Biocompatible polyurethane matrix

Abstract

The present invention relates to a substantially water-free biocompatible polyurethane (PU) matrix in which free fatty acids are present, but whose content is up to 19%, 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 PU matrices for use in bone-related methods, as well as kits comprising a polyol component and a prepolymer component.

Description

Technical Field

[0001] This invention relates to a biocompatible polyurethane (PU) matrix that is substantially anhydrous and contains a limited amount of free fatty acids, and a method for preparing the PU matrix, wherein the method includes the steps of providing a polyol component and a prepolymer component. The invention also relates to PU matrices for bone-related methods, and kits comprising a polyol component and a prepolymer component. Background Technology

[0002] Treating undesirable bone conditions or defects such as fractures or bone loss has a long history in medicine. For example, fractures are treated conservatively, such as by immobilization with a cast, or by surgical procedures using external or internal fixation devices such as screws, plates, or wires.

[0003] 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 or orthopedic implants; these implants require stable insertion into the bone tissue, for example, by means of adhesives or bonding agents, to apply the necessary strength.

[0004] The main drawback of these procedures is the prolonged healing process, which depends entirely on the individual bone's regenerative potential and its specific integration capacity and ability to fix foreign bodies to or within the bone tissue. Natural healing typically requires a longer period of fixation, along with all its individual and economic consequences and disadvantages, before the natural cascade of bone regeneration leads to the necessary mechanical stability.

[0005] Dental and medical implants most commonly made of titanium or hot isostatically pressed zirconia have a high failure rate due to infection or implant loosening.

[0006] Numerous methods have been described and partially put into practice in the prior art to overcome these limitations and ensure a stable connection between the foreign body and bone, or to shorten the time before, for example, a fracture can be exposed to mechanical forces. However, the materials described in the prior art to date have various drawbacks; for example, there are currently no bone cements on the market that can functionally fix and stabilize instantaneous fractures; furthermore, bone cement used in orthopedic medicine to anchor implants hardens in a strong exothermic reaction, leading to osteoblast necrosis, which is crucial at the bone-implant interface. Typically, such prostheses must be removed after bone stabilization, thus requiring a second surgical procedure. In addition, commercially available materials previously used to cover bone defects have been withdrawn from the market due to unpredictable hardening time and variable volume changes during and after hardening.

[0007] Hatt et al. further disclosed some requirements that an ideal implant must meet.

[0008] Therefore, a necessary and thus an object of the present invention is to provide an improved material that overcomes at least one, preferably all, of the aforementioned disadvantages. Advantageously, the improved material is suitable for use in the treatment of bone defects and / or undesirable bone conditions and exhibits one or more, preferably all, of the following properties: the improved material should be flexible in ex vivo and in vivo to achieve the desired shape; it should provide relatively high adhesive properties, such as allowing rapid exposure to mechanical forces; it should have predictable hardening properties; during hardening (curing / polymerization), there should be no increase in intracellular temperature at the site of injury; the improved material should be highly biocompatible with living tissue, particularly bone, without causing local inflammation and toxicity, and it should integrate with bone tissue; the improved material should exhibit osteoconduction, i.e., bone cells such as mesenchymal stem cells, osteointegrative protein-expressing cells, and osteoblasts attract and naturally incorporate into the material, thereby gradually replacing the implant / adhesive interface with natural bone; it should prevent bacterial growth and biofilm formation; and / or the improved material should be able to load substances such as calcium salts (e.g., calcium carbonate or calcium phosphate), peptides, proteins, and other materials with osteopromoting and pH-regulating properties. Furthermore, advantageously, the PU matrix should provide a surface that does not support the colonization of activated macrophages, which play an important role in inducing inflammation.

[0009] Another object of the present invention is to provide a method for producing such a material, and to provide a kit for providing components of an improved material.

[0010] These and other objectives will become apparent from the following description of the invention, and 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. Summary of the Invention

[0011] The summarization, individually or in combination, of the various aspects, advantageous features, and preferred embodiments of the invention in the following entries helps to achieve the objectives of the invention.

[0012] (1) Polyurethane (PU) matrix, wherein i) The water content of the PU matrix is ​​equal to or less than 1%, preferably equal to or less than 0.1%, and more preferably free of water, as determined by a moisture content measurement method (drying method); and / or ii) Free fatty acids are present, but their content is at most 19%, preferably between 7% and 19%, more preferably between 5% and 15%, and most preferably between 7% and 10%, as determined by titration with sodium hydroxide. Each property was measured at 25°C.

[0013] In a preferred embodiment, the free fatty acids present in the PU matrix are derived from castor oil. The castor oil is derived from up to 93% (approximately 81%-93%) ricinoleic acid and approximately 7% to 19% of the remaining acids (i.e., other components). These other components are oleic acid (approximately 2%-8%), linoleic acid (approximately 1%-6%), α-linolenic acid (approximately 0.5%-2%), stearic acid (approximately 0.5%-1%), palmitic acid (approximately 0.5%-1%), dihydroxystearic acid (approximately 0.3%-0.5%), and other components (approximately 0.2%-0.5%).

[0014] In a particularly preferred embodiment, the free fatty acids are derived from castor oil, but are not, or only to a limited extent, ricinoleic acid. Therefore, preferably, the free fatty acids are derived from oleic acid, linoleic acid, α-linolenic acid, stearic acid, palmitic acid, dihydroxystearic acid, and / or other components. Thus, in a particularly preferred embodiment, the content of free fatty acids (excluding ricinoleic acid) in the PU matrix is ​​up to 19%, preferably between 7% and 19%, and the content of ricinoleic acid-derived components in the PU matrix is ​​81% or higher. In other words, the content of ricinoleic acid-derived components in the PU matrix is ​​81% or higher, and the remaining free fatty acid content is up to 19%.

[0015] (2) The PU matrix according to (1), wherein the matrix further exhibits one or more of the following properties, preferably all of them: iii) Physical resistance capacity against traction in the range of 26 MPa to 42 MPa, preferably in the range of 30 MPa to 38 MPa, as determined by ASTM D695 mm from the American Society for Testing and Materials. iv) The modulus of elasticity in the range of 1700 MPa to 2400 MPa, preferably in the range of 1900 MPa to 2200 MPa, as determined by ASTM D695MM of the American Society for Testing and Materials; v) Compressive strength in the range of 48 MPa to 57 MPa, preferably in the range of 50 MPa to 55 MPa, as determined by ASTM D695MM of the American Society for Testing and Materials; vi) Deformation within the range of 3.7% to 5.5%, preferably between 4.0% and 5.0%, as determined according to ASTM D695 mm; and vii) Shore hardness D in the range of 72 to 84, preferably in the range of 75 to 80, determined by a hardness tester according to the American Standard for Testing and Materials (ASTM) D2240. Each property was measured at 25°C.

[0016] (3) The PU matrix according to (1) or (2) further includes 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.

[0017] (4) The PU matrix described in any of the preceding items is in liquid or solid form.

[0018] (5) The PU matrix according to any of the preceding items is in the form of a solid biocompatible flexible sheet and can be thermoformed into a changed shape by deformation under heating, without elastic memory and returning to the original shape. Preferably, the thickness of the solid biocompatible flexible sheet is in the range of 0.01 mm or greater to 20.00 mm or less.

