WO1996032136A1 - Polysaccharide-bound nitric oxide-nucleophile adducts - Google Patents
Polysaccharide-bound nitric oxide-nucleophile adducts Download PDFInfo
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- WO1996032136A1 WO1996032136A1 PCT/US1996/004899 US9604899W WO9632136A1 WO 1996032136 A1 WO1996032136 A1 WO 1996032136A1 US 9604899 W US9604899 W US 9604899W WO 9632136 A1 WO9632136 A1 WO 9632136A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
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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
- A61K47/61—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 the organic macromolecular compound being a polysaccharide or a derivative thereof
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- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B15/00—Preparation of other cellulose derivatives or modified cellulose, e.g. complexes
- C08B15/05—Derivatives containing elements other than carbon, hydrogen, oxygen, halogens or sulfur
- C08B15/06—Derivatives containing elements other than carbon, hydrogen, oxygen, halogens or sulfur containing nitrogen, e.g. carbamates
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
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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
Definitions
- the present invention relates to compositions comprising a nitric oxide/nucleophile adduct capable of releasing nitric oxide.
- the present invention relates to compositions comprising nitric oxide/nucleophile adducts which are bound to a polysaccharide and which release nitric oxide in a physiological environment, pharmaceutical compositions comprising such nitric oxide/nucleophile adduct compositions, and methods of using same to treat a biological disorder for which the administration of nitric oxide is indicated.
- Nitric oxide has recently 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,” Excerpta Medica. International Congress Series 897 (Elsevier Science Publishers B.V. : Amsterdam, 1990); Marietta et al., “Unraveling the Biological Significance of Nitric Oxide," Biofactors. 2., 219-225 (1990); Ignarro, "Nitric Oxide. A Novel Signal Transduction Mechanism for Transcellular Communication," Hypertension (Dallas) . 16.
- nitric oxide nitric oxide upon being metabolized
- compounds which release nitric oxide*spontaneously in aqueous solution include the widely used nitrovasodilators glyceryl trinitrate and sodium nitroprusside (Ignarro et al., J. Pharmacol. EXP. Ther.. 218. 739-749 (1981); Ignarro, Annu. Rev. Pharmacol. Toxicol.. 30. 535-560 (1990); Kruszyna et al., Toxicol. APPI. Pharmacol..
- nitric oxide-nucleophile complexes Numerous nitric 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.
- Endothelium-derived relaxing factor is a labile humoral agent which is part of a cascade of interacting agents involved in the relaxation of vascular smooth muscle. EDRF 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 endothelial cells. (See Furchgott, Ann.Rev.Pharmacol.Toxicol. 24. / 175-197, 1984.) In 1987, Palmer et al., presented evidence that EDRF is identical to the simple molecule, nitric oxide, NO (Nature 317.
- Nitric oxide in its pure form is a highly reactive gas having limited solubility in aqueous media (WHO Task Group on Environmental Health Criteria for Oxides of Nitrogen, Oxides of Nitrogen. Environmental Health Criteria 4 (World Health Organization: Geneva, 1977)). Nitric oxide, therefore, is difficult to introduce reliably into most biological systems without premature decomposition.
- nitric oxide 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 redox activation (Ignarro et al., J. Pharmacol. Exp. Ther.. 218. 739-749 (1981); Ignarro, Annu. Rev. Pharmaco1. Toxicol.. 2£, 535-560
- nitric oxide- nucleophile complexes A very important class of such agents is the nitric oxide- nucleophile complexes. Recently, a method for treating cardiovascular disorders in a mammal with certain nitric oxide-nucleophile complexes has been disclosed, e.g. in U.S. 4,954,526. These compounds contain the anionic N 2 0 2 ⁇ group or derivatives thereof. See also, Maragos et al., J. Med. Chem. 34, 3242-3247, 1991.
- the NONOate function can be coordinated via the two oxygen atoms to metal centers; it can be attached to peptides; and it can be bound in solid polymeric matrices to provide a point source of NO.
- Nitric oxide/nucleophile complexes which release nitric oxide in aqueous solution are also disclosed in U.S. Patent 4,954,526, U.S. Patent 5,039,705, U.S. Patent 5,212,204, U.S. Patent 5,155,137, U.S. Patent 5,208,233, U.S. Patent 5,250,550, U.S. Patent 5,366,997, and U.S. Patent 5,389,675 (see also Maragos et al., J. Med. Chem.. 2A, 3242-3247 (1991)).
