WO2004087197A1

WO2004087197A1 - Drug production process corresponding carrier and use

Info

Publication number: WO2004087197A1
Application number: PCT/BR2003/000052
Authority: WO
Inventors: Cristiano Alberto Ribeiro Santana; Gilberto De Nucci
Original assignee: Santana Cristiano Alberto Ribe; Gilberto De Nucci
Priority date: 2003-04-01
Filing date: 2003-04-01
Publication date: 2004-10-14
Also published as: AU2003213901A1

Abstract

The present patent application refers to a process for production of a drug carrier, the drug itself and its usage. Said process for production of a drug carrier comprises the following steps: a) addition of oil and preservative, keeping the temperature warm; b) cooling to a temperature near 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.

Description

"DRUG PRODUCTION PROCESS, CORRESPONDING CARRIER AND USE".

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.

DESCRIPTION OF THE INVENTION

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.

According to the classic book "Histologia dos epitelios", by Walter A. Hadler and Sineli R. Silveira, Editora Campus, Campinas, 1993, it is considered that: "bearing in mind the general morphological characteristics and the specialized functions that they perform, 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. With the purpose of forming the coating epithelii 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. On the contrary, 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 . Among the various functions performed by the coating epithelia some 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, i 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. However two different specific forms of absorption must be distinguished from one another: the passive absorption, that occurs according to the osmotic laws, and the active absorption, that entails the effective participation of the epithelium cell and that does not follow such physic laws. On the other hand it must be considered that every single substance that penetrates the interior of a multi-cellular organism, or else is excreted or eliminated, must cross at least one coating epithelium, because every superior organism is penetrated internally and externally by epithelia. It must also be observed that the coating epithelia, although continuously covering and protecting those surfaces it coats, are not impervious at all; that is why they do not behave as inert "membranes" . On the contrary, they allow for the exchange of gases, water, several kinds of electrolytes and certain other solutes between the internal and the external media, or between the various internal compartments, which characterizes its permeability. The coating epithelium cells limit in a controlled and selective way the permeability of the respective epithelia, with the purpose of protecting the organism and still participate of the control of its homeostasis.

In order to perform such function 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 . There are many evidences in favor of the idea that 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:

1) wide permeability;

2) reduced permeability and

3) absence of permeability. When there is a wide permeability, the epithelia allow intense metabolic exchanges through their walls, with poor control and selectivity of its permeability. In these circumstances 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. The coating epithelia with a reduced degree of permeability, due to the characteristic that is so peculiar to them, present the property of partially controlling their own permeability, and above all their selectivity. As a consequence, 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. In this case 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:

1) pervious epithelia;

2) poorly pervious epithelia and 3) impervious 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. Several experimental investigations confirm that 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;

2) isolation and functional individualization of the internal media and of its distinct compartments, due to their cells ' selective permeability;

3) controlling the homeostasis of the internal medium and its compartments due to their cells ability to interfere in the epithelium selective permeability; the epithelium cells manifest the capacity to effect the absorption, secretion and excretion; such functions interfere on the epithelium permeability; 4) performance of the metabolic functions due to their ability to effect hydrosalinic exchanges and to effect metabolites transfers due to their cells and intracellular spaces high degree of poorly selective permeability;

5) transport of products along the epithelial surface due to the participation of the cilia;

6) sensorial perception and

7) germinative function.

Among these functions, 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. Among the general functions performed by the coating epithelia, 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. On the contrary, 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 epithelia even more specialized. Considering their cell's morphological characteristics, the coating epithelia 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 epithelia and the stratified ones, conforming to their cells format, are in turn subdivided into pavimentous, cubic or prismatic. 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. The cubic-prismatic epithelia, being less pervious than the pavimentous, are more effective to control their permeability. Based on the format of the epithelium cell, in its permeability and the coating epithelia most common adaptations, it is possible to generate a provisional classification for these epithelia. Thus, the simple coating epithelia are divided into two classes: pavimentous and cubic-prismatic . Each class is subdivided according to its functional properties in open or pervious epithelia, in semi-occlusive or poorly pervious and occlusive or impervious. In the simple coating epithelia classification, the cubic epithelia and the prismatic epithelia are usually considered distinct, being defined and identified according to the format of the epithelium cells that make them up. However 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. According to this criterion these epithelia are denominated cubic-prismatic comprising the semi-occlusive and occlusive epithelia. Following the same criterion 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 epithelia 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 transcannular or trancitose way. It has been demonstrated, experimentally, that the coating epithelia 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) .

