Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/18—Iodine; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/02—Local antiseptics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/20—Antivirals for DNA viruses
  • A61P31/22—Antivirals for DNA viruses for herpes viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• This invention relates a new composition containing halogenated compounds for (1) the treatment of viral, bacterial, parasitical, fungal infections, or infections generated from non-conventional transmissible agents; (2) the treatment of chronic, progressive or acute inflammation; (3) immuno-modulator treatments, and/or tissue healing stimulator treatments; and (4) pre- and/or per- and/or post-surgical irrigations.
• the invention composition is particularly helpful as a local use antiseptic.
• Alkaline metal hypochlorite is an alkaline metal salt of hypochlorous acid.
• the available chloride level of sodium hypochlorite solutions is equal to the addition of HOCl (hypochlorous acid) and OCl ⁇ (hypochlorous anion) concentrations (Bloomfield & Miles, 1979).
• the hypochlorite active form, i.e., the hypochlorous acid is a highly strong oxidant that plays a role in the mammalian defense system.
• HOCl is synthesized in polymorphonuclear neutrophils and monocytes (Wright et al., 1986) during the respiratory burst by the myeloperoxidase-H 2 O 2 -halide system. Hypochlorous acid is unstable and reacts readily with primary and secondary amines to generate various N-chloramines (Zgliczynski et al., 1971).
• taurine an amino acid
• tauCl taurine N-chloramine
• This chloramine is less toxic and reactive than hypochlorous acid.
• TauCl is the most stable of the chloramines (Zgliczynski et al., 1971; Marquez & Dunford, 1994).
• taurine seems to have a high protective role in both intra- and extra-cellular environments, via its high scavenger activity with hypochlorous acid (Cantin, 1994; J. Marcinkiewicz et al., 1998).
• long-lived taurine N-chloramines can move and react (i.e., oxidize and/or chlorinate) at distance from their formation to generate tissue damage (Zgliczynski et al., 1971).
• taurine and hypochlorous acid react spontaneously and with a 1/1-molecule stoechimetry to yield a taurine N-monochloramine.
• this reaction generates both taurine N-monochloramines and taurine (N,N)-dichloramines.
• Taurine and, particularly, nitrites (NO 2 ⁇ ) compete with other antioxidants to scavenge hypochlorous acid in the extracellular medium. Their concentrations are roughly equal.
• the main hypo-chlorous acid scavengers are nitrites, which react together to yield a lesser toxic derivative than TauCl.
• taurine is the main scavenger of hypochlorous acid (J. Marcinkiewicz, 2000).
• the sodium hypochlorite (NaOCl) is well known to be caustic. It is a non-specific agent able to hydrolyze necrotic tissues. This property is due to the presence of sodium hydroxide (NaOH).
• the tissue dissolving level (e.g. mainly necrotic tissues) is in accordance with NaOCl concentration, contact surface (Hand et al., 1978), contact time and NaOCl solution amount used (The et al., 1979).
• Sodium hypochlorite is a highly unstable molecule. At levels below 5 g/l of available chlorine, its stability is under 2 weeks and depends on the following factors:
• hypochlorite aqueous solution containing HOCl molecules (i.e.: NaOCl+H 2 O HOCl+NaOH) is neutralized by organic matter.
• Hypochlorite solution is efficient both when it can act readily and when it is in excess in comparison to an organic matter amount.
• pH value EP 0471129 A1 has established that a pH value between 10 and 10.5 yields a high stability to NaOCl oxidative activity (greater than 24 months).
• Cell toxicity results mainly from an intracellular protein loss, which generates both an adherence decrease to substrates and cell deformation.
• cell systems with a high cell organization e.g. in epithelium and dental plaque are less sensitive (i.e. surface cells are sacrificed for profound cells) than one-cell systems (prokaryotes, mammalian mobile cells, or other one-cell systems).
• Membrane type that protects intracellular elements (i.e. membrane permeability level to oxidants). The most efficient are viral proteinic membranes.
• a membrane presence that protects key intracellular systems e.g., DNA (nucleus), energetic production (mitochondria), secretion process (Golgi's apparatus), etc.
• Prokaryotes do not possess these protector systems and, consequently, are more vulnerable.
• the intracellular antioxidant amount i.e., gluthatione, acetyl N-cysteine, taurine, amino acids, thiol groups, etc.
