A new bone substitute composition

Background of the invention

The life expectancy of the world population has increased tremendously over the past 50 years. Our population lives longer than ever. It is expected that there will be more people over the age of 60 in the next ten years than under 20 in Europe. More people will require medical attention for age-related diseases, which will increase pressure on hospitals.

Bone is the second most common transplanted material after blood. A reliable method of repairing bone damage is the use of autogenous bone, i.e. bone taken from another place in the body. However, there may be problems elsewhere in the surgery where the transplant comes from. To avoid this additional injury, allografts, i.e. bone grafts between individuals of the same species, may be used. Allografts have a lower osteogenic capacity than autografts and the rate of new bone formation may be lower. They also have a higher rate of resorption, a stronger immunogenic response and worse vasculature in the recipient. Allografts must also be checked for viruses because they can transmit, e.g., HIV and hepatitis. The use of allografts is currently the most common way to transplant bone and repair bone defects.

To address delivery problems, unpredictable strength and risk of infection, synthetic bone substitutes have become a realistic alternative. Thus, the demand for synthetic bone substitutes and their use is increasing rapidly.

Calcium sulphate hemihydrate, CaSCą · UH₂Oh, he was one of the first materials studied as a substitute for bone transplants. Studies have been undertaken since 1892 to show its tissue uptake and high rate of resorption. It was found that calcium sulfate hemihydrate implanted in the subcortical areas of the bone does not cause further adverse reaction in the tissue that normally occurs at fracture. The new bone growing in calcium sulfate hemihydrate is normal bone. There were no side effects attributed to the implantation of calcium sulfate hemihydrate in adjacent tissues or distant organs.

The most important benefit of using calcium sulfate is its excellent biocompatibility. The disadvantages are fast resorption and low strength, which makes it less useful in larger or open defects and when the duration of fracture treatment exceeds 4-6 weeks.

The dissolution rate of calcium sulfate makes it suitable as a carrier for drug release. US 5,614,206 discloses calcium sulfate hemihydrate pellets that are useful for controlled drug delivery. When implanted in a human or other animal, the pellets provide extended and controlled delivery at a given site for 25 to 45 days.

Calcium phosphates, on the other hand, are suitable as bone substitutes because of their bioactive properties, i.e. they have an effect or effect on living tissue. The rate of their resorption is relatively slow, lasting up to several years.

There are two different categories of calcium phosphate: CaP obtained by precipitation from an aqueous solution at room temperature (low temperature CaP) and CaP obtained by heat treatment (high temperature CaP).

Hydroxyapatite (HA) is the most stable calcium phosphate and the basic inorganic component of bones. Most bone graft substitutes on the market are made of hydroxyapatite. High temperature treated hydroxyapatite is highly crystalline and the least soluble of calcium phosphates.

Hydroxyapatite and tricalcium phosphate are the most common calcium phosphates used to fill bone defects and as implant coatings. Their resorption rate is relatively low, from six months to several years. It is possible to increase the degradation rate by increasing the surface area of ​​the material, reducing the crystallinity and perfection of the crystal and reducing the size of the crystals and grains of the material. A faster resorption rate may be beneficial for improving bone formation.

However, the biological characteristics and anatomical location of the transplant are also important for the behavior and results of the implant. The success of a biomaterial in one specific application does not guarantee its universal acceptance.

Mineral bone substitute materials can be made as a paste that can be injected directly into the fracture site. The paste is injected into an empty space in the bone, and after hardening, an implant is obtained that matches the contours of the gap and supports the spongy bone. Calcium sulfate and hydroxyapatite have been thoroughly investigated as materials that are a possible alternative to autogenous bone transplants to assist in the restoration of bone defects and immobilization of bone fractures.

It is therefore important to achieve full stability as soon as possible during or after surgery to prevent movement at the healing site. This is especially true for fractures, but also when filling bone defects or replacing lost bone during tumor removal, healing is inhibited by movements and new bone growth is prevented. Thus, the injected material must cure quickly and stick firmly to bone tissue.

However, complications such as infections can occur during or after surgery. Defects can also be infected earlier and must be treated with e.g. antibiotics.

It is also important that the cured material is so similar in structure to bone that it can be gradually resorbed by osteoclasts and replaced with new bone. This process may be easier if the cured cement contains pores that can transport nutrients and ensure the ingrowth of vessels allowing the formation of new bone.

M. Bohner et al. disclosed in the materials of the Sixth World Congress of Biomaterials (15-20 / 5 2000) a method of producing calcium phosphate block with open macropores using a hydrophobic lipid (oil) emulsion in calcium phosphate water cement paste or calcium phosphate cement oil emulsion. After solidification, the cement block was sintered at 1250 ° C for 4 hours. Similarly, porous calcium phosphate bone cement for repairing human hard tissue is disclosed in CN 1193614. The cement contains a blowing agent, which may be a non-toxic surfactant or a non-toxic slightly soluble salt, acid salt and basic salt.

However, high temperature treatment (> 1000 ° C) is usually necessary to burn off the added substances. Thus, the emulsion technique cannot, however, be used to prepare a bone substitute in vivo. Attempts to mix mannitol and sucrose crystals with calcium phosphate were carried out to produce two-phase bone substitute pastes, where one of the phases dissolves causing porosity in the solidified material. Another technique for making pores is to add air-entraining agents to stabilize air bubbles formed in the paste during mixing to form a porous solidified material (Sarda et al., Bioceramics 2002; 218 (2): 335).

