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

Abstract

A hemostatic in the form of a paste is presented. The hemostatic comprises a) at least one particulate sugar alcohol; b) at least one saturated triglyceride having a melting point greater than or equal to 40 DEG C; and c) at least one saturated triglyceride having a melting point below 0 DEG C. Furthermore, the use of the hemostatic agent in the form of the paste and a method for the preparation thereof are described.

Description

[0001] introduction

[0002] This invention relates to hemostatic agents in paste form, which can be used for mechanical sealing of bleeding bone tissue. Another object of the invention is an active agent release system based on the hemostatic agent in paste form. The invention also relates to the use of the hemostatic agent and the active agent release system according to the invention, and to methods for producing the hemostatic agent and the active agent release system according to the invention. Background Technology

[0003] During surgery, depending on the anatomical conditions, different methods are used to stop bleeding (hemostasis), such as electrocoagulation (cauterization) of blood vessels. In many surgeries in the skull region, and especially on the sternum, bone wax is used to seal capillaries to stop bleeding in the event of severe bleeding, due to the anatomical situation. For this purpose, the surgeon applies malleable bone wax directly onto or into the bleeding area of ​​bone. This causes obstruction of blood flow, leading to the aggregation of clotting cells; and the supplying vessels are eventually blocked by platelet aggregation and fibrin.

[0004] Bone wax has been known since at least the 19th century and typically contains bleached beeswax and plasticizers. Almond oil, petrolatum, palmitic acid, isopropyl myristate, and other plasticizers used are among the plasticizers employed. Beeswax-based bone wax is considered non-biodegradable in the human body. Due to the chemical composition of the beeswax used, bone wax is not broken down by human enzymes. Therefore, bone wax remains in or on bone tissue after hemostasis and forms a barrier to new bone growth.

[0005] The hemostatic effect of bone waxes is due to their good adhesion to moist and fatty bone tissues, as well as their high toughness. Currently available bone waxes exhibit very good hemostatic properties.

[0006] However, over a longer period of time, undesirable side effects and consequences have often occurred in human organisms (SE. Katz, J. Rotmann: Adverse effects of bone wax in surgery of the orbit. OphthalPlast. 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 acause of foreignbody reaction alter lumbar disc surgery: A case report. Adv. Ther. 2007, 24(3) 594-7).

[0007] Alternatives to conventionally formulated bone waxes are known.

[0008] EP 0 109 310 A discloses waxy aggregates based on fatty acid calcium salts and hydroxycarboxylic acid oligomers.

[0009] Documents US 4,595,713 A, DE 322 95 40 A, DE 382 52 11 A, and EP 1 142 597 A disclose wax compositions containing low-polyesters of hydroxycarboxylic acids (such as lactic acid and 6-hydroxycarboxylic acid). It has been shown that when using these wax compositions, acidic degradation products are formed during hydrolytic degradation, which can affect bone tissue due to a decrease in local pH.

[0010] Alternatives include polyether-based compositions (US 2009 / 286886 A and US 2011 / 002974 A). For example, polypropylene glycol / ethylene glycol copolymers can be used as polyethers. These compositions become kneadable and spreadable when the hands are warm. However, the good solubility of these polyethers in aqueous media is a disadvantage. This means that in cases of severe bleeding in bone tissue, adhesion of these compositions may be difficult due to the dissolution of the waxy composition. This can lead to subsequent bleeding, which in turn can lead to rapid separation or dissolution of the seal. However, the advantage of these mixtures is that they do not act as a barrier to 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).

[0011] Patents DE 10 2011 016277B and DE 10 2011 122 752 B describe a hemostatic agent in paste form. The hemostatic agent comprises: (a) at least one saturated glycerol-1,2,3-triglyceride ester having a melting temperature above 37°C; (b) at least one filler having a melting temperature above 37°C, at least partially present in particulate form; and (c) at least one compound having a melting temperature not higher than 37°C, the compound having a solubility of less than 50 g / L in water at 25°C. Polymers of at least one epoxide and copolymers of at least one epoxide and a calcium compound are proposed as fillers. The described calcium compounds 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 (poloxam) are preferably used as polymers. Liquid fatty acid esters constitute the third component. Our own in vitro cytotoxicity studies, according to the updated ISO 1993-5, indicate that the hemostatic agents according to patent specifications DE 10 2011 016 277 B and DE 10 2011 122 752B are non-cytotoxic according to ISO 10993-5. These hemostatic agents consist of solid triglycerides, liquid triglycerides, and fillers of calcium carbonate and calcium sulfate. In contrast, hemostatic agents with similar compositions but using polypropylene glycol / polyethylene glycol copolymers (poloxam) instead of inorganic calcium salts as fillers are significantly cytotoxic. Calcium compounds are also disadvantageous due to their abrasive properties.

[0012] Therefore, there is a need for hemostatic agents that are malleable and biodegradable, and which generally do not have the aforementioned disadvantages.

[0013] In particular, hemostatic agents in paste form, consisting entirely of non-abrasive organic biocompatible substances, are required. If the hemostatic agent is used near an intra-articular prosthesis, the abrasive component is especially critical because abrasive particles can cause abrasive damage to the sliding surfaces if they enter between the joint moving surfaces of the intra-articular prosthesis. Technical Field

[0014] The object of this invention is to develop a hemostatic agent in paste form, preferably composed of biocompatible and absorbable materials, and free from in vitro cytotoxicity according to ISO 10993-5. In this context, it is also particularly preferred that the hemostatic agent in paste form according to the invention does not possess amphiphilic properties. Amphiphilic substances penetrate both the hydrophilic and lipophilic components of cells, and thus weaken the cell membrane. This means they can increase cytotoxicity. It is also intended to be free of any abrasive inorganic calcium salts. Furthermore, the hemostatic agent to be developed should not contain any components that can be used as an energy source by microorganisms. In addition, the hemostatic agent should not release large amounts of any acidic or basic components to avoid damage to bone tissue due to non-physiological pH. Furthermore, the material should be biodegradable or renally excretable so that the permanent barrier effect of the material does not hinder bone tissue healing methods. The hemostatic agent should be easily spread by hand. Furthermore, the paste-form material should not stick to rubber gloves during kneading and application. It is intended to adhere to moist bone tissue and also to the surface of metal implants. Furthermore, the hemostatic agent should be able to be mixed with any powdered pharmaceutical active agent without significantly impairing its adhesive properties and plasticity. The viscosity of the hemostatic agent should be high enough that the paste-like material can withstand bleeding pressure. Additionally, the hemostatic agent should possess sufficient cohesive strength so that it does not decompose or dissolve within minutes upon contact with blood or other aqueous fluids.

