WO2009083263A2

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

Info

Publication number: WO2009083263A2
Application number: PCT/EP2008/011155
Authority: WO
Inventors: Arne Briest
Original assignee: Ossacur Ag
Priority date: 2007-12-31
Filing date: 2008-12-31
Publication date: 2009-07-09
Also published as: WO2009083263A3; DE102007063395A1

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

Transport, transfer and / or action system in aseptic administration

The invention relates to a transport, transfer and / or active system, which, inter alia, has a nonwoven fabric, its use, a process for its preparation and an aseptic dosage form of the system.

Biomaterials in the form of polymers as carrier materials for the controlled in vivo release of drugs or other active substances have been intensively researched for some time. Such systems usually consist of substantially spherical, polymeric matrices (microparticles) as carrier materials which contain an active ingredient which is intended to be released at a defined point in the body of a patient in a time-controlled manner.

Meanwhile, a larger number of suitable biomaterials for use as such a carrier material are known and used depending on the type of use. Thus, polyurethanes are preferably used when it comes to uses in which the highest possible elasticity is required, polysiloxanes are used because of their insulating or shielding properties, polymethyl (meth) acrylates stand for material strength and transparency, Polyvinyl alcohols show a pronounced hydrophilic property and strength, polyethylenes are characterized for certain applications by their resilience and their lack of swelling power and polyvinylpyrrolidones are used because of their good suspensibility. As bioresorbable materials for medical use, polylactide (PLA), polyglycolidene (PGA), polylactide-co-glycolide (PLGA), polyanhydride, and polyorthoester-based excipients have been the talk of the past.

Active substances which are to be transported in combination with such bioresorbable polymers to specific locations in a body can be of diverse nature. These include e.g. Medicines, such as analgesics, antibiotics, cytostatics and / or anticoagulants, to name a few groups of drugs. Another field of application is in the field of osteoinductive or chondroinductive agents.

In order to heal bones, cartilage or generally damaged organs damaged by an accident or other influences, a large number of bioresorbable bone replacement materials have already become known in the prior art together with different therapeutic approaches, which generally aim to support and promote the body's own healing mechanisms accelerate. In this case, carrier materials are of importance, which are implanted at the site of the damaged bone, cartilage or organ, which allow the immigration of required for the healing process cells and possibly also specify a structure that facilitate the bone, cartilage or organ regeneration or the structure of the same , and then but after a certain time of the body degraded, ie be metabolized. The research of carrier materials, including the development of new carriers or the improvement of existing systems, has in this area commonly found under the name Tissue Engineering entrance into the professional world.

By US-A-5,222,987 a composite material has become known, which is to serve as a carrier material for a new bone formation. This composite is provided as a sheet comprising at least one layer of a fibrous web or web and at least one further layer of a composition comprising a polymer, a curable resin, and an adhesion polymerization initiator. The resulting support material is intended to replace e.g. metallic implants based on tantalum, titanium or stainless steel.

Denture implants of this type serve to replace missing bones or bone areas and to stabilize fractures. They themselves are unable to form bones. The missing or defective bone area must be regenerated on its own. This often requires too much time for convalescence or bone regeneration is limited.

US-A-4,950,483 discloses a porous collagen matrix for wound healing consisting of uncrosslinked collagen fibers. This wound healing matrix may also serve to release a synergistic combination of the growth factors FGF and TGF-β. This supports and accelerates the body's own healing process.

On this basis, the object of the present invention was therefore to provide a transport, transfer and / or active system which can be used in a variety of ways to deliver medicaments or other active substances in vivo to a location in the

On the other hand, in particular, it is capable of promoting and inducing bone formation in an organism by supplementing a targeted selection of one or more active substances, thereby providing a structure, which for a defined

Period of time can be used in the area of the bone defect. This object is achieved by a transport, transfer and / or active system with a layer or sandwich structure which has a nonwoven fabric as a builder, is incorporated into the collagen for forming the layer and / or is attached to the collagen for forming the sandwich structure, and that is at least partially bioresorbable, wherein at least one of the surfaces of the transport, transfer and / or active system has a substantially porous surface.

