BRPI0900858A2 - pharmaceutical composition containing active substances - Google Patents
pharmaceutical composition containing active substances Download PDFInfo
- Publication number
- BRPI0900858A2 BRPI0900858A2 BRPI0900858-6A BRPI0900858A BRPI0900858A2 BR PI0900858 A2 BRPI0900858 A2 BR PI0900858A2 BR PI0900858 A BRPI0900858 A BR PI0900858A BR PI0900858 A2 BRPI0900858 A2 BR PI0900858A2
- Authority
- BR
- Brazil
- Prior art keywords
- pharmaceutical composition
- arginine
- encapsulating
- configurations
- composition according
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 31
- 239000013543 active substance Substances 0.000 title claims abstract description 14
- 239000004475 Arginine Substances 0.000 claims abstract description 31
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract description 31
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- 239000000126 substance Substances 0.000 claims abstract description 12
- 229960003121 arginine Drugs 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 14
- 229960001259 diclofenac Drugs 0.000 claims description 10
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 claims description 10
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- 239000000006 Nitroglycerin Substances 0.000 description 1
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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
Landscapes
- 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
COMPOSIçAO FARMACEUTICA CARREADORA DE SUBSTANCIAS ATIVAS A presente invenção refere-se a uma nova composição farmacêutica carreadora de substâncias ativas. A dita composição farmacêutica carreadora de substâncias ativas compreendendo configurações encapsuladoras supramoleculares, arginina e enzimas proteolíticas comporta nanopartículas. A composição referida é de aplicação tópica, não tóxica, com rápida e eficiente penetração transportando inúmeras substâncias até a hipoderme.PHARMACEUTICAL COMPOSITION CARRYING ACTIVE SUBSTANCES The present invention relates to a new pharmaceutical composition carrying active substances. Said active pharmaceutical composition containing active substances comprising supramolecular encapsulating configurations, arginine and proteolytic enzymes comprises nanoparticles. The referred composition is topically applied, non-toxic, with fast and efficient penetration, transporting numerous substances to the hypodermis.
Description
"COMPOSIÇÃO FARMACÊUTICA ----SUBSTÂNCIAS ATIVAS""PHARMACEUTICAL COMPOSITION ---- ACTIVE SUBSTANCES"
Refere-se a presente invenção a uma novacomposição farmacêutica carreadora de substâncias ativas. A ditacomposição farmacêutica carreadora de substâncias ativascompreendendo configurações encapsuladoras supramoleculares,arginina e enzimas proteoliticas comporta nanoparticulas. Acomposição referida é de aplicação tópica, não tóxica, com rápidae eficiente penetração transportando inúmeras substâncias até ahipoderme.The present invention relates to a novel active ingredient carrier pharmaceutical composition. The active substance carrier pharmaceutical composition comprising supramolecular encapsulating configurations, arginine and proteolytic enzymes comprises nanoparticles. Said composition is topical, non-toxic, with rapid and efficient penetration carrying numerous substances to the hypodermis.
Tem sido confirmada a hipótese que permiteefetuar a intercomunicação entre células epiteliais, notadamenteatravés de estruturas especializadas situadas na membranaplasmáticas das células contíguas. Tais estruturas recebem o nomede nexus, sendo também denominadas junções de intercomunicaçãocelular ou máculas comunicantes. Bioquimicamente assinala-se apresença nas junções de intercomunicação celular de uma proteínacom tendência a formar fendas quando disposta em camadas sobrelipossomas, tal propriedade sendo inibida pelo correspondenteanticorpo. De outra parte proteínas homólogas foram encontradas emvárias espécies animais, estando presentes em diferentes tecidosepiteliais, variando suas características em função dos tipos detecidos epiteliais. Verifica-se que estas proteínas comportam-secomo moléculas integrantes da membrana plasmática, com extremidadeN-terminal em contato com o citoplasma da célula epitelial eextremidade C-terminal penetrando no espaço intercelular. Entre asduas extremidades encontra-se um segmento intermediário,hidrófobo, relacionado com a camada lipídica da membranaplasmática. Na seqüência correlacionou-se esta proteína com apresença dos conexons, estruturas especializadas naintercomunicação celular.The hypothesis that allows intercommunication between epithelial cells has been confirmed, especially through specialized structures located in the plasma membranes of contiguous cells. Such structures are named nexus, and are also called cell intercommunication junctions or communicating macules. Biochemically, the presence in the cellular intercommunication junctions of a protein with a tendency to form cracks is noted when arranged in overliposome layers, such property being inhibited by the corresponding antibody. On the other hand, homologous proteins were found in several animal species, being present in different epithelial tissues, varying their characteristics according to the epithelial types detected. These proteins are found to behave as plasma membrane integrating molecules, with N-terminal end in contact with the epithelial cell cytoplasm and C-terminal end penetrating the intercellular space. Between both ends is a hydrophobic intermediate segment related to the lipid layer of the plasma membrane. In sequence, this protein was correlated with the presence of connexons, specialized structures in cellular intercommunication.