• the intracellular antioxidant amount i.e., gluthatione, acetyl N-cysteine, taurine, amino acids, thiol groups, etc.
• Prokaryotes possess a down antioxidant level.
• the extracellular antioxidant amount i.e. taurine, thiol groups, organic matter, metal, blood, extracellular matrix, etc.
• the local physicochemical environment e.g. surface-active, oxidants, olfactory or gustatory properties, pH, pKa, density, solubility, viscosity, coloration, water-ectanol sharing factor.
• NaOCl has a high toxicity.
• HOCl is not toxic.
• HOCl does not alter in vitro human fibroblast skin viability and does not induce cell apoptose (Vile G. F. et al., 2000).
• TauCl is cytotoxic (Marcinkiewicz J. et al., 1998).
• HOCl is a lipophilic oxidant and, consequently, easily and readily cross cell membranes (i.e. ⁇ 80% of HOCl molecules are taken up by human fibroblasts within the first 10 minutes) (Vile G. F. et al., 2000).
• Membrane transport systems are specific to each of these molecules and depend on Na + level, temperature, and energy.
• Sodium hypochlorite is a very strong and efficient bactericidal, virucidal and fungicidal agent (Shih et al., 1970; Bloomfield & Miles, 1979, Harrison & Hand, 1980).
• the bactericidal minimum concentration of NaOCl i.e. for Gram ⁇ and Gram+bacteria
• the bactericidal minimum concentration of NaOCl is 3.36 mM (0.025%)
• the minimum virucidal concentration for VIH is 19.062 mM (1%) of available chlorine.
• TauCl has a very low bactericidal activity. Only dichloramines generate some bactericidal activity (i.e. with E. Coli in acidic conditions) (Marcinkiewicz J. et al., 2000).
• Inflammation is a defense mechanism toward all aggression types.
• Sentinel cells e.g. macrophages and dendritic cells (DC)
• DC dendritic cells
• mediators detect an aggressor (Marcinkiewicz J. et al., 1999).
• aggressor agents induce a reaction cascade and both activate and regulate the immune system in an adaptive manner to the aggression type.
• a regulatory system After the aggressor agents are removed, a regulatory system generates an inflammation turnover followed by a healing/regeneration process.
• the cell part of the innate (natural) immunity is made up of monocytes (mononuclear phagocytes), polymorphonuclear neutrophils (PMN), and natural killer cells (NK). These cells use the complement cascade, or some recognition protein, e.g., reactive protein C and amyloid protein. These proteins are able to attach themselves to carbohydrate molecules present on bacteria membranes.
• PMNs are included in the first mammalian defense line and cooperate closely with macrophages (one of the major effector cells of the immune system). PMNs are responsible for the non-specific defense in acute inflammation and macrophages take a similar role in both acute and chronic inflammations (Marcinkiewicz J. et al., 1994).
• T cell receptors and antibodies are recognition molecules.
• B cells recognize carbohydrates, proteins, and some simple chemical structures while T cells recognize only peptides.
• DC Dendritic cells
• Cytokines are the most important intercellular messenger molecules of the immune system (Megarbane B. et al., 1998). Cytokines are generated and released from activated immune cells and they induce some particular biological activities after binding to a specific target cell receptor, in an autocrine or a paracrine manner. Macrophages and T cells are main productive cells of cytokines, although many other cells also can produce them. Cytokines are main and real regulators of both humoral and cellular immune response.
• Cytokines travel together and the balance of their activities is crucial for immune system regulation, e.g., via a competition between TH1 (IL-2, INF- ⁇ , TNF- ⁇ and IL-12) and TH2 (IL-4, IL-5, IL-10 and IL-13) T cells.
• TH1 IL-2, INF- ⁇ , TNF- ⁇ and IL-12
• TH2 IL-4, IL-5, IL-10 and IL-13
• TH1 cells are involved in cell immunity and are responsible for cytotoxic activities of macrophage, T cells and natural killer cells.
• TH2 cells are associated with humoral response, and, for example, IL-10 (i.e. a TH2 type cytokine) strongly inhibits effective functions of macrophages and TH1 cells (Marcinkiewicz J., 1997).
