Rolled collagen carrier

One aspect of the present invention relates to a process for twisting a collagen carrier.

Another aspect of the present invention relates to a stable shaped twisted collagen carrier.

The present invention also relates to a process for delivering the twisted collagen carrier to the target location, and to methods of treatment or surgery using the twisted collagen carrier, such as a method of performing minimally invasive surgery. The present invention also relates to a twisted collagen carrier for the use of m-therapy and / or to the method of surgery, such as the method of performing minimally invasive surgery. Another aspect of the present invention relates to an apparatus for making available a twisted collagen carrier.

The present invention also relates to a process for preparing a rolled collagen carrier, or a compressed collagen carrier or a compressed and rolled collagen carrier.

In addition, the present invention relates to a compressed and rolled collagen carrier, the respective collagen carrier being possible to obtain by the aforementioned process.

Also, the present invention relates to a process for rolling a rolled collagen carrier, or a compressed and rolled collagen carrier. Also, the present invention relates to a compressed, rolled and rolled collagen carrier, the respective collagen carrier being possible to obtain by the aforementioned process.

In another embodiment, the present invention relates to a rolled collagen carrier or a compressed collagen carrier or a compressed and rolled collagen carrier. In another embodiment, the present invention relates to a rolled and rolled collagen carrier or a rolled and rolled compressed collagen carrier. In addition, the present invention relates to a rolled and rolled compressed collagen carrier, the respective collagen carrier being possible to obtain by the aforementioned process.

In another embodiment, the invention relates to a collagen carrier compressed and rolled for use in minimally invasive surgery.

In particular, the present invention relates to a compressed and rolled collagen carrier for use in the prevention and / or treatment of tissue and organ injury during open and, in particular, minimally invasive surgery.

During open surgery, medication sponges are used to stop local bleeding (hemostasis). They react on contact with blood, other organic fluids or saline solution, forming a clot that sticks sponges to the surface of the tissue and hemostasis is reached within minutes. Drug sponges are burrs, such as a collagen carrier as defined below, such as a cellulose sponge as described in the patent [1].

Collagen is used as a hemostatic agent for several decades. A product that combines the hemostatic characteristics of fibrin adhesive with the advantage of collagen as a carrier has been developed and manufactured under the brand name TachoSil®. TachoSil® is a collagen carrier ready for use with a coating of active fibrin adhesive components: human fibrinogen and human thrombin. The product is described in [2] (WO 02/058749 A2 2002.08.01, WO 02/058750 A2 2002.08.01).

TachoSil® confines fibrinogen and thrombin in the form of a dry coating on the surface of a collagen sponge. In contact with organic fluids, e.g. blood, lymph or physiological saline solution, the components of the coating dissolve and diffuse partially on the surface of the wound. This step is followed by fibrinogen-thrombin reaction, which initiates the last phase of physiological blood coagulation. The fibrinogen is converted to fibrin monomers that spontaneously polymerize to form the fibrin clot. In this way, the collagen sponge is tightly glued to the wound surface.

TachoSil® has been marketed since 2004 by Nycomed and is used for open hemostasis and tissue sealing surgery. Traditional open surgeries usually require a long incision of the skin.

Contrary to open surgery, minimally invasive procedure is any procedure (surgical or other), which is rather invasive than open surgery used for the same purpose. Minimally invasive surgery (CMI) procedures are performed through one or more access holes, e.g. short incisions (surgery

MD 4471 Cl 2017.10.31 through the keyhole ”) or through the natural holes of the body. Thus, CMI procedures require specially designed surgical instruments, which are introduced through such access holes. In abdominal surgery, access to the instruments is usually done through so-called trocars, which are generally rigid tubes with a typical inner diameter of 5 to 12 mm. The small size of the access holes used in the CMI restricts the number of instruments that can be inserted into the holes. Therefore, all surgical instruments and materials used in CMI procedures must be of such size and condition, that they can be inserted through the access holes and they require, of course, all medical instruments to be sterile. Thus, tools and materials are most often designed for use in CMI.

Described is a surgical instrument comprising an applicator element, characterized in that the applicator element comprises a bar-shaped portion to allow a foil of the surgical material, such as e.g. TachoComb® (coated horse tendon sponge / Nycomed sponge) is rolled to form a protective layer of surgical material on the bar-shaped portion of the applicator element [3]. However, this manual tool for manually running surgical materials, such as collagen carriers, has several disadvantages described below.

The non-sterile introduction of TachoComb® into endoscopic equipment is described, where the sample is manually leveled so that it is possible to manually wrap it around a "pivot" driver [4]. In source [4] it is claimed that the collagen product '' must remain flexible enough in the dry state to be bent and rolled (pg. 29, lines 19-20). Thus, the source [4] refers only to the manual (ie manually operated), non-sterile running of TachoComb® and further describes that the running process must be dry. A significant problem related to the abovementioned methods that use an applicator element or a driving pivot for manually rotating the collagen carrier occurs if it is necessary to apply several collagen carriers rolled / twisted in rapid succession (e.g. either because a collagen carrier is insufficient to completely stop the bleeding, or because of an error in applying the first collagen carrier (s). In this case the same applicator element cannot be used for the application of the second collagen carrier: instead, multiple applicator elements must be prepared. This is because for the correct application of collagen-based products, such as the TachoComb® product, the applicator element must be completely dry to avoid activating the adhesive properties of the collagen carrier. If the collagen carrier becomes wet ahead of time by contact with an applicator element or a wet conductive pivot, the carrier will attach to the applicator element / conductive pivot and / or become a useless sticky piece of material. Another way of rolling the collagen-based surgical sheets is for the surgeon to use his hands in the same way as for rolling a cigarette, but for this, as well as for all the cases mentioned above, the rolled surgical product does not have о stable shape and, therefore, it is more difficult to handle in a controlled manner after insertion into the body: the product with an unstable shape can open suddenly in an uncontrolled way during the unfolding process and stick incorrectly. This is a special problem for CMI surgery, where it is more difficult to handle the product when it is in the body, because only one person has indirect access to the surgical foil through endoscopic surgical instruments. One way to reduce the effect of the collagen-based surgical product having an unstable shape is to bind the rolled product to the suture, however, this solution is only appropriate when the twisted carrier is not rolled in vivo, but is rather kept in the patient in a twisted state. (eg in a partial nephrectomy procedure).

For applications such as CMI, therefore, there is a need to produce an improved collagen-based surgical product, which has useful dimensions for CMI applications and useful properties for accelerating coagulation and wound sealing, but allowing for easy application of more than a collagen carrier in rapid succession and at the same time to provide the surgeon with an improved control over the complex process of movement of the carrier towards the desired tissue and its application.

Another problem related to all the aforementioned types of manual collagen carriers is that the results depend, of course, to a large extent on the skills of the individual physician performing the spinning process, and are therefore strongly variable in reproducibility, and can lead to a non-sterile product, to uneven and thus irreproducible twisting / rolling of the collagen carrier, as well as the unpredictable loss of the coating.

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Thus, there is a need in the field given by a collagen carrier coated with human fibrinogen and human thrombin, specially designed for use in minimally invasive surgery that is ready for use, maintains sterility and has о hemostatic efficiency and tissue sealing. acceptable and о adhesive capacity on living tissue, and also allowing the easy application of more than one collagen carrier in rapid succession for CMI techniques, and, also, to give the surgeon more control over the application on the desired tissue during a CMI procedure to avoid adhesion of the collagen carrier to the wrong place, would be advantageous.

Thus, a ready-to-use collagen carrier coated with human fibrinogen and human thrombin, specially designed for use in CMI, such as designed to fit a tube and / or access hole in CMI, preferably to be introduced. in endoscopic devices it would be advantageous, and especially a ready-to-use collagen carrier coated with human fibrinogen and human thrombin with hemostatic efficiency, adhesive capacity on living tissue and acceptable sterility to be ready for use in CMI, to allow the application of more than one collagen carrier m rapid succession for CMI techniques, and also to allow the surgeon more control over tissue application wished during the CMI procedure to avoid the adhesion of the collagen carrier in the wrong place, it would be advantageous.

Brief description of the invention

The object of the present invention is to provide a ready-to-use collagen carrier coated with human fibrinogen and human thrombin, designed, for example, for use in minimally invasive surgery, as designed, preferably, to be introduced into endoscopic devices, which to solve the aforementioned problems.

One aspect of the present invention relates to a process for twisting a collagen carrier, the collagen carrier being comprised of (i) a collagen layer and (ii) a coating layer including fibrinogen and thrombin, the aforementioned process comprising steps : wetting, at least, of a part of the collagen carrier, twisting of the collagen carrier by engaging the collagen carrier between a pair of elongated elements, and rotating the pair of elongated elements about an axis parallel to the longitudinal extension of the elements elongated to twist the collagen carrier on the elements, while the collagen carrier is supported by a support device, drying the collagen carrier twisted, thus providing a stable shaped twisted collagen carrier.

The embodiment of the present invention relates to a process for turning a collagen carrier, the collagen carrier being formed by a (i) collagen layer and (ii) a coating layer which includes, in particular, solid fibrinogen and, in particular, solid thrombin, the aforementioned process comprising successive steps of:

wetting, at least, a shaft of the collagen carrier, twisting of the collagen carrier by engaging the collagen carrier between a pair of elongated elements, and rotating the pair of elongated elements about an axis parallel to a longitudinal extension of the elements elongated to twist the collagen carrier on the elements, while the collagen carrier is supported by a support device, drying of the twisted collagen carrier, thus providing a stable shaped twisted collagen carrier.

The present invention also relates to a twisted collagen carrier which can be obtained by - or is otherwise obtained by - the process of the present invention.

Another aspect of the present invention relates to a twisted collagen carrier,

- comprising a collagen layer and a coating layer above the collagen layer, the coating layer containing thrombin and fibrinogen, and

- which is in the form of an elongated element with numerous coils of the collagen carrier around the longitudinal axis of the elongated element and, at least, the outer coil (s) being oriented such that the coating layer constitutes the outer surface of the cuff ( or) outer coils mentioned above (s), characterized in that

- the collagen carrier is of stable shape and defines a collagen carrier in a twisted configuration, wherein said outer coil (s) extends along a spiral in cross-section of the collagen carrier.

The present invention also relates to a process for delivering the twisted collagen carrier from the present invention to the target locus, which comprises the step of passing the mentioned carrier through an orifice or access tube to the target locus.

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The present invention also relates to the use of the twisted collagen carrier according to the present invention in therapy and / or in a surgical method.

Another aspect of the present invention is an apparatus for providing a twisted collagen carrier, the apparatus comprising:

- a device for applying humidity to a collagen carrier before the collagen carrier is twisted,

- a spinning device comprising

- rotary clamping means for attaching the collagen carrier along one edge and twisting the collagen carrier, and

- a support device that supports the collagen carrier m during twisting.

Another aspect of the invention relates to a process for preparing a compressed and rolled collagen carrier comprising the steps:

a) providing a collagen carrier having a coating comprising solid fibrinogen and solid thrombin, evenly distributed and fixed to the aforementioned collagen carrier,

b) optional humidification of, at least, a wool of the mentioned collagen carrier offering an optional humidified collagen carrier,

c) compression of the optional humidified collagen carrier offering a compressed collagen carrier,

d) rolling of the aforementioned compressed collagen carrier,

e) obtaining a compressed and rolled collagen carrier,

f) optional drying of the compressed and rolled collagen carrier from step e),

g) optional sterilization of the collagen carrier compressed and rolled in step e) or f),

h) optional packing of the compressed and rolled collagen carrier from step e), f) or g) in a suitable container, and thus obtaining a compressed and rolled collagen carrier having, at least, one of the following physical properties:

I. a diameter not exceeding 10 mm,

II. о adhesive capacity of, at least, 30 mmHg, such as, at least, 35 mmHg, such as, preferably, 40 mmHg, measured by a pressure test (TCP) after running the compressed and rolled collagen carrier, and

III. a sterility assurance level (NAS) of 10 '⁶.

Another aspect of the present invention relates to a process for preparing a compressed collagen carrier comprising the steps:

a. providing a collagen carrier having a coating comprising solid fibrinogen and solid thrombin, evenly distributed and attached to the mentioned collagen carrier,

b. Optional humidification of, at least, a part of the mentioned collagen carrier offering an optional humidified collagen carrier,

c. compression of the humidified collagen carrier optionally providing a compressed collagen carrier,

d. optional drying of the compressed collagen carrier mentioned in step c),

e. Optional sterilization of the compressed collagen carrier mentioned in step c) or d),

f. packing the compressed collagen carrier mentioned in step c), d) or e) in a suitable container, and thus obtaining a compressed collagen carrier having, at least, one of the following physical properties:

I. о thickness not exceeding 4 mm,

II. о adhesive capacity of, at least, 30 mmHg, such as, at least, 35 mmHg, such as preferably 40 mmHg, measured by a pressure test (TCP),

III. a level of sterility assurance (NAS) of IO '⁶.

Another aspect of the present invention is to provide a process for preparing a rolled collagen carrier comprising the steps:

a. providing a collagen carrier having a coating comprising solid fibrinogen and solid thrombin, evenly distributed and attached to the mentioned collagen carrier,

b. Optional humidification of, at least, a part of the mentioned collagen carrier offering an optional humidified collagen carrier,

c. rolling of said collagen carrier providing a rolled collagen carrier,

d. optional drying of the rolled collagen carrier from step c),

e. Optional sterilization of the collagen carrier rolled in step c) or d),

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f. Optionally packing the rolled collagen carrier from step c), d) or e) into a suitable container, and thus obtaining a rolled collagen carrier having at least one of the following physical properties:

I. a diameter not exceeding 10 mm,

II. о adhesive capacity of, at least, 30 mmHg, such as, at least, 35 mmHg, such as, preferably, 40 mmHg, as measured by a pressure test (TCP) after running said collagen carrier, and

III. a level of sterility assurance (NAS) of IO '⁶.

Another aspect of the present invention is to provide a process for developing a compressed and rolled collagen carrier comprising the steps:

a) providing a compressed and rolled collagen carrier prepared according to the invention,

b) unpacking the compressed and rolled collagen carrier mentioned from the appropriate container mentioned,

c) passage of the compressed and rolled collagen carrier mentioned through an access hole, such as a trocar,

d) unfolding of the compressed and rolled collagen carrier mentioned after exiting said access hole,

e) Obtaining of a compressed, rolled and rolled collagen carrier having an adhesive capacity of, at least, 40 mmHg, measured by means of a pressure test (TCP), and a sterility assurance level (NAS) of 10 '⁶.

Another aspect of the present invention is to provide a process for rolling a rolled collagen carrier comprising the steps:

a) offering a rolled collagen carrier prepared according to the invention,

b) unpacking the rolled collagen carrier mentioned from the appropriate container mentioned,

c) passage of the rolled collagen carrier mentioned through an access hole, such as a trocar,

d) unfolding of the rolled collagen carrier mentioned after exiting said access hole,

e) Obtaining a rolled and rolled collagen carrier having an adhesive capacity of, at least, 40 mmHg, measured by means of a pressure test (TCP), and a level of sterility assurance (NAS) of IO '⁶.

Another aspect of the present invention is to provide a compressed and rolled collagen carrier, prepared according to the process of the invention, the carrier having a coating that includes solid fibrinogen and solid thrombin, which is uniformly distributed and fixed to the mentioned collagen carrier, and having , at least, one of the following physical properties:

I. a diameter not exceeding 10 mm,

II. о adhesive capacity of, at least, 40 mmHg, as measured by a pressure test (TCP),

III. a level of sterility assurance (NAS) of IO '⁶.

Another aspect of the present invention is to provide a compressed and rolled collagen carrier, which can be obtained by a process comprising the steps:

a. providing a collagen carrier provided with a coating including solid fibrinogen and solid thrombin, which is evenly distributed and secured to the said collagen carrier,

b. Optional humidification of, at least, a portion of the mentioned collagen carrier providing an optional humidified collagen carrier,

c. compression of the optional humidified collagen carrier by providing a compressed collagen carrier,

d. rolling of the aforementioned compressed collagen carrier,

e. Obtaining a compressed and rolled collagen carrier,

f. optional drying of the compressed and rolled collagen carrier from step e),

g. Optional sterilization of the collagen carrier compressed and rolled in step e) or f),

h. Optional packing of the compressed and rolled collagen carrier mentioned in the step

e), f) or g) in a suitable container, and thus obtaining a compressed and rolled collagen carrier having, at least, one of the following physical properties:

I. a diameter not exceeding 10 mm,

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II. о adhesive capacity of at least 40 mmHg, measured by means of a pressure test (TCP) after the aforementioned collagen carrier,

III. a level of sterility assurance (NAS) of IO '⁶.

Next, another aspect of the invention relates to a collagen carrier compressed, rolled and rolled according to the invention having, at least, one of the following physical properties:

I. о thickness not exceeding 4 mm,

II. о adhesive capacity of at least 40 mmHg, measured using a pressure test (TCP),

III. a level of sterility assurance (NAS) of IO '⁶,

IV. the aforementioned compressed and rolled collagen carrier can adhere to the cleft as it is rolled without being twisted back.

Another aspect of the invention relates to a compressed, rolled and rolled collagen carrier according to the invention, provided with a coating that includes solid fibrinogen and solid thrombin, which is evenly distributed and fixed to the mentioned collagen carrier, and having, the shear, one of the following physical properties:

I. о thickness not exceeding 4 mm,

II. о adhesive capacity of at least 40 mmHg, measured using the TCP camera,

III. a sterility assurance level (NAS) of 1 O '⁶,

IV. the aforementioned compressed and rolled collagen carrier can adhere to the cleft as it is rolled without being twisted back.

Another aspect of the invention relates to a compressed collagen carrier according to the invention, provided with a coating which includes solid fibrinogen and solid thrombin, which is uniformly distributed and fixed to the mentioned collagen carrier, and having, at least, one of the following properties. physical:

I. о thickness not exceeding 4 mm,

II. о adhesive capacity of at least 40 mmHg, measured using a pressure test (TCP),

III. a sterility assurance level (NAS) of 10 '⁶.

Another aspect of the invention relates to a collagen carrier according to the invention, provided with a coating including solid fibrinogen and solid thrombin, which is uniformly distributed and fixed to the mentioned collagen carrier, and having, at least, one of the following properties. physical:

I. a diameter not exceeding 10 mm,

II. о adhesive capacity of, at least, 40 mmHg, measured using a pressure test (TCP) after the mentioned collagen carrier,

III. a sterility assurance level (NAS) of 10 '⁶.

Another aspect of the invention relates to a collagen carrier compressed and rolled according to the invention for use in tissue sealing, tissue adhesion and hemostasis.

Another aspect of the invention relates to a compressed and rolled collagen carrier, according to the invention, for use in minimally invasive surgery.

Another aspect of the invention relates to a compressed and rolled collagen carrier according to the invention for use in endoscopic surgery.

Next, another aspect of the invention relates to a compressed, rolled and rolled collagen carrier, according to the invention, for use in the sealing of the tissues, the adhesion of the tissues and haemostasis.

Another aspect of the invention relates to a collagen carrier, rolled and rolled according to the invention for use in minimally invasive surgery.

One aspect of the invention relates to a collagen carrier, rolled and rolled, according to the invention, for use in endoscopic surgery.

Another aspect of the invention relates to a collagen carrier, the puffer, mechanically rolled, and unfolded, according to the invention, for use in sealing the tissues, adhesion of the tissues and hemostasis.

Another aspect of the invention relates to a collagen carrier, the puffer, mechanically rolled and partially rolled, according to the invention, for use in minimally invasive surgery.

One aspect of the invention relates to a collagen carrier, the puffer, mechanically rolled, and rolled, according to the invention, for use in endoscopic surgery.

Another aspect of the invention relates to a collagen carrier compressed and rolled in accordance with the invention for use in the prevention or treatment of tissue requiring sealing and / or adhesion.

MD 4471 Cl 2017.10.31

One aspect of the invention relates to a collagen carrier compressed and rolled according to the invention for use in the prevention or treatment of bleeding in the liver requiring hemostasis.

Another aspect of the invention relates to a collagen carrier compressed and rolled according to the invention for use in the prevention or treatment of lesions associated with performing minimally invasive surgery.

Another aspect of the invention relates to a collagen carrier compressed and rolled according to the invention for use in the prevention or treatment of injuries associated with performing endoscopic, laparoscopic, or thoracoscopic treatment.

Further, further aspects of the present invention relate to a process for twisting a collagen carrier, the given carrier being comprised of (i) a collagen layer and (ii) a coating layer which preferably includes fibrinogen and thrombin, the aforementioned process comprising successive steps:

• humidification of, at least, a part of the mentioned collagen carrier, • twist of the mentioned collagen carrier, • drying of the twisted collagen carrier, thus providing a stable shaped twisted collagen carrier.

The invention is explained by figures 1-11, which represent:

FIG. 1, the adhesion of a collagen carrier (in the unsaturated state) of the present invention on a piece of liver tissue (see description in Example 2);

FIG. 2, the outward appearance of the pre-roll collagen carriers (in the unstressed state) applied in vivo in a porcine liver, 7 days after surgery (example 7);

FIG. 3, collagen carriers pre-roll according to the invention in a trocar over a measuring roller (top of the photograph). The bottom of the photo shows the length and width of the collagen carriers pre-roll according to the invention. The fibers are of medium size (lot 10419312 and 10431721);

FIG. 4, TCP test chambers and a blood pressure monitor;

FIG. 5, a TachoSil® product, which broke away from the twisted configuration after being run using an applicator element (shown on the left side of the figure), as described in [3]. The twisted TachoSil® that has detached from the twisted configuration is shown on the right side of the figure. Fragmented shells that have fallen out of twisted TachoSil® are visible in the figure;

FIG. 6, TachoSil® (collagen carriers with a weight of approximately 1000 mg), which were twisted directly, ie without being humidified and compressed previously. Draw attention to the cracked surface of the shell. The weight of the collagen carriers is taken into account the weight of the collagen carrier excluding the weight of the coating;

FIG. 7, an example of an application of a collagen carrier twisted inside, e.g., a cavity or an opening in an organ or cleft, such as in lung surgery. An applicator element is shown in the upper right part of the figure;

FIG. 8, a twisted collagen carrier carried on the оf the bladder in an organ or liver, such as in lung surgery. The unfolded collagen carrier is supported and maintained on the cleft box with the help of pliers. An applicator element is shown on the left side of the image;

FIG. 9, the wetting of a twisted (uncoiled) collagen carrier applied internally, e.g., to a cavity or orifice in an organ or cleft, such as in lung surgery. The wetting is performed using, for example, a saline solution, and / or applying pressure to the collagen carrier using pads or wipes moistened with saline. Figure 9 shows a wet wipe with a saline wipe, used for shaping the TachoSil® product on the application segment, and a wet wipe with a saline solution is used in cases where a wipe is not sufficient and wetting and compressing is required. further;

FIG. 10, a twisted (collapsed) collagen carrier applied internally, e.g., to a cavity or hole in an organ or cleft, such as lung surgery, being unpacked from a sterile plastic bag with о minimum amount of air inside with two sets of pliers;

FIG. 11, schematic о preferred embodiment of an apparatus for providing the twisted collagen carrier according to the present invention.

In the figures, the same characteristics are indicated by identical numbers - see e.g. detailed description of figure 11 for numbers.

