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WO2009083263A2 - Transport, distribution and/or effective system in aseptic administration - Google Patents

Transport, distribution and/or effective system in aseptic administration

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Publication number
WO2009083263A2
WO2009083263A2 PCT/EP2008/011155 EP2008011155W WO2009083263A2 WO 2009083263 A2 WO2009083263 A2 WO 2009083263A2 EP 2008011155 W EP2008011155 W EP 2008011155W WO 2009083263 A2 WO2009083263 A2 WO 2009083263A2
Authority
WO
Grant status
Application
Patent type
Prior art keywords
system
collagen
active
bone
transport
Prior art date
Application number
PCT/EP2008/011155
Other languages
German (de)
French (fr)
Other versions
WO2009083263A3 (en )
Inventor
Arne Briest
Original Assignee
Ossacur Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56Porous materials, e.g. foams or sponges
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L26/00Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0028Polypeptides; Proteins; Degradation products thereof
    • A61L26/0033Collagen
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L26/00Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061Use of materials characterised by their function or physical properties
    • A61L26/0066Medicaments; Biocides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L26/00Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061Use of materials characterised by their function or physical properties
    • A61L26/0085Porous materials, e.g. foams or sponges
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L26/00Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061Use of materials characterised by their function or physical properties
    • A61L26/009Materials resorbable by the body
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14Macromolecular materials
    • A61L27/22Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/24Collagen
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58Materials at least partially resorbable by the body
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404Biocides, antimicrobial agents, antiseptic agents
    • A61L2300/406Antibiotics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412Tissue-regenerating or healing or proliferative agents
    • A61L2300/414Growth factors
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/45Mixtures of two or more drugs, e.g. synergistic mixtures

Abstract

The invention relates to an at least partially bioresorbable transport, distribution and/or effective system having a layer or sandwich structure, comprising a nonwoven material as a frame, into which collagen is built for configuring the layer and/or onto which collagen is bonded for configuring the sandwich structure. At least one of the surfaces of the transport, distribution and/or effective system comprises a substantially porous surface. Additionally, a pharmaceutical can be present. Furthermore, the system may comprise at least one osteoinductive or chondroinductive active substance, such as one of the differentiation and/or growth factors of the TGF ß-super family. The nonwoven material comprises fibers that are selected from cellulose fibers, such as rayon, polyester, polyacryl nitrile, optionally in combination with a super absorber. The invention further relates to a method for the production of the system and to the system as aseptic administration. To this end, the system is located in a container that is closed off by means of a plastic film molded part in the shape of a membrane-like film as a sterile barrier.

Description

Transportation, Weitergabe- and / or active system in aseptic administration

The invention relates to a transport, Weitergabe- and / or active system comprising a nonwoven fabric, among other things, its use, a process for its preparation and an aseptic dosage form of the system.

Biomaterials in the form of polymers as carriers for the controlled in vivo release of drugs or other agents are being researched intensively for some time. Such systems usually consist of a substantially spherical, polymeric matrices (microparticles) as support materials which contain an active ingredient which is to be released time controlled at a defined location in the body of a patient.

Meanwhile, a larger number of suitable biomaterials are known for use as such a support material is used and depending on the type of use. So polyurethanes are preferred when it comes to applications in which a very high elasticity is required, polysiloxanes are used for their insulating or shielding properties, polymethyl (meth) acrylates are for material strength and transparency, polyvinyl alcohols exhibit a pronounced hydrophilic property and strength, polyethylenes are characterized for certain applications by their resilience and their lack of swelling capacity and polyvinylpyrrolidones are used because of their good suspensibility. have as bioresorbable materials for medical use in recent times above all carriers on the basis of polylactide (PLA), polyglycolides (PGA), polylactide-co-glycolides (PLGA), made headlines polyanhydrides and polyorthoesters of himself.

Active ingredients which are to be transported in combination with such bioresorbable polymers to specific locations in a body may be varied in nature. These include drugs such as painkillers, antibiotics, cytostatics and / or anticoagulant agents, to name a few examples drug groups. Another area of ​​application is the field of osteoinductive or chondroinductive agents.

