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WO2018145185A1 - Utilisation du diéthylcarbamazine incorporée dans des compositions pharmaceutiques pour le traitement et/ou la prévention de maladies inflammatoires chez l'homme ou l'animal - Google Patents

Utilisation du diéthylcarbamazine incorporée dans des compositions pharmaceutiques pour le traitement et/ou la prévention de maladies inflammatoires chez l'homme ou l'animal Download PDF

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Publication number
WO2018145185A1
WO2018145185A1 PCT/BR2018/050027 BR2018050027W WO2018145185A1 WO 2018145185 A1 WO2018145185 A1 WO 2018145185A1 BR 2018050027 W BR2018050027 W BR 2018050027W WO 2018145185 A1 WO2018145185 A1 WO 2018145185A1
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Prior art keywords
dec
pharmaceutically acceptable
pharmaceutical
acceptable salts
diethylcarbamazine
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Inventor
Francisco JAIME BEZERRA MENDONÇA JUNIOR
Elquio ELEAMEN DE OLIVEIRA
Christina ALVES PEIXOTO
Gabriel BARROS RODRIGUES
Brennda MARTINS GABÍNIO
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UNIVERSIDADE ESTADUAL DA PARAIBA
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UNIVERSIDADE ESTADUAL DA PARAIBA
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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5192—Processes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid

Definitions

  • the present invention refers to the field of inflammation and treatment and/or prevention of acute or chronic inflammatory pathologies, which may be associated with fibrotic processes for human and/or animal use.
  • the present invention is directed to the use of diethylcarbamazine (DEC) , and/or its pharmaceutically acceptable salts, incorporated to pharmaceutical and veterinary compositions, in the manufacture of a medicament for the treatment or prevention of acute and/or chronic inflammatory pathologies, which may be associated with fibrotic processes in human beings and animals.
  • DEC diethylcarbamazine
  • the present invention also refers to a pharmaceutical composition containing an effective amount of DEC, and/or its pharmaceutically acceptable salts, and excipients.
  • the present invention was developed mainly for the treatment and/or prevention of acute or chronic human and veterinary inflammatory diseases associated or not with fibrotic processes, in particular, but not exclusively, or limited to: chronic obstructive disease, asthma, pulmonary hypertension, acute pulmonary inflammation such as respiratory distress syndrome (ARDS), pleuritis, hepatitis, cirrhosis, asthma, arthritis, arthrosis, systemic sclerosis, sclerodermatous graft-versus-host disease in bone marrow transplant recipients, Crohn's disease, cystic fibrosis, pulmonary fibrosis, intestinal fibrosis, liver fibrosis, kidney fibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, and keloid.
  • chronic obstructive disease asthma, pulmonary hypertension, acute pulmonary inflammation such as respiratory distress syndrome (ARDS), pleuritis, hepatitis, cirrhosis, asthma, arthritis, arthrosis, systemic sclerosis,
  • the present invention is based on experiments demonstrating that DEC, and/or its pharmaceutically acceptable salts, incorporated into a pharmaceutical and/or veterinary composition (generally called NANO-DEC) when administered via one of the administration routes described below, exhibits greater anti ⁇ inflammatory and anti-fibrotic response than DEC administered alone.
  • a pharmaceutical and/or veterinary composition generally called NANO-DEC
  • the NANO-DEC may be administered or combined with one or more anti-inflammatory, or immunomodulatory, corticoid, analgesic, anti-fibrotic, antitumor, antimycobacterial , fungicidal or antibiotic or immunobiological agents commonly indicated or used for the treatment or prophylaxis of inflammatory and fibrosis diseases.
  • compositions containing DEC, and/or its pharmaceutically acceptable salts may help prevent or treat various acute or chronic conditions
  • compositions as a filaricidal agent, in the treatment of microfilariae infections.
  • Inflammation is "the body's immediate response to damage to its tissues and cells by pathogens, noxious stimuli such as chemicals, or physical injury" [Weiss, 2008].
  • the inflammation can be of two types: acute or chronic.
  • Acute inflammation is a short-term response that usually results in healing: polymorphonuclear leukocytes (neutrophils) infiltrate the damaged region, removing the stimulus and repairing the tissue.
