Patent Application: US-97641410-A

Abstract:
a method of stimulating tissue healing in humans or animals includes administering to a human or animal suffering from lesions and infections linked to chronic and / or acute periodontitis a pharmaceutically effective amount of a pharmaceutical composition including at least one sodium halopohalite , and at least one n - halogenated taurine , wherein halogens from the at least one sodium halopohalite and from the at least one n - haloamine taurine , which may be the same or different , are selected from the group consisting of fluorine , iodine , bromine and chlorine .

Description:
i have discovered that in inflammatory sites , beyond any bactericidal activity , 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 . these abilities are induced from sodium hypochlorite ( i . e ., hypochlorous acid ( hocl ) properties and the hydrolysis generated from sodium hydroxide ( naoh )) and its n - chlorinated derivatives . consequently , i provide 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 . amino acids included in the constitution of compositions can be natural amino acids , derivatives or analogous of the latter . more particularly , the halogen of the ( i ) halogenated compounds and the ( ii ) n - halogenated derivatives of the composition , similar or different , may be fluorine , iodine , bromine , and mainly chlorine . favorably , the halogenated compound ( i ) is an alkaline metal hypochlorite , and preferably the sodium hypochlorite , and 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 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 composition is preferably below or equal to about 1 mole / liter of available chlorine , and can be adapted to clinical use . usefully , the composition contains a hypochlorite of alkaline metal . preferably , the 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 composition is preferably less than or equal to abut 5 moles / liter , and may be adapted to clinical use . usefully , the 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 . preferably , the 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 with an excipient , such as purified water , in accordance with therapeutic use . preferably , 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 composition via a suitable agent addition . the 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 composition active agents . this disclosure also concerns the preparation of the composition described above . thus , 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 . however , even in a presentation where the constituting products would be associated , the 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 . in addition , 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 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 . the composition can also be prepared before its administering to the patient via a mixture comprising : ( ii ) at least one n - halogenated derivative of at least one compound selected from zwitterionic and / or amino acid compounds , and their derivatives . more particularly , 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 . favorably , the halogenated compound ( i ) is a halide such as an alkaline metal hypochlorite , and preferably the sodium hypochlorite , and 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 . the aforementioned 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 . these 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 . the aforementioned 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 . favorably , the 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 . in addition , this excipient can contain diverse agents , pharmaceutically compatible with all molecules of the final mixing to modify some physicochemical properties of the 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 ). in addition to the process described above , the composition may be prepared via a mixture of the two following solutions : ( i ) at least one halogenated compound as defined above , which is usefully displayed in a liquid or a semi - liquid ( such as a gel ) solution form , preferably within an excipient as described above , ( iii ) at least one zwitterionic compound and / or at least one amino acid and / or at least one primary or secondary amine , ( the zwitterionic compound and / or amino acid and / or primary or secondary amino amine are later referred to as “ zw / aam ”), which is usefully displayed in a liquid or a semi - liquid ( such as a gel ) solution form , favorably within an excipient as described above , to obtain an association of both ( i ) at least one halogenated compound and ( ii ) at least one n - halogenated derivative , and this with a sufficient therapeutic amount of molecules to inhibit myeloperoxidase activity . this mixture is preferably realized with an excipient as defined above . in case zw / aam is an amino acid , it preferably concerns taurine or a taurine pharmaceutical analog . in this realization method , when 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 . the 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 composition active agents . in case the stoichimetry is 1 / 1 and with a complete reaction ( e . g ., between hypochlorous acid and taurine ), 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 . in this preparation method , the halide solution ( i ) favorably contains an alkaline metal hypochlorite . even more preferably , the haloid solution ( i ) contains sodium hypochlorite q . s . with an available chlorine titer between abut 6 moles / liter and about 1 , 000 . 01 femtomoles / liter . the taurine titer of the second solution ( iii ) of this 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 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 . in addition , 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 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 . the composition can also be sold in a form adapted to local use , e . g ., a gel or an aerosol . the above - mentioned 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 . in addition , the therapeutic composition may be used in pre - surgical irrigations and / or per - surgical irrigations and / or post - surgical irrigations . this disclosure concerns particularly the local treatment of infections due to herpesviridiae family virus . the 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 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 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 . for endodontic treatment , 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 ). with highly stained keratinized mucous ( with profuse presence of organic matter ( infectious agents , blood , profuse and varying secretions , suppurating discharge , etc . )), 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 ). with moderately stained keratinized mucous ( with some organic matter visible on a compress after a gentle friction , for 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 ). with clean keratinized mucous ( without organic matter visible ), 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 ). with highly stained non - keratinized mucous , 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 ). with moderately stained non - keratinized mucous , 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 ). with clean non - keratinized mucous , 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 ). with important and sensible organs ( eyes ), concentrations must both be the least toxic ( via a high dilution or a specific scavenge of naocl by an antioxidant addition ) and executed with a profuse diluted irrigation : for stained organs , 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 ). for non - stained organs , 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 ). ii ) for the treatment of non - stained organs with the object of immune stimulation and / or tissue regeneration , 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 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 . this disclosure more particularly concerns a treatment method of lesions and infections described above , which comprises contacting the 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 solution should not stay static . concentrations of the composition should be adapted to the evolution of the clinical status until healing . this disclosure more particularly concerns the local treatment of lesions and infections linked to chronic and / or acute parodontitis . thus , the 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 . whatever the treatment phase of chronic periodontitis , 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 . i ) attack treatment ( i . e ., between two and three weeks up to the disappearance of bleeding in probing depth of periodontal pockets ). 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 . in the other sessions , the following process will be recommended : education , checking , and motivation for periodontal hygiene ; meticulous irrigation ( 1 ml minimum of the highly stained keratinized mucous solution for each periodontal site ); meticulous scaling and root planning . when all root surfaces are planned and cleaned , 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 . meticulous irrigation of periodontal pockets once every ten days applying the solution for moderately stained keratinized mucous , except for sites with a profuse dental plaque ( such as interdental furcations ) where the solution for highly stained keratinized mucous should be applied . at the last session of the primary curative treatment , an irrigation follows probing depth and root planning . iii ) secondary curative treatment ( until clinical removal of the periodontal pockets ). meticulous irrigation of periodontal pockets once every ten days with the solution for clean keratinized mucous , except for sites with + or − profuse dental plaque ( e . g ., interdental furcations ) where the therapeutic composition for highly or moderate stained keratinized mucous should be used . every three sessions of the secondary curative treatment , an irrigation follows probing depth of periodontal pockets and root planning in any diagnostic of clinical healing , 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 . if after two mouths of treatment a notable healing rather than a recurrence is observed , the last treatment phase — supervision — can be initiated . in case of recurrence , 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 . an appointment should be made once every six weeks . a meticulous probing depth will be practiced . in case of no - recurrence , all crevicular spaces should be irrigated with the solution for moderate stained or clean keratinized mucous , followed by a meticulous root planning in case of recurrence , 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 ). in addition , this disclosure also concerns bone - filling surgical periodontal treatments with some biomaterials associated with the composition and / or one of its components . the subject matter of the bibliographical references listed below is incorporated by reference . 1 . bloomfield s f , miles g a .— the antibacterial properties of sodium dichloro - isocyanurate and sodium hypochlorite formulations .— j appl bacteriol . 1979 february ; 46 ( 1 ): 65 - 73 . 2 . 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 - 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