JP2002519317A - Use of growth factors for drug manufacture - Google Patents

Abstract

(57) Abstract: The present invention relates to an injection drug used locally for treatment of a fracture when the fracture part is mechanically fixed by an osteosynthesis graft or an external fixation device. The drug contains a growth factor that promotes the regeneration of bone tissue in the fracture area and is introduced into the biodegradable base material, where the base material forms microcapsules or nanocapsules or microspheres or nanospheres . The use of growth factors in the manufacture of such drugs is also described.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to the use of growth factors for the manufacture of a medicament for use locally for the treatment of fixed fractures according to claim 1.

[0002] from more than 200 years ago in the background art medicine, metal implants have been used to fix the fracture. In the last few decades, the selection of a suitable biocompatible alloy has been successful in optimizing mechanical load carrying properties, and in particular for implants with little corrosion and rejection. However, the decisive drawback of a stable osteosynthesis graft is that, after its removal from the treated fracture, calvarial bone sclerosis is formed and the area of the screw hole remains weakened. Thus, especially in elderly patients, the graft does not tend to be removed by the second operation. As shown in FIG. 1, the bone area F fixed by the implant 21 is largely free of mechanical loads. In this area, the absence of mechanical loading initiates the bone destruction process. Thus, in the area adjacent to the bone portion F fixed by the stable implant, bone destruction occurs, which leads to complex fractures, especially in elderly patients. This bone destruction phenomenon often occurs in the vicinity of the screw wings 32, resulting in undesirable loosening of the screws 22 in the bone.

[0003] For example, the fracture external fixation illustrated in FIG. 2 also suffers from essentially the same problems as described above for implant fixation. By applying the modern fixation device 3 after the initial joint fixation, the fixation system can be made dynamic and thus a constant preload can be applied to the fracture area Fa. In this way, bone destruction caused by rigid fixation during treatment of the fractured part is avoided. The area Ff between the shunt screws 31 and 31, 33 and 34 is due to the dynamism of this fixing device and its very short-term application.
Practically no bone destruction.

[0004] For elderly patients, slow and long-term treatment using these two types of fixation not only poses a physical and psychological burden, but also a significant financial burden. For the general public, the latter burden includes costs in the form of: a) relatively long hospital stays for patients; b) overall deterioration of constitution due to long stays; c) treatment costs during convalescence.

[0005] If the next fracture occurs in a weakened bone part as a result of bone destruction associated with bone fixation, the problem will not only be repeated, but will be even more severe. In particular, elderly patients are entrained in the circulation of a fracture and the next fracture associated with the treatment, and this circulation is broken only by a large expenditure of treatment.

Accordingly, there is a need for the following therapeutically efficient compositions. a) Fracture treatment is accelerated and bone fixation time is minimized. And at the same time, b) bone destruction in the bone fixation area is reduced or completely stopped.

[0007]

Summary of the Invention

It is an object of the present invention to use a medicament which fulfills the features of claim 1 which is used locally for fracture treatment in which the fractures are internally and externally fixed to one another, Achieved by using a growth factor for the manufacture of a medicament to be applied to

[0008]

DETAILED DESCRIPTION OF THE INVENTION

The rate of bone healing is accelerated by various growth factors (GF). Soluble low molecular weight proteins, such as insulin-like growth factor (IGF), were known at some time to have local effects on cartilage and bone growth (Canalis, E. and L. et al.
G. Raisz, Endocr. Rev. 4: 62-77, 1983). These authors have demonstrated a positive effect of IGF on bone DNA synthesis in periosteal and non-periosteal bone tissue. In degenerative joint disease, topical use of IGF-1 has been claimed to stimulate osteoblast activity and produce collagen. An advantage of using IGF for the treatment of trauma and fractures is that it has been shown that IGF does not have the previously known relevance for tumorigenesis.

[0009] Currently, two insulin-like growth factors are commercially available. IGF-1 (also called somatomedin C) is a basic polypeptide consisting of 70 amino acids,
It has a molecular weight of 7649 D. IGF-1 is particularly associated with chondrodit coalescence of proteoglycans in cartilage (Froger-Gaillard et al., Endocrynology 124: 236
5-2372, 1989) and stimulates the synthesis of DNA, RNA and proteins. The slightly acidic polypeptide IGF-2 consists of 4 domains, like IGF-1, and 7471
D molecular weight. IGF-2 consists of 67 amino acids. These IGFs are mainly dependent on growth hormone (somatotropin; GH). IGF-1 is primarily active in adults, whereas IGF-2 is the major growth factor for the fetus.

[0010] Of the group of transforming growth factors (TGFs), various active ingredients which have a growth stimulating action and promote wound healing are known. A protein known as Bone Morphogenetic Protein (BMP) can induce octopus-like bone development. Sampath et al. (J.
Biol. Chem. 27: 2-352-62, 1992).
It has been shown that (hOP-1; BMP-2a) stimulated bone formation in vivo as well as osteoblast proliferation and differentiation in vitro. DLGriffi
th et al. (Proc. Natl. Acad. Sci. Biophysics 93 (2): 878-883, 1996) discloses a bone protein 1 (OP1; BMP-7) capable of inducing bone formation in a living body.
) Is described.