[0015] The objective of this invention is achieved primarily through the hemostatic agent according to the invention. Summary of the Invention

[0016] This invention initially relates to hemostatic agents in paste form. The hemostatic agent is characterized by the fact that it contains...

[0017] a) at least one granular sugar alcohol;

[0018] b) at least one saturated triglyceride having a melting point greater than or equal to 40°C; and

[0019] c) At least one saturated triglyceride having a melting point below 0°C.

[0020] The components of the hemostatic agent according to the present invention are described below.

[0021] In a preferred embodiment, in each case the hemostatic agent comprises, based on the total weight of the hemostatic agent according to the invention, [amount missing].

[0022] a) at least one particulate sugar alcohol, 30%-60% by weight, preferably 40%-60% by weight, more preferably 50%-60% by weight.

[0023] b) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight of at least one saturated triglyceride having a melting point greater than or equal to 40°C, and

[0024] c) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight of at least one saturated triglyceride having a melting point below 0°C.

[0025] The hemostatic agent according to the invention has, for example, the following advantages.

[0026] The hemostatic agent in paste form according to the invention is preferably non-cytotoxic according to ISO 10993-5, as determined by the MTT test ((3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazole bromide) test) or by the XTT test (((3'-[1-(aniline carbonyl)-3,4-tetrazole]-bis-(4-methoxy-6-nitro))-benzenesulfonate sodium hydrate) test).

[0027] The hemostatic agent in paste form according to the invention is characterized by its plasticity, biodegradability, and resistance to liquids (especially aqueous environments). It maintains dimensional and volume stability in the absence of external forces, particularly in the absence of external forces. Nevertheless, the hemostatic agent is biodegradable as described herein.

[0028] The hemostatic agent in paste form according to the invention is suitable for treating damaged bone tissue and can be used both for mechanical hemostasis and as a local active agent release center in paste form. The hemostatic agent according to the invention generally adheres equally to bone, glass, and metal.

[0029] Furthermore, a solid or preferably particulate pharmaceutical active agent can be added to the hemostatic agent according to the invention. In this embodiment, when used to treat bone tissue injury, the hemostatic agent can be used as a local active agent release center in paste form.

[0030] The hemostatic agents in paste form according to the invention can generally be obtained by simply kneading their components in a laboratory or industrial scale. Detailed Implementation

[0031] i) Hemostatic agents in paste form

[0032] According to the present invention, a hemostatic agent is provided.

[0033] According to the present invention, hemostatic agents should be understood to mean compositions having hemostatic properties.

[0034] This invention is based on the surprising discovery that a mixture of components a), b), and c) as defined above forms a hemostatic agent in the form of a paste, which can be used to seal bleeding bone tissue. Particularly surprising is that the hemostatic agent according to the invention exists as a waxy, kneadable mass that typically adheres to both dry and wet surfaces. The hemostatic agent adheres particularly well to metal surfaces, glass, and bone tissue. The toughness and mechanical stability of the mixture are surprisingly high enough to function as an effective hemostatic agent to stop bleeding and withstand the bleeding pressure encountered during injury. Although the mixture is generally biodegradable, it surprisingly exhibits such great mechanical stability that it does not decompose upon contact with water or aqueous solutions such as blood.

[0035] In the context of this invention, substances that can be broken down by human organisms and / or excreted by the kidneys are referred to as biodegradable.

[0036] The hemostatic agent according to the present invention contains at least one sugar alcohol.

[0037] Sugar alcohols (such as mannitol) generally do not affect insulin levels in patients treated with the hemostatic agents according to the invention. The sugar alcohols in the hemostatic agents according to the invention also have a surprising effect on the consistency of their paste form. Unbound by any theory, during the manufacturing process of the hemostatic agents in the paste form according to the invention, they reduce the crystal growth of other possible components by wetting the formed microcrystalline surfaces and thus making them inaccessible to other crystal-forming molecules. Therefore, the microcrystals remain small, and the hemostatic agents in the paste form do not form lumps but remain in the paste form according to the invention, which has a uniform consistency. According to the invention, it is assumed that the sugar alcohols will be excreted from the human body via the kidneys without degradation and without causing any harm. Furthermore, they have a particularly positive effect on the properties of the hemostatic agents in the paste form and are therefore a surprisingly useful component of the hemostatic agents in the paste form according to the invention.

[0038] The hemostatic agent according to the invention comprises triglycerides as an additional component. In the context of this invention, triglycerides are understood to be organic compounds that are cleaved by lipases into glycerol and fatty acids. As a natural component of human organisms, glycerol is typically broken down into carbon dioxide and water via the pyruvate and citric acid cycles. Fatty acids are also natural components of human organisms, and in the case of fatty acids having an even number of carbon atoms, they are typically completely broken down into carbon dioxide and water via β-oxidation.

[0039] Further definitions of the components of the hemostatic agent according to the present invention are provided below.

[0040] The hemostatic agent according to the invention is plastically deformable. In this context, plasticity should be understood as the ability of the hemostatic agent to deform irreversibly when force is applied and to retain that shape after the force is applied.

[0041] Another advantage of the hemostatic agent in paste form according to the invention is that it generally does not have cytotoxic properties. In the context of the invention, this is preferably achieved by using only those substances or mixtures of substances that have in vitro cytotoxicity according to ISO 10993-5 in the hemostatic agent according to the invention, which have an activity greater than 70% at 100% v / v in either the MTT test ((3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazole bromide) test) or the XTT test (((3'-[1-(aniline carbonyl)-3,4-tetrazole]-bis-(4-methoxy-6-nitro))-sodium benzenesulfonate hydrate) test). This means that, in the MTT or XTT test according to ISO 10993-5, the activity of the hemostatic agent in paste form according to the invention at 100% v / v is preferably greater than 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%, 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%. Preferably, at 100% v / v, the activity is at least between 70.0% and 80.0%.

[0042] ii) Composition of hemostatic agents in paste form

[0043] The hemostatic agent in paste form contains at least one granular sugar alcohol.

[0044] In the context of this invention, sugar alcohols should be understood to mean noncyclic polyols having a hydroxyl group bonded to each carbon atom of its carbon atoms. Suitable sugar alcohols according to the invention are generally obtained as reduction products of carbohydrates (sugars), i.e., obtained by the reduction (hydrogenation) of the ketone or aldehyde groups of the sugar. Therefore, sugar alcohols are generally more oxidatively and storagely stable than the parent sugars. Furthermore, they generally have little or no effect on blood glucose concentrations in human organisms and cannot or can only be used as an energy source for many microorganisms.

