Hemostatic agent in the form of a paste, use thereof and method for producing a topical active agent release system

Abstract

To provide a paste-form hemostatic agent, its use, and a method for producing a topical active agent release system.SOLUTION: The paste-form hemostatic agent comprises a) at least one particulate sugar alcohol, b) at least one saturated triglyceride having a melting point of 40 °C or more, and c) at least one saturated triglyceride having a melting point of less than 0 °C.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a hemostatic agent in paste form that can be used for mechanical sealing of bleeding bone tissue. A further object of the present invention is an active agent delivery system based on the hemostatic agent in paste form. The present invention further relates to the use of the hemostatic agent according to the invention and the active agent delivery system according to the invention, as well as methods for producing the hemostatic agent according to the invention and the active agent delivery system according to the invention. [Background technology]

[0002] During surgery, bleeding is stopped (hemostasis) using various methods, such as electrocoagulation (cauterization) of blood vessels, depending on the anatomical conditions. In many surgeries on the skull region, especially the sternum, when severe bleeding occurs there due to the anatomical situation, bone wax is used to seal the capillaries and thereby stop the bleeding. For this purpose, the surgeon presses plastically deformable bone wax directly onto or into the bleeding bone region. This leads to congestion of blood flow and causes platelet aggregation; and the supplying vessels are eventually blocked by platelet aggregation and fibrin.

[0003] Bone wax has been known since at least the 19th century and generally contains bleached beeswax and a plasticizer. Examples of plasticizers used include almond oil, petrolatum, palmitic acid, isopropyl ester, and isopropyl myristate. Beeswax-based bone waxes are considered non-biodegradable in the human body. Due to the chemical composition of the beeswax used, bone wax is not degraded by human enzymes. As a result, bone wax remains in or on bone tissue after hemostasis, forming a barrier to new bone tissue growth.

[0004] The hemostatic effect of bone wax is due to its good adhesion to moist and fatty bone tissue and its high toughness. Currently available bone waxes have very good hemostatic effect.

[0005] However, in the long term, there are often undesirable side effects and consequences in the human body (SE Katz, J. Rotmann: Adverse effects of bone wax in surgery of the orbit. Ophthal Plast. Reconstr. 1996, 12(2) 121-126.; M. Lavigne et al.: Bone-wax granuloma of old femoral neck osteoplasty. Can. J. Surg. 2008, 51(3) E58-60.; RT Allison: Foreign body reactions and an associated histological artifact due to bone wax. Br. J. Biomed. Sci. 1994, 51(1) 14-17.; O. Eser et al.: Bone wax as a cause of foreign body reaction alter lumbar disc surgery: A case report. Adv. Ther. 2007, 24(3) 594-7).

[0006] Substitutes for bone wax of traditional composition are known.

[0007] EP 0109310(A) discloses a waxy mass based on calcium fatty acid salts and oligomers of hydroxycarboxylic acids.

[0008] The documents U.S. Pat. No. 4,595,713 (A), DE-A-3229540 (A), DE-A-3825211 (A) and EP-A-1142597 (A) disclose waxy compositions containing oligoesters of hydroxycarboxylic acids, such as lactic acid and 6-hydroxycarboxylic acids. It has been shown that the use of these waxy compositions leads to the formation of acidic degradation products during hydrolysis, which can affect bone tissue as a result of a local pH drop.

[0009] An alternative is polyether-based compositions (US Patent Application Publication Nos. 2009 / 286886 A and 2011 / 002974 A). For example, polypropylene glycol / ethylene glycol copolymers can be used as polyethers. These compositions can be kneaded and spread with the heat of the hands. However, the good solubility of these polyethers in aqueous media is a drawback. This means that adhesion of these compositions can be difficult when the bone tissue is severely bleeding due to the dissolution of the waxy composition. This can lead to subsequent bleeding, in which case the seal can quickly dissociate or dissolve. However, the advantage of these mixtures is that they do not have a barrier function in bone healing and are completely excreted via the kidneys (A. Suwan et al.: Controversial role of two different local hemostatic agents on bone healing. J. Am Sci. 2010, 6(12)15-163).

[0010] German Patent Nos. 102011016277(B) and 102011122752(B) describe hemostatic agents in paste form. The hemostatic agents are composed of (a) at least one saturated glycerol-1,2,3-trifatty acid ester having a melting temperature higher than 37°C, (b) at least one filler present in at least partially particulate form having a melting temperature higher than 37°C, and (c) at least one compound having a melting temperature of 37°C or lower and a solubility of less than 50 grams per liter of water at 25°C. At least one alkylene oxide polymer, at least one alkylene oxide copolymer, and a calcium compound are proposed as fillers. The calcium compounds described include calcium carbonate, dolomite, α-tricalcium carbonate, β-tricalcium carbonate, hydroxyapatite, carbonate apatite, octacalcium phosphate, amorphous calcium phosphate, calcium sulfate dihydrate, and calcium sulfate hemihydrate. Polyethylene glycol and polypropylene glycol / polyethylene glycol copolymers (poloxamers) are preferred polymers. Liquid fatty acid esters constitute the third component. Our own in vitro cytotoxicity studies according to ISO 1993-5 have newly demonstrated that hemostatic agents according to German Patent Nos. 102011016277(B) and 102011122752(B), which are composed of solid triglycerides, liquid triglycerides, and calcium carbonate and calcium sulfate fillers, are not cytotoxic according to ISO 10993-5. In contrast, hemostatic agents with similar compositions but containing polypropylene glycol / polyethylene glycol copolymers (poloxamers) as fillers instead of inorganic calcium salts, are clearly cytotoxic. Calcium compounds are also disadvantageous due to their abrasive properties.

[0011] Therefore, there is a need for a plastically deformable biodegradable hemostatic agent that does not generally suffer from the above-mentioned drawbacks.

[0012] In particular, there is a need for a paste-form hemostatic agent composed entirely of organic biocompatible materials that are non-abrasive. Abrasive components are particularly critical when the hemostatic agent is used near an articular endoprosthesis, as abrasive particles can get between the articular surfaces of the articular endoprosthesis and cause abrasive damage to the sliding surfaces.

[0013] Object of the invention The objective of the present invention is to develop a paste-form hemostatic agent, preferably made of a biocompatible and absorbable material, that does not exhibit cytotoxicity according to ISO 10993-5 in vitro. In this context, it is particularly preferred that the paste-form hemostatic agent according to the present invention does not have amphiphilic properties. Amphiphilic substances penetrate both the hydrophilic and lipophilic components of cells, thereby weakening cell membranes. This means that they may increase cytotoxicity. It is also intended that the hemostatic agent be completely free of abrasives and inorganic calcium salts. Furthermore, the hemostatic agent to be developed should not contain components that microorganisms can use as an energy source. Furthermore, the hemostatic agent should not release large amounts of acidic or basic components to avoid damage to bone tissue due to non-physiological pH values. Additionally, the material should be biodegradable or excretable by the kidneys so that a permanent barrier effect from the material does not interfere with the healing process of bone tissue. The hemostatic agent should also be easily malleable by hand. Furthermore, the paste-form material should not stick to rubber gloves during kneading and application. The hemostatic agent is intended to adhere to moist bone tissue and also to the surface of metal implants. Furthermore, it is intended that the hemostatic agent be mixable with any powdered pharmaceutically active agent without significantly impairing the adhesive properties and plastic deformability of the hemostatic agent. The viscosity of the hemostatic agent must be sufficiently high so that the paste-form material can withstand the extrusion pressure. Furthermore, the hemostatic agent should have sufficient cohesive strength so that it does not disintegrate or dissolve within minutes upon contact with blood or other aqueous fluids.