[0011] In addition to BMP-2, BMP-4 and BMP-7 are obtained as recombinant proteins as BMPs as members of the TGFbeta main family. Pure recombinant BMP in vivo would be able to induce bone development as long as it was bound to a suitable scaffold substance or carrier (E. Tsurunga et al.).
al., J. Biochem. 121: 317-324, 1997).

Tests using recombinant BMP-2 (rhBMP-2) and a suitable carrier material to promote and ensure the healing of bone defects (20 mm long critical size defects in the radius of rabbits) have been reported by Zegzula, HD The Journal of Bone an
d Joint Surgery, 79-A (12) 1778-1790, 1990. Bone material in the body (
Instead of "autograft"), a porous polyactide carrier material cylinder similar to collagen described in EP-A 0,206,801 serves as a space holder and bearing structure for newly formed bone tissue.

The collagen claimed in EP-A 0,206,801 has a very good affinity for tissues and functions as a carrier material of BMP in tape or solid form. However, these collagen preparations have certain inherent antigenic effects, probably due to the telopeptides present, which prevent eccentric bone formation.

As shown in FIG. 3, increasing bone stability is a dynamically advancing process represented by an S-shaped curve. Typically, an osteosynthesis implant or external fixation device can be removed when the stability of the fracture area reaches a certain threshold. FIG. 3 shows a hypothetical course of bone healing when only an osteosynthesis graft or external fixation device is used. The implant / fixation device must be able to take on all the mechanical loads at zero time, increasing the stability of the healing bone tissue (plus a certain stability margin) and being able to bear these loads again It can only be removed at times.

As shown in FIG. 3, the implant / fixation device is used until bone material newly formed between the bone fragments can fix the fracture pieces in a fixed relative position to each other. , These fragments must be fixed in this position. In contrast, the mechanical load acting on the fractured piece must be supported by the stabilizing action until the healing bone has regained its mechanical properties to the extent that it does not require any form of stabilizing action. . This does not mean that the bone must have already restored its mechanical load-carrying capacity upon removal of the external stabilizing effect. It is common for all methods that these fractured areas have to be rested for longer than the treatment period, so apart from the healing of bone destruction conditions as described above, reduced muscle movement reduces muscle weakness and performance. Leads to deterioration. To remedy this, a time-consuming and expensive treatment must be performed after the removal of the external stabilizing means.

The growth factor (GF) used in the present invention may be epidermal growth factor (EGF), insulin-like growth factor (IGF), transforming growth factor β (TGF-β), or fibroblast growth factor (FGF). ). Of course, some suitable combinations of these factors can also be used. Many of these growth factors are commercially available as lipophilic powders.

According to the invention, these growth factors are present in an injectable formulation. Thus, growth factors can be injected directly into the fracture area or into adjacent parts thereof and into the rigidly fixed area of the bone. In a preferred embodiment, the growth factors can be associated with or encapsulated in a suitable biodegradable carrier material. The size of the carrier substance particles or capsules is such that the injection capacity remains. Also, particles or capsules loaded with growth factors can be suspended in adjuvant fluids or gels, which improves the ability of the growth factors to be injected.

[0018] To produce a therapeutically effective composition, the growth factors are introduced into the following formulations. That is, the growth factor is encapsulated or loaded within the biodegradable polymeric material. In this case, the encapsulation of the growth factor in microcapsules or nanocapsules of a suitable biodegradable substance such as polylactide can be carried out, for example, by using the w / o / w-emulsion "
Drying in water "can be carried out. Also, for example, solid microspheres can be produced by "spray drying" from a GF-polymer solvent mixture.

All the above-mentioned formulations are known to the person skilled in the art and are described in many documents and are described, for example, in D.G., published by Thomas Graham House, Cambridge, 1996. R.
Casa and R.C. A. Stephenson's book, Aspects of Drug Delivery System
ms ”or D, published by Cambridge, Thomas Graham House, 1993
. R. Casa and R.C. A. Stephenson's book encapsulation and control
References such as "lled release" or from the Journal of Controlled Release issued by the Journal of Elsevier Science. A recent summary of micro- and nano-encapsulations of drugs and their uses can be found in Benita, et al., Volume 73 in the Drugs and the pharmaceutical Science series of Marcel Decker, Inc., New York, 1996. "Microencapsulation: Methods and industrilal app published by S.
lications ".

[0020] Other forms of drug, such as storage in lyogel or xerogel, or carrier
Equivalent binding with proteins or other carrier substances has its own disadvantages. The biological activity of the growth factors in such formulations in biological tests has been shown to be very low.

FIG. 3 schematically illustrates the process of healing a fracture by a normal treatment using only the fixation method and a treatment using the agent according to the present invention. On the other hand, the solid line graph shows the fracture area F
2a shows an increase in the mechanical load carrying capacity of bone during the formation or healing process of new bone tissue in FIG. Slow increase without growth factor application is indicated by the dashed line. At time zero, the fracture is equipped with a fixation device that can carry the entire mechanical load, but since this fixation device is worn for only a short period of time, the fixation device can be removed much more quickly. it can.

