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WO2010121334A1 - Composition pharmaceutique de transport de substances actives - Google Patents

Composition pharmaceutique de transport de substances actives Download PDF

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Publication number
WO2010121334A1
WO2010121334A1 PCT/BR2009/000224 BR2009000224W WO2010121334A1 WO 2010121334 A1 WO2010121334 A1 WO 2010121334A1 BR 2009000224 W BR2009000224 W BR 2009000224W WO 2010121334 A1 WO2010121334 A1 WO 2010121334A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
arginine
configurations
encapsulating
proteolytic enzymes
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/BR2009/000224
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English (en)
Inventor
Cristiano Alberto Ribeiro Santana
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Individual
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Publication of WO2010121334A1 publication Critical patent/WO2010121334A1/fr
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Classifications

    • 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
    • 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
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

  • the present invention relates to a new active substances-carrying pharmaceutical composition.
  • Said active substances-carrying pharmaceutical composition comprising supramolecular encapsulating configurations, arginine and proteolytic enzymes contains nanoparticles .
  • Said composition is intended to topic application, non-toxic, with fast and efficient penetration, transporting numberless substances to the hypodermis.
  • the hypothesis allowing performing intercommunication between epithelial cells, notably by means of specialized structures located in the plasmatic membrane of contiguous cells, has been confirmed.
  • Said structures receive the name of nexus, and are also named cellular intercommunication junctions or macula communicans.
  • Biochemically the presence is signaled in the cellular intercommunication junctions of a protein, tending to form gaps, when arranged as layers over liposomes, said property being inhibited by the corresponding antibody.
  • homologous proteins were found in several animal species, and are present in different epithelial tissues, varying their characteristics in keeping with the types of epithelial tissues. It is verified that these proteins behave as molecules integrating the plasmatic membrane, with an N- terminal end in contact with the epithelial cell cytoplasm, and C- terminal end penetrating the intercellular space. Between both ends there is an intermediate, hydrophobic segment, related to the plasmatic membrane lipidic layer. Thereafter, this protein has been correlated to the presence of conexons, structures specialized in cellular intercommunication.
  • each unit composing the cellular intercommunication junctions each conexon, consists of a hexagonal, symmetric structure, binding the interior of two contiguous cells containing a central, hydrophilic portion, behaving as a channel.
  • Said type of intercellular junction very common in epithelial cells, is absent only in some kinds of epitheliums.
  • a number of units or conexons are orderly arranged within each adherence region, although not homogeneously; these structures concentrating in areas in which cellular intercommunication is established, forming the nexus. It is understood that the junctional units or conexons are located between two adjoining cells, forming continuous channels.
  • each hemiconexon contains a protochannel, whose binding to the adjacent cell protochannel, forms the complete channel.
  • This is internally outlined by hydrophilic proteins, i.e., it would contain predominantly hydrophilic amino acids. It is admitted that hemiconexons would be transmembranous proteins molecules, integrating the plasmatic membrane, present only in these specialized areas, insinuating in the intercellular space. The external limits of molecules composing the hemiconexons, instead, would have a sheath formed by hydrophobic amino acids. Thus, each hemiconexon would contain a channel involved by double coating, the hydrophilic (internal) one and the hydrophobic (external) one.
  • ion Ca and the glycoprotein complex present in the glycocalix have that function. It has been verified that Ca 2 + concentration is usually low inside the epithelial cell. The increase in intracellular Ca 2 + level increases transjunctional strength, decreasing cellular intercommunication channels permeability to fluorescein bound to peptides. Ca 2 + mechanism of action is not known. It is admitted that the cellular intercommunication junctions occlude when Ca 2 + level inside the cell increases beyond a certain threshold. Usually, Ca 2 + level is maintained by means of active mechanisms determining Ca 2 + efflux. When the cell dies, intracellular Ca 2 + level increases, and the cellular intercommunication junctions occlude. Occlusion would be a passive event, unlike conexons channel opening.
  • the intercellular communication system in addition to happening by means of ions or small molecules passing with signals transmission, may operate by means of another mechanism. It has been shown that the nexus may amplify a response originating from a primary signal, having as a result the transmission of secondary signals from cell to cell, with an additive effect.
  • Basal membrane defined according to a concept established by means of the results provided by electronic microscopy, when having its structure analyzed, discloses the presence and the predominance of a little structured component, usually arranged as a blade between 15 and 30 nm thick, varying between 10 and 100 nm.
  • the dense blade is composed of weaved short filaments, between 1 and 3 nm diameter, arranged randomly or, sometimes, in a net immersed in an amorphous or granular matrix.
  • the basal blade is similar to the dense blade.
  • the basal membrane is considered composed by the dense blade and by both rare blades, the external one and the internal one.
  • the basal membrane apparently adapting to epithelial cells basal portion outline, is shown under the electronic microscope as a blade provided with higher electronic density (dense blade) , arranged parallel to the epithelial cell deep surface, from which it is separated by a thin blade, less electron-dense, between 3 and 4 ran thick, consisting of lucid blade or external rare blade.