Mixtures of the abovementioned mineral bone substitute materials were also studied. US 4,619,655 discloses a bone substitute mineral material comprising a mixture of ceramic particles of calcium sulfate hemihydrate and calcium phosphate, preferably consisting of hydroxyapatite or tricalcium phosphate, or a mixture thereof. According to this publication, calcium sulfate hemihydrate was completely resorbed within a few weeks and replaced with connective tissue when a material consisting of a 50/50 mixture of hydroxyapatite / calcium sulfate hemihydrate was implanted into experimentally created defects in the mandible of the rat. The hydroxyapatite was not resorbed and some particles were eventually completely surrounded by bone. It was therefore concluded that calcium sulfate hemihydrate acted as a filler and suit for incorporating hydroxyapatite into the bone.

In studies presented at the "Combined Orthopedic Research Societies Meeting", September 28-30, 1998, Hamamatsu, Japan, additional tests were also shown regarding mixtures of calcium sulfate hemihydrate and hydroxyapatite. According to this study, the combination of hydroxyapatite particles and calcium sulfate hemihydrate has a viscosity that allows easy placement of the implant material and prevents the migration of hydroxyapatite particles into surrounding tissues during and after implantation. Experiments have shown that calcium sulfate hemihydrate was absorbed in a relatively short time, it was easy to manipulate with hydroxyapatite particles and did not interfere with bone healing.

WO 9100252 discloses a composition that can harden in blood in about 10-45 min. The composition essentially contains calcium sulfate hemihydrate with small amounts of calcium sulfate dihydrate. Organic and inorganic materials such as hydroxyapatite may also be included in the composition. After hardening, hydroxyapatite particles in cement are obtained from calcium sulfate. Calcium sulfate cement dissolves rapidly in aqueous body liquids over four weeks, leaving solid hydroxyapatite particles.

Similarly, such hydroxyapatite particles in calcium sulfate cement are obtained using the method outlined in WO 9117722. The composition for use as an implant for an animal comprises calcium sulfate hemihydrate, calcium phosphate and sodium sulfate. Calcium phosphate is hydroxyapatite and sodium sulfate allows the composition to be used in the presence of blood or other body liquids.

WO 200205861 discloses an injectable composition that is useful as a bone mineral substitute material. The dry powder composition contains calcium sulfate hemihydrate, calcium phosphate and at least one accelerator. In contact with aqueous liquid, the composition cures during surgery allowing early control of displacement of fragments in fracture. A permanent implant is created, which has a higher mechanical strength than the trabecular bone and the implant obtains with time the porous as well as the irregular structure of the growing bone.

Invention

The object of the invention is to provide an injectable mineral substitute bone composition that hardens in the body fluid in vivo during surgery, and that gives a durable implant during the year with high mechanical strength, resulting in a porous structure whose dimensions and formation you can control.

Another object of the present invention is to provide such an improved bone mineral substitute composition for filling defects in osteoporotic bone and for additional immobilization of the fracture in substantially spongy bone that does not exhibit the disadvantage of high viscosity when used.

Another object of the invention is to provide a bone mineral substitute composition that can be used with minimally invasive surgical techniques that can be cured in situ and that causes the stability of each defect geometry.

Yet another object of the invention is to provide a bone mineral substitute composition that has excellent biocompatibility as well as beneficial biological and rheological properties.

Another object of the invention is to provide a bone mineral substitute composition that is biodegradable and can be sterilized by irradiation or gas without significant deterioration.

To achieve these aims, the injectable composition of the invention has the features of claim 1. 1.

The invention relates to a composition for injecting a bone substitute mineral material that has the ability to harden in a body fluid in vivo. The injectable composition comprises at least one calcium phosphate component and at least one calcium sulfate component as a dry mixture, an aqueous liquid mixed with the dry mixture, at least one additive that is included in and associated with the calcium sulfate component, and at least one accelerator of hardening of powdered calcium phosphate to calcium phosphate cement in reaction with an aqueous liquid, at least one calcium phosphate component which is powdered calcium phosphate with the ability to cure calcium phosphate to cement with reaction with an aqueous liquid under the influence of at least one accelerator, where the additive is a bioactive agent that is contained and associated with the calcium sulfate component, wherein the at least one calcium sulfate component is hardened calcium sulfate in the form of particles comprising 20 to 60% by weight of the dry mixture and having a particle size of less than 100 µm, wherein the injectability of the composition is provided. The composition also includes at least one accelerator.

The particle size of the hardened calcium sulfate in the form of particulate matter is adjusted to a size small enough for the composition to be injectable. The suitable particle diameter of the hardened calcium sulfate in the form of solid particles is between 1 - 50 pm, preferably between 1 - 10 pm. This means that the composition can be injected through a needle having a diameter of about 1-2 mm or even smaller.

Cured particulate calcium sulfate should preferably be between 20-40% by weight of the dry composition of the injectable composition.

Preferably, the hardened calcium sulfate in the form of particles is calcium sulfate dihydrate (gypsum).

