WO2018191802A1

WO2018191802A1 - Device for applying fibrin biopolymers

Info

Publication number: WO2018191802A1
Application number: PCT/BR2018/050103
Authority: WO
Inventors: Ana Silvia SARTORI BARRAVIERA SEABRA FERREIRA; Moacyr RAMOS BIGHETTI
Original assignee: Kaivo Pesquisa E Desenvolvimento Em Saúde Ltda
Priority date: 2017-04-18
Filing date: 2018-04-16
Publication date: 2018-10-25
Also published as: BR102017008028B1; BR102017008028A2

Abstract

Device for applying fibrin biopolymers, formed by two or more components which need to be mixed only at the time of use, said device (1) being formed by a spraying vial (2) internally provided with independent, watertight chambers (2a), which house the biopolymer components, and from which independent ducts emerge (3), which are interlinked with respective, also independent, conduits (5), designed with tilted segments (5a) and helical segments (5b) wound together, ending in spraying nozzles (6); the components contained in the chambers (2a) are sprayed and mixed, mixture thereof occurring outside the device, after said components have been sprayed from the spraying nozzles (6) and reach the outside of the vial, which components, by inertia, continue to disperse into the ambient air in helical movements, mixing together along the path created between the spraying nozzles (6) and the wound.

Description

"DEVICE FOR THE APPLICATION OF FIBRINE BIOPOLYMERS".

TECHNICAL FIELD

The present invention relates to a novel device for applying fibrin biopolymers, and more specifically for applying fibrin biopolymers consisting of two or more components that need to be mixed only at the time of use. More particularly, but not restrictively, the invented applicator device is intended for the application of fibrin biopolymers obtained exclusively from materials of animal origin, notably:. snake venom-purified thrombin-like, or the use of the same component from its synthesis in the laboratory by methods known to science (produced by recombinant technology to extract its active, synthetic form from prokaryotic organisms, eg bacteria, or eukaryotes, eg fungi and yeast, or other methods for the same purpose); and //. fibrinogen-rich cryoprecipitate from large animals such as oxen and horses, and more particularly buffalo (buffalo). Said applicator device can be purchased commercially in pharmacies without the need for a prescription, and allows the user to apply the fibrin biopolymer topically without the assistance of a specialized medical professional.

DESCRIPTION OF TECHNICAL STATE

As is well known in the art, some medicines are made up of two or more biological components which necessarily have to be mixed only at the time of application to achieve certain properties. An example of such a medicine is fibrin biopolymers obtained from human blood, long known in the art. Said biopolymers are used in surgical procedures, with the purpose of reducing the bleeding and provide a firm grip between the tissues.

In fact, as is known, fibrin is a natural biopolymer which, due to its bioactivity, biocompatibility and biodegradability characteristics, has been widely used in wound healing. Because they provide excellent tissue sealing and bonding properties, such fibrin biopolymers have commonly been called fibrin "sealants" or "glues".

Also as is well known, the first research on fibrin biopolymers dates from the 1940s, which were biopolymers consisting of fibrinogen and thrombin, both from humans.

Since the 1970s, several new proposals for fibrin biopolymers have been developed, also involving the mixing of these two components (fibrinogen and thrombin), but only one of them continues to be extracted from humans (fibrinogen). , while human thrombin was replaced by bovine thrombin or snake venom purified thrombin.

[006] An example of such fibrin biopolymer is that described in BR PI 9103724-7, published 30/03/1993, concerning a "COBRA POIS DERIVATED FIBRIN ADHESIVE FOR PREPARATION". According to that proposal, the fibrin glue consisted of two solutions, one consisting of a fibrinogen-rich cryoprecipitate obtained from fresh human plasma, and the other consisting of a fraction of lyophilized snake venom.

Other examples of fibrin biopolymers already known in the art are those described in WO 2007/121748, published 11/01/2007, and US 9,446,166, published 7/24/2014.

As can be seen from proposals known in the art, one of the components of fibrin biopolymer (cryoprecipitate containing fibrinogen) invariably comes from humans. In addition, in commercially approved fibrin biopolymers, both components (human fibrinogen and thrombin) need to be kept frozen at negative 20 ° C to avoid losing their properties, and at the time of biopolymer use they need to be kept frozen. be thawed and mixed.