To cure due to an accident or other influences damaged bone, cartilage or generally damaged organs, a variety of bioresorbable bone substitute materials in the prior art already known with different therapeutic approaches that aim generally to support the body's own healing mechanisms and accelerate. In this case, support materials of importance that are implanted at the site of the damaged bone, cartilage or organ that enable the migration of needed for the healing process cells and optionally also specify a structure that facilitate the bone, cartilage or organ regeneration or the structure thereof , and then degraded but after a certain time by the body that are metabolized. The exploration of support materials, including the development of new vehicles or the improvement of existing systems has generally under the name of tissue engineering found in this area entrance into the professional world.

By US-A-5,222,987 a composite material has been known to serve as a support material for new bone formation. This composite material is provided as a planar structure, having at least one layer of a fiber-like web or fabric and at least one further layer of a composition comprising a polymer, a curable resin and an initiator for a Adhäsionspolymerisation. The support material thus obtained is to serve as a substitute for, for example, metallic implants on the basis of tantalum, titanium or stainless steel.

Prosthetic implants of this type are used to replace missing bone or bone areas and stabilize fractures. They themselves are not able to form bone. The missing or damaged bone area must be regenerated on their own. This often requires too long a period of convalescence or bone regeneration is limited.

The US-A-4,950,483 discloses a porous collagen matrix for wound healing, which consists of non-crosslinked collagen fibers. This wound healing matrix may also serve for the release of a synergistic combination of the growth factors FGF and TGF-ß. This allows the body's own healing process is supported and accelerated.

On this basis therefore, the present invention was based on the object to provide a transport, Weitergabe- and / or operative system, which is versatile in application to drugs or other agents in vivo at a location in the

transporting organism, where they may be selectively released, and the other hand is in particular able to promote bone formation in an organism by supplementing a targeted selection of one or more active ingredient (s) and induce, in which it defines a structure defined for a

Time can be used in the area of ​​the bone defect. This object is achieved by a transport, Weitergabe- and / or knitting system with a layered or sandwich structure, comprising a nonwoven fabric as a builder incorporated in the collagen to form the layer and / or attached to the collagen to form the sandwich structure, and that is at least partially bioresorbable, wherein at least one of the surfaces of the transport, Weitergabe- and / or operative system having a substantially porous surface.

In this way a flat structure, which is a highly efficient support system is created. Preferably, the carrier system, and thus the erfϊndungsgemäße transport, Weitergabe- and / or active system comprises at least one porous surface. Such a system such permits. As the delayed release of active ingredients such. B. of diverse pharmaceuticals. The

Agents and / or pharmaceutical active ingredients are not only transported to the desired site of action in the body, but there also deliberately released. In this respect, the inventive system provides not only for the

Transport of the active ingredient or drug ingredient, but it also provides a

Relay system. In addition, it can,. Example, in an application in the field of

Osteogenesis intrusion of required for the growth of bone cells from the environment into which it has been implanted, allow and thus represent a scaffold for bone (new) formation. Here, the property of the system according to the invention is used as an effective system for supporting.

Basically, is called the present system as transport, Weitergabe- and / or active system for the fact that his special

enables design of both the transport of drugs of all kinds in an organism, as well as their release and thus its distribution to targeted, selected sites allowed in an organism, in which case depending on the type of the selected agent or the selected agents and / or drugs is a partial longer ongoing interaction between the inventive

system can take place and the vicinity of the place to which the system has been placed so that it can be described also as an active system. This is true even if the system according to the invention without the addition of an active ingredient and / or pharmaceutical active substance is introduced into an organism. Due to its special non-woven collagen structure, it can be used both in the effect in its embodiment in the shift as the sandwich form a partially longer-lasting interaction with the environment and be at least promotes healing. This will be explained below in particular with regard to its suitability as transport, Weitergabe- and / or active system in the field of bone formation once more closer.

Special mention is also the exclusive or additional suitability of transport according to the invention, Weitergabe- and / or active system for hemostasis as Haemostypticum. So far as such Hämostyptica essentially collagen have been used fleeces and investigated. The transportation of the invention, Weitergabe- and / or active system can also serve as a local supplier of painkillers. As such, it can be used in conjunction with an effective system for bone or skin (new) education or other active system exclusively or in addition.

The nonwoven fabric of the transport, Weitergabe- and / or operative system preferably includes fibers selected from cellulose, polyester, polyacrylonitrile, optionally in combination with at least one superabsorbent or a combination of two or more of said components.

