ES2178556B1 - CEMENT OF CALCIUM SULPHATE WITH CONTROLLED BIODEGRADATION. - Google Patents

Abstract

Cement of calcium sulfate with controlled biodegradation. A calcium sulfate cement has been invented that can be used as a biomaterial. The essential active ingredients are calcium sulfate hemihydrate (CaSO4.1 / 2H2O) and tricalcium phosphate alpha (a-Ca3 (PO4) 2). To improve its properties, other ingredients such as sulfates, phosphates and / or carbonates of Na +, K +, Mg2 +, Ca2 + and / or Zn2 + are added. A special feature of this new cement for biomedical applications related to hard tissues is that it produces after setting a composite material formed by a network of crystals of calcium sulfate dihydrate (CaSO4.2H2O) and crystals of calcium deficient hydroxyapatite (Ca9 (HPO4) ) (PO4) 5OH) interconnected. By controlling the initial proportions of the essential active ingredients, the proportion of the final setting products and therefore the passive and active resorption rate of the live composite material is controlled.

Description

Biodegradation calcium sulfate cement controlled.

Technical sector

Biomaterials for the stabilization of bone fractures and / or the filling of bone cavities. Biomaterials for coating prostheses and / or implants. Biomaterials for the fixation of prostheses and / or implants. Biomaterials for drug delivery systems . Biomaterials for cell growth supports in Tissue Engineering scaffolds .

State of the art

Both the number of patents and the number of scientific publications of calcium phosphate cement type materials to be used as biomaterials have increased dramatically to the present day since Brown and Clow filed their first patent in 1985 (WE Brown and LC, Chow , Dental restorative cement pastes, US Patent 4,518,430 of May 21, 1985). The main idea of these biomaterials formed essentially by calcium phosphates is to use the difference in acidity and basicity between the different known calcium phosphates to form, in aqueous solution, a salt of chemical composition different from that of the reactive products. initial but close to the chemical composition of hydroxyapatite, which is the mineral phase that forms hard tissues. In this way the material thus formed after the setting of the cement, as a consequence of the chemical dissolution and precipitation reactions that take place during the setting, forms a stable structure of interconnected hydroxyapatite crystals that can only be reabsorbed in vivo by cellular activity, is that is, through osteoclast and osteoblastic activity. Due to the apatitic structure of the products of the setting reaction these materials possess osteoconductive properties. However, some of the problems that have been referenced for this type of materials indicate a slow reabsorption in vivo as well as high initial setting times for those formulations with high final mechanical properties. This practical disagreement, of vital importance in biomedical applications, between setting times and mechanical properties makes these materials unfit for applications that require rapid initial mechanical stabilization.

Similarly, the state of the art for calcium sulfate cements currently indicates a decrease in the number of patents and scientific publications for this material in biomedical applications. The main reason is its rapid in vivo resorption rate that occurs passively, that is, without cellular activity. In spite of everything, calcium sulphate cements have the advantage of having a fast setting and a high initial mechanical resistance that confer a very good initial mechanical stability of the implant. In addition, calcium sulfate is an excellent drug carrier. However, the use of calcium sulfate as the only component in the cement gives this material a lack of flexibility in the control of bioreabsorption. When implanting calcium sulfate cement, it is reabsorbed too quickly to be replaced by new bone tissue during bone growth.

Brief Explanation of the Invention

The objective of the present invention is to provide a new cement consisting of a powder and a liquid that, when mixed in the form of paste, quickly hardens over time. The new hardened material owes its properties to the characteristic hydration reactions of calcium sulfate hemihydrate (CaSO4 .1 / 2H2O) and of tricalcium phosphate alpha (? -Ca3 (PO4) ) 2) which give as final products the reactions of setting calcium sulfate dihydrate (CaSO 4. 2 H 2 O) and calcium deficient hydroxyapatite (Ca 9 (HPO 4) (PO_ {4) 5 OH), respectively.

Under optimal conditions, the cement must be injectable and / or with a sufficient maximum compressive strength 50 MPa and / or with 60-80% of this attainable value in a sufficient time of 30 minutes.

These new cements can be injectable to through injection needles with an inside diameter from 1 to 15 mm and with a needle length from 25 to 150 mm.

The volume of cement that can be injected each time can vary up to a maximum of 200 ml according to application needs.

The temperature at which the New cement can be controlled during the injection process from 5ºC to 50ºC. The injection pressure can be controlled during the injection process depending on the viscosity of the cement.

The above objectives of the invention and others they will be clear from the following description that follows.