In the first instance the epithelium cell can effect the permeability control of the epithelium through its biological activity, making this process selective. As for 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, in this instance, comprises the determination, exceptionally, the enlargement of the corresponding intercellular space. By means of the action of the icrofilaments that constitute its cito-skeleton, the epithelium cell, specially those of certain types of simple coating epithelia 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 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.

Several experimental results have confirmed that the transposition of solutions through the epithelia is subject to multiple control mechanisms, among which is paramount the intrinsic functional activity of its cells. On the contrary, the intercellular space permeability is generally not controlled, because in this case the transposition of a molecule through the epithelium follows only the corresponding physical laws and is directly related to its diameter, its electrical cargo and, obviously, to the intercellular space size; these three variables constitute the main limiting factors 'that interfere on the intercellular permeability of the simple coating epithelia. The transcellular permeability of the simple coating epithelia can be exercised through two distinct and independent ways: the transmembrane way, which is the true transcellular way, and the transcannular way, which happens through the vesicles and the cannules or tubes of the vesicle-cannular system, found inside the cytoplasm of many types of coating epithelium cells". Consequently, the coating epithelia 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 epithelia function.

Three types of coating epithelia are thus considered:

1) Of wide permeability;

2) Of reduced permeability; 3 ) Of null permeability.

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 epithelia permeability. Ex. : Hemoglobin, Ferritin, Lipoproteins and enzymes. It is also known the transcitose on the transposition of the epithelia by the macro and micro molecules until the vascular eye depending of their association. 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.

In a way similar to what happens to the papaine, 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 .

The presence of an enzyme with notorious proteolitic activity in fresh pineapple juice has been known for a 1ong time . An enzyme can be isolated from the fruit and all the remaining parts of the plant. It was detected that the BROMELINE's activity in the fruit is higher in some crops than in others and also in the juicy portions of the fruit. The levels of BROMELINE are relatively high in the juice extracted from the partially ripe fruit, decreasing remarkably with the development of full ripeness.

Some studies have indicated that the resin is not present in the first stages of fruit development, increasing rapidly until the ripening, when a slight decrease is detected. The sensitive decrease on the protease activity during the final ripening period is not followed by a corresponding change in the protein concentration.

Pineapple is therefore the only fruit presenting relatively high protease concentrations in the ripe stage of the fruit.

In order to produce BROMELINE different parts of the plant are used: leaves, stem, fruit juice, skin, as well as the industrial residues.

It is more frequent to use as raw material the stems of the ripe pineapple bushes, used after the fruits are collected.

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.

Several research studies relate those properties of 'BROMELINE"" extracted from the pineapple'-' -juice and from its stem. Said studies disclose the existence of differences in the enzymatic properties between the stem and the fruit juice, as well as indicate that the proteolitic activity of the enzyme depends on factors such as the variety, placement, part and age of the plant.

The existence of at least 2 main components in the stem BROMELINE is known, with similar "molecular properties and proteolitic activities. In the same way 5 proteolitically active components were separated from a BROMELINE enzymatic preparation with BROMELINE extracted from the stem. Said fractions presented similar results for some parameters and different properties for ^' others . Said studies disclosed that the raw material contains several proteolitically active components, some differing in their molecular weight and their charge, others being so similar that they could only be fractionated by means of using special conditions . Normally the BROMELINE is obtained by means of the addition of precipitating agents, such as ketones, alcohol and some salts, among others, to the juices of the stem and the pineapple plant.

In an industrial scale prevails the obtainment of the enzyme from the stem of the pineapple plant, which is a byproduct derived from the plant's exploitation.

The literature presents patents for the obtainment of the raw enzyme from the stem. Said patents teach the extraction of Bromeline through precipitation with organic solvents and water-soluble salts.

Some patents describe the path for obtainment of BROMELINE through the saline precipitation of the enzyme retrieving it by means of an agglutinating organic agent.