  • Chronic inflammation by contrast, is a prolonged, dysregulated and maladaptive response that involves active inflammation, tissue destruction and attempts at tissue repair.
  • the main characteristic cells in chronic inflammation are the mononuclear leukocytes (lymphocyte and macrophage) .
  • This inflammation (chronic) is usually associated with many chronic human diseases, and diseases, including cancer, allergies, atherosclerosis, arthritis, autoimmune diseases, among others [Weiss, 2008].
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • steroids steroids
  • Fibrosis is a pathological process characterized by excessive accumulation of connective tissue components in an organ or tissue as part of a healing process or fibroid degeneration. Fibrogenesis is a multistage process, now increasingly seen as the result of deregulated tissue repair responses, that occurs in response to chronic tissue injury and/or chronic inflammation, in which aberrantly sustained production of cytokines, growth factors, and angiogenic factors tilt tissue homeostasis towards interstitial hyperplasia and excessive accumulation of extracellular matrix. Progressive fibrosis, which disrupts the normal tissue architecture and results in progressive loss of organs functions, which ultimately leads to their dysfunction and failure, is recognized to be one of the major causes of morbidity and mortality in individuals [Rosenbloom et al . , 2010; Ho et al., 2014] .
  • Fibrotic diseases affect a wide spectrum of organs and a large number of persons, and their devastating effects cause an enormous burden on health resources with severe economic
  • the fibrotic diseases encompass a broad spectrum of clinical diseases, including multisystemic diseases, such as systemic sclerosis, multifocal fibrosclerosis , Crohn's disease, sclerodermatous graft-versus-host disease in bone marrow transplant recipients, as well as organ-specific disorders, such as pulmonary, liver, intestine, myocardium, peritoneum and kidney fibrosis.
  • multisystemic diseases such as systemic sclerosis, multifocal fibrosclerosis , Crohn's disease, sclerodermatous graft-versus-host disease in bone marrow transplant recipients, as well as organ-specific disorders, such as pulmonary, liver, intestine, myocardium, peritoneum and kidney fibrosis.
  • Inflammatory and fibrotic diseases are commonly associated with high morbidity and mortality.
  • conventional drug treatments in particular through the use of nonsteroidal anti ⁇ inflammatory drugs (NSAIDs) and steroids have low efficacy and serious adverse effects. It is clear the need to
  • the present invention discloses the use of pharmaceutical and/or veterinary compositions containing diethylcarbamazine (DEC) as a safe anti-inflammatory and anti- fibrotic, for use in the treatment or prophylaxis of acute and/or chronic inflammatory conditions, associated or not to fibrotic processes, for human or animal uses.
  • DEC diethylcarbamazine
  • Dietilcarbamazine has as chemical name 1- diethylcarbamyl-4-methylpiperazine, its CAS Registry Number is 90- 89-1. Its molecular formula is C10H21N3O, it molecular weight is 199,293 g/mol, and its structural formula is presentd below in Figure 1.
  • Diethylcarbamazine is a widely used drug in the treatment of filariasis and has excellent tolerability with low side effects.
  • DEC is sold as salts, where the most common are hydrochloride, citrate or phosphate.
  • DEC citrated salt
  • DEC is rapidly absorbed from the gastrointestinal tract, reaching a peak plasma concentration between one and three hours after oral intake, not concentrating on any specific organ, being metabolized in the liver and its excretion is basically renal [Ilondu et al. , 2000] .
  • the arachidonic acid pathway includes the lipoxygenase (LOX) and cyclooxygenase (COX) enzymes.
  • LOX lipoxygenase
  • COX cyclooxygenase
  • the COX pathway exhibits similarity to the nitric oxide pathway, both of which have constitutive and inducible isoforms of their enzymes and control inflammatory responses [McGarry et al . , 2005].
  • DEC lipoxygenases
  • COX cyclooxygenase
  • Rodrigues et al . (2015) demonstrated that treatment with DEC was able to reduce liver damage, collagen content, expression of inflammatory markers; (total cholesterol, high-density lipoprotein cholesterol, triglyceride content and aspartate aminotransferase) , as well as increasing the expression of anti ⁇ inflammatory markers (AMPK and interleukin-10) .