In accordance with the present invention, a calcium sulphate cement is provided comprising as main reactive ingredients in the powder phase crystals of calcium sulfate hemihydrate (CaSO 4 .1 / 2H 2 O) and tricalcium phosphate alpha (α-Ca 3 (PO 4) 2). In addition, other ingredients such as sulfates, phosphates and / or carbonates of Na +, K +, Mg 2+, Ca 2+ and / or Zn ^ can be added in the powder phase {2+} The liquid phase comprises water or an aqueous solution that can incorporate inorganic and / or organic salts in solution and / or in emulsion as accelerators and / or retarders and / or porogenic agents.

Description of the invention

The first main ingredient, calcium sulfate hemihydrate is hydrated according to the following chemical reaction: CaSO_ {4}. 1 / 2H 2 O + 3/2 H 2 O → CaSO 4. 2H_ {2} O \ eqnum {(1)}

During the hydration process the cement of Calcium sulfate hardens over time due to the formation of the crystals of calcium sulfate dihydrate that grow and form, physical points of attachment to each other to form a structure three-dimensional interconnected glass capable of supporting load mechanics. The calcium sulfate hydration reaction Hemihydrate is exothermic. The energy released during the process it is absorbed by the cement and therefore the temperature of the cement increases.

The second main ingredient, tricalcium phosphate alpha is hydrated according to the following chemical reaction: 3? -Ca 3 (PO 4) 2 + H 2 O → Ca 9 (HPO 4) (PO 4) 5 OH \ eqnum { (two)}

The hydration process of alpha tricalcium phosphate is accelerated with an increase in temperature during setting.

The new cement, which consists of a mixture of both active ingredients, will be hydrated accordingly, theoretically according to the following basic chemical reaction: CaSO_ {4}. 1 / 2H 2 O + 3? -Ca 3 (PO 4) 2 + 5 / 2H 2 O \ rightarrow \ belowdisplayskip = .5 \ baselineskip ? CaSO_ {4}. 2H 2 O + Ca 9 (HPO 4) (PO 4) 5 OH \ eqnum {(3)}

The advantage of having both active ingredients in a single mixture, that is, calcium sulfate hemihydrate and tricalcium phosphate alpha is clear after the explanations given so far and those that will follow. As a consequence of the partial hydration reactions as expressed in Equations (1) and (2) and which will now occur at the same time according to the hydration reaction expressed in Equation (3), a material will be obtained that Once hardened, it will be formed by a three-dimensional structure of interlaced and / or interconnected crystals of calcium sulfate dihydrate (CaSO4 .2H2O) and calcium deficient hydroxyapatite (Ca9 (HPO4)) ( PO 4) 5 OH). Since calcium sulfate dihydrate undergoes passive reabsorption in vivo , that is, without cellular activity, and calcium deficient hydroxyapatite undergoes active reabsorption in vivo , that is, with cellular activity, the cement of the present invention provides a solution to the control of the rate of reabsorption of the new cement in vivo by controlling the relative proportions of the active ingredients in the initial mixing of the powder phase of the cement. From the point of view of the initial setting properties, the new cement also brings new advantages since the energy released during the setting reaction of the calcium sulfate hemihydrate will raise the temperature of the cement paste and help accelerate the setting reaction. of the second active component, that is, of the tricalcium phosphate alpha .

The cement of this invention may contain as additional compounds sulfates, phosphates and / or carbonates of Na +, K +, Mg 2+, Ca 2+ and / or Zn 2+ that can have the function of moderating the reaction rate of setting.

In the present invention of sulfate cement calcium, the cement powder is premixed with the compounds additional, if necessary, to form a homogeneous powder mixture. As a liquid substance in cement, use distilled water or a saline solution that may contain inorganic and / or organic salts. Both resistance and time setting depends on the particle size of the ingredients in the cement powder In general an average particle size between 0.05 µm and 50 µm, produced by any grinding method, It can give acceptable properties.

After mixing the powder and the liquid from the cement, a period of time is available to mold the cement paste and place it in situ directly or by an injection method. The injection time and setting times can be emptied by mainly modifying the relative proportion between the powder phase and the liquid phase of the cement.

The cement of the present invention can be used as controlled reabsorption cement in vivo in applications that involve the immediate stabilization of fractures bone, the filling of bone cavities, in osteoporosis, such as coating of prostheses and / or implants and / or as material of fixation of prostheses and / or implants. Other applications may found when using the new cement as a release system of drugs since both calcium sulfate dihydrate and calcium deficient hydroxyapatite are excellent carriers and They can act selectively. Likewise, the cement of the The present invention can be used as a support material in Tissue engineering.

Previous applications are not mentioned in a restrictive sense and therefore any subject matter expert you can find new applications in biomedical fields related to hard tissues.