No plano morfológico demonstrou-se que cadaunidade que compõe as junções de intercomunicação celular, cadaconexon consiste em uma estrutura hexagonal, simétrica, unindo ointerior de duas células contíguas contendo uma parte centralhidrófila, comportando-se como um canal. Tal tipo de junçãointercelular, muito comum nas células epiteliais, encontra-seausente apenas em alguns tipos de epitélios. Numerosas unidades ouconexons dispõem-se ordenadamente no interior de cada região deaderência, ainda que não homogeneamente, concentrando-se estasestruturas em áreas nas quais se estabelece intercomunicaçãocelular formando os nexus. Depreende-se que as unidades juncionaisou conexons situam-se entre duas células adjacentes formandocanais contínuos. Cada metade do conexon pertencente a uma dascélulas adjacentes, ou seja, cada hemiconexon, contém umprotocanal, cuja reunião com o protocanal da célula adjacenteforma o canal completo. Este é delimitado internamente porproteínas hidrófilas, isto é, conteria predomínio de aminoácidoshidrófilos. Admite-se que os hemiconexons seriam moléculas deproteínas transmembranosas, integrantes da membrana plasmática,presentes apenas nestas áreas especializadas, insinuando-se noespaço intercelular. Os limites externos das moléculasconstituindo os hemiconexos, ao contrário, possuiriam uma bainhaformada por aminoácidos hidrófobos. Assim cada hemiconexonconteria um canal envolvido por duplo revestimento, o hidrófilo(interno) e o hidrófobo (externo).Informações provenientes dos resultados deestudos químicos pertinentes confirmam que os nexus ou junções deintercomunicação celular apresentam algumas proteínas especiaisconstituindo seus conexons, destacando-se dentre estas uma queapresenta peso molecular entre 26000 e 27000 dáltons.In the morphological plane it was demonstrated that each unit that makes up the cellular intercommunication junctions, cadaconexon consists of a symmetrical hexagonal structure, joining the interior of two contiguous cells containing a central hydrophilic part, behaving as a channel. This type of intercellular junction, very common in epithelial cells, is absent only in some types of epithelium. Numerous units or connexions are arranged neatly within each region of coherence, albeit not homogeneously, concentrating these structures in areas where cellular intercommunication is established forming the nexus. It is understood that the junctional units or connexons lie between two adjacent continuous forming canals. Each half of the connexon belonging to one of the adjacent cells, that is, each hemiconexon, contains a protochannel, whose meeting with the protochannel of the adjacent cell forms the complete channel. This is internally delimited by hydrophilic proteins, ie, would contain predominance of hydrophilic amino acids. It is assumed that the hemiconexons would be transmembrane plasma membrane protein molecules present only in these specialized areas, insinuating into the intercellular space. The outer boundaries of the molecules constituting the hemiconxes, in contrast, would have a sheath formed by hydrophobic amino acids. Thus each hemiconxoncontain a channel surrounded by double coat, the hydrophilic (internal) and the hydrophobic (external). Information from the results of pertinent chemical studies confirm that the nexus or junctions of cellular intercommunication present some special proteins constituting their connexons, among which one stands out. which has a molecular weight of between 26000 and 27000 Daltons.
Existem alguns fatores que alteram o grau deabertura e a eficiência dos canais dos conexons e interferem nograu de intercomunicação celular. Assim o íon Ca e o complexoglicoprotéico presente no glicocálice apresentam essa função.Verificou-se que a concentração do Ca2+ normalmente é baixa nointerior da célula epitelial. O aumento do nível do Ca2+intracelular eleva a resistência transjuncional, diminuindo apermeabilidade dos canais de intercomunicação celular àfluoresceína unida aos peptídeos. O mecanismo de ação do Ca2+ nãoé conhecido. Admite-se que as junções de intercomunicação celularocluam-se quando o nível de Ca2+ no interior da célula eleve-sealém de certo limiar. Normalmente o nível de Ca2+ é mantidoatravés de mecanismos ativos que determinam o efluxo do Ca2+,Quando a célula morre o nível de Ca2+ intracelular eleva-se e asjunções de intercomunicação celular ocluem-se. A oclusão seria umevento passivo, ao contrário da abertura do canal dos conexons.There are some factors that alter the degree of opening and the efficiency of the connexion channels and interfere with the degree of cellular intercommunication. Thus the Ca ion and the glycoprotein complexoglycoprotein present this function. It was found that Ca2 + concentration is usually low inside the epithelial cell. Increasing intracellular Ca2 + level increases transjunctional resistance, decreasing the permeability of the peptide-linked cellular intercommunication channels. The mechanism of action of Ca2 + is not known. Cellular intercommunication junctions are allowed to occlude when the Ca2 + level within the cell rises to a certain threshold. Normally the Ca2 + level is maintained through active mechanisms that determine Ca2 + efflux. When the cell dies the intracellular Ca2 + level rises and the cellular intercommunication junctions occlude. Occlusion would be a passive event, unlike the opening of the connexion channel.
Observa-se que os canais de comunicação entre ascélulas, presentes nas junções intercelulares de célulashomólogas, apresentam igual permeabilidade nos dois sentidos. OCa2+ seria o elemento capaz de regular o sentido dapermeabilidade. Quando sua concentração no interior das célulasvizinhas se modifica os canais de intercomunicação se fechamapenas em um sentido. Todavia quando a concentração de Ca2+intracitoplasmática é baixa a permeabilidade dos canais decomunicação aferentes é alta e vice-versa. A permeabilidadediminui quando a concentração de Ca2+ aumenta. Outro fatorintracelular importante para a regulação da permeabilidade dasjunções de intercomunicação celular é a concentração do AMPcíclico em seu citoplasma. Elevando-se o nível do AMP cíclico nocitoplasma das células adjacentes, não apenas aumenta suapermeabilidade recíproca, como também formam-se novos canais deintercomunicação celular. Esta interpretação é confirmada emculturas de células epiteliais cujos elementos tornam-se maispermeáveis às comunicações intercelulares quando se fornece AMPcíclico exógeno às células cultivadas. O mesmo efeito é logradoquando o AMP cíclico endocelular aumenta pela ação de inibidor defosfodiesterase como a cafeína. A ação do AMP cíclico é retardadapor várias horas sugerindo que se efetivaria através da formaçãode novos canais de intercomunicação celular.It can be observed that the communication channels between the cells, present in the intercellular junctions of homologous cells, present equal permeability in both directions. Ca2 + would be the element capable of regulating the sense of permeability. When their concentration within the neighboring cells changes the intercommunication channels close in one direction only. However, when the intracytoplasmic Ca2 + concentration is low, the permeability of the afferent communication channels is high and vice versa. Permeability decreases when Ca2 + concentration increases. Another important intracellular factor for regulating the permeability of cellular intercommunication junctions is the concentration of cyclic AMP in its cytoplasm. Raising the level of the nocitoplasma cyclic AMP of adjacent cells not only increases their reciprocal permeability, but also new channels of cellular intercommunication are formed. This interpretation is confirmed in epithelial cell cultures whose elements become more permeable to intercellular communications when exogenous cyclic AMP is supplied to cultured cells. The same effect is achieved when endocellular cyclic AMP increases by the action of dephosphodiesterase inhibitor such as caffeine. The action of cyclic AMP is delayed for several hours suggesting that it would be effective through the formation of new cellular intercommunication channels.