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Detailed description of the invention

Defmifii

Before the detailed description of the present invention the following terms and conditions will be defined first:

the term "collagen carrier" means in this context any suitable carrier consisting of collagen which may have a coating that comprises / consists of a collagen layer and / or a coating layer. In one embodiment, the collagen carrier may be rolled or twisted (the words rolled and twisted are used alternatively here). In another embodiment, the collagen carrier may be unwound or twisted after twisting, that is, as a rolled or unwrapped collagen carrier (the terms unwrapped and twisted are alternatively used here). The twisted collagen carrier of the present invention may, in one embodiment, be a compressed, twisted collagen carrier, or another embodiment may be a rolled variant of the compressed and twisted collagen carrier. Preferably, the collagen carrier is a collagen sponge that includes or consists essentially of type I collagen fibers and a coating. Although the carrier material is preferably a collagen sponge that includes type I collagen material from mammalian, transgenic or recombinant sources, it may also include another type of collagen, e.g., one or more muffins. type I, II, III, IV, VII and / or X. collagen. Preferably, the collagen carrier, such as a collagen sponge, is coated with human coagulation factors, fibrinogen and thrombin and optionally riboflavin (a yellow dye used to help identify the active collagen carrier's paraphrase). Thus, in an embodiment of the present invention, the collagen carrier is a collagen sponge consisting essentially of type I collagen fibers and a fibrinogen, thrombin and riboflavin coating. Fibrinogen and thrombin may be, for example, fibrinogen and thrombin of human origin, and may be purified from a natural source, or may be alternatively, e.g., fibrinogen or thrombin of transgenic or recombinant human origin, or may be produced by other methods, such as, for example, chemical synthesis. Fibrinogen and thrombin are preferably solid or nearly solid and in one embodiment may be of human origin. In another embodiment, at least one or more preferably both fibrinogen and thrombin components have the human amino acid sequence and can be produced by recombinant technology, inclusion bodies, or chemical synthesis. Thrombin and fibrinogen in one embodiment are dried, such as containing more than 5% water, such as more than 4% water, such as more than 3% water, such as 2% water puff, such as more than 1% water puff, such as 0.8% puff more water, such as 0.6% puff more water, such as more 0.4% water, such as less than 0.2% water, such as less than 0.1% water.

In an embodiment of the present invention, the collagen carrier comprises or consists of (i) a collagen layer and (ii) a coating layer that includes fibrinogen and optionally a dye, such as riboflavin. The collagen carrier may include in another embodiment other peptides, such as other peptides capable of producing haemostasis.

In an embodiment of the present invention, the expressions collagen sponge, collagen fiber, collagen patch or simply fiber or patch are terms that are used synonymously to designate a collagen carrier. A collagen carrier may alternatively comprise a co-polymer or a biodegradable polymer, such as a polyhydraluronic acid, polyhydroxy acid, e.g. lactic acid, glycolic, hydroxybutanoic, о cellulose, or gelatin. Another alternative carrier may be polyglactin 910, i.e. a synthetic co-polymer, 90% adsorbable glycolide (C2H2O2) and 10% lactide (СбН₈О₄) such as e.g. with the molecular formula (C₂H2O₂)_m ȘÎ (СзН₄О₂)_п- Another alternative carrier may be horse collagen, such as e.g. Indigenous horse collagen extracted from tendons.

Thus, the collagen portion of the collagen carrier may be substituted in an embodiment of the present invention with a о-collagen-free mold which is coated in the same manner as for the collagen carrier described herein, that is, in an embodiment of the present invention. A carrier comprising or consisting of a collagen-free matrix coated with a coating comprising or consisting of fibrinogen and thrombin is proposed. An example of a suitable collagen-free mold is cellulose fabric. In an embodiment of the present invention, the collagen-free mold is a film of oxidized regenerated cellulose tissue attached to a non-woven polyglactin 910 felt.

However, a collagen carrier is preferred which is preferably in the form suitable for a medicinal sponge. In one embodiment of the invention, the collagen carrier to be passed through the twisting process of the present invention is identical to TachoSil® or

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TachoComb® available from Nycomed, as described in [2] and (WO 02/058749 A2 2002.08.01, WO 02/058750 A2 2002.08.01). .

A preferred collagen layer is preferably used to mean a collagen sponge produced by the process according to the invention as described in [2]. The collagen layer used in the present invention preferably meets the shearwater, one, such as, shearwater, two or, shearwater, three of the following criteria:

- pH value between 5.0 and 6.0,

- Lactic acid content of maximum 5%,

- the maximum ammonium content of 0.5%,

- soluble protein content, calculated as albumin content, not more than 0.5%,

- the content of sulphated ash of not more than 1,0%,

- heavy metal content of maximum 20 ppm,

- microbiological purity, of maximum 103 CFU / g,

- collagen content between 75% and 100%,

- density of 1 ... 10 mg / cm³, especially 2 ... 7 mg / cm³,

- modulus of elasticity of 5 ... 100 N / cm², especially 10 ... 50 N / cm², and where during isolation of the parts of the sponge, it will have the following properties:

- modulus of elasticity ranging from 5 to 100 N / cm²,

- density ranging from 1 to 10 mg / cm³,

- the diameter of the chamber over 0,75 mm and less than 4 mm, or an average of the diameter of the chamber of maximum 3 mm.

The density of a collagen carrier is the density of the collagen carrier excluding the coating.

Preferably, the collagen layer fulfills, at least, the following criteria:

- pH value between 5.0 and 6.0,

- Lactic acid content of maximum 5%,

- the maximum ammonium content of 0.5%,

- soluble protein content, calculated as albumin content, not more than 0.5%,

- the content of sulphated ash of not more than 1,0%,

- heavy metal content of maximum 20 ppm,

- microbiological purity, of maximum 103 CFU / g,

- collagen content between 75% and 100%,

- density of 1 ... 10 mg / cm³, such as 2-7 mg / cm³.

Also, the collagen layer is airtight and liquid in the sense that, once the collagen layer is applied to the wound, it will not allow air or liquid to pass through the collagen layer. Liquids are absorbed into the layer. This effect is mainly due to the fact that the collagen layer has a three-dimensional structure with separate superimposed chambers and is closed substantially completely by the collagen material sheaths, as opposed to the known collagen strands that have a fibrous structure.

In this context, the term diameter of the room will mean the largest rectilinear distance from wall to wall in a room, ie the largest diagonal rectilinear distance of a room. The rooms can be polygonal in shape, such as octagonal in shape. Thus, when the carrier is cut, the chambers are divided and cut into cavities.

It has been found that a chamber diameter of more than 0.75 mm and less than 4 mm, or an average chamber diameter of up to 3 mm, makes collagen sponge particularly useful for coating with a fibrin glue preparation. . When the carrier is cut, the chambers are divided and cut into cavities. Preferably solid fibrinogen and preferably solid thrombin is attached to the collagen layer and most of it is present in cavities, thus providing substantially uniform distribution of preferably solid thrombin and preferably solid fibrinogen. Due to this fact and fixation, it is possible to introduce substantial amounts of fibrinogen and thrombin on the carrier as opposed to the situation when the liquid compositions of thrombin and fibrinogen are e.g. dripping or splashing on the material.

Each coated collagen carrier as well as the uncoated collagen layer is visually checked for pore size distribution - pores larger than 4 mm and deeper than 2 mm are not allowed. These dimensions are measured with a ruler, if necessary.

By fixing the coating layer on the collagen layer, it is preferably contemplated that the coating layer adheres through the mechanical interactions, that is, by including on the pores surface of the collagen carrier and inside the coating layer.

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In a preferred embodiment of the present invention, the amount of fibrinogen and thrombin / cm² in the coating layer it can be:

thrombin 1.3 ... 2.7 IU / cm² and / or fibrinogen 3.6 ... 7.4 mg / cm².

In one embodiment, the aforementioned quantities of fibrinogen and thrombin / cm² are identical to the TachoSil® or TachoComb® products available from Nycomed as described in [2] and (WO 02/058749 A2 2002.08.01, WO 02/058750 A2 2002.08.01).

By substantially uniform distribution of solid thrombin and solid fibrinogen, it is assumed that the coating layer is distributed evenly over the collagen layer, which means that local changes in the thickness of the coating layer are visually observed through the MEB cross sections, i.e. cover may be located on the surface and sometimes at a lower level in an open cell. There must be no cracks (cracks) pierced in the coating layer.

In one embodiment, a collagen carrier according to the present invention may have a size of 92 ... 98 mm * 46 ... 50 mm * 4 ... 7 mm and this carrier is a large collagen carrier. and is shaped like a box with a rectangular cross section with all smooth parts. Therefore, the surface of the largest rectangular cross-section is about 42.3 ... 49.0 cm². In another embodiment, a medium-sized collagen carrier according to the present invention is 46 ... 49 mm * 46 ... 50 mm * 4 ... 7 mm, and has the shape of a square box with cross-section. quadrant. Therefore, the surface of the quadrant cross-section is about 21.2 ... 24.5 cm². A medium-sized collagen carrier according to the invention is preferred. In another embodiment, a medium-sized collagen carrier according to the invention is 28 ... 33 mm * 23 ... 27 mm * 4 ... 7 mm and has the shape of a box with a rectangular cross-section with all smooth parts. Therefore, the surface of the largest rectangular cross-section is about 6.4 ... 8.9 cm².

In one embodiment of the invention, a collagen carrier has, at least, one of the following physical properties, such as, at least, two of the following physical properties, such as, at least, three of the following physical properties, such as, at least, four of the following physical properties: elasticity mode of about 5 ... 100 N / cm², the density of 1 ... 10 mg / cm³, the diameter of the chamber over 0.75 mm and less than 4 mm and / or having an average diameter of the chamber below 3 mm and solid fibrinogen and solid thrombin evenly distributed and fixed on the above-mentioned collagen carrier. The density of a collagen carrier is the density of the collagen carrier excluding the coating.

According to the invention, a collagen carrier may become handled, e.g., such as by manual and / or mechanical handling (ie, humidification, compression, rolling, rolling, and passing through an access hole, such as a trocar) resulting in various collagen-depleted carriers, such as:

1. a humidified collagen carrier,

2. a compressed collagen carrier, optionally a humidified compressed collagen carrier,

3. a rolled collagen carrier, optionally a humidified rolled collagen carrier,

4. a rolled and compressed collagen carrier, optionally a humidified, rolled and compressed collagen carrier,

5. a collagen carrier, the puffer, mechanically humidified parfial,

6. a collagen carrier, the puffer, mechanically compressed, optionally a collagen carrier, the puffer, partially humidified and mechanically compressed,

7. a collagen carrier, the puffer, mechanically rolled parfial, optionally a collagen carrier, the puffer, partially humidified and mechanically rolled,

8. a collagen carrier, the puffer, partially rolled and mechanically compressed, optionally a collagen carrier, the puffer, partially humidified, rolled and mechanically compressed.

It is worth noting that all aspects of susmenfionafi collagen carriers also apply to collagen carriers, the puffer, partially mechanical preparations.

The term "mechanical" is meant to refer to any non-manual way of producing, obtaining or providing a medicinal sponge, such as a collagen carrier rolled and / or compressed from the present invention by means of, at least, a semi-automatic process, such as a fully automatic process.

Mechanical stable refers to stable shape.

The term "stable form" as used in the twisted collagen carrier is preferably used to define a twisted collagen carrier which is self-sustaining.

MD 4471 Cl 2017.10.31 its geometric shape without being fixed with fastening or fastening elements, which are not part of the collagen carrier. For example, a twisted collagen carrier with a stable shape can maintain its geometric shape, because the coating layer and / or the collagen layer has no pressure to act on the deformation - such as defrosting - of the twisted collagen carrier. . Another characteristic of the stable shape is that the twisted collagen carrier can be deformed elastically and restored to the shape it had before being elastic deformed by releasing the pressure exerted by elastic deformation. Another characteristic of the collagen carrier with a stable shape is that it is preferably reinforced in a twisted form.

Solid as used, e.g. Solid fibrinogen and solid thrombin are commonly used in the art to designate a solid material. Almost solid is preferably used to denote that the minor fraction of the material in question may be in a different state from the solid one (such as less than 5%, such as less than 3%, preferably less than 1). %, such as less than 0.5%). Alternatively, almost solid is used, preferably, to designate that the material in question may contain liquid, such as more than 5% liquid, or more than 1% liquid.

The term "manual" refers to any manual way of producing, obtaining or providing a carrier, such as a medical sponge or as a collagen carrier rolled and / or compressed from the present invention. Thus, by '' manual '' is meant any way in which, at least, the stage of the production method (eg the rolling stage and / or the compression stage) is performed with the help of, at least, a ( some) human hands, e.g. rolling the collagen fiber around a pivot ”with the hand or compressing the collagen fiber with the help of the hand, e.g. fiber compression directly by applying one or more human hands. In a preferred embodiment of the present invention, the puffer, the rolling step and / or the compression step are not performed manually, ie they are not performed with the help of the human hand (s). Thus, in a preferred embodiment of the present invention, collagen fiber is not rolled around an object (such as a pivot) with the hand and / or collagen fiber is not compressed by applying at least one hand of man.

By the term '' prepared / handled the mechanical perfusion shear '' is considered a process, in which, the shear parte part of a stage of the process is mechanically executed, e.g. when a collagen carrier is mechanically compressed, but it is placed by hand in the compression device, such as through a set of rollers for roll compaction.

The term rolling means any well known process for running an object, that is, manually, mechanically or by combining them.

Twist after is used, e.g. In said twisted collagen carrier it is preferably used to mean the process of wrapping the collagen carrier in an element, which is preferably provided with spiral cross-sections. The twisted collagen carrier can have an "S" shaped core.

In an embodiment according to the invention, when a collagen carrier is mechanically rolled, the rolling process comprises the steps of gripping, at least, an outer edge of a collagen carrier with the aid of, at least, a clamping device. , such as forceps, such as mechanical fingers, and for twisting at least one gripping device mentioned about its central axis and thus also for twisting, of the bladder collagen carrier and the release of the bladder collagen carrier mechanically rolled from the bladder, the blunt grip device. The process of rolling a collagen carrier according to the invention also comprises rolling, preferably, a compressed collagen carrier, such as a puffer, a mechanically perfused collagen carrier, such as a carrier. humidified collagen, such as a compressed and humidified collagen carrier. Thus, the rolling can be applied to any collagen carrier, such as a medicinal sponge, which is used directly without being previously exposed to one or more physical manipulations, such as e.g. humidification, compression, high room temperature and humidity or gamma radiation. Preferably, the rolling process can be applied to any collagen carrier, which has been previously exposed to one or more of the aforementioned physical manipulations. The words roll, roll, rotate or spin are used alternatively in the present context.

The term "compressed collagen carrier" preferably refers to a compressed collagen carrier, which has been subjected to uniformly distributed pressure (ie, compression) to achieve the following physical properties: a coating that includes solid fibrinogen and solid thrombin, which it is distributed evenly and fixed on the aforementioned collagen carrier, and having, at least, one of the following physical properties in the unfolded state:

MD 4471 Cl 2017.10.31

I. о thickness not exceeding 4 mm,

II. о adhesive capacity of at least 40 mmHg, measured after roll-out using a pressure test (TCP),

III. a sterility assurance level (NAS) of 10 '⁶.

In an embodiment of the present invention, the aforementioned compressed collagen carrier was optionally humidified either before or optionally after the compression step on, at least, part of the mentioned collagen carrier. The aforementioned compressed collagen carrier was, at least partially, mechanically processed.

The term "compression" refers to the process of compressing an object, such as a collagen carrier, and refers in the present context to the process when the collagen carrier, when compressed, is subjected to uniformly distributed pressure. The words compression and compaction are used alternatively. Also, expressions that explain that an object can be compressed, pressed or compacted are used alternatively here. The collagen carrier can, e.g. become compressed when passing through a set of rollers using о a certain size of spin. When pressed, the collagen carrier is preferably a humidified collagen carrier or a non-humidified collagen carrier. It is preferred to use a roller compressor (mechanical compression). Thus, о compression can be performed by any conventional, manual or mechanical mode of compression of an object by subjecting it to a uniformly distributed pressure, that is, preferably by passing it through a set of rollers by compacting with rollers, by placing the carrier between two sets. of uniform / smooth plates, where the upper plate is a piston, or by running a cylindrical object over the said carrier, which is placed on the lower smooth plate.

The expression of the size of the spindle refers in this context to the shortest distance measured in mm between rollers in a roller compressor. Preferably, the compression is accomplished by roller compression using a roll gap size of not more than 0.30 mm, such as not more than 0.35 mm, such as not more than 0.40 mm, such as not more than 0.45 mm, such as at most 0.50 mm, as at most 0.55, as at most 0.60 mm, as at most 0.65 mm, as at most 0.70 mm, such as preferably not more than 0.75 mm, such as not more than 0.80 mm, such as not more than 0.85 mm, as not more than 0.90 mm, such as at most 0.95 mm and not more than 1.00 mm. It is preferred to use a roll size between about 0.45 ... 0.75 mm, such as about 0.45 ... 0.70 mm, such as about 0.45 ... 0 , 65 mm, such as about 0.45 ... 0.60 mm, like about 0.45 ... 0.55 mm, like about 0.45 ... 0.50 mm, such as about 0.50 ... 0.75 mm, such as about 0.55 ... 0.75 mm, such as about 0.60 ... 0.75 mm, such as about 0.65 ... 0.75 mm, such as about 0.70 ... 0.75 mm, such as about 0.50 ... 0.70 mm, such as about 0.50 ... 0.65 mm, such as about 0.50 ... 0.60 mm, such as about 0.60 ... 0.70 mm, such as about 0.60 ... 0.65 mm. The size of the slab of about 0.40 mm results in rigid / putative compression, while the size of the slab of about 0.75 mm results in moderate compression.

Preferably, the rollers that perform the mentioned roller compaction have a diameter of about 100 mm, such as about 80 mm, such as about 70 mm, such as about 38 ... 62 mm, such as about 43 ... 57 mm, such as preferably about 48 ... 52 mm. The mentioned rollers are preferably made from an inert and inflexible material that does not transfer the roll material to the collagen carrier menfionafi after compaction, ie the surface of the rolls is important. In one embodiment, the rollers are polished.

In one embodiment, the term rolled collagen carrier is, preferably, a rolled collagen carrier characterized by the following physical properties: a coating comprising solid fibrinogen and solid thrombin, which is uniformly distributed and attached to said collagen carrier, and having, at least, one of the following physical properties:

I. a diameter not exceeding 10 mm,

II. о adhesive capacity of, at least, 40 mmHg, as measured by a pressure test (TCP),

III. a level of sterility assurance (NAS) of IO '⁶.

For example, the rolled collagen carrier may have a diameter of up to 12 mm, such as at most 11 mm, such as at most 10 mm, e.g. not more than 8 mm, such as not more than 6 mm, e.g. not more than 4 mm, together with the adhesive capacity of, at least, 30 mmHg, such as, at least, 35 mmHg, such as preferably 40 mmHg measured after roll-up using a pressure test (TCP), and, optionally, a level of sterility assurance (NAS) of IO '⁶.

It should be noted that the rolled collagen carrier may optionally be moistened before it becomes rolled onto, at least, the portion of the mentioned collagen carrier (ie the carrier has

MD 4471 Cl 2017.10.31 was rolled after being humidified on, at least, о part), preferably on the front side comprising the aforementioned casing resulting in a collagen carrier being rolled having the oriental outward casing. The mentioned rolled collagen carrier was optional, the partially perfused shifter, mechanically processed, also the mechanically humidified perfused shuffer.

By the term "rolled and compressed collagen carrier" is meant a rolled and compressed collagen carrier characterized by the following physical properties: a coating comprising solid fibrinogen and solid thrombin, which is uniformly distributed and fixed to the mentioned collagen carrier, and having , at least, one of the following physical properties:

I. a diameter not exceeding 10 mm,

II. о adhesive capacity of, at least, 40 mmHg, as measured by a pressure test (TCP),

III. a sterility assurance level (NAS) of 10 '⁶.

It is worth noting that the rolled and compressed collagen carrier may optionally be humidified before becoming mechanically rolled and / or partially perfused.

Thus, one advantage of the invention is that the compressed and rolled collagen carrier is ready for use in minimally invasive surgery, such as ready to be inserted into endoscopic devices.

By the term mechanically compressed and rolled collagen carrier is meant a collagen carrier which was mechanically compressed and then mechanically rolled and characterized by the following physical properties: a coating comprising solid fibrinogen and solid thrombin, which is uniformly distributed and fixed on the mechanically rolled and collapsed blunt collagen carrier, and having, at least, one of the following physical properties:

I. a diameter not exceeding 10 mm,

II. о adhesive capacity of, at least, 40 mmHg, as measured by a pressure test (TCP),

III. a sterility assurance level (NAS) of 10 '⁶.

Optionally, the mechanically rolled collagen carrier is mechanically moistened during processing.

By the term wetting means the process of wetting / wetting of, at least, a part of a collagen carrier with, the shear, a liquid solvent preferably over the shear or part of the mentioned carrier, which has the shear or part covered with a coating that contains biologically active substances. If more than о of the wearer's face is covered with a coating that contains biologically active substances, then the term may include wetting, such as the shearwater of two sheaves, such as the sheaf of three sheaves, such as the sheaf of four sheaves, there would be at least five hairpins, like all faces of the collagen carrier mentioned. The wetted wafer is preferably the wafer that confines a wrap, but it can also be о face that does not contain a wrap.

The term wetting as used, e.g. In wetting at least part of the mentioned collagen carrier, it is also preferably used to mean the step of applying the liquid substance to a collagen carrier.

Thus, the term "wetted collagen carrier" will mean a collagen carrier that has been exposed to the liquid solvent by the shearer or by the shearer of the said carrier, such as that of the two sheaves, such as, the sheaf of three sheaves. , such as the four-necked shearwater, such as the five-sheared shearwater, like all the shearwaters, to obtain a wetted collagen carrier.

In an embodiment of the present invention, the collagen carrier is preferably wetted on the puffer face of the blunted carrier (ie, the front one), which has the puffer face covered with a coating that confines biological substances. active before being compressed and / or running. The words moistened and moistened are used alternatively. In another embodiment, it is preferred to wet both the front and the back of a collagen carrier of the present invention, where the front comprises the aforementioned shell. The aforementioned wetted collagen carrier was optional, the perfused shear, mechanically processed.

