Bioadhesive composition

Abstract

The present invention relates to a two-component composition comprising a first component A comprising water or an aqueous solution, and a second component B comprising: a self-curing adhesive powder comprising at least a polyvalent metal salt and phosphoserine, and at least one mono-carbonate selected from the group consisting of sodium carbonate, ammonium carbonate and potassium carbonate, characterised in that the mono-carbonate is present in a concentration of from 4% to 12% by weight of component B.

Description

[0001] The present invention relates to a composition for preparing a bioadhesive composition. Also provided are kits and methods for preparing a bioadhesive composition.

[0002] Medical devices, such as general implants and especially dental implants, are widely used today. In situations where fixation or replacement of hard tissue structures is required, such as in the case of fractures or tooth loss, they have become a popular possible option. However, the success of such implants depends largely on adequate support at the implant site. If the bone mass at the site is insufficient or of poor quality, bone repair and / or bone augmentation becomes necessary. Different treatments are applied to restore sufficient bone mass, including the use of bone graft materials of different sources, shapes, and sizes.

[0003] Although there are methods for treating the quality and / or strength of bone systemically, such as in osteoporosis, it is still difficult to achieve bone formation in a reliable and controllable manner. However, local bone formation would greatly benefit the adequate treatment of events where only local enhancement of bone volume is required, such as when placing a dental implant.

[0004] Current methods for repairing bone defects include graft materials from different sources. The material is either synthetic or of natural origin. One natural graft material used is autologous bone. In contrast to bone or bone-like materials from natural sources (human, animal, plant, algae, etc.), autologous bone material does not trigger a strong immune response and is therefore not rejected by the host. However, autologous bone material requires a second surgery to harvest the bone, which increases the risk of unwanted infection and / or inflammation at the site and significantly increases the treatment cost. In addition, the removal of the bone material at least temporarily results in a weakened structure at the site and causes a painful healing process.

[0005] EP2269663A2 discloses a bone graft or biocomposite for treating bone defects and bone neogenesis. It is a composite of a biodegradable polymer and β-tricalcium phosphate particles and also contains an active ingredient embedded in the biodegradable polymer.

[0006] WO2010056811 discloses a composition that at least contains tetracalcium phosphate, an effective amount of a compound structurally similar to phosphoserine, and can be mixed with an aqueous solution. The composition provides adhesion and cohesive strength in both wet and dry environments.

[0007] WO2016196371 and WO2018060289 disclose compositions with adhesive properties and methods for fixing implants to bone. The materials have excellent adhesive properties, especially as soft tissue adhesives. However, they are very dense, which has a negative impact on new bone formation.

[0008] WO2021092062A1 discloses an adhesive composition that includes a therapeutic agent released from the composition in order to treat any number of diseases or disorders, or to help accelerate local tissue regeneration, or to assist in surgery or treatment.

[0009] The object of the present invention is to provide a bioadhesive composition that allows for good osseointegration.

[0010] This problem is solved by the composition according to claim 1. Further preferred embodiments are the subject matter of dependent claims 2 to 15.

[0011] The composition of the present invention relates to a two-component composition comprising a first component A and a second component B. The first component A comprises water or an aqueous solution. The second component B comprises a self-curing adhesive powder and at least one monocarbonate. The self-curing adhesive powder comprises at least a polyvalent metal salt and phosphoserine. The at least one monocarbonate is selected from the group consisting of sodium carbonate, ammonium carbonate, and potassium carbonate, and the at least one monocarbonate is present at a concentration of 4 wt% to 12 wt% of component B.

[0012] When the two components (i.e., component A and component B) are mixed, a cohesive viscous paste is formed, which retains its viscous properties until it solidifies. At the same time, gas is generated, which forms a porous scaffold in the paste. Such a porous paste can be used, for example, to stabilize implants, especially dental implants, or to fill bone defects. One of the main advantages of the composition of the present invention is its inherent ability to solidify and retain its adhesive properties even in an aqueous environment, while exhibiting excellent osseointegration due to the in-situ generated porosity. This allows, for example, dental implants to be adhered to bone tissue or soft tissue without negatively affecting osseointegration.