[0019] (6) The PU matrix according to item (5), wherein • A PU matrix with a thickness ranging from 0.01 mm to less than 1.00 mm is defined as a film; • A PU matrix with a thickness ranging from 1.00 mm to less than 5.00 mm is defined as a sheet (blade); • A PU matrix with a thickness ranging from 5.00 mm to less than 20.00 mm is defined as a block; (7) A method for preparing a polyurethane matrix, particularly for preparing a polyurethane matrix, preferably a matrix as defined in any of entries (1) to (6), comprising the following steps: a) Provides a polyol component (also referred to herein as "Ampoule A"), wherein said polyol component has: (ai) The 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, was determined by titration; (a-ii) The hydroxyl index, within the range of 200 to 450 mg KOH / g, preferably 250 to 400 mg KOH / g, more preferably 300 to 400 mg KOH / g, and most preferably 360 to 380, is determined by the method disclosed in “International Pharmacopoeia - 11th Edition, 2022, 4.7 Determination of Hydroxyl Value”; and b) Provides a diisocyanate component, preferably diphenylmethane-4,4'-diisocyanate (MDI), wherein the diisocyanate component has: (bi) is a free isocyanate in an amount ranging from 16% to 35%, preferably 22% to 35%, and more preferably 25% to 32% of NCO equivalent, determined by adding excess di-n-butylamine to form urea and then back-titering the unreacted amine with hydrochloric acid. (b-ii) Optionally, between 1.11 and 1.28 g / cm³ 3 The density within the range was determined by specific gravity measurement. 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 (also referred to herein as "Ampoule B"); d) Combining at least a portion of the polyol component of a) and at least a portion of the prepolymer of c) to prepare a mixture; and e) Obtain a polyurethane matrix from the mixture.

[0020] (8) The method described in entry (7), wherein The prepolymer of step c) has (ci) is a free isocyanate in an amount of NCO equivalent ranging from 10% to 25%, preferably from 19% to 23%, more preferably from 20% to 21%, determined by adding excess di-n-butylamine to form urea and then back-titrifying the unreacted amine with hydrochloric acid. (c-ii) at 1000 to 1500 g / cm 3 Preferred concentration: 1100 to 1400 g / cm³ 3 More preferably 1180 to 1270 g / cm³ 3 The density within the specified range was determined by specific gravity measurement at 25°C; and / or (c-iii) Dynamic viscosity in the range of 350-750 centipoise (cP), preferably 400 to 700 cP, more preferably 450 to 650 cP, and even more preferably 500 to 600 cP, determined by rotational viscometer according to ASTM D4878.

[0021] (9) The method described according to entry (7) or entry (8), wherein a) Polyol component (a) also has (a-iii) at 850-1200 g / cm³ 3 Optimal g / cm³ is 950 to 1200 g / cm³. 3 More preferably 1000 to 1150 g / cm 3 The optimal value is 1050 to 1100 g / cm³. 3 The densities within the specified range were determined by specific gravity measurement at 25°C; and (a-iv) Viscosity in the range of 1400 to 1800 cP, preferably 1500 to 1700 cP, determined by ASTM D4878; and / or b) Diisocyanate component (b) also has (b-iii) A moisture content equal to or less than 0.1%, preferably in the range of 0.01% to 0.1%, more preferably zero (0%), determined by moisture content measurement (drying method); and (b-iv) Viscosities in the range of 20 cP to 200 cP, preferably in the range of 20 cP to 120 cP, more preferably in the range of 40 cP to 120 cP, and even more preferably in the range of 40 cP to 100 cP, as determined by ASTM D4878.

[0022] (10) The method described according to any one of entries (7) to (9), wherein The polyol component of step a) is obtained from castor oil, preferably from chemically reacted castor oil. More preferably, the original castor oil used has one or more, particularly all, of the following characteristics: The acidity index, in the range of 0.20-1.5 mg KOH / g, preferably 0.40-1.25 mg KOH / g, more preferably 0.5 to 1.0 mg KOH / g, was determined by titration with potassium hydroxide. The hydroxyl index is in the range of 150-170, preferably 150-160, more preferably 155-165, determined by the method disclosed in "The International Pharmacopoeia - 11th Edition, 2022, 4.7 Determination of Hydroxyl Value"; and optionally... o in the range of 0.090 to 0.098 g / cm 3 Preferably, the concentration is 0.095 to 0.096 g / cm³. 3 The density within the specified range was determined by specific gravity measurement at 25°C; and / or The viscosity is measured by ASTM D4878 in the range of 500 cP to 1000 cP, preferably in the range of 600 cP to 900 cP, and more preferably in the range of 700 cP to 800 cP.

[0023] (11) The method according to any one of the entries (7) to (10), wherein in step c), the following parts of the polyol component and the diisocyanate component are combined: 1 part of polyol and 1 to 1.7 parts of diisocyanate; preferably 1 part of polyol and 1.2 to 1.6 parts of diisocyanate, more preferably 1 part of polyol and 1.3 to 1.5 parts of diisocyanate.

[0024] In a preferred embodiment, the polyol component and the diisocyanate component are combined in the above proportions, with the diisocyanate component present in the prepolymer at an amount of 20% to 32%.

[0025] (12) The method according to any of the entries (7) to (11), 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 of 0.5:1.0 to 0.8:1.0 (polyol / prepolymer).

[0026] (13) The method according to any one of entries (7) to (12), wherein step a) of providing the polyol component comprises the following steps: (a-1) Castor oil, ethylene glycol and propylene glycol are combined under a protective atmosphere, preferably a nitrogen atmosphere; preferably the combination is carried out with stirring; preferably for a period of 1 to 5 hours, more preferably for a period of 2 to 4 hours, and even more preferably for about 2 hours; thereby obtaining a mixture; (a-2) Heating the mixture of (a-1) is preferably heated to a temperature in the range of about 100°C to about 270°C, more preferably to a temperature in the range of about 200°C to about 260°C, and even more preferably to a temperature in the range of about 250°C, and then a cooling step is performed. (a-3) Optionally, the mixture is rotated, preferably under reduced pressure, preferably in a rotary evaporator, to remove residual gases; (a-4) Optionally, cool the mixture; and (a-5) Obtain the polyol component.

[0027] (14) The method according to any one of entries (7) to (13), wherein step c) of forming the prepolymer comprises the following steps: (c-1) The polyol from step (a) is mixed with a diisocyanate compound (e.g., diphenylmethane-4,4''-diisocyanate (MDI)), preferably in the proportions described above, to obtain a mixture; (c-2) Stirring the mixture of (c-1), preferably at a temperature of about 100°C; (c-3) Optionally apply a vacuum; (C-4) Removal of possible gas inclusions, preferably by evaporation of the mixture; and (c-5) Obtain the prepolymer.

[0028] (15) The method according to any one of the entries (7) to (14) includes the further step of adding other compounds, wherein said other compounds are selected from the group consisting of: • Calcium salts, such as CaCO3 or CaCO3(PO4)2, wherein, based on the sum of the weights of the main components, polyols and prepolymers, these salts are preferably 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%, and most preferably in a total amount of 30 wt% to 40 wt%. • Hydroxyapatite, wherein, based on the sum of the weights of the main components, polyol and prepolymer, hydroxyapatite is preferably present in an amount of about 15-25 wt%, more preferably in an amount of 18-22 wt.%, and most preferably in an amount of about 20 wt.%.

[0029] • Small molecules, peptides, or proteins with osteoinductive properties, wherein the total amount of said components is preferably in the range of about 1 wt% to about 5 wt%, based on the sum of the weights of the main component polyol and the prepolymer; and • Appropriate amounts of small molecules, peptides, or proteins with anti-infective and / or antibacterial properties.