O sistema de comunicação intercelular além deefetuar através da passagem de íons ou pequenas moléculas com atransmissão de sinais pode atuar através de outro mecanismo.Demonstrou-se que os nexos podem amplificar resposta provenientede um sinal primário, resultando a transmissão de sinaissecundários de célula a célula apresentando efeito aditivo.The intercellular communication system besides acting through the passage of ions or small molecules with signal transmission can act through another mechanism. It has been shown that the attachments can amplify response coming from a primary signal, resulting in the transmission of secondary signals from cell to cell presenting additive effect.
A membrana basal, definida de acordo com oconceito estabelecido através dos resultados fornecidos pelamicroscopia eletrônica, quando analisada quanto à sua estruturarevela a presença e o predomínio de um componente poucoestruturado, geralmente disposto sob a forma de uma lâmina entree 30 nm de espessura, podendo variar a mesma entre 10 e 100 nm.A lâmina densa é constituída por uma trama de filamentos curtos,entre 1 e 3 nm de diâmetro, dispostos ao acaso ou, às vezes, emrede imersa em matriz amorfa ou granular. Por tal conceito alâmina basal assemelha-se à lâmina densa. Segundo o conceito atuala membrana basal é considerada integrada pela lâmina densa e pelasduas lâminas raras, a externa e a interna. A membrana basalamoldando-se, aparentemente, ao contorno da porção basal dascélulas epiteliais apresenta-se ao microscópio eletrônico sob aforma de uma lâmina dotada de maior densidade eletrônica (lâminadensa), disposta paralelamente à superfície profunda da célulaepitelial, da qual está separada por uma delgada lâmina menoselétron-densa, apresentando entre 3 e 4 nm de espessura,consistindo da lâmina lúcida ou lâmina rara externa. Segundo esteconceito, decorrente dos primeiros resultados obtidos damicroscopia eletrônica, a membrana basal consiste em um complexotrilaminar, centrado pela lâmina basal densa.The basement membrane, defined according to the concept established by the results provided by electron microscopy, when analyzed for its structure, reveals the presence and predominance of a poorly structured component, usually arranged as a 30 nm thick blade, and may vary in size. between 10 and 100 nm. The dense slide is made up of a web of short filaments, between 1 and 3 nm in diameter, arranged randomly or sometimes embedded in an amorphous or granular matrix. By such concept basal blade resembles dense blade. According to the current concept, the basement membrane is considered to be integrated by the dense lamina and the two rare external and internal laminae. The basal membrane, apparently forming the contour of the basal portion of the epithelial cells, appears under the electron microscope in the form of a slide with higher electron density (dense lamina), arranged parallel to the deep surface of the epithelial cell, from which it is separated by a thin one. less electron-dense lamina, being between 3 and 4 nm thick, consisting of the lucid lamina or rare external lamina. According to this concept, due to the first results obtained by electron microscopy, the basement membrane consists of a complexotrilaminar, centered by the dense basal lamina.
Além dos componentes referidos sugere-se aparticipação de outro que após ter sido melhor identificado edefinido, localiza-se em área subjacente à lâmina rara interna.Tal componente incluído entre os elementos pertencentes aosconstituintes da membrana basal, segundo o conceito estabelecidopela microscopia óptica, denominado componente fibrilar,considera-se como constituído por dois componentes distintos: oprimeiro constituído por fibrilas colágenas, glicoproteínas eproteoglicanas, provenientes da condensação da matriz extracelulardo tecido conjuntivo adjacente e, embora situado nas proximidadesda lâmina rara interna não é considerado com pertencente àmembrana basal; o segundo considerado como pertencente à membranabasal e denominado lâmina reticular, apresenta fibrilas colágenasalém de outras, de natureza desconhecida, denominadas fibrilas deancoragem. Observou-se recentemente que as fibrilas colágenasestriadas (colágenos dos tipos I e III), constituindo o componentefibrilar pertencente à membrana basal e que estão situadas nasproximidades da verdadeira membrana basal são fibrilas idênticasàs presentes no tecido conjuntivo ao qual pertencem. Tais fibrilasdistinguem-se das encontradas na lâmina reticular da membranabasal que são fibrilas menores de colágenos dos tipos IV ou V.In addition to the above-mentioned components, it is suggested to participate in another one which, after being better identified and defined, is located in the area underlying the rare internal lamina. Such component included among the elements belonging to the basement membrane constituents, according to the concept established by optical microscopy, called component fibrillar, it is considered to consist of two distinct components: the first one consists of collagen fibrils, glycoproteins and proteoglycans, originating from the condensation of the extracellular matrix of the adjacent connective tissue and, although situated near the rare internal lamina, is not considered as belonging to the basal membrane; The second one, considered as belonging to the membranabasal and called the reticular lamina, presents collagen fibrils, besides others, of unknown nature, called anchoring fibrils. It has recently been observed that the striated collagen fibrils (collagen types I and III), which constitute the fibrous component belonging to the basement membrane and which are situated in the vicinity of the true basement membrane, are identical fibrils to those present in the connective tissue to which they belong. Such fibrils are distinguished from those found in the reticular membrane membrane layer which are smaller fibrils of type IV or V collagen.