[0013] It has been found that the choice of the monocarbonate and the amount of the monocarbonate present in the composition of the present invention are crucial for obtaining sufficient porosity in the cured material while maintaining sufficient stability. For example, a monocarbonate concentration of less than 4 wt% of component B results in a cured material that is too dense to ensure good osseointegration, while a monocarbonate concentration of, for example, 16 wt% of component B strongly affects the mechanical stability of the cured material. Furthermore, it has surprisingly been found that this effect can only be achieved with monocarbonates selected from the group consisting of sodium carbonate, ammonium carbonate, and potassium carbonate. In particular, it is worth mentioning that pores cannot be obtained with calcium carbonate, which is widely used in biological applications. The composition of the present invention also serves as a mechanically stable scaffold for bone regrowth as well as implant stabilization.

[0014] The composition of the present invention not only leads to optimal osseointegration by promoting the ingrowth of blood vessels and bone tissue, but also serves as a mechanically stable scaffold for these processes.

[0015] The composition of the present invention is particularly useful as a bone restorative composition. A bone restorative composition refers to a composition that can be used to restore and / or repair bone, such as bone adhesives, bone cements, bone glues, bone putties, bone void fillers, bone replacement compositions, cements and / or adhesives for fixing (i.e., stabilizing) implants (such as dental implants) to bone tissue or soft tissue. The composition of the present invention is particularly useful for treating bone defects because it has a porous scaffold and adhesive properties. In addition, as the material expands during the hardening process, it is particularly beneficial for filling complex bone defects. After mixing, the composition immediately flows smoothly and uniformly, expands in the voids and fills the entire volume of the defect. In addition, as described above, the material has excellent adhesive properties, thus allowing good adhesion to the surrounding bone, soft tissue and / or dental implant materials. In addition, it adheres not only to biological tissues, but also to materials made of metal, ceramic or plastic, especially to dental implants made of titanium, titanium alloy or Y-TZP.

[0016] The first component A of the two-component composition comprises water or an aqueous solution. In the context of the present invention, the term aqueous solution refers to water that additionally contains additives (such as salts). Preferably, component A comprises distilled water or an aqueous solution containing water and saline (0.9 wt% NaCl aqueous solution).

[0017] The second component B of the two-component composition comprises a self-curing powder. The term "self-curing" refers to the ability of a material to cure and harden due to the mixing of solid and liquid components. The self-curing powder comprises at least two different components, namely a polyvalent metal salt and phosphoserine. In addition to the self-curing powder, component B also comprises at least one monocarbonate. When contacted with water or an aqueous solution, the interaction of these components produces a sticky and adhesive reaction mixture containing pores.

[0018] Therefore, the composition of the present invention is preferably a ready-to-use system. The composition is injectable and can be used in a two-chamber system to simplify and rapidly fill bone defects in a minimally invasive manner. With the help of the two-chamber system, the formulation can significantly facilitate clinical applications by reducing the operation time, lowering the risk of contamination and ensuring reproducible results.

[0019] Preferably, the amount of phosphoserine is 20 wt% to 50 wt% of the self-curing adhesive powder, preferably 20 wt% to 30 wt% of the self-curing adhesive powder. This amount of phosphoserine results in an optimal amount of pores. In addition, it has been demonstrated that the phosphoserine content allows the regulation of porosity and curing time.

[0020] Preferably, the amount of the polyvalent metal salt is 50 wt% to 90 wt% of the self-curing adhesive powder, preferably 70 wt% to 80 wt% of the self-curing adhesive powder.

[0021] Preferably, the monocarbonate is present at a concentration of 6.5 wt% to 12 wt% of component B. It can be shown that said monocarbonate concentration achieves optimal results in terms of porosity and mechanical stability (see Figures 3 to 5).

[0022] Preferably, based on the combined weight of the total composition (i.e., components A and B together), the amount of water or aqueous solution of the composition is at most about 35 wt%, preferably at most 25 wt%. It has been shown that this liquid / solid ratio achieves the optimal setting time and compressive strength of the adhesive composition.

[0023] In one embodiment of the present invention, the composition further comprises an acidifying agent. To control pore formation, the acidifying agent is preferably part of the first component A and is thus dissolved in water or an aqueous solution. Preferably, the acidifying agent is selected from the group consisting of hydrochloric acid, ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid, propionic acid, their corresponding salts, especially trisodium citrate, tripotassium citrate, calcium citrate, magnesium citrate, ammonium citrate and ferric citrate, or mixtures thereof, most preferably citric acid, sodium citrate and calcium citrate. The presence of the acidifying agent can be used to adjust the setting time. A higher concentration of the acidifying agent increases the setting time of the material during setting. Preferably, component A comprises 0.1 wt% to 40 wt% of the acidifying agent, most preferably 5 wt% to 25 wt% of the acidifying agent. In addition, it has been shown that the acidifying agent or its corresponding salt (especially the sodium salt) can act as a retarder. Particularly good results can be obtained with trisodium citrate.

