WO2004087197A1 - Procede de production de medicament, vecteur correspondant et utilisation de ce medicament - Google Patents

Procede de production de medicament, vecteur correspondant et utilisation de ce medicament Download PDF

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Publication number
WO2004087197A1
WO2004087197A1 PCT/BR2003/000052 BR0300052W WO2004087197A1 WO 2004087197 A1 WO2004087197 A1 WO 2004087197A1 BR 0300052 W BR0300052 W BR 0300052W WO 2004087197 A1 WO2004087197 A1 WO 2004087197A1
Authority
WO
WIPO (PCT)
Prior art keywords
fact
production
bromeline
drug carrier
epithelia
Prior art date
Application number
PCT/BR2003/000052
Other languages
English (en)
Inventor
Cristiano Alberto Ribeiro Santana
Gilberto De Nucci
Original Assignee
Santana Cristiano Alberto Ribe
Gilberto De Nucci
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Santana Cristiano Alberto Ribe, Gilberto De Nucci filed Critical Santana Cristiano Alberto Ribe
Priority to AU2003213901A priority Critical patent/AU2003213901A1/en
Priority to PCT/BR2003/000052 priority patent/WO2004087197A1/fr
Publication of WO2004087197A1 publication Critical patent/WO2004087197A1/fr

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Classifications

    • 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)
    • A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • 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)
    • A61K38/4873—Cysteine endopeptidases (3.4.22), e.g. stem bromelain, papain, ficin, cathepsin H
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
    • C12Y302/01—Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
    • C12Y302/01035—Hyaluronoglucosaminidase (3.2.1.35), i.e. hyaluronidase
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/22—Cysteine endopeptidases (3.4.22)
    • C12Y304/22033—Fruit bromelain (3.4.22.33), i.e. juice bromelain