The injectability of the compositions according to the invention can be further improved in several ways. The pH lowering component may be added to the compositions of the invention to increase injectability. Such a pH lowering component is e.g. ascorbic acid or citric acid. The acids are contained in the sterile liquid or sterile powder composition in amounts of 0.1-5% by weight, preferably 0.5-2% by weight.

Another way to further improve the injectability of the composition is to add a non-aqueous biosoluble compatible oil. The oil concentration in this case should be between 0.01-5% by weight, preferably between 0.1-2% by weight. The oil can be mixed with a sterile powder or contained in a sterile aqueous liquid composition. A suitable oil for use in the composition of the invention is vitamin E. Preferably, vitamin E is α11 tocopherol.

The main aspect of the invention is that hardened particulate calcium sulfate may contain at least one additive that is slowly released from the bone mineral substitute material after solidification. The additive may be both insoluble in water and soluble in water. An example of a water insoluble additive is vitamin E.

However, it is preferred that the additive is water soluble. The water-soluble additive may have several functions. For example, it may be an antioxidant, vitamin, hormone, antibiotic, cytostatics, bisphosphonate, growth factor, or protein. Preferably, the at least one water-soluble additive is a substance that induces, stimulates and / or accelerates bone formation, such as osteoinductive compounds and / or compounds that reduce bone turnover.

Growth factors and hormones are suitable bone-inducing substances that stimulate and / or accelerate bone formation. Growth factors and their derivatives that act locally are preferred.

It is preferred to use growth factors that are autologous and effective in combination with bone, tendon or cartilage tissue. Such growth factors are e.g. transforming growth factor (TGF β3), morphogenetic bone protein (BMP^-2), ΡΊΉγΡ, osteoprotegerin (^OPGIN ^Je^from in^dyjs^ki [In^dian Hedgehog], RANKL, alkaline fibroblast, insulin-like growth factor (IgF1), platelet-derived growth factors, and vascular growth factors. These endogenously produced growth factors are used as an additive either as individual components or in combination with a mixture of growth factors to accelerate bone growth. Thus, preferably, the endogenously produced bioactive molecule is used as a bone formation inducer.

Examples of other bone stimulating compounds are parathyroid hormones and their derivatives, estrogens, progesterones, androgens, testosterones, calcitonin, somatomedin and oxytocin, preferably also autologous, but they can also be prepared according to procedures known in the art.

Enamel matrix proteins amelin-1, amelin-2 and ameloblastin, which are autologous or extracted or produced by tissues or cells of other species, or synthetically produced or produced by other living cells or organisms, may also be included as an additive in calcium sulfate in the form of particulate matter.

Similarly, a cholesterol-lowering compound, a statin, may also be present to induce, stimulate and / or accelerate bone formation.

Examples of suitable bone damage inhibitors are biphosphonates, osteocalcin, osteonectin and their derivatives, which can be included as an additive in the calcium sulfate particulate composition of the invention and the resulting substitute.

In addition, other substances that affect bone metabolism may also be included in the hardened particulate calcium sulfate component for slow release from the resulting artificial bone mineral substitute material. Such substances include calciferols, calcitriols as well as other vitamin D and derivatives thereof. These compounds help regulate calcium metabolism and normal calcification of bones in the body, as well as affect the use of mineral phosphorus. Natural or synthetically produced prostaglandins, prostaglandin precursors or metabolites, prostaglandin analogues or compounds that induce or inhibit endogenous prostaglandin production or which induce or inhibit the metabolism of prostaglandins, or compounds that affect the production of precursors or further metabolism of active prostaglandin metabolites may also be present. Painkillers such as lidocaine hydrochloride, bupivacaine hydrochloride, and ketorolac tromethamine can also be used as an additive released from a bone substitute mineral material.

Such additives should preferably be released from the bone mineral substitute material within 6-8 weeks after injection. This can be done by controlling the dissolution of calcium sulfate in the form of particles in the bone mineral substitute material, the dissolution rate depending on the size and form of the calcium sulfate particles.

The water-soluble additive may also be an anti-infective substance, i.e. a compound with static or killing effects on an attacking foreign live material. Such compounds include natural antibiotics as well as other semi-synthetic and synthetic antibacterial or bacteriostatic compounds that act against pathogenic and / or infectious microorganisms, e.g. staphylococci. Examples of antibiotics for bone infection are tetracycline hydrochloride, vancomycin, tobramycin, gentamicin and cephalosporin. Cytostatic agents such as cis-platinum, ifosfamide, methotrexate, doxorubicin hydrochloride, arsenic and retinoids or their derivatives can also be used as an additive. The additive may in a similar manner be an antiviral compound, antifungal compound, tuberculostatic or tuberculocidal compound or antiparasitic compound.

60166-93-0 (j opromide),

89797-00-2; iohexol), ioxilane), 99139-49-8

The composition of the invention may also contain a non-ionic x-ray contrast agent.