In this way, a flat structure is created, which is an extremely efficient carrier system. The carrier system and thus the transport, transfer and / or active system according to the invention preferably have at least one porous surface. Such a system allows z. B. the delayed release of drugs such. B. of different drugs. The

Active ingredients and / or active pharmaceutical ingredients are not only transported to the desired site of action in the organism, but additionally released there in a targeted manner. In this respect, the system according to the invention provides not only for the

Transport of the drug or drug, but it also stops

Transfer system. In addition, it may, for. B. in an application in the field of

Osteogenesis, the penetration of necessary for bone growth cells from the environment in which it has been implanted, allow and thus provide a framework for bone (re) education. Here comes the property of the system according to the invention as an effective system to bear.

Basically, the name of the system according to the invention as a transport, transfer and / or active system takes into account the fact that its special

Embodiment allows both the transport of drugs of all kinds in an organism, as well as their release and thus their transmission to specific, selected sites in an organism allowed, then depending on the nature of the selected drug or the selected drugs and / or drugs a partially longer ongoing interaction between the invention

System and the environment of the place to which the system has been brought, so that it can also be described as an effective system. this is also valid when the system according to the invention is introduced into an organism without addition of an active substance and / or active pharmaceutical ingredient. Due to its special fleece-collagen structure, it can bring about a partially longer-lasting interaction with the environment both in its design in the sandwich and in the sandwich form and thus at least promote healing. This will be explained in more detail below, in particular with regard to its suitability as a transport, transfer and / or active system in the field of bone formation.

Particular mention should also be made of the exclusive or additional suitability of the transport, transfer and / or active system according to the invention for haemostasis as hemostyptic. So far, such collagen fleeces have been used and examined as such hemostyptics. The transport, transfer and / or action system according to the invention can also serve as a local supplier of analgesics. As such, it may be used exclusively or additionally in conjunction with a bone or skin rejuvenation system or other active system.

The nonwoven fabric of the transport, transfer and / or active system preferably comprises fibers which are selected from cellulose, polyester, polyacrylonitrile, optionally in combination with at least one superabsorber or as a combination of two or more of said components.

The term cellulose fibers is to be understood very comprehensively. It comprises pulp-based fibers such as viscose. As part of the present

Invention suitable materials are in addition to the viscose but also includes products that have become known under the name of nanocellulose, here in particular as bacterially synthesized cellulose under the trade name BASYC of Jenpolymers. Other fibers made of cellulose and made from natural pulp can also be modal, tencel or lyocell fibers. In a preferred embodiment, the nonwoven fabric is a nonwoven based on cellulose and polyester fibers, in particular viscose and polyester fibers.

In a further preferred embodiment, the nonwoven fabric is a nonwoven based on viscose and polyacrylonitrile fibers, optionally in combination with a superabsorber.

By the optional use of a superabsorbent, said nonwoven fabric based on viscose and polyacrylonitrile fibers has the capability of a particularly high liquid absorption, measured with respect to water as a liquid at least 5000 g / qm, preferably also more than 5400 g / qm, is.

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

It can be provided that the system according to the invention contains, in addition to other active substances, a medicament which is selected from the group of analgesics, antibiotics, cytostatics, anticoagulants or mixtures thereof. The possibility of using the system according to the invention as a hemostyptic has already been mentioned above.

If, according to a further preferred embodiment, the transport, transfer and / or active system according to the invention additionally has at least one osteoinductive or chondroinductive active ingredient, it can be used as a

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

To be used by means. The osteoinductive or chondroinductive active ingredient may be selected from at least one of the differentiation and / or growth factors of the TGF-β superfamily, and more preferably selected from the group of Bone Morphogenic Protein (BMP), in which case the growth factors BMP-7 , BMP-2 and BMP-4 are to be emphasized. The selected osteoinductive or chondroinductive active ingredients may preferably be prepared recombinantly. In addition, the agent according to the invention can optionally also contain at least one drug which may be selected, for example, from the group of analgesics, antibiotics, cytostatics, anticoagulants or mixtures thereof. In this case, the system according to the invention proves to be a combined transport, transfer and active system and proves to be particularly effective in order to ensure a release of active ingredient delayed over a specific time interval or a delayed release of active substance such as drug release. In addition to its ability to be used as a transport system, it also has the special ability to serve as a delivery system with triggered drug release.

The transport, transfer and / or active system according to the invention can not only additionally have at least one osteoinductive or chondroinductive active ingredient, it can also be provided to use a precursor thereof in the form of a gene-activated material. Intracellular protein synthesis is then initiated by locally applying one or more genes, specifically BMP-2 and BMP-7 encoding plasmids.