[0030] (16) The method according to entry (15), wherein the other compound added in a further step is a calcium salt, such as CaCO3 or CaCO3(PO4)2, preferably CaCO3.

[0031] (17) The method according to any of the entries (7) to (16), wherein the other compound is added during or after step d).

[0032] In a preferred embodiment, other compounds are added during or after step d) but before step e). Preferably, other compounds are added during step d) so as to become part of the mixture in step d).

[0033] (18) The method according to any of the entries (7) to (17), wherein step e) includes the step of polymerizing the mixture of step d).

[0034] (19) The method according to any of the entries (7) to (18), wherein the highest polymerization temperature generated during the polymerization step when measured in the container during step d) is a maximum of 47°C, preferably a maximum of 46°C, or a maximum of 45°C.

[0035] In a preferred embodiment, when the mixture is applied to bone, the temperature of the mixture is below 47°C, preferably 45°C or lower, and more preferably 43°C or lower.

[0036] (20) The method according to any of the entries (7) to (19), wherein no polymerization catalyst is present during step e).

[0037] (21) PU matrix, which can be obtained by the method specified in any of the entries (7) to (20).

[0038] (22) Any of the entries (1) to (7) or the PU matrix described in entry (21) for the treatment of bone regeneration, bone fixation, bone bonding (“glue”), bone implantation and / or total or partial replacement of bone.

[0039] (23) The PU matrix according to the use described in entry (22), wherein the treatment method includes the preparation of implants, preferably for 3D bone reconstruction and bone tissue engineering, such as dental implants or orthopedic implants, preferably said implants are personalized implants, such as orthopedic or dental personalized implants; preferably for the preparation of dental implants, more preferably for the preparation of personalized dental implants.

[0040] (24) A PU matrix for the purpose described in entry (22) or (23), wherein the implant is suitable for replacing bone; for replacing part of bone; for replacing bone defects; or for stabilizing bone structure.

[0041] (25) A PU matrix for use as described in any of the entries (22) to (24), wherein the PU matrix is ​​provided subcutaneously to the subject.

[0042] (26) A kit comprising a polyol component as defined in any of the entries (7) to (10) and a prepolymer as defined in entries (7), (8), (11) or (14).

[0043] (27) The kit according to entry (25) or (26) further comprises one or more compounds selected from the group consisting of calcium salts, hydroxyapatite and small molecules, peptides or proteins. Attached Figure Description

[0044] Figure 1Various embodiments are shown—for example, implant forms of the final polymer such as dental membranes for guided tissue regeneration (GTR), spinal fusion inserts, plates, screws, buttons, granular bone grafts, bone segments, or whole-bone prostheses customized through prototyping.

[0045] Figure 2 The bending stress of the glued miniature pig femur is shown. It can be seen that the glued bone has relatively high strength.

[0046] Figure 3 This demonstrates the strength of the glued bone.

[0047] Figure 4 The temperature curves show the mixture and stirring of the polyol described in Example 1 and the prepolymer described in Example 2 over the next 15 minutes until the desired viscosity is reached. It can be seen that the temperature reaches a peak of 46°C after 13 minutes. Detailed Implementation

[0048] The invention will now be described in more detail by way of preferred embodiments and examples; however, these embodiments and examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

[0049] Previously, the use of polymers based on castor oil for implant preparation has been described. Castor oil can be converted into a defined polyol, along with, for example, diphenylmethane-4,4'-diisocyanate (MDI), as a central component of the polymer. The conversion of castor oil into the defined polyol can be carried out by methods such as those described below. Furthermore, the polymer can be reinforced (supplemented) with various components, for example, with components that support bone formation.

[0050] The preparation of polyols from castor oil is based on the unique content of ricinoleic acid in castor oil. Castor oil is generally considered the source of ricinoleic acid because it contains up to 93% (approximately 81%-93%) of it. Other components include oleic acid (approximately 2%-8%), linoleic acid (approximately 1%-6%), α-linolenic acid (approximately 0.5%-2%), stearic acid (approximately 0.5%-1%), palmitic acid (approximately 0.5%-1%), dihydroxystearic acid (approximately 0.3%-0.5%), and other components (approximately 0.2%-0.5%). Multifunctional polyesters are prepared and produced globally; however, due to their low biocompatibility, they are generally not formulated for applications such as in vivo medical devices. These polyurethanes are generally not suitable for the pharmaceutical field and are, in most cases, polymerized through the reaction of polyols (polyfunctional alcohols) synthesized from castor oil with isocyanate groups, namely MDI or TDI (toluene diisocyanate). The reaction occurs between the isocyanate molecule and the hydroxyl moiety (partially); hypothetically, in this case, the remaining portion of the isocyanate may not react with the hydroxyl group of the polyol, but instead react immediately with the water molecules remaining in the system. This produces carbamic acid, which decomposes to form a primary amine and CO2. The primary amine can also react with the isocyanate to form a disubstituted urea. These reaction products are the determining factors for the observed low biocompatibility.

[0051] The suitability of some of these castor oil polymers for medical applications has been studied in the past, such as their suitability as implants in animal studies. In 1959, Mandarino and Salvatore implanted rigid polyurethane oil foam into bone, but it did not demonstrate the desired stabilizing or bone-growth effects.

[0052] It has been found that a key step in using castor oil in the medical field is to derive the oil into polyols.

[0053] In the past, castor oil polymers have shown reactivity with TDI and MDI and have been tested in the past for potential use in the medical field, particularly as a bone substitute. However, these materials do not show the desired properties that would make them suitable for this particular field, as they exhibit undesirable properties such as signs of toxicity, lack of elasticity in plastic deformation, and / or low strength (US Patent Application 2012 / 0265312 A1; Norton et al. 2020; Doumit et al. 2014).

[0054] Another method for producing castor oil polymers is propoxylation and ethoxylation, using catalysts such as bimetallic cyanide (DMC) (Musik et al. 2022; Valvekens and DeVos 2016). DMC fully catalyzes the reaction of castor oil with propylene oxide and ethylene oxide. However, these methods pose a toxicity risk and reduce bioavailability because the catalyst cannot be removed.

[0055] Another approach is epoxidation, followed by its use as a monomer in the synthesis of castor oil polymers (Hernandez et al. 2017). The epoxidation process is carried out using a catalyst system of H2O2, Al2O3, and ethyl acetate. However, the use of metal and aluminum-based catalysts may be cytotoxic or compromise biocompatibility.

[0056] Another example is the synthesis using castor oil, toluene diisocyanate (TDI), N-dimethylformamide, p-toluenesulfonic acid, and polyaniline under a nitrogen atmosphere.

[0057] Polyols can also be synthesized by chemical glycerolysis between castor oil and three different glycerols (Zhang et al. 2021), primarily for coating various materials.

[0058] In 1999, the Analytical Chemistry Group of the University of São Paulo, Brazil, developed, synthesized, and commercialized a castor oil-derived polyurethane (Polyqil) (Sousa et al. 2018, Beloti et al. 2003). No data exists regarding the preparation of this polymer. However, apparently due to a lack of biocompatibility and / or efficacy, the Brazilian Health Agency (ANVISA) withdrew the material from the market.

[0059] Another example of castor oil polyurethane is disclosed in U.S. Patent No. 4990586, dated February 5, 1991, entitled "Polyurethane with Improved Properties—Biocompatible Urea-Modified Polyurethane Derived from Castor Oil," which discloses the production of such polymers using diamines. The described product has never entered clinical trials or practice.