The commercial value and quality of the Bromeline are intimately associated to its proteolitic activity. Therefore there are several different methods to gauge the BROMELINE activity through its proteolitic activities, such as its catalytic potential in the hydrolysis of either proteic or synthetic substrates .

Also" of' common knowledge are its uses in the processing of leather, in the food and drink processing industry, the textile industry and the treatment of internal disturbances of the digestive system.

However its uses and applications up to now have excluded the dermatological forms, in view of its instability and degradabi1ity . In the inflammatory process there are several factors involved, among them vascular dilatation with exudation; migration of leukocytes and macrophages ; proliferation of fibroblasts; action of chemical mediators such as histamine, serotonine, bradicinine and prostaglandines ; proteolitic activity. Regarding the proteolitic activity, it refers to the involvement of proteases (chemotrypsine and catepcine) and collagenase, which presently not only facilitates the destruction of foreign bodies, but also hydrolyzes the collagen, which resulting peptides act as a chemotherapic substance stimulating the proliferation of fibroblasts.

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.

Said restriction is reflected in the previous anteriorities that were surveyed, which exclude the application of the proteolitic enzymes in the field of dermatology.

An exception is U.S. Patent 4,678,668, which 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.

Well, the use of an aqueous mean is exactly what the present invention is aiming to avoid, given the extraordinary instability of the proteolitic enzymes in it, which would render unfeasible the dermatological application of these substances.

Let '-us"^1' remark that in the American "Patent -the carrier is, for example, alcohol, and in the present invention, this function is performed by the proteolitic enzyme itself, operating in an anhydrous environment, which allows the stock and of the pharmaceutical form for a period of more than 24 months.

Therefore 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.

Preferably the temperature of step (a) lies between 50 and 98°C.

More preferably the temperature of this step lies between 65 and 80°C. Advantageously the cooling of step (b) is performed to a temperature lying between 25 and 45°C.

More advantageously 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.

The proteolitic enzyme, of easy deterioration, must be kept in a fresh, dry, ventilated and protected place.

Therefore, the present invention adheres to a process for production of a pharmaceutical composition carrier comprising, most notably: BROMELINE more than 0.01% .

Advantageously the present process comprises:

^■BROMELINE from O,01"to 15%.

More advantageously the present process comprises :

BROMELINE more than 0 , 01% .

HYALURONIDASE from 50 to 900 utr/mg.

Advantageously the present process comprises:

BROMELINE more than 0, 01%,

PAPAINE more than 0, 01%.

More advantageously the present process comprises :

BROMELINE more than 0, 01%,

PAPAINE more than 0, 01%,

HYALURONIDASE from 50 to 900 utr/mg.

Even more advantageously the present process comprises :

BROMELINE more than 0, 01%,

PAPAINE more than 0, 01%,

HYALURONIDASE from 50 to 900 utr/mg,

VITAMIN E from 10 to 2000 mg

Even more advantageously the present process comprises

BROMELINE more than 0, 01%,

PAPAINE more than 0, 01%,

VITAMIN E 10 to 2000 mg.

Even more advantageously the present process comprises

BROMELINE more than 0, 01%,

VITAMIN E 10 to 2000 mg.

Advantageously, the present process may be applied through dermic or transdermic paths.

The use of hyaluronidase as a diffusion factor is already well established and is commercially available in an injectable form. The enzyme is extracted from bovine testicles and commercialized in a lyophilized form by "Laboratόrio APSEN do Brasil Ltda." (hyalozime 2.000 UTR and 20.000 UTR) . The present carrier may be used in the production of a pharmaceutical composition.

The pharmaceutical composition ^■ comprising ^• the carrier may be used in the production of medicine. The pharmaceutical composition comprising the carrier presents the following characteristics:

Density 0,980 to 1,030 g/cm3;

Viscosity 3600 to 4800 cps; pH 5,8 to 6,5. The pharmaceutical composition comprising the carrier according to the present invention comprises a form of gel , cream, cream-gel, aerosol, liquid, spray and lyophilized, patch (transdermic adhesive) or any other dermic or transdermic form.

This 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 (150cm²), 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.

Bellow are presented some substances to be carried for a purpose of mere illustration, not limitation:

CUTANEOUS HEALERS PURE ANTIBIOTICS AND SULFA DERIVATIVES

ANTIFUNGUS

TOPICAL RUBIFACIENT ANTIREUMATICS

CORTICOSTEROIDS

ANTIMICOTICS ANTIBACTERICIDES

ANTIVARICOUS

ANTIPRURIGINOSOS

ANTIVIRAIS LOCAL ANESTHETICS

HORMONAL AND NON-HORMONAL ANTIINFLAMATORY

HISTAMINE SALTS

PHILDENAPHIL SALTS

FENTOLAMINA SALTS

PROSTAGLANDINES

Claims

1 . "PROCESS FOR PRODUCTION OF A DRUG CARRIER" characterized^' by the fact of comprising the following steps: a) addition of oil and preservative, keeping the temperature warm; b) cooling to a temperature near the room temperature ; c) ddition, 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.

2. "PROCESS FOR PRODUCTION OF A DRUG CARRIER", according to claim 1 characterized by the fact that the temperature of step a) lies between 50 and 98°C.

3. "PROCESS FOR PRODUCTION OF A DRUG CARRIER", according to claim 1 or 2 , characterized by the fact that the temperature of step a) lies between 65 and 80°C.

4. "PROCESS FOR PRODUCTION OF A DRUG CARRIER", according to claim 1, characterized by the fact that the temperature of step b) , lies between 25 and 45°C.

5. "PROCESS FOR PRODUCTION OF A DRUG CARRIER", according to claim 1 or 4 , characterized, by the fact that the temperature of step b) lies between 30 and 40°C.

6. "PROCESS FOR PRODUCTION OF A DRUG CARRIER", according to claim 1, 2, 3, 4 or 5, characterized by the fact that the proteolitic enzyme comprises Bromeline.

7. "PROCESS FOR PRODUCTION OF A DRUG CARRIER", according to claim 1, 2, 3, 4, 5 or 6, characterized by the fact that it comprises:

BROMELINE more than 0 , 01% .

8. "PROCESS FOR PRODUCTION OF 24 DRUG CARRIER", according to claim 1, 2, 3, 4 or 5 , characterized by the fact that it comprises:

BROMELINE more than 0,01%.

HYALURONIDASE 50 to 900 utr/mg.

9. "PROCESS FOR PRODUCTION OF A DRUG CARRIER", according to claim 1, 2, 3, 4 or 5 , characterized by the fact that it comprises:

BROMELINE more than 0^", 01%^'." ' ^{' '}

PAPAINE more than 0, 01%.

10. ^4%PROCESS FOR PRODUCTION OF Α. DRUG CARRIER", according to claim 1, 2, 3, 4 or 5 , characterized by the fact that it comprises:

BROMELINE more than 0, 01%.

PAPAINE more than 0 , 01% .

HYALURONIDASE 50 to 900 utr/mg.

11. "PROCESS FOR PRODUCTION OF A DRUG CARRIER", according to claim 1, 2, 3, 4 or 5, characterized by the fact that it comprises:

BROMELINE more than 0 , 01% .

PAPAINE more than 0 , 01% .

HYALURONIDASE 50 to 900 utr/mg.

VITAMIN E 10 to 2000 mg.

12. "PROCESS FOR PRODUCTION OF A DRUG CARRIER", according to claim 1, 2, 3, 4 or 5, characterized by the fact that it comprises:

BROMELINE more than 0, 01%.

PAPAINE more than 0 , 01% .

VITAMIN E 10 to 2000 mg.

13. "PROCESS FOR PRODUCTION OF A DRUG CARRIER", according to claim 1, 2, 3, 4 or 5, characterized by the fact that it comprises:

BROMELINE more than 0, 01%.

VITAMIN E 10 to 2000 mg.

14. "DRUG CARRIER" characterized by the fact that it is obtained through a process according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13.

15. "DRUG" comprising the carrier according to claim 14 characterized by the fact that it presents the following characteristics : density: 0,980 to 1,030 g/cm3: viscosity: 3600 to 4800 cps; pH: 5,80 to 6,50.

16. "DRUG" comprising the carrier according to claim 14 characterized by the fact that it is presented in the form of gel, cream, cream-gel, aerosol, spray, liquid, lyophilized or patch or any dermic or Trans-dermic form. ^s17. "USE OF THE 'DRUG" comprising the carrier according to claim 14 characterized by the fact that it is employed in the production of a medicine.