[0045] In the context of this invention, the particulate sugar alcohols are preferably aldehydes and ketols, particularly preferably D-mannitol (CAS 69-65-8), D,L-mannitol (CAS 87-78-5), D-sorbitol (CAS 50-70-4), isomaltitol (6-OaD-glucopyranosyl-D-glucol) (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. In the context of this invention, D-mannitol and D,L-mannitol are particularly preferred.

[0046] Experiments using different sugar alcohols according to the present invention have shown that D-mannitol is particularly suitable in the context of the present invention in terms of tactile properties and in terms of in vitro cytotoxicity according to ISO 10993-5. D-mannitol also has no effect on blood glucose levels and is blood-compatible.

[0047] Sugar alcohols generally do not contain any acidic or basic groups. Therefore, when they are dissolved in aqueous solutions or water, or when they come into contact with aqueous solutions or water, they have little effect on the pH of the aqueous solutions or water. Experiments have shown that the pH of distilled water in which the hemostatic agent of the present invention in paste form is introduced is in the range of pH 6.0-6.8.

[0048] For the purposes of this invention, the sugar alcohol as component a) is preferably present in the form of particulate sugar alcohol. This means that the particulate sugar alcohol is preferably in the form of solid particles, characterized by having a particle size preferably less than 100 μm. Therefore, the particle size of at least one particulate sugar alcohol is preferably less than 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, etc. The particle sizes are 76μm, 75μm, 74μm, 73μm, 72μm, 71μm, 70μm, 69μm, 68μm, 67μm, 66μm, 65μm, and 64μm, specifically 63μm, 62μm, 61μm, 60μm, 59μm, 58μm, 57μm, 56μm, 55μm, 54μm, 53μm, 52μm, 51μm, or 50μm. In this invention, the particle size is determined by sieving and grading.

[0049] The smaller the particle size of sugar alcohols, the smoother the paste produced from them.

[0050] In the context of this invention, another component of the hemostatic agent in paste form is a saturated triglyceride having a melting point greater than or equal to 40°C, as component b). Such saturated triglycerides are typically solid at room temperature. Furthermore, their melting points are above the normal human body temperature of about 36°C to 38°C, making them possible components of the hemostatic agent according to the invention, which is also solid under in vivo conditions.

[0051] In the context of this invention, particularly suitable saturated triglycerides having a melting point greater than or equal to 40°C are glyceryl tristearate (CAS 55-43-1), glyceryl tripalmitate (CAS 555-44-2), glyceryl 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 having a melting point greater than or equal to 40°C are also contemplated, and which achieve the aforementioned preferred properties of the hemostatic agent according to the invention in terms of surface adhesion, deformability, toughness, and biodegradability. These saturated fatty acid esters having a melting point greater than or equal to 40°C are preferred for adhesion of the hemostatic agent to bone tissue and to metal surfaces. Furthermore, these saturated fatty acid esters generally have high storage stability and high resistance to gamma radiation because they do not contain double bonds or other oxidation-sensitive structures. Therefore, the granular hemostatic agent according to the invention is particularly suitable for treating bone injuries or surgical damage. Any X-rays after treatment with the granular hemostatic agent of the invention generally do not damage the area treated with the granular hemostatic agent. In particular, the hemostatic agent according to the invention can also be used to treat bone injuries in patients who subsequently require radiation therapy. Radiation preferably does not affect the granular hemostatic agent according to the invention.

[0052] In the context of this invention, an additional component of the hemostatic agent in paste form is a saturated triglyceride having a melting point below 0°C, which is component c). Such saturated triglycerides are liquid at room temperature, i.e., between 20°C and 30°C.

[0053] In the context of this invention, particularly suitable saturated triglycerides having melting points below 0°C are tricaprylate (CAS 538-23-8) and tridecanoate (CAS 612-71-6), wherein mixtures of glycerol fatty acids are particularly preferred, and mixtures of glycerol fatty acids Miglyol 812N (CAS 73398-61-5), Miglyol 810N (CAS 73398-61-5), and Miglyol 829N (CAS 91744-56-8) are very particularly preferred. These liquid fatty acid esters also do not contain double bonds or other oxidation-sensitive structures, and are therefore generally stable in storage and largely resistant to gamma radiation. It is particularly advantageous to use triglycerides whose fatty acid moiety has an even number of carbon atoms. If an even number of carbon atoms are present, the fatty acids are completely metabolized into carbon dioxide and water in human organisms.

[0054] According to the present invention, preferably, different components a) (particulate sugar alcohol), b) (saturated glycerol fatty acid esters having a melting point greater than or equal to 40°C), and c) (saturated glycerol fatty acid esters having a melting point below 0°C) are each present in a certain proportion in the hemostatic agent according to the present invention. According to the present invention, the proportions of the components in the paste-form hemostatic agent can be varied according to the selected substance and the intended application of the paste-form hemostatic agent.

[0055] For the purposes of this invention, it has been shown that component a) preferably accounts for 30% to 60% by weight of the total mass of the hemostatic agent in paste form. This means that, regardless of other components, the granular sugar alcohol in each case accounts for a proportion of preferably at least 30% by weight, typically at least 31% by weight, typically at least 32% by weight, typically at least 33% by weight, typically at least 34% by weight, typically at least 35% by weight, typically at least 36% by weight, typically at least 37% by weight, typically at least 38% by weight, typically at least 39% by weight, typically at least 40% by weight, typically at least 41% by weight, typically at least 42% by weight, typically at least 43% by weight, typically at least 44% by weight, typically at least 45% by weight, typically at least 46% by weight, typically at least 47% by weight, typically at least 48% by weight, typically at least 49% by weight, typically at least 50% by weight. Furthermore, this means that the granular sugar alcohol, independently of other components, is present in each case in a proportion based on the total mass of the hemostatic agent according to the invention, preferably up to 60% by weight, typically up to 59% by weight, typically up to 58% by weight, typically up to 57% by weight, typically up to 56% by weight, typically up to 55% by weight, typically up to 54% by weight, typically up to 53% by weight, typically up to 52% by weight, typically up to 51% by weight, or typically up to 50% by weight. Particularly preferred is that component a), i.e., the granular sugar alcohol, is present in each case in a range of 40% by weight to 60% by weight, or even more preferably 50% by weight to 60% by weight, based on the total mass of the hemostatic agent according to the invention.

[0056] For the purposes of this invention, it has been shown that components b) and c) preferably each constitute 20% to 35% by weight of the total mass of the hemostatic agent in paste form.