  • the pharmaceutical industry has opted for the search of second uses of commercially available drugs. This procedure presents less cost than the process of discovering a new chemical entity (new drug) , and decrease the time required for approval of the use of the drug by regulatory agencies, due to less need for pre-clinical and clinical trials and tests.
  • the present invention has its innovative character in claiming the use of pharmaceutical and/or veterinary compositions containing DEC, or its pharmaceutically acceptable salts, for therapeutic purposes for the treatment or prophylaxis of acute and / or chronic inflammatory conditions, associated or not with fibrotic processes.
  • the present invention demonstrates that the incorporation of DEC, and/or its pharmaceutically acceptable salts, in pharmaceutical and veterinary compositions exhibits enhanced anti ⁇ inflammatory and anti-fibrotic, dose-reducing and treatment-time efficacy in experimental models of inflammation as compared to groups treated with DEC alone.
  • the present invention also includes the use of any physiologically and/or pharmaceutically acceptable salts and/or any conventional base salts of DEC that are incorporated into pharmaceutical and/or veterinary compositions for use for therapeutic purposes for the treatment or prophylaxis of acute or chronic inflammatory conditions, associated or not to fibrosis.
  • salts are selected from the group, but not limited to: alkali metal salts, preferably sodium and potassium salts, alkaline earth metal salts (calcium and magnesium salts), chloride, bromide, hydrochloride, acetates, maleate, mesylate, nitrate, tartrate, gluconate, citrates, carbonates, carbamates, phosphates, diphosphates, phosphonates , glycosides, sulfates, sulfonates and ammonium salts derived from amine or organic amines having from 1 to 16 carbon atoms.
  • the administration of pharmaceutical and/or veterinary compositions containing DEC can act systemically and/or locally, and may be performed by the following administration routes: oral, sublingual, nasal, rectal, intragingival , endovenous, intramuscular, intraarticular, subcutaneous, cutaneous (patch or transdermal patch) , inhalatory, transdermal, topical or spinal (subarachnoid and peridural), parenteral, con unctival, optic, or as an implant or stent, not being limited to these.
  • oral route is preferred.
  • the suitable forms for oral administration are those which function according to the prior art, which release the pharmaceutical compositions containing DEC, or its pharmaceutically acceptable salts, rapidly and/or in a modified/controlled manner and which contain the DEC, or its pharmaceutically acceptable salts, according to the present invention in crystalline and/or amorphous forms and/or dissolved form or in the form of salts, for example tablets (tablets uncoated or coated, for example with resistance to gastric juice or by dissolution or insoluble coatings that control the release of the compound according to the present invention) , tablets or films/wafers, which disintegrate rapidly into the oral cavity, films/lyophilisates, capsules (for example hard or soft gelatine capsules), sugar coated tablets, granules, lozenges, powders, emulsions, suspensions , pills, powders, granules, powders, aerosols or solutions.
  • tablets tablettes uncoated or coated, for example with resistance to gastric juice or by dissolution or insoluble coatings that control the
  • Parenteral administration may bypass an absorption step
  • parenteral administration include the injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilizates and sterile powders.
  • suitable examples are inhalation medications (including powder inhalers, nebulizers), nasal drops, solutions or sprays; tablets for oral, sublingual or buccal administration, films or capsules/cachets, suppositories, ear or eye preparations, vaginal capsules, ova, aqueous suspensions (lotions, stirring mixtures), gels, lipophilic suspensions, ointments, creams, ointments, therapeutic systems transdermal (eg. adhesives), milk, pastes, foams, powders, implants or stents.
  • inhalation medications including powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • tablets for oral, sublingual or buccal administration films or capsules/cachets, suppositories, ear or eye preparations, vaginal capsules, ova, aqueous suspensions (lotions, stirring mixtures), gels, lipophilic suspensions, ointments, creams, ointments, therapeutic systems transderma
  • the present invention provides pharmaceutical forms comprising pharmaceutical and/or veterinary compositions containing DEC, or its pharmaceutically acceptable salts, usually together with one or more pharmaceutically suitable auxiliaries (pharmaceutical ad uvants/excipients ) , and the use thereof for the purposes previously mentioned.
  • the DEC-containing and/or DEC salts-containing compositions according to the present invention for generating a pharmaceutical or veterinary composition is carried out in a manner known per se by converting the DEC or DEC-salts to the desired form of administration with the usual pharmaceutically acceptable excipients for pharmaceutical compositions.