Suitable such agents are conventional water-soluble non-ionic X-ray contrast media, i.e. iodinated aromatics that have one or more aromatic cores that are substituted with at least three iodine atoms. Such agents are disclosed in US 5 695 742 and include compounds with CA registration numbers^S (C^hEMIC^l AosUart ^Service) ^31112-62-6 (metrizami^d), jo^pami^dob ^78649-41-9 (jome^pro^l)^{, 73334-07-3}

877771-40-2 (jowersol), 66108-95-0 jopentol), 107793-72-6 (II-1), 75751-89-2 (yogulamide), 63941-73-1 (joglucol), 63941^74-2 (Joglukamid) ^56562-79-9 (Joglunid) ^76984-84-0 (MP7011 ^ 64965-50-0 (MP-7012), 77111-65-0 (MP-10007), 79944-49³ (VA^-7-88) ^{, 79944-51-7} (also; indicated in E^P 033426),

79211-10-2 (Josimide), 79211-34-0 (Josocidol), 103876-29-5 (also; indicated in ^{EP 0177414}different ^141660-63-1 (Jofra^tabout^lroses 92339-11-2 (iodixanol), 79770-24-4 (jotrol), 71767-13-0 (jo^tasu^lb ^81045-33-2 (jo^de^kabout^ldifferent ^143200-04-8 (as^from ws^kazan^s in ^WO 92/086), ^143199-77-3 (as^from ws^kazan^s in ^WO 92/08691), ^143200-00-4 (rdwn^ande^from ws^kazan^s in ^WO 9^08691), ^78341-84-1 (rdwn^ande^from ws^kazan^s in ^{US 4348377}different ^122731-47-9 (as^from pointedn^s in ^{EP 0308364}different ^122731-49-1 (rdwn^ande^from indicated in ^{EP 0308364}different ^99139-65-8 (rdwn^ande^from indicated in ^{WO 85 /}01727), "^13962-5 (as^from ws^kazan^s in ^{WO 85 /}01727), ^{and 78341-84-1} (also on^kazan^s in ^{EP 0023}"²).

Other such x-ray contrast agents are disclosed in US 5,447,711 and include iotrolan, ioxaglat, iodecymol and iosarkol. Other suitable contrast agents are jotusal, ioxilane and iofrotal.

Preferably, the x-ray contrast agent is a non-ionic agent and has low osmolarity, such as iohexol, iodixanol, jowersol, iopamidol and iotrolan.

For example, iohexol (C19H26I3N3O9) can be advantageously used as an X-ray contrast agent. This substance does not affect bone formation and has good bone biocompatibility. In medicine, it is used for various purposes. For example, it can be used in patients with renal failure to determine the rate of plasma clearance in the kidney.

The composition according to the invention with a non-ionic X-ray contrast agent as a water-soluble additive contained in particulate calcium sulfate can itself be used as an X-ray contrast agent. An additional x-ray effect is obtained with the composition according to the invention because the contrasting ability of its ceramic component is utilized. Incorporation of at least one water-soluble non-ionic X-ray contrast agent into the composition increases the initial x-ray density of the x-ray bone substitute. Thus, no further ceramic radiological contrast agents such as barium sulfate and zirconia are needed in the injectable composition of the invention. Such hard ceramic particles will wear down joints when detached from the bone substitute. In the joints they will cause physical damage and possibly as a result of inflammatory reactions.

Thus, the composition of the invention, when it contains a water-soluble non-ionic X-ray contrast agent, can be injected into the joints, and the resulting artificial bone mineral substitute material can be used in the case of bone defects joining the joints. Such applications include the repair of osteochondral defects of the joints as well as fractures or defects of the bones involving the joint.

In addition, a dual x-ray source can further be used, e.g., to localize the injected composition and to observe the healing process after implantation of the composition of the invention in the body of a human or animal. When the resulting artificial bone mineral substitute material, which contains a water-soluble non-ionic X-ray contrast agent, is replaced by ingrown bone, the water-soluble agent will slowly disappear. This causes a progressive decrease in x-ray density that can be monitored.

According to the invention, the hardened calcium sulfate in the form of particulates is mixed with the powdered calcium phosphate component, which is then cured to calcium phosphate cement in the bone mineral substitute material.

The term "calcium phosphate cement" refers to a recognized definition (SE Gruninger, C. Siew, L. C Chow, A. O'Youn^g NK Tsao^{, In}. ^E. Brow ^ J. Dent. Res.⁶³ (¹⁹84) 200) a reaction product of a powder or a mixture of powders, which - when mixed with water or an aqueous solution to a paste state - at a temperature near room or body temperature react with the formation of a precipitate that contains crystals of one or more calcium phosphates and which solidifies by entanglement of crystals in the sediment. Thus, various calcium phosphate products (calcium phosphate cements) can be obtained during the setting reaction depending on the component (s) of the calcium phosphate powder used in the paste in the bone mineral substitute composition of the invention for injection.

In the injectable composition of the invention, at least one calcium phosphate component is calcium phosphate powder with the ability to cure (cement) to cement calcium phosphate by reaction with an aqueous liquid under the influence of at least one accelerator. The aqueous liquid should be between 0.1 and 2 ml, preferably between 0.2 and 0.7 ml per gram of dry mixture. The aqueous liquid may be used in an amount sufficient only for the hardening reaction.

The aqueous liquid may be distilled water and / or a solution containing one or more inorganic and / or organic salts.

Under these conditions, the main requirement for the injectable composition of the bone substitute mineral material is met, i.e. it should have a viscosity such that it can be injected into the bone for 1-5 minutes after starting the mixing procedure. In addition, the initial setting time is 5-25 minutes, which is also a prerequisite for the injectable composition.