[0057] This means that saturated triglycerides having a melting point greater than or equal to 40°C, independently of other components, constitute a proportion in each case based on the total mass of the hemostatic agent according to the invention preferably at least 20% by weight, typically at least 21% by weight, typically at least 22% by weight, typically at least 23% by weight, typically at least 24% by weight, typically at least 25% by weight, typically at least 26% by weight, typically at least 27% by weight, typically at least 28% by weight, typically at least 29% by weight, and typically at least 30% by weight. Furthermore, this means that saturated triglycerides having a melting point greater than or equal to 40°C, independently of other components, constitute a proportion in each case based on the total mass of the hemostatic agent according to the invention preferably at most 35% by weight, typically at most 34% by weight, typically at most 33% by weight, typically at most 32% by weight, typically at most 31% by weight, and typically at most 30% by weight.

[0058] This also means that saturated triglycerides having a melting point below 0°C, independently of other components, constitute a proportion in each case based on the total mass of the hemostatic agent according to the invention preferably at least 20% by weight, typically at least 21% by weight, typically at least 22% by weight, typically at least 23% by weight, typically at least 24% by weight, typically at least 25% by weight, typically at least 26% by weight, typically at least 27% by weight, typically at least 28% by weight, typically at least 29% by weight, and typically at least 30% by weight. Furthermore, this means that saturated triglycerides having a melting point below 0°C, independently of other components, constitute a proportion in each case based on the total mass of the hemostatic agent according to the invention preferably at most 35% by weight, typically at most 34% by weight, typically at most 33% by weight, typically at most 32% by weight, typically at most 31% by weight, and typically at most 30% by weight.

[0059] Based on the total weight of the hemostatic agent in paste form according to the invention, the hemostatic agent in paste form specifically comprises:

[0060] a) 30%-60% by weight, preferably 40%-60% by weight, more preferably 50%-60% by weight, of at least one particulate sugar alcohol selected from the group consisting of D-mannitol, D,L-mannitol, xylitol and erythritol;

[0061] b) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight of at least one saturated triglyceride having a melting point greater than or equal to 40°C, selected from the group consisting of glyceryl tripalmitate, glyceryl tristearate and glyceryl trishenate.

[0062] c) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight, of at least one saturated triglyceride having a melting point below 0°C, selected from the group consisting of mixtures of glycerol fatty acids.

[0063] Based on the total weight of the hemostatic agent in paste form according to the invention, the hemostatic agent in paste form specifically comprises:

[0064] d) 30%-60% by weight, preferably 40%-60% by weight, more preferably 50%-60% by weight, of at least one particulate sugar alcohol selected from the group consisting of D-mannitol, D,L-mannitol, xylitol and erythritol;

[0065] e) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight of at least one saturated triglyceride having a melting point greater than or equal to 40°C, selected from the group consisting of glyceryl tripalmitate, glyceryl tristearate and glyceryl trishenate.

[0066] f) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight, of at least one saturated triglyceride having a melting point below 0°C, selected from a mixture of glycerol fatty acids Miglyol 812N, Miglyol 810N, and Miglyol

[0067] A group consisting of 829N.

[0068] Based on the total weight of the hemostatic agent in paste form according to the invention, the hemostatic agent in paste form specifically comprises:

[0069] a) 30%-60% by weight, preferably 40%-60% by weight, more preferably 50%-60% by weight of at least one particulate sugar alcohol, selected from the group consisting of D-mannitol and D,L-mannitol;

[0070] b) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight, of at least one saturated triglyceride having a melting point greater than or equal to 40°C, selected from the group consisting of triglyceride tripalmitate, tristearate, and trisorheic ester; and

[0071] c) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight, of at least one saturated triglyceride having a melting point below 0°C, selected from the group consisting of mixtures of glycerol fatty acids.

[0072] Based on the total weight of the hemostatic agent in paste form according to the invention, the hemostatic agent in paste form specifically comprises:

[0073] a) 30%-60% by weight, preferably 40%-60% by weight, more preferably 50%-60% by weight of at least one particulate sugar alcohol, selected from the group consisting of D-mannitol and D,L-mannitol;

[0074] b) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight, of at least one saturated triglyceride having a melting point greater than or equal to 40°C, selected from the group consisting of triglyceride tripalmitate, tristearate, and trisorheic ester; and

[0075] c) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight, of at least one saturated triglyceride having a melting point below 0°C, selected from a mixture of glycerol fatty acids Miglyol 812N, Miglyol 810N, and Miglyol

[0076] A group consisting of 829N.

[0077] The hemostatic agent in paste form according to the invention is particularly useful in vivo for treating all conceivable types of external injuries to bone structures.

[0078] For this purpose, in the context of this invention, in addition to the aforementioned components a), b), and c), adding at least one solid, preferably particulate, pharmaceutical active agent to a hemostatic agent in paste form may be particularly advantageous. The solid or particulate pharmaceutical active agent can be dispersed in the hemostatic agent in paste form without altering its chemical form. In this way, the active agent can be released locally, preferably over a longer period of time, and can exert all possible healing effects (sustained release) on the surrounding potentially damaged bone tissue. If the hemostatic agent according to the invention contains an active agent, an active agent delivery system according to the invention is created. The active agent can be added during the manufacture of the hemostatic agent or can be added by a healthcare professional just before administration to a patient.

[0079] Therefore, the present invention also relates to an surfactant release system, the surfactant release system comprising

[0080] a) at least one granular sugar alcohol;

[0081] b) at least one saturated triglyceride having a melting point greater than or equal to 40°C; and

[0082] c) at least one saturated triglyceride having a melting point below 0°C; and

[0083] d) Particulate pharmaceutical active agents.

[0084] In a preferred embodiment, in each case, the surfactant release system comprises, based on the total weight of the surfactant release system according to the invention,

[0085] a) at least one particulate sugar alcohol, 30%-60% by weight, preferably 40%-60% by weight, more preferably 50%-60% by weight;

[0086] b) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight of at least one saturated triglyceride having a melting point greater than or equal to 40°C;

[0087] c) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight of at least one saturated triglyceride having a melting point below 0°C; and

[0088] d) 0.5%-15% by weight, preferably 1%-12% by weight, more preferably 2%-10% by weight of particulate pharmaceutical active agent.