In one embodiment of the present invention, the wetted collagen carrier has a coating that confines solid fibrinogen and solid thrombin, which is uniformly distributed and attached to the bladder collagen carrier, and having, at least, one of the following physical properties:

I. a diameter not exceeding 10 mm,

II. о adhesive capacity of, at least, 40 mmHg, as measured by a pressure test (TCP),

III. a sterility assurance level (NAS) of 10 '⁶.

MD 4471 Cl 2017.10.31

By the term "solvent" is meant any suitable solvent, such as physiological serum, purified water, water vapor or any suitable organic solvent, such as ethanol, dehydrated ethanol with a maximum content of 0.1% water. , isopropanol or methanol. An alcohol is selected from the group consisting of ethanol, dehydrated ethanol with a maximum content of 0.1% water, 1propanol, 2-propanol, 2-methyl-2-propanol, ethylene glycol, 1-butanol, 2-butanol or any combination of these. In one embodiment, a solvent is selected from ethanol, dehydrated ethanol with a maximum content of 0.1% water, isopropanol, 1-propanol, 2-methyl-2-propanol, water or any combination thereof. In another embodiment, a solvent is selected from ethanol, dehydrated ethanol with a maximum content of 0.1% water, isopropanol, water or any combination thereof. In one embodiment, the ethanol is dehydrated ethanol with a maximum content of 0.1% water. In one embodiment the applied solvent, the amount of solvent applied is about 0.8 ... 10.75 mg / cm² collagen carrier, such as approx

1.2 .. .10.75 mg / cm² collagen carrier, such as about 0.8 ... 10.4 mg / cm² collagen carrier, such as about 0.8 ... 6.1 mg / cm² collagen carrier, such as about 1.2 ... 4.7 mg / cm² collagen carrier, such as about 2.85 ... 4.24 mg / cm². An alcohol - preferably ethanol - is a preferred solvent. In one embodiment, the solvent consists essentially of a mixture of ethanol or dehydrated ethanol with a maximum content of 0.1% water and water or isopropanol and water, where the amount of water is not more than 20%, such as maximum 18%, like maximum 16%, like maximum 14%, like maximum 12%, like maximum 10%, like maximum 8%, like maximum 6%, like maximum 5 %, such as max 4%, max 3%, max 2.4%, max 2%, such as maximum 1.5%, such as maximum 1%, such as maximum 0.5%. The solvent may also contain fibrinogen and / or thrombin and / or albumin and / or low salt. In another embodiment, ethanol or dehydrated ethanol with a maximum content of 0.1% water is the preferred solvent and is used in an amount of about 9 mg of ethanol / cm.²collagen carrier, such as about 8 mg ethanol / cm² collagen carrier, such as about 7 mg ethanol / cm² collagen carrier, such as about 6 mg ethanol / cm² collagen carrier, such as about 5 mg ethanol / cm² collagen carrier, such as about 4 mg ethanol / cm² collagen carrier, such as about 3 mg ethanol / cm² collagen carrier, such as about 2 mg ethanol / cm² collagen carrier, such as about 1.2 mg ethanol / cm² collagen carrier, such as about 1 mg ethanol / cm² collagen carrier, such as about 0.5 mg ethanol / cm² collagen carrier.

Not obliged in theory, it is assumed that the use of over 10.75 mg of ethanol or dehydrated ethanol with a maximum content of 0.1% water / cm² collagen carrier, such as about 10.4 mg ethanol / cm² collagen carrier could cause said collagen carriers to become adhesive during compression. Therefore, the use of an ethanol level of not more than 10.75 mg ethanol / cm is preferred² collagen fiber.

By the term 'relative humidity (UR)' the quantity of water vapor in a mixture of air and water vapor is considered.

In one embodiment, the process according to the present invention is performed at 10 ... 75% UR, such as 30 ... 50% UR, such as 30 ... 60%, such as 30 ... 64% UR, like 30 ... 65% UR, like 30 ... 70% UR, like 40 ... 60% UR, like 40 ... 64% UR, like fi 40 ... 70% UR and optional at о temperature between 5 ... 30 ° C, such as 18 ... 22 ° C, such as

18 .. .25 ° C. In a preferred embodiment, the RU is 30 ... 50% and the temperature is between 18 ... 22 ° C, which represents the preferred range of relative humidity and the temperature range of the room (e.g. the production), where the collagen carriers rolled and / or compressed are processed. See below where the term drying is defined ”. In another embodiment, the relative humidity range and room temperature (e.g. the production company), where the collagen carriers rolled and / or compressed are processed is about 25 ° C and 64 ... 70% RH.

By the term modulus of elasticity, the tendency of an object to be deformed is elastic, that is to say, not permanently when applying force to it. In this context the modulus of elasticity is used to describe the elasticity of a collagen carrier of the present invention. The modulus of elasticity is measured in the present invention in N / cm². The modulus of elasticity is preferably 5 ... 100 N / cm², such as 15 ... 90 N / cm², such as 25 ... 80 N / cm², such as 35 ... 70 N / cm², such as 45 ... 60 N / cm², such as 50 ... 55 N / cm². The modulus of elasticity is a well-known parameter m the given range for measuring elasticity, as described by e.g. in the book (JE Gordon, The New Science of Strong Materials or Why

MD 4471 Cl 2017.10.31

You Don't Fall Through the Floor, p 38-43 and EP 1 053 757 Bl). The modulus of elasticity thus represents the elastic flexibility of a material, the flexibility of any particular object.

The elastic modulus is taken into account the Young, E module, the physical constant, characterized by the rigidity of an elastic material. E represents the power (N) divided by the surface (mm²), written as N / mm² or MPa.

By the term density or mass density of a material is considered the mass of the material per unit volume. The most commonly used symbol for density is p, but in this context, density is defined as the weight per unit volume mg / cm.³, which is also called the specific weight. The process and equipment used to determine density are described in more detail in the example section below. The density of a collagen carrier according to the present invention is the density of the collagen carrier excluding the coating. In an embodiment of the present invention, the density of the collagen carrier before humidification and / or rolling and / or compression, such as for the collagen carrier proposed in step (a) of the present invention, is about 1 ... 10 mg / cm³, such as about 1 ... 9 mg / cm³, such as about 1 ... 8 mg / cm³, such as about 1 ... 7 mg / cm³, like about

1 .. .6 mg / cm³, such as about 1 ... 5 mg / cm³, such as about 1 ... 4 mg / cm³, such as about 1 ... 3 mg / cm³, such as about 1 ... 2 mg / cm³, such as about 2 to 9 mg / cm³, such as about 2 ... 8 mg / cm³, such as about 2-7 mg / cm³, such as about 2 ... 6 mg / cm³, such as about 2-5 mg / cm³, such as about 2 ... 4 mg / cm³, such as about 3 to 9 mg / cm³, such as about 3 ... 8 mg / cm³, such as about 3 to 7 mg / cm³, such as about 3 ... 6 mg / cm³, such as about 3-5 mg / cm³, preferably such as about 3.0 ... 4.5 mg / cm³, such as about 3.0 ... 4.4 mg / cm³, such as about 3.0 to 4.3 mg / cm³, such as about 3.0 ... 4.2 mg / cm³, such as about 3.0 to 4.1 mg / cm³, such as about 3.0 ... 4.0 mg / cm³, such as about 3.0 to 3.9 mg / cm³, such as about 3.0 to 3.8 mg / cm³, such as about 3.0 to 3.7 mg / cm³, such as about 3.0 to 3.6 mg / cm³, such as about 3.0 ... 3.5 mg / cm³, such as about 3.0 to 3.4 mg / cm³, such as about 3.0 to 3.3 mg / cm³, such as about 3.0 to 3.2 mg / cm³, such as about 3.0 ... 3.1 mg / cm³, such as about 3.1 ... 4.5 mg / cm³, such as about 3.2 ... 4.5 mg / cm³, such as about 3.3 to 4.5 mg / cm³, such as about 3.4 ... 4.5 mg / cm³, like about

3.5 .. .4.5 mg / cm³, such as about 3.6 ... 4.5 mg / cm³, such as about 3.7 ... 4.5 mg / cm³, such as about 3.8 ... 4.5 mg / cm³, such as about 3.9 ... 4.5 mg / cm³, such as about 4.0 ... 4.5 mg / cm³, such as about 4.1 ... 4.5 mg / cm³, such as about 4.2 ... 4.5 mg / cm³, such as about 4.3 ... 4.5 mg / cm³, such as about 4.4 ... 4.5 mg / cm³.

The density of a humidified and / or compressed and / or rolled collagen carrier of the present invention is preferably about 1 ... 15 mg / cm³, such as about 2 ... 15 mg / cm³, such as about 3 to 15 mg / cm³, such as about 4 ... 15 mg / cm³, such as about 5 to 15 mg / cm³, such as about 6 ... 15 mg / cm³, such as about 7 ... 15 mg / cm³, such as about 8 ... 15 mg / cm³, such as about 9 ... 15 mg / cm³, such as about 10 ... 15 mg / cm³, such as about 11 ... 15 mg / cm³, such as about 12 ... 15 mg / cm³, such as about 13 ... 15 mg / cm³, such as about 14 ... 15 mg / cm³, such as about 3 to 14 mg / cm³, such as about 3 to 12 mg / cm³, such as about 3 to 10 mg / cm³, such as about 3 to 9 mg / cm³, such as about 3 ... 8 mg / cm³, such as about 3 to 7 mg / cm³, preferably such as about 3-6 mg / cm³, such as about 3-5 mg / cm³, such as about 3.0 ... 4.5 mg / cm³, such as about 3.0 ... 4.4 mg / cm³, such as about 3.0 to 4.3 mg / cm³, such as about 3.0 ... 4.2 mg / cm³, such as about 3.0 to 4.1 mg / cm³, such as about 3.0 ... 4.0 mg / cm³, such as about 3.0 to 3.9 mg / cm³, such as about 3.0 to 3.8 mg / cm³, such as about 3.0 to 3.7 mg / cm³, such as about 3.0 to 3.6 mg / cm³, such as about 3.0 ... 3.5 mg / cm³, such as about 3.0 to 3.4 mg / cm³, such as about 3.0 to 3.3 mg / cm³, such as about 3.0 to 3.2 mg / cm³, such as about 3.0 ... 3.1 mg / cm³, such as about 3.1 ... 4.5 mg / cm³, such as about 3.2 ... 4.5 mg / cm³, such as about 3.3 to 4.5 mg / cm³, such as about 3.4 ... 4.5 mg / cm³, such as about 3.5 to 4.5 mg / cm³, like about

3.6 .. .4.5 mg / cm³, such as about 3.7 ... 4.5 mg / cm³, such as about 3.8 ... 4.5 mg / cm³, such as about 3.9 ... 4.5 mg / cm³, such as about 4.0 ... 4.5 mg / cm³, such as about 4.1 ... 4.5 mg / cm³, such as about 4.2 ... 4.5 mg / cm³, such as about 4.3 ... 4.5 mg / cm³, such as about 4.4 ... 4.5 mg / cm³.

The density of a humidified and / or compressed and rolled collagen carrier of the present invention is measured after the unfolding of the rolled collagen carrier mentioned in the present invention. The density of a collagen carrier of the present invention is the density of the collagen carrier excluding the coating.

In the present invention it is preferred to determine the density by weighing a collagen carrier of known volume, such as a rolled and / or compressed collagen carrier.

MD 4471 Cl 2017.10.31 certain dimensions (see the example section), such as a large collagen carrier (also called о band or о fiber). The density is calculated by dividing the mass of the collagen carrier by the volume of the collagen carrier. The process and equipment used to determine density are described in more detail in the section with examples below.

By the term "coating", preferably, is meant a coating which confines or consists essentially of biologically active substances, fibrinogen and thrombin, which are uniformly distributed and fixed on, at least, a collagen carrier of the present invention, such as would be a rolled and / or compressed collagen carrier, such as a rolled, rolled and / or compressed collagen carrier. The coating may also include e.g. riboflavin (yellow as an indicator of the coated surface). In an embodiment of the present invention, the active substances are preferably human solid fibrinogen, human solid thrombin and optionally solid riboflavin. Thus, in an embodiment of the invention, the coating consists essentially of human solid fibrinogen, human solid thrombin and solid riboflavin. The coating is present on at least one front of the collagen carrier, such as a rolled and / or compressed collagen carrier, such as a rolled, rolled and / or compressed collagen carrier. Thus, in one embodiment, the collagen carrier, such as a rolled and / or compressed collagen carrier, such as a rolled, rolled and / or compressed collagen carrier comprises one or more active phages, where fibrinogen is present in an amount of 1.3 ... 10 mg / cm ?, such as 2 ... 10 mg / cni, such as 4.3 ... 6.7 mg / cm², preferably, about 3.6 ... 7.4 mg / cm², such as about 5.5 mg / cm², and thrombin is present in an amount of 0.9 ... 20 IU / cm ?, such as 0.9 ... 15 IU / cm?, such as 0.9 ... 10 IU / cm ? such as 1.0 ... 5.5 IU / cm², preferably, such as about 1.3 ... 2.7 IU / cm², such as about 2.0 IU / cm². the aforementioned coating is preferably applied to the puffer о face of the mentioned collagen carrier, such as a rolled and / or compressed collagen carrier, such as a rolled, rolled and / or compressed collagen carrier.

When the collagen carrier, such as a rolled and / or compressed collagen carrier, such as a rolled, rolled and / or compressed collagen carrier, has an о-face coating on the aforementioned carrier and when it is rolled front Coated with biologically active substances may be outwardly oriented on the coated rolled collagen carrier, or the face coated with biologically active substances may be oriented inwards on the coated coated carrier. Currently, the first alternative is preferred for a collagen carrier compressed and rolled from the present invention, that is, the extreme orientation of the mentioned sheath.

By the term diameter e.g. of the rolled collagen carrier is taken into account the diameter of the cross-section of any type of collagen carrier that has been rolled or twisted according to the present invention. Thus, the diameter of the resulting rolled collagen carrier, measured on the cross-section (e.g. the shortest beam) is about 5 ... 12 mm, such as about 6 ... 11mm, such as about 7 ... 10 mm, such as about 8 ... 9 mm, such as maximum 11 mm, preferably as maximum as 10 mm, preferably as maximum as 9 mm, such as maximum 8 mm, as maximum 7 mm, as maximum 6 mm, such as maximum 5 mm, such as maximum 4.5 mm, such as maximum 4 mm, such as maximum 3.5 mm, such as maximum 3 mm, such as maximum 2.5 mm, such as maximum 2.0 mm, maximum 1.5 mm, maximum 1.0 mm. The preferred diameter is less than 10 mm for medium size fibers, ie medium size fibers have dimensions 46 ... 49 mm * 46 ... 50 mm * 4 ... 7 mm. In FIG. 3 shows the length and width of a pre-rolled collagen carrier according to the invention.

The term thickness refers to the shortest measurable distance along any collagen carrier of the invention that is rolled or unrolled, which means that the thickness depends on whether or not the collagen carrier has been previously rolled and / or whether or not it has been compressed and humidified previously. When the term thickness is used to describe any type of collagen carrier unrolled or non-coiled according to the present invention, thickness is taken to mean thickness which is about 1 ... 10 mm, such as about 2 ... 8 mm , such as about 4 ... 6 mm, such as maximum 10 mm, such as about 9 mm, such as maximum 8 mm, such as maximum 7 mm, as maximum 6 mm, such as maximum 5 mm, such as maximum 4 mm, such as maximum 3 mm, such as maximum 2 mm, such as maximum 1 mm. In one embodiment, the preferred thickness of a collagen carrier is 4-7 mm. In another embodiment, the preferred thickness of a rolled collagen carrier is up to 4 mm.

The term "adhesive capacity" refers to the ability of a collagen carrier, such as a rolled and / or compressed collagen carrier, to adhere to living tissue and thus

MD 4471 Cl 2017.10.31 The adhesive capacity reflects the pharmaceutical activity of a collagen carrier according to the invention, that is, the ability of a collagen carrier, such as a rolled and / or compressed collagen carrier to provide sealing of the liver, adhesion of the liver and haemostasis. The adhesive capacity can be measured by in vitro measurement, such as the TCP test, and has the unit mmHg. The TCP test is described in Example 4. The adhesive capacity of a collagen carrier, such as a rolled and / or compressed collagen carrier, can be measured using various pressure testing methods that investigate as a whole what a pressure / medical device can withstand prior to rupture. /break in. Thus, these methods are used to determine the adhesive / sealing capacity of a patch, such as a medicinal sponge, preferably, such as a collagen carrier, such as a rolled and / or compressed collagen carrier according to the present invenfii. Therefore, these methods simulate the adhesive / sealing capacity of a medicinal sponge in a living organism, such as a mammal, e.g. rat, dog, or man who supports о surgery, such as minimally invasive surgery. These methods include methods known to a person skilled in the art, such as e.g. Hydraulic Breakout Test (HBLT) (Crescent Design), such as the АТС (АТС Inc.) pressure breaker, such as the hydraulic breaker tester (AE Solutions, Inc.). In the present context, a pressure test called TCP is used for in vitro simulation of the adhesive capacity of a collagen carrier, such as a rolled and / or compressed collagen carrier of the present invention on a fused sample or a simulated sample. of yarn. Thus, TCP is preferred in the present invention.

By TCP ”a pressure test is used which is used to measure the adhesive / sealing capacity of a collagen carrier, such as a collagen carrier rolled and / or compressed on a synthetic membrane that mimics adhesion to mammalian fat. The test is performed e.g. with о sample of the rolled collagen carrier which after the cut is cut into the shape of a 3 x 3 cm square. The active face of the cut samples is moistened with saline solution and placed on the synthetic membrane which was provided with a hole in the center (0 1 cm). The membrane with the glued sample of the collagen carrier, such as a rolled and / or compressed collagen carrier, is placed and secured over the air chamber in which air is pumped. The pressure required to break / break the seal formed by the collagen carrier, such as a rolled and / or compressed collagen carrier, is measured in mmHg and is called '' adhesive capacity '' as defined above. The test is described in more detail in Example 4.

The embodiment of the present invention relates to a process according to the invention, wherein each individual collagen carrier, such as a rolled and / or compressed collagen carrier from a sample of 10 collagen carriers has an adhesive capacity of over about 40 mmHg and in which the average of 10 collagen carriers, such as a collagen carrier rolled and / or compressed in the mentioned sample, has an adhesive capacity of over 50 mmHg measured with the pressure test (TCP).

By the term "adhesion" is meant the in vitro ability of a collagen carrier, such as a collagen carrier rolled and / or compressed to adhere to the living liver according to the present invention. Adhesion is qualitatively investigated by visually examining the adhesion of a collagen carrier to a yeast and thus the near adhesion to some of the pharmaceutical activity of a collagen carrier, such as a collagen carrier rolled and / or compressed according to the invention, that is, the ability of a collagen carrier, such as a collagen carrier rolled and / or compressed to adhere to an isolated organ or a fragment of the liver. An example of an adhesion test is shown in Example 2 and FIG. 1 illustrates accession.

By the term '' loss of the coating '' is taken into account the adhesion / fixation capacity of the coating layer on the collagen layer, such as the coating layer on a twisted / rolled and / or compressed collagen carrier. Loss of coverage is described in more detail in Example 1. The term should not be confused with '' accession '' mentioned above.

The loss of the coating is indirectly measured by weighing, e.g. of a rolled collagen carrier with a predetermined size prior to rolling and weighing it immediately after it has been rolled, where the amount of coverage that may have been lost is expressed in mg / cnr or in percent, see below.

The hard handling of a collagen carrier of the invention, such as by mechanical handling (ie, wetting, compression, rolling, rolling, and passing through an access hole, such as a trocar) may result in the collagen carrier being dropped. , such as a rolled and / or compressed collagen carrier. О such hard handle is shown in FIG. 5. The method that can be used to determine the loss of coverage is described in Example 1. The rolled and compressed collagen carrier is substantially unchanged after exiting the mentioned trocar.

MD 4471 Cl 2017.10.31 or simply after running without having to go through a trocar and lost more than 20% of the coating material, such as more than 18%, such as more than 16%, like more than 14%, like more than 12%, like more than 10%, like more than 8%, like more than 6%, like more 4%, such as more than 2%, such as more than 1.5%, such as more than 1%, such as more than 0.5%, such as less than 0.2%, such as 0% as an indication of the flexibility of the collagen carrier and the coating. In an embodiment of the present invention the percentages are calculated as follows: a rolled collagen carrier of the invention is weighed before being passed through a trocar. After exiting the aforementioned trocar the aforementioned rolled collagen carrier is unwound and weighed again immediately thereafter, so the amount of the sheath that could be lost is expressed in percent. It should be noted that a collagen carrier of the present invention has an acceptable TCP value, even if it loses less than 20% of the coating material.

The loss of the coating is preferably less than 1.0 mg / cm², such as less than 0.9 mg / cm², such as less than 0.8 mg / cm², such as less than 0.7 mg / cm², preferably less than 0.6 mg / cm², such as less than 0.5 mg / cm², such as less than 0.4 mg / cm², such as less than 0.3 mg / cm², such as less than 0.2 mg / cm², such as less than 0.1 mg / cm², such as 0.01 mg / cm².

Obviously, it is not possible to measure the in vivo loss of the coating after the exit of a collagen carrier rolled or rolled and compressed of the invention from an access hole, such as a trocar inside a living organism.

The term sterility assurance (NAS) refers to a term used in microbiology to describe the probability of a single unborn baby being subjected to a sterilization process. For example, medical device manufacturers are designing their sterilization processes for a very small NAS that leads to a probability of microbial survival of IO '.⁶, i.e. assuring less than or equal to the 1 million chance that viable microorganisms are present in the sterilized device, as defined in USP 34 <1211> (US Pharmacopoeia version 32, chapter 1211. NAS is also used for describe the effectiveness of destroying a sterilization process, where a very efficient sterilization process has a very low NAS.

Sterilization may take place before and / or after any packaging step.

Gamma radiation can be used as a sterilization method to kill living organisms in a process called irradiation. The applications of irradiation include medical sterilization equipment as an alternative to autoclaves or chemical means. In an embodiment of the present invention, a collagen carrier, such as a rolled and / or compressed collagen carrier, is subjected to gamma radiation. Gamma radiotherapy can reduce the TCP value of the collagen carrier, such as not more than 0.5%, such as not more than 1%, such as not more than 2%, such as not more 3%, such as not more than 4%, such as not more than 5%, such as not more than 6%, as not more than 7%, as not more 8%, such as not more than 9%, such as, preferably, not more than 10%, such as not more than 11%, such as not more than 12%, such as not more than 13%, such as not more than 14%, such as not more than 15%, such as not more than 16%, as not more than 17%, such as not more than 18%, such as not more than 19%, such as not more than 20%, such as not more than 25%. This was evaluated in vitro by visual examination of the adhesion of a collagen carrier rolled according to the invention to the liver tissue. Fibrinogen is preferably present in an amount of 2-10 mg / cm² and thrombin is preferably present in an amount of 1.0 ... 5.5 IU / cm² after the irradiation process and it is preferred that the levels can exceed their respective levels such as not more than 0.5%, such as not more than 1%, such as not more than 2%, such as not more than 3%, such as not more than 4%, such as not more than 5%, such as not more than 6%, such as not more than 7%, such as not more than 8%, such as not more than 9%, such as, preferably, not more than 10%, such as not more than 11%, such as not more than 12% , such as not more than 13%, such as not more than 14%, such as not more than 15%, such as not more than 16%, as not more than 17%, such as not more than 18%, such as not more than 19%, such as not more than 20%, such as not more than 25%.

It is observed that exceeding their respective levels denotes that the values ​​can increase or decrease.

It is preferred that the rolled and / or compressed collagen carrier can be retained over an acceptable period of time, while at the same time undermining its biological and physiochemical properties, ie, preferably, its retention does not affect the physical and chemical properties of the collagen.

MD 4471 Cl 2017.10.31 of the collagen carrier and / or tablet mentioned and neither the in vitro adhesion (on the liver tissue) and the adhesive capacity (TCP value) of the collagen carriers rolled and / or tablets.

An acceptable validity period of up to 60 months, such as up to 54 months, such as up to 48 months, such as up to 42 months, such as up to 36 months, is preferred. like up to 30 months, like up to 24 months, like up to 18 months, like up to 12 months, like up to 6 months, like up to 5 months, like up to 4 months, like up to 3 months, like up to 2 months, like up to 1 month. Therefore, it is preferred that the collagen carriers rolled and / or tablets of the present invention are stable.

By the stable term it can be seen that the collagen carriers and / or the menfionaph tablets are physiochemically and biologically active, which means that they maintain the same properties that they had when they were prepared. Thus, carriers of collagen carriers and / or tablets menfionafi maintain stability during transport, storage (storage), logistics, sales, and up to and including during the final destination of collagen carriers carriers and / or menfionaf compressors, ie carriers menstrual collagen regulations and all requirements regarding the final destination.