For the application of such biopolymers, applicator devices are also known in the art, formed either by two communicable chambers, or by two contiguous syringes, each comprising one of the biopolymer components, as well as by a mixing chamber capable of mix them when applying the biopolymer to the surface of the tissue or organ to be treated; Such devices also need to be stored in freezers to keep frozen components inside. Similarly, shortly before the biopolymer is applied, it is necessary to remove such devices from the freezer so that the components contained in their chambers or syringes are thawed, said devices being then employed to mix the components as well as to apply the biopolymer. newly formed on the surface of the site to be treated. Obviously, given the complexity of the application provided by these devices (by spraying with syringes and needles), these devices can only be handled by medical professionals (doctors or nurses) who are already used to operating surgical instruments.

On the other hand, methods for providing drugs and / or biopolymers by fluidization thereof are already known in the art. As is known, fluidization is the process by which solid particles are transformed into liquid state by suspending them in a gas or liquid. Thus, according to methods already developed, the fine particles of a drug and / or biopolymer are fluidized by a carrier gas. (preferably carbon dioxide or nitrogen dioxide) or any liquid solution. For such, such components are injected into a microtube, where the powder and liquid or gas come into contact and are mixed. The resulting mixture is then sprayed from the tip of the microtube to the body site to be treated.

Although such a fluidization method has been attempted to provide fibrin biopolymers, this has never been achieved in practice due to the aforementioned need for freezing of the components.

Furthermore, through experimental testing, it was found that upon injection of the powder and liquid / gas into the microtube, contacting such components causes the resulting mixture to clot inside. of said microtube, and the consequent clogging of the valve, thereby preventing the desired spraying of the mixture. Thus all attempts to spray fibrin biopolymers to date have been totally unsuccessful.

Said fibrin biopolymers known in the art, being obtained from human blood, present a number of problems. One of them lies in the fact that human blood used in biopolymer production can contain contaminating factors, such as contagious viruses, among others, and can therefore be a potentially transmitting element of infectious diseases.

[014] Another major drawback is the scarcity of human blood, which is the raw material for obtaining those biopolymers. In fact, as is well known, in Brazil and in various countries of the world, the commercialization of human blood is prohibited, which, therefore, can only be obtained through the voluntary donation of people. Particularly in Brazil, the number of permanent donors is still very low. Blood bank stocks are always at very low levels.

Thus, with the constant lack of blood in the blood banks, there is a shortage of this raw material, essential for the manufacture of fibrin biopolymers. In some countries, the small amount of fibrin biopolymer that can be manufactured is only used in situations of extreme need, more specifically in so-called "noble" applications (major surgeries such as liver transplant surgery and cardiac and cardiac surgeries). among others). Therefore, these major surgical procedures with the use of fibrin biopolymer, even abroad, happen only in specific situations of use, and in Brazil, the use of fibrin biopolymers in many of these surgeries is avoided, since it requires importation of fibrin biopolymer manufactured in other countries at a substantially high cost.

[016] As it turns out, fibrin biopolymers are an expensive and scarce product that is handcrafted within laboratories on a very small scale, and which can be used only and only in hospital settings by skilled professionals in the field. doctor. Currently, this production only occurs in laboratories abroad, there is no production by the Brazilian national industry.

[017] For all these reasons, fibrin biopolymers to date have never been able to constitute a commercially available, commercially available end-consumer product that can be purchased as an over-the-counter (OTC) drug. , that is, a drug that could be purchased at points of sale (pharmacies and drugstores), without the need for medical prescription, or even prescription, but directly by the end consumer.

As already mentioned above, fibrin biopolymers, being an extremely expensive and scarce product, are only available between the walls of hospital and university laboratories (and produced only abroad), where they are kept frozen, and only employed when urgently needed in major surgeries, in the hospital setting itself, where they are thawed shortly before their application by doctors or nurses themselves during surgery.

More recently, an innovative ﬁ brine biopolymer has been developed, in which not only thrombin but also fibrinogen has come to be of animal origin. Such a fibrin biopolymer is described in document BR 10 2014 011436-0, published on 23/02/2016, referring to a "FIBRIN SEALANT FOR TOPICAL USE, METHOD OF FORMATION AND ITS USE "

According to that document, the fibrin sealant provided therein is comprised of a serinoprotease purified from snake venom, a fibrinogen-rich cryoprecipitate extracted from large animals, preferably buffalo (buffalo), and by a diluent configured by calcium chloride. Such components are kept separately in individual vials, which need to be contained inside freezers, so that their contents are kept frozen at negative 20 ° C until use, without which the properties of the components are fully promised.