[0089] In principle, any pharmaceutically active agent is suitable for this purpose. According to the invention, anti-infectives, coagulation activators, fibrinolysis inhibitors, immunomodulators, steroid hormones, and growth factors are particularly preferred. Especially preferred are gentamicin (CAS1403-66-3), vancomycin (CAS1404-90-6), tobramycin (CAS 32986-56-4), clindamycin (CAS18323-44-9), colistin (CAS1066-17-7), meropenem (CAS 96036-03-29), metronidazole (CAS 443-48-1), caspofungin (CAS162808-62-0), fluconazole (CAS 86386-73-4), amphotericin B (CAS1397-89-3), calcium gluconate (CAS299-28-5), tranexamic acid (CAS11197-18-8), 6-aminohexanoic acid (CAS 60-32-2), p-aminomethylbenzoic acid (CAS150-13-0), and prednisolone (CAS 1403-66-3). 50-24-8), dexamethasone (CAS 50-02-2), and cyclosporine A (CAS 79217-60-0).

[0090] Therefore, the present invention particularly relates to an active agent release system, which, in each case, comprises based on the total weight of the active agent release system:

[0091] a) at least one particulate sugar alcohol, 30%-60% by weight, preferably 40%-60% by weight, more preferably 50%-60% by weight;

[0092] b) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight of at least one saturated triglyceride having a melting point greater than or equal to 40°C;

[0093] c) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight of at least one saturated triglyceride having a melting point below 0°C; and

[0094] d) 0.5%-15% by weight, preferably 1%-12% by weight, more preferably 2%-10% by weight of particulate pharmaceutical active agent, selected from the group consisting of anti-infective drugs, coagulation activators, fibrinolytic inhibitors, immunomodulators, steroid hormones and growth factors.

[0095] Furthermore, the present invention relates to an surfactant release system, which, in each case, comprises based on the total weight of the surfactant release system:

[0096] a) at least one particulate sugar alcohol, 30%-60% by weight, preferably 40%-60% by weight, more preferably 50%-60% by weight;

[0097] b) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight of at least one saturated triglyceride having a melting point greater than or equal to 40°C;

[0098] c) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight of at least one saturated triglyceride having a melting point below 0°C; and

[0099] d) 0.5%-15% by weight, preferably 1%-12% by weight, more preferably 2%-10% by weight of particulate pharmaceutical 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, dapoxetine and cyclosporine A.

[0100] The active agent release system according to the invention contains a particulate pharmaceutical active agent selected from the aforementioned active agents. Among these aforementioned active agents, anti-infective drugs are particularly preferred. Even more preferred are antibiotics, especially the antibiotics gentamicin, vancomycin, clindamycin, and daptomycin.

[0101] Therefore, the present invention particularly relates to an active agent release system, which, in each case, comprises based on the total weight of the active agent release system:

[0102] a) at least one particulate sugar alcohol, 30%-60% by weight, preferably 40%-60% by weight, more preferably 50%-60% by weight;

[0103] b) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight of at least one saturated triglyceride having a melting point greater than or equal to 40°C;

[0104] c) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight of at least one saturated triglyceride having a melting point below 0°C; and

[0105] d) 0.5%-15% by weight, preferably 1%-12% by weight, more preferably 2%-10% by weight of granular antibiotics.

[0106] Furthermore, the present invention particularly relates to an active agent release system, which, in each case, comprises based on the total weight of the active agent release system:

[0107] a) at least one particulate sugar alcohol, 30%-60% by weight, preferably 40%-60% by weight, more preferably 50%-60% by weight;

[0108] b) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight of at least one saturated triglyceride having a melting point greater than or equal to 40°C;

[0109] c) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight of at least one saturated triglyceride having a melting point below 0°C; and

[0110] d) 0.5%-15% by weight, preferably 1%-12% by weight, more preferably 2%-10% by weight of particulate pharmaceutical active agent, selected from the group consisting of gentamicin, vancomycin, clindamycin and daptomycin.

[0111] Based on the total weight of the surfactant release system in paste form according to the invention, the surfactant release system specifically comprises:

[0112] a) 30%-60% by weight, preferably 40%-60% by weight, more preferably 50%-60% by weight, of at least one particulate sugar alcohol selected from the group consisting of D-mannitol, D,L-mannitol, xylitol and erythritol;

[0113] b) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight of at least one saturated triglyceride having a melting point greater than or equal to 40°C, selected from the group consisting of glyceryl tripalmitate, glyceryl tristearate and glyceryl trishenate.

[0114] c) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight, of at least one saturated triglyceride having a melting point below 0°C, selected from the group consisting of mixtures of glycerol fatty acids; and

[0115] d) 0.5%-15% by weight, preferably 1%-12% by weight, more preferably 2%-10% by weight of particulate pharmaceutical active agent, selected from the group consisting of gentamicin, vancomycin, clindamycin and daptomycin.

[0116] Based on the total weight of the surfactant release system in paste form according to the invention, the surfactant release system specifically comprises:

[0117] a) 30%-60% by weight, preferably 40%-60% by weight, more preferably 50%-60% by weight, of at least one particulate sugar alcohol selected from the group consisting of D-mannitol, D,L-mannitol, xylitol and erythritol;

[0118] b) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight of at least one saturated triglyceride having a melting point greater than or equal to 40°C, selected from the group consisting of glyceryl tripalmitate, glyceryl tristearate and glyceryl trishenate.

[0119] c) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight, of at least one saturated triglyceride having a melting point below 0°C, selected from a mixture of glycerol fatty acids Miglyol 812N, Miglyol 810N, and Miglyol

[0120] The group consisting of 829N; and

[0121] d) Each of the following based on the total mass of the active agent release system according to the invention, 0.5%-15% by weight, preferably 1%-12% by weight, more preferably 2%-10% by weight, of particulate pharmaceutical active agent selected from the group consisting of gentamicin, vancomycin, clindamycin and daptomycin.

[0122] Based on the total weight of the surfactant release system in paste form according to the invention, the surfactant release system specifically comprises:

[0123] a) at least one particulate sugar alcohol, selected from the group consisting of 30%-60% by weight, preferably 40%-60% by weight, more preferably 50%-60% by weight;

[0124] b) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight of at least one saturated triglyceride having a melting point greater than or equal to 40°C, selected from the group consisting of glyceryl tripalmitate, glyceryl tristearate and glyceryl trishenate.

[0125] c) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight, of at least one saturated triglyceride having a melting point below 0°C, selected from the group consisting of mixtures of glycerol fatty acids; and

[0126] d) 0.5%-15% by weight, preferably 1%-12% by weight, more preferably 2%-10% by weight of particulate pharmaceutical active agent, selected from the group consisting of gentamicin, vancomycin, clindamycin and daptomycin.