Preferably, the at least one calcium phosphate component of the injectable bone mineral substitute composition is cured to hydroxyapatite (HA). These reactions that form hydroxyapatite, i.e. precipitated hydroxyapatite (PHA) or calcium depleted hydroxyapatite (CDHA), can be classified into three groups. The first group consists of calcium phosphates, which are converted into hydroxyapatite by hydrolysis in an aqueous solution (equations 1-5).

5Ca (H2PO₂) H2O - Ca5 (PO4) sOH + 7H3PO4 + 4H2O (1)

5CaHPO4 · 2H2O - Ca5 (PO4)₃OH + 2H₃AFTER₄ + 9H₂O (2)

5Ca₈H2 (PO4) -5H2O - 8Ca5 (PO4)₃OH + 6H3PO4 + 17H₂About (3)

5Ca3 (PO4) 2 + 3H2O - 3Ca₅ (POJsOH + H3PO4 (4)

3Ca4 (PO4hO + 3H2O - 2Ca5 (PO4) 3OH + Ca (OH)₂ (5)

Precipitated hydroxyapatite is the least soluble calcium phosphate at a pH above 4.2. This means that any other calcium phosphate present in the aqueous solution in this pH range will tend to dissolve, with precipitation of PHA as the product. This hydrolysis process (Ca (OH) 2 - H3PO4 - H2O) is very slow due to a decrease in supersaturation as the reaction progresses.

The only calcium phosphate that can react through the hydrolysis process to apatite without creating sub-products, is calcium α-triphosphate (Eq. 6), and the apatite formed in this reaction is calcium-depleted hydroxyapatite.

3a-Ca3 (PO4) + H2O - Ca₉(HPO4) (PO4)₅OH (6)

The second group of reactions to hydroxyapatite, i.e. precipitated hydroxyapatite (PHA) or calcium depleted hydroxyapatite (CDHA), are combinations between TTCP and other calcium phosphates. TTCP is the only calcium phosphate with a Ca / P ratio above 1.67. Thus, this substance can be mixed with other calcium phosphates with a lower Ca / P ratio to produce PHA or CDHA without forming acids or bases as by-products. Theoretically, any calcium phosphate more acidic than PHA can react directly with TTCP to form HA or CDHA according to the following chemical reactions.

7Ca4 (PO4hO + 2Ca (H2PO4) 2 <H2O - 6Ca₅(PO4)₃OH + 3H₂AT 7)

2Ca4 (PO4hO + Ca (H₂AFTER₄ )₂-H₂O - Ca₂ (HPO4HPO4) 5OH +

2H₂ABOUT ())

Ca4 (PO4hO + CaHPO4 · 2H₂O - Ca₅ (AFTER₄) 3OH + 2H₂ABOUT ())

3Ca4 (PO4kO + 6CaHPO₄-2H₂O - 2Ca₉ (HPO₄) (AFTER₄) ₅OH +

13H2O (1))

Ca4 (PO4) 2O + CaHPO4 - Ca₅ (PO4)₃OH (1))

3Ca4 (PO4) 2O + 6CaHPO4 - 2Ca₉ (HPO4) (PO4) 5OH +

H2O (12)

<td></td><td>3ca₄(PO4) 2O</td><td>+ Ca8H2 (PO₄) 6</td><td>• 5H2O</td><td>- 4Ca5</td><td>(AFTER₄) 3OH +</td>

<td>4HyO</td><td> (13)</td><td></td><td></td><td></td><td></td>

<td></td><td>3ca⁴ (Appointment</td><td>+ 3Ca⁸H²(AFTER⁴)⁶</td><td>• 5H2O -</td><td>4ca₉ (ΗΡ?)</td><td>(POWOH +</td>

<td>14H₂ABOUT</td><td> (14)</td><td></td><td></td><td></td><td></td>

<td></td><td>Ca⁴ (AFTER⁴)₂O +</td><td>2 Ca³(AFTER⁴) ² + H2O</td><td>- Ca5 (PO4</td><td> ) ₃OH</td><td> (15)</td>

In equations (7) and (8), DCPD is formed as an intermediate reaction product, but with PHA or CDHA at the end of the reaction. All reactions (13), (14) and (15) are very slow. However, by using formulas (9) - (12) it is possible to obtain cement setting and hardening with time at room or body temperature and neutral pH.

It is also possible to produce PHA as the final cured product using mixtures of calcium phosphates with a Ca / P ratio less than 1.67. This is done by using additional calcium sources such as Ca (OH) 2 or CaCCg instead of TTCP. One example is the reaction β-TCP + DCPD + CaCO3 -&gt; PHA. Initially formed PHA crystals from the reaction between DCPD and CaCO3 act as binders between β-TCP particles. When DCPD is consumed, the reaction occurs between the remaining calcium carbonate and β-TCP with the formation of PHA. However, it seems that the latter process has a detrimental effect on the mechanical strength of cement.

Preferably, the at least one calcium phosphate powder that has the ability to cure the calcium phosphate cement by reaction with an aqueous liquid is tetra calcium phosphate (TTCP), monocalcium phosphate monohydrate (MCPM), dicalcium phosphate dihydrate (DCPD), anhydrous dicalcium phosphate (DCPA), phosphate dicalcium (DCP), tricalcium phosphate (TCP), or octalcium phosphate (OCP). Preferably, the calcium phosphate is α-triphosphate.