Definitions

  • the present invention refers to a new process for the production of a drug carrier, as well as the drug produced and its use.
  • Said drug is, preferably, of topical application, non- toxic and features a high penetration rate through the skin.
  • the skin permeability varies according to the region of the body, being the skin folds and the face those that present the highest absorption rate. A product applied over the skin will present a longer period of contact and percutanial absorption.
  • the epithelium cells are predominantly classified into two categories, which correspond to two epithelium classes: coating epithelium cells and secreting epithelium cells.
  • the cells of these two classes mix with each other to constitute, respectively, the coating epithelium and the secreting epithelium, each one of them performing specific functions that are inherent to them.
  • Such division is also fundamented in the distribution of these two classes of epithelium in the organism, which although wide is distinctive for both.
  • the epithelium cells associate side-by-side, so as to originate "membranes” or layers superimposed over the base membrane, which function is to coat surfaces.
  • the secreting cells unite to form organized functional units, better suited for performing their specialized function, related to the secretion product synthesis; thus are constituted the secreting units.
  • the coating epithelia are defined as living membranes, usually featuring a discontinuity, that isolate the organism from the environment, separating the internal media from the external one. Furthermore, these epithelia isolate from each other the various internal media compartments, among which are the intravascular compartment, the serum compartment and several others .
  • the epithelia are organized and arrange their cells in a special form, in order to build up coatings which cells abut the base membrane and are united with each other by means of intracellular junctions; in turn the cells are coated by the plasmatic membrane, which features special characteristics, and by the glycochalice, both able to express well defined functional properties.
  • the functional characteristics expressed by the plasmatic membrane portion that coats the cells apical surface are different from those expressed by the portion situated in its basal or basolateral face; such ' ' differences, which occur mainly on the functional - aspect, contribute for the remarkable degree of polarization expressed by the coating epithelium cells.
  • the prime function performed by the coating epithelia correspond essentially to the protection rendered to the surface that they coat, characterizing their protective coating function.
  • Such function features a * special characteristic, being a coating that, besides offering mechanical, physical and chemical protection to the coated surface, is not inert.
  • the coating epithelia are pervious, which allows for the controlled and selective passage of several products through its wall .
  • the coating epithelia permeability constitutes a fundamental property, with significant functional expression, for it is essential for the performance of several functions featured by the epithelia, even more so because it is selective and its permeability degree presents a wide variation. It is fairly well demonstrated that the permeability degree influences strongly the function performed by the coating epithelia:
  • these coating epithelia present selective permeability, which allows them to interfere and qualitatively control their functional activity, as well as making them more able to actuate over the homeostasis control.
  • the absence of epithelium permeability is correlated to the comp'lex isolation of the coated surface and, on the other hand, to the better controlling of this epithelium function, because its cells, although very poorly pervious, present selective permeability.
  • the coated surface has its boundaries limited by a "membrane" impervious or very poorly pervious and very effective, that performs an important protective function, for it is able to discriminate * exactly what can cross the epithelium.
  • the coating epithelia permeability is such an expressive functional property that it has been used as an important classification criterion to rank them in three classes:
  • the epithelia Because of their selective permeability, even in the inferior animals the epithelia have assumed the function of coating the organism, constituting its external coating, with limiting and protective properties, not only morphological but also functional. Their cells, in principle very similar, behaved as a semi-pervious "membrane" poorly effective that acted passively, but which function allowed the separation, tough precarious and more morphological than functional, between the internal and the external media. It seem to be that the majority of the coating epithelia acts as a barrier that prevents the free passive diffusion, because their permeability, which is selective, is conditioned to several factors among which stands out the electric potential present in their cells plasmatic membrane.
  • the continuity of the epithelium coating is established as much through the intimate abutment of adjacent cells as through the presence of intercellular union devices.
  • the epithelium cells are enveloped by the glycochalice, that also takes part of the coating function performed by the epithelium, in addition to aid the union between adjacent cells, because the intracellular adhesive is formed also by the glycochalice.
  • the coating epithelia selective permeability is associated to other specific functions expressed by their cells, namely: absorption, excretion and secretion. These functions, beyond their permeability, which constitutes their prime function, are responsible by the general functioning of the epithelium cell.
  • the general functions performed by the coating epithelia are basically the following: 1) surfaces protective coating function;
  • the first four derive mostly from the epithelium cells selective permeability, over which are additionally superimposed the additional affects corresponding to their properties of absorption, excretion and secretion.
  • the selective permeability is responsible by the efficiency regarding the ability to coat, protect and isolate the surfaces, as well as to effect the control of the homeostasis; the passive absorption and the metabolites transfer capacity are executed normally by the majority of the cells of these epithelia, which demand only minor adaptations to become able to effectively perform such functions.
  • the simple epithelia are usually adapted to manifest wholly their most expressive fundamental property that consists in their permeability, which degree and selectivity vary.
  • the simple coating epithelia constituted by a single layer of pavimentous or cubic-prismatic cells, present major differences regarding their functional properties, correlated not only to their cell's morphology, but also to the intracellular space's properties.
  • the simple pavimentous epithelia are usually very pervious; the cubic- prismatic ones are less pervious.
  • the coating epithelia permeability in addition to being selective, is controlled by their cell's functional activity, although the control looses efficiency in the same order as the intracellular space's permeability increases.
  • these epithelia are denominated cubic-prismatic comprising the semi-occlusive and occlusive epithelia.
  • the stratified epithelia can be subdivided into: pavimentous and cubic-prismatic.
  • the stratified ' epithelia are adapted to p'erform primarily the mechanical protection function, because they are impervious or poorly pervious.
  • the epithelium cell can effect the permeability control of the epithelium through its biological activity, making this process selective.
  • the epithelium cell although not behaving in a totally passive form, does not interfere directly in the transport selectivity.
  • the sole form of cell active participation comprises the determination, exceptionally, the enlargement of the corresponding intercellular space.
  • the transcellular permeability of the simple coating epithelia is perfectly distinct from the intercellular permeability, because both are subordinated to very different mechanisms.
  • the epithelium cell permeability which is selective, is influenced by its biological activity; on the contrary, the intercellular permeability is totally passive, and thus is not selective.
  • BROMELINE is the generic name given to the proteolitic enzymes found in pineapple and other species of plants of the BROMELIACEAE family. The bromelines hydrolyze a vast series of proteins, peptides, esters and amides. The enzyme, obtained from the stem, is of glycoproteic nature.
  • Bromeline presents, in it's mechanism of activation and deactivation, a sulphydrillic protease, that is, the action of its enzymes depends on the sulphydric group ' of a cisteyne residue. Conversely, and different from the papaine, on the hydrolysis of the glucagon the later is cleaved by BROMELINE in different spots .
  • BROMELINE occurs in a higher concentration in the lower parts of the stems of ripe plants, and the core portion of it contains more protease than the external part.
  • proteolitic enzymes The manipulation of proteolitic enzymes has been posing a true challenge to the technicians involved. Said instability, which is inherent to it, has been limiting and restricting their application in the fields of odontology, diets and, now regarding the administration path, the consolidation of the oral path, with the consequent exclusion of the dermatological path.
  • U.S. Patent 4,678,668 describes a dermatological composition to alleviate the pain and reduce the swelling in the affected area comprising proteolitic enzymes such as papaine, hyaluronidase, tripsine and Bromeline and as carrier vehicle glycerin, alcohol, hydro-alcoholic or aqueous solution.
  • the object of the present invention is a new process for production of a pharmaceutical composition carrier comprising the following steps: a) Addition, in a recipient, of oil and preservatives, keeping the temperature warm; b) cooling to a temperature close to the room temperature ; c) Addition, in another recipient, of an humidifying substance, EDTA and hyaluronidase, incorporating proteolitic enzyme, surfactant and vitamin E; d) Addition of the mixture obtained on step c) to the mixture obtained on step b) ; e) homogenization.
  • step (b) More preferably the temperature of this step lies between 65 and 80°C.
  • the cooling of step (b) is performed to a temperature lying between 25 and 45°C.
  • the cooling is performed between 30 and 40°C.
  • Said composition is soluble in water and glycerol, but is practically insoluble in alcohol, ether and chloroform. It is non-active upon reacting with oxidizing agents such as iron, oxygen, iodine derivatives, hydrogen peroxide and silver nitrate.
  • proteolitic enzyme of easy deterioration, must be kept in a fresh, dry, ventilated and protected place.
  • the present invention adheres to a process for production of a pharmaceutical composition carrier comprising, most notably: BROMELINE more than 0.01% .
  • PAPAINE more than 0, 01%.
  • HYALURONIDASE from 50 to 900 utr/mg.
  • VITAMIN E from 10 to 2000 mg
  • the pharmaceutical composition ⁇ comprising • the carrier may be used in the production of medicine.
  • the pharmaceutical composition comprising the carrier presents the following characteristics:
  • composition comprising the carrier can be applied dermicaly or transdermicaly .
  • the present invention was proved through studies performed with 24 outpatients, in 3 different sessions with groups of 8 outpatients, being the Bromeline concentration of more than 0,01%.
  • the area delimited was 15 cm x 10 cm (150cm 2 ), with application of cream. After 15 minutes the measurements were started, through liquid chromatography, coupled to mass spectrophotometry .
  • the results obtained revealed that the use of a Bromeline carrier, with values of more than 0,01%, allow for penetration rates of more than 100%, relative to what could be expected without the mentioned carrier.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Dermatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention porte sur un procédé de production d'un vecteur de médicament, sur le médicament proprement dit et sur l'utilisation de ce médicament. Ce procédé de production d'un vecteur de médicament comprend les étapes suivantes consistant : a) à ajouter de l'huile et un conservateur et à maintenir une température relativement élevée ; b) à refroidir la température afin qu'elle soit proche de la température ambiante ; c) à ajouter, dans un autre récipient, une substance d'humidification, de l'EDTA et de l'hyaluronidase, à incorporer une enzyme protéolytique, un surfactant et de la vitamine E ; d) à ajouter le mélange obtenu à l'étape c) au mélange obtenu à l'étape b) ; et e) à homogénéiser ces mélanges.
PCT/BR2003/000052 2003-04-01 2003-04-01 Procede de production de medicament, vecteur correspondant et utilisation de ce medicament WO2004087197A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2003213901A AU2003213901A1 (en) 2003-04-01 2003-04-01 Drug production process corresponding carrier and use
PCT/BR2003/000052 WO2004087197A1 (fr) 2003-04-01 2003-04-01 Procede de production de medicament, vecteur correspondant et utilisation de ce medicament

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/BR2003/000052 WO2004087197A1 (fr) 2003-04-01 2003-04-01 Procede de production de medicament, vecteur correspondant et utilisation de ce medicament

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WO2004087197A1 true WO2004087197A1 (fr) 2004-10-14

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001070258A1 (fr) * 2001-03-19 2001-09-27 Santana, Cristiano, Alberto, Ribeiro COMPOSITION PHARMACEUTIQUE POUR EXCIPIENT POUR PRODUITS A BASE DE VITAMINE E, DE BROMELINE ET D'HYALURONIDASE
WO2002008962A1 (fr) * 2000-07-25 2002-01-31 Energy E-Comm.Com, Inc. Procede et dispositif d'extraction de donnees sur internet
WO2003015811A1 (fr) * 2001-08-17 2003-02-27 Santana Cristiano Alberto Ribe Procede permettant d'obtenir une composition pharmaceutique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002008962A1 (fr) * 2000-07-25 2002-01-31 Energy E-Comm.Com, Inc. Procede et dispositif d'extraction de donnees sur internet
WO2001070258A1 (fr) * 2001-03-19 2001-09-27 Santana, Cristiano, Alberto, Ribeiro COMPOSITION PHARMACEUTIQUE POUR EXCIPIENT POUR PRODUITS A BASE DE VITAMINE E, DE BROMELINE ET D'HYALURONIDASE
WO2003015811A1 (fr) * 2001-08-17 2003-02-27 Santana Cristiano Alberto Ribe Procede permettant d'obtenir une composition pharmaceutique

Also Published As

Publication number Publication date
AU2003213901A1 (en) 2004-10-25

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