[0127] Based on the total weight of the surfactant release system in paste form according to the invention, the surfactant release system specifically comprises:

[0128] a) 30%-60% by weight, preferably 40%-60% by weight, more preferably 50%-60% by weight of at least one particulate sugar alcohol, selected from the group consisting of D-mannitol and D,L-mannitol;

[0129] b) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight of at least one saturated triglyceride having a melting point greater than or equal to 40°C, selected from the group consisting of glyceryl tripalmitate, glyceryl tristearate and glyceryl trishenate.

[0130] c) 20%-35% by weight, preferably 20%-30% by weight, more preferably 20%-28% by weight, of at least one saturated triglyceride having a melting point below 0°C, selected from a mixture of glycerol fatty acids Miglyol 812N, Miglyol 810N, and Miglyol

[0131] The group consisting of 829N; and

[0132] d) Each of the following based on the total mass of the active agent release system according to the invention, 0.5%-15% by weight, preferably 1%-12% by weight, more preferably 2%-10% by weight, of particulate pharmaceutical active agent selected from the group consisting of gentamicin, vancomycin, clindamycin and daptomycin.

[0133] Therefore, according to the invention, preferably 0.5% to 15.0% by weight of at least one solid pharmaceutical active agent, preferably a particulate pharmaceutical active agent, is added to a hemostatic agent in paste form to form an active agent release system according to the invention. This means that if added to a hemostatic agent in paste form, the pharmaceutical active agent preferably accounts for 0.5% to 15.0% by weight of the total mass of the active agent release system. Therefore, the proportion of the particulate pharmaceutical active agent in the total mass of the active agent release system according to the 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 pharmaceutical active agent in the total mass of the active agent release system according to the invention can be up to 15% by weight, up to 14% by weight, up to 13% by weight, up to 12% by weight, up to 11% by weight, or up to 10% by weight.

[0134] The active agent release system according to the invention preferably contains 1% to 12% by weight, particularly preferably 2% to 10% by weight of particulate pharmaceutical active agent.

[0135] The granular hemostatic agent according to the invention, or the active agent release system according to the invention having the corresponding components, is preferably designed such that it remains dimensionally stable in distilled water at room temperature under laboratory conditions for a period of at least 7 days. This allows it to maintain its desired shape in environments exposed to the effects of polar liquids. This is, for example, when the granular hemostatic agent according to the invention or the active agent release system according to the invention is applied to damaged bone to stop any bleeding that may occur.

[0136] The advantage of this invention is that it eliminates the need to add inorganic calcium or magnesium salts to the claimed granular hemostatic agent or active agent release system. Hemostatic agents known in the prior art typically contain these inorganic salts, and their disadvantage is that they generally have a Mohs hardness of ≥2. Due to their high Mohs hardness, they have an abrasive effect on the surrounding material. Because it is preferably not necessary to add inorganic salts (such as calcium and magnesium salts) to the granular hemostatic agent or active agent release system according to the invention, the granular hemostatic agent or active agent release system according to the invention does not have abrasive properties and can therefore also be used in the field of intra-articular prostheses without affecting the sliding surface through wear.

[0137] In one embodiment of the invention, the hemostatic agent and the active agent release system according to the invention are free of any inorganic calcium and magnesium salts. However, in the context of the invention, in other embodiments, calcium or magnesium salts with a Mohs hardness ≥ 2.0 may still be added to the granular hemostatic agent or the active agent release system according to the invention. In this case, the mass fraction of calcium or magnesium salts with a Mohs hardness ≥ 2.0 is preferably no more than 10.0% by weight based on the granular hemostatic agent or the active agent release system according to the invention in each case. This means that, based on the total weight of the hemostatic agent or the active agent release system according to the invention in each case, preferably less than 10.0% by weight, more preferably less than 9.5% by weight, more preferably less than 9.0% by weight, more preferably less than 8.5% by weight, more preferably less than 8.0% by weight, more preferably less than 7.5% by weight, more preferably less than 7.0% by weight, more preferably less than 6.5% by weight, more preferably less than 6.0% by weight, more preferably less than 5.5% by weight, more preferably less than 5.0% by weight of calcium or magnesium salts with a Mohs hardness ≥ 2.0.

[0138] According to the above statement, calcium or magnesium salts with a Mohs hardness of less than 2, i.e., a Mohs hardness of less than 2.0, less than 1.9, less than 1.8, less than 1.7, less than 1.6, less than 1.5, less than 1.4, less than 1.3, less than 1.2, less than 1.1, less than 1.0, less than 0.9, less than 0.8, less than 0.7, less than 0.6, less than 0.5, less than 0.4, less than 0.3, less than 0.2, or less than 0.1, can be added to the granular hemostatic agent according to the invention or the active agent release system according to the invention.

[0139] In summary, the hemostatic agent according to the present invention and the active agent release system according to the present invention have the following advantages:

[0140] The hemostatic agent in paste form according to the invention comprises biodegradable substances that together form a deformable paste that can irreversibly transform into a desired shape under applied force. The paste is suitable for in vivo use and, when degraded in vivo, generally does not form acidic or alkaline degradation products that could cause localized damage.

[0141] As mentioned above, all conceivable granular pharmaceutical active agents can also be added to hemostatic agents in paste form. In this variant, the resulting active agent delivery system is particularly suitable for treating any type of bone tissue injury.

[0142] Hemostatic agents or active agent release systems in paste form typically remain dimensionally stable over extended periods after application, even when exposed to liquid media. Furthermore, it is preferable that no inorganic particles are added, thus eliminating any abrasive properties, such as those applicable to metallic objects.

[0143] All these properties allow for the treatment of all types of injuries to bone tissue using the hemostatic and active agent release system in paste form according to the invention.

[0144] iii) Uses of hemostatic agents in paste form

[0145] When pressure is applied, the hemostatic agent and active agent release system in paste form typically adheres to bone tissue and metal surfaces. This allows, for example, the use of hemostatic agents in paste form to treat damaged bone tissue, such as by stopping bone bleeding, as in cases of fractures, surgery, or even amputation.

[0146] Because it typically also adheres to metal surfaces, hemostatic agents in paste form are particularly suitable for mechanical hemostasis and / or as a paste-like local active agent release system that adheres to bone tissue surfaces and metal implant surfaces by applying pressure. When applied to the treatment site on bone, the paste-like local active agent release system is generally able to release dispersed particulate pharmaceutical active agent. The local active agent release system preferably adheres to the surfaces of intra-articular prostheses of the knee, hip, and shoulder joints, intramedullary nails, and bone plates, preferably under pressure. A significant advantage of the hemostatic agent according to the invention is that, as a local active agent release system, it generally remains stationary after adhesion in vivo. This allows the solid, preferably particulate, pharmaceutical active agent dispersed in the local active agent release system to be specifically released at the desired location.