The at least one calcium phosphate component powder should comprise 40-98% by weight, preferably 6090% by weight of the dry mixture containing the calcium phosphate component and the calcium sulfate component.

The calcium phosphate powder component must be rapidly cured with a limited amount of water available to produce a bone substitute with acceptable properties within 15 minutes of injection. Thanks to the composition according to the invention, the hardening reaction of this component to cement calcium phosphate can be controlled to set for 18 hours as a bone mineral substitute material with a strength of about 30 MPa.

This can be done in different ways. In a preferred embodiment of the invention, the water-soluble additive is an accelerator of hardening of calcium phosphate powder to a calcium phosphate cement in reaction with an aqueous liquid. Such an accelerator may be a phosphate, e.g. disodium hydrogen phosphate (Na2HPO4). The rate of in vivo hardening reactions can be varied by varying the amount of phosphate between 0.01 and 10% by weight of the total composition, the salt being contained in the hardened calcium sulfate in the form of particulates and slowly released from it.

The phosphate can also be dissolved in an aqueous liquid. In this case, the accelerator should be present in the aqueous liquid in concentrations of 0.1-10% by weight, preferably 1-5% by weight.

The reaction of the powdered calcium phosphate component to calcium phosphate cement can also be accelerated by adding hardened calcium phosphate cement particulate to the composition of the invention as an accelerator. The cured calcium phosphate cement may be hydroxyapatite (HA), precipitated hydroxyapatite (PHA), or preferably calcium depleted hydroxyapatite (CDHA), or a mixture thereof. It should have a Ca / P ratio between 1.5 and 2. The particulate calcium phosphate cement as accelerator should have a particle size less than 20 pm, preferably less than 10 pm and constitute 0.1-10% by weight, preferably 0.5-5% by weight, of calcium phosphate which is to react with the aqueous liquid.

Various methods to accelerate the calcium phosphate reaction to calcium phosphate cement can be used alone or in combination.

Accordingly, the hardening reaction can be adapted to last about 18 hours for a concentration in a high strength material. During this period, the already cured sulfate will give the implant initial strength, and when the reaction of the setting of the calcium phosphate component into the high strength material is completed, the final strength will be obtained. Artificial bone mineral substitute material will remain stable for 3-4 years.

Each particle of calcium sulfate dihydrate will contain larger amounts of sulfate crystals. When the artificial bone mineral substitute material is resorbed in the body, the water in the blood will finally dissolve the crystals of hardened sulfate ceramics and release any additions. It should be noted that this reaction is several orders of magnitude slower than the hardening reaction of the calcium phosphate component to calcium phosphate cement.

Additives that are associated with sulfate crystals will be released in vivo along with calcium sulfate when the body fluid comes into contact with the bone mineral substitute material over time. Thus, the formation of pores is accompanied by controlled slow release from the hardened bone substitute of at least one additive that has favorable in vivo properties. Water-soluble additives will be released and dissolved to work effectively at the site of action.

Accordingly, as the sulfate degrades, pores, holes and cavities will gradually form, which act as a cartilage cavity, and finally a concentrated and hardened implant of high strength material will look like a normal bone. Elongated particles are preferred. The result is that contact can be established between the blood and most particles of hardened calcium sulfate in the bone mineral substitute material that dissolve within 6-12 months.

Particles as aggregates of single crystals can also be used to achieve short distances between crystals. Calcium sulfate hemihydrate in the form of particles can provide such particles. In this case, instead of the β form, the α form of calcium sulfate hemihydrate is preferred, not only because of its increased mechanical strength, but also because of the size of the crystals.

In one aspect, the invention relates to hardened calcium sulfate in the form of solid particles comprising and associated with at least one additive, as stated above.

The water-soluble as well as water-insoluble additive may be incorporated into the hardened calcium sulfate in the form of particulates during its manufacture. Thus, the water-soluble additive at an appropriate concentration in an aqueous solution is mixed with calcium sulfate hemihydrate, and reaction with gypsum as a product:

(^ cSOo ^ Ho ^) + 3H2O - 2 (CaSO4-2H2O) + heat (16)

The plaster structure consists of alternating layers of OO4 ions²- strongly associated with Ca²⁺ and layers of water molecules, and the additives will bind to the sulfate crystals of calcium sulfate in the form of particles.

When calcium sulfate hemihydrate is used, the water-soluble additive is similarly contained in the calcium sulfate in the form of particulates during its manufacture. In this case, the gypsum is ground and heated, until about 75% of the water has evaporated and CaSO4-RH is obtained.₂A. However, two known forms (α and β) of calcium sulfate hemihydrate are produced differently according to:

heating (CaSO₄.2H2O) -&gt; 2 (CaSO₄-bh₂O) + 3H2O (17)

Form α is obtained by dehydrating gypsum hydrothermally in the presence of electrolytes. The β form is produced by dehydrating gypsum in an atmosphere of water at temperatures above 100 ° C. Accordingly, a water-soluble additive at a suitable concentration in an aqueous solution may be present during these reactions.

Similarly, the water-soluble additive will similarly stick due to the electrostatic interactions with the residual crystal water of the hardened calcium sulfate in the form of particles.