[0014] The object of the present invention is first achieved by the hemostatic agent according to the present invention. Summary of the Invention

[0015] The present invention first relates to a hemostatic agent in the form of a paste. a) at least one particulate sugar alcohol; b) at least one saturated triglyceride having a melting point of 40°C or higher, and c) at least one saturated triglyceride having a melting point below 0°C It is characterized by the fact that it contains

[0016] The individual components of the hemostatic agent according to the present invention are described below.

[0017] In a preferred embodiment, the hemostatic agent according to the invention comprises: a) 30% to 60% by weight, preferably 40% to 60% by weight, more preferably 50% to 60% by weight, of at least one finely divided sugar alcohol; b) 20% to 35% by weight, preferably 20% to 30% by weight, more preferably 20% to 28% by weight of at least one saturated triglyceride having a melting point of 40°C or higher, and c) 20% to 35% by weight, preferably 20% to 30% by weight, more preferably 20% to 28% by weight of at least one saturated triglyceride having a melting point below 0°C Includes.

[0018] The hemostatic agent according to the present invention has the following advantages, for example:

[0019] The hemostatic agent in paste form according to the present invention is preferably non-cytotoxic according to ISO 10993-5 as determined by the MTT test ((3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) test) or the XTT test (((sodium 3'-[1-(phenylaminecarbonyl)-3,4-tetrazolium]-bis-(4-methoxy-6-nitro))-benzenesulfonic acid hydrate) test).

[0020] The paste-form hemostatic agent according to the present invention is characterized by its plastic deformability, biodegradability, and resistance to liquids, particularly aqueous environments. The hemostatic agent maintains dimensional and volume stability in the absence of external forces, particularly ex vivo. Nevertheless, the hemostatic agent is degradable as described herein.

[0021] The paste-form hemostatic agent according to the present invention is suitable for treating damaged bone tissue and can serve both for mechanical hemostasis and as a local active agent release center in paste form. The hemostatic agent according to the present invention generally adheres equally well to bone, glass, and metal.

[0022] Additionally, it is possible to add a solid or preferably particulate pharmaceutically active agent to the hemostatic agent according to the present invention, in which embodiment the hemostatic agent can serve as a local active agent release center in paste form when used to treat injuries to bone tissue.

[0023] A hemostatic agent in paste form according to the present invention is generally obtainable by simply kneading its components on a laboratory or industrial scale. DETAILED DESCRIPTION OF THE INVENTION

[0024] i) Hemostatic agent in paste form According to the present invention, a hemostatic agent is provided.

[0025] According to the invention, a hemostatic agent is understood to mean a composition having hemostatic properties.

[0026] The present invention is based on the surprising discovery that a mixture of components a), b), and c) as defined above forms a paste-form hemostatic agent that can be used to seal bleeding bone tissue. What is particularly surprising is that the hemostatic agent according to the present invention exists as a waxy, kneadable mass that adheres entirely to both dry and wet surfaces. The hemostatic agent adheres particularly to metal surfaces, glass, and bone tissue. The toughness and mechanical stability of this mixture are surprisingly high enough to be used as an effective hemostatic agent to stop bleeding and to withstand the exudative pressures encountered in wounds. The mixture is biodegradable overall, yet surprisingly exhibits excellent mechanical stability, such that it does not decompose even when in contact with water or aqueous solutions such as blood.

[0027] In the context of the present invention, substances that can be broken down by the human organism and / or excreted by the kidneys are called biodegradable.

[0028] The hemostatic agent according to the present invention comprises at least one sugar alcohol.

[0029] Sugar alcohols, such as mannitol, generally do not affect the insulin levels of patients treated with the hemostatic agent of the present invention. The sugar alcohols of the hemostatic agent of the present invention also have a surprising effect on the consistency of the paste form. Without being bound by any theory, sugar alcohols reduce the crystal growth of other components during the manufacturing process of the paste form of the hemostatic agent of the present invention by wetting the surface of the formed crystallites, thereby making them inaccessible to additional crystal-forming molecules. As a result, the crystallites remain small, and the paste form of the hemostatic agent does not form lumps, but rather remains in the form of a paste of the present invention with a uniform consistency. According to the present invention, it is believed that sugar alcohols are excreted from the human body together with blood in the kidneys without being broken down, without causing any damage. Furthermore, they have a particularly positive effect on the properties of the paste form of the hemostatic agent, and are therefore surprisingly useful components of the paste form of the hemostatic agent of the present invention.

[0030] The hemostatic agent according to the present invention further comprises triglycerides as components.In the context of the present invention, triglycerides are understood to be organic compounds that are decomposed by lipase into glycerol and fatty acids.Glycerol, as a natural component of the human body, is generally decomposed into carbon dioxide and water via pyruvate and the citric acid cycle.Fatty acids, also natural components of the human body, are generally completely decomposed into carbon dioxide and water via β-oxidation in the case of fatty acids with an even number of C atoms.

[0031] Further definitions of the individual components of the hemostatic agent according to the present invention can be found below.

[0032] The hemostat according to the present invention is plastically deformable. In this context, plastic deformability is understood to mean the ability of the hemostat to be irreversibly deformed upon application of a force and to maintain this shape after application of the force.

[0033] A further advantage of the hemostatic agent in paste form according to the invention is that it does not have cytotoxic properties as a whole. In the context of the present invention, this is preferably achieved by using in the hemostatic agent according to the invention only substances or mixtures of substances that have in vitro cytotoxicity according to ISO 10993-5, with a viability in the MTT test ((3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) test) or the XTT test (((sodium 3'-[1-(phenylaminecarbonyl)-3,4-tetrazolium]-bis-(4-methoxy-6-nitro))-benzenesulfonic acid hydrate) test) of more than 70% at 100% v / v. This means that in the MTT or XTT test according to ISO 10993-5, the hemostatic agent in paste form according to the present invention has a viscosity of 100% v / v, preferably 70.0%, 70.5%, 71.0%, 71.5%, 72.0%, 72.5%, 73.0%, 73.5%, 74.0%, 74.5%, 75.0%, 75.5%, 76.0%, 76.5%, 77.0%, 77.5%, 78.0%, 78.5%, 79.0%, 79.5, 80.0%, 80.5%. By "viability" it is meant having a viability of greater than 81.0%, 81.5%, 82.0%, 82.5%, 83.0%, 83.5%, 84.0%, 84.5%, 85.0%, 85.5%, 86.0%, 86.5%, 87.0%, 87.5%, 88.0%, 88.5%, 89.0%, 89.5%, 90.0%, 90.5%, 91.0%, 91.5%, 92.0%, 92.5%, 93.0%, 93.5%, 94.0%, 94.5% or 95.0%. It is preferred that a viability of at least between 70.0% and 80.0% at 100% v / v is achieved.