Atualmente confirmou-se o conceito que considerao componente fibrilar constituindo a lâmina reticular da membranabasal conformado por delgadas fibrilas de colágeno dos tipos IV eV, cuja situação é ligeiramente mais profunda em relação à lâminarara interna apresentando-se compreendidas dentro do limite damembrana basal.Currently, the concept that considers the fibrillar component constituting the reticular membrane of the membranabasal formed by thin type IV and V collagen fibrils, whose situation is slightly deeper in relation to the internal lamina being within the limit of the basal membrane, has been confirmed.
Todas estruturas compondo a membrana basal sãoconstituídas por proteínas e carboidratos associados de diversasmaneiras formando distintos tipos de glicoproteínas eproteoclicanas algumas dotadas de estrutura fibrilar.All structures that make up the basement membrane are made up of proteins and associated carbohydrates in different ways forming distinct types of glycoproteins and protein proteins, some with fibrillar structure.
As glicoproteínas colágenas contidas na membranabasal exibem estrutura em tríplice hélice, análoga aos colágenosem geral, além de sensíveis à colagenase. Considerando osresultados histoquímicos e as análises químicas a lâmina densaseria constituída predominantemente por colágeno do tipo IV. Asglicoproteínas da membrana basal são insolúveis na água, massolúveis em presença de uréia ou de dodecil-sulfato de sódio. Aeletroforese em gel de poliacrilamida efetuada após sua hidrólisepermite a separação dos seus componentes dentre os quais foramidentificados numerosos polipetideos com peso molecular variandoentre 25000 e 200000 dáltons. As análises químicas confirmam apresença de peptídeos distintos destacando a semelhança com ospolipetideos do colágeno unidos aos dissacarideos encontrando-sepolissacarídeos ligados a aminoácidos mais polares dispostos emseqüência. Os dois tipos de hidratos de carbono contidos naglicoproteinas colágenas, dissacarideos e polissacarídeos podemestar unidos ao mesmo peptídeo. Identificam-se na membrana basalcertos polipetideos dotados de várias regiões polares que não sãoencontrados entre as proteínas do colágeno exceto no estágio depró-colágeno.The collagen glycoproteins contained in the membranabasal exhibit triple helix structure, analogous to collagen in general, and sensitive to collagenase. Considering the histochemical results and the chemical analysis, the dense slide consisted predominantly of type IV collagen. Basal membrane glycoproteins are water insoluble, massoluble in the presence of urea or sodium dodecyl sulfate. Polyacrylamide gel electrophoresis after hydrolysis allows the separation of its components from which numerous polypetides with molecular weight ranging from 25,000 to 200,000 Daltons have been identified. Chemical analysis confirms the presence of distinct peptides highlighting the similarity with collagen polypeptides attached to disaccharides, finding sepolysaccharides linked to more polar amino acids subsequently disposed. The two types of carbohydrates contained in collagen naglycoproteins, disaccharides and polysaccharides may be attached to the same peptide. Polypeptide basalts with several polar regions that are not found between collagen proteins are identified in the membrane except in the deprocollagen stage.
Na membrana basal identificam-se inúmeroscomponentes peptídicos. Admite-se que seriam produtos atuando nabiossíntese das glicoproteinas colágenas e não colágenas, podendotais componentes originarem-se da proteólise que ocorre durante oisolamento da membrana basal. Os diversos resultados experimentaiscitados confirmam que as glicoproteinas da lâmina densa são denatureza colágena, assinalando-se nessa lâmina a presença decolágenos dos tipos IV, V e VIII, predominando o primeiro. Amolécula do colágeno do tipo IV, elemento predominante ecaracterístico da lâmina basal, é constituída por domínio alfa-helicoidal unido a um domínio não helicoidal, que termina sob aforma de um glóbulo, onde se situa o grupo C-terminal da molécula.Este tipo de colágeno caracteriza-se por apresentar moléculacontendo três cadeias alfa 1 idênticas com peso molecular de108000 dáltons e possuir ainda um carboidrato que se apresenta soba forma de unidades dissacarídicas ligadas à hidroxilisina. 0colágeno do tipo IV difere do colágeno do tipo I por apresentartríplice hélice mais longa, além de freqüentes interrupções naseqüência gli-X-Y e por exibir segmentos com estrutura fibrilarbem definida, pois geralmente agregam-se para formar microfibrilasdispostas sob a forma de rede. 0 colágeno do tipo IV representa1,4% do total da membrana basal. A presença do colágeno do tipo IVna lâmina basal tem grande interesse funcional, pois as célulasepiteliais possuem receptor para este tipo de colágeno com o qualse unem. De outra parte este colágeno possui tendência a unir-secom a laminina, fibronectina e com as proteoglicanas contendosulfato de heparana determinando a união da célula epitelial comos componentes da membrana basal.In the basement membrane numerous peptide components are identified. It is assumed that they would be products acting on the synthesis of collagen and non-collagen glycoproteins, which may originate from the proteolysis that occurs during the isolation of the basement membrane. The several experimental results mentioned above confirm that the glycoproteins of the dense lamina are collagen in nature, indicating the presence of type IV, V and VIII collagen, the former predominating. The collagen type IV molecule, the predominant and characteristic element of the basal lamina, is an alpha-helical domain joined to a non-helical domain, which ends in the form of a globule, where the C-terminal group of the molecule is located. Collagen is characterized by having a molecule containing three identical alpha 1 chains with a molecular weight of 108,000 daltons and a carbohydrate in the form of hydroxylisine-linked disaccharide units. Type IV collagen differs from type I collagen in that it has a longer triple helix, frequent disruptions in the gly-X-Y sequence, and segments with well-defined fibrillar structure because they generally aggregate to form microfibrils arranged as a network. Type IV collagen represents 1.4% of the total basement membrane. The presence of type IV collagen in the basal lamina is of great functional interest, since the epithelial cells have a receptor for this type of collagen to which they attach. On the other hand, this collagen tends to unite with laminin, fibronectin and the heparan-containing proteoglycans containing the epithelial cell union with the components of the basement membrane.