[0060] The aforementioned polymers contain free isocyanate molecules after polymerization, which react violently with residual water molecules to form biuret. These reactions interfere with bone integration and biocompatibility. Another drawback is the need for a catalyst to promote polymer formation.

[0061] The most advanced polymer used in bone implants is a polymer called "Kryptonite," developed in the early 2000s by the Doctors Research Group. This material was approved by the FDA for use in cranioplasty. The material consists of castor oil-derived fatty acids, with triglycerides synthesized with NCO (isocyanate) groups to form prepolymer chains, which are then polymerized after being mixed with a second component that also contains naturally occurring castor oil-derived hydroxyl-terminated fatty acids. Furthermore, using a catalyst and water, the NCO groups react to release carbon dioxide, thereby creating pores in the final material. The third component is calcium carbonate, a non-reactive filler that increases porosity and helps achieve the desired mechanical and structural properties (US2012 / 0265312 A1). The main drawback was (i) the volume changes observed after implantation (Doumit et al. 2014), which led to fatal disease progressions after use in spinal surgery; ultimately, the product was withdrawn from the market due to an FDA decision (Doumit et al. 2014).

[0062] Petroleum-based polyurethanes with limited biocompatibility were obtained by using polyurethane bonds and urea bonds. The use of transparent polyurethanes with aliphatic diisocyanates in the construction of artificial organs also facilitates foreign body reactions. The use of castor oil modified via transesterification, for example with diethanolamide, resulted in polyurethane foams with limited strength (Palanisamy et al. 2011).

[0063] In this invention, a polyurethane (PU) is provided that overcomes one or more of the above-mentioned disadvantages, preferably all of them, and a method for preparing the polyurethane is also provided.

[0064] This invention discloses a novel polyurethane matrix and polyurethane polymer that unexpectedly encompass the aforementioned desired features and overcomes the problems described in conventional polyurethane matrices and polymers. It has been found in this invention that the controlled content of free fatty acids and the control of water content, as disclosed herein, contribute to obtaining an unexpectedly improved PU matrix. Furthermore, it has been found in this invention that it is the combination of components exhibiting the specific selected features and properties disclosed herein that results in this improved PU matrix.

[0065] Therefore, the PU matrix of the present invention is particularly valuable in medical applications, such as as a bone adhesive and / or implantable material, overcoming one or more disadvantages of prior art products, such as in terms of biocompatibility issues. In view of this, the PU matrix of the present invention can further avoid the use and / or generation of potentially harmful catalysts such as metal catalysts, diamines, and residual water. The polymer matrix of the present invention preferably exhibits high biocompatibility after implantation, due to its chemical characteristics and the unprecedented effect of polymerization and hardening occurring at relatively low temperatures (preferably equal to or below 47°C, or equal to or below 42°C), thus avoiding persistent inflammation and necrosis at the implantation site. It integrates tightly with the bone surface, a process known as osseointegration. This intimate "adhesive" interaction with bone tissue results in strong adhesion between the two bone surfaces, giving the PU matrix of the present invention the function of an "adhesive," whether it is used in liquid form or introduced into the body as a solid bone graft, solid implant, or solid prosthesis.

[0066] The PU matrix of this invention can also be used in the cosmetic field, for example, to treat undesirable cosmetic appearances of the skin, such as wrinkles. Depending on the circumstances or intended use, cosmetic applications may be separated from and / or distinguished from therapeutic applications.

[0067] Therefore, the present invention relates to a PU matrix wherein the water content is equal to or less than 1%, preferably equal to or less than 0.1%, more preferably anhydrous, as determined by a moisture content method; and / or wherein the content of free fatty acids is present, but controlled to a maximum of 19%, preferably between 7% and 19%, more preferably between 5% and 15%, and most preferably between 7% and 10%, as determined by titration with sodium hydroxide, with each property measured at a temperature of 25°C. In a preferred embodiment, the PU matrix exhibits the water content and free fatty acid content defined above.

[0068] The PU matrix exhibiting the aforementioned water content and / or free fatty acids represents an improvement over one or more, preferably more or even all, of the properties disclosed herein. For example, it exhibits improved biocompatibility, lower toxicity (e.g., due to the absence of a catalyst), improved adhesive properties (“gluing”), improved plasticity, and improved processability. The PU matrix of the present invention is particularly advantageous because it exhibits a temperature not exceeding 47°C during polymerization and / or curing. Furthermore, the PU matrix of the present invention is biocompatible and exhibits osteointegration properties, meaning that it undergoes gradual and slow absorption when it comes into contact with bone (such as defective bone to be repaired or bone to be glued), as a portion of the PU matrix, composed of fatty acids present in living receptors, is replaced by new bone.

[0069] In a preferred embodiment, in addition to the above-described characteristics, the PU matrix of the present invention also exhibits one or more, preferably all of the following characteristics, which are determined according to ASTM D695, "Standard Test Method for Compression Properties of Rigid Plastics," Volume 8.01, DOI:10.1520 / D0695-15, effective from the effective date: Physical tensile strength in the range of 26 MPa to 42 MPa; preferably in the range of 30 MPa to 38 MPa; elastic modulus in the range of 1700 MPa to 2400 MPa; preferably in the range of 1900 MPa to 2200 MPa; compressive strength in the range of 48 MPa to 57 MPa; preferably in the range of 50 MPa to 55 MPa; deformation in the range of 3.7% to 5.5%; preferably in the range of 4.0% to 5.0%, determined by ASTM D695MM; Shore hardness D in the range of 72 to 84; preferably in the range of 75 to 80, according to ASTM D695. D2240, "Standard Test Methods for Rubber Properties—Hardness Tester," Volume 0.01, DOI:10.1520 / D2240-15R21, is effective from the effective date and is tested using a hardness tester. All properties are measured at 25°C.

[0070] Depending on the intended purpose, in another embodiment, the PU matrix of the present invention may also include other compounds. These other compounds, which preferably do not interact negatively with the PU matrix, increase bioactivity. Preferably, they are 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.

[0071] As described elsewhere in this document, the content of free fatty acids is up to 19%, preferably between 7% and 19%, more preferably between 5% and 15%, and most preferably between 7% and 10%, as determined by titration with sodium hydroxide. These unreacted (free) fatty acids can form a support or wall for the PU matrix. Reacted acids, such as ricinoleic acid, can form cross-linked structures that contribute to the hardness of the PU matrix. Added calcium carbonate (present in the PU matrix after addition) forms randomly distributed microspheres that attract osteoblasts due to increased local alkaline phosphatase, thus stimulating the presence of these osteoprogenitor cells.

[0072] In this invention, it is assumed that at least one of these compounds helps to significantly reduce antigen-antibody reactions.

[0073] The PU matrix of this invention can be in liquid or solid form. The form of the PU matrix depends on the degree of polymerization of the matrix: the higher the degree of polymerization, the higher the rigidity or hardness of the PU matrix. The degree of fluidity (plasticity) can be changed (controlled) by varying the corresponding concentration of the components. For example, a higher polyol content results in higher plasticity. As disclosed elsewhere herein, during the preparation of the PU matrix of this invention, when the polyol component (also referred to herein as "Ampoule A") is initially mixed with the prepolymer (also referred to herein as "Ampoule B"), the resulting mixture becomes creamy during mixing and then reaches a plastic molding and rubbery state. Upon complete curing (polymerization), the PU matrix will reach its maximum hardness.

