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CN-122003255-A - Biocompatible polyurethane matrix

CN122003255ACN 122003255 ACN122003255 ACN 122003255ACN-122003255-A

Abstract

The present invention relates to a biocompatible Polyurethane (PU) matrix that is substantially free of water, wherein free fatty acids are present, but in an amount of up to 19%, and a process for preparing the PU matrix, wherein the process comprises the steps of providing a polyol component and a prepolymer component. The invention also relates to a PU matrix for use in the bone-related method, and a kit comprising a polyol component and a prepolymer component.

Inventors

  • Paul virtue. Asevedo
  • Antonio Carlos Rosie

Assignees

  • B2联结有限责任公司

Dates

Publication Date
20260508
Application Date
20241010
Priority Date
20231013

Claims (15)

  1. 1. A Polyurethane (PU) matrix, wherein I) The PU substrate has a water content of 1% or less, optionally 0.1% or less, or is free of water, as determined by a moisture content measuring method (drying method), and Ii) free fatty acids are present, but in an amount of up to 19%, as determined by titration with sodium hydroxide, Each characteristic was measured at a temperature of 25 ℃.
  2. 2. The PU matrix of claim 1, wherein the matrix additionally exhibits one or more, preferably all, of the following properties: iii) Physical tensile strength in the range of between 26 MPa and 42 MPa, preferably in the range of between 30 MPa and 38 MPa, as measured according to american society for testing and materials ASTM D695 MM; iv) an elastic modulus in the range between 1700 Mpa and 2400 Mpa, preferably in the range between 1900 Mpa and 2200 Mpa, measured according to american society for testing and materials ASTM D695 MM; v) a compressive strength in the range between 48 Mpa and 57 Mpa, preferably in the range between 50 Mpa and 55 Mpa, as determined according to american society for testing and materials ASTM D695 MM; vi) a deformation in the range between 3.7% and 5.5%, preferably in the range between 4.0% and 5.0%, measured according to American society for testing and materials ASTM D695MM, and Vii) a Shore D hardness in the range between 72 and 84, preferably in the range between 75 and 80, as determined by durometer according to ASTM D2240 for American Material and test Standard, Each characteristic was measured at a temperature of 25 ℃.
  3. 3. The PU matrix according to claim 1 or 2, further comprising other compounds selected from the group consisting of calcium salts, hydroxyapatite, small molecules, peptides or proteins with osteoinductive properties, and small molecules, peptides or proteins with anti-infective and/or antibacterial properties.
  4. 4. A process for preparing a polyurethane matrix comprising the steps of: a) Providing a polyol component, wherein the polyol component has: (a-i) an acidity index in the range of 0.8-8.5 mg KOH/g, preferably 1.0-7.5 mg KOH/g, more preferably 1.5 to 7.0 mg KOH/g, even more preferably 2.5-6.5 mg KOH/g, even more preferably 4.0-5.5 mg KOH/g and most preferably 4.5-5.0 mg KOH/g, as determined by titration; (a-ii) a hydroxyl index in the range of 200 to 450 mg KOH/g, preferably 250 to 400 mg KOH/g, more preferably 300 to 400 mg KOH/g, most preferably 360 to 380, as determined by the method disclosed in the International pharmacopoeia, eleventh edition, 2022,4.7 hydroxyl number determination, and B) Providing a diisocyanate component, preferably diphenylmethane-4, 4' -diisocyanate (MDI), wherein the diisocyanate component has: (b-i) as free isocyanate in an amount ranging from 16% to 35%, preferably from 22% to 35%, more preferably from 25% to 32% of NCO equivalent weight, by adding excess di-n-butylamine to form urea and subsequently back-titrating the unreacted amine with hydrochloric acid; (b-ii) optionally, a density in the range of 1.11 to 1.28 g/cm 3 , as determined by gravimetric techniques; c) Combining at least a portion of the polyol component of a) and at least a portion of the diisocyanate component of b) to form a prepolymer; d) Combining at least a portion of said polyol component of a) and at least a portion of said prepolymer of c) to produce a mixture, and E) Obtaining the polyurethane matrix from the mixture.
  5. 5. The process according to claim 4, wherein in step c) the polyol component and the diisocyanate component are combined in parts of 1 part polyol and 1 to 1.7 parts diisocyanate, preferably 1 part polyol and 1.2 to 1.6 parts diisocyanate, more preferably 1 part polyol and 1.3 to 1.5 parts diisocyanate; And/or Wherein in step d) the prepolymer of step c) is combined with the polyol of step a) to obtain a polyurethane mixture in a ratio in the range of 0.5:1.0 to 0.8:1.0 (polyol/prepolymer).
  6. 6. The method according to claim 4 or 5, comprising the further step of adding a further compound, wherein the further compound is selected from the group consisting of: Calcium salts, such as CaCO 3 or CaCO 3 (PO 4 ) 2 , wherein preferably these salts are present in a total amount of 10 wt% to 55 wt%, preferably 20 wt% to 50 wt%, more preferably 30 wt% to 50 wt%, even more preferably 30 wt% to 45 wt%, most preferably 30 wt% to 40 wt%, based on the sum of the weight of the polyol and prepolymer; Hydroxyapatite, wherein preferably the hydroxyapatite is present in an amount of about 15-25 wt%, more preferably in an amount of 18-22 wt%, most preferably in an amount of about 20wt.%, based on the sum of the weight of the polyol and prepolymer; A small molecule, peptide or protein having osteoinductive properties, wherein the total amount of said components is preferably in the range of about 1 wt% to about 5wt% based on the sum of the weight of said polyol and prepolymer, and A suitable amount of small molecules, peptides or proteins with anti-infective and/or antibacterial properties.
  7. 7. The method according to any one of claims 4 to 6, wherein step e) comprises a step of polymerizing the mixture of step d).
  8. 8. The process of any of claims 4 to 7, wherein no polymerization catalyst is present during step e).
  9. 9. A PU matrix obtainable by the method defined in any one of claims 4 to 8.
  10. 10. Use of the PU matrix according to any one of claims 1 to 3 or claim 9 in a method of treatment for bone regeneration, bone fixation, bone adhesion, bone implantation and/or total or partial bone replacement.
  11. 11. PU matrix for use according to claim 10, wherein the method of treatment comprises preparing an implant, preferably a dental implant or an orthopaedic implant, more preferably the implant is a personalized implant, in particular an orthopaedic or dental personalized implant for preparing a dental implant, more preferably for preparing a personalized dental implant.
  12. 12. The PU matrix for use according to claim 10 or 11, wherein the implant is adapted for replacing bone, for replacing part of bone, for replacing a bone defect, or for stabilizing a bone structure.
  13. 13. The PU matrix for use according to any one of claims 10 to 12, wherein the PU matrix is provided to a subject subcutaneously.
  14. 14. A kit comprising a polyol component as defined in claim 4 and a prepolymer as defined in claim 4 or 5.
  15. 15. The kit of claim 13 or 14, further comprising one or more compounds selected from the group consisting of calcium salts, hydroxyapatite and small molecules, peptides or proteins.