Embodiment of the invention Example 1

The compounds CaSO 4 .1 / 2H 2 O and α-Ca 3 (PO 4) 2 were weighed in relative proportions by weight of 100: 0, 80:20, 60:40, 40:60, 20:80, 0: 100. These powder mixtures were identified as different series and were used as a cement powder phase after homogenization by mixing. As a liquid phase used an aqueous sodium phosphate buffer solution. The phase in powder and liquid phase prepared above were mixed in a Liquid ratio: 0.35 ml / g powder. With the pasta so formed 6 mm diameter cement cylindrical specimens were prepared by 12 mm high in a Teflon mold and allowed to set in a solution of Ringer at 37 ° C for a maximum of 14 days.

3 specimens were selected for each series ready They were lyophilized and prepared in powder for analysis X-ray diffraction chemical. The analysis by X-ray diffraction revealed the existence of two phases, one corresponding to calcium sulfate dihydrate and another typically apatitic associated with hydroxyapatite deficient in calcium. These results confirm the hypothesis about the reaction of setting that controls the properties of this cement as it expressed through Equation (3).

The comparative analysis of intensities relative of the characteristic peaks of diffraction of the setting reaction products allowed to calculate a line of calibration based on the relative percentages of the reagents initials of the cement powder phase.

Example 2

1 test piece was selected after 14 days for each series prepared according to Example 1. Each test tube cylindrical fractured longitudinally according to the Brazil method in a universal testing machine and protected for observation microscopic in a Scanning Environmental Electronic Microscope. The observations made agree with the diffraction results X-ray. Typical crystals of calcium sulfate dihydrate and hydroxyapatite deficient in calcium entwined and forming colonies. The relative proportion of crystals of calcium sulfate dihydrate and hydroxyapatite Calcium deficient was adjusted as expected according to proportions Relatives of the active ingredients that formed the powder phase of cement.

Example 3

Five specimens set at 14 were selected days for each series prepared according to Example 1. Each test tube cylindrical was tested under compression until broken in a machine Universal essays The average value of resistance to compression was calculated from the individual results of each of the five specimens for each series. It was observed that the maximum compressive strength thus obtained 14 days after setting could be expressed as a linear combination of values of maximum compressive strength obtained for the series 100: 0 and 0: 100. It was observed that the coefficients of the combination linear ranged from 0 to 1 and were directly correlated with the theoretical weight proportions of calcium sulfate dihydrate and of calcium deficient hydroxyapatite in the mixtures set.

Claims (26)

1. Injectable composition for a bone replacement material with the ability to harden in a body fluid in vivo , comprising a powder phase mixed with a liquid phase, characterized in that said powder phase is formed by: a) a first reactive component based on calcium sulfate hemihydrate (CaSO4 .½H2O) that has the total or partial ability to hydrate to calcium sulfate dihydrate (CaSO4 .2H2O) when reacting with said liquid phase ; b) a second reactive component based on tricalcium phosphate alpha (α-Ca 3 (PO 4) 2) which has the total or partial capacity to hydrate to calcium deficient hydroxyapatite (Ca 9) HPO 4) (PO 4) 5 OH) when reacting with said liquid phase; c) at least one accelerator for the reaction with said liquid phase of said first and / or second reactive component. 2. Injectable composition according to claim 1 characterized in that the two reactive components that make up the powder phase, together or separately containing their respective accelerators, can be mixed totally or partially, in order, with all or part of the liquid phase until a mixture is completed Total homogeneous of both solid and liquid phases. 3. Injectable composition according to claim 1 and 2 characterized in that the tricalcium phosphate alpha can be totally or partially substituted by any other calcium phosphate that can be obtained by precipitation in liquid phase or by sintering at high temperature. 4. Injectable composition according to claim 3 characterized in that the calcium phosphates that totally or partially replace the tricalcium alpha phosphate are one of the following compounds:

 Ca {Ca (H 2 PO 4) 2 

,

 Ca {Ca (H 2 PO 4) 2. 