The term "drying" refers to any well-known method of drying an object, such as by passive evaporation, dehydration, blowing air over the mentioned object with a humidity level lower than the object that needs to be dried, applying heat, etc. In one embodiment, the drying is carried out in a drying tunnel, that is, the tunnel comprises a conveyor belt of trays containing collagen carriers running through the tunnel with an air flow that ensures drying. In one embodiment, tunneling, ie drying, lasts approximately 30 minutes. In another embodiment, the drying tunnel completely dries the solvent, such as ethanol drying, eg, isopropanol drying, e.g. dry isopropanol and ethanol. The water is completely dried by means of a dehydrating agent, such as e.g. silica gel. Water drying can take up to about 48 hours, such as up to about 36 hours, such as up to about 24 hours, such as up to about 18 hours, such as up to about 12 hours, such as up to at about 6 hours, such as up to about 2 hours. The drying of the water lasts preferably up to about 24 hours.

Silicagel is preferably used to designate a granular, glassy, ​​porous form of silicon dioxide obtained synthetically from sodium silicate. Silicagel is a dehydrating agent widely used in the form of granules packed in a permeable pouch.

Endoscopic instrument: endoscopic instrument refers to any endoscopic instrument known to a specialist in the given field, for example, endoscopic clamp, endoscopic tweezers, endoscopic dissector, endoscopic forceps, Johansons clip or other type of endoscopic clip, endoscopic scissors, one endoscopic forceps, two or more forceps, laparoscopic swabs (fixed, preferably, on long needles or pliers), or another suitable endoscopic instrument.

In an embodiment of the present invention, drying of an optionally humidified rolled and / or compressed collagen carrier according to the invention does not affect the physical and chemical properties of the mentioned collagen carrier, nor the in vitro adhesion (on the liver tissue) and adhesive capacity. (TCP value) of the collagen carrier mentioned. In an embodiment of the present invention, an optionally humidified rolled and / or compressed collagen carrier is dried by passive evaporation of a solvent, preferably ethanol, by controlling the room temperature and room humidity up to about 3 ... 35 ° C, 5 ... 80% RH, such as

13 .. .35 ° C, 36 ... 65% RH, such as 23 ... 35 ° C, 36 ... 65% RH, such as 33 ... 35 ° C, 36 ... 65% RH, such as 3 ... 25 ° C, 36 ... 65% RH, such as 3 ... 15 ° C, 36 ... 65% RH, such as 3 ... 5 ° C, 36 ... 65% UR, preferably 18 ... 22 ° C, 40 ... 60% UR, such as 18 ... 22 ° C, 36 ... 65% UR, such as the girl

20 .. .25 ° C, 40 ... 60% RH, such as at 22 ... 25 ° C, 40 ... 60% RH, such as at 24 ... 25 ° C, 40. ..60% RH, such as at 18 ... 23 ° C, 40 ... 60% RH, such as at 18 ... 21 ° C, 40 ... 60% RH, such as at

18 .. .19 ° C, 40 ... 60% RH, such as at 18 ... 25 ° C, 35 ... 60% RH, such as at 18 ... 25 ° C, 30. ..60% RH, such as at 18 ... 25 ° C, 40 ... 65% RH, such as at 18 ... 25 ° C, 40 ... 70% RH, such as at

18 .. .25 ° C, 40 ... 75% RH, such as at 18 ... 25 ° C, 40 ... 80% RH, such as at 18 ... 25 ° C, 45. ..80% RH, such as at 18 ... 25 ° C, 50 ... 80% RH, such as at 18 ... 25 ° C, 55 ... 80% RH, such as at

18 ... 25 ° C, 60 ... 80% RH, such as at 18 ... 25 ° C, 65 ... 80% RH, such as at 18 ... 25 ° C, 70. ..80% UR, such as at 18 ... 25 ° C, 75 ... 80% UR. The optically optionally humidified, above-mentioned collagen carrier is preferably dried for 30 minutes by blowing air at a lower humidity than the mentioned collagen carrier (such as a rolled and / or compressed collagen carrier that requires drying) over the mentioned collagen carrier

MD 4471 Cl 2017.10.31 followed by passive evaporation of the solvent by placing the mentioned collagen carrier in a desiccator.

Preferred evaporation and / or drying period of maximum 24 hours, such as maximum 20 hours, such as maximum 15 hours, such as maximum 10 hours, such as maximum 5 hours, such as not more than 1 hour, such as maximum 50 minutes, such as maximum 40 minutes, preferably, as maximum as 30 minutes, as maximum as 20 minutes, as maximum as 10 min., such as maximum 5 min., such as maximum 1 min., such as maximum 50 s., such as maximum 40 s., such as maximum 30 s, such as maximum 20 s, such as maximum 10 s, such as maximum 5 s.

The residual amount of, at least, a liquid solvent applied to the collagen carrier, such as a rolled and / or compressed collagen carrier, is acceptable, such as at most 0.1% m / m, or such not more than 0.2% m / m, or as not more than 0.5% m / m, or as not more than 0.8% m / m or as not more than 1.0% m / m, or such as not more than 1,2% m / m, or as not more than 1,4% m / m, or preferably as not more than 1,6% m / m, or as not more than 1.8% m / m, or such as not more than 2.0% m / m, or as not more than 2.5% m / m, or as not more than 3.0% m / m, or as not more than 3, 5% m / m, or as not more than 4.0% m / m, or as not more than 5.0% m / m, or as not more than 8.0% m / m, or as not more than 10.0% m / m, or not more than 12.5% ​​m / m, or not more than 15.0% m / m, or not more than 17.5% m / m, or such as at most 20.0% m / m, or as at most 22.5% m / m, or as at most 25.0% m / m, or such as at most 27.5% m / m, or as at most 30.0% m / m, or as at most 32.5% m / m, or as at most 35, 0% m / m. If the applied liquid solvent is ethanol, at most 1.6% m / m residual ethanol is preferred and / or if the liquid solvent applied is water at most 8.0% m / m residual water, preferably e.g. not more than 5.0% m / m. A residual amount of, the shearwater, an applied liquid solvent, such as, the shear, two liquid solvents, such as, the shear, three liquid solvents on the collagen carrier, such as a rolled collagen carrier, is acceptable. / or tablet.

It may happen that one or more solvents or moisture in the room (water vapor) is passively absorbed by a collagen carrier, such as a collagen carrier rolled and / or compressed during processing. In one embodiment, if such passive moisture absorption, such as water, occurs, a residual amount of the mentioned moisture is accepted, such as at most 0.1% m / m, or such not more than 0.2% m / m, or as not more than 0.5% m / m, as not more than 0.8% m / m as as not more than 1.0% m / m, such as at most 1.2% m / m, as at most 1.4% m / m, as at most 1.6% m / m, as at not more than 1.8% m / m, such as at most 2.0% m / m, such as at most 2.5% m / m, such as at most 3.0% m / m, or as at most 3.5% m / m, or as at most 4, 0% m / m, such as at most 5.0% m / m, such as at most 8.0% m / m, as at most 10.0% m / m, as be at most 12.5% ​​m / m, such as at most 15.0% m / m, such as at most 17.5% m / m, such as at most 20.0% m / m, such as at most 22.5% m / m, as at most 25.0% m / m, as at most 27.5% m / m, as at not more than 30.0% m / m, such as at most 32.5% m / m, such as at most 35.0% m / m. If the passively absorbed solvent is water, at most 8.0% w / w residual water is preferred, such as at most 5.0% w / w. The residual solvent is measured by conventional methods known to the person skilled in the art, such as by means of gas chromatography (CG). CG is a widespread type of chromatography used in analytical chemistry for the separation and analysis of compounds that can be vaporized without decomposition. In the present invention, CG is used to determine one or more solvents or moisture in the chamber (water vapor) in the collagen carrier.

The residual solvent and its passive absorption by a collagen carrier is described in more detail in Example 9.

By the term "sterilization" is meant any well known method of sterilizing an object, such as a collagen carrier in the present invention, such as a rolled and / or compressed collagen carrier. Any such appropriate method of sterilization should result in the required probability of a single unborn child being subjected to the sterilization process. Therefore, preferably at most one collagen carrier, such as one rolled and / or one million collagen carrier must be non-sterile after the sterilization process. An example of a sterilization process is gamma radiation. Sterilization can also be achieved by applying the appropriate combinations of heat, chemicals, irradiation, and high temperature, but these methods are less preferred. In a preferential embodiment , sterilization is performed using gamma irradiation.

MD 4471 Cl 2017.10.31

By the term "packing" is meant any well known method of packing an object, such as a collagen carrier in the present invention, such as a rolled and / or compressed collagen carrier. Packaging and packaging are words used alternatively in the given context. Packaging involves a coordinated system of preparation of products for transportation, storage, logistics, sale and destination. The packaging may be confined, e.g. protecting, preserving, transporting, informing and selling an object, preferably, an object such as a collagen carrier, such as a rolled and / or tablet collagen carrier proposed in the present invention. A suitable container is used for packaging the collagen carrier, such as a rolled and / or compressed collagen carrier of the present invention.

By the term "suitable container", in an embodiment, any container that is suitable for the transport, storage (storage), logistics, sale and for the intended use of a collagen carrier, such as a rolled collagen carrier, is considered. and / or tablet of the present invention. Thus, the suitable recipient mentioned comprises and / or protects the said collagen carrier. Thus, preferably, the aforementioned collagen carrier, such as a rolled and / or compressed collagen carrier, retains substantially its properties as they were during packing. An example of a suitable container is a PET tray (polyethylene terephthalate) or polystyrene molded to fit the collagen carrier proposed in the present invention. A suitable container according to the present invention is filled with a lid, such as, e.g. a Tyvec cover. In an embodiment of the invention, the closed tray with a lid is subsequently placed inside a double aluminum foil, preferably with a dehydrating agent. In another embodiment of the invention, the double aluminum foil is labeled to indicate that the contents have been sterilized (see below). Other suitable containers are well known in this area.

In an embodiment, the testing of the packaging is conducted and documented to ensure that the packaging complies with the regulations and all final destination requirements. Production processes are controlled and validated to ensure consistent operation.

Preferably, a suitable container of the present invention is sterilized in the package. The packaging of the medical device is tightly regulated and sterility must be maintained throughout the distribution to allow immediate use by physicians. О series of tests Special packaging are well known in the art and used to measure the ability of the packaging to maintain sterility. Relevant standards include: ASTM DI585 guide to testing the integrity of spongy medical packaging, ASTM F2097 - standard guide for designing and evaluating primary flexible packaging for medical products, EN 868 packaging materials and systems for medical devices to be sterilized. General requirements and test methods, ISO 11607 - packaging for end-stage sterilized medical devices and others.

In one embodiment, the container is a foil packaging material, such as a single or double aluminum foil or a plastic wrapping material, such as a polystyrene or PET (polyethylene terephthalate) or a combination of a foil. and plastic packaging material, such as о single or double aluminum foil and a polystyrene or PET (polyethylene terephthalate).

Minimally invasive surgery (CMI) is a relatively new kind of surgical procedure that causes more shocks to the body, thus usually resulting in faster patient recovery and more pain for the patient. CMI procedures are usually more technically complicated than open surgery, and the surgeon may have to resort to open surgery, in the event of complications.

CMI procedures require specially designed surgical instruments, such as laparoscopic devices and remote manipulation of instruments with indirect observation of the surgical field through an endoscope or similar device. The given instruments are placed through small incisions or natural holes.

For example. In abdominal surgery, access to the instruments is usually performed through the so-called trocars, which are of the type of access tube. Trocars are tubes, such as rigid tubes, and preferably have a typical inner diameter of between 5 and 12 mm, e.g. 5 ... 10 mm.

In the present invention, the trocars preferably have a diameter of at most 12 mm, such as, preferably, at most 10 mm, such as at most 8 mm, such as at most 6 mm, such as not more than 4 mm, such as not more than 2 mm. In this context a trocar can also be a flexible tube. The trocar allows the introduction of tools and material, while creating visibility (using video endoscopes) and surgical manipulation.

MD 4471 Cl 2017.10.31

CMI procedures also include robotic surgery. The small hole size used in the CMI limits the types of instruments and materials that can be inserted into the holes. All surgical instruments and materials used during CMI procedures should be of such size and condition that they would be allowed to be inserted through the access holes. The tools and materials are most often specially designed for use in minimally invasive surgery.

Therefore, the term 'minimally invasive surgery' (CMI) refers to any procedure (surgical or other), which is less invasive than open surgery used for the same purpose. Multiple medical procedures are called minimally invasive, such as hypodermic injection, pressure injection, subdermal implants, endoscopy, percutaneous surgery, laparoscopic surgery, thoracoscopic surgery, arthroscopic surgery, cryosurgery, microsurgery, surgery with minimal intervention, endovoplasty surgery, such as anovascular surgery coronary artery, permanent electrodes for the spine and brain, stereotactic surgery, Nuss procedure, medical imaging methods based on radioactivity, such as the gamma camera, positron emission tomography and SPECT (single photon emission tomography). The related procedures are image guided surgery, robotic surgery and interventional radiology.

Minimally invasive procedures are performed through one or more short incisions (keyhole surgery) or through natural holes in the body. The terminology varies depending on the method of surgical access, the type of surgery, and the tools used, e.g. endoscopy, laparoscopy or thoracoscopy.

Endoscopy means internal visualization and specifically refers to the internal visualization of the body for medical purposes with the help of an endoscope, a tool used to examine the inside of a cavity or body cavity. Therefore, by the words endoscopic surgery, any surgery performed by means of endoscopy is considered, such as endoscopy involving the gastrointestinal tract (GI tract): esophagus, stomach and duodenal (esophagogastroduodenoscopy), small intestine (enteroscopy), large intestine / colon (colonoscopy, sigmoidoscopy), endoscopy with magnification of the bile duct, (retrograde endoscopic cholangiopancreatography (ERCP), cholangiopancreatic cholangiopathy anoscope, proctoscope, rectoscope with approximate lengths for, rect (rectoscopy) and anus (anoscopy), both of which are also called (proctoscopy). This subsequently includes the respiratory tract: nose (rhinoscopy), lower respiratory tract (bronchoscopy), ear (otoscope); urinary tract (cystoscopy); the female reproductive system (gynoscopy), cervix (colposcopy), uterus (hysteroscopy), and uterine fallopian tubes (faloscopy). The normally closed body cavities can be seen through a small incision: the abdominal or pelvic cavity (laparoscopy), the inside of a joint (arthroscopy), the chest organs (thoracoscopy and mediastinoscopy); during pregnancy: amnion (amnioscopy), fetus (fetoscopy). This further includes plastic surgery (or triple endoscopy) panendoscopy, which combines laryngoscopy, esophagoscopy and bronchoscopy. In addition, orthopedic surgery and arm surgery, such as endoscopic release of the wrist canal and epidural space (epiduroscopy) is also a form of endoscopy.

Laparoscopic surgery includes surgery inside the abdominal or pelvic cavity, while minimally invasive surgery performed on the thoracic or chest cavity is called thoracoscopic surgery. Laparoscopic and thoracoscopic surgery both refer to a wider area of ​​endoscopy.

Through the access orifice the entry point through which the twisted collagen carrier of the invention is passed before reaching the target locum is considered. For the embodiments of the present invention regarding the CMI procedures, the term orifice or access hole means the entry point of the surgical instruments and materials used during the CMI procedures. Therefore, such surgical instruments and materials must be of such size and be in such a state that would allow them to be inserted through the access holes. The access hole may be, e.g. a natural orifice in the body or can be, e.g. in a trocar. However, the access hole or hole is not necessarily a narrow entry point, it may also be a wide surface, such as an access hole created during the open operation, such as the open abdominal operation or the access hole / orifice. created during the open heart surgery.

By the term haemostasis is considered, e.g. a complex process, which causes a bleeding process to stop. It refers to the process of blood clotting in one

MD 4471 Cl 2017.10.31 blood vessel (the opposite of hemostasis is hemorrhage). Most of the time this includes changing the blood from a liquid state to a solid (coagulation) or e.g. by the physical sealing of the open vessels.

By the expression of the lesion is meant the damage of a biological organism, such as the lesion associated with performing CMI. Tissue injury may include conditions in which leakage occurs, eg, blood, lymph, bile, cerebrospinal fluid or air / gas, so local treatment is required to control bleeding (hemostasis) or stop exudation (tissue sealing).

By the terms "organ" or "tissue" is meant any organ or tissue in the human or animal body, whether it is isolated from the human or animal body, or alternatively in vivo, e.g. an organ or tissue that is operated on during a surgical procedure. For example, the term '' organ, as used herein, may refer, for example, to any of the organs in the following non-limiting list: - heart, blood vessels, salivary glands, esophagus, stomach, liver, gallbladder, pancreas, intestine, colon, rectum, anus, hypothalamus, pituitary gland, pituitary gland, epiphysis, pineal gland, thyroid gland, parathyroid gland, adrenal glands , ureter, bladder, urethra, lymph node, lymph vessel, tonsil, adenoid vegetation, thymus, spleen, skin, hair, nails, muscles, brain, spinal cord, nerves, ovaries, uterine tubes, uterus, vagina, mammary glands, testicles, deferential canal, seminal vesicles, prostate, penis, spleen, pharynx, larynx, trachea, bronchi, lungs, diaphragm, bones, cartilage, ligaments and tendons. The term "tissue", as used herein, may refer to e.g. in any of the following types of tissue from the following non-limiting list: - epithelial tissue, connective tissue, muscle tissue and / or nerve tissue.

By the term percentage mass / mass or "% m / m" we see m grams, the substance per grams of another substance in percent (to 100 grams). Thus, if, for example, the waste water is present in an amount of 2% m / m in a collagen carrier, this is meant to mean that 2 grams of water are present in 98 grams of collagen carrier. The total mass will be 100 grams of collagen carrier, including waste water, but the volume of 100 grams of residue may be different from 100 ml.

We note that the weight of the collagen carrier takes into account the weight of the collagen carrier, excluding the weight of the coating.

It should be noted that the embodiments and features described in the context of one of the aspects of the present invention also apply to other aspects of the invention, ie all aspects relating to a compressed and rolled collagen carrier also apply to a a collagen carrier or a rolled collagen carrier or a compressed collagen carrier, rolled and rolled or a twisted collagen carrier (because the terms twisted and rolled are used alternatively here), and similarly for aspects of the process.

One aspect of the present invention relates to a process for twisting a collagen carrier, the collagen carrier being composed of (i) a collagen layer and (ii) a coating layer that confines fibrinogen and thrombin, the aforementioned process comprising steps successive of:

• wetting, at least, part of the collagen carrier, • twisting of the collagen carrier by engaging the collagen carrier between a pair of elongated elements, and rotating the pair of elongated elements about a parallel axis with a longitudinal extension of elongated elements to twist the collagen carrier on the elements, while the collagen carrier is supported on a support device, • drying the twisted collagen carrier, thus providing a stable shaped twisted collagen carrier.

Another aspect of the present invention relates to a process for twisting a collagen carrier, the collagen carrier being composed of (i) a collagen layer and (ii) a coating layer that confines fibrinogen and thrombin, the aforementioned process comprising successive stages of:

• wetting, at least, one of the bladder of the collagen carrier, • twisting of the blunt collagen carrier, • drying the collagen carrier, thus providing a stable shaped twisted collagen carrier.

Any type of fibrinogen and / or thrombin can be used in the coating layer, preferably, the fibrinogen and / or thrombin used in the coating layer is close to solid and / or solid. It is preferred that the fibrinogen and / or thrombin be dried. Preferably, the successive stages

MD 4471 Cl 2017.10.31 mentioned are consecutive stages. In one embodiment of the present invention, the process consists of the abovementioned steps. In another embodiment, the process comprises or consists of the aforementioned steps and the subsequent packaging step, where the twisted product is hermetically sealed in a container, and sterilized. In an embodiment of the present invention, the twist is performed by gripping the collagen carrier with the aid of, at least, a gripping device. In a variant embodiment of the present invention, the twist is executed by gripping the collagen carrier with the help of, at least, a pair of pliers or tweezers.

The drying of the twisted collagen carrier can be done by any suitable drying process, such as e.g. by blowing the air with a lower humidity level than the twisted collagen carrier and optionally heating the air. Preferably, said drying lasts, at most, for 5 minutes, such as between 5 minutes. and о hours, such as between 20 and 40 minutes, such as between 25 and 35 minutes. For example, a ventilation channel may be used for the drying step.

Any surface of the collagen carrier can be moistened. Preferably, at least the coating layer of the mentioned collagen carrier is moistened. In one embodiment of the present invention, only the coating layer is moistened, in another embodiment of the invention both the upper and the lower side of the collagen carrier are moistened. In another embodiment of the present invention, the wetted surface is the collagen layer.

Preferably, the collagen layer is moistened with a solvent. Any suitable solvent can be used, such as an organic solvent or water. In an embodiment of the present invention, the solvent comprises or consists of ethanol, such as dehydrated ethanol with a maximum content of 0.1% water. In another embodiment, the solvent comprises or consists of ethanol, such as dehydrated ethanol with a maximum content of 0.1% water and water. The solvent may also comprise or consist of isopropanol. The solvent may alternatively be a mixture of at least 70% ethanol, such as dehydrated ethanol with a maximum content of 0.1% water and another solvent (such as water), such as at least 80% ethanol. , such as 90% ethanol shearwater, such as 95% shearwater ethanol. In another embodiment, the solvent may be a mixture of at least 80% isopropanol and another solvent (such as water), such as 90% or 95% isopropanol. The solvent may also comprise fibrinogen and / or thrombin and / or alpha factors. In a preferred embodiment, the ethanol may be dehydrated ethanol with a maximum content of 0.1% water.

In an embodiment of the present invention, the rolling / twisting step is performed after the coating layer has been softened.

Preferably, the coating layer of the collagen carrier is moistened with a solvent. In an embodiment of the present invention, the collagen carrier is humidified on the coating layer with a solvent in an amount between 0.1 and 25 cm.² on the surface of the coating layer, such as e.g. 1.2 ... 10.75 mg / cm² on the surface of the coating. For variants of the dimensions of a standard TachoSil®, available on the plate (such as e.g. medium size fibers), the following amounts of solvent are preferred over the coating: 30 ... 160 mg solvent (such as ethanol) per collagen carrier, such as 30 ... 100 mg solvent (such as ethanol) ) per collagen carrier, such as preferably 90 ... 100 mg solvent (such as ethanol) per collagen carrier, such as for a collagen carrier with о 25 cm coating surface², such as for Tachosil® small and medium size collagen carrier. In an embodiment of the present invention, the solvent comprises or consists of ethanol or dehydrated ethanol with a maximum content of 0.1% water.

In a variant embodiment of the process of twisting a collagen carrier, the process subsequently comprises the step of compressing the collagen carrier to reduce its thickness. For example. the collagen carrier can be compressed with a compression ratio of 2 to 18, such as e.g. 4 ... 14, such as, preferably, 6 ... 12. The compression step can be performed, in an embodiment, by passing the humidified collagen carrier through a set of rolls with о size smaller than the thickness of the collagen carrier before passing through the roll set. An example of a sliver size is 0.2 mm ... 2 mm, such as e.g. 0.4 ... 1.6 mm, such as 0.5 ... 1.0 mm, or at most 0.75 mm, such as e.g. 0.5 ... 0.75. The preferred size of the strand is 0.6 mm. The compression is preferably performed before the collagen carrier is twisted.