• IL-10 i.e. a TH2 type cytokine
• Cytokine regulatory functions can be extended to a selection of immunoglobulin isotypes during humoral response. Thus, selective inhibitions of cytokines generate an immune response modulation.
• Eicosanoids prostaglandins and leukotrienes
• NO nitric oxide
• Eicosanoids are generated from arachidonic acid, which is derived from cell membrane phospholipides.
• Prostaglandines are generated under the cyclooxygenase (COX) catalyzing action.
• COX cyclooxygenase
• Two cyclooxygenase types are distinguished: the constitutive form (COX1) and the induced form (COX2).
• COX2 production is activated within inflammatory cells by pro-inflammatory mediators.
• COX2 catalyzes the synthesis of prostaglandins E 2 (PGE 2 ) and prostacyclins I 2 (PGI 2 ) in macrophages, and prostaglandines D 2 in mast cells.
• Prostaglandins particularly PGE 2
• leukotrienes particularly LTB 4
• Nitric oxide (NO) is synthesized from L-arginine under the catalyzing action of the constitutive nitric oxide synthetase ((cNOS) that is calcium dependent) or the induced nitric oxide synthetase ((iNOS) that is calcium independent).
• cNOS constitutive nitric oxide synthetase
• iNOS induced nitric oxide synthetase
• cNOS permits the synthesis of the basic form of nitric oxide (NO) in cells of both endothelium and nervous system.
• iNOS is found in a variety of cells including macrophages, neutrophils and hepatocytes. NO generation plays an important role in macrophage cytotoxicity and their ability to kill pathogen microorganisms and, consequently, in mammalian non-specific defense against many pathogens and tumor cells.
• Rat peritoneal macrophages stimulated by non-chlorinated Gram+bacteria ( Staphylococcus aureus, S. epidermidis , and Escherichia coli ) release high concentrations of nitric oxide, TNF- ⁇ , and IL-6.
• non-chlorinated Gram+bacteria Staphylococcus aureus, S. epidermidis , and Escherichia coli
• the same bacteria chlorinated by HOCl lose their abilities to induce a nitric oxide and TNF- ⁇ release while IL-6 production and phagocytosis are not altered (Marcinkiewicz J. et al., 1994).
• HOCl increases the endothelium permeability and promote leukocyte adherence to microcirculation endothelium.
• Taurine N-chloramine reduces an endothelium permeability increase generated by PMN activities. Taurine alone is without effect (Tatsumi & Flies, 1994).
• HOCl down level (5 nM/1.2 ⁇ 10 5 cells) does not induce a cell death but a temporary stop of cell growth (Vissers M C et al., 1999).
• low concentrations of both HOCl and physiological chloramines lead in vitro to an inhibition of DNA synthesis and cell division on skin fibroblasts (Vile G F et al., 2000).
• Non-free Proteins e.g. Collagen, etc.
• HOCl is a very strong oxidant.
• HOCl chlorinates proteins and makes them more vulnerable to an endopeptidase-degradation.
• TauCl is an oxidant with lower strength and seems to have a lesser responsibility for damage to these tissues.
• TauCl induces a direct inhibition/inactivation of collagenases while it has no effect on the collagen proteolytic susceptibility.
• leucine and alanine N-monochloramines have no inhibitory effect on collagenases and increase the proteolytic susceptibility of collagen (Davies JMS et al., 1994).
• Free protein chlorination enhances their immune sensitivity, likely via an improvement of both their treatment and presentation by antigen-presenting cells (i.e. macrophages and dendritic cells). This chlorination is ten times more important for HOCl than taurine-N-monochloramines (TauCl) but, in vivo, TauCl is more stable and, consequently, TauCl can be regarded as the main physiological chlorinating agent (Marcinkiewicz J. et al., 1999).
• ROS reactive oxygen agents
• the lipopolyssacharide-induced expression of MHC type II and molecule B7-2 is also inhibited.
• Antigens chlorinated by HOCl or TauCl do not induce an production of inflammatory mediators by the phagocytes that phagocytosed these antigens (Marcinkiewicz J. et al., 1994 & 1997).
• Chloramines such as taurine N-mono and (N,N)-dichloramine, N-monochloro-ethanolamine and N-dichlorophosphoethanolamine as well as NaOCl (sodium hypochlorite), all inhibited the release of nitric oxide in a dose-dependent manner.