H2O, CaHPO4, CaHPO4.2H2O,

 ? {? -Ca3 (PO4) 2 

,

 ? {Ca9 (HPO4) (PO4) 5 OH 

, Ca 4 (PO 4) 2 O, Ca 2 NaK (PO 4) 2,

 Ca Ca 8 (HPO 4) 2 (PO 4) 4 .5H 2 O 

. 5. Injectable composition according to claim 1 and 2 characterized in that the calcium sulfate hemihydrate can be totally or partially substituted by calcium sulfate hemihydrate of the alpha and / or beta type. 6. Injectable composition according to claim 1 and 2 characterized in that sulfates, phosphates and / or carbonates of L <+>, Na <+>, K <+>, Mg <> can be added in the powder phase of the cement 2+}; Ca 2+, Ba 2+ and / or Zn 2+, as modifiers (accelerators and / or retarders) of the hydration reactions. 7. Injectable composition according to claim 1 and 3 characterized in that the tricalcium phosphate alpha has been obtained by wet methods and / or by dry methods and a subsequent solid-state heat treatment at a sintering temperature between 800 and 1550 ° C . 8. Injectable composition according to claim 1, 3 and 7 characterized in that the tricalcium phosphate alpha has been ground by any grinding method and has an average particle size of less than or equal to 100 µm. 9. Injectable composition according to claim 8 characterized in that the alpha tricalcium phosphate has a particle size of less than 100 µm, preferably less than 50 µm, preferably less than 20 µm, preferably less than 10 µm, preferably less than 5 µm mum 10. Injectable composition according to claim 1 and 5 characterized in that the calcium sulphate hemihydrate of the alpha and / or beta type has an average particle size of less than 100 µm, preferably less than 50 µm, preferably less than 20 µm, preferably less than 10 µm, preferably less than 5 µm. 11. Injectable composition according to claim 1 characterized in that the liquid phase of the cement is formed by distilled water and / or an aqueous solution and / or a saline solution and / or a solution of inorganic salts and / or a solution of organic salts. 12. Injectable composition according to claim 1, 2 and 11 characterized in that the liquid phase of the cement may contain sulfates, phosphates and / or carbonates of Li +, Na +, K +, Mg 2 +, Ca 2+, Ba 2+ and / or Zn 2+, as modifiers (accelerators and / or retarders) of the hydration reactions. 13. Injectable composition according to claim 1, 2, 11 and 12 characterized in that the liquid phase of the cement may contain biopolymers and / or organic acids and / or inorganic acids and / or synthetic polymers. 14. Injectable composition according to any of the preceding claims 1-13 characterized in that the cement may contain antioxidants and / or vitamins and / or antibiotics and / or bone growth factors. 15. Injectable composition according to claim 1 and 2, characterized in that the relative weight ratio of the two reactive components (calcium sulfate hemihydrate and tricalcium phosphate alpha ) of the powder phase of the cement is between the ratios 100: 0, 99: 1, 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80, 10:90; 1:99, 0: 100. 16. Injectable composition according to claim 1 and 6 characterized in that the amount of these modifiers of the hydration reactions in relation to the cement powder phase is between 0 and 50% by weight. 17. Injectable composition according to claim 6 and 12 characterized in that the amount of these additives in relation to the liquid phase is between 0 and 25% by weight. 18. Injectable composition according to claim 1, 2, and 11 characterized in that the relative proportion between the liquid phase and the powder phase of the cement is between 0.1 ml / g and 10 ml / g, preferably less than 10 ml / g and / or preferably less 5 ml / g and / or preferably less than 1 ml / g. 19. Injectable composition according to any of the preceding claims 1-18 characterized in that it has a maximum compressive strength after setting between 5 and 10 MPa and / or preferably between 10 and 20 MPa and / or preferably between 20 and 40 MPa and / or preferably between 40 and 80MPa and / or preferably greater than 80 MPa and less than 150 MPa. 20. Injectable composition according to claim 19 characterized in that the cement reaches 60-80% of the maximum value of the compressive strength in a minimum time of 24 hours, preferably in a minimum time of 12 hours, preferably in a minimum time of 6 hours, preferably in a minimum time of 3 hours, preferably in a minimum time of 1 hour, preferably in a minimum time of 30 minutes, preferably in a minimum time of 15 minutes. 21. Injectable composition according to any of the preceding claims 1-20 characterized in that it can be injected through injection needles with a minimum internal diameter of 1 mm and a maximum of 15 mm and a minimum injection length of 25 mm and a maximum of 200 mm 22. Injectable composition according to any of the preceding claims 1-21 characterized in that it can be injected in amounts from 1 ml of cement to 200 ml of cement. 23. Injectable composition according to any of the preceding claims 1-22 characterized in that it can be set ex vivo at a controlled temperature from 5 to 100 ° C. 24. Injectable composition according to any of the preceding claims 1-23 characterized in that it can be injected in vivo at a controlled temperature for the cement from 5 to 50 ° C, preferably at 37 ° C. 25. Injectable composition according to any of the preceding claims 1-24 characterized in that it can be injected at the appropriate injection pressure depending on the viscosity of the cement and the characteristics of the injection gun. 26. Injectable composition according to any of the preceding claims 1-25 characterized in that it has an injection time of less than 5 minutes and / or preferably about 3 minutes, and / or because it has a setting time of less than 15 minutes and / or preferably less than 10 minutes, and / or because it has an approximate compressive strength of 30 MPa in an approximate time of 10 minutes, and / or because it maintains the compressive strength of approximately 30 MPa during the first 3 months of implantation.