During the drying step m the twisting process, the twisted collagen carrier can be supported by a support device, e.g. by contacting the support device. For example. the wedge, the edge of the collagen carrier is fixed by the support device

MD 4471 Cl 2017.10.31 with respect to the collagen carrier twisted during drying, ie the collagen carrier edge is pushed to the support device. The support device can be of any suitable shape, such as e.g. U-shaped, rounded, tubular or any other shape capable of supporting and maintaining the twisted form of the collagen carrier during its drying, before the product becomes stable in the dry state. In a preferred embodiment, the support device represents a cavity in the form of a segment of a cylinder having at least one open end, and wherein the curved portion of the cylinder segment extends at least to 180 ° ( Fig. 11). In an embodiment of the present invention, the edge of the twisted collagen carrier is mounted inside the cylinder segment and the edge is bordered with the inner surface of the cylinder.

Preferably, the process of the present invention subsequently comprises the step of extracting the elongated elements from the twisted collagen carrier. For example, extraction of elongated elements is performed prior to drying the collagen carrier. Elongated elements can be о pair of pliers. So, extracting at least one pair of pliers can be done before drying the twisted collagen carrier. Preferably, the elongated elements form a clamping device.

In an embodiment of the present invention, the process also comprises the step of placing the twisted collagen carrier with a stable form in a container and then hermetically closing the container. For example, the twisted carrier may be placed in an internal container, and the internal container may be placed in an external container, which optionally comprises the step of placing a desiccator inside the external container before hermetically closing the container.

Preferably, the process of the present invention comprises the sterilization step of the twisted collagen carrier. This can be achieved, e.g. with the help of gamma radiation. The embodiment of the present invention comprises the sterilization step of the twisted collagen carrier up to a sterility assurance level (NAS) of 10 ... 6 with the help of gamma radiation.

The process of the present invention may comprise a step wherein a label with information relating to the product of the present invention, such as e.g., is placed on the outside of the outer container. regarding the level of sterilization.

In an embodiment of the present invention, the process of twisting a collagen carrier possesses the particularity that the atmosphere around the collagen carrier and the humidification device during humidification, compression and twisting is maintained at the set temperature and / or humidity. . Temperature and / or humidity can, e.g. to be between 1O ... 4O ° C and 10 ... 70% RH. Preferably, the temperature is 18 ... 22 ° C and the relative humidity is

30.. .50%.

In one embodiment, the temperature is 5 ... 30 ° C, such as 1O ... 25 ° C, such as

10 .. .30 ° C, such as 15 ... 30 ° C. In another embodiment, the relative humidity is

2 .. .60% UR, such as 10 ... 55% UR, such as 20 ... 55% UR, such as 30 ... 55% UR, such as

40 .. .55% UR. Preferably, the relative humidity is 30 ... 50% RH.

Another aspect of the present invention relates to a twisted collagen carrier which can be obtained by any of the twisting or rolling processes described herein (the terms "twisting" and rolling are used alternatively herein). For example, the present invention relates in an embodiment to a twisted collagen carrier obtained by a process of the present invention.

Another aspect of the present invention relates to a twisted collagen carrier

- comprising a collagen layer and a coating layer above the collagen layer, the coating layer containing thrombin (preferably near solid) and fibrinogen (preferably almost solid), and

- which is in the form of an elongated element with numerous coils of the collagen carrier around the longitudinal axis of the elongated element and, at least, the outer coil (s) being oriented such that the coating layer constitutes the outer surface of each outer coils mentioned above, characterized in that

- the collagen carrier is of stable shape and defines a collagen carrier in a twisted configuration, wherein said outer coil (s) extends along a spiral in the cross section of the collagen carrier.

The coils called the outer coils are preferably each coil of the twisted collagen carrier with the exception of the inner coil, which is usually "S" twisted when viewed from a transverse profile. In some embodiments, the collagen carrier

MD 4471 Cl 2017.10.31 twisted can comprise only о single outer coil and in these cases the coil called outer coil is preferably this unique outer coil.

The twisted collagen carrier comprises a collagen layer. The collagen layer can be made from any suitable collagen, such as e.g. о collagen foam or sponge, such as, for example, the TachoTop product available for sale from Nycomed. A preferred type of collagen is human collagen, such as solidified human collagen foam. The twisted collagen carrier also comprises a coating layer above the collagen layer, which comprises thrombin and fibrinogen. The thrombin is preferably almost solid or solid. The fibrinogen is preferably almost solid or solid. Preferably, both thrombin and fibrinogen are in solid form. Preferably, the coating also comprises riboflavin, which provides a yellow color and allows the physician to determine which is the active face of the collagen carrier.

In the preferred embodiments of the present invention, the shear, the outer coils or each coil of the twisted collagen carrier is oriented such that the coating layer constitutes the inner surface of each coil. In other embodiments of the present invention, each coil or, at least, the outer coils of the twisted collagen carrier is / are oriented such that the coating layer constitutes the outer surface of each mentioned coil.

In an embodiment of the present invention, the collagen carrier is preferably a о stratified construction, e.g. which consists of a collagen layer and a coating layer above the collagen layer.

The twisted collagen carrier of the present invention is of stable form. This may mean, e.g. that the twisted collagen carrier is stable in the sense that it does not crumble when it is still. In an embodiment of the present invention, the stability of the twisted collagen carrier form is reduced, when it is moistened, thereby taking into account that the product becomes more flexible (with a less stable shape). In a preferred embodiment of the present invention, the stability of the twisted collagen carrier form is substantially ensured only by the coating. At least, some stability of the shape of the twisted collagen carrier can be ensured in an embodiment of the outer coil of the carrier. In an embodiment of the present invention, the stability of the twisted collagen carrier shape is ensured by a zone on the edge of the twisted collagen carrier adhering to the underlying coil. In another embodiment, the stability of the twisted collagen carrier shape is ensured by adhesion between coils. In an embodiment of the present invention, the stability of the twisted collagen carrier shape is ensured by the twisted collagen carrier having no mechanical strain. In an embodiment of the present invention, the stability of the twisted collagen carrier shape is ensured by the predominance of mechanical stress acting to dislodge the twisted collagen carrier by adhesion between the coils. In an embodiment of the present invention, the stability of the twisted collagen carrier shape is ensured by the coil having a modulus of elasticity of 5 ... 100 N / cm².

In an embodiment of the present invention, the stability of the shape is ensured by the twisted collagen carrier which forms a fragile coil which deteriorates when subjected to pressure without significant deformation.

In a preferred embodiment of the present invention, the collagen carrier twisted in a unfolded configuration is о foil (preferably rectangular or square in shape), preferably having о width, о length and о thickness. Preferably, the aforementioned unfolded collagen carrier is a rectangular or square sheet. Preferably, the foil has a thickness of 0.5 to 10 mm, such as e.g. 0.5 ... 8 mm, e.g. 0.5 ... 6 mm. In a preferred embodiment of the present invention, said thickness is preferably 1 ... 4 mm, such as preferably 1 ... 3 mm. The thickness may, in an embodiment, be not more than 4 mm or not more than 5 mm or not more than 6 mm or not more than 7 mm. The unfolded collagen carrier preferably has a surface over its upper surface (which is preferably coated with the coating layer) of 4 ... 100 cm.², more preferably 5 ... 75 cm², such as 10 ... 50 cm², such as 20 ... 30 cm², for example. 25 cm² which may be, e.g. offered by the upper surface of a square collagen film with dimensions of 5 cmx5 cm.

In one embodiment of the present invention, the twisted collagen carrier comprises or consists of three, four or five coils.

In an embodiment of the present invention, the twisted collagen carrier has a cylindrical shape with an outer diameter of less than 12 mm, such as less than 11 mm, such as

MD 4471 Cl 2017.10.31 less than 10 mm, such as less than 9 mm, such as less than 8 mm, such as less than 7 mm, such as less than 6 mm, such as be less than 5 mm, such as less than 4 mm, such as less than 3 mm. For example, the twisted collagen carrier has an outside diameter of 1 ... 12 mm, such as e.g. 3 to 11 mm, such as e.g. 5 to 10 mm, such as, preferably, 5 to 9 mm, e.g. 6 ... 8 mm.

In an embodiment of the present invention, the twisted collagen carrier has an S-shaped inner coil about the longitudinal axis of the twisted collagen carrier. It is preferred that the coating of the coated collagen carrier layer does not have pierced cracks, such as pierced cracks visible to the naked eye.

The present invention further relates to a twisted and packaged collagen carrier, which comprises the twisted collagen carrier according to the present invention placed in a container. The container may, for example, be hermetically sealed to prevent contamination and / or degradation and / or to maintain the stability of the twisted collagen carrier shape. Preferably, the container is hermetically sealed to prevent contamination and / or absorption of liquid solvents, such as water. The container may also comprise, in an embodiment, a dehydrating agent, such as silica gel placed in the container.

The container may comprise, in an embodiment, an inner container and an outer container. Preferably, the inner container comprises a cavity in the form of a segment of a cylinder, and in which the curved part of the segment of the cylinder extends, at least, to 180 °, the cavity being sealed by a removable or fragile foil. It is preferred that the outer container comprises a hermetically sealed m inside which the hermetically sealed inner container is placed together with a dehydrating agent.

The collagen carrier twisted and packaged in accordance with the invention may also comprise a label placed for visual examination without opening the package and indicating whether the package with the collagen carrier twisted was exposed to radiation sterilization, such as X-rays, such as high energy X-rays, or gamma radiation, or electron beams!, or ultraviolet light. The label can be placed e.g. on the outside of the outer container.

The collagen carrier twisted and packaged according to the invention may also comprise о sterile plastic bag with о minimal amount of air inside, preferably no air, the bag being specially adjusted to protect the activation of the collagen carrier twisted by the organic fluids in it. the use time e.g. in operafies. This is illustrated in FIG. 10. This plastic sub bag can be used optionally after unpacking the collagen carrier twisted and packaged according to the invention.

One aspect of the invention relates to a process for preparing a rolled and compressed collagen carrier comprising the steps:

a) providing a collagen carrier having a coating comprising solid fibrinogen and solid thrombin, evenly distributed and fixed to the aforementioned collagen carrier,

b) the optional wetting, the puffer, of a parfion of the mentioned collagen carrier offering an optional humidified collagen carrier,

c) compression of the optional humidified collagen carrier offering a compressed collagen carrier,

d) rolling of the aforementioned compressed collagen carrier,

e) obtaining a compressed and rolled collagen carrier,

f) optional drying of the compressed and rolled collagen carrier from step e),

g) optional sterilization of the collagen carrier compressed and rolled in step e) or f),

h) optional packing of the compressed and rolled collagen carrier from step e), f) or g) in a suitable container, and thus obtaining a compressed and rolled collagen carrier having, at least, one of the following physical properties:

I. a diameter of maximum 10 mm,

II. о adhesive capacity of, at least, 40 mmHg, measured by means of a pressure test (TCP) after running the compressed and rolled collagen carrier mentioned, and

III. a sterility assurance level (NAS) of 10 '⁶.

The embodiment of the invention refers to a process according to the invention, wherein the steps of preparing the compressed and rolled collagen carrier comprise the steps:

a) wetting, at least, a part of the mentioned collagen carrier providing a humidified collagen carrier,

MD 4471 Cl 2017.10.31

b) compression of the humidified collagen carrier by providing a compressed collagen carrier,

c) rolling of the mentioned compressed collagen carrier offering a compressed and rolled collagen carrier,

d) drying of the aforementioned compressed and rolled collagen carrier,

e) optional sterilization of the collagen carrier compressed and rolled in step c) or d),

f) optional packaging of the compressed and rolled collagen carrier mentioned in the step

c), d) or e) in a suitable container.

The embodiment of the invention refers to a process according to the invention, wherein the steps of preparing the mentioned compressed and rolled collagen carrier comprise the steps:

a) wetting, at least, a part of the mentioned collagen carrier providing a humidified collagen carrier,

b) compression of the humidified collagen carrier by providing a compressed collagen carrier,

c) rolling of the mentioned compressed collagen carrier offering a compressed and rolled collagen carrier,

d) drying of the aforementioned compressed and rolled collagen carrier,

e) sterilization of the compressed and rolled collagen carrier mentioned in step c) or d),

f) optional packaging of the compressed and rolled collagen carrier mentioned in the step

c), d) or e) in a suitable container.

The embodiment of the invention refers to a process according to the invention, wherein the steps of preparing the mentioned compressed and rolled collagen carrier comprise the steps:

a) wetting, at least, a part of the mentioned collagen carrier providing a wetted collagen carrier,

b) compression of the aforementioned wetted collagen carrier providing a compressed collagen carrier,

c) rolling of the mentioned compressed collagen carrier offering a compressed and rolled collagen carrier,

d) drying of the aforementioned compressed and rolled collagen carrier,

e) sterilization of the compressed and rolled collagen carrier,

f) packing the compressed and rolled collagen carrier mentioned in a suitable container.

The embodiment of the invention relates to a process according to the invention, in which the mentioned collagen carrier and compressed carrier has an adhesive capacity of at least 50 mmHg measured by a pressure test (TCP) after the collagen carrier is deployed and run mentioned.

The embodiment of the invention relates to a process according to the invention, wherein the mentioned collagen carrier and compressed carrier have an adhesive capacity of at least 60 mmHg measured by a pressure test (TCP) after the compressed collagen carrier is run and mentioned mentioned.

The embodiment of the invention relates to a process according to the invention, in which ethanol is used to moisten, at least, a part of the mentioned collagen carrier.

The embodiment of the invention relates to a process according to the invention, wherein said ethanol is applied in an amount of about 0.8 ... 10.4 mg / cm² on the collagen carrier.

The embodiment of the invention relates to a process according to the invention, wherein said ethanol is applied in an amount of about 0.8 ... 6.1 mg / cm² on the collagen carrier.

The embodiment of the invention relates to a process according to the invention, in which the mentioned ethanol is applied in an amount of about 1.2 ... 4.7 mg / cm.² on the collagen carrier.

The embodiment of the invention refers to a process according to the invention, in which the mentioned ethanol is applied to, at least, the face of the mentioned collagen carrier comprising the mentioned coating, e.g. Mentioned ethanol is applied to the puffer о face of the phage collagen carrier, wherein the puffer mentioned puffer comprises a coating.

The embodiment of the invention relates to a process according to the invention, in which the mentioned ethanol is applied to, at least, the face of the mentioned collagen carrier which does not comprise the mentioned coating.

MD 4471 Cl 2017.10.31

The embodiment of the invention relates to a process according to the invention, wherein said ethanol is applied to at least two opposing faces of said collagen carrier, wherein, at least one of said faces comprises said coating.

The embodiment of the invention relates to a process according to the invention, wherein said shell is oriented outwardly on said compressed and rolled collagen carrier.

The embodiment of the invention relates to a process according to the invention, wherein said coating is inwardly oriented on said compressed and rolled collagen carrier.

The embodiment of the invention relates to a process according to the invention, wherein said compression is performed by means of a cylindrical roll with a о size of spacing of not more than 0.75 mm and in which the diameter of the rollers is about 10 ... 100 mm.

The embodiment of the invention relates to a process according to the invention, wherein said sterilization is performed by means of gamma radiation.

The embodiment of the invention relates to a process according to the invention, wherein said collagen carriers are processed at 3 ... 35 ° C and 5 ... 80% RU (relative humidity).

The embodiment of the invention relates to a process according to the invention, wherein said collagen carriers are processed at 18 ... 22 ° C and 36 ... 65% RU (relative humidity).

The embodiment of the invention relates to a process according to the invention, wherein said drying means that said compressed and rolled collagen carrier comprises at most 2.0% m / m ethanol (residual).

The embodiment of the invention relates to a process according to the invention, wherein said drying results in the said compressed and rolled collagen carrier comprising at most 1.6% m / m ethanol (residual).

The embodiment of the invention relates to a process according to the invention, wherein said drying means that said compressed and rolled collagen carrier comprises at most 10.0% m / m water (residual).

The embodiment of the invention relates to a process according to the invention, wherein said drying means that said compressed and rolled collagen carrier comprises at most 8.0% m / m water (residual).

The embodiment of the invention relates to a process according to the invention, wherein said coating comprises solid human fibrinogen in an amount of about 5.5 mg / cm² and solid human thrombin in an amount of about 2.0 IU / cm².

The embodiment of the invention relates to a process according to the invention, wherein said compressed and rolled collagen carrier registers о loss of the coating immediately after rolling of less than 0.6 mg / cm.² measured by weighing.

The embodiment of the invention relates to a process according to the invention, wherein said compressed and rolled collagen carrier is at least partially mechanically processed, thus providing a compressed and rolled collagen carrier, at least partially mechanical, such as a collagen carrier mechanically rolled and rolled.

The embodiment of the invention relates to a process according to the invention, wherein said collagen carrier has a density of 3.0 to 4.5 mg / cm.³. The density of a collagen carrier of the present invention is the density of the collagen carrier excluding the coating.

One aspect of the invention relates to a process for preparing a compressed collagen carrier comprising the steps:

a. providing a collagen carrier having a coating comprising solid fibrinogen and solid thrombin, evenly distributed and fixed to said collagen carrier,

b. Optional wetting, at least, of a part of said collagen carrier providing an optionally wetted collagen carrier,

c. compression of the humidified collagen carrier optionally providing a compressed collagen carrier,

d. optional drying of the compressed collagen carrier mentioned in step c),

e. Optional sterilization of the compressed collagen carrier mentioned in step c) or

d)

f. packing the compressed collagen carrier mentioned in step c), d) or e) in a suitable container,

MD 4471 Cl 2017.10.31 and such obtaining of a compressed collagen carrier having, at least, one of the following physical properties:

I. о thickness not exceeding 4 mm,

II. о adhesive capacity of at least 40 mmHg, measured using a pressure test (TCP),

III. a level of sterility assurance (NAS) of IO '⁶.

The embodiment of the invention relates to a process according to the invention, wherein the aforementioned compressed collagen carrier has an adhesive capacity of at least 50 mmHg measured by means of a pressure test (TCP).

The embodiment of the invention relates to a process according to the invention, wherein the aforementioned compressed collagen carrier has an adhesive capacity of at least 60 mmHg measured by means of a pressure test (TCP).

The embodiment of the invention relates to a process according to the invention, wherein the mentioned collagen carrier has a density of 3.0 to 4.5 mg / cm.³. The density of a collagen carrier of the present invention is the density of the collagen carrier excluding the coating.

One aspect of the invention relates to a process for preparing a rolled collagen carrier comprising the steps:

a. providing a collagen carrier having a coating comprising solid fibrinogen and solid thrombin, evenly distributed and attached to the mentioned collagen carrier,

b. Optional wetting, the puffer, of a parfion of the mentioned collagen carrier offering an optionally wetted collagen carrier,

c. rolling of said collagen carrier providing a rolled collagen carrier,

d. optional drying of the rolled collagen carrier from step c),

e. Optional sterilization of the collagen carrier rolled in step c) or d),

f. optional packaging of the rolled collagen carrier of step c), d) or e) in a suitable container, and thus obtaining a rolled collagen carrier having, at least, one of the following physical properties:

I. a diameter not exceeding 10 mm,

II. о adhesive capacity of, at least, 40 mmHg measured by means of a pressure test (TCP) after running the mentioned collagen carrier, and

III. a level of sterility assurance (NAS) of IO '⁶.

The embodiment of the invention relates to a process according to the invention, wherein the mentioned rolled collagen carrier has an adhesive capacity of at least 50 mmHg measured by means of a pressure test (TCP) after the mentioned collagen carrier is run.

The embodiment of the invention relates to a process according to the invention, in which the mentioned rolled collagen carrier has an adhesive capacity of at least 60 mmHg measured by means of a pressure test (TCP) after the collagen carrier has been run.

The embodiment of the invention relates to a process according to the invention, in which the mentioned rolled collagen carrier registers о loss of the coating immediately after rolling of less than 0.6 mg / cm.² measured by weighing.

The embodiment of the invention refers to a process according to the invention, in which the collagen carrier has, at least, one of the following physical properties: the elasticity mode ranging from 5 to 100 N / cm², the density of 1 ... 10 mg / cm³, the diameter of the chamber over 0,75 mm and less than 4 mm and / or having an average о of the diameter of the chamber below 3 mm and evenly distributed and fixed on the mentioned collagen carrier:

a) solid fibrinogen

b) solid thrombin.

The embodiment of the invention relates to a process according to the invention, wherein the mentioned collagen carrier has a density of 3.0 to 4.5 mg / cm.³.

The density of a collagen carrier of the present invention represents the density of the collagen carrier excluding the coating.

One aspect of the invention relates to a process for developing a compressed and rolled collagen carrier comprising the steps:

a) providing a compressed and rolled collagen carrier, prepared according to the process of the invention,

b) unpacking the compressed and rolled collagen carrier mentioned from the appropriate container mentioned,

MD 4471 Cl 2017.10.31

c) passage of the compressed and rolled collagen carrier mentioned through an access hole, such as a trocar,

d) unfolding of the compressed and rolled collagen carrier mentioned after exiting said access hole,

e) Obtaining a compressed, rolled and rolled collagen carrier having an adhesive capacity of, at least, 40 mmHg, measured using a pressure test (TCP), and a sterility assurance level (NAS) of IO '⁶.

The embodiment of the invention relates to a process according to the invention, in which the compressed and rolled collagen carrier mentioned has a loss of the coating immediately after rolling of less than 0.6 mg / cm.² measured by weighing.

The embodiment of the invention relates to a process according to the invention, in which the mentioned compressed and rolled collagen carrier has an adhesive capacity of at least 50 mmHg measured by means of a pressure test (TCP) after running.

The embodiment of the invention relates to a process according to the invention, in which the mentioned compressed and rolled collagen carrier has an adhesive capacity of at least 60 mmHg measured by means of a pressure test (TCP) after running.

One aspect of the invention relates to a process for developing a rolled collagen carrier comprising the steps:

a) offering a rolled collagen carrier, prepared according to the invention process,

b) unpacking the rolled collagen carrier mentioned from the appropriate container mentioned,

c) passage of the rolled collagen carrier mentioned through an access hole, such as a trocar,

d) unfolding of the rolled collagen carrier mentioned after exiting said access hole,

e) Obtaining of a rolled and rolled collagen carrier having an adhesive capacity of at least 40 mmHg, measured using a pressure test (TCP) and a sterility assurance level (NAS) of 10 '⁶.

A process according to the invention, in which the mentioned rolled collagen carrier registers о loss of the coating immediately after rolling of less than 0.6 mg / cm² measured by weighing.

The embodiment of the invention relates to a process according to the invention, wherein the mentioned rolled collagen carrier has an adhesive capacity of, at least, 50 mmHg measured by means of a pressure test (TCP) after running.

The embodiment of the invention relates to a process according to the invention, wherein the mentioned rolled collagen carrier has an adhesive capacity of, at least, 60 mmHg measured by means of a pressure test (TCP) after running.

Another aspect of the invention relates to a compressed and rolled collagen carrier, prepared according to the process of the invention, the blistered compressed and rolled collagen carrier having a coating comprising solid fibrinogen and solid thrombin, which is uniformly distributed and fixed to the blunt collagen carrier. , and having, at least, one of the following physical properties:

I. a diameter not exceeding 10 mm,

II. о adhesive capacity of, at least, 40 mmHg, as measured by a pressure test (TCP),

III. a level of sterility assurance (NAS) of IO '⁶.

The embodiment of the invention relates to a collagen carrier compressed and rolled according to the invention, wherein the mentioned coating comprises solid human fibrinogen in an amount of about 5.5 mg / cm.² and solid human thrombin in an amount of about 2.0 IU / cm².

The embodiment of the invention relates to a collagen carrier compressed and rolled according to the invention, wherein said collagen carrier has a diameter of up to 8 mm.