[0147] Furthermore, according to the invention, it is possible to fill bone cavities using a hemostatic agent in paste form, wherein the hemostatic agent is particularly preferably used to fill previously infected and debrided medullary cavities and screw holes in bone tissue. In particular, when a hemostatic agent in paste form is applied to an area such as a local active agent center, it can release granular pharmaceutical active agents, which then, for example, alleviate inflammatory symptoms.

[0148] The hemostatic agent in paste form according to the invention is particularly useful for the mechanical cessation of bone bleeding in vivo. If a granular pharmaceutical active agent is added to the hemostatic agent in paste form according to the invention, it can also be used as a local active agent release system in paste form at the site of treatment. There, the dispersed pharmaceutical active agent can then be continuously released over a period of time.

[0149] Therefore, the present invention also relates to hemostatic agents in the form of pastes as described above, or active agent release systems in the form of pastes as described above, which are used as medicines, particularly for treating damaged bone tissue.

[0150] Hemostatic agents in paste form or active agent release systems in paste form can be used to treat bone cavities by filling, preferably by filling infected and debrided medullary cavities and screw holes in bone tissue.

[0151] For this purpose, hemostatic agents in the form of pastes or active agent release systems in the form of pastes can be adhered to the surface of bone tissue and the surface of metal implants by applying pressure, wherein the hemostatic agents in the form of pastes or active agent release systems in the form of pastes are preferably adhered to the surface of intra-knee prostheses, intra-hip prostheses, intra-shoulder prostheses, intramedullary nails and bone plates.

[0152] Hemostatic agents in paste form can be administered to patients manually or using a dispensing device. Due to the triglycerides contained within, good lubricity and squeezeability are achieved, for example, in syringes and similar squeeze-based dosing systems.

[0153] The compositions described herein can also be used to coat medical implants, such as spacers, artificial joints, and bone plates. For this purpose, the compositions according to the invention can be provided, for example, as an application pen or syringe system.

[0154] iv) Methods for producing hemostatic agents and active agent release systems in paste form

[0155] According to the present invention, a hemostatic agent and active agent release system in paste form is produced by mixing all components.

[0156] This means placing at least one particulate sugar alcohol (a), at least one saturated triglyceride with a melting point greater than or equal to 40°C (b), at least one saturated triglyceride with a melting point below 0°C (c), and optionally a particulate pharmaceutical active agent in a suitable container (such as a beaker or industrial mixing container) and mixing them.

[0157] Preferably, 30% to 60% by weight of particulate sugar alcohol, 20% to 35% by weight of saturated triglycerides having a melting point greater than or equal to 40°C, 20% to 35% by weight of saturated triglycerides having a melting point below 0°C, and optionally 0.5% to 15% by weight of particulate pharmaceutical active agent are weighed.

[0158] The preferred proportions of each component have been disclosed above and, with necessary modifications, have been applied to the method according to the present invention.

[0159] In the context of this invention, it may be advantageous to first heat the weighed components a), b), c), and optionally d) and pre-stir at a low speed. Heating is typically carried out above the melting temperature of saturated triglycerides having a melting point greater than or equal to 40°C. Preferably, it is not high enough to alter the chemical properties of the components used. For example, it is between 50°C and 90°C, specifically at 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.

[0160] The pre-mixed mixture is then typically cooled and mixed at high speed at least once using a suitable mixer or agitator. It is conceivable that this process could take 1500 minutes. -1 and 3000min -1 The speed between, for example, 1500 min -1 1600min -1 1700min -1 1800min -1 1900min -1 2000min -1 2100min - 1. 2200min -1 2300min -1 2400min -1 2500min -1 2600min -12700min -1 2800min - 1. 2900min -1 Or 3000min -1 In principle, as shown in the figure, any mixer capable of achieving a high stirring rate is suitable. For the purposes of this invention, the stirring step can be performed once at a high speed or repeated multiple times.

[0161] In the context of this invention, a particulate pharmaceutical active agent can be added to a hemostatic agent in paste form so that it can subsequently be used as a local active agent delivery system in paste form. In such a case, the particulate pharmaceutical active agent can be weighed together with the other components a), b), and c) at the beginning.

[0162] The method according to the invention for producing a hemostatic agent in paste form (which is intended to be used as a local active agent release system in paste form) is characterized in particular by mixing at least one pharmaceutical active agent, preferably granules, which is present in a solid state, with the hemostatic agent in paste form by kneading. Attached Figure Description

[0163] Figure 1 It is a hemostatic agent in the form of a paste produced by mixing all the components; it indicates the spreadability in the hand.

[0164] Figure 2 It is a hemostatic agent in the form of a paste that has been pressed onto the metal surface of the scraper. Clearly, the paste...

[0165] Hemostatic agents in the form of acetylene adhere to metal surfaces.

[0166] Exemplary Implementation

[0167] For exemplary implementations, pharmaceutical-grade Lytrol micro, poloxamer 185, glyceryl tripalmitate, glyceryl tristearate, glyceryl trisorheic ester, Miglyol 812N, and Miglyol 810N are used.

[0168] To prepare the paste in a simple way: First, weigh all components into a beaker. Then heat the mixture to 90°C for 1 hour, stirring occasionally. After cooling, transfer the mixture to a plastic container and mix using a high-speed mixer at 2000 rpm for 60 seconds each time. Repeat the mixing method twice. A colorless paste-like mass will form.

[0169] Table 1: Active agent release system according to the invention using D-mannitol and glyceryl tripalmitate

[0170]

[0171] Table 2: Active ingredients according to the invention using D-mannitol, glyceryl tristearate, and glyceryl tris(oxalate). Sex agent release system

[0172] Example D-Mannitol [g] Glyceryl tristearate [g] Glyceryl tris(oxalate)[g] Miglyol 812N[g] Miglyol 812[g] 4 9.1 4.6 - 4.4 5 9.1 - 4.6 4.0 6 9.1 4.6 - 4.4 7 9.1 - 4.6 4.0

[0173] Table 3: Active agent release systems according to the invention using xylitol, erythritol, and triglyceride.