The preferred method for producing calcium sulfate hemihydrate is to use the already formed particulate dihydrate with a water-soluble additive. In this case, the ground gypsum is subjected to the necessary heat treatment, e.g. in an autoclave, with crystals that can be used as calcium sulfate in the form of particulates.

It is obvious that water-soluble additives must be thermostable if they are contained in the calcium sulfate in the form of particles to be converted into calcium sulfate hemihydrate.

An effective mixing system must be available to produce an injectable composition according to the invention. Mixing can occur in a conventional cement mixing system and the composition is injected using a convenient delivery system. The mixing container is preferably of the type that can suck the aqueous component into the powder component (German Patent No. 4409610). Such a Prepack ™ system is a closed mixing system for delivery in combination with packaged ingredients in a flexible foil bag. Of course, other mixing devices can also be used, e.g. two soft bags connected together that can be adapted to the delivery cylinder.

The formation of air bubbles in the composition that may interfere with the hardening reaction of the calcium phosphate component and reduce the initial mechanical strength of the implanted material during surgery can be prevented by mixing the composition of the invention under subatmospheric pressure, e.g., under vacuum. However, atmospheric pressure can also be used. Preferably, the dry mixture of the composition is radiation sterilized before mixing with a sterile aqueous liquid.

The hardened bone mineral substitute material can be initially shaped into the appropriate shape, e.g. as pellets or spheres containing at least one additive, which allows implant attachment and / or treatment of diseases, etc. The bioactive agent is therefore preferably a water-soluble additive.

Hardened calcium sulfate, on the other hand, is, for example, produced in the form of massive blocks that are processed, e.g. ground, into particles having specific sizes, which are also suitable for bone ingrowth. The shape of these blocks does not affect the invention.

The invention also relates to a bone mineral substitute material produced from the compositions of the invention. Such an implant may be introduced into the body of an animal or human being cured.

The composition of the invention, or the bone mineral substitute material itself, can be used in many applications, such as fracture healing, prosthetic implants, and foreign material implants in other situations. Such situations may include filling gaps or gaps in the bone, or prior bone defect, such as fractures, osteotomy, for fixing prostheses or other foreign material, for surgical checking of prostheses, for plastic surgery, for surgical reconstruction, or for cosmetic surgery.

In both cases, the composition as well as the bone mineral substitute material are suitable for topical application in dental pockets and / or splits in the treatment of periodontitis or in combination with other periodontitis treatment options included herein, such as supporting matrix proteins or locally acting growth inducing factors .

Thus, the invention further relates to the use of the composition according to the invention for the production of artificial bone mineral substitute material.

Similarly, they can be used together with collagen or other support substances that are important for support tissue growth.

The injectable composition is also moldable and can therefore be used to fill the maxillary, frontal, sieve or acetabular sinuses to allow the attachment of screws, needles, etc., such as the attachment of dental implants on a pivot or screw or needle through the maxillary sinus.

In addition, the injectable composition can be used to fill skeletal defects due to removal of orthopedic screws, plugs or needles that are used for internal or external fracture fixation. It is preferred on such occasions that antibiotics are included in the composition as additives.

Injectable compositions can also be used together with expanders to create space for insertion material, such as an inflatable balloon or metal expander that is removed prior to the introduction of the composition or an expander filled with the composition, or a stent filled with the composition or attached to a bone mineral substitute material.

Accordingly, the invention also relates to a method of implanting a bone substitute into a support tissue in a human or non-human animal, wherein the composition for injecting the bone substitute mineral material is introduced into the tissue, the injectable composition being able to cure in vivo and containing aqueous fluid liquid;

at least one calcium sulfate component composed of calcium sulfate in the form of particulates; and at least one calcium phosphate component composed of calcium phosphate powder having a curing ability to cement calcium phosphate by reaction with an aqueous liquid under the influence of at least one accelerator, wherein the aqueous liquid is provided in an amount sufficient only for this curing reaction;

the at least one calcium phosphate component and the at least one calcium sulfate component are provided as a dry mixture.

Instrumental or non-instrumental non-invasive or invasive surgical joint surgery can be performed using the composition of the invention or the bone mineral substitute material itself, e.g. in connection with the spine or joints, such as finger joints, vertebral joints, shoulder joints, etc.

Another variation of the invention that can be used in connection with the abovementioned uses includes topical injection of the composition with simultaneous systemic treatment of the biologically active agent. Such systemic treatment can be used as a single or prolonged treatment. Suitable biologically active agents are the above-mentioned water-soluble additives that induce, stimulate and / or accelerate bone formation, or inhibit bone degradation, e.g. bone inducing agents such as parathyroid hormones, growth factors or statins. Similarly, systemic treatment with agents that inhibit bone metabolism, such as biphosphonates, can be used.

Accordingly, the invention also relates to the use of the composition of the invention in a method for the manufacture of a medicament for preventing or treating a disorder related to supporting tissues in a human or non-human animal, the method comprising providing the subject with a composition of a bone substitute mineral material having the ability to cure in a body fluid in vivo. which contains an aqueous liquid;

at least one calcium sulfate component composed of calcium sulfate in the form of particulates; and at least one calcium phosphate component composed of calcium phosphate powder having a cure ability to cement calcium phosphate by reaction with an aqueous liquid under the influence of at least one accelerator, wherein the aqueous liquid is provided in an amount sufficient only for this curing reaction;

the at least one calcium phosphate component and the at least one calcium sulfate component are provided as a dry mixture;

with systemic and simultaneous administration of a preventive or therapeutic amount of at least one biologically active agent.