- 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.
- compositions which includes a nitric 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.
- a more specific object of the present invention is to provide polysaccharide compositions including nitric oxide/nucleophile adducts capable of releasing nitric oxide in the body and which are readily eliminated from the body after the release of NO.
- the present invention provides a composition capable of releasing nitric oxide which includes a nitric oxide- releasing N 2 0 2 ⁇ functional group bound to a polymer, specifically a polysaccharide.
- bound to a polymer it is meant that the N 2 0 2 " functional group is associated with, part of, incorporated with or contained within the polymer matrix physically or chemically. Physical association or bonding of the N 2 0 2 " 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 N 2 0 2 " group to the polymer.
- Chemical bonding of the N 2 0 2 " functional group to the polymer may be by, for example, covalent bonding of the nucleophile moiety of the nitric oxide/nucleophile adduct to the polymer such that the nucleophile residue to which the N 2 0 2 " 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 N 2 0 2 " functional group is associated, part of, or 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 composition which includes a pharmaceutically acceptable carrier and a polymer, specifically a polysaccharide, having a nitric oxide-releasing N 2 0 2 " functional group bound to said polymer.
- a pharmaceutically acceptable carrier specifically a polysaccharide, having a nitric oxide-releasing N 2 0 2 " functional group bound to said polymer.
- the polymer-bound nitric oxide- releasing N 2 0 2 " 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, specifically a polysaccharide, and a nitric oxide-releasing N 2 0 2 ⁇ functional group bound to said polymer in an amount sufficient to release a therapeutically effective amount of nitric oxide.
- the present invention is predicated on the discovery that useful pharmacological agents can be provided by incorporating nitric oxide-releasing N 2 0 2 " functional groups into a polymeric matrix, specifically a polysaccharide. Accordingly, the N 2 0 2 ⁇ functional group is "bound to the polymer" as that term has been defined herein. It has been discovered that incorporation of the N 2 0 2 " functional group into a polymeric matrix provides a polymer-bound nitric oxide/nucleophile adduct composition that can be applied with specificity to a biological site of interest.
- N 2 0 2 " functional groups attached to the polymer are necessarily localized, then the effect of their nitric oxide release will be concentrated in the tissues with which they are in contact. If the polymer is soluble, selectivity of action can still be arranged, for example, by attachment to or derivatization of an antibody specific to the target tissue.
- N 2 0 2 " containing polysaccharides 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.
- incorporation of the N 2 0 2 ⁇ functional group into a polymeric 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 N 2 0 2 " 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/nucleophile adduct compositions of the present invention is to be attributed both to the physical structure of the composition and to electrostatic effects.
- N 2 0 2 " 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.
- increasing positive charge in the vicinity of an N 0 2 " functional group also tends to increase 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 + -repelling positive charges in the vicinity of the N 2 0 2 " groups inhibits attack of positively charged H + ions on the N 0 2 " functional group and slows the rate of its H + - catalyzed decomposition.
- 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 N 2 0 2 " group that electrostatically inhibit the approach of H + ions capable of initiating nitric oxide loss from the nitric oxide releasing N 2 0 2 ⁇ functional group.
- nitric oxide-releasing N 2 0 2 " 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-fN(0)NO] ⁇ group in the vicinity of the particular cells of interest.
- covalent attachment of a protecting group to the anionic [N(0)N0] ⁇ function provides a means of postponing nitric oxide release until the molecule reaches an organ capable of metabolically removing the protecting group.
- a protecting group that is selectively cleaved by enzymes specific to a tumor, biological disorder, cell, or tissue of interest, for example, the action of the nitric oxide/nucleophile complex can be targeted to maximize the desired effect.
- the polymer-bound, i.e., polysaccharide-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 N 2 0 2 " 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 moiety [N(0)NO ⁇ -X or X-fN(0)N0], where X is any suitable nucleophile residue and may be an organic or inorganic moiety.