[0024] Preferably, the monocarbonate is selected from the group consisting of sodium carbonate and ammonium carbonate, as they achieve optimal pore formation. The best results can be obtained with sodium carbonate, as the composition containing sodium carbonate is easier to handle and does not have a tendency to disintegrate.

[0025] In one embodiment of the present invention, the polyvalent metal salt contained in the composition includes tetracalcium phosphate. Tetracalcium phosphate with a comparable particle size distribution achieves a slightly faster time and is particularly preferred for larger bone defects.

[0026] In another embodiment of the present invention, the polyvalent metal salt contained in the composition includes tricalcium phosphate, more preferably α-tricalcium phosphate. α-TCP is more soluble in the bone material of the body, which can increase its absorption rate and shorten the healing process.

[0027] Preferably, the phosphoserine in the composition of the present invention is L-phosphoserine. L-phosphoserine is a component of many endogenous proteins, especially osteopontin (bone sialoprotein), and is a normal metabolite found in human biological fluids. It has a high affinity for poorly crystalline apatite, indicating its important role in the mineralization process.

[0028] Preferably, the composition of the present invention further comprises calcium silicate, which enhances the strength of the setting reaction and beneficially affects bone healing and promotes osseointegration.

[0029] On the other hand, it relates to a kit comprising the adhesive composition of the present invention. The kit comprises a first compartment and a second compartment. The first compartment has component A containing water or an aqueous solution, and the second compartment has component B. Component B comprises a self-setting adhesive powder and at least one monocarbonate selected from the group consisting of sodium carbonate, ammonium carbonate, and potassium carbonate, wherein the monocarbonate is present at a concentration of 4 wt% to 12 wt% of component B. The self-setting adhesive powder comprises at least a polyvalent metal salt and phosphoserine. The first compartment and the second compartment are physically separated from each other. The separation of the two compartments allows for the provision of a ready-to-use system with a long shelf life.

[0030] The kit preferably comprises 10 wt% to 35 wt% of component A and 65 wt% to 90 wt% of component B, preferably 15 wt% to 20 wt% of component A and 80 wt% to 85 wt% of component B, wherein the sum of component A and component B is 100%. It has been shown that this liquid / solid ratio achieves the optimal setting time and compressive strength of the adhesive composition.

[0031] The kit comprising the composition of the present invention can be provided in a container selected from the group consisting of a tube, a syringe, a bottle, a double-barrel syringe, an automatic mixing system, a titratable capsule, a foil package, and combinations thereof. Such a kit allows for the direct in-situ preparation of the material before use.

[0032] The composition of the present invention is preferably used for treating bone defects (such as voids, gaps, or cracks) in order to fill the bone defect while ensuring mechanical stability during the healing process. Preferably, the bone defect is a large bone defect because such bone defects are particularly difficult to treat with conventional bone graft materials. In addition, the composition also provides a mechanically stable scaffold for bone regrowth and implant stabilization. In particular, the composition of the present invention can be used in oral or dental surgeries requiring repair, such as implant placement.

[0033] According to another aspect of the present invention, the composition is used for fixing implants, particularly dental implants. Since the composition of the present invention shows excellent adhesive affinity for bone, metal, and ceramic, the implant has good initial stability, which allows the implant to heal without interference. In addition, the porosity of the cured material enables good osseointegration. Therefore, the composition of the present invention achieves excellent primary and secondary stability.

[0034] Another aspect of the present invention relates to a method for treating bone defects, which is carried out by directly applying the adhesive composition to the bone defect site after mixing components A and B, thereby repairing the bone defect.

[0035] According to some embodiments of the present invention, the method for repairing bone defects further includes shaping the composition at the bone defect site, which can be done, for example, with a spatula or a dedicated delivery system.

[0036] According to some embodiments of the present invention, the method for repairing bone defects further includes solidifying and curing the composition to form a solidified material.

[0037] Another aspect of the present invention relates to a method for fixing a dental implant at the site of a missing tooth root, which is carried out by directly applying the adhesive composition to the site of the missing tooth or the surface of the dental implant after mixing components A and B, and placing the dental implant at the site of the missing tooth.