No que tange à disposição dos colágenos namembrana basal confirma-se que na lâmina densa está presente umarede de finas micro fibrilas de colágeno do tipo IV que é seuprincipal componente. Outra glicoproteína colágena abundante namembrana basal, não obstante menos abundante que o colágeno dotipo IV, é a denominada colágeno do tipo 7S, resistente à ação dacolagenose e possuindo alto teor de ligações S-S, assim como decarboidratos. Atualmente esta glicoproteína tem sido denominadacomo colágeno do tipo VIII.With regard to the disposition of the basal membrane collagen it is confirmed that in the dense lamina there is a network of fine type IV collagen micro fibrils which is its main component. Another abundant collagen glycoprotein in the basal membrane, although less abundant than type IV collagen, is called type 7S collagen, resistant to dacolagenose action and having a high content of S-S bonds, as well as decarbohydrates. Currently this glycoprotein has been termed as type VIII collagen.
A presente invenção reporta-se a uma novacomposição farmacêutica carreadora de substâncias ativascompreendendo configurações encapsuladoras supramoleculares.The present invention relates to a novel active substance carrier pharmaceutical composition comprising supramolecular encapsulating configurations.
Tais configurações encapsuladorassupramoleculares comportam nanopartículas aptas a transportarsubstâncias ativas ou princípios ativos até a hipoderme.Nanopartículas são configurações supramoleculares organizadas emtorno de um núcleo central sólido. Diferentes substâncias, comoenzimas proteoliticas, vitaminas e princípios ativos, dentreoutras, não mantém a atividade quando formuladas em meio aquoso,tornando impossível sua formulação em bases destinadas a agir nahipoderme. Quando encapsuladas em microsferas estas substânciassão mantidas inalteradas, sendo liberadas no momento em que amicrosfera atinge a camada gordurosa da hipoderme. Cada microsferasupostamente tem a medida de 200 m, podendo conduzir enzimas deaté 200000 dáltons.Such supermolecular encapsulator configurations carry nanoparticles capable of carrying active substances or active principles 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 maintain activity when formulated in aqueous medium, making it impossible to formulate them in bases designed to act in the hypodermis. When encapsulated in microspheres these substances are kept unchanged and released as the microsphere reaches the fatty layer of the hypodermis. Each microspheres is supposed to measure 200 m and can conduct enzymes deaté 200000 Daltons.
Como já é de conhecimento geral, o DiclofenacoAs is well known, Diclofenac
Dietilamônio é um antiinflamatório largamente estudado. A Argininaé um dos aminoácidos codificados pelo código genético, sendoportanto um dos componentes das proteínas dos seres vivos. Emmamíferos, a arginina pode ou não ser considerada como aminoácidoessencial dependendo do estágio do desenvolvimento do indivíduo oudo seu estado de saúde.Diethylammonium is a widely studied anti-inflammatory. Arginine is one of the amino acids encoded by the genetic code, thus being one of the protein components of living things. However, arginine may or may not be regarded as essential amino acid depending on the individual's stage of development or health.
Nos vasos sangüíneos, a formação contínua de NOpelas células endoteliais promove o relaxamento da musculaturalisa, produzindo vasodilatação. No sistema imune, macrófagos,quando estimulados, produzem grande quantidade de NO, que funcionacomo uma molécula assassina, destruindo células-alvo (cancerosas)e micro-organismos. 0 NO atua também em outros sistemas, tais comoo sistema nervoso central, gastrintestinal, respiratório, cardíacoe genitourinário.In blood vessels, the continuous formation of NO by endothelial cells promotes relaxation of musculaturalisa, producing vasodilation. In the immune system, macrophages, when stimulated, produce large amounts of NO, which function as a killer molecule, destroying (cancerous) target cells and microorganisms. NO also acts on other systems such as the central nervous, gastrointestinal, respiratory, cardiac and genitourinary systems.
Ao difundir-se para a musculatura lisa o NOgerado irá ligar-se ao ferro do grupo prostético heme da enzimaguanilato ciclase (GC), que é então ativada e converte GTP em c-GMP. A c-GMP é a molécula responsável pelo relaxamento damusculatura lisa e conseqüentemente pelo aumento do diâmetro dosvasos sangüíneos, aumentando o fluxo sangüíneo e reduzindo apressão arterial. O processo de dilatação pode ocorrer tambémquando nitro-vasodilatadores, como a nitroglicerina, liberam NOdiretamente para o endotélio e para a musculatura vascular lisa.When diffused into smooth muscle, the generated NO will bind to the iron of the heme prosthetic group of the enzymemagimaguanylate cyclase (GC), which is then activated and converts GTP to c-GMP. C-GMP is the molecule responsible for smooth muscle relaxation and consequently for increasing the diameter of blood vessels, increasing blood flow and reducing arterial pressure. The dilation process may also occur when nitro-vasodilators such as nitroglycerin release NO directly to the endothelium and smooth vascular musculature.