The term of the cellulose fibers is very comprehensive understanding. It comprises fibers based on cellulose, such as viscose. As in the present

Invention, suitable materials should be in addition to the viscose also includes products that have become known under the term nano cellulose, especially as bacterially synthesized cellulose under the brand name of BASYC Jenpolymers. Even more fibers made of cellulose and are made of natural pulp, also modal fibers, Tencel lyocell fibers, or may be used. In a preferred embodiment, the nonwoven is a nonwoven based of cellulose and polyester fibers, in particular of viscose and polyester fibers.

In a further preferred embodiment, the nonwoven is a nonwoven based on viscose or polyacrylonitrile fibers, optionally in combination with a superabsorbent.

Through the optional use of a super-absorber, the said non-woven fabric on the basis of viscose and acrylic fibers the ability to particularly high liquid absorption on that measured with respect to water as the liquid at least 5000 g / sqm, preferably more than 5400 g / square meter, is.

The collagen of the transportation according to the invention, Weitergabe- and / or active system is preferably selected from collagen type I. Also, as an advantageous collagens those of type II, to name III, V and XI, which are all known as so-called fibrillar collagens.

It can be provided that the system according to the invention contains in addition to other active ingredients a drug which is selected from the group of analgesics, antibiotics, cytostatic agents, anticoagulant agents or mixtures thereof. On the possibility of using the inventive system as Haemostypticum, has already been mentioned above.

When the transport of the present invention, Weitergabe- and / or active system comprises at least one osteoinductive or chondroinductive agent according to another preferred embodiment, in addition, it can be considered a

Active system in the sense of promoting the bone and / or cartilage growth

By means used. The osteoinductive or chondroinductive agent can be selected from at least one of differentiation and / or growth factors of the TGF-ß superfamily, and particularly preferably it is selected from the group consisting of bone morphogenic proteins (BMP), wherein here especially the growth factors are BMP-7 , BMP-2 and BMP-4 are to be emphasized. The one or more selected osteoinductive or chondroinductive active ingredients may preferably be produced recombinantly. In addition, optionally, at least one drug may agent of the invention here also included, which may for example be selected from the group of analgesics, antibiotics, cytostatic agents, anticoagulant agents or mixtures thereof. Here, the inventive system proved as combined transport, Weitergabe- and effective system and proves to be particularly effective in order to ensure sustained over a certain period of time-release or delayed drug as drug release. Here it, even the special ability to come in addition to its ability to be used as a transport system to serve as a relay system with triggered drug release.

The transport of the present invention, Weitergabe- and / or active system not only can additionally comprise at least one osteoinductive or chondroinductive agent, it can also be provided, of which employ a precursor in the form of a genaktivierten material. Then, an intracellular protein synthesis is thereby set in motion, that locally one or more genes are applied, wherein BMP-2 and BMP-7 coding plasmids to be expressly mentioned here.

Particularly preferred transportation to the invention, Weitergabe- and / or active system has a double-layered and has most preferably a sandwich structure. The Doppelschichtigkeit turns out in terms of the periosteum as important. This outermost layer of the bone, which mainly has protective and nutritive function for the bone is extremely thin, while well supplied with blood and many nerve endings. It is also known that a bone fracture healing of these bone skin starts. The inventive Doppelschichtigkeit or sandwich structure, the one side of the transport, Weitergabe- and / or operative system, which preferably consists of the fleece, this bone skin facing, while the other side of the double system, faces outward and thus an outer surface becomes separation and for separating the various components of the vicinity of a part, and the release of the active compound or compounds, such as the bone or cartilage forming means on the other hand allows. The nonwoven fabric of the sandwich structure so formed thus acts as a diaphragm, serves as a boundary surface or semi-permeable barrier, such as for shielding soft tissue ingrowth.

The preferably porous on both sides of the nonwoven fabric and thus at least partially transmissive surface of the transport, Weitergabe- and / or telecontrol system is used on the one hand the transfer of cells to the site where new bone formation is to take place, and on the other hand, it is a delayed release of active ingredient, the formation of new bone to stimulate over a longer period. . But they also simultaneously a barrier between the two different tissues, namely the non-woven fabric and the bone tissue is And since the nonwoven -As previously mentioned-at the same time acts as a release layer, it guarantees - and the system according to the invention, in its capacity as an active system - a protected place for an undisturbed and efficient bone formation.

As just described above, the invention therefore relates to the use of transport, Weitergabe- and / or operative system, which has at least one osteoinductive or chondroinductive agent, inducing a bone agent.