The embodiment of the invention relates to a collagen carrier compressed and rolled according to the invention, in which the aforementioned shell is oriented outward.

The embodiment of the invention refers to a collagen carrier compressed and rolled according to the invention, in which said sheath is oriented inward.

The embodiment of the invention relates to a collagen carrier compressed and rolled according to the invention, wherein said drying results in the mentioned collagen carrier comprising at most 2.0% m / m ethanol (residual).

The embodiment of the invention relates to a collagen carrier compressed and rolled according to the invention comprising at most 1.6% m / m ethanol (residual).

MD 4471 Cl 2017.10.31

The embodiment of the invention relates to a collagen carrier compressed and rolled according to the invention comprising not more than 8.0% m / m water (residual).

The embodiment of the invention relates to a collagen carrier compressed and rolled according to the invention comprising at most 5.0% m / m water (residual).

The embodiment of the invention relates to a compressed and rolled collagen carrier according to the invention, in which the mentioned collagen carrier is irradiated by means of gamma radiation.

The embodiment of the invention relates to a compressed and rolled collagen carrier according to the invention, wherein the mentioned collagen carrier has an adhesive capacity of at least 50 mmHg measured by means of a pressure test (TCP) after the carrier has been run. menfionate collagen.

The embodiment of the invention relates to a collagen carrier compressed and rolled according to the invention, wherein the mentioned collagen carrier has an adhesive capacity of at least 60 mmHg measured by means of a pressure test (TCP) after the collagen carrier has been deployed. .

The embodiment of the invention relates to a product according to the invention, in which the mentioned collagen carrier and rolled carrier is, the puffer, mechanically processed parfial, thus providing a compressed and rolled collagen carrier, the puffer, mechanically perfused. be a collagen carrier and mechanically rolled.

One aspect of the invention relates to a compressed and rolled collagen carrier, which can be obtained by a process comprising the steps:

a. providing a collagen carrier having a coating comprising solid fibrinogen and solid thrombin, evenly distributed and attached to the mentioned collagen carrier,

b. Optional wetting of at least part of the mentioned collagen carrier by providing an optional humidified collagen carrier,

c. compression of the optional humidified collagen carrier by providing a compressed collagen carrier,

d. rolling of the aforementioned compressed collagen carrier,

e. Obtaining a compressed and rolled collagen carrier,

f. optional drying of the compressed and rolled collagen carrier from step e),

g. Optional sterilization of the compressed and rolled collagen carrier from step e) or f),

h. Optional packing of the compressed and rolled collagen carrier of step e), f) or g) in a suitable container, and thus obtaining a compressed and rolled collagen carrier having, at least, one of the following physical properties:

I. a diameter not exceeding 10 mm,

II. о adhesive capacity of, at least, 40 mmHg, measured using a pressure test (TCP) after the mentioned collagen carrier,

III. a level of sterility assurance (NAS) of IO '⁶.

The embodiment of the invention relates to a compressed and rolled collagen carrier, which can be obtained by a process according to the invention, in which the mentioned compressed and rolled collagen carrier is, at best, mechanically machined, thus providing a carrier. of compressed and rolled collagen, the puffer, mechanical perfusion, such as a mechanically rolled and compressed collagen carrier.

One aspect of the invention relates to a collagen carrier compressed, rolled and rolled according to the invention which has, at least, one of the following physical properties:

I. о thickness not exceeding 4 mm,

II. о adhesive capacity of at least 40 mmHg, measured using a pressure test (TCP),

III. a level of sterility assurance (NAS) of IO '⁶,

IV. the aforementioned compressed and rolled collagen carrier can adhere to the cleft as it is rolled without being twisted back.

The embodiment of the invention relates to a compressed, rolled and rolled collagen carrier according to the invention, wherein the mentioned compressed, rolled and rolled collagen carrier is, at most, mechanically machined, thus providing a compressed and rolled collagen carrier. , the puffer, mechanical and unfolded, such as a mechanically rolled and rolled collagen carrier.

One aspect of the invention relates to a collagen carrier, rolled and rolled according to the invention, having a coating comprising solid fibrinogen and solid thrombin, which is

MD 4471 Cl 2017.10.31 evenly distributed and fixed on the mentioned collagen carrier, and having, at least, one of the following physical properties:

I. о thickness not exceeding 4 mm,

II. о adhesive capacity of at least 40 mmHg, measured using the TCP camera,

III. a level of sterility assurance (NAS) of IO '⁶,

IV. the aforementioned compressed and rolled collagen carrier can adhere to the cleft while being rolled without being twisted back.

The embodiment of the invention relates to a compressed, rolled and rolled collagen carrier according to the invention, wherein said compressed, rolled and rolled collagen carrier is or has been, at least, mechanically processed, thus providing a collagen carrier. compressed and rolled, the sheared one, mechanically and unfurled, such as a mechanically rolled and rolled collagen carrier.

One aspect of the invention relates to a compressed collagen carrier according to the invention, having a coating comprising solid fibrinogen and solid thrombin, which is uniformly distributed and fixed to the mentioned collagen carrier, and having, at least, one of the following physical properties:

I. о thickness not exceeding 4 mm,

II. о adhesive capacity of at least 40 mmHg, measured using a pressure test (TCP),

III. a sterility assurance level (NAS) of 10 '⁶.

The embodiment of the invention relates to a compressed collagen carrier according to the invention, wherein the mentioned compressed collagen carrier is the mechanically processed parfial shear, thus providing a compressed collagen carrier to the mechanical perfused shear, such as a collagen carrier. mechanical tablet.

Another aspect of the invention relates to a collagen carrier rolled according to the invention, having a coating comprising solid fibrinogen and solid thrombin, which is uniformly distributed and fixed to the mentioned collagen carrier, and having, at least, one of the following physical properties. :

I. a diameter not exceeding 10 mm,

II. о adhesive capacity of at least 40 mmHg, measured by means of a pressure test (TCP) after the mentioned collagen carrier,

III. a sterility assurance level (NAS) of 10 '⁶.

The embodiment of the invention relates to a collagen carrier rolled according to the invention, wherein the mentioned collagen carrier is the mechanically processed partial shear, thus providing a mechanically sheared collagen carrier, such as a collagen carrier. mechanically rolled.

Delivery of the rolled / twisted collagen carrier according to the present invention to the target locum

One aspect of the present invention relates to a process for delivering the twisted collagen carrier according to the present invention to the target location. The aforementioned process comprises the step of passing the twisted collagen carrier mentioned through an orifice or access tube to the borehole. Any suitable instrument or device, or even the doctor's hand, can be used to pass the collagen carrier twisted through the access hole or tube. Suitable tools can be e.g. one or more: surgical scissors, pliers, tweezers, dissectors or retractors.

In an embodiment of the present invention, an access tube is used, and it is preferably dry (ie it does not contain moisture). The aforementioned access tube is preferably a surgical trocar, such as a disposable trocar. The target locus preferably refers to any locus to which it is desired to bind and / or adhere the twisted collagen carrier of the present invention. In one embodiment, the fine locafia is a synthetic surgical model for demonstration / training purposes. In the other embodiment, the target locafia may be an organ or cleft. In one embodiment of the present invention, the fin locafia is an organ or liver that has been isolated from a human or animal creature, such as a pore. In a further embodiment of the present invention, said target locust is in vivo in a human or animal being, such as e.g. an organ (eg selected from the group consisting of: lungs, kidneys, liver, blood vessel) or e.g. any, but not limited to the organs listed above in the present invention, the section of the definition.

After delivery to the target box, the twisted collagen carrier can be kept in a twisted state and not rolled. This can be advantageous, for example, when applying the collagen carrier twisted inside, e.g. a cavity or hole in an organ or cleft, such as linen

MD 4471 Cl 2017.10.31 pulmonary surgery, as e.g. is illustrated in FIG. In another embodiment of the present invention, the process of delivering the twisted collagen carrier also comprises the step of the twisted collagen carrier rolling before or during application at the target location. This step can be e.g. carried out by joining and maintaining the edge of the twisted collagen carrier on the target location, as, for example, illustrated in Figure 8. In another embodiment of the present invention, the twisted collagen carrier is unwound before coming into contact. with the target location, such as e.g. is illustrated in FIG. 10. In another embodiment of the present invention, the twisted collagen carrier is packaged in a sterile plastic bag with a minimum amount of indoor air specifically adjusted to protect the activation of the twisted collagen carrier by organic fluids when is used e.g. in surgery. This is also illustrated in FIG. 10, although the plastic bag shown is large compared to the bags preferably used. The sterile plastic bag preferably used with a minimum amount of air inside can be optionally used after unpacking the wrapped collagen carrier according to the invention, but before passing the collagen carrier twisted through the hole or access tube.

One or more guide devices suitable for guiding the collapse of the twisted collagen carrier, such as any suitable standard surgical instrument, such as any suitable endoscopic instrument, may be used. In another embodiment, a specific cutting device may be used, which may be suitable e.g. for catching the collagen carrier twisted on one end and unfolding it at another end. In a preferred embodiment, the twisted collagen carrier is gripped by one end with a guide device (such as a pair of clamps or a clamp) and another guide device (such as a pair of clamps). ) is used to carefully roll the collagen carrier to the target location.

In an embodiment of the present invention, the collagen carrier is positioned on the target site with at least one pair of pliers. Optionally, another guiding device is used to guide the process of rolling, such as with the aid of a second tool, such as a pair of pliers.

In an embodiment of the present invention, the twisted collagen carrier is used in open surgery. For applications in open surgeries, the twisted carrier may be, e.g. deboned with the help of, for example, the doctor's hands or any standard surgical instrument, such as one or more: surgical scissors, pliers, tweezers, dissectors or retractors.

During the process of unwinding / shredding a coated collagen carrier, the guiding device, surgical instrument, or physician's hand (s) should preferably only touch the uncoated portion of the collagen carrier to prevent damage to the coated portion. During and after the process at the target location, the surgeon may choose to further moisten the collagen carrier, e.g., with the help of saline, and / or apply pressure to the collagen carrier, e.g., with the help of the physician's hand. or to a pad or napkin, such as a damp pad or napkin, optionally applied with the help of, for example, a pliers. Also, the optional wetting of the collagen carrier can be applied using a rinsing / absorption / spraying system. In one embodiment, several wet pads or wipes are applied (eg applied with more than one pliers), such as two pads or wet wipes applied with two sets of pliers, as, e.g. , is illustrated in FIG. 9. If pressure is applied to the collagen carrier after application to the target location, then e.g. this may take between 30 s and 6 min., such as e.g. for 1 to 5 min., such as e.g. for 3 to 5 minutes, or 2 to 3 minutes, or for 2 minutes, or 3 minutes. Numerous humidification and compression cycles can be applied to the collagen carrier. If the bleeding is not completely stopped by applying a collagen carrier, additional collagen carriers, for example 1 or 2 additional collagen carriers, may be applied.

Preferably, if a coated collagen carrier (such as TachoSil®) is used in the rolling process, the collagen carrier is rolled with the coated portion of the collagen carrier oriented to the target location.

After delivery to the target segment, the collagen carrier will preferably adhere to the target segment and cause the haemostasis to occur on and around the target segment. Any pads or wipes used are preferably carefully removed, optionally while the collagen carrier is held in place by means of a suitable surgical instrument, such as a о tweezers or pliers.

MD 4471 Cl 2017.10.31

In a preferred embodiment of the unfolding procedure, all objects that come into contact with the twisted collagen carrier before the collagen carrier comes into contact with the target location (eg surgical gloves, surgical instruments and access tube or orifice) ) are dry and do not contain moisture or fluids. It is also preferred that the collagen carrier remains dry until applied to the fine surface. This can, for example, be achieved either by the very accurate and careful handling of the collagen carrier or by keeping the collagen carrier inside a plastic bag until delivery to the target location. Thus, in an embodiment of the present invention, the twisted collagen carrier is delivered to the target compartment in a sterile plastic bag with о minimal amount of indoor air. The twisted collagen carrier may be prepackaged in a sterile plastic bag with a minimum amount of air inside the product package, or alternatively the collagen carrier may be inserted into the sterile bag after removal from the product package. The plastic bag can be removed after the collagen carrier reaches the target box.

The sterile plastic bag with о the minimum amount of air inside can be used to apply pressure on the collagen carrier after application to the segment. This plastic bag may be optional as part of the initial packaging of the product, that is, in an embodiment of the present invention, the twisted collagen carrier is prepackaged in a sterile plastic bag with a minimum amount of air inside.

In an embodiment of the roll-out / delivery method described herein, the collagen carrier roll has an outer diameter of at most 12 mm and wherein the orifice or access tube (such as a trocar) has a diameter of at most 12 mm. The delivery / delivery method may also comprise the step of unpacking the twisted collagen carrier from the container. This, for example, can be done with the aid of an unpacking device and / or with the hands in gloves.

In particular, the rolled / twisted collagen carrier of the present invention is intended for use in m-therapy and / or in a method of surgery, such as, for example, practiced on the human or animal body. The terms surgery and '' method of surgery '' are alternatively used here. Thus, an embodiment of the present invention relates to the twisted collagen carrier according to the present invention for use in therapy. Another embodiment of the present invention relates to the twisted collagen carrier according to the present invention for use in surgery.

For this therapy and / or surgery method, it is preferred to use at least some (or all) of the characteristics of one or more methods of delivery of the collagen carrier twisted to the target locus as described in the present invention.

A variant of using the twisted collagen carrier of the present invention for use in therapy and / or in a surgical method is a method of stopping the bleeding associated with performing minimally invasive surgery with the help of the twisted collagen carrier according to the present invention. Another embodiment is the method of treating the lesions associated with performing minimally invasive surgery with the help of the twisted collagen carrier according to the present invention. Another embodiment is a method of treating lesions associated with performing endoscopic treatment, laparoscopic treatment, or thoracoscopic treatment using the twisted collagen carrier according to the present invention. Another embodiment is the method of treating and / or preventing the injuries associated with performing endoscopic surgery with the help of the collagen carrier twisted according to the present invention. Another embodiment is a method of treating or preventing haemorrhage in human or animal feces or in a liver sample that requires hemostasis with the help of the twisted collagen carrier according to the present invention. Another embodiment is a method of treating human or animal tissue or a tissue sample that requires sealing and / or adhesion with the help of the collagen carrier twisted according to the present invention. Another alternative embodiment is the use of the twisted collagen carrier according to the present invention in surgery with minimal intervention. Another embodiment is the use of the twisted collagen carrier according to the present invention in open surgery, wherein the twisted collagen carrier can either be applied and left deboned in vivo, or where the collagen carrier is shredded (e.g. with the help of two or more sets of ordinary surgical pliers). Another embodiment is a method of treating human or animal tissue or a tissue sample that requires coverage to prevent the development of post-surgical tissue adhesions. Another embodiment is the use of the twisted collagen carrier according to the present invention in endoscopy, laparoscopy, or thoracoscopy.

MD 4471 Cl 2017.10.31

Examples of suitable surgical procedures include, but are not limited to: colon resection, kidney cryotherapy, partial nephrectomy, pulmonary surgery, video-assisted thoracoscopic surgery, liver resection surgery, hypodermic injection, air pressure injection, subdermal implants, endoscopy, percutaneous surgery, laparoscopic surgery, thoracoscopic surgery, thoracoscopic surgery , microsurgery, surgery with minimal intervention, endovascular surgery (such as angioplasty), coronary catheterization, permanent electrodes for spinal cord and brain, stereotactic surgery, Nuss procedures, medical imaging methods based on radiation, such as camera range, positron emission tomography and SPECT (single photon emission tomography), image guided surgery, robotic surgery, radiology interventional, esophagogastroduodenoscopy, enteroscopy, colonoscopy, sigmoidoscopy, magnification endoscopy, bile duct, retrograde endoscopic cholangiopancreatography (ERCP), colangiopancreatoscopia assisted duodenoscop, colangioscopia intraoperative Rectoscopy, proctoscope, rhinoscopy, brohoscopie, otoscopy, cystoscopy, ginoscopie, colposcopy, hysteroscopy, falloposcopie, laparoscopy, arthroscopy, thoracoscopy, mediastinoscopy, amnioscopie, fetoscopic, panendoscopia plastic surgery, laryngoscopy, esophagoscopy, bronchoscopy, orthopedic surgery, arm surgery (such as endoscopic release of the joint canal and epidural space (epiduroscopy).

Preferably, the rolled / twisted collagen carrier of the present invention is intended for use as a substitution therapy in surgical procedures or as an adjuvant prophylactic therapy in surgical procedures. The rolled / twisted collagen carrier of the present invention can also be used as a hemostasis adjuvant for use in surgery (such as e.g. cardiovascular surgery), such as when bleeding control by standard surgical techniques (such as suturing, ligation, or cauterization) is inefficient or impractical. For example, the twisted collagen carrier can be used to improve hemostasis and / or accelerate tissue healing, and / or to treat sutures (such as vascular surgery).

Another aspect of the invention relates to a collagen carrier compressed and rolled according to the invention for use in sealing the tissues, adhesion of the tissues and haemostasis.

One aspect of the invention relates to a collagen carrier compressed and rolled according to the invention for use in minimally invasive surgery.

One aspect of the invention relates to a collagen carrier compressed and rolled according to the invention for use in endoscopic surgery.

The embodiment of the invention is to provide a collagen carrier compressed and rolled to the mechanical perfusion shear according to the invention for use in sealing the tissues, adhesion of the tissues and haemostasis.

The embodiment of the invention is to provide a collagen carrier compressed and rolled to the mechanical perfusion shear according to the invention for use in minimally invasive surgery.

The embodiment of the invention is to provide a collagen carrier compressed and rolled to the mechanical perfusion shear according to the invention for use in endoscopic surgery.

One aspect of the invention is to provide a compressed, rolled and rolled collagen carrier according to the invention for use in sealing the tissues, adhesion of the tissues and haemostasis.

One aspect of the invention is to provide a collagen carrier, rolled and rolled according to the invention for use in minimally invasive surgery.

One aspect of the invention is to provide a collagen carrier, rolled and rolled according to the invention for use in endoscopic surgery.

The embodiment of the invention is to provide a compressed and rolled collagen carrier, the puffer, mechanical and unfolded according to the invention for use in sealing the tissues, adhesion of the tissues and hemostasis.

The embodiment of the invention is to provide a collagen carrier which is compressed and rolled, the puffer, mechanically perfused and according to the invention for use in minimally invasive surgery.

The embodiment of the invention is to provide a collagen carrier which is compressed and rolled, the sheared, mechanically perfused and according to the invention for use in endoscopic surgery.

The embodiment of the invention refers to a method of prevention or treatment of the liver that requires sealing and / or adhesion, the method including applying a compressed and rolled collagen carrier according to the invention to the mentioned liver.

MD 4471 Cl 2017.10.31

The embodiment of the invention relates to a method of preventing or treating bleeding in the liver that requires hemostasis, the method including applying a compressed and rolled collagen carrier according to the invention to the mentioned liver.

The embodiment of the invention refers to a method of preventing or treating lesions associated with performing minimally invasive surgery, the method including applying a collagen carrier compressed and rolled according to the invention to said lesions.

The embodiment of the invention relates to a method of preventing or treating injuries associated with performing endoscopic treatment, laparoscopic treatment, or thoracoscopic treatment, the method including applying a collagen carrier compressed and rolled according to the invention to said lesions.

The embodiment of the invention relates to the use of a compressed and rolled collagen carrier according to the invention for the preparation of a medicament for the prevention or treatment of the liver which requires sealing and / or adhesion.

The embodiment of the invention relates to the use of a compressed and rolled collagen carrier according to the invention for the preparation of a medicament for the prevention or treatment of bleeding in the liver requiring hemostasis.

The embodiment of the invention refers to the use of a compressed and rolled collagen carrier according to the invention for the preparation of a medicament for the prevention or treatment of lesions associated with performing minimally invasive surgery.

The embodiment of the invention refers to the use of a compressed and rolled collagen carrier according to the invention for the preparation of a medicament for the prevention or treatment of lesions associated with performing endoscopic, laparoscopic or thoracoscopic treatment.

Another aspect of the invention relates to a collagen carrier compressed and rolled in accordance with the invention for use in the prevention or treatment of tissue requiring sealing and / or adhesion.

One aspect of the invention relates to a collagen carrier compressed and rolled according to the invention for use in the prevention or treatment of bleeding in the liver requiring hemostasis.

Another aspect of the invention relates to a collagen carrier compressed and rolled according to the invention for use in the prevention or treatment of lesions associated with performing minimally invasive surgery.

Another aspect of the invention relates to a collagen carrier compressed and rolled according to the invention for use in the prevention or treatment of lesions associated with performing endoscopic treatment, laparoscopic treatment or thoracoscopic treatment.

Another embodiment of the invention relates to a twisted collagen carrier according to the invention for use in the prevention or treatment of haemorrhage in human or animal feces or in a liver sample that requires hemostasis.

Another embodiment of the invention relates to a twisted collagen carrier according to the invention for use in the prevention or treatment of lesions associated with performing minimally invasive surgery.

Another embodiment of the invention relates to a twisted collagen carrier according to the invention for use in the prevention or treatment of injuries associated with performing endoscopic, laparoscopic or thoracoscopic treatment.

Another embodiment of the invention relates to a twisted collagen carrier according to the invention for use in the prevention or treatment of injuries associated with performing endoscopic surgery.

Another embodiment of the invention relates to a twisted collagen carrier according to the invention for use in the prevention or treatment of post-surgical tissue adhesions.

Another embodiment of the invention relates to a twisted collagen carrier according to the invention for use in the prevention or treatment of post-surgical tissue adhesions in human or animal tissue or in a tissue sample requiring coverage.

Another embodiment of the invention relates to a twisted collagen carrier according to the invention for use in the prevention or treatment of yeast or a yeast sample that needs to be sealed and / or bonded.

It is necessary to mention that the embodiments and characteristics described in the context of one of the aspects of the present invention also apply to other aspects of the invention, that is, all aspects relating to a compressed and rolled collagen carrier.

MD 4471 Cl 2017.10.31 also applies to a compressed collagen carrier or a rolled collagen carrier or a compressed, rolled and rolled collagen carrier.

All references to patents and non-patents mentioned in the present application, are hereby incorporated by reference in their entirety.

The invention will be further described in the following non-limiting examples.

Device

Reference is made to FIG. 11, in which the preferential embodiment of a device (10) for providing a twisted collagen carrier is shown schematically. The apparatus comprises numerous elements as shown in the figure and comprises, in particular, a device for applying humidity (2) on a collagen carrier (3) before twisting a collagen carrier as described herein.

The device for applying humidity (2) comprises a spray nozzle (4) oriented towards the surface of the coating layer of the collagen carrier, the spray nozzle (4) provides drops in the form of solvent spray. Thus, the collagen carrier is oriented with its coating surface upwards towards the spray nozzle (4). The solvent enters the collagen carrier (3) and softens it. It has been found that it may be sufficient to wet only the top layer or the upper layer thereof, although it may be preferable to impregnate the entire collagen carrier (3), ie to impregnate both the coating layer and the collagen layer. .

The apparatus (10) also comprises a twisting device (5), which is adapted to catch the wet collagen carrier (3) along one edge and to turn it into a twisted collagen carrier (1). . The twisting device (5) comprises rotary fastening means (6) for engaging the collagen carrier along a margin (7) of the collagen carrier (3) and twisting the collagen carrier (3) by rotating the fastening means (6). ) around an axis parallel to the longitudinal extension of the fastening means (6).

