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WO2003018063A1 - Composition d'une substance d'excipient destinee a des produits a base de papaine et d'hyaluronidase - Google Patents

Composition d'une substance d'excipient destinee a des produits a base de papaine et d'hyaluronidase Download PDF

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Publication number
WO2003018063A1
WO2003018063A1 PCT/BR2001/000109 BR0100109W WO03018063A1 WO 2003018063 A1 WO2003018063 A1 WO 2003018063A1 BR 0100109 W BR0100109 W BR 0100109W WO 03018063 A1 WO03018063 A1 WO 03018063A1
Authority
WO
WIPO (PCT)
Prior art keywords
epitheliums
permeability
papain
hyaluronidase
coating
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/BR2001/000109
Other languages
English (en)
Inventor
Cristiano Alberto Ribeiro Santana
Gilberto De Nucci
Marcio Falci
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medtopic Empreendimentos E Particapacoes S/c Ltda
Original Assignee
Medtopic Empreendimentos E Particapacoes S/c Ltda
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 Medtopic Empreendimentos E Particapacoes S/c Ltda filed Critical Medtopic Empreendimentos E Particapacoes S/c Ltda
Priority to BR0115182-7A priority Critical patent/BR0115182A/pt
Priority to PCT/BR2001/000109 priority patent/WO2003018063A1/fr
Publication of WO2003018063A1 publication Critical patent/WO2003018063A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/0012—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
    • 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
    • A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts

Definitions

  • the present invention refers to a new composition of a carrier substance for products to aggregate papain and hyaluronidase.
  • composition is of topical application, non-toxic and features a high penetration rate through the skin. It can be presented in the form of gel, cream, gel cream, aerosol, spray, liquid, lyophilized or patch (transdermic adhesive) .
  • 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 epitheliums and the secreting epitheliums, 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 products synthesis; thus are constituted the secreting units.
  • the coating epitheliums 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 epitheliums isolate from each other the various internal media compartments, among which are the intravascular compartment, the serum compartment and several others.
  • the coating epitheliums include those that are performed by specialized variants that are specifically adapted to perform one or more functions. Others are incorporated as general functions presented without distinction by every coating epithelium cell.
  • the coating epithelium cell in the same way as most of the living cells, passively absorbs water and electrolytes and eliminates them actively; this function is well developed in the epithelium cells. On that account it is very important to observe that generally it is understood as absorption the penetration of solutions through the cells plasmatic membrane.
  • the coating epithelium cells limit in a controlled and selective way the permeability of the respective epitheliums, with the purpose of protecting the organism and still participate of the control of its homeostasis .
  • the epitheliums are organized and arrange their cells in a special form, in order to build up coatings which cells abbut 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 glicochalice, 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 epitheliums 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 epitheliums are pervious, which allows for the controlled and selective passage of several products through its wall.
  • the coating epitheliums permeability constitutes a fundamental property, with significant functional expression, for it is essential for the performance of several functions featured by the epitheliums, 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 epitheliums:
  • the epitheliums allow intense metabolic exchanges through their walls, with poor control and selectivity of its permeability.
  • the epithelium acts on the filtration and transfer of metabolites, these functions requiring little qualitative control; the exercise of these functions is subordinated to the epithelium intrinsic structure, which is adapted to act, mainly passively, being low the level of selective permeability.
  • these coating epitheliums 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 complex 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 epitheliums permeability is such an expressive functional property that it has been used as an important classification criterion to rank them in three classes :
  • the epitheliums Because of their selective permeability, even in the inferior animals the epitheliums 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 epitheliums 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 cell's 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 glicochalice, 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 glicochalice.
  • glicochalice 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 glicochalice.
  • 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 epitheliums, which demand only minor adaptations to become able to effectively perform such functions.
  • the functions of absorption, excretion and secretion depend of properties that develop successively and would become paramount, mostly in some specialized types of coating epithelium, which adapted following a new and specific direction.
  • the sensorial perception and the germinative function are more specific functions that are only manifest by certain epitheliums even more specialized.
  • the coating epitheliums have been classified according to the same number of cellular extracts they bear in: simple (a single extract) and stratified (two or more extracts) . Both the simple epitheliums and the stratified ones, conforming to their cell's format, are in turn subdivided into pavimentous, cubic or prismatic.
  • the simple epitheliums are usually adapted to manifest wholly their most expressive fundamental property, which consists in their permeability, which degree and selectivity vary.
  • the simple coating epitheliums constituted by a single layer of pavements 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 epitheliums are usually very pervious; the cubic-prismatic ones are less pervious.
  • the coating epitheliums 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.
  • the cubic-prismatic epitheliums being less pervious than the pavimentous, are more effective to control their permeability.
  • the simple coating epitheliums are divided into two classes: pavimentous and cubic-prismatic . Each class is subdivided according to its functional properties in open or pervious epitheliums, in semi-occlusive or poorly-pervious and occlusive or impervious.
  • the cubic epitheliums and the prismatic epitheliums are usually considered distinct, being defined and identified according to the format of the epithelium cells that make them up.
  • some functional studies have showed that the correlation between form and function presents several exceptions. For this reason a functional classification is adopted considering predominantly it's permeability.
  • these epitheliums are denominated cubic-prismatic comprising the semi-occlusive and occlusive epitheliums.
  • the stratified epitheliums can be subdivided into: pavimentous and cubic- prismatic.
  • the stratified epitheliums are adapted to perform primarily the mechanical protection function, because they are impervious or poorly pervious.
  • the epitheliums comprise, in addition to the cells, the intercellular space and the base membrane, which interfere in their permeability degree; their permeability derives not only from their cell's peculiar properties, responsible for the transcellular permeability way, but also from the presence of another permeability way of their walls, constituting the intercellular or paracellular way.
  • the transcellular way comprises two different ways that consist of the transmembranous way and the transcanicular or trancitose way.
  • the coating epitheliums can be transposed by water and by substances of various natures, both through their epithelium cells (transcellular way) and through the way situated between their cells (intercellular way) .
  • the epithelium cell can effect the permeability control of the epithelium through its biological activity, making this process selective.
  • the intercellular way permeability 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 epithelium cell By means of the action of the microfilaments that constitute its cito-skeleton, the epithelium cell, specially those of certain types of simple coating epitheliums pavimentous of the open type, can change its format and retract segments of its cytoplasm; thus being able to influence the size of the intercellular space and regulate it. It has been established that the transcellular permeability of the simple coating epitheliums 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.
  • the transcellular permeability of the simple coating epitheliums can be exercised through two distinct and independent ways: the transmembrane way, which is the true transcellular way, and the transcanicular way, which happens through the vesicles and the cannules or tubes of the vesicle-cannule system, found inside the cytoplasm of many types of coating epithelium cells". Consequently, the coating epitheliums are pervious, which allows the controlled and selective passage of various products through its wall. It is demonstrated that the permeability degree affects strongly the coating epitheliums function. Three types of coating epitheliums are thus considered:
  • the purpose is to prove through the formulation that there is an intense metabolic exchange demonstrating that the epithelium actuates on the transfer of metabolites. This penetration of substances is complete and gradual and trespasses these epithelium layers until it penetrates the small blood vessels, reaching the circulatory current . There is a description of the molecules to estimate the coating epitheliums permeability. Ex. : Hemoglobin, Ferritine, Lipoproteins and enzymes.
  • the object of the present invention is a "COMPOSITION OF A CARRIER SUBSTANCE FOR PRODUCTS BASED ON PAPAIN AND HYALURONIDASE" comprising in it's formulation:
  • composition of a carrier substance comprises: PAPAIN more than 0.5% and
  • composition of a carrier substance comprises:
  • composition of a carrier substance according to the present invention comprises: PAPAIN more than 0.01% and
  • composition of a carrier substance according to the present invention may be presented in the form of gel, cream, gel cream, aerosol, spray, liquid, lyophilized or "patch" (transdermic adhesive) .
  • Said composition of a carrier substance, based on papain and hyaluronidase may be used, notably, in the preparation of medicine.
  • This technique was proofed through studies performed with 24 outpatients, in 03 distinct sessions with groups of 8 outpatients, being the concentration of papain above 0.01%.
  • the delimited area measured 15x10 cm, with the application of cream. After 15 minutes the measurements were started through liquid chromatography coupled to mass spectrometry .
  • the results yielded by papain, in concentrations above 0.01% were 151% more effective than when it was mixed with other substances .

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Botany (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Cosmetics (AREA)

Abstract

La présente invention concerne une nouvelle composition de substance d'excipient destinée à des produits à agréger comprenant dans leur préparation plus de 0,01% de papaïne et de 50 utr/mg à 900 utr/mg d'hyaluronidase.
PCT/BR2001/000109 2001-08-27 2001-08-27 Composition d'une substance d'excipient destinee a des produits a base de papaine et d'hyaluronidase Ceased WO2003018063A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
BR0115182-7A BR0115182A (pt) 2001-08-27 2001-08-27 Composição de substância carreadora de produtos à base de papaìna e hialuronidase
PCT/BR2001/000109 WO2003018063A1 (fr) 2001-08-27 2001-08-27 Composition d'une substance d'excipient destinee a des produits a base de papaine et d'hyaluronidase

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/BR2001/000109 WO2003018063A1 (fr) 2001-08-27 2001-08-27 Composition d'une substance d'excipient destinee a des produits a base de papaine et d'hyaluronidase

Publications (1)

Publication Number Publication Date
WO2003018063A1 true WO2003018063A1 (fr) 2003-03-06

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PCT/BR2001/000109 Ceased WO2003018063A1 (fr) 2001-08-27 2001-08-27 Composition d'une substance d'excipient destinee a des produits a base de papaine et d'hyaluronidase

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BR (1) BR0115182A (fr)
WO (1) WO2003018063A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4678668A (en) * 1985-10-28 1987-07-07 Md Associates Method of reducing soft tissue swelling and pain
WO2001054647A2 (fr) * 2000-01-28 2001-08-02 Topic Empreendimentos E Participações S/C Ltda. Composition pharmaceutique comprenant des transporteurs de produits a base de vitamine e, de papaine et d'hyaluronidase
WO2001060399A1 (fr) * 2000-02-21 2001-08-23 Topic Empreendimentos E Participações S/C Ltda. Composition pharmaceutique de diclofenac a base de vitamine e, papaine et hyaluronidase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4678668A (en) * 1985-10-28 1987-07-07 Md Associates Method of reducing soft tissue swelling and pain
WO2001054647A2 (fr) * 2000-01-28 2001-08-02 Topic Empreendimentos E Participações S/C Ltda. Composition pharmaceutique comprenant des transporteurs de produits a base de vitamine e, de papaine et d'hyaluronidase
WO2001060399A1 (fr) * 2000-02-21 2001-08-23 Topic Empreendimentos E Participações S/C Ltda. Composition pharmaceutique de diclofenac a base de vitamine e, papaine et hyaluronidase

Also Published As

Publication number Publication date
BR0115182A (pt) 2004-02-17

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