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WO2008031182A1 - Procédé pour la synthèse et l'incorporation de donneurs d'oxyde nitrique dans des compositions macromoléculaires - Google Patents

Procédé pour la synthèse et l'incorporation de donneurs d'oxyde nitrique dans des compositions macromoléculaires Download PDF

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Publication number
WO2008031182A1
WO2008031182A1 PCT/BR2007/000236 BR2007000236W WO2008031182A1 WO 2008031182 A1 WO2008031182 A1 WO 2008031182A1 BR 2007000236 W BR2007000236 W BR 2007000236W WO 2008031182 A1 WO2008031182 A1 WO 2008031182A1
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Prior art keywords
fact
thiol
nitrosable
nitrosothiol
macromolecular
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Ceased
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English (en)
Inventor
Ogari Pacheco
Roberto Moreira
Amedea Seabra
Gabriela Souza
Marcelo Oliveira
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Cristalia Produtos Quimicos e Farmaceuticos Ltda
Universidade Estadual de Campinas UNICAMP
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Cristalia Produtos Quimicos e Farmaceuticos Ltda
Universidade Estadual de Campinas UNICAMP
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Priority to US12/441,341 priority Critical patent/US20090311292A1/en
Publication of WO2008031182A1 publication Critical patent/WO2008031182A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/04—Nitro compounds
    • 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
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/44—Medicaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B21/00—Nitrogen; Compounds thereof
    • C01B21/20—Nitrogen oxides; Oxyacids of nitrogen; Salts thereof
    • C01B21/24—Nitric oxide (NO)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14—Details; Accessories therefor
    • A61J1/20—Arrangements for transferring or mixing fluids, e.g. from vial to syringe
    • A61J1/2003—Accessories used in combination with means for transfer or mixing of fluids, e.g. for activating fluid flow, separating fluids, filtering fluid or venting
    • A61J1/202—Separating means
    • A61J1/2027—Separating means having frangible parts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14—Details; Accessories therefor
    • A61J1/20—Arrangements for transferring or mixing fluids, e.g. from vial to syringe
    • A61J1/2003—Accessories used in combination with means for transfer or mixing of fluids, e.g. for activating fluid flow, separating fluids, filtering fluid or venting
    • A61J1/202—Separating means
    • A61J1/2041—Separating means having removable plugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14—Details; Accessories therefor
    • A61J1/20—Arrangements for transferring or mixing fluids, e.g. from vial to syringe
    • A61J1/2003—Accessories used in combination with means for transfer or mixing of fluids, e.g. for activating fluid flow, separating fluids, filtering fluid or venting
    • A61J1/2048—Connecting means
    • A61J1/2051—Connecting means having tap means, e.g. tap means activated by sliding
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14—Details; Accessories therefor
    • A61J1/20—Arrangements for transferring or mixing fluids, e.g. from vial to syringe
    • A61J1/2093—Containers having several compartments for products to be mixed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/114—Nitric oxide, i.e. NO
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention is situated in the field of devices for pre- application formulation of drugs and describes a device, and its variations, which allows the synthesis of S-nitrosothiols and their subsequent incorporation in hydrophilic macromolecular compositions, immediately prior to application.
  • Nitric oxide has been identified as the endothelium- derived relaxing factor responsible for the control of blood pressure [LJ Ignarro, GM Buga , KS Wood, S Byrns, Endothelium- derived relaxing factor produced from artery and vein is nitric oxide. Proc. Natl. Acad. Sci. 84: 9265-9269 (1978) 1-4) . Later, it has been found out that this diatomic molecule is also involved in neurotransmission, inhibition of platelet aggregation and immunological responses of a large number of pathological conditions. These findings have motivated an extensive research on the biochemical mechanisms involved in these actions and on exogenous sources of nitric oxide for biomedical applications.
  • the nitric oxide molecule produced in several cells of the human skin plays a key role in skin physiology and pathophysiology, regulating homeostasis and acting as a mediator of the cutaneous wound healing process.
  • Nitric oxide is one of the molecules synthesized endogenously at the site of injury through the action of the inducible nitric oxide synthase (iNOS) enzyme.
  • iNOS inducible nitric oxide synthase
  • vasodilatation inhibition of platelet aggregation
  • reduction of leukocyte cell adhesion reduction of leukocyte cell adhesion
  • promotion of vascular smooth muscle cell proliferation it is considered that nitric oxide plays an important role not only on the wound healing process, but also on the immunomediator responses of dermatological and inflammatory diseases .
  • nitric oxide exerts a powerful cytostatic and cytotoxic action against several intracellular pathogenic agents, such as Trypanosoma cruzi parasites responsible for malaria and leishmaniasis.
  • pathogenic agents such as Trypanosoma cruzi parasites responsible for malaria and leishmaniasis.
  • the involvement of nitric oxide in the intracellular elimination of Leishmania by macrophages is well demonstrated (IV Solbach, T Laskay. The host response to Leishmania infection. Adv Immunol. 2000;74 : 275-317) .
  • the development of biomaterials that allow the topical or transdermal application and release of nitric oxide to leishmaniasis cutaneous ulcers is of great interest.
  • the localized release of nitric oxide may provide beneficial results in ischemic tissues by the increase of the local blood flow and stimulation of angiogenesis .