[021] Only at the time of use are such vials removed from the freezer and kept at room temperature (between 15 and 25 ° C) for 10 to 20 m in order to thaw the components contained therein.

Once thawed, the diluent is first injected into the vial containing serinoprotease and shaken and set aside. Using a syringe and needle, the whole contents of this vial (diluted serinoprotease) are aspirated. With another syringe and needle, aspirate the entire contents of the vial containing cryoprecipitate. Then, the topical application of the two components, with both syringes in parallel and their respective bevels directed to the site to be treated, said components polymerizing "in situ", after being properly mixed.

[023] As it no longer contains any components from human blood and is now exclusively a product of animal origin, the fibrin sealant described in that application BR 10 2014 011436-0 presents no risk of transmission of diseases transmitted by human blood, eliminating the disadvantage of conventional fibrin biopolymers being potential transmitters of infectious diseases.

[024] In addition, by no longer using the extracted human blood component, which was replaced by an extracted animal blood component (buffalo, or buffalo), the once scarce and expensive raw material has now become abundant and making it possible to manufacture the fibrin sealant on a large scale.

Additionally, the predicted fibrin sealant described in BR 10 2014 011436-0 has a highly coagulant effect, capable of clogging blood vessels, and thus stopping bleeding immediately, and yet creates a transparent film over the application site, which accelerates cell multiplication, speeding tissue healing and recovery by stimulating the emergence of new blood vessels.

[02 6] However, despite the above advantages over conventional fibrin biopolymers, the fibrin sealant described in BR 10 2014 011436-0 still requires that its components (serinoprotease purified from snake venom and fibrinogen-rich cryoprecipitate extracted from large animals) are kept frozen until the time of use, thus continuing to limit the manufacture and use of hospital environments.

[027] In addition, as the components must be mixed and applied at the time of use (through the use of needles and syringes), the use of this fibrin sealant continues to require the performance of a practitioner in the art. necessarily being preached by doctors or nurses during the occurrence of surgeries.

[02 8] Accordingly, it has never been possible to provide the filament sealant provided for in that document BR 10 2014 01 1436-0 as an industrialized, large-scale finished product commercially available on the market, ie can be purchased at retail outlets (pharmacies and drugstores) as an over-the-counter (OTC) drug without the need for a prescription.

[02 9] In view of the above, it is concluded that, to date, a fibrin biopolymer that has been supplied as a low-cost, industrialized finished product has not been developed. , which could be purchased directly by the consumer at points of sale, without the need for a medical prescription (OTC product), and which could be used and applied by the consumer directly over the place of his body to be treated, outside the workplace. hospital, and without the need for assistance from a medical professional.

OBJECTIVES OF THE INVENTION

With the intention of obtaining a solution that could simultaneously meet all these needs, the Depositor began studies and research on the subject in order to develop a device for the application of fibrin biopolymers consisting of two or more with components that necessarily have to be mixed only at the time of use, a device which allows the aforementioned components with a simple, practical and immediate application, eliminating the need for freezing components, as is still needed in many types of biopolymers.

[031] Such a device should have such features as to enable end-user acquisition of the biopolymer at the point of sale, without the need for medical prescription, and to enable the user to apply this biopolymer in a simple and easy manner without the assistance of any medical professional (doctor or nurse).

To achieve these objectives, the Depositor has created this new "FIBRINE BIOPOLYMER APPLICATION DEVICE", which is configured by a spray bottle, internally provided with independent chambers, which house the various components of the biopolymer. From said chambers, respective independent ducts depart, which, within the spray nozzle of the vial, are interconnected with respective, equally independent, helical channels, duly coiled together, terminating in respective equally independent spray nozzles.

Particularly, and not restrictively, said flask is provided with three independent and watertight chambers, designed to house respectively two powder components and a diluent liquid. More particularly, the two powdered components may be serinoprotease purified from snake venom and fibrinogen-rich cryoprecipitate extracted from large animals. In this case, the applicator device is more specifically intended for the application of fibrin biopolymers consisting of components of animal origin only, notably:. serinoprotease purified from snake venom, or the use of the same component from its synthesis in the laboratory by methods known to science (produced by recombinant technology for the purpose of extracting its synthetic form, active, being from prokaryotic organisms, eg bacteria, or eukaryotes, eg fungi and yeast, or other methods with the same purpose); and //. the fibrinogen-rich cryoprecipitate extracted from large animals, said device thus lending more particularly, but not restrictively, to the application of the fibrin sealant described in BR 10 2014 011436-0.