[0034] ii) Hemostatic composition in paste form The hemostatic agent in paste form comprises at least one particulate sugar alcohol.

[0035] In the context of the present invention, sugar alcohol is understood to mean an acyclic polyol having a hydroxyl group attached to each of its carbon atoms.Sugar alcohols suitable for the present invention are generally obtained as reduction products of carbohydrates (sugars), i.e., by reducing (hydrogenating) the keto or aldehyde groups of sugars.As a result, sugar alcohols generally have much higher oxidation and storage stability than their parent sugars.In addition, they generally have little or no effect on blood glucose concentration in the human body, and are not or only partially usable as an energy source for many microorganisms.

[0036] In the context of the present invention, the finely divided sugar alcohols are preferably alditols and ketol, and particularly preferably D-mannitol (CAS 69-65-8), D,L-mannitol (CAS 87-78-5), D-sorbitol (CAS 50-70-4), isomalt (6-OAd-glucopyranosyl-D-glucitol) (CAS 534-73-6), 1-OAd-glucopyranosyl-D-mannitol (CAS 20942-99-8), erythritol (CAS 149-32-6) and xylitol (CAS 87-99-0). More preferred sugar alcohols are erythritol, xylitol, D-mannitol and D,L-mannitol. D-mannitol and D,L-mannitol are particularly preferably used in the context of the present invention.

[0037] Experiments according to the invention with different sugar alcohols show that D-mannitol is particularly suitable in the context of the present invention with regard to tactile properties and with regard to in vitro cytotoxicity according to ISO 10993-5. D-mannitol also does not affect blood glucose levels and is hemocompatible.

[0038] Sugar alcohols generally do not contain any acidic or basic groups. Therefore, when dissolved in or contacted with an aqueous solution or water, sugar alcohols do not substantially affect the pH of the aqueous solution or water. Experiments have shown that the pH value of distilled water containing the paste-form hemostatic agent of the present invention is in the range of pH 6.0 to 6.8.

[0039] For the purposes of the present invention, the sugar alcohol as component a) is preferably present in the form of a microparticulate sugar alcohol.This means that the microparticulate sugar alcohol is preferably in the form of solid particles, and is preferably characterized by a particle size of less than 100 μm.Therefore, the particles of at least one microparticulate sugar alcohol are preferably 100 μm, 99 μm, 98 μm, 97 μm, 96 μm, 95 μm, 94 μm, 93 μm, 92 μm, 91 μm, 90 μm, 89 μm, 88 μm, 87 μm, 86 μm, 85 μm, 84 μm, 83 μm, 82 μm, 81 μm, 80 μm, 79 μm, 78 μm. , 77 μm, 76 μm, 75 μm, 74 μm, 73 μm, 72 μm, 71 μm, 70 μm, 69 μm, 68 μm, 67 μm, 66 μm, 65 μm, 64 μm, i.e., smaller than 63 μm, 62 μm, 61 μm, 60 μm, 59 μm, 58 μm, 57 μm, 56 μm, 55 μm, 54 μm, 53 μm, 52 μm, 51 μm or 50 μm. In the present invention, particle size is measured by sieve fractionation.

[0040] The smaller the particle size of the sugar alcohol, the smoother the paste that can be made therefrom.

[0041] Further components of the hemostatic agent in paste form in the context of the present invention are saturated triglycerides having a melting point of 40° C. or higher as component b). Such saturated triglycerides are generally solid at room temperature. Furthermore, their melting point is higher than normal human body temperature, which is about 36° C. to 38° C., making them possible components of the hemostatic agent according to the present invention, which is also solid under in vivo conditions.

[0042] In the context of the present invention, particularly suitable saturated triglycerides having a melting point of 40°C or higher are glycerol tristearate (CAS 55-43-1), glycerol tripalmitate (CAS 555-44-2), glycerol trilaurate (CAS 555-44-2), and mixed triglycerides formed from stearate and / or palmitate and / or laurate with glycerol. However, other possible types of saturated fatty acid esters are also contemplated, which have melting points of 40°C or higher and enable the aforementioned desirable properties of the hemostatic agent according to the present invention with respect to surface adhesion, deformability, toughness, biodegradability, etc. These saturated fatty acid esters having a melting point of 40°C or higher are preferred for adhesion of the hemostatic agent to bone tissue and metal surfaces. Furthermore, since these saturated fatty acid esters do not contain double bonds or other oxidation-sensitive structures, they generally have high storage stability and high resistance to gamma irradiation. Therefore, the particulate hemostatic agent according to the present invention is particularly suitable for treating bone injuries or surgically induced damage. Any X-rays following treatment with the particulate hemostatic agent of the present invention generally do not damage the area treated with the particulate hemostatic agent.In particular, the hemostatic agent of the present invention can also be used to treat bone damage in patients who must subsequently undergo radiation therapy.Irradiation preferably does not affect the particulate hemostatic agent of the present invention.

[0043] A further component of the hemostatic agent in paste form in the context of the present invention is, as component c), a saturated triglyceride having a melting point below 0° C. Such saturated triglycerides are liquid at room temperature, i.e., between 20° C. and 30° C.

[0044] In the context of the present invention, particularly preferred saturated triglycerides having a melting point below 0°C are glycerol trioctanoate (CAS 538-23-8) and glycerol tridecanoate (CAS 612-71-6), with glycerol-fatty acid mixtures being particularly preferred, and the glycerol-fatty acid mixtures Miglyol 812N (CAS 73398-61-5), Miglyol 810N (CAS 73398-61-5), and Miglyol 829N (CAS 91744-56-8) being very particularly preferred. These liquid fatty acid esters also do not contain double bonds or other oxidation-sensitive structures and are therefore generally storage-stable and highly resistant to gamma radiation. The use of triglycerides in which the fatty acid moiety has an even number of C atoms is particularly advantageous. When an even number of C atoms is present, the fatty acid is completely metabolized in the human body to carbon dioxide and water.

[0045] According to the present invention, it is preferred if the different components a) (microparticulate sugar alcohol), b) (saturated glycerol fatty acid ester with a melting point above 40° C.) and c) (saturated glycerol fatty acid ester with a melting point below 0° C.) are each present in a specific proportion in the hemostatic agent according to the present invention. According to the present invention, it is possible to vary the proportion of each component in the hemostatic agent in paste form according to the selected substances and the intended use of the hemostatic agent in paste form.