However, a preferred embodiment of the invention includes the use of the composition of the invention in a method of making a medicament for preventing or treating a disorder related to supporting tissues in a human or non-human animal, which method comprises topically administering to the subject, preferably by injection, a composition comprising a preventive or therapeutic amount of at least one additive that is slowly released from this composition, optionally with systemic and / or simultaneous administration of a preventive or therapeutic amount of at least one biologically active agent, preferably at least one of such additives.

The invention is especially useful for the topical treatment of an infection or infestation in the musculoskeletal system, such as osteomyelitis caused e.g. by bacteria. Therefore, combined supportive or osteoconductive treatment and prevention of skeletal infection can be obtained, e.g. in sternotomy, prosthetic implants, reconstructive surgery, traumatic surgery, cancer surgery, cosmetic surgery and mouth and jaw surgery.

The invention is also useful for local treatment with cytostatic agents, such as for musculoskeletal tumors, e.g., metastases in the vertebrae of breast or prostate cancers requiring treatment with support material, which at the same time gives the possibility of local treatment with tumor suppressants. In addition, they can be used topically together with agents that enhance the clinical effects of radiation in diseases such as cancer.

In preferred embodiments, the invention relates to the use mentioned above, wherein the prevention or treatment of a disorder related to supporting tissues includes fracture healing; inserting prosthetic implants and implants of foreign materials in connection with fractures, bone defects and osteotomy; non-instrumental non-invasive or invasive surgical procedure for connection to the spine or joints, preferably finger joints, vertebral joints and shoulder joints; surgical denture checking; plastic surgery; reconstructive surgery; cosmetic surgery; sternotomy; traumatic surgery; cancer surgery; mouth and jaw surgery; periodontitis; filling of maxillary, frontal, ethmoidal or acetabular sinuses; creating space for an inflatable balloon or metal expander; and infections or infestations of the musculoskeletal system, preferably osteomyelitis caused by bacteria.

The invention can also be used for local and adjunct treatment with agents that inhibit bone resorption or stimulate bone formation.

The invention further relates to compositions of the invention for use as an artificial bone mineral substitute material.

Furthermore, the invention relates to a composition of the invention for use as a medicament for preventing or treating a disorder related to supporting tissues in a human or non-human animal, which method comprises topically administering to the subject, preferably by injection, a composition comprising the preventive or therapeutic amount of at least one additive, which is slowly released from the composition, optionally with systemic and / or simultaneous administration of a preventive or therapeutic amount of at least one biologically active agent, preferably at least one of these additives.

In a preferred embodiment of the invention, the prevention or treatment of a disorder associated with supporting tissues includes fracture healing; inserting prosthetic implants and foreign substance implants in connection with fractures, bone defects, and osteotomy; non-instrumental non-invasive or invasive surgical procedure for connection to the spine or joints, preferably finger joints, vertebral joints and shoulder joints; surgical denture checking; plastic surgery; reconstructive surgery; cosmetic surgery; sternotomy; traumatic surgery; cancer surgery; mouth and jaw surgery; periodontitis; filling of maxillary, frontal, ethmoidal or acetabular sinuses; creating space for an inflatable balloon or metal expander; and infections or infestations of the musculoskeletal system, preferably osteomyelitis caused by bacteria.

EXAMPLES

The invention is described below and illustrated with reference to the following examples, which have been carefully chosen to define the invention. Accordingly, they should not be construed as limiting the invention in any way.

Example 1. Slow release of an x-ray contrast agent.

A composition according to the invention was prepared which contained 40% by weight of hydroxyapatite and 60% by weight of hardened calcium sulfate in the form of particulates, which had previously been doped with 5% by weight of non-ionic x-ray contrast agent iohexol (12.1 g johexo^lat^{/ 100 g} particles).

Release of iohexol based on calcium sulfate in isotonic buffer was carried out in vitro. The results are shown in Figure 1.

Release from day 1 means complete release during that day. In total, more than 94% of the doped agent was released.

Example 2. Slow release of an antibiotic.

Compositions of the invention were prepared which contained 80% by weight of hydroxyapatite and 20% by weight of hardened calcium sulfate in the form of particulates, which had previously been doped with two different concentrations (3 and 6% by weight) of the antibiotic gentamycin sulfate.

Release of gentamicin from calcium sulfate based material in isotonic buffer was carried out in vitro. The results are shown in Figure 2.

The release was faster at 6% by weight (□) than at 3% by weight (*) of gentamicin.

A comparison was made between the release of gentamicin only from particles of hardened calcium sulfate, which had previously been doped with two different concentrations of gentamycin as above.

The release of gentamicin from calcium sulfate particles in isotonic buffer was carried out in vitro. The results are shown in Figure 3.

Example 3. In vivo injection.

A composition of the invention was prepared with a particle size distribution of less than 100 µm.

The composition was successfully injected into the channels of the narrow trabecular piglet bone as well as the spine of human corpses and concentrated in situ.

Micrographs reveal that the composition was introduced and penetrated bone microchannels that are 200-300 pm or smaller.