In the presence of at least one osteoinductive or chondroinductive agent, the bone formation stimulating effect of the inventive system can be selectively inserted at a predetermined site of action for a predetermined period of time.

The invention also relates to a process for the preparation of said transport, Weitergabe- and / or active system according to one of its embodiments the present invention, natural wherein the collagen from a

dissolved starting material or a solution or suspension of a collagen commercially available prepared which allowed to precipitate collagen by changing the pH, is applied to a nonwoven fabric and is freeze-dried therewith to form a carrier system, wherein doing a Kapillaren- or pore structure in the support system forms , It is particularly advantageous that the quality of the forming pore structure can be thereby controlled by the choice of temperature during freeze-drying and the speed of cooling down. The faster drops the temperature and the further cooled down, the more uniform pores. According to the invention it is preferred that at least partially a directional pore structure is formed. The aligned pore structure is obtained by setting a defined temperature gradient.

If the transport, Weitergabe- and / or active system is to have a drug or other active ingredient, the collagen according to one embodiment of the inventive method, prior to the precipitation of such a drug or other active ingredient by mixing blank added. A co-lyophilizing is accounted for.

The active substance is preferably selected from at least one osteoinductive or chondroinductive agent, a drug, or mixtures thereof.

Another variant is that the collagen initially with the at least one osteoinductive or chondroinductive active compound is mixed and applied and then at least a drug is applied to the support system of the transport, Weitergabe- and / or operative system in a further step. In this way, a multilayer system can be obtained as a sandwich structure. but it can also target the surface on the one hand, the mixed with the osteoinductive or chondroinductive agent collagen is deposited and on the other hand, the drug, which is preferably is an antibiotic are selected. Further, it is possible that different types of drugs are applied to the respectively different surfaces of the carrier system of the transport, Weitergabe- and / or operative system. Then, a drug species is preferably mixed with the collagen and the osteoinductive or chondroinductive agent and the other drug species, for example the antibiotic applied to the other surface. In this way, a selective development of the effectiveness of different drugs used can be achieved.

The invention also relates to a transport, Weitergabe- and / or active system, the characteristics of the present invention have been already been described above, in the form of an aseptic administration. In this case, the system or support system is in a container, which in turn is finished by means of a plastic sheet molded in the form of a membrane-like sheet. The film acts as a sterile barrier so that the water introduced into the container under sterile conditions for transport, Weitergabe- and / or active system is protected from harmful outside influences in the form of bacterial or other contamination.

According to a preferred embodiment, the said film which is used for the closure of the container, open to vapor diffusion.

It is thus achieved that moisture, eg in the form of water vapor, can escape to the outside from the container, without compromising the sterility of the interior.

The container is preferably a blister pack, which is also referred to as a blister. These blister packaging can be connected to the plastic film molding in the form of a weld to form a seal packaging. Then, the plastic film molded part is welded to the edges of the provided for the filling of the container opening.

Preferably, the plastic material of the membrane-like sheet of a polyolefin, a combination of polyolefins or a combination of a

Polyolefin formed with another polymer. A particularly preferred

Plastics material is high density polyethylene (HDPE) or polytetrafluoroethylene (PTFE), preferably expanded PTFE (ePTFE) may be mentioned. PTFE membranes are known as "Gore-Tex".

Most preferably, the plastic material of the membrane-like film is selected from a PE spun-bonded, preferably of a HDPE-spunbond. Membrane films from HDPE are available commercially in various execution under the trademark "Tyvek". Tyvek films are resistant to tearing, puncture-resistant and of high abrasion and chemical resistance. They are made of very fine woven fibers, which are welded with heat and pressure. in general, they are characterized by an easy processability, which is great for the present use. Compared with PTFE membranes has the advantage that it is more easily heat sealable, the HDPE film. the water vapor fusion of membranes made of PTFE, however, is excellent.

Preferably, the transport, Weitergabe- and / or active system in the aseptic administration additionally contains a drug and / or an osteoinductive or chondroinductive agent.

The invention is illustrated with reference to embodiments.

1. Preparation of a collagen solution or suspension

Is preferably used as a main component I collagen, which is obtained from tendons, since they have a particularly high proportion of collagen I to collagen suspension. Alternatively, even skin can be used as raw material for collagen production.