- sulfite e.g., S0 3 "
- Other suitable nitric oxide/nucleophile complexes include those having the following formulas:
- J is an organic or inorganic moiety, preferably a moiety which is not linked to the nitrogen of the N 2 0 2 " group through a carbon atom
- 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, preferably such that the compound is not a salt of alanosine or dopastin, as described in U.S. Patent 5,212,204 and incorporated herein by reference;
- R x , R 2 , R 3 , R 4 , and R 5 are the same or different and may be hydrogen, C 3 _ 8 cycloalkyl, C j . ⁇ 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 and incorporated by reference;
- R 6 and R 7 are the same or different and may be hydrogen, c 3 - 8 cycloalkyl, C 1 _ 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
- f is an integer from 2 to 12, as described in U.S. Patent 5,250,550 and incorporated by reference;
- R 8 is hydrogen, C 3 _ 8 cycloalkyl, C 1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, or 2,2,2-tri- chloro-t-butoxycarbonyl
- R 9 is hydrogen or a C-_-c 12 straight or branched chain alkyl, and g is 2 to 6, as described in U.S. Patent 5,250,550 and incorporated by reference;
- R 1 and R are independently selected from the group consisting of a straight chain or branched chain C x - C 12 alkyl group and a benzyl group, with the proviso that no branch occur on the alpha carbon atom, or else R 1 and R 2 together with the nitrogen atom 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 and incorporated by reference;
- 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 (R 1 R 2 N-N 2 0 2 ) and is bound to at least one metal, R 1 and R 2 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 R 1 or R 2 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 5,389,675 and incorporated by reference; and
- R is C 2 _ 8 lower alkyl, phenyl, benzyl, or C 3 _ 8 cycoloalkyl, 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, C 1 _ 8 alkoxy, -NH 2 , -C(0)NH 2 , -CH(O), -C( ⁇ )OH, and -N0 2
- X is a pharmaceutically acceptable cation, a pharmaceutically acceptable metal center, or a pharmaceutically acceptable organic group selected from the group consisting of C 1-8 lower alkyl, -C(0)CH 3 , and -C(0)NH 2
- y is one to three, consistent with the valence of X, as described in U.S. Patent No. 4,954,526 and incorporated by reference;
- R ⁇ and R 2 are independently chosen from C- ⁇ 2 straight chain alkyl, C ⁇ alkoxy or acyloxy substituted straight chain alkyl, C 2 _ 12 hydroxy or halo substituted straight chain alkyl, C 3 _ 12 branched chain alkyl, C 3 _ 1 hydroxy, halo, alkoxy, or acyloxy substituted branched chain alkyl, C 3 _ 12 straight chain olefinic and C 3 _ 12 branched chain olefinic which are unsubstituted or substituted with hydroxy, alkoxy, acyloxy, halo or benzyl, or R j and R 2 together with the nitrogen atom to which they are bonded form a heterocyclic group, preferably a pyrrolidino, piperidino, piperazino or orpholino group, and R 3 is a group selected from C 1 _ 12 straight chain and C 3 _ 12 branched chain alkyl which are unsubstituted or
- the polymer is a polyether.
- the polyether is a polysaccharide.
- Polysaccharides include cellulose, starch, dextran, and xylans.
- the polysaccharides may be modified or derivatized.
- suitable modified polysaccharides include hydroxyethylcellulose, carboxymethyl cellulose, hydroxyethyl starch, dextran ethers, dextran esters, dextran carbamates and the like.
- the physical and structural characteristics of the polymers suitable for use in the present invention are not narrowly critical, but rather will depend on the end use application.
- the polymer-bound nitric oxide/nucleophile adduct compositions of the present 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 polymer-bound compositions slowly dissolves in a physiological environment or that it is biodegradable.
- the polymer-bound nitric oxide releasing compositions of the present invention will find utility in a wide variety of applications and in a wide variety of forms depending on the biological disorder to be treated.
- the polymer may itself be structurally sufficient to serve as an implant, patch, stent or the like.
- the polymer-bound composition may be incorporated into other polymer matrices, substrates or the like, or it may be microencapsulated, or the like.
- nitric oxide-releasing complexes having N 2 0 2 " functional groups may be bound to the polymer support in a number of different ways.
- the compounds described above may be bound to the polymer by coprecipitation of such compounds with the polymer. Coprecipitation involves, for example, solubilizing both the polymer and the nitric oxide/nucleophile compound and evaporating the solvent.
- nitric oxide-releasing N 2 0 2 " functional groups may be bound to the polymer by formation of a nitric oxide/nucleophile complex of the types and having the formulas of those described above, in situ on the polymer.
- the N 0 2 ⁇ 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 matrix.
- the polymer includes in its backbone sites which are capable of reacting with nitric oxide to bind the nitric oxide for future release.