Clamping along the edge (7) and rotating the clamping means (6) may not provide the twist or a twisted collagen carrier (1) of the desired shape, unless the collagen carrier is supported during the twist. To ensure the twist and help determine the shape of the twisted collagen carrier (1), the twist device (5) also comprises a support device (8) that supports the collagen carrier during the twist. The support device (8) is, typically, a cavity located in relation to the fastening means (6), so that the surface of the support device (8) acts as a means against the pressure, with which it is bounded, at least, by the part. of the collagen carrier (3), the puffin, or part of the inner surface of the cavity during twisting. As mentioned, the shape of the surface of the support device helps, at best, to determine the shape of the twisted collagen carrier (1).

The clamping device (6) comprises a pair of elongated members (9), such as a pair of pliers or tweezers. The elongated elements (9) have a longitudinal extension that matches the collagen carrier width (1) - the collagen carrier width is considered to be parallel to the extension of the elongated elements (9) - so the collagen carrier is trapped by the edge along the entire tear by elongate elements (9).

The collagen carrier (3) is gripped by narrowing the gap between the two elongated elements (9), after the collagen carrier (3) is placed between the elongated elements (9) to a degree that provides sufficient clamping to ensure the twist , once the elongated elements (9) are rotated.

As shown in FIG. 11, the support device (8) represents a cavity comprising the lower part in the form of a segment of a cylinder having, at the apex, an open end, through which the elongated members extend, and through which the curved part of the cylinder segment extends , the puffin, at 180 °. The upper part of the cavity consists of two straight, parallel wall segments (8a), so that the cavity has the form of an open channel.

The elongated members (9) of the clamping device (6) extend into the cavity of the support device (8) through the open end. Elongated elements (9) may also be extracted so that once the collagen carrier (3) has been twisted and is located in the cavity of the support device (8), the elongated elements (9) are extracted from the twisted collagen carrier ( 1). The elongated elements (9) are drawn in a direction parallel to the longitudinal extension of the elements. When another collagen carrier (3) is to be twisted, the elongated elements (9) are inserted back into the cavity of the support device (8) by moving the elongated elements (9) in the opposite direction, rather than during extraction.

MD 4471 Cl 2017.10.31

As shown in FIG. 11, the result of the twist is a collagen carrier twisted into an elongated element with an "S" shaped core. The two curves of the S-shaped core are defined by the elongated elements (9). In addition, the rotation of the clamping device (6) is adapted to position the edge (14) so ​​that it borders with the wall of the cavity, which secures the edge (14) relative to the other side of the twisted collagen carrier (1).

The apparatus (10) also comprises a compression device (11). The compression device (11) mounted to compress the moistened collagen carrier (3) before twisting the moistened collagen carrier, ie as shown in Fig. 1, the compression device being mounted after the humidity application device (2). ) and before the turning device (5).

The compression device comprises a pair of rollers (12) mounted to compress the moistened collagen carrier (3) prior to twisting the moistened collagen carrier. Compression is ensured by the fact that the space between the rollers is smaller than the thickness of the moistened collagen carrier. As shown in FIG. 11, the rollers (12) rotate in opposite directions to transport the collagen carrier through the pair of rollers (12) to the twisting device (5).

After the collagen carrier (3) has been twisted into a twisted collagen carrier, it is still moistened (solvent bound) and still moistened. To provide a stable shaped twisted collagen carrier (1), the collagen carrier is dehydrated, which is provided by drying the twisted collagen carrier (1). The apparatus, respectively, also includes the puffin, a drying means (not shown in the figures) for drying one or more twisted collagen carriers after twisting.

The drying means can typically be executed as a drying channel through which the twisted collagen carrier (1) passes and within the drying channel the temperature is raised relative to the temperature of the twisted collagen carrier (1) and the relative content of the solvent in air is down to the low level. These two measures (high temperature and relatively low solvent content) accelerate the transport of the solvent from the twisted collagen carrier (1) into the air inside the drying channel. Forced circulation of air can be advantageously applied to enhance removal of the solvent from the twisted collagen carrier (1).

The apparatus is advantageously executed to ensure the automatic production of carcinogenic collagen carriers (1). As shown in FIG. 11, the apparatus is executed as an assembly line that transports collagen carriers (3) through various stages of the production process.

Thus, the apparatus (10) comprises a first conveyor device (13), which transports the collagen carriers (3) prior to twisting in addition to the wetting device (2) and to the twisting device (5).

In their path from the wetting device (2) and to the twisting device (5), the wet collagen carriers (3) tree through the pair of rollers (12) mounted to compress the moistened collagen carrier before turning the wet collagen carrier , and the first conveyor device (13) carries the moisture-collagen carriers (3) to the pair of rollers (12). Attention is drawn to the fact that the transport of the wet collagen carrier (3) from the end of the first conveyor device (13) and to the gap between the pair of rollers (12) can be assisted by guide pieces (not shown) that guide the wet collagen carriers ( 3) towards the pair of rollers (12). Since the compression is performed by the pair of rollers (12), the rotation of the rollers (12) transports the wet collagen carrier (3) through the compression device (11) and to the twisting device (5). Again, suitable guiding means (not shown) may be applied to guide collagen carriers (3) to the position in the cavity of the twisting device (5), wherein the fastening means (6) can engage the collagen carrier ( а along one edge and twist the collagen carrier (3). The guide pieces and the guide means are made of an inert material, which does not damage the collagen carriers eg. by shedding the material.

In addition, to facilitate the automatic production of the collagen carrier carriers (1), the cavity of the resuscitation device (5) is formed in a second conveyor device. While the first conveyor device (13) transports the collagen carrier (3) at a constant speed, the second conveyor device, as a rule, gradually transports the twisted collagen carriers (1), that is, as long as the twisting occurs. , the second conveyor device is at rest and once the twist has ended (the edge (14) is located so as to limit the surface of the cavity and the elongated elements (9) extracted) the second conveyor moves to place the empty cavity under the pair of rolls and in front of the elongated elements (9) extracted.

MD 4471 Cl 2017.10.31

The transport speed of the first conveyor device is set according to the amount of solvent applied in the nozzles (14) to obtain a predefined amount of solvent applied to the collagen carrier surface (3).

The orientations and reciprocal locations of the various parts presented in fig. 11 are implemented in the machine as they are implemented in the figure. That is, the first conveyor device (13) is located above the turning device (5), the pair of rollers (12) being located between them.

Contamination of collagen carriers is often an issue that should be given attention during humidification, compression, twisting and drying. To avoid contamination, various parts used to produce the twisted collagen carrier are protected by the environment through a housing. Thus, the apparatus may include, in particular, a housing that seals the wetting device (2), and / or the pair of rollers (12), and / or the twisting device (5), and / or the support device (8), and / or the first (13) and / or second carrier device.

procedures

The apparatus described herein is adapted to perform a process of twisting a collagen carrier, comprising a collagen layer and a coating layer comprising near solid fibrinogen and near solid thrombin. The following will be disclosed preferential variants of executing the procedures according to the present invention. Refer to FIG. 11 and the elements and parts presented in this context are mentioned by reference, this fact does not intend to limit the procedures to the apparatus disclosed in fig. 11.

The processes according to the invention typically include successive steps of wetting, at least, a part of a collagen carrier (3), and of twisting the collagen carrier (3) by engaging the collagen carrier (3) between о pair. of elongated members (9), and rotating the pair of elongated members (9) about a parallel axis with longitudinal extension of the elongated members (9) to twist the collagen carrier (3) on the elements while the collagen carrier (3) is supported by a support device (8).

The wetting and twisting steps are preferably performed as two separate steps as described above with respect to the embodiment of the apparatus (10), the respective steps being executed consecutively one after another. The time between wetting and twisting is selected so that the softening effect obtained by humidifying the collagen carrier (3) is present during the collagen carrier twist (3).

After the collagen carrier is twisted (3), the process includes the drying step of the twisted collagen carrier (1). The drying steps remove the solvent from the twisted collagen carrier and the drying step is typically and preferably performed while the twisted collagen carrier is suspended to maintain its twisted form during drying. The result of the process is a stable-shaped twisted collagen carrier (1).

Twisting is accomplished by gripping the collagen carrier with the aid of a snap device, and the collagen carrier is attached along a collagen carrier edge (3). Twisting is achieved by gripping the collagen carrier with the help of the shearer, a pair of pliers or tweezers (9).

The drying of the twisted collagen carrier (1) is usually done by blowing the air with lower humidity than the twisted collagen carrier and optionally by heating the air to enhance e.g. evaporation of the liquid used to humidify the collagen carrier (3). It should be noted that the term "humidity" must be understood widely and is not limited to water. For example, humidity is also used with respect to the air concentration of the solvent used to moisten the collagen carrier (3).

As mentioned above, the process involves humidifying, at least, a part of the collagen carrier and in some embodiments of the invention the humidified part is the coating layer. Typically, the humidification step is accomplished by spraying drops of liquid on the surface of the coating layer, and the humidification is obtained by penetrating the liquid into the coating layer of the collagen carrier (3) e.g. by capillary action. Thus, the amount of the liquid present, for example, in the coating layer may vary depending on the depth; however, since one purpose of humidification is to soften the collagen carrier (3), such variations in the amounts of the liquid are acceptable. In many preferential embodiments, the coating layer is moistened with a solvent applied on the surface of the coating layer in an amount of 1.20 ... 10.75 mg / cm² collagen carrier surface (3). The solvent used comprises or consists, in particular, of ethanol.

MD 4471 Cl 2017.10.31

A process according to the present invention may also comprise the collagen carrier compression step (3), the respective compression reducing the collagen carrier thickness. While different compression ratios, e.g. the ratio between the thickness of the collagen carrier (3) before and after compression may vary, the collagen carrier is preferably compressed with a compression ratio between 6 and 12. Compression is performed after the humidification step and before the twisting step, ie the compression is performed before the collagen carrier is twisted.

Efficient compression has been shown to be carried out by passing the humidified collagen carrier through a set of rollers (12) having a grain size smaller than the thickness of the collagen carrier (3) before passing through the roll set (12). The size of the strand is selected in such a way as to ensure the desired compression ratio. Typically, preferred figures for the size of the slab are not more than 0.5 mm, preferably not more than 0.6 mm or between 0.5 ... 1.0 mm, or not more than 0.75 mm. However, the size of the strand should be selected according to the thickness of the collagen carrier (3), to obtain the desired compression ratio.

After the collagen carrier (3) has been humidified, optionally compressed and twisted, the twisted collagen carrier (1) is still soaked and may have a tendency to become loose during drying e.g. due to gravitational effects and / or some mechanical pressure in the twisted collagen carrier (1). To ensure that the twisted collagen carrier (1) is reinforced in a twisted form, the edge (see number (14) in fig. 11 the twisted collagen carrier (1), located on the outside of the roller, after twisting is bordered by the surface of the cavity and is thus fixed by the support device (8) relative to the twisted collagen carrier (1) during drying.

After the collagen carrier (1) has dried, the softened parts of the collagen carrier have been strengthened and the collagen carrier (1) has a stable shape.

The support device (8) is as described above with reference to FIG. 11 - a cavity comprising a lower part in the form of a segment of a cylinder having, at the apex, an open end, through which the elongated elements extend into the cavity, and through which the curved part of the segment of the cylinder extends, at the apex, at 180 °. During the twisting process, the outer edge (14) of the collagen carrier is located inside the cavity portion formed as a segment of the cylinder and the edge (14) is bordered by the inner surface of the cavity. Once the edge (14) is bordered with the inner surface, the twisting process is completed and the means of attachment in the form of о pair of elongated elements (9) are extracted from the collagen carrier twisted through the open end of the cavity.

Removing the elongated elements (9) from the twisted collagen carrier (1) may involve fixing the twisted collagen carrier (1) m inside the cavity, if the elongated elements (9) do not slip easily from the twisted collagen carrier (1). Such fixation may be provided by mechanical pressing of the collagen carrier twisted to the bottom of the cavity m while the elongated members are extracted, or it may be mounted in a reticular structure to prevent the collagen carrier from sliding through the open end of the cavity. , while allowing the extraction of the elongated elements; thus, the effect of pulling elongated elements on the twisted collagen carrier (1) may be exceeded by the lattice structure, or by the pressing effect.

Once the elongated elements (9) have been removed, any fixing can be removed. Extraction of the elongated elements (9) is usually performed before the collagen carrier is dried. The pair of elongated elements can consist of о pair of pliers and the procedure described above is the same.

The atmosphere around the collagen carrier (3) and the wetting device (2) while the collagen carrier (3) is humidified, compressed and twisted is usually reduced to о temperatures of 18 ... 22 ° C and relative humidity of 30 ... 50%.

After the twisted collagen carrier (1) has been dried to form a stable-form collagen carrier, the method may include the step of placing the stable-form collagen carrier (1) in a container and subsequently hermetically closing container. The step of placing the twisted collagen carrier in an airtight container prevents the collagen carrier from wetting and / or contamination (1). At the same time, the step of placing the twisted collagen carrier (1) in an airtight container may also comprise the steps of placing the twisted collagen carrier (1) in an inner container and placing the inner container in an outer container. . In addition, a desiccator may be placed inside the outer container prior to the hermetic closing of the container.

MD 4471 Cl 2017.10.31

While an objective of the process is to provide a sterile twisted collagen carrier packaged in one or more containers, the process may also comprise a sterilization step during which the container (s) with the twisted collagen carrier are exposed. a sterilization process. Sterilization can usually be radiation sterilization. To ensure rapid detection of the fact that a particular twisted collagen carrier (1) has been sterilized, on the outside of the outer container, or of the container in general, a label indicating whether or not sterilization has been performed may be applied. .

The preferred sterilization step often involves the sterilization of the twisted collagen carrier (1) using gamma radiation. Sterilization of the twisted collagen carrier (1) is often performed up to a sterility assurance level (NAS) of IO '⁶ with the help of gamma radiation.

The twisted collagen carrier

As mentioned above, processes and apparatus are used to produce the twisted collagen carrier (1) with stable form. The processes and apparatus described above or proved to be effective for the production of the twisted collagen carrier (1), however, the twisted collagen carriers (1) as such are examined within the scope of the present invention.

Thus, the present invention comprises a twisted collagen carrier (1) having a collagen layer and a coating layer above the collagen layer. The coating layer comprises almost solid thrombin and almost solid fibrinogen, although all thrombin and / or all fibrinogen may be solid.

The twisted collagen carrier usually has the shape of an elongated element with numerous coils of the collagen carrier (3) around the longitudinal axis of the elongated element and, at the most, the outer coils and preferably each coil being oriented so that the coating layer constitutes the surface. outer of each coil. Another characteristic of the twisted collagen carrier (1) is that it has a stable shape and defines a collagen carrier in a twisted configuration, where, at most, the outer coils extend along a spiral in cross-section of the collagen carrier. .

Shape stability is often ensured by the collagen layer and / or the coating layer being reinforced in a twisted form, so no additional elements, such as fasteners, are required to maintain the twisted collagen carrier in its twisted form.

The twisted collagen carrier (1) is о rectangular foil in a rolled configuration having, preferably, width, length and thickness not exceeding 4 mm, such as maximum 5 mm, preferably not more than 6 mm , such as at most 7 mm. The twisted collagen carrier is usually twisted about its width so that the width of the twisted collagen carrier (1) constitutes the width of the unfolded configuration. However, twisted collagen carriers, which are twisted around the length, are also оf opfion. A twisted collagen carrier will often comprise three, four or five coils.

A preferred twisted collagen carrier (1) is cylindrical in shape with an outer diameter of less than 12 mm, such as less than 11 mm, such as less than 10 mm, such as less than 9 mm, such as less than 8 mm, such as less than 7 mm, such as less than 6 mm, such as less than 5 mm, such as less than 4 mm, such as smaller 3 mm. In addition, the twisted collagen carrier has an inner "S" shaped coil around the longitudinal direction of the twisted collagen carrier as disclosed, e.g. in FIG. 11.

The coating layer of twisted collagen carriers (1) has no cracks. In most cases this is achieved by producing the collagen carrier twisted in a way, in which the coating layer and / or the collagen layer is (are) softened by wetting before turning, the respective softening allowing the coating layer and / or the collagen layer. to stretch without causing cracks or cracks during twisting. Subsequent drying strengthens the softened layer that holds the roll shape to a stable shape. Preferably, the coating layer is moistened.

The twisted collagen carrier (1) is often placed in a container. The container is usually hermetically sealed to prevent contamination and / or degradation and / or to maintain the stability of the twisted collagen carrier. A dehydrating agent, such as silica gel, can be placed in the container. Such containers with twisted collagen carrier (1) are examined within the scope of the invention.

In a special preferred embodiment, the wrapped collagen carrier packaged (1) comprises an inner and an outer container. The inner container comprises a cavity having the lower part in the form of a segment of a cylinder, and in which the curved part of the segment of the cylinder extends to, at least, 180 °, as shown in FIG. 11 under number (8).

MD 4471 Cl 2017.10.31

The cavity is sealed with a cutable or brittle foil and the outer container comprises a sealed bag inside which the sealed inner container is placed together with a dehydrating agent.

Although the present invention is described in connection with the specified embodiments, it should not be understood that it is in any way limited to the examples provided. The scope of the present invention is defined by the set of accompanying claims. In the context of the claims, the terms comprising "or" encompass "do not exclude other possible elements or steps. Also, mentioning references, such as one or one, etc. should not be construed as excluding о plurality. The use of the reference signs in the claims regarding the elements indicated in the figures, also, should not be construed as limiting the scope of the invention. In addition, the individual characteristics mentioned in different claims can be advantageously combined, and mentioning these features in different claims does not exclude the fact that a combination of features is not possible and advantageous.

Examples

Example 1 - loss of the coating.

Example 1.1 - the loss of the coating immediately after the roll

The loss of the coating is determined immediately after the collagen carrier is developed according to the present invention. The collagen carrier must not lose more than 0.6 mg / cm²measured by weighing immediately after running.

The rolling is performed by fixing one end of a prerolled TachoSil® product, such as a twisted collagen carrier according to the present invention between the fingers of a glove hand, while the rest of the prerolled TachoSil® product, such as a twisted collagen carrier, according to the present invention it is rolled with the help of the fingers more often covered with glove, ensuring that the coating layer is face down after the roll. The operation is performed in a standard laboratory setting, well known to the person skilled in the art.

Example 1.2 - loss of the coating without rolling

This analytical procedure describes determining the adhesion of the coating of a prerolled TachoSil® product, such as a twisted collagen carrier according to the invention by gravimetry. In other words, the procedure describes the loss of the twisted collagen carrier sheath when exposed to a controlled physical action as described below. The measurements are performed in a standard laboratory setting, well known to the person skilled in the art. As a standard condition, gloves are always used.

1.1 Analytical system, analytical balance, Vortex agitator, ruler with millimeter degrees, tube with reagent with an inner diameter of about 2 cm.

1.2. samples

It disassembles the prerolled TachoSil®, such as a twisted collagen carrier according to the invention in its packaging with the help of gloved hands. The length and width of the sample are measured. The sample should enter the reagent tube without bending.

1.3 Execution

Place the sample in a tube with a balanced and stirred reagent on the Vortex shaker (frequency: about 1000 rpm), for 2 minutes. Remove the sample and weigh again the residual amount of the coating material (mass of the residue).

1.4 Calculation

Surface (cm²) = length (cm) x width (cm)

Abrasion (mg / cm²) = (mass of residue (g) - country of the tube with reagent (g)) x 1000 surface (cm²)

Reported value: abrasion in mg / cm²; values ​​<0.1 mg / cm² are reported as <0.1 mg / cm².

Prerolled TachoSil®, such as a twisted collagen carrier, cannot lose more than 0.6 mg / cm² measured by weighing immediately after unpacking and testing according to the analytical procedure described in the example given.

Example 2 - measuring membership

By the term "adhesion" is meant the in vitro ability of a collagen carrier to adhere to living tissue according to the present invention. Adhesion is qualitatively investigated by visually examining the adhesion of a rolled and unfolded collagen carrier to a mammalian tissue, ie the ability of a collagen carrier to adhere to a tissue.

MD 4471 Cl 2017.10.31

A portion of freshly slaughtered pig liver tissue is placed in a Petri dish and a rolled collagen carrier of the present invention is placed with the hands in gloves on the liver tissue, while it is rolled with the hands in gloves and then is subjected to a slight squeeze of the hand in the glove. Fig. 1 illustrates the adhesion of the unfolded collagen carrier to the living tissue.

Example 3 - density measurement

The density was determined by weighing the collagen fiber combined with the knowledge of the size, ie the volume of the fiber making it possible to calculate the density of the collagen fiber. Standard laboratory equipment was used to measure the weight of collagen fibers (we note that the weight of the "collagen carriers" means the weight of the collagen carrier excluding the weight of the coating). The average density of the compressed collagen carrier is shown below in Example 4. We note that the density of a collagen carrier of the present invention represents the density of the collagen carrier excluding the coating layer.

Example 4 - Adhesive Capacity (TCP Test)

The following (Example 4.1) describes an in vitro pressure test for measuring the adhesive capacity on a simulated sample of latex (membrane) of a twisted collagen carrier of the present invention. The test can also be used during the assessment of the adhesive capacity of a prerolled TachoSil®.

Examples 4.2 - 4.3 demonstrate the obtained values ​​of TCP during the measurement of carcinogenic and collagen carriers of the present invention, where carcinogenic collagen carriers have different mean densities of 3.62 mg / cm.³-4.05 mg / cm³. Example 4.4 demonstrates the adhesive capacity of a collagen carrier that has not been subjected to the humidification, compression and rolling process.

Example 4.1

The product tested: a prerolled TachoSil® or a twisted collagen carrier of the present invention. The tested product has о medium size, ie 46 ... 49 mm * 46 ... 50 mm * 4 ... 7 mm.

4.1.1 Introduction

The protocol is applied to perform the pressure chamber test (TCP) to determine the adhesiveness of a twisted collagen carrier of the present invention or of a prerolled TachoSil® on a latex membrane.

4.1.2 Analysis and conditions

When the coating layer of a twisted and rolled collagen carrier of the present invention or of a prerolled and rolled TachoSil® is moistened, the maximum pressure to which the wearers can resist, their adhesive capacities and their air permeability can be measured by the chamber. pressure.

4.1.3 Equipment

The pressure chamber (TCP chamber) is made of 20x20x20cm synthetic glass, from MHM Morawitz, Nuremberg, TCP test membrane (THM red with standard о hole О 1cm; from MHM Morawitz, Nuremberg), TCP test membrane (THM red without hole) ; from MHM Morawitz, Nuremberg), blood pressure tester, GMP qualified equipment. Another suitable GMP-qualified blood pressure monitoring device, Teflon weight (150.0 g О 3 cm), may be used.

о hermetic plastic box with a dehydrating agent, model for cutting a piece of collagen carrier (3x 3cm), tweezers, scalpel and scissors, stopwatch.

Fig. 4 illustrates the TCP test chambers and a blood pressure monitor.

4.1.4 Reagents

0.9% NaCl solution (isotonic saline solution).

4.1.5 Probe

As a minimum number, it is recommended to perform 5 copies per lot / packing. NB: It is very important to focus on minimizing the humidity exposure of the twisted collagen carrier from the present invention or TachoSil®.

MD 4471 Cl 2017.10.31

Therefore, it is necessary to keep the fibers unpackaged in an airtight box with a dehydrating agent. Before performing a TCP test, it is necessary to perform a system matching test on all TCP cameras to be used.