[0046] For the purposes of the present invention, component a) is preferably indicated to constitute 30% to 60% by weight of the total mass of the hemostatic agent in paste form, which means that the particulate sugar alcohol preferably constitutes a proportion of at least 30% by weight, generally at least 31% by weight, generally at least 32% by weight, generally at least 33% by weight, generally at least 34% by weight, generally at least 35% by weight, generally at least 36% by weight, generally at least 37% by weight, generally at least 38% by weight, generally at least 39% by weight, generally at least 40% by weight, generally at least 41% by weight, generally at least 42% by weight, generally at least 43% by weight, generally at least 44% by weight, generally at least 45% by weight, generally at least 46% by weight, generally at least 47% by weight, generally at least 48% by weight, generally at least 49% by weight, generally at least 50% by weight, in each case based on the total mass of the hemostatic agent according to the present invention, regardless of the other components. Furthermore, this means that the particulate sugar alcohol, independently of the other components, preferably constitutes at most 60% by weight, generally at most 59% by weight, generally at most 58% by weight, generally at most 57% by weight, generally at most 56% by weight, generally at most 55% by weight, generally at most 54% by weight, generally at most 53% by weight, generally at most 52% by weight, generally at most 51% by weight, generally at most 50% by weight, in each case based on the total weight of the hemostatic agent according to the invention. It is particularly preferred if component a), i.e. the particulate sugar alcohol, is present in an amount ranging from 40% to 60% by weight, even more preferably from 50% to 60% by weight, in each case based on the total weight of the hemostatic agent according to the invention.

[0047] For the purposes of the present invention, it has been indicated that components b) and c) preferably each constitute 20% to 35% by weight of the total mass of the hemostatic agent in paste form.

[0048] This means that saturated triglycerides having a melting point of 40° C. or higher, independently of other components, preferably constitute at least 20% by weight, generally at least 21% by weight, generally at least 22% by weight, generally at least 23% by weight, generally at least 24% by weight, generally at least 25% by weight, generally at least 26% by weight, generally at least 27% by weight, generally at least 28% by weight, generally at least 29% by weight, generally at least 30% by weight, in each case based on the total weight of the hemostatic agent according to the invention. Furthermore, this means that saturated triglycerides having a melting point of 40° C. or higher, independently of other components, preferably constitute at most 35% by weight, generally at most 34% by weight, generally at most 33% by weight, generally at most 32% by weight, generally at most 31% by weight, generally at most 30% by weight, in each case based on the total weight of the hemostatic agent according to the invention.

[0049] This also means that saturated triglycerides having a melting point below 0° C. preferably constitute at least 20% by weight, generally at least 21% by weight, generally at least 22% by weight, generally at least 23% by weight, generally at least 24% by weight, generally at least 25% by weight, generally at least 26% by weight, generally at least 27% by weight, generally at least 28% by weight, generally at least 29% by weight, generally at least 30% by weight, in each case based on the total weight of the hemostatic agent according to the invention, independently of other components. Furthermore, this means that saturated triglycerides having a melting point below 0° C. preferably constitute at most 35% by weight, generally at most 34% by weight, generally at most 33% by weight, generally at most 32% by weight, generally at most 31% by weight, generally at most 30% by weight, in each case based on the total weight of the hemostatic agent according to the invention, independently of other components.

[0050] The paste-form hemostatic agent according to the invention may in particular comprise, based on the total weight of the paste-form hemostatic agent: a) 30% to 60% by weight, preferably 40% to 60% by weight, more preferably 50% to 60% by weight, of at least one finely divided sugar alcohol selected from the group consisting of D-mannitol, D,L-mannitol, xylitol, and erythritol; b) 20% to 35% by weight, preferably 20% to 30% by weight, more preferably 20% to 28% by weight of at least one saturated triglyceride having a melting point of 40°C or higher selected from the group consisting of glycerol tripalmitate, glycerol tristearate, and glycerol tribehenate; c) 20% to 35% by weight, preferably 20% to 30% by weight, more preferably 20% to 28% by weight of at least one saturated triglyceride selected from the group consisting of glycerol fatty acid mixtures and having a melting point below 0°C Includes.

[0051] The paste-form hemostatic agent according to the invention may in particular comprise, based on the total weight of the paste-form hemostatic agent: d) 30% to 60% by weight, preferably 40% to 60% by weight, more preferably 50% to 60% by weight of at least one finely divided sugar alcohol selected from the group consisting of D-mannitol, D,L-mannitol, xylitol, and erythritol; e) 20% to 35% by weight, preferably 20% to 30% by weight, more preferably 20% to 28% by weight of at least one saturated triglyceride selected from the group consisting of glycerol tripalmitate, glycerol tristearate, and glycerol tribehenate, and having a melting point of 40°C or higher; f) 20% to 35% by weight, preferably 20% to 30% by weight, more preferably 20% to 28% by weight of at least one saturated triglyceride selected from the group consisting of glycerol fatty acid mixtures Miglyol 812N, Miglyol 810N and Miglyol 829N, having a melting point below 0°C Includes.

[0052] The paste-form hemostatic agent according to the invention may in particular comprise, based on the total weight of the paste-form hemostatic agent: a) 30% to 60% by weight, preferably 40% to 60% by weight, more preferably 50% to 60% by weight, of at least one finely divided sugar alcohol selected from the group consisting of D-mannitol and D,L-mannitol; b) 20% to 35% by weight, preferably 20% to 30% by weight, more preferably 20% to 28% by weight of at least one saturated triglyceride selected from the group consisting of glycerol tripalmitate, glycerol tristearate, and glycerol tribehenate, the saturated triglyceride having a melting point of 40°C or higher, and c) 20% to 35% by weight, preferably 20% to 30% by weight, more preferably 20% to 28% by weight of at least one saturated triglyceride selected from the group consisting of glycerol fatty acid mixtures and having a melting point below 0°C Includes.

[0053] The paste-form hemostatic agent according to the invention may in particular comprise, based on the total weight of the paste-form hemostatic agent: a) 30% to 60% by weight, preferably 40% to 60% by weight, more preferably 50% to 60% by weight, of at least one finely divided sugar alcohol selected from the group consisting of D-mannitol and D,L-mannitol; b) 20% to 35% by weight, preferably 20% to 30% by weight, more preferably 20% to 28% by weight of at least one saturated triglyceride selected from the group consisting of glycerol tripalmitate, glycerol tristearate, and glycerol tribehenate, the saturated triglyceride having a melting point of 40°C or higher, and c) 20% to 35% by weight, preferably 20% to 30% by weight, more preferably 20% to 28% by weight of at least one saturated triglyceride selected from the group consisting of glycerol fatty acid mixtures Miglyol 812N, Miglyol 810N and Miglyol 829N, having a melting point below 0°C Includes.

[0054] The hemostatic agent in paste form according to the invention is used in the treatment of all possible types of trauma to bone structures, in particular in vivo.

[0055] For this purpose, in the context of the present invention, it may be particularly advantageous to add at least one solid, preferably particulate, pharmaceutically active agent to the paste-form hemostatic agent in addition to the aforementioned components a), b), and c). The solid or particulate pharmaceutically active agent can be dispersed in the paste-form hemostatic agent without changing its chemical form. In this way, the active agent can be released locally, preferably over a longer period of time, and can exert any possible healing effect on the surrounding, potentially damaged bone tissue (sustained release). When the hemostatic agent according to the present invention contains an active agent, an active agent release system according to the present invention is created. The active agent may be added during the production of the hemostatic agent or by a medical professional immediately before administration to a patient.