[0074] Depending on the intended use and / or function of the PU matrix, it may be preferable that the matrix exhibits higher plasticity than that preferred in another intended use / function.

[0075] It is noteworthy and unexpected that during the preparation of the PU matrix and during the polymerization process, the temperature of the PU matrix will not exceed 47°C, preferably measured inside a container, and preferably not exceeding 42°C, preferably when applied to the implantation site such as bone. The temperature of the PU matrix is ​​measured according to convention. This, in turn, provides the beneficial effect of reducing the occurrence of inflammatory processes or other damage in the recipient body, and preferably, no inflammation or other damage based on the presence of the PU matrix occurs. However, on the other hand, the PU matrix can withstand any commonly used form of sterilization without damage to itself.

[0076] Furthermore, among other properties, this minimal heat generation enables the polymerization (or degree of polymerization) of the PU matrix in a moist tissue environment, such as in vivo at the intended site. Additionally, the in-situ generated PU matrix is ​​insoluble in liquid media such as blood or saliva. This further contributes to the improved applicability of the PU matrix of the present invention in bone applications, particularly in the dental and orthopedic fields. Moreover, unlike some prior art products, the PU matrix of the present invention does not exhibit volume loss after reossification.

[0077] Therefore, the PU matrix of the present invention is particularly suitable for medical fields, such as dentistry and orthopedics.

[0078] For example, the beneficial properties of the PU matrix of this invention, particularly its specially adjustable plasticity, provide immediate and predictive fixation for applications such as dental implants, thereby allowing for immediate functional loading. Furthermore, the improved processing of the PU matrix allows for rapid and reliable 3D reconstruction of any bone defect, such as local enhancement, sinus lift, bone splitting, block grafting, etc. In addition, the improved bonding properties enable immediate fixation and bonding of fractures and autografts, as well as limbs. Moreover, the PU matrix of this invention further contributes to the protection against osteoporosis and the prevention of fractures through internal stability of the bone and vertebrae.

[0079] In the dental field, PU matrix offers an improved 3D reconstruction treatment for conditions such as peri-implantitis, refixation of fully removable and lost superstructures, and reconstruction of periodontal defects.

[0080] In a preferred embodiment, the PU matrix of the present invention is in the form of a solid biocompatible flexible sheet and can be thermoformed (i.e., the PU matrix is ​​thermoformable) into a changed shape by thermal deformation without elastic memory / returning to its original shape. More preferably, the thickness of the solid biocompatible flexible sheet is in the range of 0.01 mm or greater to 20.00 mm or less. The thickness depends on the intended use of the PU matrix. For example, the thickness of the PU matrix can be in the range of 0.01 mm to less than 1.00 mm, in which case the PU matrix is ​​referred to as a film. The thickness of the PU matrix can also be in the range of 1.00 mm to less than 5.00 mm, in which case it is referred to as a sheet. Furthermore, the thickness of the PU matrix can also be in the range of 5.00 mm to less than 20.00 mm; in which case it is referred to as a block. The PU matrix blocks of the present invention are particularly suitable for bone segment processing. For example, a plate-shaped PU matrix can be formatted using a heat source, after which it has no elastic memory.

[0081] The present invention also relates to a method for preparing a PU matrix, preferably the PU matrix disclosed herein. The method comprises the steps (a) to (e): In the first step a), a polyol component (also referred to herein as "Ampoule A") is provided, which exhibits the following characteristics (ai) and (a-ii): (ai) The acidity index, within 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, was determined by titration; and (a-ii) The 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, and most preferably 360 to 380, is determined by the method disclosed in “International Pharmacopoeia - 11th Edition, 2022, 4.7 Determination of Hydroxyl Value”.

[0082] Then, in step b), a diisocyanate component is provided, preferably diphenylmethane-4,4'-diisocyanate (MDI), wherein the diisocyanate component exhibits the following characteristics (bi) and optionally (b-ii): (bi) is a free isocyanate in an amount ranging from 16% to 35%, preferably 22% to 35%, more preferably 25% to 32% of NCO equivalent, determined by adding an excess of di-n-butylamine to form a urea and then back-titering the unreacted amine with hydrochloric acid.

[0083] Optionally (b-ii) is between 1.11 and 1.28 g / cm³. 3 The density is within a certain range and is determined by specific gravity measurement.

[0084] Then, in step c), a portion of the polyol component from a) and a portion of the diisocyanate component from b) are combined to form a prepolymer. This prepolymer is also referred to herein as the “prepolymer” and “ampoule B”.

[0085] In a preferred embodiment, the amount of free isocyanate in the prepolymer formed in step c) as an NCO equivalent is in the range of 10% to 25%, preferably 19% to 23%, more preferably 20% to 21%, and is determined by adding excess di-n-butylamine to form urea and subsequently back-titrifying the unreacted amine with hydrochloric acid; the density is in the range of 1000 to 1500 g / cm³. 3 Within the range, preferably 1100 to 1400 g / cm³ 3 More preferably 1180 to 1270 g / cm³ 3 The dynamic viscosity is determined according to description elsewhere herein; and / or, preferably, in the range of 350-750 centipoise (cP), more preferably 400 to 700 cP, more preferably 450 to 650 cP, and even more preferably 500 to 600 cP, by rotational viscometer as specified in American Standard for Testing and Materials ASTM D4878: Standard Test Methods for Polyurethane Raw Materials: Determination of Viscosity of Polyols, Volume 08.02 (DOI:10.1520 / D4878-15) on the effective date.

[0086] Furthermore, in step c), it is preferable to combine the following parts of polyol component and diisocyanate component: 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. In a preferred embodiment, by combining the above-mentioned parts of polyol component and diisocyanate component, the diisocyanate component is present in the prepolymer at an amount of 20% to 32%.

[0087] Then, in step d), at least a portion of the polyol component from a) and at least a portion of the prepolymer from c) are combined to obtain a mixture. In a preferred embodiment, in step d), the prepolymer from c) is combined with the polyol from a) to obtain a polyurethane matrix ratio in the range of 0.5:1.0 to 0.8:1.0 (polyol / prepolymer).

[0088] Then, in the final step e), the PU matrix is ​​obtained.

[0089] In another preferred embodiment, the polyol component (a) further has (a-iii) at 850-1200 g / cm³ 3 Optimal g / cm³ is 950 to 1200 g / cm³. 3 More preferably 1000 to 1150 g / cm 3 The optimal value is 1050 to 1100 g / cm³. 3 The densities within the specified range were determined by specific gravity measurement at 25°C; and (a-iv) Viscosity in the range of 1400 to 1800 cP, preferably 1500 to 1700 cP, determined by ASTM D4878, Volume 08.02 (DOI:10.1520 / D4878-15), effective date.

[0090] b) Diisocyanate component (b) also has (b-iii) A moisture content equal to or less than 0.1%, preferably in the range of 0.01% to 0.1%, more preferably 0%, determined by moisture content (oven drying method); and (b-iv) Viscosities in the range of 20 cP to 200 cP, preferably in the range of 20 cP to 120 cP, more preferably in the range of 40 cP to 120 cP, and even more preferably in the range of 40 cP to 100 cP, determined by ASTM D4878, Volume 08.02 (DOI:10.1520 / D4878-15), effective date.