[0038] The solidified material is formed by mixing a first component and a second component and allowing the resulting composition to solidify for a sufficient time. Initial solidification can generally be achieved within 15 seconds to 90 seconds, and final solidification can generally be achieved within 1 to 15 minutes. This short solidification time is acceptable because the mixing of the components can be carried out near or at the application site and applied immediately after mixing, thus avoiding surgical delays due to long solidification times.

[0039] In one embodiment of the present invention, the pH of the first component is less than 7, preferably less than 4. A pH less than 4 results in a longer solidification time for the composition. In this case, initial solidification can be achieved after more than 60 seconds. Such pastes are desirable for larger load-bearing bone defects where a longer solidification time may be required. The pastes can be manipulated, carved, and cured in place and have immediate high-strength capabilities. Examples

[0040] Materials

[0041] Self-curing adhesive powder (76% α-TCP (Innotere GmbH), 24% phosphoserine (Merck)

[0042] Sodium carbonate (Na2CO3) and ammonium carbonate ((NH4)2CO3)

[0043] Citric acid

[0044] Water (Millipore)

[0045] Experiments

[0046] The different ratios of the listed substances were tested to evaluate their effect on the porosity of the solidified material. All experiments were carried out according to the following protocol:

[0047] 1) Mix the monocarbonate with the self-curing adhesive (mixing is carried out in a plastic vial by thorough shaking)

[0048] 2) Add the citric acid solution or pure water

[0049] 3) Mix with a spatula in the plastic vial for 10 seconds

[0050] 4) Fill the mixture into a syringe

[0051] The different ratios can be found in the table below. The ratio of the self-curing adhesive powder and water or aqueous solution (with or without citric acid) was kept constant.

[0052]

[0053] Figures 1 to 7 show the effect of the monocarbonate on the porosity of the solidified material. In samples 1 and 2, the solidified material was too dense, while in sample 7, the pores had a negative impact on the mechanical stability. The best results were obtained using samples 3, 4 and 5.

[0054] Example 2: Acidifying agent

[0055] Prepare 15% and 30% [w / v] citric acid solutions and determine the pH of the solutions. The pH values of the two solutions were comparable:

[0056] - 15% [w / v] -> pH = 3.3

[0057] - 30% [w / v] -> pH = 3.1

[0058] Evaluate whether using different concentrations of citric acid has an impact on solidification or bubble formation.

[0059] Compared with the experiment without citric acid, the bubble formation was slow and seemed to last longer.

[0060] It was found that citric acid can affect the setting time and compressive strength of the solidified material.

[0061] Example 3: Comparison of sodium carbonate and calcium carbonate

[0062] Prepare the self-curing adhesive powder in the case of 7% [w / w] Na2CO3.

[0063] Prepare the self-curing adhesive powder in the case of 7% [w / w] CaCO3.

[0064] Na2CO3 caused a greater (by approximately 100%) volume increase than CaCO3.

[0065] No visible pore formation (no gas generation) was observed for CaCO3.

[0066] Example 4: Influence of citric acid on Na2CO3 and CaCO3

[0067] In the case of 7% [w / w] Na2CO3 and 15% citric acid, a self-curing adhesive powder was prepared.

[0068] In the case of 7% [w / w] CaCO3 and 15% citric acid, a self-curing adhesive powder was prepared.

[0069] No bubble formation was observed for CaCO3.

[0070] The use of citric acid prolonged the setting time of the material during mixing (compared to when using water).

[0071] For the Na2CO3 sample, the volume growth seemed slower, however the growth continued for a longer time.

[0072] Example 5: Carbonates dissolved in the liquid phase

[0073] Citric acid was added as a powder to the self-curing adhesive powder, and the carbonate was dissolved in the aqueous phase, and then the self-curing adhesive powder containing citric acid was mixed.

[0074] For Na2CO3, adding the solution to the self-curing adhesive powder containing citric acid resulted in initial vigorous foaming (within seconds of contact between the solution and the powder), after which no more gas was generated, so there was no volume increase or pore formation.

[0075] For CaCO3, nothing happened. There was no volume increase or pore formation.

[0076] Example 5: Ammonium carbonate

[0077] An equimolar formulation corresponding to the 7% [w / w] Na2CO3 formulation was prepared

[0078] The sample containing (NH4)2CO3 produced an ammonia odor during the mixing of the components.

[0079] (NH4)2CO3 produced even more bubbles than the corresponding Na2CO3 sample. The sample containing (NH4)2CO3 was more difficult to remove from the syringe because it could disintegrate when force was applied / the piston was pushed. This finding indicates that the type of carbonate used affects the mechanical properties of the cured material.