[0056] Therefore, the present invention also provides a method for producing a method for manufacturing a semiconductor device comprising: a) at least one particulate sugar alcohol; b) at least one saturated triglyceride having a melting point of 40°C or higher, and c) at least one saturated triglyceride having a melting point below 0°C, and d) Particulate Pharmaceutically Active Agents The present invention also relates to an active agent delivery system comprising:

[0057] In a preferred embodiment, the active agent delivery system according to the invention comprises, in each case based on the total weight of the active agent delivery system: a) 30% to 60% by weight, preferably 40% to 60% by weight, more preferably 50% to 60% by weight, of at least one finely divided sugar alcohol; b) 20% to 35% by weight, preferably 20% to 30% by weight, more preferably 20% to 28% by weight of at least one saturated triglyceride having a melting point of 40°C or higher; c) 20% to 35% by weight, preferably 20% to 30% by weight, more preferably 20% to 28% by weight of at least one saturated triglyceride having a melting point below 0°C, and d) 0.5% to 15% by weight, preferably 1% to 12% by weight, more preferably 2% to 10% by weight of a particulate pharmaceutical active agent Includes.

[0058] In principle, any pharmaceutically active agent is suitable for this purpose. According to the invention, anti-infective agents, blood coagulation activators, fibrinolytic system inhibitors, immunomodulators, steroid hormones and growth factors are particularly preferred. In particular, gentamicin (CAS 1403-66-3), vancomycin (CAS 1404-90-6), tobramycin (CAS 32986-56-4), clindamycin (CAS 18323-44-9), colistin (CAS 1066-17-7), meropenem (CAS 96036-03-29), metronidazole (CAS 443-48-1), caspofungin (CAS 162808-62-0), fluconazole (CAS 863 86-73-4), amphotericin B (CAS 1397-89-3), calcium gluconate (CAS 299-28-5), tranexamic acid (CAS 11197-18-8), 6-aminocaproic acid (CAS 60-32-2), p-aminomethylbenzoic acid (CAS 150-13-0), prednisolone (CAS 50-24-8), dexamethasone (CAS 50-02-2) and cyclosporin A (CAS 79217-60-0) are preferred.

[0059] The present invention therefore provides in particular: a) 30% to 60% by weight, preferably 40% to 60% by weight, more preferably 50% to 60% by weight, of at least one finely divided sugar alcohol; b) 20% to 35% by weight, preferably 20% to 30% by weight, more preferably 20% to 28% by weight of at least one saturated triglyceride having a melting point of 40°C or higher; c) 20% to 35% by weight, preferably 20% to 30% by weight, more preferably 20% to 28% by weight of at least one saturated triglyceride having a melting point below 0°C, and d) An active agent release system comprising 0.5% to 15% by weight, preferably 1% to 12% by weight, more preferably 2% to 10% by weight of a particulate pharmaceutically active agent selected from the group consisting of anti-infective agents, blood coagulation activators, fibrinolytic system inhibitors, immunomodulators, steroid hormones and growth factors.

[0060] Furthermore, the present invention provides a method for preparing a pharmaceutical composition comprising: a) 30% to 60% by weight, preferably 40% to 60% by weight, more preferably 50% to 60% by weight, of at least one finely divided sugar alcohol; b) 20% to 35% by weight, preferably 20% to 30% by weight, more preferably 20% to 28% by weight of at least one saturated triglyceride having a melting point of 40°C or higher; c) 20% to 35% by weight, preferably 20% to 30% by weight, more preferably 20% to 28% by weight of at least one saturated triglyceride having a melting point below 0°C, and d) 0.5% to 15% by weight, preferably 1% to 12% by weight, more preferably 2% to 10% by weight of a particulate pharmaceutically active agent selected from the group consisting of gentamicin, vancomycin, tobramycin, clindamycin, colistin, meropenem, metronidazole, caspofungin, fluconazole, amphotericin B, calcium gluconate, tranexamic acid, 6-aminocaproic acid, p-aminomethylbenzoic acid, prednisolone, dexamethasone, daptomycin, and cyclosporin A. The present invention relates to an active agent delivery system comprising:

[0061] The active agent delivery system according to the present invention contains a particulate pharmaceutical active agent selected from the active agents described above. Of these aforementioned active agents, anti-infective agents are particularly preferred. Even more preferred are antibiotics, particularly the antibiotics gentamicin, vancomycin, clindamycin, and daptomycin.

[0062] The present invention therefore provides in particular: a) 30% to 60% by weight, preferably 40% to 60% by weight, more preferably 50% to 60% by weight, of at least one finely divided sugar alcohol; b) 20% to 35% by weight, preferably 20% to 30% by weight, more preferably 20% to 28% by weight of at least one saturated triglyceride having a melting point of 40°C or higher; c) 20% to 35% by weight, preferably 20% to 30% by weight, more preferably 20% to 28% by weight of at least one saturated triglyceride having a melting point below 0°C, and d) 0.5% to 15% by weight, preferably 1% to 12% by weight, more preferably 2% to 10% by weight of a particulate antibiotic The present invention relates to an active agent delivery system comprising:

[0063] Furthermore, the present invention particularly provides, in each case based on the total weight of the active agent delivery system: a) 30% to 60% by weight, preferably 40% to 60% by weight, more preferably 50% to 60% by weight, of at least one finely divided sugar alcohol; b) 20% to 35% by weight, preferably 20% to 30% by weight, more preferably 20% to 28% by weight of at least one saturated triglyceride having a melting point of 40°C or higher; c) 20% to 35% by weight, preferably 20% to 30% by weight, more preferably 20% to 28% by weight of at least one saturated triglyceride having a melting point below 0°C, and d) 0.5% to 15% by weight, preferably 1% to 12% by weight, more preferably 2% to 10% by weight of a particulate pharmaceutical active agent selected from the group consisting of gentamicin, vancomycin, clindamycin, and daptomycin. The present invention relates to an active agent delivery system comprising:

[0064] The active agent delivery system in paste form according to the invention comprises in particular: a) 30% to 60% by weight, preferably 40% to 60% by weight, more preferably 50% to 60% by weight, of at least one finely divided sugar alcohol selected from the group consisting of D-mannitol, D,L-mannitol, xylitol, and erythritol; b) 20% by weight to 35% by weight, preferably 20% by weight to 30% by weight, more preferably 20% by weight to 28% by weight of at least one saturated triglyceride having a melting point of 40°C or higher and selected from the group consisting of glycerol tripalmitate, glycerol tristearate, and glycerol tribehenate; c) 20% to 35% by weight, preferably 20% to 30% by weight, more preferably 20% to 28% by weight of at least one saturated triglyceride having a melting point below 0°C and selected from the group consisting of glycerol fatty acid mixtures, and d) 0.5% to 15% by weight, preferably 1% to 12% by weight, more preferably 2% to 10% by weight of a particulate pharmaceutical active agent selected from the group consisting of gentamicin, vancomycin, clindamycin, and daptomycin. Includes.