Based on the tendons, (alternatively the skin) of young cattle are the tendons (or whose skin layer) cleaned and, if freed from epidermal shares. The starting material is then with chloroform / methanol 1: 1 defatted, frozen in liquid nitrogen and ground in a freezer mill to a particle size of 400-1000 microns.

As another alternative, beef bones are used for the production of collagen suspension. Then, appropriate action is taken, as described for the bovine tendons or -Haut. However, it still follows a Deminerali- sierungsschritt by treatment with about 0.1 N hydrochloric acid.

The tendons or the skin or bone particles are then dried in a high vacuum at about 0.05 Torr with cooling, in a 4 M aqueous solution of guanidinium chloride and stirred at room temperature for about 12 hours. The soluble fraction thereafter obtained contains the desired collagen, which is treated in a further step with the desired active ingredients and then precipitated in an appropriate manner.

As another alternative, a commercially available collagen can be used, such as that sold under the name "InVitrogen 100" for example.

Basically, all experiments were performed as described below with three collagen variants, the collagen of animal origin, which has been obtained as just described, from human collagen and recombinant preserved collagen.

2. Preparation of a bone growth inducing agent

The collagen solution thus prepared is then added to a recombinantly produced osteoinductive agent and as such a drug osteoinductive BMP-7 is used. Furthermore, the solution is added an antibiotic. The solution or suspension thus obtained is then applied to a prepared in a suitable size non-woven fabric whose fibers are made of rayon and polyester, and as a dry non-woven under the name "Vilmed Ml 550 Basic" by Freudenberg Nonwovens, Weinheim, Germany, is obtainable . The nonwoven fabric has a thickness of about 2.9 mm and a weight of about 150g / sqm.

The amount of applied solution or suspension of collagen with active ingredients being selected such that an attachment of the offset with the active ingredients collagen obtained after the subsequent freeze-drying, which leads to the formation of a coating of the web. In the freeze-drying also pores whose size and structure can be varied by a targeted temperature setting in the freeze-drying and adjusted arise. Present undirected, unequal pores are preferred. Freeze-drying is therefore carried out by targeted setting of a temperature gradient up to -30 ° C. Basically attempts C were conducted at an interval of -20 ° C to -50 °.

Additionally or alternatively, the collagen solution, an osteoinductive agent in

Form of recombinantly produced BMP-2 is added by mixing with the collagen.

After freeze-drying the web has a porous structure with a coating of collagen, BMP-7 and / or BMP-2.

In another experimental procedure a double layer as a sandwich is made by having first the non-woven with the collagen solution or suspension, the BMP-7 and / or BMP-2, and the mixture is then freeze-dried. The mixture is then aseptically also applied as a further surface an antibiotic.

Another experiment was carried out in accordance, as outlined above. However, it was chosen as a nonwoven fiber system made of viscose, polyacrylonitrile and a superabsorbent. It also is a dry fleece, sold under the name "Vilmed M66 / 031" also by Freudenberg Nonwovens, Weinheim, Germany, is available. This fleece is characterized by a particularly high Wasseraufhahmekapazität of more than 5400 g / sqm . Its thickness is about 1.2 mm and weight of 270 g / square meter. the particularly high Wasseraumahmekapazität is particularly preferred in the intended application here.

The experiments mentioned before were performed as described, but used in place of the osteoinductive active ingredient BMP-7 a term used for the formation of cartilage active ingredient in the form of BMP-2.

The experiments were mentioned before the further performed as described, but a drug in the form of the antibiotics gentamicin and Talcoplanin used in place of the osteoinductive active ingredient BMP. 7 In this starting respectively wt .-% of the antibiotic carried out several field trials of at least 10, the best of which results are shown in the table below.

Aseptic presentation in a blister pack

The bone produced according to one of the variants described above, or cartilage growth promoting agent has been introduced for use under sterile conditions in a blister pack and then the opening of the blister covered with a membranous film, wherein the edges of the blister with the foil welded were. As a membranous film is a HDPE film was used on the one, which is available under the trademark Tyvek and on the other hand made of PTFE foil in the form of a Gore-Tex membrane.

Thus, a sterile composition is obtained, the entire preparation process must be carried out under aseptic conditions, with the individual ingredients added, as far as possible in advance sterile filtered.

hi the manner described compositions of the invention are obtained from the following ingredients: Table 1

Li animal experiments has in all samples using the growth factors are BMP-7 and BMP-2 prepared by recombinant methods as well as to the

Growth factors of human origin after about 5 days a clearly visible

Osteogenesis shown with the first vascularization.