  • the localized application of formulations capable of releasing nitric oxide or nitric oxide donors to target tissues may be used to promote transdermal absorption of other drugs as well as to attain the beneficial effects of NO at the site of application, thus avoiding the occurrence of undesirable side effects resulting from systemic administration. Therefore, there is a great interest in the development of NO-releasing systems.
  • NO is a gas and reacts rapidly with the oxygen in the air, its localized and controlled release may be obtained with the use of substances that present a
  • NO molecule chemically bound to its structure and that are able to donate this NO to other recipient molecules in the tissues or blood.
  • NO-donor molecules are currently in clinical use, among which are the organic nitrates and nitrites, and sodium nitroprusside .
  • the clinical applications of these classic NO-donors have limitations.
  • the prolonged administration of sodium nitroprusside and organic nitrates may cause cyanide poisoning and vascular tolerance, respectively (Joahanning RJ, Zaske DE, Tschida SJ, Johnson SV, Hoey LL,
  • Vancebryan K A retrospective study of sodium-nitroprusside use and assessment of the potential risk of cyanide poisoning. Pharmacotherapy 1995;15 : 773-777; Shishido SM, de Oliveira MG. Photosensitivity of aqueous sodium nitroprusside solutions : Nitric oxide release versus cyanide toxicity. Progress in reaction kinetics and mechanisms 2001,-26:239-261 ; Thadani U. Prevention of nitrate tolerance with angiotensin II receptor type 1 blocker in patients with stable angina: Yet another failed strategy to prevent tolerance. Cardiovascular drugs and therapy 2004/18:339-342) . In addition, these drugs have a weak antiplatelet action in therapeutic concentrations.
  • nitric oxide donors comprises the S- nitrosothiols (RSNOs) , such as, S-nitrosoglutathione (GSNO) and S-nitrosoalbumin, which have already been identified as endogenous nitric oxide carriers and releasers in mammals.
  • S-nitrosothiols present all physiological actions of free NO, such as, vasodilatation and inhibition of platelet aggregation, and have been subject of several studies and pharmacological strategies referring to the importance of nitric oxide in living systems.
  • the nitric oxide is covalently bound to a sulfur atom through the -CSNO group and may be released by the homolytic or heterolytic cleavage of the S-N bond.
  • the nitric oxide released in this way may be transferred to specific receptors such as enzymes containing iron atoms, to which nitric oxide may coordinate as a ligand (nitrosylation reactions) or proteins containing thiol groups (SH) , to which nitric oxide may bound as an nitrosonium ion (NO + ) in transnitrosation reactions (Carvalho-Filho, Ueno M, Hirabara SM, Seabra AB, Carvalheira JBC, de Oliveira MG, Velloso LA, Curi R, Saad MJA. S-nitrosation of insulin receptor, insulin receptor substrate-1 and protein kinase B/Akt: a novel mechanism of insulin resistance. Diabetes 2005;54 : 959-967) .
  • S-nitrosothiols may undergo in the biological environment are: thermal or photochemical decomposition with release of free NO, transnitrosation reactions and S-thiolation reactions (Hogg N. Biological chemistry and clinical potential of S-nitrosothiols . Free Radical Biology and Medicine 2000/28:1478-86) .
  • the S-transnitrosation reaction may be defined as the transference of the nitroso functional group from a RSNO to a thiol residue (RSH) , as displayed in the following equation:
  • RSNO + R'SH RSH + R 'SNO
  • R represents the organic radical of the S-nitrosothiol
  • R' represents the organic radical of the nitrosated substrate.
  • This reaction occurs by the nucleophilic attack of the thiolate anion on the nitrogen of the RSNO molecule.
  • the reaction is reversible (Hogg N. The kinetics of S- transnitrosation - A reversible second-order reaction. Analytical Biochemistry 1999/272:257-262) .
  • the S-transnitrosation reaction is of paramount importance from a biological standpoint because it allows NO transference from one species to another within the cells, representing an important mechanism of modification of protein activity.
  • the S-nitrosation reaction represents a new mode of cell control and signalization. The transference of the nitrosyl residue from one thiol to another has been suggested as the mechanism of signalization by which nitric oxide controls the cell processes.
  • the S-nitrosothiols present as promising drugs for attaining the pharmacological effects of nitric oxide, without the inconveniences of the toxic action of sodium nitroprusside or development of tolerance to nitroglycerine and other organic nitrates .
  • S-nitrosothiols are thermodynamically unstable (Wang PG, Xian M, Tang XP, Wu XJ, Wen Z, Caj TW, Janczuk AJ. Nitric oxide donors: Chemical activities and biological applications. Chemical Reviews 2002; 102: 1091-1134, Baciu C, Gauld JW. Assessment of theoretical methods for the calculation of accurate structures and S-N bond dissociation energies of S- nitrosothiols (RSNOs). Journal of Physical Chemistry A 101: 2003: 46; 9946-9952; Singh RJ, Hogg N, Joseph J, Kalyanaramant B. Mechanism of Nitric Oxide Release from S-nitrosothiols . The Journal of Biological Chemistry 211; 1996; 18596-18603) and their potential use in diverse medical-hospital or pharmaceutical applications is limited because their transport and storage conditions demand constant refrigeration.
  • the thermal stability of the S-nitrosothiols can be increased by their incorporation in hydrophilic polymeric matrices that reduce the velocity of nitric oxide release through the cleavage of the S-N bond.
  • Previous studies have demonstrated that the incorporation of S-nitrosothiols in liquid and solid polymers and in hydrogels promotes an stabilizing effect on the S-nitrosothiols, compared to what is observed in solution, thus improving their perspectives of use in topical or transdermal applications (patent applications PI 0004238-2, PI0201167-0 and PI0201168-9; Seabra AB, Fitzpatrick A, Paul J, De Oliveira MG, Weller R.
  • the stabilizing effect produced by a polyethylene glycol (PEG) polymeric matrix on the thermal and photochemical decomposition of S-nitroso-N-acetylcysteine and S- nitrosoglutathione is significant in relation to the aqueous solution, both in the dark and under irradiation with visible light.
  • PEG polyethylene glycol
  • S-nitrosothiol continues to decompose in this matrix (Shishido SM, de Oliveira MG.
  • Polyethylene glycol matrix reduces the rates of photochemical and thermal release of nitric oxide from S-nitroso-N-acetylcysteine .
  • S-nitrosothiols S-nitrosoglutathione (GSNO) and S-nitroso-N-acetylcysteine (SNAC) in poly (ethylene oxide) -poly (propylene oxide) -poly (ethylene oxide) (PEO-PPO-PEO) hydrogel reduces the rate of thermal and photochemical decomposition of RSNOs in relation to the aqueous solution. However, the RSNOs continue to decompose in this matrix.
  • the polymeric matrices exert a partial stabilizing effect reducing the rate of thermal decomposition but not preventing its continuity at room temperature.
  • the hydrophilic polymeric matrices may allow the use of S-nitrosothiols immediately after preparation of their formulations, for periods that may be sufficient to obtain their pharmacological actions, without appreciable decomposition, but do not allow the stabilization of these formulations for prolonged periods during their transport and storage.
  • the patent application WO 99/38472 describes gels containing the following NO generators: nitroglycerin, nitroprusside, sodium nitrate, isosorbide dinitrate, L-arginine, pentaerythritol tetranitrate, mannitol hexanitrate and/or their analogues for topical applications for stimulation of the blood flow, blood vessel dilatation and treatment of vascular insufficiency. These molecules act as indirect NO generators.
  • Acrylate is the polymer referred to in the formulations and the solvent is propylene glycol .
  • the patent US 6,579,543 describes a preparation of a composition for dermatological application to obtain analgesic and antiinflammatory activities from formulations containing at least one antioxidant agent, at least one compound with anti- neuralgic action and at least one compound capable of promoting blood circulation, such as L-arginine, which induces endogenous NO production, and at least one compound with anti-depressive activity.
  • NO is generated in an indirect manner, that is, by the physiological action of L-arginine.
  • the patent WO 2002/34303 describes methods for treatment of vascular diseases characterized by NO insufficiency, such as Raynaud's syndrome, employing transdermal release patches.
  • the formulations contain at least one antioxidant agent and at least one NO donor, for example, isosorbide dinitrate and isosorbide mononitrate, and/or at least one nitrosated inhibitor of the enzymatic conversion of angiotensin, one nitrosated calcium channel blocker, one nitrosated endothelial antagonist, one nitrosated angiotensin II receptor antagonist, and one nitrosated renin inhibitor.
  • at least one antioxidant agent and at least one NO donor for example, isosorbide dinitrate and isosorbide mononitrate
  • at least one nitrosated inhibitor of the enzymatic conversion of angiotensin one nitrosated calcium channel blocker, one nitrosated endothelial antagonist, one nitrosated angiotensin II receptor antagonist, and one nitrosated renin inhibitor.
  • the patent US 6,747,062 describes the promotion of cutaneous wound healing of injured tissues (e.g., muscles, tendons, ligaments, skin, mucosas, bones and corneas) by tissue exposure to the presence of nitric oxide.
  • the NO donors may be a NONOate, to increase NO concentration in the tissue, and monomethyl arginine, to reduce NO concentration in the tissue, and therefore adjust NO concentration in the tissue to the desired condition.
  • the patent application WO 2000/12112 describes a new coverage for the treatment of injuries in humans and animals composed of a substrate and the enzyme xanthine oxidase for enzymatic production of free NO.
  • the documents WO 2003/063923 and US 2002122771 describe the preparation of hydrogels for covering of ulcers and wounds in topical applications on skin and bone cavities, with cuts, abrasions, surgical incisions or ulcers, by means of the in situ application of a liquid composition that is directly sprayed on the injured area.
  • the mentioned active agent is any substance capable of releasing NO at the site of the wound.
  • the patent application WO 2003/049593 describes a composition for topical use composed of NO, its donor or pro-drug for prevention of necrosis, the drug being nitrosylated polythiolated cyclodextrin, nitrosylated polymer or long-life coating gel (for example, cyclodextrin) .
  • the vasodilating composition contains alkyl nitrite and S-nitrosothiol (preferentially NO- cyclodextrin) or nitrosyl metallic complexes.
  • the composition may be administered topically, orally, locally or may be inhaled.
  • the patent document US 4,479,578 refers to a syringe-shaped or ampoule-shaped receptacle constituted of more than one compartment.
  • One of the compartments containing a solid pharmaceutical product is temporarily isolated from another compartment containing an aqueous solution and the content of both compartments may be promptly mixed at the moment of application.
  • This type of receptacle is intended to ready-to-use pharmaceutical products (active ingredient) that should be solubilized in an aqueous solution at the moment of application.
  • the document WO 2005/030111 refers to a device to treat wounds that comprises a receptacle with two or more separate compartments.
  • the first compartment contains a first component and the second compartment contains a second component.
  • the device is preferentially adequate for products used in wound healing treatment, specifically papain, in hydrogels comprising components that are unstable in their presence.
  • S-nitrosothiols as agents for wound healing treatment.
  • the patent US 7,182,949 refers to a composition for topical application of an extemporaneous C vitamin preparation comprising a C vitamin precursor, except for esters, in contact with at least one enzyme that is capable of converting such precursor in
  • C vitamin This composition is intended to overcome the stabilization problems of C vitamin formulations by direct generation during or immediately before its application on the skin.
  • This patent does not specifically describe a device but, in its examples, it explains, for instance, that both ingredients formulated in different emulsions should be stored in distinct compartments and mixed right before the application in order to allow the reaction of C vitamin formation to occur immediately before the topical application.
  • WO 2006/100155 refers to a device, with presentation form of bandage, intended to the treatment of wounds, which involves the use of nitric oxide.
  • the device comprises the nitric oxide eluted in a polymeric matrix organized to remain in contact with the wound area, incorporated to a carrier material that regulates and controls the elution of the therapeutic dose of nitric oxide.
  • the present invention proposes a device, and its variations, which allows the synthesis of active S-nitrosothiols and their subsequent incorporation in hydrophilic macromolecular compositions, immediately before the topical application.
  • the devices described in the present invention offer an innovative solution to the transport and storage of S- nitrosothiol precursors and the formulation components at room temperature, and preparation of thermally unstable S-nitrosothiol formulations for medical, pharmaceutical or cosmeceutical applications .
  • the devices presented herein combine the pre-application synthesis of the S-nitrosothiols with their subsequent incorporation in delivery vehicles that yield a relative stabilization of the S-nitrosothiols for adequate periods in such a way that the resulting formulations in the device may be employed under room conditions in their several possible applications.
  • the field of application of the formulations prepared using the device of the present invention includes the stimulation of blood flow, blood vessel dilatation, treatment of vascular insufficiencies, treatment of Raynaud's syndrome, modification of skin pigmentation, promotion and acceleration of skin, muscle, tendon, ligament, mucosa, bone and corneal wound healing, prevention of necrosis, treatment de eczemas and arthritis, systemic lupus erythematosus and cutaneous leishmaniasis, among other applications.
  • the present invention describes a device, and its variations, which allows the synthesis of S-nitrosothiols and the subsequent incorporation of these compounds to hydrophilic macromolecular compositions, immediately prior to application.
  • the S-nitrosothiols are synthesized in a first step from the S-nitrosation reaction of their respective precursor thiols, promoted by a mechanical action that puts the thiols in contact with the nitrous acid formed from nitrite anions in acidic medium; in a second mechanical operation, the freshly prepared S-nitrosothiols are incorporated in a delivery vehicle based on hydrophilic macromolecular compositions that increase their thermal stability.
  • FIGURES Figure 1. Schematic presentation of a device developed according to the instructions of the present invention, which comprises two storage compartments and one reaction compartment, the formulation compartment that encloses the macromolecular matrix being uncoupled from the remainder of the device system.
  • Figure 2. Schematic presentation of a device developed according to the instructions of the present invention, which comprises three compartments, the formulation compartment that encloses the macromolecular matrix being coupled to the remainder of the device system.
  • Figure 3 Dermal blood flow after topical application of GSNO and SNAC in Pluronic F-127 hydrogels directly to the skin of healthy volunteers .
  • Figure 4 Percentage of retraction of the injured area due to wound treatment with topical application of GSNO incorporated to a hydrogel matrix and pure hydrogel (used as a control) 3 (d3) , 5 (d5), 7 (d7), 14 (dl4) and 21 (d21) days after injury.
  • B Macroscopic detail of the wound area 5 (d5) , 14 (dl4) and 21 (d21) days after injury.
  • Figure 5. Percentage of reepithelization of injured areas of animals treated with GSNO incorporated in a hydrogel and pure hydrogel (used as a control) .
  • FIG. Granulation tissue in control animals (A) and animals treated with GSNO (B) 21 days after injury (d21) .
  • the devices of the present invention allow the synthesis of S-nitrosothiols and their subsequent incorporation in hydrophilic macromolecular compositions, immediately prior to application.
  • the device for the synthesis of S-nitrosothiols and incorporation in macromolecular compositions immediately before their application comprises storage compartments that enclose separately the precursor reagents for the synthesis of the S-nitrosothiol in the reaction compartment immediately before its incorporation in a macromolecular composition enclosed in a formulation compartment, which is either coupled to or uncoupled from the remainder of the device system, thus constituting alternatively a kit.
  • the device of the present invention allows the transport and storage of the S-nitrosothiol precursors and the components of the formulation at room temperature, and preparation of the formulation right before its application.
  • the device for the pre- application synthesis of S-nitrosothiols and incorporation of the freshly prepared S-nitrosothiol in macromolecular compositions comprises :
  • a reaction compartment containing an acid aqueous solution (i) a reaction compartment containing an acid aqueous solution; (ii) one storage compartment containing a mixture of a nitrosable thiol, or an acid salt of the nitrosable thiol, and a nitrite salt, both in the solid form, or optionally, two storage compartments to enclose separately a nitrosable thiol in the solid form and a nitrite salt in the solid form; and
  • a formulation compartment containing a hydrophilic macromolecular matrix or composition which may be either coupled to or uncoupled from the reaction compartment, which, by means of a first mechanical action, promotes the contact of the nitrosable thiol and nitrite salt deriving from different storage compartments or from the same storage compartment with the acid aqueous solution enclosed in the reaction compartment, thus forming an S-nitrosothiol through an immediate S-nitrosation reaction, and by means of a second mechanical or transference action, the device promotes the incorporation of the freshly synthesized S-nitrosothiol in the macromolecular matrix, thus resulting in a pharmaceutical formulation in the form of a viscous solution or a hydrogel proper for use in topical medical or pharmaceutical applications.
  • a nitrosable thiol is any molecule that contains one or more sulfhydryl groups (-SH) in its structure.
  • the nitrosable thiols may be, more specifically, an amino acid, a peptide or a protein containing one or more sulfhydryl groups (-SH) .
  • the nitrosable thiol employed in the device of the present invention should be selected from the group consisting of glutathione (GSH) , N- acetyl-cysteine (NAC) and N-acetylpenicillamine, or their pharmaceutically acceptable salts.
  • GSH glutathione
  • NAC N- acetyl-cysteine
  • N-acetylpenicillamine or their pharmaceutically acceptable salts.
  • a mixture of nitrosable thiols may be used.
  • the acid aqueous solution may be constituted by a mineral acid, such as hydrochloric acid, or by an organic acid, such as citric acid.
  • the concentration of the acid aqueous solution may range from 1 to 4 mol L "1 .
  • the macromolecular matrix or composition may be constituted of one or more biocompatible hydrophilic macromolecular components, and each component may either have or not tissue adhesion properties.
  • the macromolecular matrix can be, for example, poly (ethylene glycol) (PEG) in any of its commercially available presentations or triblock copolymer of poly (ethylene glycol) -poly (propylene glycol) -poly (ethylene glycol) (PEO-PPO-PEO) in any of its commercially available presentations, or hydroxyethyl cellulose (HEC) in any of its commercially available presentations, or hydroxymethyl cellulose (HMC) in any of its commercially available presentations, or Carbopol ® in any of its commercially available presentations, or poly (vinyl alcohol) in any of its commercially available presentations, or poly (vinyl pyrrolidone) in any of its commercially available presentations.
  • PEG poly (ethylene glycol)
  • PEO-PPO-PEO triblock copolymer of poly (ethylene glycol) -poly (propylene glycol) -poly (ethylene glycol) (PEO-PPO-PEO) in any of its commercially available presentations
  • HEC
  • any of the macromolecular components may already be crosslinked or undergo crosslinking by the action of a crosslinking agent, or any other substance used to improve the adhesion properties of the macromolecular composition.
  • the macromolecular composition can contain buffering, conserving, colorant, dispersing agents and metal complexants, or mixtures thereof.
  • a dispersing agent such as mannitol and/or citric acid, may alternatively be packed in the storage compartment of the device of the present invention.
  • the mixture of the nitrite salt with the nitrosable thiol in acid medium leads to the formation of the corresponding S- nitrosothiols .
  • RSH represents the nitrosable thiol
  • HO-NO represents the nitrous acid originating from the dissolution of sodium nitrite in acid solution
  • RSNO represents the S-nitrosothiol, which is the active principle of the formulations prepared with these devices.
  • HO-NO represents the associated nitrous acid and may also be represented as HNO 2 .
  • the acid medium for thiol nitrosation may also be obtained from the dissolution of the thiol itself in water, if the thiol is used in the form of chloride, because the chlorides of the thiols under consideration are acid salts.
  • nitrosable thiols and nitrite salts present separately or conjunctly in the storage compartments of the device in the solid forms should be equimolar or there may be a slight excess in the molar quantity of nitrite salt (approximately up to 10%) in relation to the molar quantity of thiol.
  • concentrations of S-nitrosothiols incorporated in the delivery vehicles may range from 0.1 ⁇ mol L '1 to 600 mmol L "1 . If the nitrite salt and the solid thiols are diluted in inert water- soluble diluents, nanomolar concentrations may be obtained in the incorporation of the synthesized S-nitrosothiols in the delivery vehicles based on the hydrophilic macromolecular compositions.
  • the formulation containing one or more S-nitrosothiols can be applied in the form of liquid solution or gel, or may jellify after contact with the target tissue or through a thixotropic activity inherent to the macromolecule .
  • the operation of the device of the present invention involves the following steps:
  • the formulation containing the S-nitrosothiol is ready to be topically applied to patient and, depending on the viscosity of the final formulation, the possible applications of the prepared formulation include: use of a spatula to remove the desired amount of the formulation from the compartment; adaptation of a device shaped as a spray, sprinkler or similar to the formulation compartment of the device, containing the freshly prepared formulation; or fabrication of the final compartment of the device shaped as a tube or syringe.
  • the device should be stored under refrigeration in a domestic refrigerator (temperature around 5°C) for approximately 30 minutes before operating the device.
  • a domestic refrigerator temperature around 5°C
  • the decrease of the temperature allows that the PEO-PPO-PEO macromolecular composition is presented as a viscous liquid, facilitating the incorporation of the S-nitrosothiol and the homogenization of the final formulation.
  • the formulation can be maintained at room temperature, at which the composition will pass to a gel state.
  • it is recommendable to maintain the prepared formulation stored in a domestic refrigerator.
  • the PEO-PPO-PEO matrix can be used as a viscous polymeric solution.
  • the use of PEO-PPO-PEO viscous aqueous solution does not implicate in previous refrigeration of the device in a domestic refrigerator, prior to the mechanical actions.
  • the macromolecular composition of the PEO-PPO-PEO aqueous solution is less viscous than the solution that jellifies at room temperature (10% versus 30%, respectively) , S- nitrosothiol incorporation and its homogenization in the polymeric solution is facilitated.
  • the pH of the macromolecular composition can be adjusted with the presence of buffering salts in order to achieve the desired final pH for the formulation, for example, within the 5.5 to 7.4 range.
  • the devices in all variations described in this patent application can be transported and stored at room temperature, as the stability of thiols and nitrite salt, particularly sodium nitrite, solid and dry, packed separately or conjunctly, is relatively high at room conditions, differently from the S- nitrosothiols that are unstable.
  • the formulations prepared with this device may be used for stimulation of blood flow, blood vessel dilatation, treatment of vascular insufficiencies, treatment of Raynaud's syndrome, modification of skin pigmentation, promotion and acceleration of skin, muscle, tendon, ligament, mucosa, bone and corneal wound healing, prevention of necrosis, treatment de eczemas and arthritis, systemic lupus erythematosus and cutaneous leishmaniasis, among other applications.
  • Example 1 Device for the pre-application synthesis of S- nitrosothiols and incorporation in a macromolecular matrix, in which the formulation compartment is uncoupled from the reaction compartment.
  • a schematic presentation of a possible device prepared according to the instructions of the present invention is illustrated on Figure 1.
  • Panel I of Figure 1 displays the integrating components of a device that contains two storage compartments [ (a) + (c) ] and [ (b) + (d) ] and a reaction compartment (e) .
  • the components (a) and (b) enclose, separately, the nitrosable thiol and the nitrite salt, both in the solid and dry form, while the components (c) and (d) have cup-shaped format and have the function of wrapping the components (a) and (b) in a way to isolate the storage compartments from the reaction compartment (e) , which encloses an acid aqueous solution.
  • the components (a) and (b) have a sharp format in their open end towards the base of the components (c) and (d) , which will be disrupted as the device is put in operation.
  • the storage compartments are located at the end of a vial that represents the reaction compartment.
  • Panel II of Figure 1 displays the device constituted by 3 compartments mounted and ready to operate. Device operation will occur by simultaneous pressing of both components (a) and (b) towards the reaction compartment (e) causing the rupture of the base of components (c) and (d) .
  • Panel III of Figure 1 displays the result of the simultaneous pressing of the components (a) and (b) , indicating that, with this action, the nitrosable thiol and the nitrite salt get in contact with the acid aqueous solution in the reaction compartment (e) , where, after agitation, the nitrosable thiol and the nitrite salt react instantaneously by S-nitrosation, obtaining the S-nitrosothiol of therapeutic interest, in an acid solution.
  • Panel IV of Figure 1 displays the addition of the S- nitrosothiol solution to the formulation compartment, which encloses the macromolecular matrix and is uncoupled from the remainder of the device. This simple operation allows the formation of the final product that will be applied to the patient.
  • the horizontal format of the reaction compartment (e) is not restrictive for the adequate performance of the present invention, and a vertical format of this compartment is also acceptable.
  • the storage compartments may optionally be positioned on the lateral walls of the reaction compartment .
  • the device comprises, for example, 12.3 mg of GSH and 170 mg of mannitol in the storage compartment (a) , 3 mg of sodium nitrite and 180 mg of mannitol in the storage compartment (b) , 2 mL of HCl solution 2.0
  • Example 2 Device for pre-application synthesis of S- nitrosothiols and incorporation in a macromolecular matrix in which the formulation compartment is coupled to the reaction compartment
  • Figure 2 displays an alternative for fabrication of the device of the present invention, in which the compartment that encloses the macromolecular matrix is coupled to the device, forming a single system.
  • the device illustrated in the panel I of Figure 2 comprises four sections (1, 2, 3 and 4) and three compartments (A, B and C) .
  • compartment B is both the storage compartment (prior to device operation) and the reaction compartment (after device operation) .
  • Compartments A and C are the storage and formulation compartments, respectively.
  • the section 1 is coupled to the section 3 by means of the notch represented between both sections. This notch allows that the section 1 rotates freely over section 3.
  • Section 2 consists of a t-shaped piston with an upper screw threaded to section 1.
  • the horizontal bar on section 2 consists of two pawls that insert bilaterally into two diametrically opposed grooves that run vertically on the internal wall of section 3.
  • Section 3 posses two internal compartments (A and B) isolated from each other by a first septum on its central portion (compartment A septum) . Compartment B is separated from the compartment C of section 4 by a second septum (septum of compartment C) . Section 4 posses an internal compartment (C) .
  • Compartment A encloses an acid aqueous solution. Compartment B encloses a nitrosable thiol and nitrite salt mixture, both in solid and dry form. Compartment C encloses the macromolecular composition in the form of solution.
  • section 2 When section 1 is rotated against section 3, section 2 is pushed downwards by the counter-thread movement of the upper screw. As it is pushed downwards, section 2 breaks the septum of compartment A releasing the acid aqueous solution from compartment A to the compartment B. When the components of compartments A and B are mixed, an S-nitrosation reaction of the thiol will instantaneously occur under stoichiometric conditions. As the rotation movement of section 1 in relation to section 3 continues, section 2 will reach the septum of the compartment B and will cause its rupture, making that the solution of S- nitrosothiol freshly synthesized in the compartment B be added to the macromolecular matrix enclosed in the compartment C.
  • both pawls of section 2 will reach the inferior limit of the internal lateral notches of section 3, stopping the rotation of section 1 in relation to section 2.
  • sections 3 and 4 will be disconnected at the threaded connection existing between them. This means that sections 1 and 3 can be removed as a single cover of section 4.
  • section 4 may be covered with either a regular threaded cover, if the final formulation is a hydrogel, or a sprinkler or spray, if the final formulation is a solution. Both options of cover should be supplied in the device's package.
  • Panel II of Figure 2 depicts the same device displayed on the panel I of Figure 2, representing the section 3 in its lower position, after device operation and the consequent rupture of the septa of the compartments A and B. It should be noted that, in this situation, the inferior end of the vertical axis of section 2 should be situated below the base containing the septum of compartment B, in order to provide a space through which the solution in compartment B can flow over the macromolecular composition solution enclosed in compartment C.
  • the nitrosable thiol and the nitrite salt may be packed individually, separated by a horizontal division of compartment B, i.e., a septum that will also be disrupted with the dislodgment of section 2.
  • the nitrosable thiol will be packed in the upper division of compartment B, which firstly will receive the acid aqueous solution.
  • the nitrite salt will be packed in the lower division of compartment B, which will further receive the nitrosable thiol freshly solubilized in the acid aqueous solution, allowing the occurrence of the S- nitrosation reaction with immediate production of the desired S- nitrosothiol .
  • joint rings or gaskets made from flexible polymeric materials compatible with the chemical nature of the reagents to be used and with the purposes of packaging of products for medical or pharmaceutical applications .
  • the materials that can be used in the fabrication of the devices presented as examples on Figures 1 and 2 include all rigid polymers compatible with the chemical nature of the reagents to be used and with the purposes of packaging of products for medical or pharmaceutical applications. Ideally, the polymeric materials to be used in the fabrication of the device should be light-proof in order to prevent the photodegradation of the components of the device.
  • Example 3 Stability of the components enclosed in the compartments of the device of the present invention.
  • S-nitrosothiols such as S-nitrosoglutathione and S-nitroso- N-acetylpenicillamine
  • S-nitrosothiols are unstable in aqueous solution and are therefore commercialized as dry powders with label information indicating that the products should be stored under refrigeration (0 0 C for S-nitrosoglutathione and -20° for S-nitroso-N- acetylpenicillamine) .
  • thiols such as glutathione and N-acetylcysteine
  • GSNO content in the samples at day 0, after 48 hours (day 2) and after 5 days was quantified from the absorbance readings of the aqueous solutions 500 ⁇ mol L "1 at 336 nm.
  • Table 1 displays the results of the GSNO percent content calculated from the differences in the absorbance readings at day 0 and at days 2 and 5. According to the results, after 48-hours of storage at room temperature, decomposition of approximately 52% of the initial GSNO content occurs.
  • the sodium nitrite used in the device is already marketed in the solid form, not requiring refrigeration, inert atmosphere or light-proof containers. Therefore, the solid sodium nitrite is recognizably stable. However, sodium nitrite decomposes into an acid solution with N 2 O 3 evolution.
  • the macromolecular composition in aqueous solution is stable for at least 2 years.
  • Example 4 Stability of the S-nitrosothiols prepared and incorporated in PEO-PPO-PEO matrix using the device of the present invention.
  • Table 3 displays the results of the stability of the GSNO incorporated in PEO-PPO-PEO matrix (commercial brand Pluronic F- 127) obtained using the device described in the present invention, at three different concentrations: 50, 100 and 200 ⁇ mol L "1 .
  • the gathered stability data make up a study duration of 110 days under refrigeration in domestic refrigerator (5-8 0 C) and demonstrate that the GSNO incorporated in the PEO- PPO-PEO macromolecular matrix is relatively stable at all three tested concentrations presenting little decomposition (about 20% decrease in relation to the initial GSNO content) , which does not compromise its application.
  • the 7-cm-diameter guides were placed on the volunteers' skin exactly on the site of application of the hydrogel.
  • a perfusion monitor was connected to a personal computer and the vasodilatation readings were obtained continuously using specific software (moorLAB vl.31 for Windows 0 Moorsoft Instruments Ltd) .
  • Hydrogel without S- nitrosothiol served as a control.
  • Figure 3 shows the variations in blood flow as a function of time secondary to the topical application of a formulation prepared using the device of the present invention (0.3 molL "1 of nitrosothiol in Pluronic F-127 24% m/m hydrogel) , compared to the control.