Particularly preferably, the transport, transfer and / or active system according to the invention has a double-layer structure and very particularly preferably has a sandwich structure. The double-layeredness proves to be important with regard to the periosteum. This outermost layer of the bone, which has mainly protective and nutritional function for the bone, is extremely thin, while well-supplied with blood and supplied with many nerve endings. It is also known that bone fracture healing originates from this periosteum. As a result of the double-layered structure or sandwich structure according to the invention, one side of the transport, transfer and / or active system, which preferably consists of the nonwoven, faces this periosteum, while the other side of the double-layered system faces outwards and thus has an outer surface Demarcation and separation of the various components from the environment on the one hand and the release of the active substance or substances, such as the bone or cartilage-forming agent on the other hand allows. The fleece of the sandwich structure thus formed acts as a membrane, as an interface or partially permeable barrier, which serves as a shield for soft tissue ingrowth, for example.

The surface of the transport, transfer and / or active system, which is preferably porous on both sides of the flat nonwoven fabric and thus at least partially permeable, serves on the one hand for the transfer of cells to the place where the new bone formation is to take place and on the other hand serves for a delayed release of the active ingredient. to stimulate new bone formation over a longer period of time. At the same time, however, it also represents a barrier between the two different fabrics, namely the nonwoven fabric and the bone tissue. And since the nonwoven fabric also acts as a separating layer, as mentioned above, it secures the system according to the invention in its capacity as an active system. a protected place for undisturbed and therefore efficient new bone formation.

As already described, the invention therefore also relates to the use of the transport, transfer and / or active system, which has at least one osteoinductive or chondroinductive active ingredient, as a bone inducing agent.

In the presence of the at least one osteoinductive or chondroinductive active ingredient, the bone formation stimulating effect of the system of the present invention can be targeted to a predetermined site of action over a predetermined period of time.

The invention also relates to a method for the production of said transport, transfer and / or active system according to one of its embodiments according to the invention, wherein the collagen consists of a natural one

Solubilized starting material or a solution or suspension of a commercially available collagen, the collagen precipitated by changing the pH value, applied to a nonwoven fabric and freeze-dried with this to form a carrier system, thereby forming a capillary or pore structure in the carrier system. It is particularly advantageous that the quality of the forming pore structure can be controlled by the choice of the temperature during freeze-drying and the speed during cooling down. The faster the temperature drops and the further it is cooled down, the more uniform pores are formed. According to the invention, it is preferred that at least partially a directed pore structure is formed. The directional pore structure is obtained by setting a defined temperature gradient.

If the transport, transfer and / or active system is to have a drug or another active substance, according to one embodiment of the method according to the invention before precipitation, such a drug or another active substance is added by mixing. A Colyophilisieren deleted it.

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

A further variant is that initially the collagen is mixed with the at least one osteoinductive or chondroinductive active substance and applied and subsequently in a further step at least one drug is applied to the carrier system of the transport, transfer and / or active system. In this way, a multilayer system can be obtained as a sandwich structure. However, it is also possible to select the surface on which the collagen mixed with the osteoinductive or chondroinductive active substance is applied, on the one hand, and the medicament, for example, which is preferably an antibiotic. Furthermore, it is possible that various drugs are applied to the respective different surfaces of the carrier system of the transport, transfer and / or active system. Then a drug species preferably mixed with the collagen and the osteoinductive or chondroinductive agent and the other drug species, eg the antibiotic, applied to the other surface. In this way, a selective unfolding of the efficacy of the various drugs used can be achieved.

The invention also relates to a transport, transfer and / or active system whose features according to the invention have already been described above, in the form of an aseptic administration. In this case, the system or carrier system is in a container, which in turn is closed by means of a plastic film molding in the form of a membrane-like film. The film acts as a sterile barrier, so that the introduced under sterile conditions in the container transport, transfer and / or active system is protected from damaging external influences in the form of bacterial or other contaminants.

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

This ensures that moisture, e.g. in the form of water vapor, can escape from the container to the outside, without endangering the sterility of the interior.

The container is preferably a visual packaging, which is also referred to as blister. This blister package may be bonded to the plastic film molding in the form of a weld to form a weld package. Then, the plastic film molding is welded to the edges of the opening provided for filling the container.