  • the basal membrane consists of a trilaminar complex, centered by the dense basal blade.
  • fibrilar component Said component included among the elements belonging to basal membrane components, according to the concept established by optical microscopy, named fibrilar component, is considered as composed of two different components: the first one composed of collagen fibrils, glycoproteins and proteoglycans, originating in the condensation of the adjacent conjunctive tissue extracellular matrix and, although located close to the internal rare blade, it is not considered as belonging in the basal membrane; the second one is considered as belonging in the basal membrane and is named reticular membrane, having collagen fibrils, additionally to other of unknown nature ones, named anchoring fibrils.
  • striated collagen fibrils (collagen types I and III), composing the fibrilar component belonging in the basal membrane, and being located around the true basal membrane, are fibrils identical to the ones present in the conjunctive tissue in which they belong. Said fibrils are different from the ones found in the basal membrane reticular blade, being smaller, types IV or V collagen fibrils .
  • Every structure composing the basal membrane is composed of proteins and carbohydrates associated in several ways, forming different types of glycoproteins and proteoclycans, some of which are provided with fibrilar structure.
  • Collagen glycoproteins contained in the basal membrane show a triple helix structure, analogue to collagens in general, and also sensitive to collagenase. Considering histochemical results and chemical analyses, the dense blade would be composed mostly of type IV collagen. Basal membrane glycoproteins are insoluble in water, but soluble in the presence of urea or sodium dodecyl sulfate. Electrophoresis in polyacrylamide gel performed after its hydrolysis allows the separation of its components, among which a number of polypeptides have been identified, with molecular weight varying between 25000 and 200000 daltons.
  • the chemical analyses confirm the presence of distinct peptides, mainly the similarity with collagen polypeptides bound to disaccharides, and also polysaccharides bound to more polar amino acids are found, arranged in a sequence. Both types of carbon hydrates contained in collagen glycoproteins, disaccharides and polysaccharides may be bound to the same peptide. Certain peptides are identified in the basal membrane, provided with several polar regions, being not found among collagen proteins, except in the pro-collagen step.
  • Type IV collagen molecule predominant and characteristic element in the basal blade, is composed of an alpha-helicoidal domain bound to a non-helicoidal domain, ending with the shape of a globule, in which the molecule C-terminal group is located.
  • Type IV collagen is characterized by having a molecule containing three identical alpha 1 chains with molecular weight of 108000 daltons, and also having a carbohydrate showing as disaccharide units bound to hydroxylysine .
  • Type IV collagen differs from type I collagen for having a longer triple helix, in addition to frequent interruptions in gly-X-Y sequence, and for showing segments with well defined fibrilar structure, as they generally aggregate to form microfibrils arranged with a net shape.
  • Type IV collagen represents 1.4% of the total in the basal membrane.
  • the presence of type IV collagen in the basal blade is of great functional interest, as the epithelial cells have a receptor for this type of collagen, to which they bind.
  • this collagen tends to bind to laminine, fibronectine and to proteoglycans containing heparan sulfate, determining the binding of the epithelial cell to the basal membrane components .
  • the dense blade contains a net of fine type IV collagen microfibrils, being its main component.
  • this glycoprotein has been named type VIII collagen.
  • the present invention relates to a new active substances-carrying pharmaceutical composition comprising supramolecular encapsulating configurations .
  • Said supramolecular encapsulating configurations contain nanoparticles able to transport active substances or active ingredients to the hypodermis.
  • Nanoparticles are supramolecular configurations organized around a solid central nucleus. Different substances, such as proteolytic enzymes, vitamins and active ingredients, among others, do not keep their activity when formulated in an aqueous medium, making their formulation as bases intended to act on the hypodermis impossible. When encapsulated in microspheres, these substances are kept unchanged, and are released at the moment when the microsphere reaches hypodermis fatty layer. Each microsphere supposedly measures 200 nm, and is able to conduct enzymes up to 200000 daltons .
  • Arginine is one of the amino acids encoded by the genetic code, being, thus, one of the components of human beings proteins. In mammals, arginine may or may not be considered an essential amino acid, depending on the individual development step or on his health condition.
  • NO In blood vessels, the continuous formation of NO by endothelial cells promotes smooth musculature relaxation, producing vasodilation.
  • macrophages when stimulated, produce a large amount of NO, which behaves as a killer molecule, destroying target (cancerous) cells and microorganisms. NO also acts on other systems, such as central nervous, gastrointestinal, respiratory, cardiac and genitourinary systems.
  • c-GMP is the molecule responsible for smooth musculature relaxation, and consequently, for the increased diameter of blood vessels, by increasing blood flow and reducing blood pressure.
  • the dilation process may also occur when nitro- vasodilators, such as nitroglycerin, release NO directly to the endothelium and to smooth vascular musculature. Ignarro et al (Ignarro et al .
  • Nitric oxide in addition to relaxing the vascular smooth muscle, causing vasodilation, has the function to inhibit other processes, such as platelets aggregation, leukocytes adhesion to endothelium and endothelin production. Nitric acid also causes variation in contractile properties and in heart rate. In the cardiovascular system, nitric oxide release acts by regulating blood flow and blood pressure, by acting on the smooth musculature .
