Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Animal or plant cell
Reexamination Certificate
2001-06-21
2004-03-02
Witz, Jean C. (Department: 1651)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Animal or plant cell
C514S054000
Reexamination Certificate
active
06699471
ABSTRACT:
SUBJECT OF THE INVENTION
The present invention is directed to an injectable, biocompatible and biodegradable composition, comprising at least one hyaluronic acid benzyl ester or auto-cross-linked derivative, in combination with at least one mammalian cell and/or at least one pharmacologically or biologically active substance and/or micro-particles such as fibres, granules, microspheres or sponge fragments of a hyaluronic acid derivative.
BACKGROUND OF THE INVENTION
Although injectable compositions and carriers for such compositions have been known in the art, there still exists a need for injectable compositions which are biocompatible, are biodegradable, offer protective aspects to the active component, and provide enhanced bioavailability of the active components. This is important, for instance, in the field of joint cartilage repair.
The aim of joint cartilage repair is to restore the surface of the joint, reduce pain and prevent further deterioration of the tissues. Many methods have been applied to date for the treatment of cartilage defects, each of which has presented disadvantages (Tom Minas et al., “Current Concepts in the treatment of Articular Cartilage Defects”, Orthopedics, June 1997, vol. 20, No. 6).
The marrow stimulation technique consists of reaching subchondral bone tissue areas by means of abrasion or perforation, thus stimulating the formation of a fibrin 30 clot containing pluripotent stem cells. The clot subsequently differentiates and takes shape, forming fibrocartilage repair tissue. However, this tissue does not have the mechanical properties or the physiological and structural characteristics of healthy, lasting joint cartilage.
Another technique consists of implanting into the site of the defect a piece of periosteal and perichondral tissue taken, for example, from the rib cartilage. Such treatment does trigger the development of hyaline cartilage, but the repair tissue is poorly integrated with the surrounding healthy tissues and the implanted tissue subsequently becomes ossified.
Autologous and homologous osteochondral grafts are invasive, require complex surgical techniques and carry the risk of, for example, viral infection.
Other attempts to reconstruct the joint cartilage consist of implanting synthetic matrices with allogenic chondrocytes dispersed within them, or growth factors able to stimulate the proliferation of the chondrocytes. These methods require that the cartilage tissue is grown in vitro and then implanted into the defect. The synthetic matrices most commonly used are collagen gels, matrices of polyanhydrides, polyorthoesters, polyglycolic acid and its copolymers. The chief disadvantage of the use of such matrices is represented by the immune response directed against the implanted material. Chondrocytes are known to be cultured in gel constituted by agarose, hyaluronic acid, fibrin glue, collagen and alginate. However, these cultures in gel do not provide the mechanical stability necessary for them to adhere to the site once implanted and to allow the reconstruction of the cartilage structure. Moreover, chondrocyte cultures in substances such as fibrin de-differentiate into cells which appear to be similar to fibroblasts. Lastly, although gels constituted by substances such as agarose induce chondrocyte re-differentiation, the use of this compound has not been approved for internal applications to humans.
Joint cartilage defects have also been treated with suspensions of isolated chondrocytes in the absence of supporting matrices. It is thought, however, that chondrocytes lose their viability and/or do not remain at the site of the defect and that they form fibrocartilage or islets of cartilage immersed in fibrous tissue (see U.S. Pat. No. 5,723,331).
Some biological materials consisting of hyaluronic acid derivatives have been used to fabricate porous degradable scaffolds for tissue repair, reconstruction and wound healing (WO 97/45532). Others have been shown to support the growth of poor resistant and weak cells (WO 98/56897). These materials, however, are not injectable.
These disadvantages of the prior art are overcome by the present invention by providing an injectable composition such as one containing chondrocytes or bone marrow stroma cells dispersed in a gel containing at least one hyaluronic acid benzyl ester derivative or auto-cross-linked derivative.
Various pieces of evidence have emerged in the literature (see enclosed abstract) recently concerning the use of cell suspensions for injection purposes, in particular keratinocytes for the treatment of chronic ulcers and burns. See Silverman et al, Plast. Reconstr. Surg., June 1999, 103(7) 1809-18 (combination of fibrinogen and chondrocytes); Atala et al., J. Urol., Aug. 1993, 150 (2 Ptd. 2) p. 745-7 (chondrocyte-alginate gel)). Keratinocyte cultures can be developed according to various methods cited in the literature (in the presence or absence of foetal calf serum, with chemically defined culture medium, etc.). These cultures are then vehicled in the host bed suspending them in various media, one of the most frequently cited of which is fibrin both of autologous and commercial origin. There are considerable disadvantages to the use of such methods. Firstly, the cell suspension has to be prepared immediately before use, so the cells have to be stored in a medium with a different composition from the one used for their application, while other problems may arise with the fibrin glue used as a vehicle, particularly when this is not autologous.
These problems are overcome by the present invention by dispersing epithelial cells (such as keratinocytes) or derivatives of other embryonic origin in a hyaluronic-acid-based medium for various reasons. The preparation is perfectly biocompatible and biologically safe and the cell survival rate is higher than in cell suspensions in completely liquid media. This last point in particular is important. In cases where the patient or application site is a long distance from the site of production for the component, safe transport becomes a problem. The product will inevitably be shaken about during transport damaging the cells, and this problem needs to be solved. However, when the cells are dispersed in a highly viscous medium according to the present invention, this problem is overcome because the host medium acts as a cushion. Another advantage derives from the possibility of spreading the cell suspension efficiently over the surface to be treated, which is a simpler way of applying it than the methods currently used, involving sprays based on fibrin glue.
Another application of the present invention concerns the possibility of suspending the cells in the medium and then applying them by injection. Other non-limiting applications are the administration of fibroblasts (autologous) for aesthetic surgical purposes or as fillers for tissue defects, preparations of adipocytes (autologous, heterologous or homologous) for soft tissue augmentation for applications such as the reconstruction of breasts or other soft body parts, injections of urethral cells such as fibroblastoids or cartilage cells for the treatment of urinary incontinence. In all these examples, the Hyaluronic acid-based material has the double function of acting as a vehicle for injections and of protecting the cell preparation during transport.
As is known, hyaluronic acid plays a vital role in many biological processes such as tissue hydration, proteoglycan organization, cell differentiation, proliferation and angiogenesis (J. Aigner et al. L. Biomed. Mater. Res. 1998, 42, 172-181). Hyaluronic acid derivatives maintain all the properties of said glycosaminoglycan, with the advantage of being able to be processed in various forms and having solubility and degradation times which vary according to the type and percentage of derivation (EP 0216453 B1). Moreover, the hyaluronic acid derivatives offer new properties due to the insertion of specific molecules in the structure of the hyaluronic acid. For example, the sulfated derivatives of hyaluronic acid have anticoagulant pr
Callegaro Lanfranco
Pastorello Andrea
Pavesio Alessandra
Radice Marco
Birch & Stewart Kolasch & Birch, LLP
Fidia Advanced Biopolymers SRL
Witz Jean C.
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