Thus, when using the now innovating applicator device to treat any injury, the two powder components and the diluent liquid contained in the three independent chambers of the vial are helically sprayed into the ambient air independently and concomitantly. from the respective three independent spray nozzles at a predetermined distance from the surface of the wound to be treated, the three components being then properly mixed in the air during the course of that distance to achieve the already properly homogenized and polymerized wound in the form of a transparent sealant film.

It is important to note that mixing between the three components occurs outside the device, ie in external ambient air, caused by the inertial continuation of the helical movement caused by the properly coiled internal helical channels of the spray nozzle. . Thus, there is no risk of clots forming inside the canals, nor clogging of the nozzles, thus enabling the spraying of the components and their effective mixing in the air, more specifically during the travel between the channels. sprinkler nozzles and the wound to be treated.

As it turns out, with the new applicator device, it is possible to mix and apply the fibrin biopolymer components at the time of use, in a simple, practical and immediate way, eliminating the need for freezing of the components. And as already mentioned, although such a device may be employed in the application of any fibrin biopolymers consisting of two or more components which need to be mixed only at the time of use, it is more specifically intended for the application of biopolymers of fibrin. fibrin consisting of components of animal origin only, notably:. serinoprotease purified from snake venom, or the use of the same component from its synthesis in the laboratory by methods known to science (produced by recombinant technology to extract its active synthetic form from from prokaryotic organisms, eg bacteria, or eukaryotes, eg fungi and yeast, or other methods for the same purpose); and //. the fibrinogen-rich cryoprecipitate extracted from large animals.

In this sense, the new applicator device will allow, for the first time, the supply of fibrin biopolymers in the form of an end product itself, which can be manufactured on an industrial scale at low cost without requiring the freezing of its components, which product will be commercially available at points of sale (pharmacies and drugstores), and that can be purchased and used by the consumer, outside the hospital environment, without the need for medical prescription, and without the presence of a specialized professional. from the medical field.

[039] This product can be applied to general injuries, from small cuts resulting from simple household accidents (knife cuts, razor blades, scratches, tearing injuries, etc.) to large wounds, constituting a highly complex product. effective for stopping bleeding and accelerating tissue healing by stimulating the emergence of new blood vessels.

DESCRIPTION OF DRAWINGS In addition to the present description, in order to gain a better understanding of the characteristics of the subject matter of the patent, a set of drawings accompanies this report, in which, by way of example and not limitation, the following was represented:

Figure 1 is a schematic view of the fibrin biopolymer applicator device now innovated;

Figures 2 and 3 illustrate said device respectively by longitudinal and transverse sections; and

Figures 4 and 5 are enlarged and equally schematic details of said applicator device.

DETAILED DESCRIPTION OF THE INVENTION

[041] The present invention relates to a "FIBRINE BIOPOLYMER APPLICATION DEVICE", device (1) which is configured by a spray bottle (2) internally provided with two or more independent and watertight chambers ( 2a), which house, respectively, the various components of the sealant. From said chambers (2a), respective independent ducts (3) depart which, within the spray nozzle (4) of the vial (1), interconnect with respective independent channels (5) initially developed in inclined sections (5a). ), and then in coiled sections (5b) duly wound together, terminating in respective equally independent spray nozzles (6).

More particularly, said vial (2) is provided with three independent, watertight chambers (2a) for respectively housing two powdered components (serinoprotease purified from snake venom and fibrinogen-rich cryoprecipitate extracted from large animals). ) and a diluent liquid, which are the components of the fibrin sealant provided for in BR 10 2014 011436-0.

[043] To use the now innovative applicator device (1), press if the spray nozzle (4) of the vial (2) at a predicted distance from the wound surface to be treated, whereby the components, more specifically the two powder components and the diluent liquid contained in the three chambers (2a) from the vial (2), are helically and independently directed outwardly through the independent helical channels (5) and also the independent spray nozzles (6), from which the two products in The dust and liquid are helically sprayed into the ambient air independently and concomitantly with each other, and the three components are then properly mixed in the air during the travel between the spray nozzles (6) of the spray nozzle (4) and the wound to be treated so as to reach the already properly homogenized and polymerized wound by forming on it a transparent sealant film as mentioned above.