• TauCl inhibits COX2 expression either in non-stimulated and INF- ⁇ -stimulated macrophages. In contrast, in INF- ⁇ -stimulated macrophages TauCl inhibits both the iNOS expression and the production of TNF- ⁇ and IL-6. TauCl had no effect on IL-1 ⁇ production for all stimulation levels. The native taurine alone had no effect on cytokine production.
• HOCl-oxidized plasma lipoproteins had an ability to reduce iNOS mRNA synthesis and, thus, to inhibit the nitric oxide production and contribute to atherosclerotic lesion development (Moeslinger T et al., 2000).
• HOCl reduces myeloperoxidase activity in a retroactive dose-dependent manner.
• TauCl and HOCl inhibit myeloperoxidase extracted from neutrophils.
• HOCl 250 ⁇ M inhibits hydrogen peroxide production in a dose-dependent manner.
• Taurine 500 ⁇ M or nitrite (250 ⁇ M) neutralizes this inhibition.
• TauCl has no effect on this production.
• HOCl and TauCl induce a chemiluminescence dose-dependent decrease
• TauCl and taurine inhibit superoxide anion (O 2 ⁇ ) production by stimulated neutrophils. This inhibition involves a different mechanism than those implicated in TauCl formation (i.e., association of the taurine (or TauCl) with a myeloperoxydase specific inhibitor generates a synergic effect).
• HOCl inactivates sulfidopeptide LTC4 sulfoxides and 6-trans-LTB4 leukotrienes only in an extracellular environment (Owen W F et al., 1987).
• TauCl inhibits production of monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-2 (MIP-2) both in dose-dependent and post-transcriptional manners (Liu Y et al., 1999).
• MCP-1 monocyte chemoattractant protein-1
• MIP-2 macrophage inflammatory protein-2
• TauCl inhibits both the iNOS gene transcriptional expression (i.e., nitric oxide production) and the COX2 expression (i.e., PGE 2 production) via a post-transcriptional mechanism (Liu Y et al., 1998).
• TauCl inhibits fibroblast-like synoviocyte proliferation and decreases the activity of major transcriptional factors of both IL-6 (IC 50 ⁇ 225 ⁇ M) and IL-8 (IC 50 ⁇ 450 ⁇ M) in a dose-dependent manner.
• IL-6 IC 50 ⁇ 225 ⁇ M
• IL-8 IC 50 ⁇ 450 ⁇ M
• TauCl reduces both IL-6 proinflammatory action and immune cell ability to migrate within an inflammatory site (via an IL-8 inhibition).
• IL-6 inhibition is independent of the fibroblast stimulating agent used (e.g. TNF- ⁇ , IL-1 ⁇ or IL-17)
• IL-8 inhibition is dependent on the stimulation via TNF- ⁇ or IL-1 ⁇ , but not via IL-17.
• NF- ⁇ B-dependent gene expression may be altered by TauCl activity.
• transduction TauCl-inhibition of IL-6 and IL-8 is executed via a DNA-bonding ability reduction of NF- ⁇ B and AP-1.
• IL-6 transcription is under a NF- ⁇ B control, while both NF- ⁇ B and AP-1 control IL-8 transcription.
• TauCl acts on both NF- ⁇ B and AP-1 transcription factors to inhibit the IL-6 and IL-8 transduction.
• TauCl decreases the DNA-bonding activity of both NF- ⁇ B and AP-1 (i.e., the transcription of IL-6 and IL-8 is reduced)(Kontny E et al., 2000).
• These two transcription factors are regulated via a redox mechanism ((Sen C. K., Packer L., Fased J. 1996; 10:709-20), (Li N. & Karin M., Fased J. 1999; 13:1137-43), (Kunsch C. & Medford R. M., Circ Res. 1999 October 15; 85(8):753-66.)).
• TauCl may interfere the intracellular redox status of these transcription factors and, therefore, some anti-inflammatory properties may be suggested from TauCl (Kontny E et al., 2000).
• the C 5 component of the human complement may be activated by oxidants, e.g., hydroxyl radicals, hypochlorite or chloramines (i.e., TauCl and mainly NH 2 Cl).
• oxidants e.g., hydroxyl radicals, hypochlorite or chloramines (i.e., TauCl and mainly NH 2 Cl).
