Link:  Pharm/Biotech Resources

Title:  Resorbable polymer composition, implant and method of making implant

United States Patent:  6,926,903

Issued:  August 9, 2005

Inventors:  Pirhonen; Eija (Tampere, FI); Nieuwenhuis; Jan (Gorinchem, NL); Kaikkonen; Auvo (Tampere, FI); Nieminen; Tuomo (Tampere, FI); Weber; Franz (Singen, DE)

Assignee:  Inion Ltd. (Tampere, FI)

Appl. No.:  006800

Filed:  December 4, 2001

Novel polymer compositions that are useful in the manufacture of medical implants, implants having osteogenic properties and methods of making said implants are disclosed. Polymer compositions comprise a base material including a polymer matrix of resorbable polymer(s) or copolymer(s), and N-methyl-2-pyrrolidone (NMP), wherein NMP is present in an amount imparting osteogenic properties for the composition.

FIELD OF THE INVENTION

The present invention relates to novel polymer compositions that are useful in the manufacture of medical implants. More particularly, embodiments of the invention relate to polymer compositions having osteogenic properties. The polymer compositions are biodegradable or bioresorbable and they can be fashioned into medical implants for implantation in the body. Implants having osteogenic properties and methods of making said implants are also disclosed.

BACKGROUND OF THE INVENTION

The healing process of bone is a complicated cascade of events. Rapid and diverse events are activated by a fracture or osteotomy of a bone in order to limit the loss of blood and initiate cellular migration resulting in repair. Current concepts suggest that these cellular events are controlled to a large part by growth factors, low-molecular-weight glycoproteins, inducing migration, proliferation and differentiation of an appropriate subset of cells in the site of the fracture.

Despite of the amount of known details the bone healing as a whole is still a poorly understood process. Based on this lacking information and experimental data research has revealed several methods to enhance bone growth, such as mechanical stimulation, electromagnetic fields, low-intensity ultrasound, osteoconductive materials, for instance hydroxyapatite, tricalcium phosphate, bioactive glass etc., and osteoinductive materials, such as growth factors.

Osteoinduction is a process where any substance, stimulation etc. starts or enhances a cellular response resulting in a bone formation process. Growth factors are a wide group of molecules known to possess this effect. According to the current knowledge, bone morphogenetic proteins (BMP) are the only growth factors known to induce bone formation heterotopically by inducing undifferentiated mesenchymal cells to differentiate into osteoblasts. Consequently, several BMPs are shown to boost the bone healing process when supplementary doses are given.

For example, U.S. Pat. No. 5,725,491 discloses a biodegradable film dressing as a delivery system of various therapeutic agents, such as BMPs. The therapeutic agent is delivered from the film dressing in a certain and controlled release rate. However, BMPs are produced by genetic engineering, which is still rather expensive. Also, delivery of a correct dose of BMPs is difficult and presents great challenges for the future.

Known materials, methods and implants are expensive and exploitation of such materials, methods and implants is constrained.

BRIEF DESCRIPTIONS OF THE INVENTION

An object of the present invention is to provide novel resorbable polymer compositions having osteogenic properties so as to alleviate the above disadvantages. Another object is to provide novel resorbable implants having osteogenic properties. A further object is to provide methods of making resorbable implants having osteogenic properties.

These objects are achieved by providing resorbable polymer compositions, resorbable implants and methods of making resorbable implants comprising a base material including a polymer matrix of resorbable polymer(s) or copolymer(s) and N-methyl-2-pyrrolidone (NMP).

According to one embodiment of the invention, the polymer matrix comprises Polylactide/Polyglycolide/Trimethylene carbonate copolymer (PLA/PGA/TMC) with a composition of 80/10/10.

According to another embodiment of the invention, the polymer matrix comprises Poly D, L-lactide/Poly L-lactide/Trimethylene carbonate copolymer (PLDLA/PLA/TMC) with a composition of 55/40/5.

According to a third embodiment of the invention, the polymer matrix comprises 80 wt-% P(L/DL)LA (70/30) and 20 wt-% PLLA/TMC (70/30).

According to a fourth embodiment of the invention, the implant is a membrane.

According to one embodiment of the method of the invention, the method comprises the steps of selecting polymer(s) or copolymer(s) of a polymer matrix of the implant, mixing said polymer(s) or copolymer(s) to form the polymer matrix, forming the implant from said polymer matrix, and adding NMP to the implant in an amount imparting osteogenic properties for said implant.

According to another embodiment of the method of the invention, the method comprises the steps of selecting polymer(s) or copolymer(s) of a polymer matrix of the implant, adding NMP to the polymer matrix in an amount imparting osteogenic properties for the implant, and forming the implant from the mixture of said polymer matrix and NMP.

An advantage of polymer compositions, implants and methods of the invention is that substantially inexpensive products are achieved as compared with known solutions enhancing bone healing.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a combination of N-methyl-2-pyrrolidone (NMP) and resorbable polymers or copolymers. The invention is based on the unexpected realization that by combining a resorbable matrix material and NMP in a certain ratio, an implant having osteogenic properties is achieved. The implant thus induces bone growth due to the osteogenic properties of the polymer composition and enhances bone healing after osteotomies and bone fractures.

The implant forms include, but are not limited to, membranes, films, plates, mesh plates, screws, taps or other formed pieces.

The implant can be prepared for example of polyglycolide, polylactides, polycaprolactones, polytrimethylenecarbonates, polyhydroxybutyrates, polyhydroxyvalerates, polydioxanones, polyorthoesters, polycarbonates, polytyrosinecarbonates, polyorthocarbonates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(maleic anhydride), polypeptides, polydepsipeptides, polyvinylalcohol, polyesteramides, polyamides, polyanhydrides, polyurethanes, polyphosphazenes, polycyanoacrylates, polyfumarates, poly(amino acids), modified polysaccharides (like cellulose, starch, dextran, chitin, chitosan, etc.), modified proteins (like collagen, casein, fibrin, etc.) and their copolymers, terpolymers or combinations or mixtures or polymer blends thereof. Polyglycolide, poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(L-lactide), poly(D,L-lactide), poly(L-lactide-co-D,L-lactide), polycaprolactone, poly(L-lactide-co-caprolactone), poly(D,L-lactide-co-caprolactone) polytrimethylenecarbonate, poly(L-lactide-co-trimethylenecarbonate), poly(D,L-lactide-co-trimethylenecarbonate), polydioxanone and copolymers, terpolymers and polymer blends thereof are highly preferred polymers.

EXAMPLE 1

Polylactide/Polyglycolide/Trimethylene carbonate copolymer (PLA/PGA/TMC), with a composition of 80/10/10, granulates were compression moulded to form a film with a thickness of 0.2 mm. Used compression temperature was 180° C. and pressure 130 bar. From the film 10 rectangular pieces were cut, each with a width of 20 mm.

The weight of the individual film pieces were measured with balance with an accuracy of 1 mg. The film pieces were then immersed individually into NMP for 30 seconds. After immersion the film pieces were air dried for 20 minutes and the weight of the pieces was measured again.

The weight of the film pieces before and after immersion into NMP are shown in table 1. The average amount of NMP diffused into polymeric film was 44.19%.

Claim 1 of 23 Claims

1. A resorbable polymer composition comprising:

a melt processed base material including a polymer matrix of resorbable polymer(s) or copolymer(s), and

N-methyl-2-pyrrolidone (NMP),

wherein the NMP is present in an amount imparting osteogenic properties to the resorbable polymer composition, and wherein the NMP is present in an amount between 0.05 and 50 weight-%.

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