- the polymer is polyethylenimine
- the polymer includes nucleophilic nitrogen atoms which react with nitric oxide to form the N 2 0 2 ⁇ functional group at the nitrogen in the backbone.
- the polymer contains, or is derivatized with, a suitable nucleophilic residue capable of reacting with nitric oxide to form the N 2 o 2 " functionality. Reaction of the polymer which contains a suitable nucleophilic residue, or of the suitably derivatized polymers with nitric oxide thus provides a polymer-bound nitric oxide-releasing N 2 0 2 " functional group.
- the polymer-bound nitric oxide/nucleophile compositions of the present invention have a wide range of biological utility.
- nitric oxide is an especially versatile and important bioeffective species, having been implicated mechanistically in such critical bodily functions 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.
- the polymer-bound nitric oxide releasing N 2 0 2 " functional groups may be bound to the surface of a vascular graft to reduce its thrombogenicity.
- the polymer-bound nitric oxide/nucleophile adduct compositions of the present invention may be incorporated into suitable penile implants, dermal patches or condoms for treatment of impotence in men.
- stents fabricated with polymer-bound nitric oxide-releasing N 2 0 2 ⁇ functional 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.
- polymer-bound nitric oxide/nucleophile compositions may be used to reduce the risk of metastasis in cancer patients.
- polymer-bound nitric oxide/nucleophile adduct compositions of the present invention may 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 carcinogenisis associated therewith.
- the compositions of this invention may be used for those applications as well.
- compositions of the present invention suitable methods of administering the polymer-bound nitric oxide- releasing N 2 0 2 " 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 carrier 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.
- 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 granules, (c) suspensions in an appropriate liquid, and (d) suitable emulsions.
- liquid solutions such as an effective amount of the polymer-bound composition dissolved in diluents, such as water or saline
- diluents such as water or saline
- capsules, sachets or tablets each containing a predetermined amount of the active ingredient, as solids or granules
- 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 pastilles 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.
- a flavor usually sucrose and acacia or tragacanth
- pastilles 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 can be made into aerosol formulations to be administered via inhalation. These aerosol formulations can be placed into pressurized acceptable propeHants, such as dichlorodifluoromethane, propane, nitrogen, and the like.
- pressurized acceptable propeHants such as dichlorodifluoromethane, propane, nitrogen, and the like.
- Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render 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 multi-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.
- Extemporaneous injection 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 sufficient to effect 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 existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular composition.
- EXAMPLE I This example illustrates the preparation of a polysaccharide polymer containing pendant [N 2 0 2 ] groups by two different methods.
- Sodium hydroxide (8 ml, 10 M, 80 mmole) and cyanogen bromide (CNBr, 8 g, 75 mmole) , freshly dissolved in 100 ml water, were added to the dextran solution.
- Diethylenetriamine (DETA, 24.7 g, 222.9 mmole) or dipropylenetriamine (DPTA, 31.8 g, 222.9 mmole) was added quickly to the activated dextran solution. The pH was adjusted to 10.0 and the solution was continuously stirred overnight.
- the solution was extracted with two 150-ml volumes of methylene chloride and dialyzed overnight against cold running water. After adjusting the pH of the solution to 7.0, the solution was freeze-dried to yield a white solid, which was crushed to a powder (9.6 g for DETA-grafted dextran and 9.2 g for DPTA-grafted dextran) . The success of the grafting was ensured by a titration of the grafted dextran (DETA- dextran) against 1 N NaOH.
- the DPTA- or DETA-grafted dextran (3.6 g) was crosslinked by dissolution in 15.6 ml of water and 2 ml of 10 M NaOH, pouring the resulting solution into 300 ml of light mineral oil in a Waring blender, stirring for two minutes and adding CNBr (2 g, 18.87 mmole), freshly dissolved in water (16 ml), to the suspension, and stirring for an additional two minutes followed by extraction of the suspension with petroleum ether (300 ml, 3X) , ethanol (95%, 500 ml, 2X) and absolute ethanol (500 ml) .
- the resulting DETA-grafted icrospheres (1 g) were suspended in dry tetrahydrofuran (THF, 25 ml) and stirred under NO pressure (70 psi) for 48 hrs. At the end of this period, the microspheres were filtered, washed with 200 ml THF, and dried.
- DPTA-grafted microspheres (0.6 g) were likewise suspended in acetonitrile (25 ml) , reacted with NO and worked up under similar conditions. Approximately 40 nmoles NO per mg in IN HC1 wee obtained from DETA- grafted microspheres. Approximately 650 nmoles NO per mg in 1 N HC1 were obtained from DPTA-grafted microspheres.