  • Suitable carriers and compositions are known to those skilled in the art or may be obtained from, for example, United States Pharmacopoeia, European Pharmacopoeia, British Pharmacopoeia, Brazilian Pharmacopoeia, Remington's Pharmaceutical Sciences, 18th ed. (1990) .
  • the pharmaceutically acceptable excipients used may, but not exclusively, or limited to: carrier substances, fillers, disintegrants , binders, wetting agents, absorbents and adsorbents, diluents, solvents, cosolvents, emulsifiers, solubilizers, flavoring agents, colorants, preservatives, stabilizers, wetting agents, salts for modifying osmotic pressure or buffers.
  • auxiliary agents are lipids, cyclodextrins , nonionic surfactants, polymers such as (acrylates and derivatives thereof, poly- ⁇ - caprolactone, poly (lactic acid), polyglycolic acid, co-glycolic poly lactic acid, methacrylated derivatives, cholesterol, among others .
  • the pharmaceutically acceptable excipients used in the context of the present invention may for example be, without being limited to: saccharides salts (mono-, di-, tri-, oligo- and / or polysaccharides), proteins, amino acids, peptides, fats, waxes, oils, hydrocarbons and the derivatives thereof and the auxiliaries may be of natural or synthetic or partially synthetic origin.
  • compositions of the present invention may be in solid form, for example, without being limited to: tablets, lozenges, pellets, suppositories, capsules, pills, powders, granules, films, cachets, sugar-coated or semi-solid transdermal systems, for example, as ointments, creams, gels, suppositories, emulsions or in liquid form, for example as solutions, tinctures, suspensions or emulsions.
  • compositions of this invention may further be in the form of novel pharmaceutical forms including: liposomes, cyclodextrin complexes, nanospheres, nanocapsules , nanoparticles , microcapsules, microspheres, nanoemulsions , microemulsions and solid lipid particles.
  • the present invention further provides the use of DEC, or its pharmaceutically acceptable salts, in pharmaceutical and/or veterinary compositions according to the present invention for the preparation of a therapeutic scheme for the treatment and/or prevention of acute and/or chronic inflammatory diseases, which may be associated with fibrotic processes, in humans and/or animals.
  • compositions of DEC, and its pharmaceutically acceptable salts, according to the present invention may be employed alone, individually or, if necessary, in combination with one or more other pharmacologically active substances, provided that this combination does not lead to unacceptable side effects. Accordingly, the present invention further provides a pharmaceutical and/or veterinary composition of DEC, and its pharmaceutically acceptable salts, according to the present invention and one or more other active compounds or medicaments and/or drugs, in particular used in the prophylaxis and/or therapy of inflammatory diseases associated or not with fibrotic processes.
  • the present invention demonstrates a second use of an active ingredient (diethylcarbamazine- DEC) already known and used in treatment for filariasis (a medicine of choice) , which upon evaluation has been shown to also exhibit potent anti-inflammatory and anti-fibrotic action, especially when incorporated to a pharmaceutical and/or veterinary composition.
  • an active ingredient diethylcarbamazine- DEC
  • the pharmaceutical and/or veterinary compositons of DEC, or its pharmaceutically acceptable salts, according to the present invention may be combined with other anti ⁇ inflammatory or immunomodulatory, anti-fibrotic, corticoid, analgesic, antitumor, antimycobacterial , fungicidal or antibiotic substances or agents, commonly used in combination or for treatment or prophylaxis of acute or chronic inflammatory diseases, and fibrotic processes.
  • the pharmaceutical composition of DEC, or its pharmaceutically acceptable salts, according to the present invention may also be combined with biological therapies, for example of antibodies and other recombinant proteins.
  • the objective of the present invention is to provide alternatives for the treatment and/or prevention of acute and/or chronic inflammatory pathologies, which may be associated with fibrotic processes for human and/or animal use.
  • the present invention proposes the use of DEC, or its pharmaceutically acceptable salts, incorporated to pharmaceutical and/or veterinary compositions, in the manufacture of a medicament for the treatment or prevention of acute and/or chronic inflammatory pathologies, which may be associated with fibrotic processes.
