112/02—Monomers containing only one unsaturated aliphatic radical
    • C08F112/04—Monomers containing only one unsaturated aliphatic radical containing one ring
    • C08F112/14—Monomers containing only one unsaturated aliphatic radical containing one ring substituted by hetero atoms or groups containing heteroatoms
    • C08F112/16—Halogens
    • C08F112/18—Chlorine

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Abstract

A polymeric composition capable of releasing nitric oxide including a polymer and a nitric oxide-releasing N2O2- functional group bound to the polymer;
pharmaceutical compositions including the polymeric composition; and methods for treating biological disorders in which dosage with nitric oxide is beneficial. The compositions can be used as and/or incorporated into implants, injectables, condoms, prosthesis coatings, patches, and the like for use in a wide variety of medical applications.

Description

POLYMER-BOUND MaTU:TC OXIAE/MLTCI,EOPHIT,E
ADDUCT CdMP'CISITICN3O FHARnCEUTICAI, t".t7.'~POSI'fIONS
INCORPORATING SAME AND METHODS oF T12EATING
BIOLOGICAL DISORDERS USING SAME

MACKGRCUND QF THE INVENTION
The present invention relates to compositions comprising a nitric oxide/nucleophile adduct capable of releasing nitric oxide. In particular, the present invention relates to oompositions comprising nitric oxide/nucleophile adducts which are bound to a polymer and which release nitric oxide in a physiological environment, to pharmaceutical compositions, a..0oluding implants, patches and the like, incorporating the polymer-bound nitric oxide/nucl,eophi].e adduo.t compositions, and to methods of treating biological disorders with polymer-bound nitric oxide/nucleophile adduct compositions.
Nitric oxide (NO) has recdntly been implicated in a variety of bioregulatory processes, including normal physiological control of blood pressure, macrophage-induced cytostasis and cytotoxicity, and neurotransmission (Moncada et al., "Nitric Oxide. from L-Arginine: A Bioregulatory System," Exaerpta Med3ca, Internationa7. Congress Serias 897 (Elsevier Science Publishers B.V.: Amsterdam, 1990); Marletta et al., "Unraveling the Sio7.ogical Signif"ioance of.Nitrac Oxide," Biofactors, 2, 219-225 (1990); Ignarro, "Nitric Oxide. A Novel Signal. Transduction Mechanism for Transcellular Communication," Hypertension (Dallas), 16, 477-483 (1990)). A number of compounds have been developed which are capable of delivering nitric oxide,
2 including compounds which release nitric oxide upon being metabolized and compounds which release nitric oxide spontaneously in aqueous solution.
Those compounds which release nitric oxide upon being metabolized include the widely used nitrovasoda.lators glyceryl trinitrate and sodium nitroprusside (2gnarro et al., J Pharznaaol, Exp...Ther., 218, 739-749 (1981); Ignarro, Annu. Rev. Pharmacol.
Toxicol.,a, 535-560 (1990) ; Kruszyna e-t, al., Toxicol.
Appl. Pharmacol., 91, 429-438 (1987); Wilaox et al., Chem. Res. ToXicQl., 3, 71-76 (1990). Another compound, S-nitros4-N-acetylpenicillamine, has been reported to release nitric oxide in solution and to be effective at inhibiting DNA, synthesis (Carg et al., Eiochem. arad $iophys. Res. Comm., 171, 474-479 (1990)).
Numerous nitrio oxide-nucleophile complexes have been described, e.g., Drago, ACS Adv. Chem.Ser., Vol.
36, p. 143-149 (1962). See also Longhi and Drago, Inorg. Chem. 2 85, (1963). Some of these complexes are known to evolve nitric oxide on heating or hydrolysis, e.g., Maragos et al., J. Med. Chem. 34, 3242-3247, 1991.
The cytostatic effect of nitric oxide solutions on tumor cells in vitro has been demonstrated. In particulax, it has been shown that solutions of nitric oxide inhibit DNA synthesis and mitochondrial respiration of tumor cells in vitro (Hibbs et al.., B19ch9fi. and giophys. Res. Comm , 157, 87-94 (1988);
Stuehr et al., J._Exp. Med., 169, 1543-1555 (1989)).
Endothelium-derived relaxing factor (EDRF) is a labile humDral agent which is part of a cascade of interacting agents involved in the relaxation of vascular smooth muscle. EDRY is thus important in the control of vascular resistance to blood flow and in the control of blood pressure. Some vasodilators act by causing EDRF to be released from e.ndothelial cells.
(See F'urchgott, Ann.Rev.Pharmacol.Toxicol. 24, 175-197, 1984,) In 1987, Palmer et al., presented evidenoe that
3 EDRF is identical to the simple molecule, nitric oxide, NO (Nature 317, 524-526, 1987), though more recently, that conclusion has been challenged (Myers et al., Nature, 345, 161-163, 1990).
Nitric oxide in ats pure form, however, is a highly reactive gas having limited solubility in aqueous media (WHO Task Grraup on tnvironmental Health Criteria for Oxides of Nitrogen, Oxides of Nitrogen, Enviraaamen-tal Health Criteria 4 (World Health organizatioria Geneva, 1977)). Nitric oxide, therefore, is difficult to introduce reliably into most biological systems without premature decomposition.
The difficulty in administering nitric oxide can be overcome in some cases by administering nitric oxide pharmacologically in prodrug form. The compounds glyceryl trinitrate and sodium nitroprusside are relatively stable but release nitric oxide only on activation (ignaxro et al., J. Pharmacol. Exp. Ther., ~, 739-749 (1981)= Ignarro, Annu. Rev. Phar.macol..
Toxicol., ~0, 535-560 (1990); Kruszyna et al., Toxicol.
Appl. Pharmaaol., 91, 429-438 (1987); Wilcox et al., Chem. Res. 1'oxicol. , 3, 71,-76 (1990) ). While this feature may be an advantage in some applications, it can also be a significant liability, as in the development of tolerance to glyceryl trinitrate via the exhaustion of the relevant enzyme/cofactor system (Ignarro et al., Annu_.-Rov. PharmacoZ. Tcx.icol., 25, 171-191 (1985) ;Kuhn et al. , J.__ Cardioyasc_. Pt~a~macol. 4 (Suppl. 11) , S47-854 (1989)) and toxicity from metabolically produced cyanide during prolonged administration of nitroprusside (Smith et al., "A Potpourri of Biologically Reactive Intermediates" in Biological Reactive Interme iates IV.
Molecular and Ce11u1ar _Effects and Their Impact on Human Health (Witmer et al., eds.), Advances in Experimental MediCa.ne and Biology Volume 283 (Plenum Press: New York, 1991), pp. 365-369).
4 Evidence that nitric oxide is released from the endothelial cells and is responsible for the relaxation of the vascular smooth muscle, and hence the control of blood pressure, has resulted in the developmerit of artificial agents that can deliver nitric oxide in vivo.
A very important class of such agents is the riitric oxide-nucleophile complexes. Recently, a method for treating cardiovascular disorders in a mammal with certain nitric oxide-nucleophile complexes was disclosed, e.g. in U.S. 4,954,526. These compounds contain the anionic NZOZ' group or derivatives thereof.
See also, Maragos et al., J. Med. Chem. 34, 3242-3247, 1991. Many of these compounds have proven especially promising pharmacologically because, unlike nitrovascdilators such as nitroprusside and nitroglycerin, they release nitric oxide without first having to be metabolized. The only other series of drugs currently known to be capable of releasing nitric oxide purely spontaneously is the S-nitrosothiol series, compounds of structure R-S-Np (Stamler et al., Proc.
Natl. Acad. Sci. U.S.A. 89, 444-448, 1992); however, the R-S-NQ--}No reaction is kinetically complidated and difficult to control (Morley et al., J. Cardiovasc.
Pharmacol. 21, 670-676, 1993). The N202 containing compounds are thus unique among drugs Currently known in that they decompose at any given pH via a cleanly first order reaction to provide doses of nitric oxide that can be predicted, quantified, and controlled. See, e.g., Maragos et al., J. Med. Chem. 34, 3242-3247, 1991.
Nitric oxide/nucleophile complexes which release nitric oxide in aqueous solution are also disclosed in U.S. Patent Nos. 5,039,705, 5,185,376, 5,155,137,
5,208,233, 5,212,204, 5,366,997 and 5,389,675 as being useful cardiovascular agents (see also Maragos et al., J. Med. Chem., 34, 3242-3247 (1991)).