- NONOate grafted microspheres i.e., those containing the [N(0)NO] ⁇ functional group
- the jLn vitro NO release profiles were determined using a nitric oxide analyzer (Lear-Siegler Corp., Englewood, CO).
- the sampling chamber consisted of a gas impinger (bubbler) bottle modified at both ends with a two-way valve that allowed NO gas to accumulate in the chamber.
- One end of the sampling chamber was connected to the NO analyzer while the other end was connected to a flow meter and a helium gas tank.
- Helium gas was pumped through the system at 10 psig and the flow meter was adjusted to 150-200 ml/min.
- the resulting signals were integrated by a Hewlett-Packard 350 integrator.
- Standard curves for NO were prepared by injecting various volumes of potassium nitrate (100 or 1000 ⁇ M) into a hot solution of vanadium(III) chloride (1 M in 1 N HC1) . The resulting NO was similarly swept into the NO analyzer. The peak areas from the generated NO were plotted against the corresponding nanomoles of nitrate, with the assumption that nitrate was quantitatively reacted to form NO in the vanadium chloride-reducing medium. Approximately 190 nmoles of NO were obtained per mg of the microspheres produced from DPTA-NONO.
- EXAMPLE II This example illustrates the preparation of polyethyleneimine cellulose NONOates.
- Polyethyleneimine cellulose (PEI Cellulose) (7.0 g, 15.4 mmol) with 70 ml acetonitrile was placed in a modified Ace thread reaction bottle equipped with a magnetic stir bar.
- the solution was charged with nitrogen gas for 10 minutes through a 4-way gas valve setup that consisted of two gas inlets for NO and N 2 that could be delivered simultaneously; a third outlet was used to keep the system open. All gas connections were made with transparent Teflon tubes and stainless steel swagelock fittings. Nitric oxide gas was then administered at a pressure of 70 psig for 30 minutes and the reaction bottle was closed, keeping the reaction under pressure.
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP96911671A EP0822833A1 (en) | 1995-04-10 | 1996-04-10 | Polysaccharide-bound nitric oxide-nucleophile adducts |
CA002216696A CA2216696C (en) | 1995-04-10 | 1996-04-10 | Polysaccharide-bound nitric oxide-nucleophile adducts |
JP8531128A JPH11503456A (en) | 1995-04-10 | 1996-04-10 | Polysaccharide-bound nitric oxide-nucleophile adduct |
AU54483/96A AU695579C (en) | 1995-04-10 | 1996-04-10 | Polysaccharide-bound nitric oxide-nucleophile adducts |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/419,424 US5691423A (en) | 1992-08-24 | 1995-04-10 | Polysaccharide-bound nitric oxide-nucleophile adducts |
US08/419,424 | 1995-04-10 |
Publications (1)
Publication Number | Publication Date |
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WO1996032136A1 true WO1996032136A1 (en) | 1996-10-17 |
Family
ID=23662207
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1996/004899 WO1996032136A1 (en) | 1995-04-10 | 1996-04-10 | Polysaccharide-bound nitric oxide-nucleophile adducts |
Country Status (5)
Country | Link |
---|---|
US (1) | US5691423A (en) |
EP (1) | EP0822833A1 (en) |
JP (2) | JPH11503456A (en) |
CA (1) | CA2216696C (en) |
WO (1) | WO1996032136A1 (en) |
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- 1996-04-10 CA CA002216696A patent/CA2216696C/en not_active Expired - Fee Related
- 1996-04-10 EP EP96911671A patent/EP0822833A1/en not_active Withdrawn
- 1996-04-10 WO PCT/US1996/004899 patent/WO1996032136A1/en not_active Application Discontinuation
-
2009
- 2009-12-10 JP JP2009281020A patent/JP2010111675A/en active Pending
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Also Published As
Publication number | Publication date |
---|---|
JPH11503456A (en) | 1999-03-26 |
EP0822833A1 (en) | 1998-02-11 |
AU695579B2 (en) | 1998-08-13 |
US5691423A (en) | 1997-11-25 |
AU5448396A (en) | 1996-10-30 |
CA2216696C (en) | 2009-01-06 |
JP2010111675A (en) | 2010-05-20 |
CA2216696A1 (en) | 1996-10-17 |
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