Preferably, the plastic material of the membranous film is a polyolefin, a combination of polyolefins or a combination of one

Polyolefin formed with another polymer. As a particularly preferred

Plastic material is high density polyethylene (HDPE) or polytetrafluoroethylene (PTFE), preferably called expanded PTFE (ePTFE). PTFE membranes are known by the name "Gore-Tex".

Most preferably, the plastic material of the membrane-like film is selected from a PE spunbonded nonwoven, preferably from a HDPE spunbonded nonwoven. HDPE membrane films are commercially available under various trademarks "Tyvek." Tyvek films are tear-resistant, puncture-resistant, high-abrasion and chemical-resistant, and are made from very fine interwoven fibers that are heat and pressure bonded. In general, they are easy to process, which is very much in accordance with the purpose of the present invention.As compared to PTFE membranes, the HDPE film has the advantage that it is easier to weld, but the water vapor diffusion of the PTFE-made membranes is excellent.

In the case of aseptic administration, the transport, transfer and / or active system preferably additionally contains a drug and / or an osteoinductive or chondroinductive active ingredient.

In the following, the invention will be explained in more detail with reference to embodiments.

1. Preparation of a collagen solution or suspension

Collagen I is preferably used as the main constituent of the collagen suspension, which is obtained starting from tendons, since they have a particularly high proportion of collagen I. Alternatively, skin can also be used as a starting material for collagen production.

Starting from the tendons, (alternatively the skin) of a young cattle, the tendons (or its skin layer) are cleaned and optionally freed from epidermal components. The starting material is then with Chloroform / methanol degreased 1: 1, deep-frozen in liquid nitrogen and ground in a freezer mill to a particle size of 400-1000 microns.

As another alternative, bovine bone is used for the preparation of the collagen suspension. Then the procedure is as described for the bovine tendon or skin. However, this is followed by a demineralization step by treatment with about 0.1 N hydrochloric acid.

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

As a further alternative, a commercially available collagen may also be used, e.g. sold under the name "Vitrogen 100".

Basically, all experiments described below were carried out with three collagen variants, the collagen of animal origin obtained as just described, from human collagen and recombinant collagen.

2. Preparation of a bone growth inducing agent

The collagen solution thus prepared is then treated with a recombinantly produced osteoinductive agent and BMP-7 is used as such an osteoinductive agent. Furthermore, an antibiotic is added to the solution. The solution or suspension obtained in this way is then applied to a nonwoven fabric prepared in suitable size, the fibers of which are made of viscose and polyester and which are used as dry nonwoven under the name "Vilmed Ml 550 Basis". from Freudenberg Nonwovens KG in Weinheim, Germany. The nonwoven fabric has a thickness of about 2.9 mm and a weight of about 150 g / m 2.

The amount of applied solution or suspension of collagen with active ingredients is just chosen so that after the subsequent freeze-drying results in an accumulation of the collagen mixed with the active ingredients, which leads to the formation of a coating of the web. Freeze-drying also produces pores whose size and structure can be varied and adjusted by a specific temperature setting during freeze-drying. In the present case, undirected, uneven pores are preferred. The freeze-drying is therefore carried out by targeted adjustment of a temperature gradient down to -30 ° C. Basically, experiments were carried out at an interval of -20 ° C to -50 ° C.

Additionally or alternatively, the collagen solution becomes an osteoinductive agent

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

After lyophilization, the nonwoven fabric has a porous structure with a coating of collagen, BMP-7 and / or BMP-2.

In another experimental procedure, a bilayer is made as a sandwich by first adding the collagen solution or suspension comprising BMP-7 and / or BMP-2 to the web and then freeze-drying. Subsequently, a further antibiotic is applied aseptically as a further surface.

Another experiment was carried out as described above. However, a fiber system of viscose, polyacrylonitrile and a superabsorbent was chosen as the nonwoven fabric. This is also a dry nonwoven, which is also available from Freudenberg Nonwovens KG in Weinheim, Germany, under the name "Vilmed M66 / 031." This nonwoven is characterized by a particularly high water absorption capacity of more than 5400 g / sqm. Its thickness is about 1.2 mm and its weight is 270 gsm. The particularly high water storage capacity is particularly preferred in the application provided here.

The above-mentioned experiments were carried out as described, but instead of the osteoinductive agent BMP-7, an agent used for cartilage formation in the form of BMP-2 was used.