  • arginine is synthesized from citrulline by sequential action of enzymes argininesuccinate synthetase and agininesuccinate lyase (or argininesuccinase, with argininesuccinate being an intermediate metabolite (synthesized from aspartate citrulline-Amp condensation) .
  • Arginine is also synthesized in other cells, although in smaller scale. Upon induction of nitric oxide synthase (iNOS) , arginine synthesis capacity also increases. iNOS, whose primary function is synthesizing nitric oxide (NO) , does it from guanidine group oxidation, with consequent conversion of arginine to citrulline. This may be converted back in arginine through arginine-citrulline pathway.
  • iNOS nitric oxide synthase
  • arginine synthesis is similar to the synthesis in animals. Although they many times do not have all enzymes required for the tricarboxylic acids cycles and the urea cycle, they are able to synthesize arginine from a-ketoglutarate and ornitine.
  • arginine plays an important role in cellular division, in wounds healing, articulations inflammation or not, occurring peripheral vascular vasodilation, giving, thus, higher perfusion for diclofenac to act on those regions attacked by those processes.
  • arginine takes preferably a positive charge, due to which it tends to bind to negatively charged groups. For that reason, it is common to find this amino acid on the surface of proteins, and it occurs that that enzyme is able to release NO (nitric oxide) , which substance is a peripheral vasodilator. Thus, diclofenac will act on muscular receptors, which will be more pervious due to NO (nitric oxide) action.
  • Arginine is the immediate precursor of nitric oxide. Creatinine synthesis is required and may be used for polyamines, citrulline and glutamate synthesis. For being a NO precursor (which has a relaxing effect on blood vessels) , arginine is used in conditions where peripheral vasodilation is required.
  • the present invention relates to active substances-carrying pharmaceutical composition containing supramolecular encapsulating configurations, arginine and proteolytic enzymes within it, allows these configurations to penetrate up to the lipidic layer, to break involving the injury by a nexus expanding process and by cellular pressure gradient, and then fibrosis debridement or subcutaneous, periarticular circumscribed inflammation or muscular microtrauma occur.
  • the object of the present invention is a new active substances-carrying pharmaceutical composition comprising supramolecular encapsulating configurations between 10 nm and 990 run, arginine between 1 mg and 10 g and proteolytic enzymes between 0.1 and 70%.
  • the present invention relates to the new active substances-carrying pharmaceutical composition
  • the new active substances-carrying pharmaceutical composition comprising supramolecular encapsulating configurations between 10 nm and 990 nm, arginine between 10 mg and 1 g and proteolytic enzymes between 0.2 and 40%.
  • the present invention relates to the new active substances-carrying pharmaceutical composition
  • the new active substances-carrying pharmaceutical composition comprising supramolecular encapsulating configurations between 10 nm and 990 nm, arginine between 20 mg and 500 mg and proteolytic enzymes between 1.0 and 20%.
  • the present invention relates to the new active substances-carrying pharmaceutical composition
  • the new active substances-carrying pharmaceutical composition comprising supramolecular encapsulating configurations between 10 nm and 990 nm, arginine between 40 mg and 200 mg and proteolytic enzymes between 2.0 mg and 10%.
  • the present invention relates to a new active substances-carrying pharmaceutical composition comprising supramolecular encapsulating configurations, arginine, proteolytic enzymes and diclofenac. More advantageously, the present invention comprises said active substances-carrying pharmaceutical composition comprising as supramolecular encapsulating configurations, nanoparticles . Still more advantageously, the present invention comprises said active substances-carrying pharmaceutical composition comprising as nanoparticles, nanospheres, nanocapsules, microspheres or glycocapsules .
  • the present invention comprises said active substances-carrying pharmaceutical composition
  • said active substances-carrying pharmaceutical composition comprising, as active substances, healing agents, antibiotics, antifungal agents, antirheumatic drugs, steroidal or non-steroidal antiinflammatory drugs, pain killers, antiviral drugs, antivaricose drugs, anesthetics, antitumor drugs and antipruritic drugs.
  • the present invention comprises an active substances-carrying pharmaceutical composition may be used for the treatment of inflammatory pathologies.
  • the present invention comprises an active substances-carrying pharmaceutical composition contains diclofenac.
  • the present invention relates to a process to treat inflammatory pathologies comprising the administration of a carrying pharmaceutical composition comprising encapsulating configurations, arginine, proteolytic enzymes and diclofenac.
  • the present invention relates to a process to treat inflammatory pathologies, comprising the administration of a carrying pharmaceutical composition, comprises encapsulating configurations, such as nanoparticles, arginine, proteolytic enzymes and diclofenac.
  • the present invention relates to a process to treat inflammatory pathologies, comprising a carrying pharmaceutical composition comprising nanoparticles, such as nanospheres, nanocapsules, microspheres, and glycocapsules, arginine, proteolytic enzymes and diclofenac.
  • nanoparticles such as nanospheres, nanocapsules, microspheres, and glycocapsules, arginine, proteolytic enzymes and diclofenac.
  • DOMS Delayed Onset of Muscle Soreness
  • the exercises to trigger muscle pain comprised 4 series of 12 repetitions of a predominantly eccentric knee extension exercise, with 80% of the maximum load, and 1:5 ratio between concentric and eccentric contraction, respectively.
  • the maximum load for the exercise was established at the day of the test, by determining a maximum repetition (1 MR) , consisting of the maximum load a subject is able to lift, being impossible to lift it for a second time. • Both the maximum load and the exercises were performed unilaterally.
  • the strength loss magnitude reflects the muscular injury magnitude.
  • the LL with A3 tended to lose less strength (Pre 36.67 Post 35.0) than the LL with Al (Pre 36.67 Post 33.3) .