Description

Biocompatible polyurethane matrix Technical Field The present invention relates to a biocompatible Polyurethane (PU) matrix that is substantially free of water and wherein the free fatty acid content is limited, and a process for preparing the PU matrix, wherein the process comprises the step of providing a polyol component and a prepolymer component. The invention also relates to a PU matrix for use in the bone-related method, and a kit comprising a polyol component and a prepolymer component. Background There is a long history in medicine to treat undesired bone conditions or bone defects such as fractures or bone loss. For example, fractures are treated with conservative methods, such as by plaster fixation or by performing surgical procedures using external or internal fixation means, e.g. screws, metal plates or wires. On the other hand, bone defects are covered by inserting metal or plastic plates and/or bone material from the same organism. Comparable procedures are used for implants such as dental implants or orthopedic implants, which require stable insertion into bone tissue, for example by means of cements or cements, to apply the necessary strength. The main disadvantage of these procedures is the durable healing process, which is entirely dependent on the individual bone regeneration potential of the bone and its specific integration capacity and the ability of foreign bodies to be fixed to or in bone tissue. The natural healing process generally requires a longer period of fixation and all its individual and economic consequences and drawbacks before the natural cascade of bone regeneration processes results in the necessary mechanical stability. Dental and medical implants made of titanium or hot isostatic pressed zirconia most often fail at a high rate due to infection or loosening of the implant. Numerous methods are described in the prior art and are partially put into practice to overcome these limitations and ensure a stable connection between the foreign body and the bone or to shorten the period of time before, for example, a fracture can be exposed to mechanical forces. However, the materials described so far in the prior art have various disadvantages, for example, no bone cement is currently available on the market to functionally fix and stabilize momentary fractures, and in addition, bone cements used to anchor implants in orthopedics harden in a strong exothermic reaction, leading to important osteogenic necrosis in the bone-implant-interface. Often, such endoprostheses must be removed after bone stabilization, thus requiring a second surgical procedure. In addition, commercial materials previously used to cover bone defects have been withdrawn from the market due to unpredictable hardening times and variable volume changes during and after hardening. Hatt et al further disclose some of the requirements that an ideal implant must meet. It is therefore a need and it is thus an object of the present invention to provide an improved material which overcomes at least one, preferably all, of the above-mentioned disadvantages. Thus, advantageously, the improved material is suitable for use in the treatment of bone defects and/or undesired bone disorders and exhibits one or more, preferably all, properties that should be flexible to shape ex vivo and in vivo to obtain the desired shape, that should be able to provide relatively high adhesive properties, which for example allow for rapid exposure to mechanical forces, that should have predictable hardening properties, that should not exhibit an increase in vivo temperature during hardening (curing/polymerization) that damages the affected site, that should have a high degree of biocompatibility with living tissue, in particular bone, that does not cause local inflammation and toxicity, and that should integrate with bone tissue, that should show bone conduction, i.e. bone cells such as mesenchymal stem cells, osteointegrin expressing cells and osteoblasts, that are attracted and naturally incorporated into the material such that the implant/interface is gradually replaced by natural bone, that should prevent bacterial growth and biofilm formation, and/or that should be able to carry substances such as calcium salts (e.g. calcium carbonate or phosphate, calcium and bone, pH-regulating materials and other properties. Furthermore, advantageously, the PU matrix should provide a surface that does not support surface colonization with activated macrophages, which play an important role in inducing inflammation. It is a further object of the invention to provide a method of producing such a material and to provide a kit of parts providing improved materials. These and other objects, which will become apparent from the following description of the invention, are achieved by the subject matter of the independent claims. Some preferred embodiments of the invention are defined by the subject matter of the dependent claims. Disclosure of Invention T