4.1.6 Conducting the TCP test • The о membrane (with hole) is placed on the TCP test chamber, • the twisted collagen carrier of the present invention or the prerolled TachoSil® is carefully rolled and placed with the yellow face (i.e. the coating layer) downwards. . Using the cut model, a piece of square collagen carrier 3x3 cm is cut from the rolled collagen carrier, • the cut collagen carrier is placed immediately in a dry box, if it is not possible to place it directly on the membrane, • the layer of The coating is completely moistened by immersing the coated yolk (yellow) in a 0.9% NaCl solution (for about 5 s). The cut collagen layer should not become damp. Immediately thereafter, the cut collagen carrier is placed on the membrane of the TCP chamber with the yellow face down relative to the membrane. It is lightly pressed with one finger on the edges, and above it is carefully placed о weight of Teflon. The stopwatch is set at 5 minutes, • after 5 minutes the weight is carefully removed and the pressure device is added pressure to the TCP chamber, • the maximum voltage in the blood pressure checker is noted and written on a label (see (see below), • to evaluate the adhesiveness, each cap of the cut portion is pushed with the tweezers. The results are listed in table 2 (see below), • also the air leakage is recorded through the cut collagen carrier (see table 1 below), • the used membrane is removed and a new one is applied.

4.1.7 Level of acceptance

The average TCP value for collagen carrier cuts should be above 50 mmHg. No collagen carrier cut-off should be below 30 mmHg shear, such as 35 mmHg shear, preferably 40 mmHg.

4.1.8 System compliance test

A system matching test is performed for all cameras that are used for TCP measurement. Each time a new membrane is used (no hole), it is necessary to apply pressure to it once (activation of the membrane) before performing the actual pressure leak test, because the new membrane offers a higher TCP value for the first time when used.

The activated membrane can be used about 4 to 6 times or until it breaks. It can only be used during the same day. If the membrane breaks, the measurement is dropped. О another membrane is activated and used instead.

The test is performed both before and after measuring the TCP of the samples.

Activation of membranes:

1. The membrane is placed in the TCP chamber.

2. Pressure is applied to the chamber and the membrane is swollen.

Testing:

1. The membrane is placed on the first TCP chamber.

2. Pressure is applied to the chamber and the value is entered.

3. The test is repeated for all used rooms.

Table for the number of tests

<td colspan="4">Number of tests to be performed with one, two or three TCP cameras (after membrane activation)</td>

<td>Number of rooms</td><td rowspan="2">О TCP camera</td><td rowspan="2">Two TCP cameras</td><td rowspan="2">Three TCP rooms</td>

<td>Number of tests</td>

<td>Number of tests performed before samples per room</td><td> 2</td><td> 1</td><td> 1</td>

<td>Number of tests performed after testing</td><td> 1</td><td> 1</td><td> 1</td>

MD 4471 Cl 2017.10.31

I per room. | | |

Test requirements: The value (after membrane activation) must be&gt; 75 mmHg.

The difference in values ​​between different chambers may not exceed 10 mmHg and greater than 5 mmHg for the same room.

Example 4.2 In the next experiment, collagen carriers with an average density of 3.62 mg / cm³ were compressed between two rollers (50 mm roll diameter), after applying ethanol on the fibrinogen and thrombin coated face of the collagen carrier. Compressed collagen carriers were run using a fastener. The rolled collagen carriers were then rolled to be tested in an adhesive capacity test (TCP test). As can be seen from the table below, the average TCP value of the rolled collagen carriers was 78 mmHg and all TCP detected values ​​were over 50 mmHg. The results indicate that collagen carriers according to the invention may undergo a process of humidification, compression and rolling according to the invention, while maintaining the adhesive capacity. The value of the adhesive capacity constitutes о indirect measurement of the hemostatic / sealing properties of the rolled carrier.

The collagen carriers used for the experiment had initially, at least, one of the following physical properties: the elasticity mode ranging from 5 ... 100 N / cm², density of

1 ... 10 mg / cm³, the diameter of the chamber over 0.75 mm and less than 4 mm and / or having an average diameter of the chamber below 3 mm and solid fibrinogen and solid thrombin evenly distributed and fixed on the above-mentioned collagen carrier.

Table 1

<td>The average density of the carrier collagen (mg / cm³)</td><td>Applied ethanol (mg / cm²)</td><td>The size of the spur between the wheels</td><td>TCP value (mmHg)</td>

<td> 3,62</td><td> 4,3</td><td> 0,6</td><td> 92</td>

<td> 3,62</td><td> 4,3</td><td> 0,6</td><td> 79</td>

<td> 3,62</td><td> 4,3</td><td> 0,6</td><td> 77</td>

<td> 3,62</td><td> 4,3</td><td> 0,6</td><td> 81</td>

<td> 3,62</td><td> 4,3</td><td> 0,6</td><td> 52</td>

<td> 3,62</td><td> 4,3</td><td> 0,6</td><td> 101</td>

<td> 3,62</td><td> 4,3</td><td> 0,6</td><td> 81</td>

<td> 3,62</td><td> 4,3</td><td> 0,6</td><td> 70</td>

<td> 3,62</td><td> 4,3</td><td> 0,6</td><td> 72</td>

<td> 3,62</td><td> 4,3</td><td> 0,6</td><td> 71</td>

<td></td><td></td><td></td><td>average: 78</td>

The average density of collagen carriers was 3.62 mg / cm³

The average density of collagen carriers above-menfionafi is calculated as the average density of the collagen carrier excluding the coating layer.

Example 4.3

In the next experiment, collagen carriers with an average density of 4.05 mg / cm³ were compressed between two wheels (50 mm roll diameter), after ethanol was applied to the fibrinogen and thrombin coated face of the collagen carrier. The collagen carriers were compressed using a clamping device. The collagen carriers were then rolled out to be tested in an adhesive capacity test (TCP test). As can be seen from the table below, the average TCP value of derulafi collagen carriers was 94 mmHg and all TCP detected values ​​were over 50 mmHg. The results indicate that collagen carriers according to the invention may undergo a process of humidification, compression and rolling according to the invention, while maintaining the adhesive capacity. The value of the adhesive capacity constitutes о indirect measurement of the hemostatic / sealing properties of the rolled carrier.

MD 4471 Cl 2017.10.31

The collagen carriers used for the experiment initially had at least one of the following physical properties: the elasticity mode between 5 ... 100 N / cm², density of

1 ... 10 mg / cm³, the diameter of the chamber over 0.75 mm and less than 4 mm and / or having an average о of the diameter of the chamber below 3 mm and solid fibrinogen and solid thrombin evenly distributed and fixed on the abovementioned collagen carrier.

Table 2

<td>The average density of the carrier collagen (mg / cm³)</td><td>Applied ethanol (mg / cm²)</td><td>The size of the space between the rollers</td><td>TGP value (mmHg) ^U</td>

<td> 4,05</td><td> 4,2</td><td> 0,6</td><td> 107</td>

<td> 4,05</td><td> 4,2</td><td> 0,6</td><td>⁶⁷ 15</td>

<td> 4,05</td><td> 4,2</td><td> 0,6</td><td> 95</td>

<td> 4,05</td><td> 4,2</td><td> 0,6</td><td> 103</td>

<td> 4,05</td><td> 4,2</td><td> 0,6</td><td> 89</td>

<td> 4,05</td><td> 4,2</td><td> 0,6</td><td>⁹⁸ 20</td>

<td> 4,05</td><td> 4,2</td><td> 0,6</td><td> 86</td>

<td> 4,05</td><td> 4,2</td><td> 0,6</td><td> 114</td>

<td> 4,05</td><td> 4,2</td><td> 0,6</td><td> 103</td>

<td> 4,05</td><td> 4,2</td><td> 0,6</td><td> 75 „</td>

<td></td><td></td><td></td><td>average: 94</td>

The average density of collagen carriers was 4.05 mg / cm³. The average density of collagen carriers is calculated as the average density of the collagen carrier excluding the coating.

Example 4.4

Tab. 3 shows the results of the adhesive capacity of a collagen carrier measured using a TCP test. We would like to point out that the wearer was not subjected to the humidification, compression and rolling process as in the examples above, ie example 4.1 and 4.2.

The collagen carriers used for the experiment initially had at least one of the following physical properties: the elasticity mode between 5 ... 100 N / cm², density of

1 ... 10 mg / cm³, the diameter of the chamber over 0.75 mm and less than 4 mm and / or having an average о of the diameter of the chamber below 3 mm and solid fibrinogen and solid thrombin evenly distributed and fixed on the abovementioned collagen carrier.

Table 3

<td>The average density of the carrier collagen (mg / cm³)</td><td>TCP value (mmHg)</td>

<td> 4,08</td><td> 96</td>

<td> 4,08</td><td> 83</td>

<td> 4,08</td><td> 81</td>

<td> 4,08</td><td> 59</td>

<td> 4,08</td><td> 82</td>

<td> 4,08</td><td> 76</td>

<td> 4,08</td><td> 102</td>

<td> 4,08</td><td> 82</td>

<td> 4,08</td><td> 83</td>

<td> 4,08</td><td> 90</td>

<td></td><td>average: 83</td>

MD 4471 Cl 2017.10.31

The average density of collagen carriers was 4.08 mg / cm³. The average density of collagen carriers is calculated as the average density of the collagen carrier excluding the coating.

Example 5 - amounts of ethanol

The present example was performed to test the influence of factors on TCP values; the amount of ethanol applied and the weight of the tape for о fixed size of the crack and the fixed UR in the room. The weight of the collagen carriers is taken into account the weight of the collagen carrier excluding the weight of the coating.

Successful prerolled TachoSil® products or successful collagen carriers of the present invention were those with mean TCP values&gt; 50 mmHg and unique TCP values&gt; 40 mm Hg.

5.1 The material used

The test was based on the use of the following three batches of medium-sized fibers (neither fiber was subjected to gamma irradiation:

- 10622250 (band weight: approx .: 920 mg based on 10-band measurement),

- 10634435 (band weight: approx. 1180 mg),

- 10657586 (band weight: approx .: 1261 ... 1500 designated as: 1380 mg.

It is worth mentioning that the weight of the above-mentioned collagen carriers signifies the weight of the collagen carrier excluding the weight of the coating.

5.2 Use factors

The model used was a whole factorial model 32 with three replicates of the central point.

Fixed factors: Fixed size of slurry: 0.6 mm. UR in the room: &lt;50% (deviation up to 55% allowed). Room temperature (18 ° C) 2O ... 22 ° C.

Variable factors: Ethanol levels: 30 ... 40 mg / fiber; 90 ... 100 mg / fiber; 150 ... 160 mg / fiber. Weight of tape.

5.3 The reactions

TCP (mmHg).

Fiber dimensions after rolling (diameter (cm) and length (cm)).

5.4 Results

Tab. 4 shows the temperature and UR m during fiber processing.

By the weight of the tape, the weight of the collagen carrier is excluded, excluding the weight of the coating.

Table 4

<td>experiences</td><td>Ethanol (mg / fiber)</td><td>Band weight (mg)</td><td>Temp. (° C) UR% During running</td><td>Temp. (° C) UR% Before drying</td><td>Temp. (54.0 ° C) UR% After drying</td>

<td>no. 10</td><td> 95</td><td> 1180</td><td>21.8 ... 22.1 ° C 45.2 .. .53%</td><td>22.1 ° C 55.2%</td><td>21.6 ° C 54.3%</td>

<td>no.4</td><td> 39</td><td> 1180</td><td>20.5 .. .20.9 ° C 46.8 .. .47.7%</td><td>21.0 ° C 48.1%</td><td>22.2 ° C 53.8%</td>

<td>no.L</td><td> 39</td><td> 920</td><td>21.1 .. .21.4 ° C 48.6 .. .48.8%</td><td>21.4 ° C 49.0%</td><td>22.2 ° C 54.3</td>

<td>no.5</td><td> 98</td><td> 1180</td><td>20.5 .. .20.7 ° C 50.6 .. .51.0</td><td>20.8 ° C 51.4%</td><td>21.0 ° C 55%</td>

<td>no.7</td><td> 39</td><td> 1380</td><td>20.8 ... 20.9 ° C 53.0 ... 53.2%</td><td>21.0 ° C 53.5%</td><td>21.0 ° C 59.2%</td>

<td>no.6</td><td> 153</td><td> 1180</td><td>21.2 .. .21.3 ° C 54.5 .. .54.6%</td><td>21.4 ° C 55.0%</td><td>20.9 ° C 56.6%</td>

MD 4471 Cl 2017.10.31

<td>no. 11</td><td> 94</td><td> 1180</td><td>19.0 ... 19 ° C it 51.7 ... 51.9%</td><td>19.2 ° C 51.8%</td><td>19.9 ° C 55.0%</td>

<td>no. 12</td><td> 94</td><td> 1180</td><td>19.3 .. .19.4 ° C 51.8 .. .51.9%</td><td>19.4 ° C 52.0%</td><td>20.1 ° C 55.2%</td>

<td>no. 8</td><td> 94</td><td> 1380</td><td>19.4 .. .19.6 ° C 52.2 .. .52.4%</td><td>19.6 ° C 52.3%</td><td>20.2 ° C 55.9%</td>

<td>no.3</td><td> 158</td><td> 920</td><td>19.6 .. .19.8 ° C 53.5 .. .53.4%</td><td>19.9 ° C 53.5%</td><td>19.8 ° C 56.7%</td>

<td>no.2</td><td> 104</td><td> 920</td><td>18.9 ... 19.2 ° C 53.0%</td><td>19.3 ° C 53.0%</td><td>20.0 ° C 52.9%</td>

<td>no.9</td><td> 154</td><td> 1380</td><td>19.8 .. .19.9 ° C 53.9 .. .54.0%</td><td>20.0 ° C 54.0%</td><td>20.8 ° C 55.8%</td>

Tab. 5 shows the fiber dimensions after rolling (diameter (cm) and length (cm)) and the average TCP value obtained in mmHg.

By '' tape weight '' is considered the weight of the collagen carrier excluding the weight 5 of the coating.

Table 5

<td>experiences</td><td>Ethanol (mg / fiber)</td><td>Band weight (mg band)</td><td>Medium fiber length (Cm)</td><td>Diameter of the average rolled fiber (cm)</td><td>Average TCP value (mmHg)</td>

<td>no.L</td><td> 39</td><td> 920</td><td> 4,72</td><td> 0,88</td><td> 90</td>

<td>no.2</td><td> 104</td><td> 920</td><td> 4,76</td><td> 0,86</td><td> 77</td>

<td>no.3</td><td> 158</td><td> 920</td><td> 4,68</td><td> 0,81</td><td> 72</td>

<td>no.4</td><td> 39</td><td> 1180</td><td> 4,85</td><td> 0,91</td><td> 95</td>

<td>no.5</td><td> 98</td><td> 1180</td><td> 4,76</td><td> 0,88</td><td> 79</td>

<td>no.6</td><td> 153</td><td> 1180</td><td> 4,62</td><td> 0,86</td><td> 85</td>

<td>no.7</td><td> 39</td><td> 1380</td><td> 4,64</td><td> 0,90</td><td> 92</td>

<td>no. 8</td><td> 94</td><td> 1380</td><td> 4,69</td><td> 0,87</td><td> 86</td>

<td>no.9</td><td> 154</td><td> 1380</td><td> 4,63</td><td> 0,84</td><td> 80</td>

<td>no. 10</td><td> 95</td><td> 1180</td><td> 4,75</td><td> 0,86</td><td> 84</td>

<td>no. 11</td><td> 94</td><td> 1180</td><td> 4,72</td><td> 0,86</td><td> 98</td>

<td>no. 12</td><td> 94</td><td> 1180</td><td> 4,80</td><td> 0,87</td><td> 90</td>

From the tab. 5 with the mentioned results it is clear that all the fibers tested are successful, ie they all have mean TCP value&gt; 50 mm Hg and single TCP values&gt; 40 mm Hg (data not shown).

In addition, as is evident from the results mentioned, the diameter of the twisted fiber media is well below 10 mm and the length of the twisted fibers is well below 5 cm. It was also evident from the mentioned results that while using the process according to the invention, maintaining the atmosphere around the collagen carrier and the delivery device

MD 4471 Cl 2017.10.31 humidification during humidification, compression and twisting at a temperature of about 18 ... 22 ° C and the relative humidity of about 30 ... 50% results in the successful fibers using ethanol levels of 30. .40 mg / fiber; 90 ... 100 mg / fiber; 150 ... 160 mg / fiber.

Example 6 - Direct twisting of TachoSil®

The present example investigates the steps of humidification and compression of a collagen carrier of the present invention, namely a TachoSil®.

A TachoSil® has been subjected to direct twisting without prior wetting and compression. The twist was performed in an apparatus according to the invention, except for the wetting and compression steps.

The directly twisted TachoSil® products had a fluffy appearance and their coating layer had visible open cracks in the eye (fig. 6).

By comparing the twisted TachoSil® products directly with the twisted collagen carriers of the present invention (see Fig. 3), it was easy to see the differences, namely the twisted collagen carriers of the present invention, in the sense that they are not stable. they crumble when at rest, such as while sitting on a smooth surface without being sneezed. Also, their coating layers did not have pierced cracks and a fluffy appearance, but had a smooth, significantly uniform surface.

Example 7 - Use of prerolled TachoSil® in minimally invasive surgery in a pig model.

To examine the hemostatic properties of the prerolled TachoSil® product, a female swine model was operated by laparoscopy and hemostasis was performed using the ready-to-use prerolled TachoSil® product.

Protocol:

After orotracheal intubation, the pneumoperitoneum was established in the traditional Hasson technique. We used a 12 mm trocar. CO gas was pumped₂ slow to a maximum of 12 mmHg. After insertion of the optic, a 12 mm open trocar was placed in the upper left quadrant and a 5 mm trocar was placed in the upper right quadrant under the direct gaze. The 3x3 cm lesion was surgically produced on the right lobe of the liver with a depth of 2 mm. Diffuse bleeding began. A prerolled TachoSil® was inserted instead of bleeding using a dissector through a 12 mm trocar. The introduction was made easily without damaging the roll. Opening the roller with a dissector and a pliers was successful. The prerolled TachoSil® model was placed on the wounds produced and pressed to the liver with a wet sponge for 2 minutes. A similar procedure was performed on the left side of the liver. The control of bleeding on the wound sites showed that the hemostasis was successful. After surgery, the pig was monitored for 7 days to check for complications (no complication was determined). More than 7 days after the operation, the pig was sacrificed and the irregularities of the collagen carriers TachoSil® on the surface of the liver were checked (fig.2). No irregularities were detected in contrast to what one might expect from a TachoSil® product (in flat, non-rolled packaging) available for sale. Bleeding was successfully controlled on both areas.

Example 8 - water absorption in ethanol and impact on TCP value.

for the purpose of examining the amount of water absorbed in pure ethanol as a function of time when exposed to conditions of approx. 50% RH and 20 ° C, the following experiment was performed.

Absolute ethanol absorbed moisture from me while it was being kept in an open glass.

8.1 Results - Ethanol water absorption.

The interval from 0.5 to 1.5 hours: approx. 0.5% (ethanol concentration: approx. 99.5%).

Range up to approx. 20 hours: maximum 2.4% (ethanol concentration:&gt; 97.6%).

8.2 - impact on TCP value.

Based on the water absorption data in ethanol, it was investigated whether the use of ethanol containing 2.4% water would have an impact on the spin process or on the TCP value, when tested after twisting and drying.

8.3 Test scheme - TCP value and the twist process.

Nr. lot 10657586 (band weight: approx .: 1261 ... 1500 designated as: 1380 mg. These fibers were not subjected to gamma irradiation.

By '' the weight of the tape '' is considered the weight of the collagen carrier excluding the weight of the coating.

MD 4471 Cl 2017.10.31

factors

Constants: space size = 0.6 mm, room UR = &lt;50%, deviation up to 55% allowed), ethanol levels = 80 mg / fiber ± 10 mg / fiber

Variables: ethanol concentration = 99.9% and 97.6%.

Reactions: TCP (mm Hg)

Model: 10 fibers were twisted on 97.6% ethanol wetting and fibers were twisted on pure ethanol (99.9%) wetting.

8.4 Results - TCP value and the spin process.

Lot 10657586 («1380 mg band weight):

- 99.9% ethanol used for wetting: average TCP values: 107 mm Hg and single TCP values: 107, 111, 108, 122, 112, 113, 119, 76, 98, 105 mm Hg.

- 97.6% ethanol used for wetting: average TCP values: 101 mm Hg and single TCP values: 95, 110, 85, 113, 119, 100, 109, 90, 114, 71 mmHg.

By '' tape weight '' is considered the weight of the collagen carrier excluding the weight of the coating.

A t-test on the possible difference between ethanol use of 99.9% and 97.6%: P (T &lt;t) = 0.32 indicated that no significant difference could be found.

Thus, the addition of up to 2.4% water in the ethanol used for wetting m the twisting process, ie approx. 20 hours of exposure to UR of maximum 50% at 20 ° C did not have a significant impact on TCP values ​​or fiber behavior during running.

Example 9 - the impact on the collagen carrier of the surrounding air UR during processing.

9.1 The objective.

This example demonstrates the impact of room conditions (2O ... 22 ° C / 40 ... 60% UR) on TCP values ​​during the manufacture of prerolled TachoSil® fibers. The water content (KF values) was measured using Karl Fischer standard titration method.

Factors: grain size: 0.6 mm and ethanol levels: 94 mg / fiber.

9.2 Results - TCP (TachoSil® lot 10634435 - was not subjected to gamma radiation).

Table 6

<td>Room conditions</td><td>TCP values ​​(mm Hg)</td>

<td>I (2O ... 21 ° С / UR 45 ... 49%)</td><td>unique values: 90, 112, 115, 41, 57, 104, 44, 71, 112, 68, 65 average value: 80 (std .: 28)</td>

<td>II (2O ... 21 ° C / UR51 ... 52%)</td><td>unique values: 66, 104, 77, 97, 75, 110, 95, 67, 87.51,74, 53, 89 average values: 80 (std .: 18)</td>

<td>III (2O ... 21 ° C / UR 57 ... 58%)</td><td>unique values: 69, 61, 40, 59, 112, 60, 75, 64, 97, 39, 67, 73, 73 average value: 68 (std .: 20)</td>

<td>IV (20 ... 21 ° C / UR 61 ... 63%)</td><td>unique values: 61, 67, 54, 51, 66, 89, 61, 74, 81.60, 54, 66, 59 average value: 65 (std .: 11). Commentary: Adhesive roles over time to perform TCP measurements</td>

As can be seen from table 6, UR of 57 ... 58% produces a single TCP value less than 40 mm Hg, ie room conditions III.

MD 4471 Cl 2017.10.31

Table 7

<td>Room conditions</td><td>KF,% of water content; n = 2 ... 4. Measured immediately after 30 min drying with ethanol</td>

<td>I (2O ... 21 ° С / UR 45 ... 49%)</td><td>average: 11.21% (DRS%: 1.28)</td>

<td>II (2O ... 21 ° C / UR 51 ... 52%)</td><td>average: 12.48% (DRS%: 0.83)</td>

<td>III (2O ... 21 ° C / UR 57 ... 58%)</td><td>average: 13.42% (DRS%: 4.02)</td>

<td>IV (2O ... 21 ° C / UR 61 ... 63%)</td><td>average: 16.12% (DRS%: 0.61)</td>

As you can see from the tab. 7,% of the water content of collagen carriers increases as UR increases, but TCP values ​​were still successful.

The description shall be published in the wording of the applicant.

(56) Bibliographic references cited in the description:

1. EP 2052746 A2 2009.04.29

2. WO 02070594 A2 2002.09.12

3. WO 9721383 TO 1997.06.19

4. WO 02058749 A2 2002.08.01 (57) Claims: