• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:

    公开号:ES2642151T9
    申请号:ES12724564.5T
    申请日:2012-05-24
    公开日:2018-01-08
    发明作者:Wolfgang Schönhofer；Pernille Dybendal Pedersen；Poul Bertelsen；Henrik BRÆNDER；Ingrid BLANKA；Henrik Neuschäfer LARSEN
    申请人:Takeda AS；
    IPC主号:
    专利说明:

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    Another aspect of the invention relates to a compressed collagen carrier according to the invention having a coating comprising solid fibrinogen and solid thrombin that is uniformly distributed and fixed on said collagen carrier, and having at least one of the following properties physical:
    5 I. a thickness of a maximum of 4 mm
    II. an adhesive force of at least 40 mmHg measured by a pressure test (PCT)
    III. a sterility guarantee (SAL) level of 10-6.
    Another aspect of the invention relates to a rolled collagen carrier according to the invention having a coating comprising solid fibrinogen and solid thrombin that is uniformly distributed and fixed on said collagen carrier, and having at least one of the following properties physical:
    15 I. a diameter of a maximum of 10 mm
    II. an adhesive force of at least 40 mmHg measured by a pressure test (PCT) after unwinding said collagen carrier
    III. a sterility guarantee (SAL) level of 10-6.
    Still another aspect of the invention relates to a carrier of compressed collagen wound according to the invention for use in tissue sealing, tissue bonding and hemostasis.
    Yet another aspect of the invention relates to a carrier of compressed collagen wound according to the invention for use in minimally invasive surgery.
    Another aspect of the invention relates to a carrier of compressed collagen wound according to the invention for use in endoscopic surgery.
    A further aspect of the invention relates to a coiled rolled collagen carrier unwound according to the invention for use in tissue sealing, tissue bonding and hemostasis.
    Another aspect of the invention relates to a coiled rolled collagen carrier unwind according to the invention for use in minimally invasive surgery.
    One aspect of the invention relates to an unrolled compressed collagen carrier according to the invention for use in endoscopic surgery.
    Still another aspect of the invention relates to a carrier of compressed collagen mechanically wound at least in part, unwound according to the invention for use in tissue sealing, tissue bonding and hemostasis.
    Still another aspect of the invention relates to a carrier of compressed collagen mechanically wound at least in part, unwound according to the invention for use in minimally invasive surgery.
    One aspect of the invention relates to a carrier of compressed collagen mechanically wound at least in part, unwound according to the invention for use in endoscopic surgery.
    Another aspect of the invention relates to a carrier of compressed collagen wound according to the invention for use in the prevention or treatment of tissue that requires sealing and / or bonding.
    One aspect of the invention relates to a carrier of compressed collagen wound according to the invention for use in the prevention or treatment of bleeding in a tissue that requires hemostasis.
    A further aspect of the invention relates to a carrier of compressed collagen wound according to the invention for use in the prevention or treatment of an injury associated with performing minimally invasive surgery.
    Still another aspect of the invention relates to a carrier of compressed collagen wound according to the invention for use in the prevention or treatment of a lesion associated with performing an endoscopic treatment, laparoscopic treatment or thoracoscopy treatment.
    Still other aspects of the present invention relate to a process for winding a collagen carrier, the collagen carrier comprising (i) a collagen layer and (ii) a coating layer preferably comprising fibrinogen and thrombin, said method comprising the sequential stages of:
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    -contained in ammonium at most 0.5%, -contained in soluble proteins, calculated as albumin content, at most 0.5%,
    5 -contained in sulphate ashes at most 1.0%, -contained in heavy metals at most 20 ppm,-microbiological purity at most, 103 CFU / g, -contained in collagen from 75% to 100%, -density of 1 -10 mg / cm3, such as 2-7 mg / cm3,
    15-modulus of elasticity of 5-100 N / cm2, such as 10-50 N / cm2, and in which when the parts of the sponge are isolated, the sponge has the following properties: - modulus of elasticity in the range of 5 to 100 N / cm2,
    - density in the range of 1 to 10 mg / cm3, - chamber diameter of more than 0.75 mm and less than 4 mm, or an average chamber diameter of at most 3 mm.
    25 Note that the density of a collagen carrier is the density of the collagen carrier excluding the coating layer. Preferably, the collagen layer complies with at least the following: - pH value between 5.0 and 6.0, - maximum lactic acid content 5%, - maximum 0.5% ammonium content, 35 - content soluble proteins, calculated as a content of albumin, at most 0.5%, -contained in sulfate ashes at most 1.0%, -contained in heavy metals at most 20 ppm, -microbiological maximum, 103 CFU / g, - 75% to 100% collagen content, 45
    - density of 1-10 mg / cm3, such as 2-7 mg / cm3. In addition, the collagen layer is air and liquid tight in the sense that, once the collagen sponge is applied to a wound, it will not allow air or liquid to pass through the collagen layer. Liquids are absorbed in the layer. This effect is mainly achieved due to the fact that the collagen layer has a three-dimensional structure with stacked chambers separated and substantially enclosed entirely by collagen material walls, unlike known collagen sponges having a fiber structure.
    55 In the present context, the term "chamber diameter" shall be understood as the maximum distance in a straight line from one wall to another in a chamber, that is to say the maximum distance in a straight and diagonal line of a chamber. The cameras can have a polygonal shape, such as an octagonal shape. Therefore, when the carrier is cut, the chambers divide and cut into deep 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 at most 3 mm, makes the collagen sponge particularly useful for coating with a preparation of fibrin adhesive. When the carrier is cut, the chambers divide and cut into deep cavities. The preferably solid fibrinogen and preferably solid thrombin is fixed to the collagen layer and most of it is present in the deep cavities, thus providing a substantially uniform distribution of the preferably solid thrombin and the preferably solid fibrinogen. Because of this and fixation, it is possible to introduce substantial amounts of fibrinogen and thrombin into the carrier unlike the situation in the
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    drug, which is used directly without prior exposure to one or more physical manipulations such as, for example, humidification, compression, humidity and high ambient temperature or gamma radiation. Preferably, the winding process can be applied to any collagen carrier that has previously been exposed to one or more of said physical manipulations. In the present context the words roll up,
    5 roll, rotate or rotate are used interchangeably.
    By the term "compressed collagen carrier" refers preferably to a compressed collagen carrier, which has been subjected to a uniformly distributed pressure (ie compression) to achieve the following physical properties: a coating comprising solid fibrinogen and thrombin solid that is uniformly distributed and fixed on said collagen carrier, and which has at least one of the following physical properties in the unwound state:
    I. a thickness of a maximum of 4 mm
    15 II. an adhesive force of at least 40 mmHg measured after unwinding by a pressure test (PCT)
    III. a sterility guarantee (SAL) level of 10-6.
    In an embodiment of the present invention, said compressed collagen carrier has been optionally moistened either before or optionally after the compression step on at least one side of said collagen carrier. Said carrier of compressed collagen has been optionally mechanically processed at least in part.
    25 By the term "compress" refers to the procedure for compressing an object such as a collagen carrier and refers in the present context to the procedure in which the collagen carrier, when compressed, is subjected to a uniformly distributed pressure . The words compression or compaction are used interchangeably. Similarly, expressions that explain that an object can be compressed, pressed
    or compacted are used interchangeably herein. The collagen carrier can be compressed, for example, when it passes through a set of rollers using a certain gap size. The collagen carrier that is pressed is preferably a moistened collagen carrier or a non-moistened collagen carrier. The use of a roller compactor (mechanical compression) is preferred. Thus, compression can be performed by any conventional manual or mechanical way of compressing an object by subjecting it to a uniformly distributed pressure, that is, preferably by passing it through
    35 a set of rollers by roller compaction, placing the carrier between two sets of uniform / flat plates, the upper plate being a plunger, or winding a cylindrical object on said carrier which is placed on a flat, uniform lower plate.
    The term "gap size" refers in the present context to the shortest distance measured in mm between the rollers in a roller compactor. Preferably, compression is performed by roller compaction using a gap size between the rollers of no more than 0.30 mm, such as no more than 0.35 mm, such as no more than 0.40 mm, such as not more than 0.45 mm, such as not more than 0.50 mm, such as not more than 0.55 mm, such as not more than 0.60 mm, such as not more than 0.65 mm, such as not more 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, such as not more than 0.90 mm, such as no more than 0.95 mm and such as no more than 1.00 mm. It is preferred to use a gap size between the rollers of about 0.45-0.75 mm, such as about 0.45-0.70 mm, such as about 0.450.65 mm, such as about 0.45-0, 60 mm, such as approximately 0.45-0.55 mm, such as approximately 0.45-0.50 mm, such as approximately 0.50-0.75 mm, such as approximately 0.550.75 mm, such as approximately 0.60-0.75 mm, such as approximately 0.65-0.75 mm, such as approximately 0.70-0.75 mm, such as approximately 0.50-0.70 mm, such as approximately 0.500, 65 mm, such as approximately 0.50-0.60 mm, such as approximately 0.60-0.70 mm, such as approximately 0.60-0.65 mm. An interstitium size of approximately 0.40 mm results in hard / strong compression, while an interstitium size of approximately 0.75 mm results in moderate compression. Preferably, the rollers that perform said roller compaction have a diameter
    55 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 4852 mm. Said rollers are preferably made of an inflexible and inert material that does not transfer roller material to said collagen carriers compressed after compaction, that is, the surface of the rollers 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 that is evenly distributed and fixed on said collagen carrier, and that it has at least one of the following physical properties:
    65
    I. a diameter of a maximum of 10 mm
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    Therefore, the term "moistened collagen carrier" is intended to refer to a collagen carrier that has been exposed to at least one liquid solvent in preferably at least one side of said carrier, such as at least two sides, such as at least three sides, such as at least four sides, such as at least five sides, such as all sides, to achieve a moistened collagen carrier.
    In an embodiment of the present invention, the collagen carrier is preferably moistened on at least one side of said carrier (ie, the anterior side) having at least one side coated with a coating comprising biologically active substances before compressed and / or before rolling. The words moisten and moisturize are used interchangeably. In another embodiment, it is preferred to moisten both the anterior and the posterior side of a collagen carrier of the present invention, said coating comprising the anterior side. Said moistened collagen carrier has optionally been mechanically processed at least in part.
    In an embodiment of the present invention said moistened collagen carrier has a coating
    15 comprising solid fibrinogen and solid thrombin that is uniformly distributed and fixed on said collagen carrier, and having at least one of the following physical properties:
    I. a diameter of a maximum of 10 mm
    II. an adhesive force of at least 40 mmHg measured after unwinding by a pressure test (PCT)
    III. a sterility guarantee (SAL) level of 10-6.
    The term "solvent" refers to any suitable solvent such as physiological saline, purified water, aqueous vapor or any suitable organic solvent such as ethanol, dehydrated ethanol with a maximum water content of 0.1%, isopropanol or methanol An alcohol is selected from the group consisting of ethanol, dehydrated ethanol with a maximum water content of 0.1%, 1-propanol, 2-propanol, 2-methyl-2-propanol, ethylene glycol, 1-butanol, 2-butanol or any combination thereof. In one embodiment a solvent is selected from ethanol, dehydrated ethanol with a maximum water content of 0.1%, isopropanol, 1-propanol, 2-methyl-2-propanol, water or any combination thereof. In a further embodiment, a solvent is selected from ethanol, dehydrated ethanol with a maximum water content of 0.1%, isopropanol, water or combinations thereof. In one embodiment the ethanol is dehydrated ethanol with a maximum water content of 0.1%. In an embodiment of the applied solvent, the amount of solvent
    35 applied is about 0.8-10.75 mg / cm2 of collagen carrier, such as about 1,210.75 mg / cm2 of collagen carrier, such as about 0.8-10.4 mg / cm2 of carrier of collagen. collagen, such as about 0.8-6.1 mg / cm2 of collagen carrier, such as about 1.2-4.7 mg / cm2 of 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 water content of 0.1% and water or isopropanol and water, where the amount of water is up to 20%, such as up to 18%, such as up to 16%, such as up to 14%, such as up to 12%, such as up to 10%, such as up to 8%, such as up to 6%, such as up to 5%, such as up to 4%, such as up to 3%, such as 2.4%, such as up to 2%, such as up to 1.5%, such as up to 1%, such as up to 0.5%. The solvent may also contain fibrinogen and / or thrombin and / or albumin and / or some salt. In
    A further embodiment, ethanol or dehydrated ethanol with a maximum water content of 0.1% is the preferred solvent and is used in an amount of about 9 mg of ethanol / cm 2 of collagen carrier, such as about 8 mg of ethanol / cm2 of collagen carrier, such as about 7 mg of ethanol / cm2 of collagen carrier, such as about 6 mg of ethanol / cm2 of collagen carrier, such as about 5 mg of ethanol / cm2 of collagen carrier , such as about 4 mg of ethanol / cm2 of collagen carrier, such as about 3 mg of ethanol / cm2 of collagen carrier, such as about 2 mg of ethanol / cm2 of collagen carrier, such as about 1.2 mg of ethanol / cm2 of collagen carrier, such as about 1 mg of ethanol / cm2 of collagen carrier, such as about 0.5 mg of ethanol / cm2 of collagen carrier.
    55 Without being limited by theory, it is assumed that the use of more than about 10.75 mg of ethanol or dehydrated ethanol with a maximum water content of 0.1% / cm2 of collagen carrier, such as about 10.4 mg of ethanol / cm2 of collagen carrier could cause said collagen carriers to become sticky when compressed. Thus, the use of an ethanol level of no more than 10.75 mg of ethanol / cm 2 of fleece with collagen is preferred.
    The term "relative humidity (RH)" refers to the amount of water vapor in a mixture of air and water vapor. In one embodiment, the process according to the present invention is performed at 10-75% RH, such as 30-50% RH, such as 30-60%, such as 30-64% RH, such as 30-65% RH, such as 30-70% RH, such as 40-60% RH, such as 40-64% RH, such as 40-70% RH and optionally 65 at a temperature of 5-30 ° C, such as 18-22 ° C, such as 18-25 ° C. In a preferred embodiment, the RH is 30-50% and the temperature is 18-22 ° C which is the relative humidity range and the temperature range
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    Preferred room (for example, the manufacturing facility) in which rolled and / or compressed collagen carriers are processed. See below when the term "dry" is defined. In another embodiment the range of relative humidity and room temperature (for example, the manufacturing facility) in which the rolled and / or compressed collagen carriers are processed is approximately 25 ° C and 64-70% of HR
    5 The term "modulus of elasticity" refers to the tendency of an object to deform elastically, that is, not permanently when a force is applied to it. In the present context, the elastic modulus 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 parameter well known in the technique of measuring elasticity, as disclosed for example in the J.E. Gordon, The New Science of Strong Materials or Why You Don’t Fall Through the Floor, pages 38-43 and EP 1 053 757 B1. Therefore, the modulus of elasticity represents the elastic flexibility of a material, the flexibility of any given object.
    15 By "modulus of elasticity" refers to Young's modulus, E, the physical constant, which is characterized by the stiffness of an elastic material. E is force (N) divided by area (mm2), written as N / mm2 or MPa.
    By the term "density" or the mass density of a material, reference is made to the mass per unit volume of the material. The symbol most often used for density is  although in the present context, density is defined as weight per unit volume mg / cm3, which is also called specific weight. The procedure and equipment used to determine the density are disclosed in more detail in the examples section below. The density of a collagen carrier according to the present invention is the density of the collagen carrier excluding the coating layer. In an embodiment of the present invention, carrier density
    25 of collagen before wetting and / or winding and / or compression, such as for the collagen carrier provided in step (a) of the present invention, is in the range of 1-10 mg / cm 3, as in the range of 1-9 mg / cm3, such as in the range of 1-8 mg / cm3, such as in the range of 1-7 mg / cm3, such as in the range of 1-6 mg / cm3, such as in the range of 1-5 mg / cm3, such as in the range of 1-4 mg / cm3, such as in the range of 1-3 mg / cm3, such as in the range of 1-2 mg / cm3, such as in the range of 2-9 mg / cm3, such as in the range of 2-8 mg / cm3, such as in the range of 2-7 mg / cm3, such as in the range of 2-6 mg / cm3, such as in the range of 2-5 mg / cm3, such as in the range of 2-4 mg / cm3, such as in the range of 3-9 mg / cm3, such as in the range of 3-8 mg / cm3, such as in the range of 3-7 mg / cm3, such as in the range of 3-6 mg / cm3, such as in the range of 3-5 mg / cm3, preferably as in the in range of 3.0-4.5 mg / cm3, such as in the range of 3.0-4.4 mg / cm3, such as in the range of 3.0-4.3 mg / cm3, as in the range of 3.0-4.2
    35 mg / cm3, such as in the range of 3.0-4.1 mg / cm3, such as in the range of 3.0-4.0 mg / cm3, such as in the range of 3.0-3 , 9 mg / cm3, such as in the range of 3.0-3.8 mg / cm3, such as in the range of 3.0-3.7 mg / cm3, such as in the range of 3.0- 3.6 mg / cm3, such as in the range of 3.0-3.5 mg / cm3, such as in the range of 3.0-3.4 mg / cm3, such as in the range of 3.0 -3.3 mg / cm3, such as in the range of 3.0-3.2 mg / cm3, such as in the range of 3.0-3.1 mg / cm3, such as in the range of 3, 1-4.5 mg / cm3, such as in the range of 3.2-4.5 mg / cm3, such as in the range of 3.3-4.5 mg / cm3, such as in the range of 3 , 4-4.5 mg / cm3, such as in the range of 3.5-4.5 mg / cm3, such as in the range of 3.6-4.5 mg / cm3, such as in the range of 3.7-4.5 mg / cm3, such as in the range of 3.8-4.5 mg / cm3, such as in the range of 3.9-4.5 mg / cm3, such as in the range 4.0-4.5 mg / cm3, such as in the range of 4.1-4.5 mg / cm3, as in the inter value of 4.2-4.5 mg / cm3, such as in the range of 4.3-4.5 mg / cm3, such as in the range of 4.4-4.5 mg / cm3,
    The density of a moistened and / or compressed and / or rolled collagen carrier of the present invention is preferably in the range of 1-15 mg / cm3, such as in the range of 2-15 mg / cm3, as in the range of 3-15 mg / cm3, such as in the range of 4-15 mg / cm3, such as in the range of 5-15 mg / cm3, such as in the range of 6-15 mg / cm3, such as in the range of 7-15 mg / cm3, such as in the range of 8-15 mg / cm3, such as in the range of 9-15 mg / cm3, such as in the range of 10-15 mg / cm3 , such as in the range of 11-15 mg / cm3, such as in the range of 12-15 mg / cm3, such as in the range of 13-15 mg / cm3, such as in the range of 14-15 mg / cm3, such as in the range of 3-14 mg / cm3, such as in the range of 3-12 mg / cm3, such as in the range of 3-10 mg / cm3, such as in the range of 3- 9 mg / cm3, such as in the range of 3-8 mg / cm3, such as in the range of 3-7 mg / cm3, such as in the range of 3-6 mg / cm3, as in the i range of 3-5 mg / cm3, as in the
    55 range of 3.0-4.5 mg / cm3, such as in the range of 3.0-4.4 mg / cm3, such as in the range of 3.0-4.3 mg / cm3, such as in the range of 3.0-4.2 mg / cm3, such as in the range of 3.0-4.1 mg / cm3, such as in the range of 3.0-4.0 mg / cm3, such as in the range of 3.0-3.9 mg / cm3, such as in the range of 3.0-3.8 mg / cm3, such as in the range of 3.0-3.7 mg / cm3, such as in the range of 3.0-3.6 mg / cm3, such as in the range of 3.0-3.5 mg / cm3, such as in the range of 3.0-3.4 mg / cm3 , such as in the range of 3.0-3.3 mg / cm3, such as in the range of 3.0-3.2 mg / cm3, such as in the range of 3.0-3.1 mg / cm3, such as in the range of 3.1-4.5 mg / cm3, such as in the range of 3.2-4.5 mg / cm3, such as in the range of 3.3-4.5 mg / cm3, such as in the range of 3.4-4.5 mg / cm3, such as in the range of 3.5-4.5 mg / cm3, such as in the range of 3.6-4.5 mg / cm3, such as in the range of 3.7-4.5 mg / cm3, such as in the range of 3.8-4.5 mg / cm3, such as in the range of 3.9-4.5 mg / cm3, such as in the range of 4.0-4.5 mg / cm3, such as in the range of 4.1-4.5 mg / cm3 , just like in the
    65 range of 4.2-4.5 mg / cm3, such as in the range of 4.3-4.5 mg / cm3, such as in the range of 4.4-4.5 mg / cm3.
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    The density of a moistened and / or compressed and rolled collagen carrier of the present invention is measured after unwinding said rolled collagen carrier of the present invention. Note that the density of a collagen carrier of the present invention is the density of the collagen carrier excluding the coating layer.
    5 It is currently preferred to determine the density by weighing a collagen carrier of known volume, such as a rolled and / or compressed collagen carrier of a certain size (see the examples section), such as a large-sized collagen carrier (also called strip or fleece). Density is calculated by dividing the mass of the collagen carrier by the volume of the collagen carrier. The procedure and equipment used to determine the density are disclosed in more detail in the examples section below.
    By the term "coating" reference is preferably made to a coating that either comprises or consists essentially of the biologically active substances of fibrinogen and thrombin that are uniformly distributed and are fixed on at least one side of a collagen carrier of the present invention, such as a carrier of rolled and / or compressed collagen, such as a carrier of rolled and / or unrolled collagen. The coating may also include, for example, riboflavin (yellow as a coated area marker). In an embodiment of the present invention, the active substances are preferably solid human fibrinogen, solid human thrombin and optionally solid riboflavin. Therefore, in one embodiment of the invention, the coating consists essentially of solid human fibrinogen, solid human thrombin and solid riboflavin. The coating is present on at least one side of the collagen carrier, such as a rolled and / or compressed collagen carrier, such as a rolled and / or unrolled collagen carrier. Thus, in one embodiment the collagen carrier, such as a rolled and / or compressed collagen carrier, such as a rolled and / or unrolled collagen carrier comprises one
    or several active sides where fibrinogen is present in an amount of 1.3-10 mg / cm2, such as 2-10
    25 mg / cm2, 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 / cm2, such as 0.9 -15 IU / cm2, such as 0.9 -10 IU / cm2, such as 1.0-5.5 IU / cm2, preferably such as about 1.3 -2.7 IU / cm2, such as approximately 2.0 IU / cm2. Said coating is preferably applied to at least one side of said collagen carrier, such as a rolled and / or compressed collagen carrier, such as a rolled and / or unrolled collagen carrier.
    When the collagen carrier, such as a rolled and / or compressed collagen carrier, such as a rolled and / or unrolled collagen carrier, has a coating on one side of said carrier and when the side coated with the substances is wound biologically active can be oriented externally on said
    The carrier of rolled collagen, or the side coated with the biologically active substances can be oriented internally on the carrier of rolled collagen. Currently, the first alternative is preferred for a carrier of compressed collagen wound of the present invention, that is, the external orientation of said coating.
    By the term "diameter" of, for example, the wound collagen carrier refers to the cross-sectional diameter of any type of collagen carrier that has been wound or wound according to the present invention. Therefore, the diameter of the resulting rolled collagen carrier measured in the cross section (for example the shortest side) is approximately 5-12 mm, such as approximately 6-11, such as approximately 7-10 mm, such as approximately 8-9 mm, such as a maximum of 11 mm, preferably such
    45 at most 10 mm, preferably at most 9 mm, at most 8 mm, at most 7 mm, at most 6 mm, at most 5 mm, at most 4.5 mm, such as a maximum of 4 mm, such as a maximum of 3.5 mm, such as a maximum of 3 mm, such as a maximum of 2.5 mm, such as a maximum of 2.0 mm, such as a maximum of 1.5 mm, at most 1.0 mm. The preferred diameter is less than 10 mm for medium-sized fleeces, that is medium-sized fleeces having the dimensions 46-49 mm * 46-50 mm * 4-7 mm. Figure 3 shows the length and width of a collagen carrier previously wound according to the invention.
    By the term "thickness" refers to the shortest measurable distance by any collagen carrier of the invention that is unwound or not rolled, which means that the thickness depends on whether the carrier of
    Collagen has been rolled or not previously and / or if it has been compressed, moistened or not previously. When the term thickness is used to describe any type of unwound or uncoiled collagen carrier according to the present invention, the thickness is intended to refer to the thickness that is about 1-10 mm, such as about 2-8, such as about 4 -6, such as maximum 10 mm, such as maximum 9 mm, such as maximum 8 mm, such as maximum 7 mm, such as maximum 6 mm, such as maximum 5 mm, such as maximum 4 mm, such as a maximum of 3 mm, such as a maximum of 2 mm, such as a maximum of 1 mm. In one embodiment, the preferred thickness of a collagen carrier is 4-7 mm. In another embodiment, the preferred thickness of an unwound collagen carrier is a maximum of 4 mm.
    The term "adhesive force" refers to the capacity of a collagen carrier, such as a carrier.
    65 of collagen wound and / or compressed, to adhere to living tissue and therefore, the adhesive strength reflects the pharmaceutical activity of a collagen carrier according to the invention, that is, the ability of a collagen carrier, such
    18
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    Isopropanol and ethanol. Water is removed by drying using a desiccant, such as, for example, silica gel. Elimination by drying the water can last 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 about 6 hours, such as until
    5 approximately 2 hours. Elimination by drying the water preferably lasts up to about 24 hours.
    Preferably, silica gel is used to refer to a granulated, vitreous and porous form of silicon dioxide which is synthetically obtained from sodium silicate. Silica gel is a desiccant commonly used as pearls packaged in a permeable bag.
    Endoscopic instrument: by "endoscopic instrument" reference is made herein to any endoscopic instrument known to one skilled in the art, for example endoscopic grip pliers, endoscopic forceps, endoscopic dissector, endoscopic forceps, Johanson clamping device or other
    15 endoscopic holding device, endoscopic scissors, an endoscopic gripping device, two or more gripping devices, laparoscopic applicators (preferably fixed to long pins or attached to gripping devices) or other suitable endoscopic instrument.
    In one embodiment of the present invention, drying an optionally moistened collagen and / or compressed collagen carrier according to the invention does not affect the physical and chemical properties of said collagen carrier or in vitro adhesion (to liver tissue ) and the adhesive strength (PCT value) of said collagen carrier. In an embodiment of the present invention, an optionally moistened collagen and / or compressed collagen carrier is dried by passive evaporation of a solvent, preferably ethanol, controlling the room temperature and the room humidity being within the ranges of these 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% RH, preferably 18-22 ° C, 40-60 % RH, such as 18-22 ° C, 36-65% RH, such as at 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 18-23 ° C, 40-60% RH, such as 18-21 ° C, 40-60% RH, such as 18-19 ° C, 40-60% RH , such as 18-25 ° C, 35-60% RH, such as 1825 ° C, 30-60% RH, such as 18-25 ° C, 40-65% RH, such as 18-25 ° C, 40- 70% RH, such as 18-25 ° C, 40-75% RH, ta 1 as at 18-25 ° C, 40-80% RH, such as at 18-25 ° C, 45-80% RH, such as at 18-25 ° C, 5080% RH, such as at 18-25 ° C, 55-80 % RH, such as 18-25 ° C, 60-80% RH, such as 18-25 ° C, 65-80% RH, such as 18-25 ° C, 70-80% RH, such as 18 -25 ° C, 75-80% RH. Said carrier of collagen wound and / or optionally moistened tablet is preferably dried 30 minutes by blowing air with a
    Moisture less than said collagen carrier (such as a rolled and / or compressed collagen carrier that needs to be dried) on said collagen carrier followed by passive evaporation of the solvent by placing said collagen carrier in a desiccator.
    Evaporation and / or drying time of up to 24 hours, such as up to 20 hours, such as up to 15 hours, such as up to 10 hours, such as up to 5 hours, such as up to 1 hour, such as up to 50 minutes, is preferred , such as up to 40 minutes, preferably such as up to 30 minutes, such as up to 20 minutes, such as up to 10 minutes, such as up to 5 minutes, such as up to 1 minute, such as up to 50 seconds, such as up to 40 seconds, such as up to 30 seconds, such as up to 20 seconds, such as up to 10 seconds, such as up to 5 seconds.
    A residual amount of at least one liquid solvent applied to the collagen carrier is acceptable, such as a rolled and / or compressed collagen carrier such as not more than 0.1% by weight, or such as not more than 0.2 % by weight, or such as not more than 0.5% by weight, or such as not more than 0.8% by weight or such as not more than 1.0% by weight, or such as not more than 1, 2% by weight, or such as not more than 1.4% by weight, or preferably such as not more than 1.6% by weight, or such as not more than 1.8% by weight, or such as not more 2.0% by weight, or such as not more than 2.5% by weight, or such as not more than 3.0% by weight, or such as not more than 3.5% by weight, or such as not more than 4.0% by weight, or such as not more than 5.0% by weight, or such as not more than 8.0% by weight, or such as not more than 10.0% by weight, or such as not more than 12.5% by weight, or such as not more than 15.0% by weight, or such as not more than 17.5% by weight, or such as not more than 20.0% by weight , or such as not more than 22.5% by weight , or such as not more than 25.0% by weight, or such as not more than 27.5% by weight, or such as not more than 30.0% by weight, or such as not more than
    55 32.5% by weight, or such as not more than 35.0% by weight. When the liquid solvent applied is ethanol, no more than 1.6% by weight of residual ethanol is preferred and / or when the liquid solvent applied is water, no more than 8.0% by weight of residual water is preferred, preferably as no more than 5.0% by weight. A residual amount of at least one liquid solvent applied, such as at least two liquid solvents, such as at least three liquid solvents to the collagen carrier, such as a rolled and / or compressed collagen carrier is acceptable.
    It may happen that one or more solvents or the humidity coming from the room (aqueous vapor) is passively absorbed by a collagen carrier, such as a carrier of rolled and / or compressed collagen during processing. In one embodiment, if such passive moisture absorption, such as water, has taken place, a residual amount of said moisture such as not more than 0.1% by weight, such as not more than 0.2% in 65, is acceptable. weight, such as not more than 0.5% by weight, such as not more than 0.8% by weight such as not more than 1.0% by weight, such as not more than 1.2% by weight, such as not more than 1.4% by weight, such as not more than 1.6% by weight, such as not
    twenty-one
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    5.1 Material used
    The test was based on the use of the following three batches of medium-sized fleeces (none of the fleeces had undergone gamma irradiation: 5 -10622250 (strip weight: approximately: 920 mg based on the measurement of 10 strips).
    -10634435 (strip weight: approximately 1180 mg).
    10 -10657586 (strip weight: approximately: 1261 -1500 designated as: 1380 mg
    Note that the "weight" of the collagen carriers mentioned above means the weight of the collagen carrier excluding the weight of the coating layer.
    15 5.2 Used factors The design used was a full 32 factorial design with three replicas of the center point. Fixed factors: fixed interstitium size: 0.6 mm. Room RH ≤ 50% (a deviation of up to 55% is allowed).
    20 Room temperature (18) 20-22ºC. Variable factors: ethanol levels: 30-40 mg / fleece; 90 -100 mg / fleece; 150-160 mg / fleece. Strip weight. 5.3 Answers
    25 pct (mmHg)
    Dimensions of the fleece after winding (diameter (cm) and length (cm))
    30 5.4 Results The table shows the temperature and RH when the fleeces are processed. By "strip weight" reference is made to the
    Collagen carrier weight excluding the weight of the coating layer. 35
    Experiment Ethanol {mg / fleece}Strip Weight (mg)Temp (ºC) RH% During windingTemp (ºC) RH% Before dryingTemp (54.0% ºC) RH% After drying
    N10 95118021.8-22.1 ° C 45.2-53%22.1 ° C 55.2%21.6ºC 54.3%
    N4 39118020.5 -20.9 ° C 46.8-47.7%21.0ºC 48.1%22.2º 53.8%
    N1 3992021-1-21.4 ° C 48.6-48.8%21.4 49.0%22.2 ° C 54.3
    N5 98118020.5-20.7 ° C 50.6-51.020.8 ° C 51.4%21º 55%
    N7 39138020.8-20.9ºC 53.0-53.2%21.0ºC 53.5%21.0ºC 59.2%
    N6 153118021.2-21.3 ° C 54.5-54.6%21.4ºC 55.0%20.9 ° C 56.6%
    N11 94118019.0-19.1 ° C 51.7-51.9%19.2ºC 51.8%19.9 ° C 55.0%
    N12 94118019.3-19.4 ° C 51.8-51.9%19.4 ° C 52.0%20.1 ° C 55.2%
    N8 94138019.4-19.6ºC 52.2-52.4%19.6 ° C 52.3%20.2 ° C 55.9%
    N3 15892019.6-19.8ºC 53.5-53.4%19.9 ° C 53.5%19.8 ° C 56.7%
    N2 10492018.9-19.2ºC 53.0%19.3ºC 53.0%20.0 ° C 52.9%
    N9 154138019.8-19.9ºC 53.9-54.0%20.0ºC 54.0%20.8ºC 55.8%
    fifty
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    权利要求:
    Claims (1)
    [1]
    image 1
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    EP11167379|2011-05-24|
    EP11167379|2011-05-24|
    PCT/DK2012/050178|WO2012159635A1|2011-05-24|2012-05-24|Rolled collagen carrier|
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