  • DEC Figure 1
  • the present invention describes the use of DEC, or its pharmaceutically acceptable salts, incorporated to pharmaceutical and veterinary compositions, in the production of a medicament for the treatment or prevention of acute and/or chronic inflammatory pathologies, associated or not to fibrotic processes.
  • a pharmaceutical and/or veterinary composition comprising: (a) DEC or its pharmaceutically acceptable salts and (b) pharmaceutically acceptable excipients for the production of a medication for treating disturbances or conditions in which inflammatory pathologies, which may be associated with fibrotic processes, predominates including the acute and chronic inflammations and fibrosis.
  • a method for the treatment or prevention of acute and chronic inflammatory pathologies comprising the administration of an effective amount of DEC and/or its pharmaceutically acceptable salts, incorporated to a pharmaceutical and/or veterinary composition, to human beings or animals.
  • a method is provided to treat and/or prevent acute and chronic inflammatory pathologies, associated or not with fibrotic processes, which comprises the administration of a pharmaceutical and/or veterinary composition comprising an effective amount of DEC and/or its pharmaceutically acceptable salts and excipients to human beings or animals.
  • a method to treat and/or prevent acute and chronic inflammatory pathologies, associated or not with fibrotic processes, which comprises the administration and/or a combination of a pharmaceutical and/or veterinary composition comprising an effective amount of DEC and/or its pharmaceutically acceptable salts and excipients, with one or more other pharmacologically active substances, of one of the following therapeutic classes, not exclusively or limited to anti-inflammatory, anti-fibrotic, corticoid, analgesic, antitumor, antimycobacterial , fungicidal, antibiotic, immunomodulatory substances or agents, and biological therapies, for example of antibodies and other recombinant proteins, commonly used in combination or for treatment or prophylaxis of acute or chronic inflammatory diseases, and fibrotic processes to human beings or animals.
  • the present invention also describes a pharmaceutical and/or veterinary composition comprising DEC and/or its pharmaceutically acceptable salts and excipients.
  • compositions refers to all pharmaceutical forms, and/or formulations containing one effective amount DEC and/or its pharmaceutically acceptable salts, associated with one or more pharmaceutically acceptable excipients, adjuvants, solvents and/or vehicles, without being limited to: solid form, for example, without being limited to: tablets (tablets uncoated or coated), tablets or films/wafers, which disintegrate rapidly into the oral cavity, sugar coated tablets, powders, granules, capsules (for example hard or soft gelatine capsules), films/lyophilisates, lozenges, pellets, capsules, pills, films, cachets, sugar-coated; or semi-solid form, for example, as ointments, creams, gels, suppositories, vaginal capsules, ova, emulsions, milk, pastes, foams, and/or therapeutic systems transdermal (eg adhesives); or in liquid form, for example
  • compositions of this invention may further be in the form of novel pharmaceutical forms including: liposomes, cyclodextrin complexes, nanospheres, nanocapsules , nanoparticles , microcapsules, microspheres, nanoemulsions and microemulsions .
  • the pharmaceutical and/or veterinary composition of the present invention may be administered by the following routes: oral, sublingual, nasal, rectal, intragingival , endovenous, intramuscular, intraarticular, subcutaneous, cutaneous (for example, patch or transdermal patch) , inhalatory, transdermal, topical or spinal (subarachnoid and peridural), parenteral, con unctival, optic, or as an implant or stent, not being limited to these.
  • the oral route is preferred.
  • mammals refers to domesticated animals, wild animals kept in captivity or not, and laboratory animals.
  • the term "effective amount”, as used in the present invention, refers to an amount of diethylcarbamazine (DEC) , or its pharmaceutically acceptable salts, that provides the desired anti- inflammatory and/or anti-fibrotic activities when administered according to a dose appropriate for each administration route.
  • DEC diethylcarbamazine
  • pharmaceutically acceptable excipients refers to ingredients compatible, and that are not harmful to human beings or animals.
  • salts refers to salts which are selected from the group, but not limited to: alkali metal salts, (eg. sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts), chloride, bromide, hydrochloride, acetates, maleate, mesylate, nitrate, tartrate, gluconate, citrates, carbonates, carbamates, phosphates, diphosphates, phosphonates , glycosides, sulfates, sulfonates, and ammonium salts derived from amine or organic amines having from 1 to 16 carbon atoms.
  • alkali metal salts eg. sodium and potassium salts
  • alkaline earth metal salts for example calcium and magnesium salts
  • chloride bromide
  • hydrochloride acetates
  • maleate mesylate, nitrate, tartrate, gluconate, citrates
  • carbonates carbamates
  • to treat refers to revert, alleviate, inhibit, prevent, or diminish the progress of inflammation and/or fibrosis in human beings or animals.
  • treatment refers to the act of treating as defined above as well as to prevention.
  • prevention or “prophylaxis”, were used in the present invention, refers to the act of preventing, which is related to the term “preemptive inflammation and/or fibrosis”. This term refers to the preventive treatment of inflammation and/or fibrosis, before its occurrence.
  • the term "for the treatment and/or prevention of”, as used in the present invention, refers to the treatment and/or prevention of one inflammatory and/or fibrotic diseases/conditions, selected from the following group, but not limited to: chronic obstructive disease, asthma, pulmonary hypertension, acute pulmonary inflammation such as respiratory distress syndrome (ARDS), pleuritis, hepatitis, cirrhosis, asthma, arthritis, arthrosis, systemic sclerosis, sclerodermatous graft-versus-host disease in bone marrow transplant recipients, Crohn's disease, cystic fibrosis, pulmonary fibrosis, intestinal fibrosis, liver fibrosis, kidney fibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, and keloid.
  • chronic obstructive disease asthma, pulmonary hypertension, acute pulmonary inflammation such as respiratory distress syndrome (ARDS), pleuritis, hepatitis, cirrhosis, asthma, arthritis, arth
  • the present invention is directed to the use of DEC ( Figure 1), or its pharmaceutically acceptable salts, incorporated to pharmaceutical and veterinary compositions, in the manufacture of a medicament for the treatment or prevention of inflammation and/or fibrosis pathologies/diseases. More specifically, the present invention describes the use of DEC, or its pharmaceutically acceptable salts, incorporated to pharmaceutical and veterinary compositions, in the prodution of a medicament for the treatment or prevention of acute and/or chronic inflammatory pathologies, which may be associated with fibrotic processes in human beings and animals
  • a method for the treatment or prevention of acute and chronic inflammatory pathologies comprising the administration of an effective amount of diethylcarbamazine or its pharmaceutically acceptable salts, incorporated to a pharmaceutical and/or veterinary composition, to human beings or animals.
  • Another incorporation of the present invention refers to a pharmaceutical and/or veterinary composition containing an effective amount of diethylcarbamazine or its pharmaceutically acceptable salts, and pharmaceutically acceptable excipients for the use as described above.
  • a pharmaceutical composition according to the present invention comprising 0.1% to 99% p/p of diethylcarbamazine or its pharmaceutically acceptable salts
  • a pharmaceutical and/or veterinary composition comprising: (a) diethylcarbamazine or its pharmaceutically acceptable salts and (b) pharmaceutically acceptable excipients for the production of a medication to treat disturbances or conditions in which inflammatory pathologies, which may be associated with fibrotic processes, predominates including the acute and chronic inflammations and fibrosis.
  • the administration of the pharmaceutical and/or veterinary composition of DEC and/or its pharmaceutically acceptable salts may be performed by the following administration routes: oral, sublingual, nasal, rectal, intragingival , endovenous, intramuscular, intraarticular, subcutaneous, cutaneous (for example, patch or transdermal patch), inhalatory, transdermal, topical or spinal (subarachnoid and peridural), parenteral, con unctival, optic, or as an implant or stent, not being limited to these.
  • oral route is preferred .
  • the pharmaceutically acceptable excipients are selected according to the final presentation of the composition of the present invention, which may be in a non-exclusive manner, or limited to: in the form of capsules or tablets for oral administration, solutions for nasal administration, injectable solutions for intramuscular, endovenous, cutaneous or subcutaneous administration, and lotion, cream or ointment for topical administration.
  • a method is provided to treat and/or prevent acute and chronic inflammatory pathologies, which may be associated with fibrotic processes, which comprises the administration and/or a combination of a pharmaceutical and/or veterinary composition comprising an effective amount of diethylcarbamazine or its pharmaceutically acceptable salts, and pharmaceutically acceptable excipients, with one or more other pharmacologically active substances, commonly used in combination or for treatment or prophylaxis of acute or chronic inflammatory diseases, and fibrotic processes to human beings or animals, belonging to one of the following therapeutic classes, not exclusively or limited to anti ⁇ inflammatory, or immunomodulatory, anti-fibrotic, corticoid, analgesic, antitumor, antimycobacterial , fungicidal, antibiotic substances or agents, and biological therapies, for example of antibodies and other recombinant proteins.
  • DEC and/or its pharmaceutically acceptable salts incorporated into a pharmaceutical composition (generally called NANO-DEC) , exhibits greater anti-inflammatory and anti-fibrotic response than DEC administered alone.
  • the group treated with DEC 50 was not able to decrease the presence of inflammatory infiltrate, nor prevent the death of several hepatocytes, and promote only a small decrease in the necrosis areas.
  • the group treated with NANO-DEC 12.5 showed a significant decrease in the necrosis and inflammatory infiltrate areas, and the liver tissue presentd similar morphology found in the control group.
  • the group treated with DEC 50 and the group treated with NANO-DEC 12.5 were able of stimulating the enzymatic activity, however, the group treated with NANO-DEC 12.5 promoted greater glutathione reductase activity than DEC 50.
  • Example 1 Preparation and characterization of polymeric nanoparticles containing DEC-citrate
  • DEC nanosystems compositions may be prepared through the technique of interfacial polymerization in an emulsified system hydrophilic/lipophilic/hydrophilic (w/o/w) type, as follows, in order to obtaining polymeric nanoparticles, containing DEC, pharmaceutically acceptable excipients and carriers:
  • Polymeric nanoparticles containing DEC citrate nanoparticles formed from the formation of a multiple emulsion w/o/w (water/oil/water) followed by the solvent evaporation, where the aqueous phase 1 comprises DEC citrate and water; and the organic phase comprises a hydrophobic polymer dissolved in an organic solvent and a low EHL surfactante, and the second aqueous phase comprises a stabilizer and water.
  • the nanoparticles preparation process consists of: the DEC citrate solubilization in water; the solubilization of the hydrophobic polymer and the low EHL surfactant in organic solvent, for example dichloromethane (so-called organic phase) .
  • organic solvent for example dichloromethane (so-called organic phase) .
  • the mixture of these two solutions provide the first water/oil emulsion.
  • this primary emulsion is added to a water phase and stabilizers under intense agitation ( sonification) to form the DEC-containing nanoparticles .
  • the organic solvent in this example, the dichloromethane
  • is removed under reduced pressure for example with the aid of a rotary evaporator.
  • Aqueous suspensions containing the DEC nanoparticles of the present invention may be obtained by varying the concentrations of the active ingredient, excipients and pharmaceutical carriers in the ranges of: 0.1 to 99% of DEC and/or its pharmaceutically acceptable salts; 0.01 to 30% hydrophobic polymer; 0.01 to 30% surfactant; 0.01 to 30% stabilizer; and 0.01 to 90% water.
  • Table 1 describes an example of a specific DEC composition obtained. However, it should be understood that such examples are presented only for illustrative purpose, and only to prove the success of the present invention. Any modifications in the light of the formulation herein, with percent active ingredient (DEC) percentages, percent excipients, solvents, or pharmaceutical carriers used for the preparation of nanoparticles containing DEC, are within the scope of this invention and its claims.
  • DEC active ingredient
  • Table 1 Materials (DEC, solvents, excipients, and vehicles) used to prepare the suspension of DEC nanoparticles.
  • the average size and the polydispersion index (PDI) of the DEC-containing nanoparticles was determined by laser diffraction using NanoZS 90 (Malvern) equipment.
  • the samples were diluted in ultra pure water in the ratio of 1:20.
  • the zeta potential was measured using the same equipment, but the suspensions were diluted in 1 mMNaCl solution.
  • the DEC-containing nanoparticles had a mean size of 315 ⁇ 5 nm with a PDI of 0.2 and unimodal distribution; the zeta potential was -5 ⁇ 1.2 mV. These same values were obtained after the lyofilization of the NANO-DEC and after a period of strage of 180 days .
  • the encapsulation efficiency ranged from 72 to 90%.
  • DEC diethylcarbamazine
  • NANO-DEC a pharmaceutical composition
  • ain vivo model of acute hepatic inflammation induced by carbon tetrachloride (CCI4) was performed.
  • CCI4 carbon tetrachloride
  • Hepatic liver fragments were obtained and weighed. Each fragment was homogenized using a manufacturer's buffer (Abnova Corporation, Taipei, Taiwa, catalog: KA0881) and centrifuged at 10, 000 x for 15 minutes at 39,2 °F. The supernatant was used to estimate the activity of hepatic glutathione reductase through the assay kit following the manufacturer's instructions.
  • a manufacturer's buffer Abnova Corporation, Taipei, Taiwa, catalog: KA0881
  • Glutathione reductase catalyzes the reduction of oxidized glutathione (GSSG) to glutathione (GSH) , an essential step in the glutathione cycle. This last one, in turn, promotes the defense of cells against oxidative stress.
  • DEC diethylcarbamazine
  • NANO-DEC a pharmaceutical composition
  • CCI4 carbon tetrachloride
  • CCI4 chronic hepatic inflammation induced by carbon tetrachloride
  • DEC 25 mg/kg and 50 mg/kg
  • NANO-DEC 12.5 mg/kg and 5 mg/kg
  • the control group received distilled water via the same route.
  • Liver fragments were fixed in 10% formalin for 24 h, processed, and embedded in paraffin. Sections of 4-5 ⁇ were cut and mounted on glass slides. Slices were stained with hematoxylin-eosin and assessed by inverted microscopy (Observer Zl; Zeiss Microimaging, Jena, Germany), a camera, and 4.7.4 image analysis software (AxionCamMRm; Zeiss, Jena, Germany) at a magnification of ⁇ 400.
  • Liver fragments were fixed in 10% formalin for 24 h, processed, and embedded in paraffin. Sections of 4-5 ⁇ were cut and mounted on glass slides. Slices were stained with picrosirius red solution of 1%, rehydrated in water, and stained with Fast Green 0.1% solution in ethanol. They were then assessed by inverted microscopy (Observer Zl; Zeiss Microimaging), a camera and 4.7.4 image analysis software (AxionCamMRm; Zeiss) at a magnification of x400.
  • the CCI4 group exhibited an elevated expression of TGF- ⁇ and IL- ⁇ when compared with the control group.
  • the CC1 4 + DEC 25 and CC1 4 + NANO-DEC 5 groups also presentd high expression when compared with the control group.
  • the treatment with DEC 50 and NANO-DEC 12.5 significantly reduced the expression of the TGF- ⁇ cytokine.
  • only NANO-DEC 12.5 treatment was able to reduce the expression of IL- ⁇ ( Figure 10) .
  • FIG. 1 Chemical Structure of Diethylcarbamazine (DEC) .
  • Figure 2 Graph of the release profile of DEC-containing nanoparticle in the formulation.
  • A- The X-axis refers to the Time in minutes.
  • B- Axis Y refers to the amount of drug released in the medium (mg) .
  • FIG. 1 Immunoblot of inflammatory markers.
  • the densitometric analysis was performed using Image J 1.38 software. Results were expressed as a mean ⁇ SEM of five animals per group. * P ⁇ 0.05 vs. CC1 4 ; #P ⁇ 0.05 vs. Control.

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Abstract

La présente invention concerne l'utilisation d'une quantité efficace de diéthylcarbamazine (DEC), ou de ses sels pharmaceutiquement acceptables, incorporés dans des compositions pharmaceutiques et/ou vétérinaires, dans la production d'un médicament pour le traitement et/ou la prévention de pathologies inflammatoires, qui peuvent être associées à des processus fibrotiques, chez les humains et les animaux. Selon l'invention, l'incorporation du DEC ou de ses sels pharmaceutiquement acceptables dans une composition pharmaceutique et/ou vétérinaire favorise une augmentation des activités anti-inflammatoires et anti-fibrotiques par rapport à l'administration du DEC seul.
PCT/BR2018/050027 2017-02-10 2018-02-09 Utilisation du diéthylcarbamazine incorporée dans des compositions pharmaceutiques pour le traitement et/ou la prévention de maladies inflammatoires chez l'homme ou l'animal Ceased WO2018145185A1 (fr)

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