[0091] In the method of the present invention, the polyol component in step a) is prepared from castor oil having the following properties: - The acidity index is determined in the range of 0.20-1.5 mg KOH / g, preferably 0.40-1.25 mg KOH / g, more preferably 0.5 to 1.0 mg KOH / g, as disclosed elsewhere herein; - A hydroxyl index in the range of 150-170, preferably 150-160, more preferably 155-165, determined according to what is disclosed elsewhere herein; and optionally - In the range of 0.090 to 0.098 g / cm 3 Preferably, the concentration is 0.095 to 0.096 g / cm³. 3 The density within the specified range was determined by specific gravity measurement at 25°C; and / or - Viscosities in the range of 500 cP to 1000 cP, preferably in the range of 600 cP to 900 cP, and more preferably in the range of 700 cP to 800 cP, as disclosed elsewhere herein; In a preferred embodiment, the polyol component in step a) is prepared from castor oil, which has all the above-mentioned properties regarding acidity index, hydroxyl index, density, and viscosity.

[0092] When the above conditions and ranges are observed during the PU matrix preparation process, the PU matrix disclosed herein can be achieved. Other suitable conditions and methodologies are described in more detail below.

[0093] In step a), a polyol component is provided. In a preferred embodiment, this step includes step (a-1) combining castor oil, ethylene glycol, and propylene glycol under a protective atmosphere, preferably a nitrogen atmosphere; preferably, the combination is carried out with stirring; preferably for a period of 1 to 5 hours, more preferably for a period of 2 to 4 hours, and even more preferably for about 2 hours; thereby obtaining a mixture; step (a-2) heating the mixture of (a-1), preferably heating it to a temperature in the range of about 100°C to about 270°C, more preferably heating it to a temperature in the range of about 200°C to about 260°C, and even more preferably heating it to a temperature of about 250°C, and then performing a cooling step; optionally step (a-3) rotating the mixture, preferably under reduced pressure, preferably in a rotary evaporator, to remove residual gases; optionally step (a-4) cooling the mixture; and step (a-5) obtaining the polyol component. In a more preferred embodiment, step a) includes all steps (a-1) to (a-5).

[0094] In step c), a prepolymer is formed by combining a portion of the polyol component a) and a portion of the diisocyanate component b). In a preferred embodiment, step c) includes the following steps (c-1) to (c-5): In step (c-1), the polyol from step (a) is mixed with a diisocyanate compound (preferably diphenylmethane-4,4'-diisocyanate (MDI)) preferably in the proportions defined above (i.e., combining the following parts of polyol and diisocyanate components: 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) to obtain a mixture. In step (c-2), the mixture from (c-1) is preferably stirred at a temperature of about 100°C. In optional step (c-3), a vacuum is applied. In step (c-4), possible gaseous inclusions are preferably removed by evaporation of the mixture; finally, in step (c-5), the prepolymer is obtained.

[0095] The method of the present invention may include the step of adding other compounds. These other components, which preferably do not negatively affect the properties of the PU matrix of the present invention, are selected from the group consisting of: calcium salts, such as CaCO3 or CaCO3(PO4)2, wherein, based on the weight sum of the main component polyol and prepolymer, these salts are preferably 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%, and most preferably in a total amount of 30 wt% to 40 wt%; hydroxyapatite, wherein, based on the weight sum of the main component polyol and prepolymer, hydroxyapatite is preferably present in an amount of about 15-25 wt%, more preferably 18-22 wt.%, and most preferably about 20 wt.%; small molecules, peptides, or proteins with osteoinductive properties, wherein, based on the weight sum of the main component polyol and prepolymer, the total amount of said components is preferably from about 1 wt% to about 5 wt%. Within the range of wt%; and appropriate amounts of small molecules, peptides or proteins with anti-infective and / or antibacterial properties.

[0096] Through the action of calcium salts, hydroxyapatite, and small molecules, peptides, or proteins, osteoconduction and / or preferential bone regeneration are induced, and anti-infective / antibacterial properties are conferred.

[0097] In a preferred embodiment, the other compound added in a further step is a calcium salt, such as CaCO3 or CaCO3(PO4)2, with CaCO3 being the preferred additional compound. CaCO3 provides randomly distributed microspheres within the PU matrix. These microspheres attract osteoblasts, ultimately stimulating the presence of osteoprogenitor cells, leading to the formation of new bone.

[0098] In the method of the present invention, other components may be added at any suitable step. Preferably, other components are added during or after step d), and more preferably, other compounds are added during or after step d) but before step e). More preferably, other compounds are added during step d) so as to become part of the mixture in step d).

[0099] In step e), a PU matrix is ​​obtained. In a preferred embodiment, this step of obtaining the PU matrix includes polymerizing the mixture from step d), i.e., the mixture obtained when at least a portion of the polyol component and a portion of the prepolymer are combined. Polymerization is initiated by mixing (combining) the polyol component (“Ampoule A”) and the prepolymer (“Ampoule B”). The degree and rate of polymerization can be controlled according to the ratio of polyol component a) and the prepolymer. For example, Ampoule A and Ampoule B are mixed in a ratio of 0.60-0.7:1.

[0100] During the polymerization reaction, when measured inside the vessel where step d) is performed, the highest polymerization temperature reached during the polymerization step is at most 47°C, preferably at most 46°C, or at most 45°C. In another preferred embodiment, no polymerization catalyst is present during step e). By controlling the precise amounts of the polyol and isocyanate-containing prepolymer as described above, the polymerization reaction is initiated in a controlled manner without further initiation. This is advantageous, for example, in terms of toxicity, because no toxic reaction products and / or byproducts are generated.

[0101] As illustrated in the examples below, polymerization can occur in vivo as a liquid or viscous prepolymer, or ex vivo to form fixed implants or complex prosthetic applications. These characteristics will allow for a variety of applications that have been impossible in surgical settings until now. Furthermore, there is no volume change in the material after the polymerization process is complete, thus avoiding the problems previously observed with castor oil polymers such as kryptonite (Doumit et al. 2014).

[0102] Polymers can also be used alone or in combination with ceramics or metals to form blocks, granules, membranes, plates, large prototype bone segments, and solid or flexible frames. Furthermore, polymers can be used to produce bone frames for cell culture and proliferation, creating suitable environments and producing autologous tissue grafts to repair major bone defects using patient stem cells.

[0103] Depending on the selected conditions, the surface of this biocompatible polyurethane can be smooth or rough, and its interior can contain numerous interchangeable tubules that facilitate the penetration of the cell matrix. These physical characteristics contribute to stabilizing, anchoring, and accelerating new bone replacement. The polymer can also be modified by adding calcium salts such as calcium carbonate or calcium carbonate phosphate.

[0104] High biocompatibility is also attributed to the observed inhibition of microbial growth and biofilm formation, a mainstay of bone implants and prostheses (Miwa et al. 2019). This can be achieved through the polymer itself and / or in combination with suitable antimicrobial agents.

[0105] The present invention also relates to a PU matrix that can be obtained or acquired by the methods defined herein. Such an acquired PU matrix exhibits one or more of the advantages listed herein, preferably all of them.

[0106] Due to the beneficial properties of the PU matrix of the present invention, it is well-suited for use in medical fields such as dentistry or orthopedics. Therefore, the present invention particularly relates to PU matrices for methods of bone regeneration, bone fixation, bone adhesion (“gluing”), bone implantation, and replacement of all or part of bone. For example, the PU matrix can be used as a gluing agent, such as in the joining of fractures during external bone ligation.