  • the results showed that the topical application of the hydrogels resulted in a 12-fold increase in local blood flow, in all volunteers, compared to the control.
  • the maximum blood flow value was reached within 30 minutes, returning to the basal values after 3 hours.
  • Example 6 Cutaneous wound healing after application of the formulation prepared using the device of the present invention.
  • GSNO was synthesized and incorporated in Pluronic F-127 hydrogel by operating the device described in the present invention.
  • the formulation of freshly prepared GSNO (100 ⁇ mol L "1 ) was topically applied to the wounds of the animals.
  • Wistar rats (n 10) were housed in individual cages with free access to water.
  • an excisional wound (2x2 cm) was made on the back of the animals, under general anesthesia.
  • the wound was covered with either pure hydrogel (control animals) or GSNO- containing hydrogel (treated group) . Thereafter, the wounds were closed with a dressing. Daily, up to the fourth day after injury, the dressings were removed, and the wounds were gently cleaned with cold saline. The hydrogel (either containing GSNO or not) was applied and the dressing was replaced. From the fifth day after injury on, the wounds were no longer closed with a dressing.
  • Wound retraction was measured and reepithelization was evaluated histologically. Wound contours were traced in a transparent paper sheet at the day of injury and after 3, 5, 7, 14 and 21 days. The tracing area was determined using image- analysis software (Image-Pro) and the results were expressed as percentages of the initial area. Blood pressure was measured at the beginning and end of the experiments. After euthanasia, a fragment containing the wound and the adjacent healthy skin was removed. The fragments were fixed in formalin solution, processed and embedded in paraffin.
  • Figure 5 shows that 7 days after injury, the area of wound reepithelization was larger in the group treated with GSNO incorporated to the hydrogel (>77%) compared to the control group. Twenty-one days after injury, a larger number of inflammatory cells were observed in superficial and deep areas of the granulation tissue in the control group, in comparison to the group treated with the GSNO-containing hydrogel. In addition, there was an increase in the number of fibroblasts in superficial and deep areas of the granulation tissue, compared to the control group. Theses cells presented as fusiform cells arranged parallel to the surface (Fig. 6) .
  • mast cells were found mainly in deep areas of the granulation tissue, most of them with an ovoid shape and localized adjacent to the blood vessels. Twenty-one days after injury, the total number of mast cells in deep areas of the granulation tissue was larger in the GSNO-treated animals (+384%), compared to the control group (Fig. 7) .
  • inflammatory cells such as fibroblasts, endothelial cells and keratinocytes
  • fibroblasts Several cell types, such as inflammatory cells, fibroblasts, endothelial cells and keratinocytes, are involved in cutaneous wound healing.
  • Mast cells are among these cells and are important in cutaneous wound healing because they are capable of regulating the inflammatory cell migration and the formation of granulation tissue by control of angiogenesis and fibroblastic proliferation, and NO synthesis.

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Abstract

La présente invention concerne un procédé pour la synthèse de S-nitrosothiols et l'incorporation ultérieure de ces composés dans des compositions macromoléculaires hydrophiles. Par le procédé décrit les présentes, les S-nitrosothiols sont synthétisés dans un dispositif (Figure 2) en une première étape à partir de la réaction de S-nitrosation de leurs thiols précurseurs respectifs (A), favorisée par une action mécanique qui met les thiols en contact avec l'acide nitreux formé à partir d'anions nitrite dans un milieu acide (B), et en une seconde opération mécanique, les S-nitrosothiols fraîchement formés sont incorporés dans un véhicule d'application (C) sur la base de compositions macromoléculaires hydrophiles qui augmentent leur stabilité thermique. Par conséquent, le procédé en question combine la synthèse de pré-application des S-nitrosothiols avec leur incorporation ultérieure dans des véhicules de distribution, qui fournissent une stabilisation relative des S-nitrosothiols pendant des périodes suffisantes, de telle sorte que les formulations préparées par ce procédé peuvent être stockées dans un réfrigérateur domestique pendant leur période d'utilisation dans leurs nombreuses applications possibles.
PCT/BR2007/000236 2006-09-14 2007-09-14 Procédé pour la synthèse et l'incorporation de donneurs d'oxyde nitrique dans des compositions macromoléculaires Ceased WO2008031182A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4779722A (en) * 1987-08-28 1988-10-25 Hall John E Material mixing container
WO1992018002A1 (fr) * 1991-04-10 1992-10-29 Brigham And Women's Hospital Nitrosation d'homocysteine en tant que procede de traitement de l'homocysteinemie
WO2002016320A2 (fr) * 2000-08-24 2002-02-28 Scimed Life Systems, Inc. Procede de s-nitrosylation a rendement eleve

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4779722A (en) * 1987-08-28 1988-10-25 Hall John E Material mixing container
WO1992018002A1 (fr) * 1991-04-10 1992-10-29 Brigham And Women's Hospital Nitrosation d'homocysteine en tant que procede de traitement de l'homocysteinemie
WO2002016320A2 (fr) * 2000-08-24 2002-02-28 Scimed Life Systems, Inc. Procede de s-nitrosylation a rendement eleve
US20030208036A1 (en) * 2000-08-24 2003-11-06 Herrmann Robert A. High yield S-nitrosylation process

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