Ignarro e colaboradores (Ignarro et al., 2001)demonstraram, em seres humanos, que a administração de argininapor via oral produz melhora da função endotelial em vasoscoronarianos de pequeno calibre, assim como uma redução nos níveisplasmáticos de endotelina (potente substância vasoconstritora). 0óxido nítrico, além de relaxar o músculo liso vascular, causandovasodilatação, tem a função de inibir outros processos como aagregação plaquetária, a adesão de leucócitos ao endotélio e aprodução de endotelina. 0 óxido nítrico causa, ainda, variação naspropriedades contráteis e na freqüência cardíaca. No sistemacardiovascular, a liberação de óxido nítrico atua regulando ofluxo sangüíneo e a pressão arterial, através de ação sobre amusculatura lisa.Ignarro et al. (Ignarro et al., 2001) have demonstrated in humans that oral argininapor administration improves endothelial function in small vasoscoronarians, as well as a reduction in plasma levels of endothelin (potent vasoconstrictor substance). Nitric oxide, besides relaxing the vascular smooth muscle, causing new dilation, has the function of inhibiting other processes such as platelet aggregation, adhesion of leukocytes to the endothelium and endothelin production. Nitric oxide also causes variations in contractile properties and heart rate. In the cardiovascular system, the release of nitric oxide acts by regulating blood flow and blood pressure, by acting on smooth amusculature.
Apesar das muitas classes de doadores de NO quetêm sido reportadas, nitratos orgânicos, diazeniodiolatos e S-nitrosotióis são ainda os três tipos mais importantes de doadores.Eles possuem a vantagem de se decompor em solução e de mimetizaros nitrosotióis endógenos.Despite the many classes of NO donors that have been reported, organic nitrates, diazeniodiolates and S-nitrosothiols are still the three most important types of donors. They have the advantage of decomposing in solution and mimicking endogenous nitrosothiols.
Em nível celular, a arginina é sintetizada apartir da citrulina pela ação seqüencial das enzimasargininosuccinato sintetase e argininosuccinato liase (ouargininosuccinase, sendo o argininosuccinato um metabólitointermediário (sintetizado a partir da condensação da citrulina-Amp de aspartato.A arginina também é sintetizada em outrascélulas, embora em menor escala. Quando da indução da enzima óxidonitrico sintase (iNOS), a capacidade de síntese da arginina tambémaumenta. A iNOS, cuja função primária é sintetizar óxido nitrico(NO) , o faz a partir da oxidação do grupo guanidina, comconseqüente conversão da arginina à citrulina. Esta pode sernovamente convertida em arginina através da via arginina-citrulina.At the cellular level, arginine is synthesized from citrulline by the sequential action of enzymesargininosuccinate synthetase and argininosuccinate lyase (orargininosuccinase, with argininosuccinate being an intermediate metabolite (synthesized from condensation of aspartate citrulline-Amp.) When inducing the enzyme oxidonitrile synthase (iNOS), the ability of arginine to synthesize also increases, while iNOS, whose primary function is to synthesize nitric oxide (NO), is based on the oxidation of the guanidine group, with consequent conversion of arginine to citrulline This can be converted back to arginine via the arginine-citrulline pathway.
Em bactérias, a síntese da arginina é similar àsíntese em animais. Embora, muitas vezes, não possuem todas asenzimas necessárias ao ciclo doa ácidos tricarboxílicos ao cicloda uréia, conseguem sintetizar arginina a partir de a-cetoglutarato e de ornitina.In bacteria, arginine synthesis is similar to animal synthesis. Although often lacking all the enzymes necessary for the cycle of tricarboxylic acids to cycloda urea, they can synthesize arginine from α-ketoglutarate and ornithine.
Além de fazer parte de proteínas, a arginina tempapel importante na divisão celular, na cicatrização de feridas,inflamação em articulações ou não, ocorrendo um vasodilataçãovascular periférica, dando assim maior perfusão ao diclofenacoatuar nesses regiões acometidas por esses processos.Besides being part of proteins, arginine plays an important role in cell division, wound healing, joint inflammation or not, and peripheral vascular vasodilation occurs, thus giving greater perfusion to diclofenacoatuatu in these regions affected by these processes.
Como descrito acima, a arginina tomapreferencialmente uma carga positiva, pelo que tem tendência aligar-se a grupos carregados negativamente. Por essa razão é comumencontrar este aminoácido na superfície de proteínas, ocorrendoque essa enzima possa liberar o NO (óxido nitrico), substânciaessa vasodilatadora periférica, agindo assim o diclofenaco nosreceptores musculares que estarão mais pérveos pela ação o NO(óxido nitrico).As described above, arginine preferably takes a positive charge, so it tends to attach itself to negatively charged groups. For this reason it is common to find this amino acid on the surface of proteins, occurring that this enzyme may release NO (nitric oxide), peripheral vasodilator substance, thus acting the diclofenac muscle receptors that will be more perplexed by the action NO (nitric oxide).
A arginina é o precursor imediato do óxidonitrico. É necessária a síntese de creatina e pode ser usada paraa síntese de poliaminas, citrulina e glutamato. Por ser precursorado NO (que tem efeito relaxador dos vasos sangüíneos) a arginina éusada em condições em qu é necessária a vasodilatação periférica.Arginine is the immediate precursor of oxidonitrile. Creatine synthesis is required and can be used for synthesis of polyamines, citrulline and glutamate. Because precursor NO (which has a blood vessel relaxing effect) arginine is used under conditions where peripheral vasodilation is required.
A presente invenção relativa a composiçãofarmacêutica carreadora de substâncias ativas comportandoconfigurações encapsuladoras supramoleculares, arginina e enzimasproteolíticas em seu interior possibilita que estas configuraçõespenetrem até a camada lipídica, rompam-se envolvendo a lesão porum processo de expansão dos nexos e por gradiente de pressãocelular, ocorrendo o debridamento de fibrose ou inflamaçãocircunscrita sub-cutânea, periarticular ou microtrauma muscular.The present invention regarding the pharmaceutical composition of active substances carrying supramolecular encapsulating configurations, arginine and proteolytic enzymes within them enables these configurations to penetrate into the lipid layer, rupture involving the lesion by a process of expansion of the nexus and the debridement of the pressure gradient. fibrosis or subcutaneous, periarticular or muscular microtrauma.