The aforementioned experiments were further performed as described, but instead of the osteoinductive agent BMP-7 a drug in the form of the antibiotics talcoplanin and gentamicin used. Starting from at least 10% by weight of the antibiotic, various field tests were carried out, of which the best results are given in the table below.

Aseptic presentation in a blister pack

The bone or cartilage growth promoting agent made in accordance with one of the variants described above was placed in a blister pack for use under sterile conditions, and then the blister opening was covered with a membranous film with the edges of the blister welded to the foil were. As a membrane-like film on the one hand, an HDPE film was used, which is available under the brand name Tyvek and on the other hand, a PTFE existing film in the form of a Gore-Tex membrane.

In order for a sterile composition to be obtained, the entire preparation process must be carried out under aseptic conditions, with the individual components added, if possible, being filtered in advance in a sterile manner.

In the manner described, compositions according to the invention are obtained from the following constituents: Table 1

Animal experiments on all samples using the recombinant growth factors BMP-7 and BMP-2 as well as in the

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

Osteogenesis shown with first vascularization.

By using the two antibiotics teicoplanin and gentamycin, a significant reduction in implant-associated infections has been achieved, with or without the additional use of growth factors.

This was after about 6 weeks in terms of bacterial growth

Follow-up examinations confirming the positive result of the first days.

The transport, transfer and / or action system according to the invention is suitable for application to all types of wounds, i. both those that have been surgically generated and those that are caused by a disease. As examples of preferred applications, the diabetic foot and open wounds of all kinds resulting from deficient circulation should be mentioned here.

The transport, transfer and / or action system according to the invention can e.g. also be used on bleeding liver wounds and is by the inventively provided fleece, e.g. in combination with a superabsorber, especially suitable for this application.

Claims

claims

1. transport, transfer and / or action system with a layer or sandwich structure having a nonwoven fabric as a builder, incorporated into the collagen to form the layer and / or attached to the collagen to form the sandwich structure, and that at least partially bioresorbable, wherein at least one of the surfaces of the transport, transfer and / or active system has a substantially porous surface.

2. System according to claim 1, characterized in that the nonwoven fabric comprises fibers which are selected from cellulose, polyester, polyacrylonitrile, a superabsorbent or combinations thereof.

3. System according to claim 2, characterized by a nonwoven on the basis of cellulose and polyester fibers, in particular of viscose and polyester fibers.

4. System according to claim 2, characterized by a nonwoven on the basis of viscose and polyacrylonitrile, 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 type I collagen.

6. System according to any one of claims 1 to 5, characterized in that it additionally contains a drug which is selected from the group of Analgesics, antibiotics, cytostatics, anticoagulants or mixtures thereof.

7. System according to any one of claims 1 to 6, characterized in that it additionally comprises at least one osteoinductive or chondroinductive agent, which is preferably selected from at least one of the differentiation and / or growth factors of the TGF ß superfamily and more preferably from the group bone morphogenetic proteins (BMP).

8. A process for the preparation of a transport-proliferating and / or active system according to any one of claims 1 to 7, wherein the collagen dissolved out of a natural starting material or a solution or suspension of a commercially available collagen, the collagen precipitate by changing the pH is left on or in a nonwoven fabric and freeze-dried therewith to form a carrier system, thereby forming a capillary or pore structure in the carrier system and lowering the freeze-drying temperature over a selected temperature gradient such that at least partially directed pores form.

9. The method according to claim 8, characterized in that the collagen before precipitation, an active ingredient is added by mixing, which is preferably selected from at least one osteoinductive or chondroinductive active ingredient, a drug or mixtures thereof.

10. The method according to claim 9, characterized in that first the collagen mixed with the at least one osteoinductive or chondroinductive active ingredient and applied and then in a further step, at least one drug is applied to the carrier system.

11. Transport-passing and / or active system according to one of claims 1 to 7 as aseptic administration, characterized by a container having the system, and which is completed by means of a plastic film molding in the form of a membranous, vapor-permeable film as a sterile barrier.

12. Aseptic preparation 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 of HDPE or PTFE and particularly preferably of expanded PTFE, or of a PE spunbonded nonwoven, particularly preferably of a HDPE spunbonded nonwoven.

13. Use of the transport-passing and / or active system according to one of claims 1 to 7, preferably in the form of the 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, wherein the builder faces the region of the bone to be induced, preferably the area of the periosteum, and which essentially comprises the collagen Layer facing outward.

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.