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention porte sur une nouvelle composition pharmaceutique de transport de substances actives. Ladite composition pharmaceutique de transport des substances actives comprend des configurations d'encapsulation supramoléculaires, de l'arginine et des enzymes protéolytiques et contient des nanoparticules. Ladite composition est destinée à une application topique, non toxique avec une pénétration rapide et efficace, transportant des substances innombrables à l'hypoderme.
PCT/BR2009/000224 2009-04-23 2009-07-29 Composition pharmaceutique de transport de substances actives Ceased WO2010121334A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
BRPI0900858-6A BRPI0900858A2 (pt) 2009-04-23 2009-04-23 composição farmacêutica carreadora de substáncias ativas
BRPI0900858-6 2009-04-23

Publications (1)

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WO2010121334A1 true WO2010121334A1 (fr) 2010-10-28

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PCT/BR2009/000224 Ceased WO2010121334A1 (fr) 2009-04-23 2009-07-29 Composition pharmaceutique de transport de substances actives

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BR (1) BRPI0900858A2 (fr)
WO (1) WO2010121334A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6086863A (en) * 1997-06-04 2000-07-11 Polyheal Ltd. Compositions of microspheres for wound healing
WO2003061718A2 (fr) * 2002-01-24 2003-07-31 Scimed Life Systems, Inc. Articles medicaux a surfaces enzymatiques pour traitement localise
WO2007021065A1 (fr) * 2005-08-18 2007-02-22 Amorepacific Corporation Composition cosmetique contenant une enzyme et un acide amine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6086863A (en) * 1997-06-04 2000-07-11 Polyheal Ltd. Compositions of microspheres for wound healing
WO2003061718A2 (fr) * 2002-01-24 2003-07-31 Scimed Life Systems, Inc. Articles medicaux a surfaces enzymatiques pour traitement localise
WO2007021065A1 (fr) * 2005-08-18 2007-02-22 Amorepacific Corporation Composition cosmetique contenant une enzyme et un acide amine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NAPOLI ET AL.: "Nitric Oxide and Atherosclerosis", BIOLOGY AND CHEMISTRY, vol. 5, no. 2, 2001, pages 88 - 97 *

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