[0107] In a preferred embodiment, the method includes preparing an implant, such as a dental implant or an orthopedic implant. In a preferred embodiment, the implant is a personalized implant. Personalized implants are particularly advantageous if they are to be tailored to a specific subject (patient) and therefore can only be used by that specific subject—in other words, if they are personalized implants. Such personalized implants are, for example, dental implants, or other bone implants that are preferably personalized, such as implants for the vertebrae or skull.

[0108] The PU matrix of the present invention can also be used to stabilize bone structures.

[0109] Examples of potential uses for PU matrix include orbital floor replacement. Other examples of custom-designed prostheses are in cranioplasty, such as cranioplasty.

[0110] An external heat source can also be used to "pre-form" the PU matrix of the present invention into the desired shape (form) and to make final adjustments to the prosthesis.

[0111] The PU matrix of the present invention can also be used in tumor surgery; for example, a portion of the jawbone can be replaced by a corresponding portion formed from the PU matrix of the present invention.

[0112] In another embodiment, the PU matrix is ​​delivered to the subject subcutaneously.

[0113] definition Within the meaning of this invention, the term "free fatty acid" refers to unesterified and possibly unbound fatty acids, i.e., fatty acids that are not bound to proteins.

[0114] method Determination of acidity index Acidity index (also known as “acid value”) is determined by titration. Specifically, the amount of free fatty acids present in a substance is measured by its acid value, referred to as the acid value in fats and oils. It is expressed as the amount of potassium hydroxide (KOH) required to neutralize the free fatty acids present in one gram of substance (or sample, respectively). In this invention, the acidity index is determined by titration, as described, for example, in Sarmila KC, “Determination of Acid Value in Fats and Oils,” *The Science Notes, Simplest Explanations of Complex Facts*, April 12, 2023.

[0115] Determination of the hydroxyl index The hydroxyl index (also known as the "hydroxyl value") is determined according to method A in "International Pharmacopoeia 11th Edition, 2022, 4.7 Determination of hydroxyl value".

[0116] Determination of free isocyanates Free isocyanates (NCO) are determined by the reaction of NCO with di-n-butylamine to form urea. According to ISO 14896, unreacted (excess) amines are determined by back titration with hydrochloric acid, July 2009 edition, effective from the effective date, as described, for example at https: / / www.iso.org / standard / 50601.html.

[0117] Determination of the density of polyols According to ASTM D4669, Determination of Specific Gravity of Polyols, Vol. 8.02, DOI:10.1520 / D4669-18, https: / / www.astm.org / d4669-18.html, the density of polyols is measured using a specific gravity bottle.

[0118] Determination of water content For example, the water content of diisocyanate is preferably determined by the moisture content method (oven drying method).

[0119] Determination of free fatty acid content The free fatty acid content (%) was determined according to the American Petroleum Chemists Institute (AOCS) Ca 5a-40 standard, reapproved in 2009 (https: / / www.scribd.com / document / 501700643 / AOCS-Ca-5a-40#). Free fatty acids were determined by titrating the sample in ethanol with a standard aqueous sodium hydroxide solution using phenolphthalein indicator solution.

[0120] Equivalent weight (adapted from Huntsman Technical Center bulletin) Bulletin)) The equivalent weight (eq.wt.) is used to calculate how many grams of product are needed for one equivalent of the reactive group. For example, for isocyanates, the reactive group is NCO (N=C=O). Its concentration is measured as a weight percentage of NCO.

[0121] Isocyanate equivalent weight =

[0122] Example: The isocyanate equivalent weight of pure MDI = 4200 ÷ 33.6 = 125 g / eq For polyols, the reactive group is -OH(OH).

[0123] OH concentration is measured by OH value (mg KOH / g sample): Polyol equivalent weight = 56100 ÷ OH value (unit: g / eq) Example: Equivalent weight of ethylene glycol = 56100 ÷ 1810 = 31.0 g / eq Molecular weight of polyols (Adapted from Huntsman Technology Center Bulletin): The molecular weight (mol. wt.) of a polyol is approximately equal to the equivalent weight (eq. wt.) of the polyol multiplied by its nominal functionality (fn). Polyol mol. wt. = (eq.wt.) x (fn) = [56100 ÷ OH value] x (fn) (unit: g / mol) The molar weight of any diol is calculated as [56100 ÷ OH value] x 2 g / mol. The molar weight of any triol is calculated as [56100 ÷ OH value] x 3 g / mol. Example: The molar weight of ethylene glycol is calculated as follows: wt. = [56100 ÷ 1810] x 2 = 62.0 g / mol. Total weight of MDI (diphenylmethane diisocyanate) required for the reaction (adapted from Huntsman Technology Center Bulletin): When isocyanates react with one or more polyols to form polyurethane, one NCO group reacts with one OH group. The stoichiometric ratio of NCO:OH is 1.0 when the number of NCO groups equals the number of OH groups. This ratio is commonly referred to as the index. To determine the amount of MDI required to react with a given polyol blend, you must know the desired index (typically 1.0), the MDI equivalent weight (MDI eq.wt.), the weight fraction (pbw) of the polyol and any water present in the blend, and their equivalent weights.

[0124] Total weight of MDI required = The index x MDI eq. wt. x {(pbw polyol A ÷ eq. wt. polyol A) + (pbw polyol B ÷ eq. wt. polyol B) + ......+(pbw polyol N ÷ eq. wt. polyol N)+(pbw water ÷ eq. wt. water) Example configuration: Given the following polyol blends, it is desirable to determine the amount of pure MDI added to obtain a fully reacted polyurethane with a slight excess of isocyanate (target index = 1.05).

[0125] X = pbw MDI = index x MDI eq. wt. x{[100 ÷ (56100 ÷ 490)] + (20 ÷ 45) + (0.15 ÷ 9)} X = 1.05 x (4200 ÷ 33.6) x {0.873 + 0.444 + 0.017} X = 1.05 x 125 x 1.334 X = 175 pbw MDI Total amount of MDI required for the reaction When an isocyanate reacts with one or more polyols, one NCO group reacts with one OH group. When the number of NCO groups equals the number of OH groups, the result is a stoichiometric NCO:OH ratio of 1.0. This ratio of 1.0 is usually referred to as the exponent.

[0126] To determine the amount of MDI required to react with any given polyol blend, the desired index (typically 1.0) must be known, along with the MDI equivalent weight (MDI eq.wt.), weight fraction (pbw), and the equivalent weights of the polyol and any water present.

[0127] Example Example 1 Polyol Synthesis Castor oil (e.g., EC / List no.:232-292-2, CAS no.:8001-78-3) was combined with ethylene glycol and propylene glycol (e.g., a castor oil / polyethylene glycol / propylene glycol ratio of 1:0.2 / 0.1), stirred for 2 hours under a nitrogen atmosphere, and heated to 250°C in a glass synthesis reactor. Distilled water was separated, and the mixture was cooled. Subsequently, the mixture was rotated in a rotary evaporator at 120°C to remove residual gases. After cooling, the product (polyol) was stored at room temperature protected from light.

[0128] Polyols were analyzed by color, hydroxyl index, density, and acidity. For further use, the polyols were selected as slightly yellow, viscous, transparent solutions with a hydroxyl index of 200 to 450 mg KOH / g and an acidity index of 0.8 to 8.5 mg KOH / g.

[0129] When used in a clinical setting, the polyol is filled into ampoules or syringes under aseptic conditions.