Through the use of two antibiotics gentamicin and teicoplanin a significant reduction in implant-associated infections could be achieved with or without the additional use of growth factors.

In this approximately 6 weeks with respect to the bacterial growth

performed check-ups, which confirmed the positive result of the first day.

The transportation of the invention, Weitergabe- and / or active system is suitable for application to all types of wounds, ie both those that have been produced operationally, as well as those that are caused by a disease. As examples of preferred applications are here are the diabetic foot and open wounds of all kinds caused by insufficient blood supply can be mentioned.

The transport of the present invention, Weitergabe- and / or active system can be used, for example on bleeding wounds liver and is especially suitable by the present invention provided non-woven, for example, in combination with a superabsorbent which for this application.

Claims

claims
1. transport, Weitergabe- and / or active system is incorporated with a layered or sandwich structure, comprising a nonwoven fabric as a builder in the collagen to form the layer and / or attached to the collagen to form the sandwich structure and the at least partially is bioresorbable, wherein at least one of the surfaces of the transport, Weitergabe- and / or operative system having a substantially porous surface.
2. System according to claim 1, characterized in that the nonwoven fabric comprises fibers selected from cellulose, polyester, polyacrylonitrile, a superabsorbent, or combinations thereof.
3. System according to claim 2, characterized by a nonwoven web based on cellulose and polyester fibers, in particular of viscose and polyester fibers.
4. System according to claim 2, characterized by a non-woven on the basis of viscose and acrylic fibers, preferably in combination with at least one superabsorbent.
5. System according to any one of claims 1 to 4, characterized in that the collagen is selected from collagen type I.
6. System according to one of claims 1 to 5, characterized in that it additionally contains a drug selected from the group of analgesics, antibiotics, cytostatic agents, anticoagulant agents or mixtures thereof.
7. System according to one of claims 1 to 6, characterized in that it comprises at least an additional osteoinductive or chondroinductive agent that is preferably selected from at least one of differentiation and / or growth factors of the TGF beta superfamily, and particularly preferably from the group the bone morphogenetic proteins (BMP).
fail 8. A process for producing a transport Weitergabe- and / or telecontrol system according to one of claims 1 to 7, wherein the collagen extracted from a natural raw material or a solution or suspension of a collagen commercially available established, the collagen by changing the pH is left on or in a nonwoven fabric and lyophilized therewith to form a carrier system, wherein doing a Kapillaren- or pore structure forms in the carrier system and the temperature is lowered during the freeze-drying over a selected temperature gradient so that at least partially aligned pore form.
9. The method according to claim 8, characterized in that the collagen prior to the precipitation of an active ingredient can be prepared by mixing is added which is preferably selected from at least one osteoindukti- ven or chondroinductive agent, a drug, or mixtures thereof ..
10. A method according to claim 9, characterized in that firstly the collagen mixed with the at least one osteoinductive or chondroindukti- ven active ingredient and is applied and then at least a drug is applied to the support system in a further step.
11. Transport Weitergabe- and / or telecontrol system according to one of claims 1 to 7 ais aseptic administration, characterized by a container having the system, and which is closed by means of a plastic sheet molded in the form of a membrane-type, vapor permeable film as a sterile barrier.
12. Aseptic administration according to claim 11, characterized in that the plastic material of the membrane-like film is selected from a polyolefin, a combination of polyolefins or a combination of a polyolefin with another polymer, preferably made of HDPE or PTFE, and most preferably of expanded PTFE, or a PE spunbond, more preferably from a HDPE spunbond.
13. The use of the transport Weitergabe- and / or telecontrol system according to one of claims 1 to 7, preferably in the form of aseptic administration according to any one of claims 11 and 12, as a bone inducing agent.
14. Use according to claim 13, characterized in that the collagen is attached to the builder and both together have a sandwich structure, the builder the area of ​​to be induced bone, preferably facing the area of ​​the periosteum, and having substantially the collagen , the layer to the outside.
15. Use according to claim 13, characterized in that the collagen is incorporated into the builder to form a layer, wherein both surfaces of the layer are porous and at least partially permeable.
PCT/EP2008/011155 2007-12-31 2008-12-31 Transport, distribution and/or effective system in aseptic administration WO2009083263A3 (en)

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