Spraying of the components, more specifically the two with powder components and the liquid diluent stored in said chambers (2a), is achieved by pumping under high pressure a propellant gas (preferably inert carbon dioxide). ) provided inside the vial (2), responsible for the exposure of the three said components of their respective chambers (2a), which, passing through the respective independent ducts (3), reach the interior of the respective also independent helical channels (5) spray nozzle (4), reaching the outside through the equally independent spray nozzles (6).

[045] In turn, the effective mixture between components, more specifically between the two powder components and the liquid diluent, occurs outside the device, that is, in the external ambient air, only after spraying them. the spray nozzles (6) of the spray nozzle (4) as they reach the outside of the bottle with continue to disperse in ambient air in helical motions, initially caused by the inner helical channels (5), mixing with each other along the path between the spray nozzles (6) of the spray nozzle (4) and the surface of the wound to be treated, and forming on said surface, the aforementioned transparent sealing film.

As a result, there is no risk of clot formation within the inner helical channels (5), nor clogging of the spray nozzle (4), thus enabling the practical implementation and operation of this device. .

As already mentioned, with the new applicator device, the biopolymer components are mixed and applied at the moment of use, in a simple, practical and immediate way, eliminating the need for freezing of the components.

Also as already mentioned, with the new applicator device more particularly is obtained the mixing and application of the components of fibrin biopolymers in general, and even more particularly of fibrin biopolymers consisting exclusively of components of animal origin, with which it was possible for the first time to provide such biopolymers in the form of a final product itself, manufactured on an industrial scale, at a low cost, commercially available at points of sale (pharmacies and drugstores), and obtainable and used by the consumer himself, without the need for medical prescription, outside the hospital environment and without the presence of a specialized medical professional.

Claims

1) "FIBRINE BIOPOLYMER APPLICATION DEVICE" means biopolymers consisting of two or more components which necessarily need to be mixed only at the time of use, said device (1) being characterized as a spray bottle (2) internally provided with two or more independent and watertight chambers (2a), which house, respectively, the various components of the biopolymer, and from said chambers (2a), respective independent ducts (3), which within the nozzle (4) of the vial (2), interconnect with respective independent channels (5), initially developed in inclined sections (5a), and then in coiled sections (5b) duly wound together, terminating in respective spray nozzles (6) .

2) "FIBRINE BIOPOLYMER APPLICATION DEVICE" according to claim 1, characterized in that said spray bottle (2) is internally provided with three independent and watertight chambers (2a), which respectively house two components. powder and a diluent liquid component.

"FIBRINE BIOPOLYMER APPLICATION DEVICE" according to claims 1 and 2, characterized in that said powder components are serinoprotease purified from snake venom and fibrinogen-rich cryoprecipitate extracted from large animals.

"FIBRINE BIOPOLYMER APPLICATION DEVICE" according to claims 1 and 2, characterized in that said diluent liquid contains calcium chloride in its composition.

5) "FIBRINE BIOPOLYMER APPLICATION DEVICE" according to claim 1, characterized in that by pressing the spray nozzle (4) at a predetermined distance from the surface of the wound to be treated, the biopolymer components contained in the independent chambers (2a) of the vial (2) are helically and independently directed outwards through the independent helical channels (5) and also the independent sprinkler nozzles (6 ), from which the two powdery products and the liquid are helically sprayed into the ambient air independently and concomitantly with each other, the three components being then properly mixed in the air during the travel between the nozzle sprinklers (6) spray (4) and the wound to be treated.

6. "FIBRINE BIOPOLYMERS APPLICATION DEVICE" according to claim 1, characterized in that the spraying of the components stored in said chambers (2a) is obtained by pumping under high pressure a propellant gas, preferably inert carbon dioxide. , provided inside the vial (2), responsible for expelling the three said components from their respective chambers (2a), which, passing through the respective independent ducts (3), reach inside the respective helical channels (5) provided in the nozzle (4) reaching the outside through the respective spray nozzles (6).

7) "FIBRINE BIOPOLYMER APPLICATION DEVICE" according to Claim 1, characterized in that the mixing between the components occurs after their spraying by the spray nozzles (6) of the spray nozzle (4) upon reaching the exterior of the sprayer. which inertia continue to disperse in ambient air in helical motions, mixing with each other along the path between the spray nozzles (6) of the spray nozzle (4) and the surface of the wound to be treated.