[0080] Example 6: Comparison of α-TCP and TTCP

[0081]

[0082] For each experiment, 0.5 g of self-curing powder and 35 mg of sodium carbonate (7% w / w) were mixed with 0.125 ml of water.

[0083] Example 6a: Comparison of Alpha24 and Tetra24

[0084] 35 mg (corresponding to 7% w / w of the powder) of sodium carbonate was added to the powder and then mixed with water for 10 seconds.

[0085] The following observations were made:

[0086] - The setting rate of TTCP is faster than that of α-TCP (by about 25%).

[0087] - The overall volume increment / final porosity of α-TCP is higher, probably due to slower setting as there is more time for gas expansion / pore formation.

[0088] Example 6b: Effect of serine phosphate (PS) content

[0089] Two different serine phosphate ratios (24% and 36%) were prepared for α-TCP and TTCP

[0090] 7% w / w sodium carbonate was added to each powder formulation and then mixed with water for 10 seconds.

[0091] The following observations were made:

[0092] - A higher serine phosphate content results in a higher overall volume increment / porosity. This was observed for both TCPs.

[0093] - The pores in the 36% PS sample seem larger compared to the 24% PS sample.

[0094] - This effect seems more pronounced for α-TCP compared to TTCP (probably due to slower setting -> more time for gas expansion / pore formation).

[0095] - The mixture of the 36% PS sample takes longer to set compared to the 24% PS sample. It seems that PS itself acts as a retarder. It is speculated that this is the reason for the higher total porosity. This effect is more pronounced for α-TCP compared to TTCP.

Claims

1. A two-component composition, comprising: a first component A comprising water or an aqueous solution, and a second component B, said second component B comprising: 1) a self-curing adhesive powder comprising at least a polyvalent metal salt and phosphoserine, and 2) at least one monocarbonate selected from the group consisting of sodium carbonate, ammonium carbonate, and potassium carbonate, It is characterized in that said monocarbonate being present at a concentration of 4 wt% to 12 wt% of component B.

2. The composition according to claim 1, wherein said monocarbonate is present at a concentration of 6.5 wt% to 12 wt% of component B.

3. The composition according to any one of the preceding claims, further comprising an acidifying agent selected from the group consisting of hydrochloric acid, ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid, propionic acid, their corresponding salts, or mixtures thereof, preferably citric acid, trisodium citrate, and calcium citrate.

4. The composition according to claim 3, wherein said acidifying agent is part of said first component A.

5. The composition according to claim 4, wherein component A comprises 0.1 wt% to 40 wt%, most preferably 5 wt% to 25 wt%, of the acidifying agent.

6. The composition according to any one of the preceding claims, wherein said monocarbonate is selected from the group consisting of sodium carbonate and ammonium carbonate, preferably sodium carbonate.

7. The composition according to any one of the preceding claims, wherein said polyvalent metal salt comprises tetracalcium phosphate.

8. The composition according to any one of claims 1 to 6, wherein said polyvalent metal salt comprises tricalcium phosphate, preferably α-tricalcium phosphate.

9. The composition according to any one of the preceding claims, wherein the self-curing adhesive powder of component B further comprises calcium silicate.

10. A kit for preparing the composition according to any one of the preceding claims, comprising: a first compartment having component A comprising water or an aqueous solution, and a second compartment having component B, said second component B comprising: 1) a self-curing adhesive powder comprising at least a polyvalent metal salt and phosphoserine, and 2) at least one monocarbonate selected from the group consisting of sodium carbonate, ammonium carbonate, and potassium carbonate, wherein said monocarbonate is present at a concentration of 4 wt% to 12 wt% of component B, and wherein said first compartment and said second compartment are physically separated from each other.

11. The kit according to claim 10, comprising 10 wt% to 35 wt% of component A and 65 wt% to 90 wt% of component B, preferably 15 wt% to 20 wt% of component A and 80 wt% to 85 wt% of component B, wherein the sum of component A and component B is 100%.

12. The composition according to any one of claims 1 to 9, which is used for restoring or repairing bones.

13. The composition according to claim 12, which is used for treating bone defects, preferably large bone defects.

14. The composition according to any one of claims 1 to 9, which is used for stabilizing implants.

15. The composition according to claim 14, which is used for stabilizing dental implants to bone tissue or soft tissue.

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