[0174] Example Xylitol [g] Erythritol [g] Glyceryl tripalmitate Glyceryl tristearate [g] Miglyol 812N 8 9.1 - 4.6 4.4 9 9.1 - 4.6 4.4 10 - 9.1 - 4, 4.4 11 - 9.1 - 4.6 4.4

[0175] Table 4: Reference embodiments based on the teachings of patent specification DE102011016277B

[0176]

[0177] The CSCA mixture consists of 80.0% by weight calcium sulfate dihydrate and 20.0% by weight calcium carbonate.

[0178] According to ISO 10993-5, in vitro cytotoxicity testing

[0179] The in vitro cytotoxicity of the pastes from Examples 1, 2, and 12 was tested. Additionally, poloxamer 185 was included in the tests.

[0180] In vitro cytotoxicity was determined according to ISO 10993-5 using the MTT assay of Eurofins BioPharma Product Testing Munich GmbH. The paste was eluted in cell culture medium at 37°C for 72 hours. The eluent was then incubated with L929 cells at 37°C for 24 hours at undiluted and three dilutions. Cell viability was then determined spectrophotometrically using tetrazolium chloride. Tetrazolium chloride was reduced to the red-purple dye 1,3,5-triphenylformazan by living cells. In the paste of Example 12, a dye with a similar structure, triphenyltetrazolium chloride (XTT assay), was used instead of tetrazolium chloride, which was also reduced to the red-purple dye by living cells. This dye is also used in ISO 10993-5 to test the described in vitro cytotoxicity.

[0181] Table 5: Results of in vitro cytotoxicity of the selected examples

[0182]

[0183] According to ISO 10993-5, samples are considered non-cytotoxic if they exhibit greater than 70% activity at 100% v / v in either the MTT or XTT test. Based on the MTT test, the pastes according to the invention of Examples 1 and 2 were evaluated as non-cytotoxic, with 73% and 72% activity, respectively. The paste of Example 12, containing poloxamer 185, was clearly cytotoxic, with less than 70% activity.

[0184] Then, using L929 cells, the in vitro cytotoxicity of the pastes from Examples 1 and 2 was tested using the agar diffusion test according to ISO 109992-5. Neither paste showed cytotoxic activity.

[0185] Assessment of antibiotic miscibility

[0186] In the following sections, the miscibility of antibiotics with the paste material according to the invention of Example 1 was tested. 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. Tactile properties and adhesion to the steel surface (1.4404 steel) were tested. It was found that the kneaded antibiotics had only a small effect on softness and kneadability compared to the pure paste of Example 1. Kneadability was similar to that of the paste of Example 2. All pastes adhered very well to 1.4404 steel. Adhesion was similar to that of the paste of Example 2.

[0187] Table 6: Results of antibiotic miscibility

[0188]

[0189] Adhesion test to metal surface in the presence of water

[0190] 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 scraper surface. 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 was observed. The pH of the distilled water was in the range of pH 6.0–6.8.

Claims

1. A hemostatic agent in the form of a paste, said hemostatic agent comprising... a) at least one granular sugar alcohol; b) at least one saturated triglyceride having a melting point greater than or equal to 40°C; and c) At least one saturated triglyceride having a melting point below 0°C.

2. The hemostatic agent in paste form according to claim 1, wherein in each case, based on the total weight of the hemostatic agent, the hemostatic agent comprises: 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 greater than or equal to 40°C; and c) 20% to 35% by weight of at least one saturated triglyceride having a melting point below 0°C.

3. The hemostatic agent in paste form according to claim 1 or 2, characterized in that, In the MTT or XTT in vitro cytotoxicity test according to ISO 10993-5, the hemostatic agent has greater than 70% activity at 100% v / v.

4. The hemostatic agent in paste form according to any one of claims 1 to 3, characterized in that... The granular sugar alcohol is selected from aldehyde alcohols and ketol alcohols.

5. The hemostatic agent in paste form according to any one of claims 1 to 4, characterized in that... The saturated triglycerides having a melting point greater than or equal to 40°C are selected from glyceryl tristearate, glyceryl tripalmitate, glyceryl trilaurate, and mixed triglycerides formed from stearate and / or palmite and / or laurate with glycerol.

6. The hemostatic agent in paste form according to any one of claims 1 to 5, characterized in that... The saturated triglycerides having a melting point below 0°C are selected from tricaprylate, tridecanoate, or mixtures of glycerol fatty acids, namely Miglyol 812N, Miglyol 810N, and Miglyol 829N.

7. The hemostatic agent in paste form according to any one of claims 1 to 6, characterized in that... The particulate sugar alcohol has a particle size of less than 100 μm, wherein the particle size is determined by sieving and grading.

8. The hemostatic agent in paste form according to any one of claims 1 to 7, characterized in that... The hemostatic agent remained dimensionally stable in distilled water at room temperature over a 7-day period.

9. A paste-like active agent release system comprising a hemostatic agent in the form of any one of claims 1 to 8 and at least one pharmaceutical active agent, preferably a granular pharmaceutical active agent, wherein the pharmaceutical active agent is preferably selected from anti-infective drugs, coagulation activators, fibrinolytic inhibitors, immunomodulators, steroid hormones, and growth factors.

10. A hemostatic agent in paste form according to any one of claims 1 to 8 or an active agent release system in paste form according to claim 9, wherein the hemostatic agent or active agent release system is used as a drug.

11. A hemostatic agent in the form of a paste according to any one of claims 1 to 8, or an active agent release system in the form of a paste according to claim 9, wherein the hemostatic agent or active agent release system is used to treat damaged bone tissue.

12. The hemostatic agent or active agent release system in paste form according to claim 10 or 11, wherein the hemostatic agent or active agent release system is used to treat bone cavities by filling, preferably by filling infected and debrided medullary cavities and screw holes in bone tissue.

13. The hemostatic agent in paste form or the active agent release system in paste form according to any one of claims 10 to 12, characterized in that... Hemostatic agents in the form of pastes or active agent release systems in the form of pastes are adhered to the surface of bone tissue and metal implants by applying pressure, wherein the hemostatic agents in the form of pastes or the active agent release systems in the form of pastes are preferably adhered to the surface of knee joint prostheses, hip joint prostheses, shoulder joint prostheses, intramedullary nails, and bone plates.

14. A method for producing a hemostatic agent in paste form according to any one of claims 1 to 8, characterized in that... Place at least one particulate sugar alcohol, at least one saturated triglyceride with a melting point greater than or equal to 40°C, and at least one saturated triglyceride with a melting point below 0°C in a mixing container and knead them together.

15. The method according to claim 14, characterized in that... Mix at least one particulate pharmaceutical active agent with a hemostatic agent.

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