[0065] The active agent delivery system in paste form according to the invention comprises in particular: a) 30% to 60% by weight, preferably 40% to 60% by weight, more preferably 50% to 60% by weight, of at least one finely divided sugar alcohol selected from the group consisting of D-mannitol, D,L-mannitol, xylitol, and erythritol; b) 20% by weight to 35% by weight, preferably 20% by weight to 30% by weight, more preferably 20% by weight to 28% by weight of at least one saturated triglyceride having a melting point of 40°C or higher and selected from the group consisting of glycerol tripalmitate, glycerol tristearate, and glycerol tribehenate; c) 20% to 35% by weight, preferably 20% to 30% by weight, more preferably 20% to 28% by weight of at least one saturated triglyceride having a melting point below 0°C and selected from the group consisting of glycerol fatty acid mixtures Miglyol 812N, Miglyol 810N, and Miglyol 829N, and d) 0.5% to 15% by weight, preferably 1% to 12% by weight, more preferably 2% to 10% by weight of a particulate pharmaceutical active agent selected from the group consisting of gentamicin, vancomycin, clindamycin and daptomycin, each based on the total weight of the active agent delivery system according to the present invention. Includes.

[0066] The active agent delivery system in paste form according to the invention comprises in particular: a) 30% to 60% by weight, preferably 40% to 60% by weight, more preferably 50% to 60% by weight, of at least one finely divided sugar alcohol selected from the group consisting of: b) 20% by weight to 35% by weight, preferably 20% by weight to 30% by weight, more preferably 20% by weight to 28% by weight of at least one saturated triglyceride having a melting point of 40°C or higher and selected from the group consisting of glycerol tripalmitate, glycerol tristearate, and glycerol tribehenate; c) 20% to 35% by weight, preferably 20% to 30% by weight, more preferably 20% to 28% by weight of at least one saturated triglyceride having a melting point below 0°C and selected from the group consisting of glycerol fatty acid mixtures, and d) 0.5% to 15% by weight, preferably 1% to 12% by weight, more preferably 2% to 10% by weight of a particulate pharmaceutical active agent selected from the group consisting of gentamicin, vancomycin, clindamycin, and daptomycin. Includes.

[0067] The active agent delivery system in paste form according to the invention comprises in particular: a) 30% to 60% by weight, preferably 40% to 60% by weight, more preferably 50% to 60% by weight, of at least one finely divided sugar alcohol selected from the group consisting of D-mannitol and D,L-mannitol; b) 20% by weight to 35% by weight, preferably 20% by weight to 30% by weight, more preferably 20% by weight to 28% by weight of at least one saturated triglyceride having a melting point of 40°C or higher and selected from the group consisting of glycerol tripalmitate, glycerol tristearate, and glycerol tribehenate; c) 20% to 35% by weight, preferably 20% to 30% by weight, more preferably 20% to 28% by weight of at least one saturated triglyceride having a melting point below 0°C and selected from the group consisting of glycerol fatty acid mixtures Miglyol 812N, Miglyol 810N, and Miglyol 829N, and d) 0.5% to 15% by weight, preferably 1% to 12% by weight, more preferably 2% to 10% by weight of a particulate pharmaceutical active agent selected from the group consisting of gentamicin, vancomycin, clindamycin and daptomycin, each based on the total weight of the active agent delivery system according to the present invention. Includes.

[0068] Therefore, the present invention preferably provides that 0.5% to 15.0% by weight of at least one solid pharmaceutically active agent, preferably a particulate pharmaceutically active agent, is added to a hemostatic agent in paste form to form an active agent delivery system according to the present invention. This means that when the pharmaceutically active agent is added to a hemostatic agent in paste form, it preferably accounts for 0.5% to 15.0% by weight of the total weight of the active agent delivery system. Therefore, the proportion of the particulate pharmaceutically active agent in the total weight of the active agent delivery system according to the present invention can be at least 0.5% by weight, at least 1.0% by weight, at least 1.5% by weight, at least 2.0% by weight, or at least 2.5% by weight. Furthermore, the proportion of the particulate pharmaceutically active agent in the total weight of the active agent delivery system according to the present invention can reach up to 15% by weight, at most 14% by weight, at most 13% by weight, at most 12% by weight, at most 11% by weight, or at most 10% by weight.

[0069] The active agent delivery system according to the invention preferably contains 1% to 12% by weight, particularly preferably 2% to 10% by weight, of the particulate pharmaceutically active agent.

[0070] The particulate hemostatic agent according to the present invention or the active agent delivery system according to the present invention, together with the respective components described above, is preferably designed to maintain dimensional stability in distilled water at room temperature for at least 7 days under laboratory conditions. This allows it to maintain a desired shape in an environment exposed to the influence of polar liquids. This is the case, for example, when the particulate hemostatic agent according to the present invention or the active agent delivery system according to the present invention is applied to an injured bone to stop any bleeding that may occur.

[0071] An advantage of the present invention is that inorganic calcium salts or magnesium salts do not need to be added to the claimed particulate hemostatic agents or active agent delivery systems. Hemostatic agents known in the prior art often contain these inorganic salts, but typically have the disadvantage that their Mohs hardness is 2 or higher. Due to their high Mohs hardness, they have an abrasive effect on the materials surrounding them. Preferably, since inorganic salts such as calcium salts and magnesium salts do not need to be added to the particulate hemostatic agents or active agent delivery systems according to the present invention, the particulate hemostatic agents or active agent delivery systems according to the present invention do not have abrasive properties and can therefore be used in the field of joint endoprostheses without the sliding surfaces being affected by wear.

[0072] In one embodiment of the present invention, the hemostatic agent according to the present invention and the active agent delivery system according to the present invention do not contain any inorganic calcium salts or magnesium salts. However, in a further embodiment within the context of the present invention, it is still possible to add calcium or magnesium salts having a Mohs hardness of 2.0 or more to the particulate hemostatic agent according to the present invention or the active agent delivery system according to the present invention. In this case, the mass fraction of calcium or magnesium salts having a Mohs hardness of 2.0 or more preferably does not exceed 10.0 wt.%, in each case based on the particulate hemostatic agent according to the present invention or the active agent delivery system according to the present invention. This means that preferably less than 10.0 wt.%, more preferably less than 9.5 wt.%, more preferably less than 9.0 wt.%, more preferably less than 8.5 wt.%, more preferably less than 8.0 wt.%, more preferably less than 7.5 wt.%, more preferably less than 7.0 wt.%, more preferably less than 6.5 wt.%, more preferably less than 6.0 wt.%, more preferably less than 5.5 wt.%, more preferably less than 5.0 wt.%, in each case based on the total weight of the hemostatic agent according to the present invention or the active agent delivery system according to the present invention, of calcium or magnesium salts having a Mohs hardness of 2.0 or more is added.

[0073] In accordance with the above, calcium or magnesium salts having a Mohs hardness of less than 2, i.e. less than 2.0, particularly less than 1.9, particularly less than 1.8, particularly less than 1.7, particularly less than 1.6, particularly less than 1.5, particularly less than 1.4, particularly less than 1.3, particularly less than 1.2, particularly less than 1.1, particularly less than 1.0, particularly less than 0.9, particularly less than 0.8, particularly less than 0.7, particularly less than 0.6, particularly less than 0.5, particularly less than 0.4, particularly less than 0.3, particularly less than 0.2, particularly less than 0.1, may be added to the particulate hemostatic agent according to the invention or to the active agent delivery system according to the invention.