Also, the time required to wear external or internal securing means is significantly reduced (Δ
t) reduces the time during which the bone material is degraded in the solid fixation zone (Ff).
If the medicament according to the invention is applied only to the fractured area, a faster healing of the fractured area and an earlier removal of the fixation device which suppresses the return of movement of the fractured area will result in a shorter disease duration and prognosis. It will have a decisive effect on the time and financial burden required. However, the growth factors according to the invention also have a firmly fixed area F, Ff
This growth factor can directly and locally resist bone material degradation since it can also be injected over bone.

[0023] Basically due to the application of the medicament according to the invention, external fixation devices could be used more frequently than in the past, and this has not always been commonly practiced for elderly patients. Furthermore, if recommended, the drug could be retrospectively injected with the graft remaining in the patient.

As will be apparent to those skilled in the art, the disclosure of the present invention can be used in virtually all vertebrates in human medicine as well as in veterinary medicine. At that time,
Ideally, growth factors are used for each animal type and species.

[Brief description of the drawings]

FIG. 1 is a side view of a bone region F fixed by an implant 21. FIG.

FIG. 2 is a side view showing a state in which a fracture portion is fixed by an external fixing device 3.

FIG. 3 Stability (%) when GF (growth factor) is used (solid line) and when GF (growth factor) is not used (dashed line)
: Time graph.

[Explanation of symbols]

 2 Graft 3 External fixation device 21 Graft 22 Screw 31, 32, 33, 34 Screw wing tf Fixation period F, Ff Bone portion firmly fixed by graft or fixation device Fa Fracture area

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY , CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP , KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZWF Term (reference) 4C076 AA64 AA65 AA66 BB11 CC09 CC30 EE24H FF68 4C084 AA02 AA03 BA44 DB53 DB54 DB58 DB60 DB61 MA05 MA38 MA66 NA05 NA10 ZA961 ZA962 ZC032

Claims (14)

[Claims] Claims: 1. An agent used locally for treating a fracture by internally or externally fixing a fracture part to each other, comprising at least one growth factor selected from a group of known growth factors. Wherein the growth factor is incorporated into a biodegradable base material and the base material forms microcapsules or nanocapsules or microspheres or nanospheres. 2. The medicament according to claim 1, wherein said medicament is injectable. 3. The growth factor is epidermal growth factor (EGF), insulin-like growth factor (IGF).
), Transforming growth factor β (TGF-β), or fibroblast growth factor (FGF)
The agent according to claim 2, comprising at least one growth factor or a combination thereof selected from the group of: 4. The method according to claim 3, wherein the growth factor is selected from the group of bone morphogenetic proteins (BMP). 5. The method according to claim 3, wherein the growth factor is insulin-like growth factor 1 (IGF-1). 6. The biodegradable basic substance is polylactide (PLA), polyglycolide (PG
A) a polymer of one of poly (ε-caprolactone) (PCL), poly (b-hydroxybutyrate) (PHB), or poly (p-dioxanone) (PDS) or a mixture thereof. 2. The drug according to 1. 7. The medicament according to claim 1, wherein the basic substance loaded with the growth factor is present as one or a combination of the following preparations (a) or (b). a) formulation loaded in gel, or b) suspension formulation in auxiliary fluid. 8. Use of a growth factor in the manufacture of a medicament for use locally in treating a fracture by internally or externally securing the fractures to one another, wherein the fixation comprises attaching the biodegradable implant to the bone. Does not include at least one selected from the group of known growth factors
Comprising one growth factor, wherein the growth factor is charged into a biodegradable base material, said base material forming a microcapsule or nanocapsule or a microsphere or nanosphere. Use of growth factors in the manufacture of drugs. 9. Use of a growth factor in the manufacture of a medicament according to claim 8, wherein said medicament is injectable. 10. The growth factor is at least selected from the group of epidermal growth factor (EGF), insulin-like growth factor (IGF), transforming growth factor β (TGF-β), or fibroblast growth factor (FGF). Use of a growth factor in the manufacture of a medicament according to claim 9, comprising one growth factor or a combination thereof. 11. The use of a growth factor in the manufacture of a medicament according to claim 10, wherein the growth factor is selected from the group of bone morphogenetic proteins (BMP). 12. Use of a growth factor in the manufacture of a medicament according to claim 10, wherein the growth factor is insulin-like growth factor 1 (IGF-1). 13. The biodegradable basic substance is polylactide (PLA), polyglycolide (PG
A) a polymer of one of poly (ε-caprolactone) (PCL), poly (b-hydroxybutyrate) (PHB), or poly (p-dioxanone) (PDS) or a mixture thereof. Use of a growth factor in the manufacture of a medicament according to claim 8. 14. Use of a growth factor in the manufacture of a medicament according to claim 8, wherein the basic substance loaded with the growth factor is present as one of the following formulations (a) or (b) or a combination thereof. a) formulation loaded in gel, or b) suspension formulation in auxiliary fluid.