• This activation is due to a C 5 structural change induced by a Met. residue oxidation within the C 5 protein without peptide cleavage.
• C 6 bonding site expression which normally is formed after a C 5 specific cleavage in C 5a and C 5b , via one of two C 3 /C 5 convertases.
• the C 5 -oxidation product is similar to C 5B .
• it is able to initiate the combination of the C 5-9 membrano-lytic complex.
• Chemotactic fragments are not directly generated, but activated C 5 components (like C 5b ) are readily attacked by enzymes such as kallikrein, which produce C 5a -like fragments that have a chemotactic activity. It is likely that the C 567 complex generated with C 5 also have a chemotactic activity (i.e., similarly to C 5b67 complex). In addition, the C 5b-9 complex is known to stimulate PMNs at non-toxic concentrations. Thus, the same property may be suggested for the corresponding C 5-9 complex and, consequently, this may lead to a vicious circle that increases tissue lesions (Vogt W, 1996).
• This invention relates to a pharmaceutical composition including at least one halogenated compound, and at least one N-halogenated derivative of at least one compound selected from zwitterionic and/or amino acid compounds, where the composition does not generate substantial stimulation of myeloperoxidase activity in a mammal.
• This invention also relates to a method of preparing a pharmaceutical composition including mixing at least one halogenated compound and at least one zwitterionic compound and/or at least one amino acid or their derivatives, and optionally at least one excipient to obtain at least one N-halogenated derivative, and at least one halogenated compound in a sufficient therapeutic amount to not substantially stimulate myeloperoxidase activity in a mammal.
• This invention further relates to a method for treatment and/or preventing viral infections, and/or bacterial infections, and/or parasitical infections and/or fungal infections and/or diseases generated from non-conventional transmissible agents, in humans or animals including administering to a human or animal a pharmaceutically effective amount of a pharmaceutical composition including at least one halogenated compound, and at least one N-halogenated derivative of at least one compound selected from zwitterionic compounds and/or the amino acids or their derivatives without substantial stimulation or myeloperoxidase activity in the human or animal.
• NaOCl contributes to (1) an increase in the transition to the cleansing of necrotic and suppurating mass, (2) stimulates local immunity and (3) activates the tissue regeneration process.
• sodium hypochlorite i.e., hypochlorous acid (HOCl) properties and the hydrolysis generated from sodium hydroxide (NaOH)
• NaOH sodium hydroxide
• this invention provides a pharmaceutical composition
• a pharmaceutical composition comprising (i) at least one halogenated compound and (ii) at least one N-halogenated derivative of at least one compound selected from zwitterionic and/or amino acid compounds.
• the halogenated compound (i) is an antiseptic.
• Amino acids included in the constitution of compositions according to the invention can be natural amino acids, derivatives or analogous of the latter.
• the halogen of the (i) halogenated compounds and the (ii) N-halogenated derivatives of the invention composition may be fluorine, iodine, bromine, and mainly chlorine.
• the halogenated compound (i) is an alkaline metal hypochlorite, and preferably the sodium hypochlorite
• the N-halogenated derivative (ii) is an N-halogen derivative of taurine and preferably a taurine N-halo-amine and even more preferably taurine N-chloramine.
• the invention composition is remarkable from its robust properties such as large spectrum of application such as anti-inflammatory, immunity modulation, and tissue healing stimulation as well as those without stimulation of myeloperoxidase activity.
• the hypochlorite titer of the invention composition is preferably below or equal to about 1 mole/liter of available chlorine, and can be adapted to clinical use.
• the invention composition contains a hypochlorite of alkaline metal.
• the invention composition contains a sodium hypochlorite q.s. with a minimum titer of available chlorine that is greater than or equal to about 1 picomole/liter.
• the N-chloramine titer of the invention composition is preferably less than or equal to abut 5 moles/liter, and may be adapted to clinical use.
• the invention composition contains an N-halogenated derivative, such as the taurine N-chloramine, with a concentration between about 5 moles/liter and about 0.01 femtomoles/liter.
• the invention composition contains a N-halogenated derivative such as the taurine N-chloramine, q.s. with a minimum titer greater than or equal to about 0.01 femtomoles/liter.
• the (i) halogenated compound and the (ii) N-halogenated derivative are associated in the composition according to the invention with an excipient, such as purified water, in accordance with therapeutic use.