O objetivo da presente invenção é uma novacomposição farmacêutica carreadora de substâncias ativascompreendendo configurações encapsuladoras supramoleculares entre10 nm e 990 nm, arginina entre 1 mg e 10 g e enzimas proteolíticasentre 0,1 e 70%.The aim of the present invention is a novel active substance carrier composition comprising supramolecular encapsulating configurations between 10 nm and 990 nm, arginine between 1 mg and 10 g and proteolytic enzymes between 0.1 and 70%.
Preferencialmente a invenção em tela relativa ànova composição farmacêutica carreadora de substâncias ativascompreende configurações encapsuladoras supramoleculares entre 10nm e 990 nm, arginina entre 10 mg e 1 g e enzimas proteolíticasentre 0,2 e 40%.Preferably the present invention relating to the novel active ingredient carrier pharmaceutical composition comprises supramolecular encapsulating configurations between 10nm and 990 nm, arginine between 10 mg and 1 g and proteolytic enzymes between 0.2 and 40%.
Mais preferencialmente a presente invençãorelativa à nova composição farmacêutica carreadora de substânciasativas compreende confugurações encapsuladoras supramolecularesentre 10 nm e 990 nm, arginina entre 20 mg e 500 mg e enzimasproteolíticas entre 1,0 e 20%.More preferably, the present invention relating to the novel substance-carrying pharmaceutical composition comprises supramolecular encapsulating confugurations between 10 nm and 990 nm, arginine between 20 mg and 500 mg, and proteolytic enzymes between 1.0 and 20%.
Ainda mais preferencialmente a invenção em telarelativa à nova composição farmacêutica carreadora de substânciasativas compreende configurações encapsuladoras supramolecularesentre 10 nm e 990 nm, arginina entre 40 mg e 200 mg e enzimasproteoliticas entre 2,0 mg e 10%.Even more preferably the invention in a telelelative to the new substance-carrying pharmaceutical composition comprises supramolecular encapsulating configurations between 10 nm and 990 nm, arginine between 40 mg and 200 mg and proteinaceous enzymes between 2.0 mg and 10%.
Vantajosamente a presente invenção reporta-se anova composição farmacêutica carreadora de substâncias ativascompreendendo configurações encapsuladoras supramoleculares,arginina, enzimas proteoliticas e diclofenaco.Advantageously the present invention relates to a new active substance carrier pharmaceutical composition comprising supramolecular encapsulating configurations, arginine, proteolytic enzymes and diclofenac.
Mais vantajosamente a presente invenção comportadita composição farmacêutica carreadora de substâncias ativascompreendendo como configurações encapsuladoras supramoleculares,nanoparticulas.More advantageously the present invention comprises active substance carrier pharmaceutical composition comprising nanoparticles as supramolecular encapsulating configurations.
Ainda mais vantajosamente a presente invençãocomporta dita composição farmacêutica carreadora de substânciasativas compreendendo como nanoparticulas, nanosferas,nanocápsulas, microsferas ou glicocápsulasEven more advantageously the present invention comprises said pharmaceutical carrier composition comprising substances such as nanoparticles, nanospheres, nanocapsules, microspheres or glycocapsules.
Preferencialmente a presente invenção comportadita composição farmacêutica carreadora compreendendo comosubstâncias ativas cicatrizantes, antibióticos, antifúngicos,antireumáticos, antiinflamatórios esteroidais ou não, analgésicos,antivirais, antivaricosos, anestésicos, antitumorais eantipruriginosos.Preferably the present invention comprises a carrier pharmaceutical composition comprising as active healing substances, antibiotics, antifungals, antirheumatics, steroidal or non-steroidal anti-inflammatories, analgesics, antivirals, anesthetics, and anti -pruritic antitumour.
Mais preferencialmente a invenção em telacompreendendo composição farmacêutica carreadora pode serutilizada no tratamento das patologias inflamatórias.More preferably the invention in teleconferencing carrier pharmaceutical composition may be used in the treatment of inflammatory conditions.
Ainda mais preferencialmente a presente invençãocompreendendo composição farmacêutica carreadora de substânciasativas comporta diclofenaco.Even more preferably the present invention comprising pharmaceutical composition comprising diclofenac carries substances.
Vantajosamente a invenção em tela relativa aprocesso para tratar patologias inflamatórias comportando aadministração de composição farmacêutica carreadora compreendeconfigurações encapsuladoras, arginina, enzimas proteoliticas ediclofenaco.Advantageously the invention relates to the process for treating inflammatory conditions comprising administering a carrier pharmaceutical composition comprising encapsulating configurations, arginine, ediclofenac proteolytic enzymes.
Mais vantajosamente a presente invenção reporta-se a processo para tratar patologias inflamatórias comportando aadministração de composição farmacêutica carreadora compreendeconfigurações encapsuladoras, como nanoparticulas, arginina,enzimas proteoliticas e diclofenaco.Most advantageously the present invention relates to a process for treating inflammatory conditions comprising administering a carrier pharmaceutical composition comprising encapsulating settings such as nanoparticles, arginine, proteolytic enzymes and diclofenac.
Ainda mais vantajosamente a invenção em telarelativa a processo para tratar patologias inflamatóriascomportando composição farmacêutica carreadora compreendendonanoparticulas, como nanosferas, nanocápsulas, microsferas eglicocápsulas, arginina, enzimas proteoliticas e diclofenaco.Even more advantageously the invention is in a process-related manner for treating inflammatory conditions comprising carrier pharmaceutical composition comprising nanoparticles such as nanospheres, nanocapsules, glycocapsule microspheres, arginine, proteolytic enzymes and diclofenac.
Para ilustrar a presente invenção apresenta-se oestudo, a titulo meramente exemplificativo não limitativo,comprovando a ação das nanoparticulas com substâncias ativas pré-determinadas no tecido subcutâneo em humanos, juntamente comdiclofenaco dietilamônio e aspartato de arginina.To illustrate the present invention the study is given by way of non-limiting example only, proving the action of nanoparticles with predetermined active substances in subcutaneous tissue in humans, together with diclofenac diethylammonium and arginine aspartate.