bespite the promise of the nitric oxide/nucleophile adducts that have been investigated, their pharmacologica], application has been limited by their tendency to distribute evenly throughout the medium.
Such even distribution is a great advantage in many research applications, but tends to comprOmisa their selectivity of action. Another limitation to the application of these nitric oxide/nucleophile adducts is their propensity for relatively rapid release of nitric oxide which may necessitate frequent dosing to achieve a prolonged biological effect. Thus there remains a need for nitric oxide-releasing compositions which are capable of concentrating the effect of the nitric oxide release to a situs of application and for which nitric Oxide release may be,controlled for effective dosing.
It is therefore a principal object of the present invention to provide a composition which includes a ni'tric oxide/nucleophile adduct whose action can be localized to enhance the selectivity of nitric oxide release. Another object of the invention is to provide a composition which includes a nitric oxide/nucleophile adduct whose release of nitric oxide can be controlled to effect efficient dosing for a prolonged biological effect. A further object of the present invention is to provide compositions including nitric oxide/nucleophile adducts capable of releasing nitric oxide wherein the nitric oxide/nucleophile adduct is associated with a polymer. These and other objects and advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.

BRIEF SUMMARY OF THE INVENTION
The present invention provides a composition capable of releasing nitric oxide which includes a
6 nitric oxide-releasing N202' functional group bound to a polymer. By --bound to a polymer," it is meant that the N202- functional group is associated with, part of, incorporated with or contained within the polymer matrix physically or chemically. Physical association or bonding of the N202 functional group to the polymer may be achieved by coprecipitation of the polymer with a nitric oxide/nucleophile complex as well as by covalent bonding of the N242 group to the polymag. Chemical bonding of the N202- functional group to the polymer may be by, for example, covalent bonding of the nucleophile moiety of the nitric oxideJnuGleophile adduct to the polymer such that the nucleophile residue to which the N202- group is attached forms part of the polymer itself, i.e., is in the polymer backbone or is attached to ' pendant groups on the polymer backbone. The manner in which the nitric oxide-releasing N202- functional group is associated, with, part of, incorporated with or contained within, i.e., "bound," to the polymer is inconsequential to the present invention and all means of association, incorporation and bonding are contemplated herein.
The present invention also provides a pharmaceutical oomposition which includes a pharmaceutically acceptable carrier and aOolymer having a nitric oxide-releasing N202- functional group bouni3 to said polymer. The polymer-bound nitrio oxide-releasing N202- functional group compositions of the present invention may themselves function as a pharmaceutical composition, as, for example, when the polymer-bound composition is in the form of an implant, stent, patch, or the like.
.The invention further provides a method of treating biological disorders in which dosage with nitric oxide would be beneficial which comprises administering a composition comprising a polymer and a nitric oxide-. re].easing N202 functional group bound to said polymer in
7 an amount suffioi.ent to release a therapeutically effective amount of nitric oxide.

BRIEF DESCRIPTION OF. THE_I21tARZ GS
Figure 1 is the chemiluminescence detector response to nitric oxide generated from the polymer-bound nitric oxide-releasing N202' functional group composition of Example III in accordance with the invention.
Fig. 2 is a graph illustrating the time course of vascular relaxation with different doses of the polymer-bound nitric oxide-releasing composition of Example T.
Fig. 3 is a graph illustrating the time course of vascular relaxation with different doses of the polymer-bound nitric oxide-releasing composition of Example II.
DETAILED DESCRIPTION OF THE PREFERREL? _JE]_jbdDIMENTS
The present invention is predicated on the disoavery that useful pharmacological agents can be provided by incorporating nitric oxide-releasing NZO2-functional groups into a polymerio matrix. Accordingly, the N242 funct.a.onal group is "bound to the polymer" as that term has been defined herein. It has been discovered that incorporation of the N202' functional group into a polymeric matrix provides a polymer-bound nitric oxideJnucleophile adduct composa.tion that can be applied with specificity to a biological site of interest.- Site specific application of the polymer-bound adduct composition enhances the selectivity of action of the nitric oxide releasing N202 functional 3-0 group. If N202- functivnal groups attached to the polymer are necessarily localized, then the effect of their nitric oxide release will be conaentrated in the tissues with which they are in contact. zf the polymer is soluble, selectivity of a.ation can still be arranged, for example, by attachment to or derivatization of an antibody specific to the target tissue. Similarly, attachment of N202" groups to small peptides that mimic the recognition sequences of ligands for important receptors provides localized concentrated effect of nitric oxide release, as would attachment to oligonucleotides capable of site-specific interactions with target sequences in a nucleic acid.
Additionally, incorporation of the N202' functional group into a polymer matrix can reduce.the propensity of the nitric oxide/nucleophile adduct for the relatively rapid release of nitric oxide, This prolongs the release of nitric oxide by the N202' functional group, and allows for efficient dosing to achieve a desired biological effect so the frequency of dosing can be reduced.
While not being bound to any particular theory, it is believed that longevity of nitric oxide release in the polymer-bound nitric oxide/nudleophile adduct compositions of the present invention is to be attributed both to the physioal structure of the composition and to electrostatic effects. Thus, it is believed that if the polymer is an insoluble solid, N202' groups near the surface of the particle should be available for rapid release while those that are more deeply imbedded are sterically shielded, requiring more time and/or energy for the nitric oxide to work its way into the medium, Unexpectedly, it has been found that increasing positive charge in the vicinity of an N202 functional group also tends to inoreaso the halflife of nitric oxide generation. The mechanism of this rate retardation may be attributable simply to repulsive electrostatic interactions, i.e., increasing the number of H-1'-repelling positive charges in the vicinity of the N202- groups inhibits attavk of positively charged H+
ions on the NZOa' functional group and slows the rate of its H+- catalyzed decomposition. For example, by attaching amino groups to the polymeric support that are capable of forming the nitric oxide-releasing N202' functional g:roup on reaction with nitric oxide, 23.06105 partially converted structures can be produced on less-than-exhaustive treatment with nitric oxide that after exposure to water contain a large number of positively charged ammonium centers surrounding the N202' group that electrostatically inhibit the approach of H'~ ions capable of initiating nitric oxide loss from the nitric oxide releasing N202" functional group. -The nitric oxide-releasing N202 functional groups that are bound to the polymer generally are capable of releasing nitric oxide in an aqueous environment spontaneously upon contacting an aqueous environment, i.e., they do not require activation through a redox reaction or electron transfer such as is required for glyceryl trinitrate and sodium nitroprusside. Some of the nitric oxide/nucleophile complexes useful in the context of the present invention do require activation by particular means, but only as necessary to free the nitric oxide releasing X[N(0)NO]' group in the vicinity of the particular cells of interest. As an example, covalent attachment of a protecting group to the anionic [N(G)NO]' function provides a means of postponing nitric oxide release until the molecule reaches an organ capable of metabolically removing the protecting group.
By choosing a protecting group that is selectively cleaved by enzymes specific to a tumor, biological disorder, cell, or tissue of interest, for example, the action af the nitric oxide/nucleophile complex can be targeted to maximize the desired effect. While the polymer-bound nitric oxide releasing compositions of the present invention are capable of releasing nitric oxide in an aqueous solution, such a compound preferably releases nitric oxide under physiological conditions.
The nitric oxide releasing N202 functional group is preferably a nitric oxide/nucleophile adduct, e.g., a complex of nitric oxide and a nucleophile, most preferably a nitric oxide/nucleophile complex which contains the anionic moiety X[N(0)N0]', where X is any suitable nucleophile residue. The nucleophile residue is preferably that of a primary amine (e.g., X=
(CH3)2CHNH, as in (CH3)2CHNH[N(O)NO]Na), a secondary amine (e.g., X = (CH3CH2)2N, as in (CH3CH2)2N(N(0)NO]Na) , a 5 polyamine (e.g., X= spermine, as in the zwitterion H2N(CH2)3NH2+(CH2)4N[N(O)NO]-(CH2)3NH2, X =
(ethylamino)ethylamine, as in the zwitterion CH3CH2N[N(0)NO]-CH2CH2NH3+, or X = 3-(n-propylamino)propylamine, as in the zwitterion 10 CH3CH2CH2N[N(0)NO]-CH2CH2CH2NH3"), or oxide (i.e., X= 0", as in NaO[N(0)NO]Na), or a derivative thereof. Such nitric oxide/nucleophile comp],exes are stable solids and are capable of delivering nitrid oxide in a biologically usable form at a predictable rate.
The nucleophile residue is preferably not an entity such as that of sulfite (e.g., X = S03', as in NH4O3S[N(O)NO]NH4) even though the complex is a stable compound, since it is capable of releasing nitric oxide in an aqueous environment only under harsh, nonphysiological conditions.
Other suitable nitric oxide/nucleophile complexes include those having the following formulas:

J N-O-I Me +x (I) N=0 a b wherein J is an organic or inorganic moiety, preferably a moiety which is not linked to the nitrogen of the N202 group through a carbon atom, M" is a pharmaceutically acceptable cation, where x is the valence of the cation, a is 1 or 2, and b and c are the smallest integers that result in a neutral compound, preferably such that the compound is not a salt o-C alanosine or dopastin, as described in U. S. Patent 5,212,204;

R1-NH+- (CHZ) x-N-[ (CHZ) yNld-i (CH2) z-N]b-R3 (II) I I I I

wherein b and d are the same or different and may be zero or one, R1, R2, R3, R4, and R5 are the same or different and may be hydrogen, C,-8 cycloalkyl, C1=12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, or 2,2,2-trichloro-t-butoxycarbonyl, and x, y, and z are the same or different and are integers from 2 to 12, as described in U.S. Patent 5,155,137;

H
R6-N}-(CH2)f B (III) wherein B is N-N2OZ or. -N N-N202 , ___J
\

R6 and R7 are the same or different and may be hydrogen, C3-$ cycloalkyl, C1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-tolixyl, t-butoxycarbonyl, or 2, 2, 2-trichloro-t-butQxycarboriyl, f is an integer from 0 to 12, with the proviso that when B is the substituted piperazine moiety ~~
WN N-NZO,-~, then f is an integer from 2 to i2, as described in U.S.
Patent 5,155,137;

N N
(CHZ) -I -Rg * (CH2) 8-NH2+-Ra (IV) wherein Rg is hydrogen, G3.8 cycloalkyl, C1.12 stxaight or branohed ohain alkyl, benzyl, benzoyl, phthaloyl, lp acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, or 2,2,2Mtri-ch7.oro-t-butoxycarbonyl, Ry is hydrogen or a CI-C12 straight or branched chain alkyl, and g ir. 2 to 6, as described in U.S. Patent 5,155,137;

fRi N - N - 0- M+X (V) R2 N0 x wherein R1 and R2 are independently selected from the group consisting of a straight chain or branched chain C1 -C12 alkyl group and a benzyl group, with the ppoviso that no branch occur on the alpha carbon atom, or else R1 and R2 together with the nitrogen atoin they are bonded to form a heterocyclic group, preferably a pyrrolidino, piperidino, piperazino or morpholino group, M+x is a pharmaceutically acceptable cation, and x is the valence of the cation, as described in U.S. Patent No. 5,039,705;
~I (~ ~ (L) y(R~R2N-NaOa) z] (VT ) wherein M is a pharmaceutically acceptable metal, or, where x is at least two, a mixture of two different pharmaceutically acceptable metals, L is a].zgand different from (R1RZN-N2Q2) and is bound to at least one~
metal, RI and RZ are each organic moieties and may be t:lze same or different (with the proviso that where Mis copper, x is one, L is methanol, and y is one, that at least one of R1 or R2 is not ethyl) , x is an integer of from 1 to 10, x' is the formal oxidation state of the metal M, and is an integer of from 1 to 6, y is an integer of from 1 to 18, and where y is at least 2, the ligands L may be the same or different, z is an integer of from 1 to 20, and K is a pharmaceutically acceptable counterion to render the compound neutral to the extent necessary, as described in U. S. Patent No. 5,389,675;

[R-N(H)N(NO)0-]yX (VTT) wherein R is C2_$ lower alkyl, phenyl, benzyl, or C3_8 cycoloalkyl, any of which R groups may be substituted by one to three substituents, whiGh are the same or different, selected from the group consisting of halo, hydroxy, C1.8 alkoxy, -NH2, -C (0) NH21 -CH (o) , -G (0) OH, and -NOZ, X is a pharmaceutically acceptable cation, a pharmaceutically acceptable metal center, or a pharmaceutically acceptable organic group selected from the group consisting of C1.8 lower alkyl, -C (4) CH3, and -C(O)NH2, and y is one to three, consistent with the valence of X, as described in U.S. Patent No. 4,954,526;

R1R2N-N-0 ( V I Z Z) 11.

wherein R1 and R. are independently chosen from C1-i2 straight chain alkyl, C1-12 alkoxy or acyloxy substituted straight chain alkyl, C2.12 hydroxy or halo substituted straight chain alkyl, C3112 branched chain alkyl, C3-12 hydroxy, halo, alkoxy, or acyloxy substituted branched chain alkyl, C3.12 straight chain olefinic and C3_12 branched chain olefinic which are unsubstituted or substituted with hydroxy, alkoxy, acyloxy, halo or benzyl, or R, and R2 together with the nitrogen atom to which they are bonded form a heterocyclic group, preferably a pyrrolidino, piperidino, piperazino or.
morpholino group, and R3 is a group selected from Ct,t2 straight chain and C3_12- branched chain alkyl whiotL are unsubstituted or substituted by hydroxy, halo, acyloxy or alkOxy, C2.12 straight chain or G3_12 branched chain olefinic which are unsubstituted or substituted by halo, alkoxy, acyloxy or hydroxy, c1-12 unsubstituted or substituted acyl, sulfonyl and carboxamido; or R3 is a group of the formula -(CR2)a ON=N(O)NR1R2, wherein n,is an integer of 2-8, and Rl and R2 are as defined above; with the proviso that R1, R2 and R3 do not contain a halo or a hydroxy substituent ac to a heteroatom, as described in U. S. Patent No. 5,366,997.