• an excipient such as purified water
• it concerns an osmotic (isotonic) purified water.
• This excipient may contain diverse agents, pharmaceutically compatible with both (i) the halogenated compound and (ii) the N-halogenated derivative, and which can allow for modification of some physicochemical properties such as stability, pH, pKa, density, solubility, viscosity, coloring, water/ectanol sharing factor, and surface-active, oxidative, olfactory, or gustatory properties of the invention composition via a suitable agent addition.
• the invention composition may also contain some anti-oxidants and/or amino acids that have a dilution effect via neutralization of some alkaline metal hypochlorite molecules.
• These anti-oxidants, amino acids and their N-halogenated derivatives should have a neutral pharmacological activity or its activity should be pointed to therapeutic aims and should not exercise a direct stimulation of myeloperoxidase activity in the presence of invention composition active agents.
• the invention also concerns the preparation of the composition described above.
• this composition can be sold in a form to prepare before use, i.e., (i) the halogenated compound(s) can be mixed with (ii) the N-halogenated derivative(s) and one or several excipients.
• This presentation form can be considered if it is required to guarantee the best time stability of the composition and, in particular, the active agents that constitute the latter.
• the invention composition can be sold with an excipient, such as purified water according to the therapeutic use. Preferably, this should be an osmotic (isotonic) purified water.
• this excipient may contain diverse agents pharmaceutically compatible with the totality of final composition molecules, which allow for the modification of some physicochemical properties of the invention composition via an addition of suitable agent(s) such as stability, pH, pKa, density, solubility, viscosity, coloring, water/ectanol sharing factor, and surface-active, oxidative, olfactory, or gustatory properties.
• suitable agent(s) such as stability, pH, pKa, density, solubility, viscosity, coloring, water/ectanol sharing factor, and surface-active, oxidative, olfactory, or gustatory properties.
• the invention composition can also be prepared before its administering to the patient via a mixture comprising:
• the halogen(s) of the halogenated compound (i) and the N-halogenated derivative (ii) may be selected from fluorine, iodine, bromine, and/or chlorine, most preferably chlorine.
• the halogenated compound (i) is a halide such as an alkaline metal hypochlorite, and preferably the sodium hypochlorite
• the N-halogenated derivative (ii) is a taurine N-halogenated derivative and preferably a taurine N-haloamine and even more preferably the taurine N-chloramine.
• halogenated compound(s) (i) are usefully displayed in a liquid or semi-liquid (such as a gel) solution form, favorably within an excipient as described below.
• solutions advantageously hypochlorite solutions, may be stabilized in accordance with the patent EP 0 471 129 A1 via a pH regulatory agent to generate a pH between 10 and 10.5 with respect to cell viability.
• N-halogenated derivative(s) (ii) are usefully displayed in a liquid or a semi-liquid (such as a gel) solution form, favorably within an excipient as described below.
• the invention composition may be prepared via a mixture of the two solutions described above with at least one excipient according to therapeutic use such as purified water. It preferably contains the osmotic (isotonic) purified water.
• this excipient can contain diverse agents, pharmaceutically compatible with all molecules of the final mixing to modify some physicochemical properties of the invention composition such as stability, pH, pKa, density, solubility, viscosity, coloring, water/ectanol sharing factor, and surface-active, oxidative, olfactory, or gustatory properties via an addition of suitable agent(s).
• the invention composition may be prepared via a mixture of the two following solutions:
• Zw/Aam zwitterionic compound and/or at least one amino acid and/or at least one primary or secondary amine
• This mixture is preferably realized with an excipient as defined above.
• Zw/Aam is an amino acid, it preferably concerns taurine or a taurine pharmaceutical analog.
• the antiseptic halogenated compound (i) is a halide such as alkaline metal hypochlorite (which is an alkaline metal salt of hypochlorous acid)
• derivatives generated will be N-chlorinated, and these will more particularly be N-chloramines.
• hypochlorite titer of the first active solution (i) should take into consideration the stoichimetry and reactivity level of the reaction between hypochlorous acid and Zw/Aam molecules. In case this reaction is not complete, remaining Zw/Aam molecules should not stimulate myeloperoxidase activity in the presence of invention composition active agents.