DOMS - DefiniçãoDOMS - Definition
0 quadro é clinicamente descrito por sinais esintomas que na literatura cientifica têm sido denominados DOMSThe picture is clinically described by signs and symptoms which in the scientific literature have been called DOMS.
(Delayed Onset o Muscle Soreness)(Delayed Onset the Muscle Soreness)
MECANISMO DA DOR MUSCULARMUSCULAR PAIN MECHANISM
EFEITO IMEDIATO DIA SEGUINTEExercício Intenso DorAcúmulo de Ácido Lático DOMSMicro Traumas Inflamação Dorcreme de nanopartículas de papaína com diclifenaco dietilamônio easpartato de arginina, através de deslizamento superficial, naparte anterior de ambas as coxas.IMMEDIATE EFFECT NEXT DAY Intense Exercise PainLactic Acid Accumulation DOMSMicro Trauma Inflammation Pain of papain nanoparticles with diethylammonium diclifenac and arginine slippage through anterior sliding of both thighs.
Procedimentos pré exercício:Pre exercise procedures:
· Todos os indivíduos foram submetidos aavaliação da amplitude de movimento de flexão de joelho (atravésdo uso de flexímetro) e percepção subjetiva de dor (visualanalogue scale -VAS) e força de extensão de joelho.· All subjects underwent knee flexion range of motion assessment (using a fleximeter) and subjective pain perception (visual analogue scale -VAS) and knee extension strength.
Procedimento 24 horas após o exercício:Procedure 24 hours after exercise:
· 24 horas após o exercício os indivíduosassinalaram a escala de dor.· 24 hours after exercise, individuals indicated the pain scale.
Procedimentos 48 horas após o exercício:Procedures 48 hours after exercise:
Todos os indivíduos foram novamentesubmetidos a avaliação da amplitude de movimento de flexão dejoelho, percepção subjetiva de dor e força de extensão de joelho.All subjects were again subjected to knee flexion range of motion, subjective pain perception and knee extension strength.
Procedimento dos exercícios:Exercise Procedure:
Os exercícios para desencadear dor muscularforam compostos de 4 séries de 12 repetições de exercíciopredominantemente excêntrico de extensão de joelho, com 80% dacarga máxima, e relação de 1:5 entre contração concêntrica eexcêntrica, respectivamente.Exercises to trigger muscle pain were composed of 4 sets of 12 repetitions of predominantly eccentric knee extension exercise, with 80% maximal load, and a 1: 5 ratio between concentric and eccentric contraction, respectively.
A carga máxima do exercício foi determinadano mesmo dia do teste, através da determinação de uma repetiçãomáxima (1 RM), que consiste na carga máxima que um indivíduo écapaz de levantar, sendo impossível levantá-la por uma segundavez.The maximum exercise load was determined on the same day of the test by determining a maximum repetition (1 RM), which is the maximum load that an individual is able to lift, and it is impossible to lift it for a second time.
Tanto a carga máxima quanto os exercíciosforam realizados unilateralmente.Aplicação dos cremes:Both the maximum load and the exercises were performed unilaterally.
Após a realização dos exercícios todos osindivíduos foram orientados a aplicar dois tipos de cremes: um nacoxa esquerda e outro na coxa direita.After the exercises, all individuals were instructed to apply two types of creams: one left thigh and one on the right thigh.
0 conteúdo dos cremes não foi informado aosvoluntários e ao examinador (modelo duplo cegoThe content of the creams was not informed to the volunteers and the examiner (double blind model
Os voluntários referiram muito menos dor nacoxa que recebeu o creme A3 (diclofenaco) , do que na coxa querecebeu o creme Al (placebo) , tanto em 24h quanto em 48h (Al24h=4,63; 48h=3,08 / A3 24h=2,02; 48h=l,33).Volunteers reported much less thigh pain receiving A3 (diclofenac) cream than thigh receiving Al cream (placebo) at both 24h and 48h (Al24h = 4.63; 48h = 3.08 / A3 24h = 2.02; 48h = 1.33).
A amplitude de movimento geralmente diminuicom a dor muscular tardia. 0 membro inferior (MI) que recebeu oplacebo apresentou esse comportamento (Pré 146,83 Pós 143,5). Já oMI que recebeu o creme com A3, não sofreu reduções naflexibilidade (Pré 139,16 Pós 139,83).Range of motion usually decreased with late muscle pain. The lower limb (MI) that received oplacebo showed this behavior (Pre 146.83 Post 143.5). The IM who received the cream with A3 did not suffer reductions in flexibility (Pre 139.16 Post 139.83).
A força muscular diminui com a dor musculartardia. A magnitude da perda de força reflete a magnitude da lesãomuscular. 0 MI com A3 apresentou tendência a perder menos força(Pré 36,67 Pós 35,0) do que o MI com Al (Pré36,67 Pós 33,3).Muscle strength decreases with muscle pain. The magnitude of the strength loss reflects the magnitude of the muscle injury. MI with A3 tended to lose less strength (Pre 36.67 Post 35.0) than MI with Al (Pre 36.67 Post 33.3).
Claims (12)
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| BRPI0900858-6A BRPI0900858A2 (en) | 2009-04-23 | 2009-04-23 | pharmaceutical composition containing active substances |
| PCT/BR2009/000224 WO2010121334A1 (en) | 2009-04-23 | 2009-07-29 | Active substances-carrying pharmaceutical composition |
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| US7407668B2 (en) * | 2002-01-24 | 2008-08-05 | Boston Scimed, Inc. | Medical articles having enzymatic surfaces for localized therapy |
| KR101165848B1 (en) * | 2005-08-18 | 2012-07-13 | (주)아모레퍼시픽 | Cosmetic composition containing enzyme and amino acid |
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