[0074] In summary, the hemostatic agent according to the present invention and the active agent delivery system according to the present invention have the following advantages:

[0075] The hemostatic agent in paste form according to the present invention comprises biodegradable materials that can be combined to form a deformable paste that can be irreversibly forced into a desired shape by the application of force, and the paste is suitable for use in vivo, where, when degraded, it typically does not form acidic or basic degradation products that could cause local damage.

[0076] All kinds of possible particulate pharmaceutically active agents, as mentioned above, can also be added to the hemostatic agent in paste form. In this variant, the resulting active agent delivery system is particularly suitable for the treatment of any kind of bone tissue damage.

[0077] The paste-form hemostatic or active agent delivery system as a whole remains dimensionally stable for extended periods of time after application, even when exposed to a liquid medium. Furthermore, it is preferred that no inorganic particles be added, so as not to have abrasive properties, for example, on metal objects.

[0078] All these properties make it possible to use the paste form of the hemostatic and active agent delivery system according to the invention to treat any kind of injury to bone tissue.

[0079] iii) Use of a paste-type hemostatic agent The paste-form hemostatic agent and active agent delivery system generally adheres to bone tissue and metal surfaces upon application of pressure, allowing the paste-form hemostatic agent to be used to treat damaged bone tissue, for example, by using the paste-form hemostatic agent to stop bleeding from the bone, such as after a fracture, surgery, or even amputation.

[0080] Because the paste-form hemostatic agent typically adheres to metal surfaces, it is particularly suitable for mechanical hemostasis and / or as a paste-form local active agent release system that adheres to bone tissue surfaces and metal implant surfaces by applying pressure. The paste-form local active agent release system typically releases dispersed, particulate pharmaceutically active agents when applied to a bone treatment site. The local active agent release system preferably adheres to the surfaces of knee joint endoprostheses, hip joint endoprostheses, shoulder joint endoprostheses, intramedullary nails, and bone plates, preferably under pressure. A major advantage of the hemostatic agent according to the present invention is that, as a local active agent release system, it typically remains stationary after adhering in vivo. This allows the solid, preferably particulate, pharmaceutically active agent dispersed in the local active agent release system to be specifically released at the desired location.

[0081] Furthermore, according to the present invention, the paste-form hemostatic agent can be used to fill bone cavities, and the paste-form hemostatic agent is particularly preferably used to fill previously infected and debrided medullary cavities and screw holes in bone tissue. In particular, when the paste-form hemostatic agent is applied to an area such as a local active agent center, it can release a microparticulate medicament active agent, which can then, for example, relieve inflammatory symptoms.

[0082] The paste-form hemostatic agent according to the present invention is particularly used for mechanically stopping bone bleeding in vivo. When a particulate pharmaceutically active agent is added to the paste-form hemostatic agent according to the present invention, it can also function as a paste-form local active agent delivery system at the site treated with it, whereby it can continuously release the pharmaceutically active agent dispersed therein over a certain period of time.

[0083] The present invention therefore further relates to a hemostatic agent in paste form as described above or an active agent delivery system in paste form as described above for use as a medicament, in particular for use in the treatment of damaged bone tissue.

[0084] The hemostatic agent in paste form or the active agent delivery system in paste form can be used to treat bone cavities by filling, preferably by filling infected and debrided medullary cavities and screw holes.

[0085] For this purpose, the paste-form hemostatic agent or paste-form active agent release system can be adhered to the surface of bone tissue and the surface of metal implants by applying pressure, where the paste-form hemostatic agent or paste-form active agent release system preferably adheres to the surfaces of knee joint endoprostheses, hip joint endoprostheses, shoulder joint endoprostheses, intramedullary nails and bone fixation plates.

[0086] The paste-form hemostatic agent can be administered to a patient manually or using a dispensing device. The triglycerides contained therein allow for good lubrication and compressibility of the hemostatic agent, for example, in syringes and similar squeeze-administration systems.

[0087] The compositions described herein can also be used to coat medical implants such as spacers, artificial joints and bone plates, etc. For this purpose, the compositions according to the invention can be provided, for example, as an application pen or syringe system.

[0088] iv) Method for preparing a hemostatic and active agent delivery system in paste form According to the present invention, the hemostatic and active agent delivery system in paste form is prepared by mixing all of the components.

[0089] This means that at least one particulate sugar alcohol a), at least one saturated triglyceride b) having a melting point above 40°C, at least one saturated triglyceride c) having a melting point below 0°C, and optionally a particulate pharmaceutically active agent are placed in a suitable container, such as a beaker or industrial mixing vessel, and mixed.

[0090] Preferably, 30% to 60% by weight of a particulate sugar alcohol, 20% to 35% by weight of a saturated triglyceride having a melting point of 40°C or higher, 20% to 35% by weight of a saturated triglyceride having a melting point of less than 0°C, and optionally 0.5 to 15% by weight of a particulate pharmaceutically active agent are measured out.

[0091] The preferred proportions of the individual components have already been disclosed above and apply mutatis mutandis to the process according to the invention.

[0092] In the context of the present invention, it may be advantageous to first heat and pre-mix the weighed components a), b), c) and optionally d) at a slower speed. Heating is generally carried out at a temperature above the melting temperature of saturated triglycerides, which have a melting point of 40° C. or higher. Preferably, the temperature is not so high that the chemical properties of the components used may be altered. For example, the temperature is between 50°C and 90°C, i.e. in particular 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C or 60°C, 61°C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C, 68°C, 69°C or 70°C, 71°C, 72°C, 73°C, 74°C, 75°C, 76°C, 77°C, 78°C, 79°C or 80°C, 81°C, 82°C, 83°C, 84°C, 85°C, 86°C, 87°C, 88°C, 89°C or 90°C.

[0093] The pre-mixed mixture is then typically cooled and mixed at least once using a suitable mixer or stirrer at high speed. -1 and 3000 minutes -1 Speeds between 1500 and 1500 min can be contemplated - for example, -1 , 1600 minutes -1 , 1700 minutes -1, 1800 minutes -1 , 1900 minutes -1 , 2000 minutes -1 , 2100 minutes -1 , 2200 minutes -1 , 2300 minutes -1 , 2400 minutes -1 , 2500 minutes -1 , 2600 minutes -1 , 2700 minutes -1 , 2800 minutes -1 , 2900 minutes -1 or 3000 minutes -1 In principle, as indicated, any mixer capable of achieving high stirring speeds is suitable. For the purposes of the present invention, the stirring step can be carried out once at high speed or may be repeated several times.

[0094] In the context of the present invention, it is possible to add a particulate pharmaceutically active agent to a paste-form hemostatic agent for subsequent use as a paste-form topical active agent delivery system. In such cases, the particulate pharmaceutically active agent can be initially weighed out together with the other components a), b) and c).

[0095] The method according to the invention for producing a hemostatic agent in paste form, to be used as a topical active agent delivery system in paste form, is characterized in that at least one pharmaceutically active agent present in solid state, preferably in particulate form, is mixed with the hemostatic agent in paste form by kneading. [Brief explanation of the drawings]

[0096] [Figure 1] A paste-type hemostatic agent prepared after mixing all components. It is malleable by hand. [Figure 2] A hemostat in paste form pressed onto the metal surface of a spatula. It is clear that the hemostat in paste form adheres to the metal surface.