[0130] Example 2 Prepolymer Synthesis The polyol of Example 1 was mixed with a diisocyanate (e.g., MDI 4,4-diphenylmethane isocyanate RUBINATE 1680 from Bayer AG, Germany) in a 3:1 ratio and stirred at 100°C. Any gases that might be present were removed by placing the liquid in an evaporator for approximately 15 minutes. The product was evaluated by color, density, viscosity, and the content of free isocyanate. The free isocyanate content can range from 10% to 35%, and for further use, it is typically selected to be in the range of 20% to 32%, preferably 22% to 30%, and particularly 28% to 29%.

[0131] Example 3 Use CaCO 3 Reinforced polymers The polyol from Example 1 and the prepolymer from Example 2 were further modified by adding CaCO3. For this purpose, CaCO3 powder (20 g) was mixed with the polyol and the prepolymer (total 40 g) respectively, and gently stirred until the Ca salt was uniformly dispersed.

[0132] After mixing, the resulting viscous polymer hardens to its final strength within a 30-minute period.

[0133] Figure 1 Various embodiments are shown, such as implants made of the final polymer (PU matrix).

[0134] Example 4 The PU polymer matrix was prepared by mixing and polymerizing the components prepared in Examples 1 and 2.

[0135] To evaluate the stability of the polymer prepared from the components prepared in Examples 1 and 2 as a bone adhesive, miniature pig femurs were cut using a bone vibrating saw. Subsequently, both surfaces were exposed to the adhesive polymer, and the two bone fragments were held in situ (before cutting). After 15 minutes, the adhesive hardened, and the fractures stabilized. The bones were left at room temperature without further fixation. The following day, bone from the same animal and a control femur were prepared using a three-point bending stress apparatus to evaluate mechanical stability. Figure 2 It can be seen that bone has high strength.

[0136] Despite its small surface area, the adhesive only loses about three times the strength of natural bone. As shown in sM, the strength of the adhesive is comparable to that of natural bone. Figure 3 ).

[0137] Example 5 Temperature distribution during polymerization The polyol described in Example 1 and the prepolymer described in Example 2 were mixed and stirred for 15 min until the desired viscosity was reached. The temperature of the mixture was measured simultaneously. Figure 4 As can be seen, the temperature curve reaches a peak of 46°C at 13 minutes. At this point, the adhesive material can be obtained in plastic form and used as an adhesive or implant, rapidly cooling to a temperature below 39°C within 5 minutes.

[0138] Example 6 The osseointegration properties of polymer implants were evaluated in a rabbit model of radial bone defect. Rabbit radii were prepared under anesthesia, a portion of the radius was removed, and implants prepared according to Examples 1 to 3 were inserted. Complete integration of the implants into the radius was observed, with gradual replacement by bone tissue.

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Claims

1. A polyurethane (PU) matrix, wherein i) The moisture content of the PU matrix is ​​equal to or less than 1%, optionally equal to or less than 0.1%, or water is absent, as determined by a moisture content measurement method (drying method); and ii) Free fatty acids are present, but their content is as high as 19%, as determined by titration with sodium hydroxide. Each property was measured at 25°C.

2. The PU matrix according to claim 1, wherein, The matrix further exhibits one or more of the following properties, preferably all of them: iii) Physical tensile strength in the range of 26 MPa to 42 MPa, preferably in the range of 30 MPa to 38 MPa, as determined by ASTM D695 mm of the American Society for Testing and Materials; iv) The modulus of elasticity in the range of 1700 MPa to 2400 MPa, preferably in the range of 1900 MPa to 2200 MPa, as determined by ASTM D695MM of the American Society for Testing and Materials; v) Compressive strength in the range of 48 MPa to 57 MPa, preferably in the range of 50 MPa to 55 MPa, as determined by ASTM D695MM of the American Society for Testing and Materials; vi) Deformation within the range of 3.7% to 5.5%, preferably between 4.0% and 5.0%, as determined according to ASTM D695 mm; and vii) Shore hardness D in the range of 72 to 84, preferably in the range of 75 to 80, determined by a hardness tester according to the American Standard for Testing and Materials (ASTM) D2240. Each property was measured at 25°C.

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 having osteoinductive properties; and small molecules, peptides or proteins having anti-infective and / or antibacterial properties.

4. A method for preparing a polyurethane matrix, comprising the following steps: a) Providing a polyol component, wherein the polyol component has: (ai) The 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, was determined by titration; (a-ii) The 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, and most preferably 360 to 380, is determined by the method disclosed in "International Pharmacopoeia—11th Edition, 2022, 4.7 Determination of Hydroxyl Value"; and b) Providing a diisocyanate component, preferably diphenylmethane-4,4'-diisocyanate (MDI), wherein said diisocyanate component has: (bi) is a free isocyanate in an amount ranging from 16% to 35%, preferably 22% to 35%, more preferably 25% to 32% of NCO equivalent, determined by adding excess di-n-butylamine to form urea and then back-titering the unreacted amine with hydrochloric acid. (b-ii) Optionally, between 1.11 and 1.28 g / cm³ 3 The density within the range was determined by specific gravity measurement. 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 the polyol component of a) and at least a portion of the prepolymer of c) to prepare a mixture; and e) Obtain the polyurethane matrix from the mixture.

5. The method according to claim 4, wherein, In step c), the following parts of polyol component and diisocyanate component are combined: 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 In step d), the prepolymer from step c) is combined with the polyol from step a) to obtain a polyurethane mixture in a ratio of 0.5:1.0 to 0.8:1.0 (polyol / prepolymer).

6. The method of claim 4 or 5, further comprising the step of adding other compounds, wherein said other compounds are selected from the group consisting of: • Calcium salts, such as CaCO3 or CaCO3(PO4)2, wherein, based on the sum of the weights of the polyol and the prepolymer, these salts are preferably 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%, and most preferably in a total amount of 30 wt% to 40 wt%. • Hydroxyapatite, wherein, based on the sum of the weights of the polyol and the prepolymer, the hydroxyapatite is preferably present in an amount of about 15-25 wt%, more preferably in an amount of 18-22 wt.%, and most preferably in an amount of about 20 wt.%. • Small molecules, peptides, or proteins with osteoinductive properties, wherein the total amount of the components is preferably in the range of about 1 wt% to about 5 wt%, based on the sum of the weights of the polyol and the prepolymer; and • Appropriate amounts of small molecules, peptides, or proteins with anti-infective and / or antibacterial properties.

7. The method according to any one of claims 4 to 6, wherein, Step e) includes the step of polymerizing the mixture from step d).

8. The method according to any one of claims 4 to 7, wherein, There is no polymerization catalyst during step e).

9. A PU matrix that can be obtained by the method defined in any one of claims 4 to 8.

10. Use of the PU matrix according to any one of claims 1 to 3 or according to claim 9 in treatment methods for bone regeneration, bone fixation, bone adhesion, bone implantation and / or whole or partial bone replacement.

11. The PU matrix for the use according to claim 10, wherein, The treatment method includes preparing an implant, preferably a dental implant or an orthopedic implant, more preferably an individualized implant, particularly an orthopedic or dental individualized implant for preparing a dental implant, and more preferably an individualized dental implant.

12. The PU matrix for the use according to claim 10 or 11, wherein, The implant is suitable for replacing bone; for replacing part of bone; for replacing bone defects; or for stabilizing bone structure.

13. The PU matrix for the use according to any one of claims 10 to 12, wherein, The PU matrix is ​​provided to the subject subcutaneously.

14. A kit comprising a polyol component as defined in claim 4 and a prepolymer as defined in claim 4 or 5.

15. The kit according to 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.

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