• the hypochlorite titer of the first active solution is preferably lower than or equal to about 6 moles/liter of available chlorine, and must be adapted both to the Zw/Aam molecule amount of the second solution and to clinical status.
• the halide solution (i) favorably contains an alkaline metal hypochlorite.
• the haloid solution (i) contains sodium hypochlorite q.s. with an available chlorine titer between abut 6 moles/liter and about1,000.01 femtomoles/liter.
• the taurine titer of the second solution (iii) of this invention preparation method is preferably lower than or equal to about 1 moles/liter and may be adapted to clinical use. It is useful for the second solution (iii) of this invention preparation method to have a taurine concentration between about 5 moles/liter and about 0.01 femtomole/liter. Even more preferably, the second solution (iii) of this preparation method has a taurine titer greater than or equal to about 0.01 femtomole/liter.
• the excipient(s) preferably added in methods described above may be used as a secondary diluting solution with the aim to adapt the treatment to the clinical status. It usefully concerns osmotic (isotonic) purified water. This excipient will favorably be similar to the excipient used for the compounds and derivatives that have been mixed, and if they are not identical, the excipient should be pharmaceutically compatible to be mixed with the other excipient(s), before all clinical uses.
• this excipient can contain diverse agents, pharmaceutically compatible with all molecules of the final therapeutic mixture with the object of modifying some physicochemical properties of the invention composition such as stability, pH, pKa, density, solubility, viscosity, coloring, water/ectanol sharing factor, and surface-active, oxidative, olfactory, or gustatory properties via an addition of a suitable agent(s).
• This excipient may contain anti-oxidants and/or amino acids that will have both a dilution effect and an oxidant neutralization of the active solution (i) (e.g., the alkaline metal hypochlorite).
• These anti-oxidants, amino acids and their halogenated derivatives should have a neutral pharmaceutical activity or a pharmaceutical activity inducing the desired therapeutic effect. In all cases they should be both less toxic than the oxidants of (i) the main active solution and pharmaceutically compatible with all molecules of the final therapeutic solution.
• composition according to the invention can also be sold in a form adapted to local use, e.g., a gel or an aerosol.
• the above-mentioned invention composition is particularly useful in humans or animals for treatments of viral infections and/or bacterial infections and/or parasitical infections and/or fungal infections and/or diseases generated from non-conventional transmissible agents; and/or for treatments of chronic, progressive or acute inflammation; and/or for immunity modulator treatments; and/or for tissue regeneration stimulator treatments.
• the therapeutic composition may be used in pre-surgical irrigations and/or per-surgical irrigations and/or post-surgical irrigations.
• the invention concerns particularly the local treatment of infections due to herpesviridiae family virus.
• the invention composition is preferably used locally aiming to remove secondary effects, e.g., atherosclerosis. It can be applied to all external or internal mucous (e.g., oral, genital, vaginal, ophthalmic, otic, sinusal, nose-and-throat, dermal, and the like).
• the invention composition may appear under an adapted form for this administration, such as in a semi-liquid form (e.g., a gel) via an addition of one or several compatible pharmaceutical substances e.g., cellulose, amino acids, peptides, and/or proteins.
• the invention composition may also be adapted to clinical status and/or injured mucous. This adaptation is executed via a concentration change of active products of the therapeutic solutions.
• concentrations between about 1 and about 0.2 moles/liter of sodium hypochlorite, and approximately between about 100 to about 0.001 picomoles/liter of TauCl are preferred (i.e., these concentrations vary with organic matter amount present in canals).
• a sodium hypochlorite concentration between about 0.1 and about 0.02 mole/liter and a TauCl concentration between about 1 and about 0.001 picomoles/liter are preferable (non-restricting example).
• a sodium hypochlorite concentration between about 20 and about 10 millimoles/liter of available chlorine and a TauCl concentration between about 1 and about 0.01 nanomole/liter are preferable (non-restricting example).
• preferred concentrations may be between about 10 and about 2 millimoles/liter of available chlorine for sodium hypochlorite (NaOCl), and between about 50 and about 1 micromoles/liter for TauCl (non-restricting example).
• concentrations may be between about 50 and about 10 millimoles/liter of available chlorine for NaOCl and between about 0.1 and about 0.001 picomoles/liter for TauCl (non-restricting example).
• concentrations may be between about 10 and about 5 millimoles/liter of available chlorine for NaOCl and between about 1 and about 0.01 nanomoles/liter for TauCl (non-restricting example).
• concentrations may be between about 5 and about 0.8 millimoles/liter of available chlorine for NaOCl and approximately between about 50 and about 1 micromoles/liter for TauCl (non-restricting example).
• concentrations may be between about 5 and about 0.1 millimoles/liter of available chlorine for NaOCl and between about 1 and about 0.01 femtomoles/liter for TauCl (non-restricting example).
• concentrations may be between about 0.1 and about 0.01 millimoles/liter of available chlorine for NaOCl and between about 50 and about 1 micromoles/liter for TauCl (non-restricting example).
• concentrations could be between about 500 and about 1 micromoles/liter of available chlorine for NaOCl and between about 200 and about 10 micromoles for TauCl (non-restricting example).
• the composition according to the invention is useful for local treatment of diseases or inflammatory processes that can be chronic, and/or progressive and/or acute.
• the composition is also recommended for pre- surgical irrigation and/or per-surgical irrigation and/or post-surgical irrigation of internal and/or external mucous and of opened-injures.
• the invention more particularly concerns a treatment method of lesions and infections described above, which comprises contacting the invention composition on mucous that must be treated, (for non-restricting example) between 2 and 3 times a day and approximately during 20 to 60 seconds, not followed by a rinsing.
• the composition amount employed should be sufficient to not generate a total neutralization of the therapeutic active agents. In the therapeutic use, the invention solution should not stay static. Concentrations of the composition invention should be adapted to the evolution of the clinical status until healing.
• the invention more particularly concerns the local treatment of lesions and infections linked to chronic and/or acute parodontitis.
• the invention composition is usefully adapted for irrigation of periodontal pockets, with the aim for removing these periodontal pockets as the composition has both antiseptic and anti-inflammatory activities, and acts as an immunity modulator and healing stimulator of periodontal tissues (i.e., alveolar bone, alveolodental ligament and gingiva).
• Chronic periodontitis is a disease mainly due to pathologic action of anaerobic bacteria, and particularly Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Bacteroides forsythus and Prevotella intermedia. These bacteria induce chronic inflammatory processes that generate a progressive destruction of periodontal tissues (teeth supporting tissue). Periodontitis may result in the removal of bone tissue followed by tooth loss.
• periodontal pocket irrigations have to be executed in the presence of a strong surgical vacuum extraction with the object of avoiding swallowing or inhalation of the therapeutic solution by the patient.
• J 1 after an assessment of the clinical status, crevicular spaces (with or without periodontal pockets) of oral cavity teeth should be irrigated. A full mouth followed by a tongue brushing, with a mixed solution of 0.1% chlorhexidine and 0.3% hydrogen peroxide, should be prescribed twice a day (far from the teeth brushing) over ten days, then twice to three times a week ad vitam aeterman (however, in halitosis, the initial attack treatment should be repeated). Two or three appointments should be scheduled.
• a probing session (this consists first of an irrigation followed by a probing depth) should be executed to evaluate the degree of periodontal disease.
• Some complementary examinations can be made such as sampling picks up and biological examinations.
• a maintenance treatment should be executed. This treatment type is similar to the secondary curative treatment except that appointments should be made once every three weeks.
• the treatment should be started again at a stage that depends on the clinical status observed, i.e., the attack treatment, or the primary or the secondary curative treatment.
• the treatment should be started again at a stage that depends on the clinical status observed (i.e., the attack treatment, or the primary or the secondary curative treatment).
• the invention also concerns bone-filling surgical periodontal treatments with some biomaterials associated with the invention composition and/or one of its components.
• Cantin A M. Taurine modulation of hypochlorous acid-induced lung epithelial cell injury in vitro. Role of anion transport.—J Clin Invest. 1994 February; 93(2):606-14.
• Huxtable R J Sources and turnover rates of taurine in nursing and weaned rat pups.—J. Nutr. 1981; 111:1275-86.
• Liu Y et al. Taurine chloramine inhibits production of nitric oxide and protaglandin E2 in activated C6 glioma cells by suppressing inducible nitric oxide synthase and cyclo-oxygenase-2 expression.—Brain res mol brain res. 1998 August 31; 59(2):189-95.

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