[0097] Illustrative Embodiments For the exemplary embodiment, pharmaceutical grade Lytrol Micro, Poloxamer 185, glycerol tripalmitate, glycerol tristearate, glycerol tribehenate, Miglyol 812N and Miglyol 810N were used.

[0098] The paste was prepared in a simple manner: first, all ingredients were weighed into a beaker. Then, the mixture was heated to 90°C for 1 hour with occasional stirring. After cooling, the mixture was transferred to a plastic container and mixed using a speed mixer at 2000 rpm for 60 seconds each. The mixing method was then repeated twice. A mass in the form of a colorless paste was formed.

[0099] [Table 1]

[0100] [Table 2]

[0101] [Table 3]

[0102] [Table 4]

[0103] The CSCA mixture consisted of 80.0 wt% calcium sulfate dihydrate and 20.0 wt% calcium carbonate.

[0104] In vitro cytotoxicity testing according to ISO10993-5 The pastes of Examples 1, 2, and 12 were tested for their in vitro cytotoxicity. Additionally, poloxamer 185 was included in the test.

[0105] In vitro cytotoxicity determination according to ISO 10993-5 was performed using the MTT test by Eurofins BioPharma Product Testing Munich GmbH. The paste was eluted in cell culture medium for 72 hours at 37°C. The eluate was then incubated undiluted and in three dilutions with L929 cells for 24 hours at 37°C. Cell vitality was then determined photometrically using tetrazolium chloride, which is reduced by viable cells to the red-purple dye 1,3,5-triphenylformazan. In the paste of Example 12, a similarly structured dye, triphenyltetrazolium chloride (XTT test), was used instead of tetrazolium chloride, which is also reduced by viable cells to the red-purple dye. This dye is also used in ISO 10993-5 to test the in vitro cytotoxicity described.

[0106] [Table 5]

[0107] According to ISO 10993-5, a sample is considered non-cytotoxic if it has a viability of more than 70% at 100% v / v in the MTT or XTT test. The pastes according to the invention of Examples 1 and 2 were evaluated as non-cytotoxic according to the MTT test with viabilities of 73% and 72%. The paste of Example 12 containing Poloxamer 185 was clearly cytotoxic with a viability of less than 70%.

[0108] The in vitro cytotoxicity of the pastes of Examples 1 and 2 was then further tested by agar diffusion test according to ISO 109992-5 using L929 cells. Both pastes showed no cytotoxic effect.

[0109] Assessment of antibiotic compatibility In the following, the incorporation of antibiotics into the paste material according to the invention of Example 1 was tested. The powdered antibiotics gentamicin hydrochloride, vancomycin hydrochloride, clindamycin hydrochloride, and daptomycin were used. In each case, 5.0 g of the paste from Example 1 was kneaded with 0.5 g of the powdered antibiotic. The tactile properties and adhesion to a steel surface (1.4404 steel) were tested. It was found that the kneaded antibiotics had only a slight effect on flexibility and kneadability compared to the pure paste of Example 1. The kneadability was similar to that of the paste of Example 2. All pastes adhered very well to the 1.4404 steel. The adhesion was similar to that of the paste of Example 2.

[0110] [Table 6]

[0111] Adhesion testing to metal surfaces in the presence of water The paste was tested on a metal surface (1.4404 steel). For this purpose, approximately 2 g of the example sample was pressed onto the surface of a spatula. The paste adhered to the metal surface. The paste adhered to the metal was stored in water at room temperature for 7 days. No dissolution occurred. The pH value of the distilled water was in the range of pH 6.0 to 6.8.

Claims

1. a) at least one particulate sugar alcohol; b) at least one saturated triglyceride having a melting point of 40°C or higher, and c) at least one saturated triglyceride having a melting point below 0°C A hemostatic agent in paste form comprising:

2. in each case based on the total weight of the hemostatic agent, a) 30% to 60% by weight of at least one particulate sugar alcohol; b) 20% to 35% by weight of at least one saturated triglyceride having a melting point of 40° C. or higher, and c) 20% to 35% by weight of at least one saturated triglyceride having a melting point below 0°C The hemostatic agent in paste form according to claim 1 , comprising:

3. 2. The hemostatic agent in paste form according to claim 1, characterized in that it has a viability of more than 70% at 100% v / v in the MTT or XTT in vitro cytotoxicity test according to the ISO 10993-5 standard.

4. 2. The hemostatic agent in paste form according to claim 1, wherein the particulate sugar alcohol is selected from alditols and ketols.

5. 2. The hemostatic agent in paste form according to claim 1, characterized in that the saturated triglyceride having a melting point of 40°C or higher is selected from glycerol tristearate, glycerol tripalmitate, glycerol trilaurate, and mixed triglycerides formed from stearate and / or palmitate and / or laurate and glycerol.

6. 2. The hemostatic agent in paste form according to claim 1, characterized in that the saturated triglyceride having a melting point below 0°C is selected from glycerol trioctanoate, glycerol tridecanoate or the glycerol fatty acid mixtures Miglyol 812N, Miglyol 810N and Miglyol 829N.

7. 2. The hemostatic agent in paste form according to claim 1, wherein the particulate sugar alcohol has a particle size of less than 100 μm, the particle size being determined by sieve fractionation.

8. 10. The hemostatic agent in paste form according to claim 1, wherein the hemostatic agent maintains dimensional stability in distilled water at room temperature for 7 days.

9. 10. An active agent release system in paste form comprising the hemostatic agent in paste form according to claim 1 and at least one pharmaceutically active agent, preferably in particulate form, wherein the pharmaceutically active agent is preferably selected from anti-infective agents, blood coagulation activators, fibrinolytic system inhibitors, immunomodulators, steroid hormones and growth factors.

10. A hemostatic agent in paste form according to claim 1 or an active agent delivery system in paste form according to claim 9 for use as a medicament.

11. A hemostatic agent in paste form according to claim 1 or an active agent delivery system in paste form according to claim 9 for use in the treatment of damaged bone tissue.

12. 11. A hemostatic agent in paste form or an active agent releasing system in paste form according to claim 10 for use in the treatment of bone cavities by filling, preferably by filling infected and debrided medullary cavities and screw holes in bone tissue.

13. 11. A hemostatic agent in paste form or an active agent releasing system in paste form according to claim 10, characterized in that it adheres to the surface of bone tissue and the surface of metal implants by applying pressure, preferably to the surfaces of knee joint endoprostheses, hip joint endoprostheses, shoulder joint endoprostheses, intramedullary nails and bone fusion plates.

14. 2. A method for producing the paste-form hemostatic agent according to claim 1, characterized in that at least one particulate sugar alcohol, at least one saturated triglyceride having a melting point of 40°C or higher, and at least one saturated triglyceride having a melting point of less than 0°C are placed in a mixing vessel and kneaded together.

15. 15. The method of claim 14, wherein at least one particulate pharmaceutically active agent is mixed with the hemostatic agent.

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