Any of a wide variety of polymers can be used in the context of the present invention. it is only necessary that the polymer selected is biologically acceptable. Illustrati.ve of polymers suitable for use in the present invention are polyolefins, such as polystyrene, polypropylene, polyethylene, polytetrafluorethylene, polyvinylidene difluoride, and polyvinylchloride, polyethylenimine or derivatives thereof, polyethers such as polyethyleneglycol, polyesters such as poly(lactide/glycolide), polyamides such as nylon, polyurethanes, biopolymers such as peptides, proteins, oligonucleotides, antibodies and nucleic acids, starburst dendrimers, and the like.
The physical and struatura,l characteristics of the polymers suitable for use in the present invention are not narrowly 'eritical, but rather will depend on the end use application. It will be appreciated by those skilled in the art that where the polymer-bound nitric oxide/nucleophile adduct compositions of the present ~~~~~~5 invention are intended for topical, dermal, percutaneous, or similar use, they need not be biodegradable. For some uses, such as ingestion or the like, it may be desirable that the polymer of the 5 polymer-bound oompositi:ons slowly dissolve in a physiological environment or that it is biodegradable.
The polymar-bQund nitrio oxide releasing compositions of the prosent invention will find utility in a widp variety of applications and in a wide variety of forms 10 depending on the biological disorder to be treated. For example, the polymer may itself be structurally suffioient to serve as an Xmpaant, patch, stent or the like. Further, by way of illustration, the polymer-bound composition may be incorporated into other polymer 15 matrices, substrates or the like, or it may be microencapsulated, or the like.
The nitric oxide-releasing complexes having N202 functional groups, including the compounds described above, may be bound to the polymer support in a number of different ways. For example, the compounds described above may be bound to the polymer by coprecipitation of such compounds with the polymer. Coprecipitata.on involves, for example, solubilizing both the polymer and the nitric oxide/nucleophile compound and evaporating the solvent. Monomers containing the NZ02- group may also be dissolved in molten polymer which, on solidifying when the temperature is lowered, contains a rather uniform distribution of N202- groups within the matrix.
Alternatively, nitric oxide releasing N202 funetional groups may be bound to the polymer by formation of a nitric oxide/nuclPophile complex of the types and having the formulas of those described above, in sAtu on the polymer. The N202 functional group may be attached to an atom in the backbone of the polymer, or it may be attached to a group pendant to the polymer backbone, or it may simply be entrapped in the polymer ~~~610"' matrix. Where the N202- functional group is in the polymer backbone, the polymer includes in itp backbone sites which are capable of reacting with nitric oxide to bind the nitric oxide for future release. F'or example, where the polymer is polyethylenimine, the polymer includes nucleophilic nitrogen atoms taha.ch react with nitric oxide to form the N202 functional group at the nitrogen in the backbone. Where the N202- functional group is a group pendant to the polymer backbone, the polymer contains, or is derivatized with, a suitable nucleophilic residue capable of reacting with nitric oxide to form the N202- functionality. Reaction of the polymer which contains a suitable nucleophilic residue, or of the suitably derivatized polymer, with nitric oxide thus provides a polymer-bound nitric oxide-releasing NZQ2 functional group. To form the polymer-bound nitric oxide releasing N202- functional group, it is generally preferred'to impart a net positive charge to the polymer near the site on the polymer where the N202 functional group is formed.
The polymer-bound nitric oxide/nucleophile compositions of the present invention have a wide range of biological utility. In view of the growing,awareness that nitric oxide is an especially versatile and important bioeffective species, having been implicated mechanistically in such critical bodily funotions as vasorelaxation, neurotransmission and the immunological response (Moncada et al., Pharmacol. Rev. 43, 109-142, 1991), the compositions of the present invention find utility in applications where nitric oxide release is needed. For example, the polymer-bound nitric oxide releasing N202 functional groups may be implanted into neoplastic tissue to arrest tumor growth.
Hy way of illustration, the N202' functional group may be incorporated into a peptide suoh as arg-qly-a.sp, to prepare the molecule arg-glv-asp-NHCH2CH2N[N(C?)NO]-17 2~~6105 Cf32C'12Nd33+). Other receptor/ligand recognition sequences may be used analogously.
The following are further illustrative of, and not in any way in limitation of, the broad uses and applications of the polymer-bound compositions of this invention. Thus, for example, in view of dramatic but short-lived pulmonary vaso- and bronchodilatory properties exhibited by nitric oxide (Roberts et al., Circulation (Suppl. II) 84:AI279, 1991), administration of po].ymer-bound nitric oxide/nucleophile adduct compositions into the lungs in aerosolized form may be used in treating a variety of pu].monary disorders.
Since natural, endogenous nitric oxide has been identified as an effector of penile erection (Blakeslee, New York Times, Jan. 9, 1992, page Al), the polymer-bound nitric oxide/nucleophile adduct compositions of the present invention may be incorporated into suitable penile implants, preparations for transurethral injection, dermal patches or condoms for treatment of impotence in men. The ability of certain monomeric nitric oxide/nucleophile adducts to inhibit platelet aggregation coupled with their demonstrated cytostatic activity allows for an invaluable two-pronged approach to prevention of restenosis following angioplasty;
stents fabricated with polymer-bound nitric oxide-releasing N202 func,tional group compositions may be used both to inhibit cell division in areas with damaged endothelium and to prevent adhesion of platelets at these locations as well, minimizing the risk of recurring blockage. With an inverse relationship between generation of nitric oxide by tumor cells and their metastatic potential having been proposed (Radoanski et al., Cancer Res. 51, 6073-6078, 1991), polymer-bound nitric oxide/nucleophile compositions can be used to reduce the risk of metastasis in cancer patients. Similarly, it is contemplated that the polymer-bound nitric oxide/nucleophile adduot compositions of the present invent,ion can be used to coat prostheses and medical implants, such as breast implants, prior to surgical connection to the body as a means of reducing the risk of solid state carcinogenesis assoaiated therewith. 'With nitrio oxide being additionally implicated in gastric motility, neurotransmissicn, noci.Geption, and other natural roles, the compositions of this invention can be used for those applications as well.
One skilled in the art will appreciate that suitable methods of administering the polymer-bound nitric oxide-releasing N202 functional group compositions of the present invention to an animal are available, and, although more than one route can be used to administer a particular composition, a particular route can provide a more immediate and more effective reaction than another route. Pharmaceutically acceptable carriers are also well-known to those who are skilled in the art. The choice of oarra.er will be determined in part by the particular composition, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention.
2.~'i Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of.the polymer-bound composition dissolved in diluents, such as water or saline, (b) capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as solids or graxsulss, (c) suspensions in an appropriate liquid, and (d) suitable emulsions> Tablet forms can include one or more of lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers. Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastill.es comprising the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
The polymer-bound nitric oxide-releasing compositions of the present invention, alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation. These aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like.
Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which oan contain anti-oxidants, buffers, bacteriostats, and solutes that rsnder the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The formulations can be presented in unit-dose or anulti-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use. Extemporaneou3 injeption solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
The dose administered to an animal, particularly a human, in the context of the present invention should be suf f icient to ef f eot a therapeutic response in the animal over a reasonable time frame. The dose will be determined by the strength of the particular compositions employed and the condition of the animal, as well as the body weight of the animal to be treated.
The size of the dose also will be determined by the 5 existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular composition.
The following examples further illus-Grate the present invention, but do not limit the scope thereof.
10 In the Examples, chemiluminescence analysis for total recoverable nitric oxide from polymers containing the nitric oxide-releasing NZ 2 functional group by acid treatment was carried out as follows:
The analysis of NO adducts, i.e., polymers 15 containing the nitric oxide-releasing N2C2' functional group, was done on a nitric oxide analyzer and was patterned after the procedure of Maragos at al., J. Med.
Chem., 34, 3242-3247 (1991). A reactor vessel fitted with a septum was charged with a small aliquot of the 20 polymer to be studied and the system was purged with helium for several minutes to remove traces of oxygen.
Two milliliters of 10 mM sulfuric acid was added by injection through the septum to begin reaction. Gaseous effluent was swept continuously via a fritted glass bubbler positioned at the bottom of the reactor vessel (i.e., immersed in the acid solution) into a chemiluminescence detector (Thermal Energy Analyzer Model 502LC, Thermedics, Inc., Woburn, MA). The area of the resulting chemiluminescence signal versus time curve was electronically computed and compared with that of a known quantity of nitric oxide gas standard to determine the amount of nitric oxide produced by acid treatment of the polymer aliquot.
This procedure was used to estimate the total amount of ni-tric oxide recoverable from the polymer. To estimate the rate of nitric oxide generation under physiological conditions, the inventive polymers were 2:1.a6 10 5 subjected to a procedure identical to that described above except that-2 ml of 10 mM phosphate buffer, pH
7.4, was injected into the reactor vessel a.n place of the sulfuric acid solution to start the reaction.
EXANPLES
The preparation and characterization of polymers containing the nitric oxide-releasing N242 functional group are illustrated in the following examples:
Exampie I
This Example illustrates the preparation of a polymer-bound nitric oxa.de/nucleophile complex by coprecipitation of a monomeric form thereof with a polymer.
One gram of polymer [paly(lactide/glycolide, 50:50) from MediSorb] was dissolved in 2 ml of tetrakaydxoi;uran.
To the solution was added 300 mg of [HZN(CH2)Z]2N-N2C2H, zw9.tterionic form, and the mixture was stirred under an argon stream to remove solvent slowly until the mixture became too viscous to sta.r.. The mixture was then placp-d in a vacuum oven (ca 1 mm) at 30 C for 5 hours to remove the residual solvent. The mixture was finally pressed on a carver press at 20,000 lbs. at 140 F for 5 minutes.
A film of 1P1 x 1 ' with thickness of 44 mills was thus prepared. Using the chemilurninescence procedure described above, nitric oxide was recovered from this polymer on treatment with acid at the rate of 8 nmol of NO per milligram of solid.
Exanle IT
This Example illustrates the preparation of a polymer-bound nitric oxide/riucloophile adduct in which the N20i functional group is bound directly to an atom in the polymer backbone.
A slurry of 10.0 g of po7.yethylenimine on silica gel (Aldrich) in 150 ml of acetonitrile was stirred for 3 days under a nitric oxide pressure of 5 atm or 75-80 psxg. The resulting orange solid was filtered, washed with acetonitrile then ether, and dried in vacuo for 6 h. Using the otaemiluminasconce procedure described above, it was determined that nitric caxide was recovered from this polymer on trea,tment with acid at the rate of 3 nmol/mg.
Control experiments with polymer that had not been exposed to NO produced no chemiluminescence signal.
Examnle ITT
This Example illustrates the preparation of a polymer containing nitric oxide-releasing N202' groups that are attached to nuGleophile residues pendant the polymer backbone by the reaction of a primary amine with a derivatized polystyrene.
An aminostyrene polymer was prepared by warming 3.0 g of chl.oroiaethylated polystyrene (1% divinylbenzene, 1.09 mEq Cl per gram; 200-400 mesh; Polysciences, Inc., Warrington, PA) in 20 ml of n-propyl-l,3-propanediamine to 60 C in an oil bath and swirling periodically for 5 days. The polymer was then filtered, washed repeatedly with water then methan4l and finally dichlaromethane, and dried in vacuo for 24 h. Elemental analysis showed this material to be 2.21% nitrogen, indicating that approximately 801 of the ohiorines had been replaced by pxopyl.propanediamino groups.
A slurry of 1.0 g of the aminopolystyrene polymer in 50 ml of acetonitrile was placed under 5 atm of nitric oxide in a Parr apparatus and shaken iritermittently for 3 days. The product was filtered and dried in vacuo to yield 0.84 g of cream colored polymer.
The elemental analysis (c: 87.32; H: 8.00; N: 2.45) revealed that approximately one-third of the amino side chains became attached to N20Z' groups under these conditions.

Using the chema.luminescence procedure described above, it was demonstrated that nitric oxide can be recovered from Id202 group containing polymer prepared as described above. The observed cbemiluminescence detector response as a function of time and the amount of nitric oxide regenerated when the polymer was treated with acid are illustrated in Figure 1. As can be seen, only small amounts of nitric oxide were evolved from the solid itself, but when 2 ml of 10 mM sulfuric acid was injectecl via a septum, a sudden pulse of nitric oxide appeared. Integration of this apparently first order generation of nitric oxide over time indicated that 11 nmol of nitric oxide was recovered from 1 mg of polymer.
The reaction was repeated using 10 mM phosphate buffer at pH 7.4 in place of the sulfuric acid to verify the slow release of nitric oxide at physiological pH.
The chomiluminescence detector showed that nitric oxide was generated from this polymer much more slowly.

ExamDle IV
This Example illustrates the preparation of a polyethylene glycol-based NO-releasing polymer using two different methods of preparation.
In one method, 20 mg of 1,1-diethyl-2-hydroxy-2-nitrosohydrazine sodium salt (DEA/NO) and 2.5 g of polyethylanaglycol-1450 (Union carbide) were dissolved in 25 ml of inethanol. The homogenous solution was placed on a rotary evaporator at 40 C and the solvent was removed under vacuum to give a uniform solid solut.ion. The sample was stored in a clear glass vial, under ordinary laboratory lighting, at ambient temperature and atmosphere. The stability of the formulation was followed over a period of seven days.
The measurements were carried out by monitoring the absorbance of the polymer at the 250 nm peak in the electronic spectrum. No changes in the absorbance were observed in this time period, In a second method, 2.5 g of polyethylene glycol-1450 was heated to 46 0 until completely melted. To the liquid polyethylene glycol was added 36 mg (0.232 mmol) of DEA/NO and the container was placed on a vortex mixer. A homogeneous solution was attained that gradually solidified upon cooling to ambient tempcrature. The stability of the solution was monitQred as described above. No change in the absorban0e for the 250 nm chromophore was observed at seven weeks of storage.

ExamDle V
This Example illustrates the preparation of a polymer composed of a polyamine/nitric oxide complex N-[4-[1 -(3-aminopropyl)-2-hy'droxy-2-nitrosohydrazino)butylJ-1,3-propanediamine, zwitterionio form (SPER/NO) and polyethylene glycol.
A 1.2% (w/w) solution of KOH in polyethylene glycol-1450 (Union Carbide) was prepared in aqtie.ous medium, and evaporated to dryness under vacuum (PEO-KOH). To 1.144 g of moltera PEG-KOH was added 11.65 mg (0.042 mmol) of SpER/NO and the resulting mixture was blended to a uniform mass. No decrease was observed in the absorbance after five weeks of storage at room temperature in a clear glass vial.
PHA,RMACOLOGY EXPERIP4ENT
In the test procedures utilized, thoraciG aortic rings from New Zealand White rabbits were suspended in pH 7.4 buffer at 37 0 and a 10 g preload was applied to each. After equilibration for 2 hours, the rings were preconstricted with norepinephrine. The percent rel.axation'caused by adding the polymer-bound compositions of the present invention to the organ baths at successively increasing concentrations was measured.
See Maragos et aJ.., L. Med. Chem., 3A, 3243-3247 (1991).

A polymer film as described in Example I was cooled on dry ice and a small piece was sliced off. This was placed onto a piece of weighed filter paper, which was reweighed to determine the amoiant of material present.
The paper was folded to entrap the polymer inside, grasped with a hemostat, and immersed into the 50-m1 buffer bath containing the prooonstrio.ted aortio ring.
As illustrated in Fig. 2, a piece of polymer weighing approximately 0.4 mg induced 30% relaxation in the ring, while 2.1 mg induced 80% relaxation. The data demonstrate that there was a positive response by the organ to the polymer-bound composition of this invention and that the response tended to increase as the dose administered was increased. Thus, the polymer-bound nucleophile/nitric oxide composition has a potent, dose-responsive cardiovascular effect.
The above experiment was repeated with the granular polymer produced in Example II. A similar effect was observed, though it was less potent because this polymer contained fewer 1Vo-releasing N202 groups per gram than the polymer of Example I.
Fig. 3 illustrates the time course of vascular relaxation when different doses of the polymer-bound nitric oxide-releasing composition of Example II are first exposed to the aortic ring, causa.ng.relaxati.on, then withdrawn from the organ bath, allowing xeconst,ription to occur, then reintroduced into the organ bath, causing the vessel to dilate again. in this experiment, a 16-mg sample of the polymer-bound nitric oxide-releasing composition of Example II was i.mmersed into the buffer bath. After 15-1 relaxation had been achieved, the sample was removed from the bath. Upon remova], of the polymer-bound composition, the degree of relaxation fell to approximately 11% over about 5 min.
The sa.mpl.e of the polymer-bound composition was then returned to the bath, and a doubling of the degree of relaxation to about 25%- was mbserved.

This experiment illustrates that the pharmacological effects of the polymer-bound nitric oxide/nucleophile composition of the present invention can be modu].ated as desirecl by controlling the extent and duration of contact between the polymer and the cells or tissue.s of int.crest. This feature is particularly advantageous, for example, to localize the effects of nitric oxide release to a specific target organ or situs.

Claims (45)

CLAIMS:
1. A polymeric composition capable of releasing nitric oxide, said composition comprising a polymer and a nitric oxide/nucleophile adduct of the formula X[N(O)NO]- bound to said polymer, wherein said nitric oxide/nucleophile adduct has a formula selected from the group consisting of wherein J is an organic or inorganic moiety, M+x is a pharmaceutically acceptable cation, where x is the valence of the cation, a is 1 or 2, and b and c are the smallest integers that result in a neutral compound;

wherein b and d are the same or different and are zero or one, R1, R2, R3, R4, and R5 are the same or different and are hydrogen, C3-8 cycloalkyl, C1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, or 2,2,2-trichloro-t-butoxycarbonyl, and x, y, and z are the same or different and are integers from 2 to 12;

wherein B is R6 and R7 are the same or different and are hydrogen, C3-8 cycloalkyl, C1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, or 2,2,2-trichloro-t-butoxycarbonyl, f is an integer from 0 to 12, with the proviso that when B is the substituted piperazine moiety then f is an integer from 2 to 12;

wherein R8 is hydrogen, C3-8 cycloalkyl, C1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, or 2,2,2-tri-chloro-t-butoxycarbonyl, R9 is hydrogen or a C1-12 straight or branched chain alkyl, and g is 2 to 6;

wherein R1 and R2 are independently selected from the group consisting of a straight chain or branched chain C1-12 alkyl group and a benzyl group, with the proviso that no branch occur on the alpha carbon atom, or else R1 and R2 together with the nitrogen atom they are bonded to form a heterocyclic group, M+x is a pharmaceutically acceptable cation, and x is the valence of the cation;

wherein M is a pharmaceutically acceptable metal, or where x is at least two, a mixture of two different pharmaceutically acceptable metals, L is a ligand different from (R1R2N-N2O2) and is bound to at least one metal, R1 and R2 are each organic moieties and may be the same or different (with the proviso that where M is copper, x is one, L is methanol, and y is one, that at least one of R1 or R2 is not ethyl), x is an integer of from 1 to 10, x' is the formal oxidation state of the metal M, and is an integer of from 1 to 6, y is an integer of from I to 18, and where y is at least 2, the ligands L may be the same or different, z is an integer of from 1 to 20, and K
is a pharmaceutically acceptable counterion to render the compound neutral to the extent necessary;

wherein R is C2-8 lower alkyl, phenyl, benzyl, or C3-8 cycloalkyl, any of which R groups may be substituted by one to three substituents, which are the same or different, selected from the group consisting of halo, hydroxy, C1-8 alkoxy, -NH2, -C(O)NH2, -CH(O), -C(O)OH, and -NO2, X is a pharmaceutically acceptable cation, a pharmaceutically acceptable metal center, or a pharmaceutically acceptable organic group selected from the group consisting of C1-8 lower alkyl, -C(O)CH3, and -C(O)NH2, and y is one to three, consistent with the valence of X; and wherein R1 and R2 are independently chosen from C1-12 straight chain alkyl, C1-12 alkoxy or acyloxy substituted straight chain alkyl, C2-12 hydroxy or halo substituted straight chain alkyl, C3-12 branched chain alkyl, C3-12 hydroxy, halo, alkoxy, or acyloxy substituted branched chain alkyl, C3-12 straight chain olefinic and C3-12 branched chain olefinic which are unsubstituted or substituted with hydroxy, alkoxy, acyloxy, halo or benzyl, or R1 and R2 together with the nitrogen atom to which they are bonded form a heterocyclic group, and R3 is a group selected from C1-12 straight chain and C3-12 branched chain alkyl which are unsubstituted or substituted by hydroxy, halo, acyloxy or alkoxy, C2-12 straight chain or C3-12 branched chain olefinic which are unsubstituted or substituted by halo, alkoxy, acyloxy or hydroxy, C1-12 unsubstituted or substituted acyl, sulfonyl and carboxamido; or R3 is a group of the formula -(CH2)n-ON=N(O)NR1R2, wherein n is an integer of 2-8, and R1 and R2 are as defined above; with the proviso that R1, R2 and R3 do not contain a halo or a hydroxy substituent a to a heteroatom.
2. The polymeric composition of claim 1 wherein said nitric oxide/nucleophile adduct is of the formula:

wherein J is an organic or inorganic moiety, M+x is a pharmaceutically acceptable cation, where x is the valence of the cation, a is 1 or 2, and b and c are the smallest integers that result in a neutral compound.
3. The polymeric composition of claim 1 wherein said nitric oxide/nucleophile adduct is of the formula:

wherein b and d are the same or different and are zero or one, R1, R2, R3, R4, and R5 are the same or different and are hydrogen, C3-8 cycloalkyl, C1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, or 2,2,2-trichloro-t-butoxycarbonyl, and x, y, and z are the same or different and are integers from 2 to 12.
4. The polymeric composition of claim 1 wherein said nitric oxide/nucleophile adduct is of the formula:

wherein B is R6 and R7 are the same or different and are hydrogen, C3-8 cycloalkyl, C1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, or 2,2,2-trichloro-t-butoxycarbonyl, f is an integer from 0 to 12, with the proviso that when B is the substituted piperazine moiety then f is an integer from 2 to 12.
5. The polymeric composition of claim 1 wherein said nitric oxide/nucleophile adduct is of the formula:

wherein R8 is hydrogen, C3-8 cycloalkyl, C1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, or 2,2,2-tri-chloro-t-butoxycarbonyl, R9 is hydrogen or a C1-12 straight or branched chain alkyl, and g is 2 to 6.
6. The polymeric composition of claim 1 wherein said nitric oxide/nucleophile adduct is of the formula:

wherein R1 and R2 are independently selected from the group consisting of a straight chain or branched chain C1-12 alkyl group and a benzyl group, with the proviso that no branch occur on the alpha carbon atom, or else R1 and R2 together with the nitrogen atom they are bonded to form a heterocyclic group, M+x is a pharmaceutically acceptable cation, and x is the valence of the cation.
7. The polymeric composition of claim 1 wherein said nitric oxide/nucleophile adduct is of the formula:

wherein M is a pharmaceutically acceptable metal, or where x is at least two, a mixture of two different pharmaceutically acceptable metals, L is a ligand different from (R1R2N-N2O2) and is bound to at least one metal, R1 and R2 are each organic moieties and may be the same or different (with the proviso that where M is copper, x is one, L is methanol, and y is one, that at least one of R1 or R2 is not ethyl), x is an integer of from 1 to 10, x' is the formal oxidation state of the metal M, and is an integer of from 1 to 6, y is an integer of from I to 18, and where y is at least 2, the ligands L may be the same or different, z is an integer of from 1 to 20, and K
is a pharmaceutically acceptable counterion to render the compound neutral to the extent necessary.
8. The polymeric composition of claim 1 wherein said nitric oxide/nucleophile adduct is of the formula:

wherein R is C2-8 lower alkyl, phenyl, benzyl, or C3-8 cycloalkyl, any of which R groups may be substituted by one to three substituents, which are the same or different, selected from the group consisting of halo, hydroxy, C1-8 alkoxy, -NH2, -C(O)NH2, -CH(O), -C(O)OH, and -NO2, X is a pharmaceutically acceptable cation, a pharmaceutically acceptable metal center, or a pharmaceutically acceptable organic group selected from the group consisting of C1-8 lower alkyl, -C(O)CH3, and -C(O)NH2, and y is one to three, consistent with the valence of X.
9. The polymeric composition of claim 1 wherein said nitric oxide/nucleophile adduct is of the formula:

wherein R1 and R2 are independently chosen from C1-12 straight chain alkyl, C1-12 alkoxy or acyloxy substituted straight chain alkyl, C2-12 hydroxy or halo substituted straight chain alkyl, C3-12 branched chain alkyl, C3-12 hydroxy, halo, alkoxy, or acyloxy substituted branched chain alkyl, C3-12 straight chain olefinic and C3-12 branched chain olefinic which are unsubstituted or substituted with hydroxy, alkoxy, acyloxy, halo or benzyl, or R1 and R2 together with the nitrogen atom to which they are bonded form a heterocyclic group, and R3 is a group selected from C1.12 straight chain and C3-12 branched chain alkyl which are unsubstituted or substituted by hydroxy, halo, acyloxy or alkoxy, C2-12 straight chain or C3-12 branched chain olefinic which are unsubstituted or substituted by halo, alkoxy, acyloxy or hydroxy, C1-12 unsubstituted or substituted acyl, sulfonyl and carboxamido; or R3 is a group of the formula -(CH2)n-ON N(O)NR1R2, wherein n is an integer of 2-8, and R1 and R2 are as defined above; with the proviso that R1, R2 and R3 do not contain a halo or a hydroxy substituent a to a heteroatom.
10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the composition of claim 1.
11. The pharmaceutical composition of claim 10 wherein said nitric oxide/nucleophile adduct is of the formula:

wherein J is an organic or inorganic moiety, M+x is a pharmaceutically acceptable cation, where x is the valence of the cation, a is 1 or 2, and b and c are the smallest integers that result in a neutral compound.
12. The pharmaceutical composition of claim 10 wherein said nitric oxide/nucleophile adduct is of the formula:

wherein b and d are the same or different and are zero or one, R1, R2, R3, R4, and R5 are the same or different and are hydrogen, C3-8 cycloalkyl, C1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, or 2,2,2-trichloro-t-butoxycarbonyl, and x, y, and z are the same or different and are integers from 2 to 12.
13. The pharmaceutical composition of claim 10 wherein said nitric oxide/nucleophile adduct is of the formula:

wherein B is R6 and R7 are the same or different and are hydrogen, C3-8 cycloalkyl, C1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, or 2,2,2-trichloro-t-butoxycarbonyl, f is an integer from 0 to 12, with the proviso that when B is the substituted piperazine moiety then f is an integer from 2 to 12.
14. The pharmaceutical composition of claim 10 wherein said nitric oxide/nucleophile adduct is of the formula:

wherein R8 is hydrogen, C3-8 cycloalkyl, C1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, or 2,2,2-tri-chloro-t-butoxycarbonyl, R9 is hydrogen or a C1-12 straight or branched chain alkyl, and g is 2 to 6.
15. The pharmaceutical composition of claim 10 wherein said nitric oxide/nucleophile adduct is of the formula:

wherein R1 and R2 are independently selected from the group consisting of a straight chain or branched chain C1-12 alkyl group and a benzyl group, with the proviso that no branch occur on the alpha carbon atom, or else R1 and R2 together with the nitrogen atom they are bonded to form a heterocyclic group, M+x is a pharmaceutically acceptable cation, and x is the valence of the cation.
16. The pharmaceutical composition of claim 10 wherein said nitric oxide/nucleophile adduct is of the formula:

K[(M)x x(L)y(R1R2N-N2O2)z] (VI) wherein M is a pharmaceutically acceptable metal, or where x is at least two, a mixture of two different pharmaceutically acceptable metals, L is a ligand different from (R1R2N-N2O2) and is bound to at least one metal, R1 and R2 are each organic moieties and may be the same or different (with the proviso that where M is copper, x is one, L is methanol, and y is one, that at least one of R1 or R2 is not ethyl), x is an integer of from 1 to 10, x' is the formal oxidation state of the metal M, and is an integer of from 1 to 6, y is an integer of from 1 to 18, and where y is at least 2, the ligands L may be the same or different, z is an integer of from 1 to 20, and K
is a pharmaceutically acceptable counterion to render the compound neutral to the extent necessary.
17. The pharmaceutical composition of claim 10 wherein said nitric oxide/nucleophile adduct is of the formula:

[R-N(H)N(NO)O-]y X (VII) wherein R is C2-8 lower alkyl, phenyl, benzyl, or C3-8 cycloalkyl, any of which R groups may be substituted by one to three substituents, which are the same or different, selected from the group consisting of halo, hydroxy, C1-8 alkoxy, -NH2, -C(O)NH2, -CH(O), -C(O)OH, and -NO2, X is a pharmaceutically acceptable cation, a pharmaceutically acceptable metal center, or a pharmaceutically acceptable organic group selected from the group consisting of C1-8 lower alkyl, -C(O)CH3, and -C(O)NH2, and y is one to three, consistent with the valence of X.
18. The pharmaceutical composition of claim 10 wherein said nitric oxide/nucleophile adduct is of the formula:

wherein R1 and R2 are independently chosen from C1-12 straight chain alkyl, C1-12 alkoxy or acyloxy substituted straight chain alkyl, C2-12 hydroxy or halo substituted straight chain alkyl, C3-12 branched chain alkyl, C3-12 hydroxy, halo, alkoxy, or acyloxy substituted branched chain alkyl, C3-12 straight chain olefinic and C3-12 branched chain olefinic which are unsubstituted or substituted with hydroxy, alkoxy, acyloxy, halo or benzyl, or R1 and R2 together with the nitrogen atom to which they are bonded form a heterocyclic group, and R3 is a group selected from C1-12 straight chain and C3-12 branched chain alkyl which are unsubstituted or substituted by hydroxy, halo, acyloxy or alkoxy, C2-12 straight chain or C3-12 branched chain olefinic which are unsubstituted or substituted by halo, alkoxy, acyloxy or hydroxy, C1-12 unsubstituted or substituted acyl, sulfonyl and carboxamido; or R3 is a group of the formula -(CH2)n-ON=N(O)NR1R2, wherein n is an integer of 2-8, and R1 and R2 are as defined above; with the proviso that R1, R2 and R3 do not contain a halo or a hydroxy substituent .alpha. to a heteroatom.
19. Use of the composition of claim 1 for the preparation of a medicament for the treatment of a biological disorder in which dosage with nitric oxide is beneficial, wherein the biological disorder is selected from the group consisting of a pulmonary disorder, erectile dysfunction, platelet aggregation, restenosis, and metastasis.
20. The use of claim 19 wherein said nitric oxide/nucleophile adduct is of the formula:

wherein J is an organic or inorganic moiety, M+x is a pharmaceutically acceptable cation, where x is the valence of the cation, a is 1 or 2, and b and c are the smallest integers that result in a neutral compound.
21. The use of claim 19 wherein said nitric oxide/nucleophile adduct is of the formula wherein b and d are the same or different and are zero or one, R1, R2, R3, R4, and R5 are the same or different and are hydrogen, C3-8 cycloalkyl, C1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, or 2,2,2-trichloro-t-butoxycarbonyl, and x, y, and z are the same or different and are integers from 2 to 12.
22. The use of claim 19 wherein said nitric oxide/nucleophile adduct is of the formula:

wherein B is R6 and R7 are the same or different and are hydrogen, C3-8 cycloalkyl, C1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, or 2,2,2-trichloro-t-butoxycarbonyl, f is an integer from 0 to 12, with the proviso that when B is the substituted piperazine moiety then f is an integer from 2 to 12.
23. The use of claim 19 wherein said nitric oxide/nucleophile adduct is of the formula:

wherein R8 is hydrogen, C3-8 cycloalkyl, C1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, or 2,2,2-tri-chloro-t-butoxycarbonyl, R9 is hydrogen or a C1-12 straight or branched chain alkyl, and g is 2 to 6.
24. The use of claim 19 wherein said nitric oxide/nucleophile adduct is of the formula:

wherein R1 and R2 are independently selected from the group consisting of a straight chain or branched chain C1-12 alkyl group and a benzyl group, with the proviso that no branch occur on the alpha carbon atom, or else R1 and R2 together with the nitrogen atom they are bonded to form a heterocyclic group, M+x is a pharmaceutically acceptable cation, and x is the valence of the cation.
25. The use of claim 19 wherein said nitric oxide/nucleophile adduct is of the formula:
K[(M)x x(L)y(R1R2N-N2O2)z] (VI) wherein M is a pharmaceutically acceptable metal, or where x is at least two, a mixture of two different pharmaceutically acceptable metals, L is a ligand different from (R1R2N-N2O2) and is bound to at least one metal, R1 and R2 are each organic moieties and may be the same or different (with the proviso that where M is copper, x is one, L is methanol, and y is one, that at least one of R1 or R2 is not ethyl), x is an integer of from 1 to 10, x' is the formal oxidation state of the metal M, and is an integer of from 1 to 6, y is an integer of from 1 to 18, and where y is at least 2, the ligands L may be the same or different, z is an integer of from 1 to 20, and K
is a pharmaceutically acceptable counterion to render the compound neutral to the extent necessary.
26. The use of claim 19 wherein said nitric oxide/nucleophile adduct is of the formula:
[R-N(H)N(NO)O-]y X (VII) wherein R is C2-8 lower alkyl, phenyl, benzyl, or C3-8 cycloalkyl, any of which R groups may be substituted by one to three substituents, which are the same or different, selected from the group consisting of halo, hydroxy, C1-8 alkoxy, -NH2, -C(O)NH2, -CH(O), -C(O)OH, and -NO2, X is a pharmaceutically acceptable cation, a pharmaceutically acceptable metal center, or a pharmaceutically acceptable organic group selected from the group consisting of C1-8 lower alkyl, -C(O)CH3, and -C(O)NH2, and y is one to three, consistent with the valence of X.
27. The use of claim 19 wherein said nitric oxide/nucleophile adduct is of the formula:

wherein R1 and R2 are independently chosen from C1-12 straight chain alkyl, C1-12 alkoxy or acyloxy substituted straight chain alkyl, C2-12 hydroxy or halo substituted straight chain alkyl, C3-12 branched chain alkyl, C3-12 hydroxy, halo, alkoxy, or acyloxy substituted branched chain alkyl, C3-12 straight chain olefinic and C3-12 branched chain olefinic which are unsubstituted or substituted with hydroxy, alkoxy, acyloxy, halo or benzyl, or R1 and R2 together with the nitrogen atom to which they are bonded form a heterocyclic group, and R3 is a group selected from C1-12 straight chain and C3-12 branched chain alkyl which are unsubstituted or substituted by hydroxy, halo, acyloxy or alkoxy, C2-12 straight chain or C3-12 branched chain olefinic which are unsubstituted or substituted by halo, alkoxy, acyloxy or hydroxy, C1-12 unsubstituted or substituted acyl, sulfonyl and carboxamido; or R3 is a group of the formula -(CH2)n-ON=N(O)NR1R2, wherein n is an integer of 2-8, and R1 and R2 are as defined above; with the proviso that R1, R2 and R3 do not contain a halo or a hydroxy substituent .alpha. to a heteroatom.
28. The polymeric composition of claim 1 wherein said polymer is a peptide.
29. The polymeric composition of claim 1 wherein said polymer is polyethylene glycol.
30. The polymeric composition of claim 1 wherein said polymer is a polystyrene derivative.
31. The polymeric composition of claim 28 wherein said peptide is arg-gly-asp tripeptide.
32. The polymeric composition of claim 1, wherein the moiety X is part of the polymer backbone.
33. The polymeric composition of claim 1, wherein the moiety X is part of a group pendant to the polymer backbone.
34. The polymeric composition of claim 2, wherein J is an organic or inorganic moiety, which is not linked to the nitrogen of the remainder of the complex through a carbon atom.
35. The composition of claim 11, wherein J is an organic or inorganic moiety, which is not linked to the nitrogen of the remainder of the complex through a carbon atom.
36. The use of claim 20, wherein J is an organic or inorganic moiety, which is not linked to the nitrogen of the remainder of the complex through a carbon atom.
37. The polymeric composition of claim 2, wherein the compound is not a salt of alanosine or dopastin.
38. The composition of claim 11, wherein the compound is not a salt of alanosine or dopastin.
39. The use of claim 20, wherein the compound is not a salt of alanosine or dopastin.
40. The polymeric composition of claim 6, wherein R1 and R2 together with the nitrogen atom they are bonded to form a pyrrolidino, piperidino, piperazino or morpholino group.
41. The composition of claim 15, wherein R1 and R2 together with the nitrogen atom they are bonded to form a pyrrolidino, piperidino, piperazino or morpholino group.
42. The use of claim 24, wherein R1 and R2 together with the nitrogen atom they are bonded to form a pyrrolidino, piperidino, piperazino or morpholino group.
43. The polymeric composition of claim 9, wherein R1 and R2 together with the nitrogen atom they are bonded to form a pyrrolidino, piperidino, piperazino or morpholino group.
44. The composition of claim 18, wherein R1 and R2 together with the nitrogen atom they are bonded to form a pyrrolidino, piperidino, piperazino or morpholino group.
45. The use of claim 27, wherein R1 and R2 together with the nitrogen atom they are bonded to form a pyrrolidino, piperidino, piperazino or morpholino group.
CA002106105A 1993-09-14 1993-09-14 Polymer-bound nitric oxide/nucleophile adduct compositions, pharmaceutical compositions incorporating same and methods of treating biological disorders using same Expired - Fee Related CA2106105C (en)

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US5691423A (en) * 1992-08-24 1997-11-25 The United States Of America As Represented By The Department Of Health And Human Services Polysaccharide-bound nitric oxide-nucleophile adducts
US5910316A (en) * 1992-08-24 1999-06-08 The United States Of America, As Represented By The Department Of Health And Human Services Use of nitric oxide-releasing agents to treat impotency
US6255277B1 (en) 1993-09-17 2001-07-03 Brigham And Women's Hospital Localized use of nitric oxide-adducts to prevent internal tissue damage
US6087479A (en) 1993-09-17 2000-07-11 Nitromed, Inc. Localized use of nitric oxide-adducts to prevent internal tissue damage
AU698748B2 (en) * 1993-09-17 1998-11-05 Brigham And Women's Hospital Use of nitric oxide-adducts to prevent thrombosis on artificial and vascular surfaces
US5700830A (en) * 1994-11-22 1997-12-23 The United States Of America As Represented By The Department Of Health And Human Services Use of nitric oxide-releasing agents for reducing metastasis risk
GB9423868D0 (en) * 1994-11-25 1995-01-11 Wellcome Found Compounds for use in medicine
US5770645A (en) * 1996-08-02 1998-06-23 Duke University Medical Center Polymers for delivering nitric oxide in vivo
EP1690532A1 (en) * 2005-02-11 2006-08-16 NOLabs AB Device for gastric treatment and manufacturing process for the same
WO2006084914A2 (en) * 2005-02-11 2006-08-17 Nolabs Ab Device for gastric treatment and manufacturing process for the same
RU2714313C2 (en) * 2014-08-14 2020-02-14 Ром Энд Хаас Компани Polymer with released gas

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