Coated active ingredient formulations for controlled in vivo uptake of CO2

Abstract

The present invention relates to coated active ingredient formulations for controlled in vivo CO2 uptake, more particularly in the form of microspheres. The present invention further relates to medical liquid compositions containing the active ingredient formulations and to the use of the medical liquid compositions for the treatment of selected diseases, particularly respiratory diseases. Finally, the present invention relates to a method for producing microspheres with controlled CO2 uptake.

Description

[Technical field]

[0001] The present invention relates to a controlled CO 2 The present invention also relates to a coated active ingredient formulation for in vivo uptake of CO, in this case in particular in the form of microspherules. The present invention further relates to a medical liquid composition containing said active ingredient formulation and to the use of said medical liquid composition for the treatment of selected diseases, in particular selected diseases in the respiratory area. Finally, the present invention also relates to a method for the controlled administration of CO 2 The present invention relates to a method for producing microspheres that receive [Background technology]

[0002] There are many respiratory diseases, but these diseases are caused by CO 2 With an increase in the content of pulmonary oxygen, it is also called hypercapnia. The cause of hypercapnia is usually a collapse of pulmonary ventilation (previously called global respiratory failure) caused by alveolar hypoventilation, a pulmonary diffusion disorder. For example, hypercapnic respiratory failure can occur when chronic obstructive pulmonary disease (COPD) worsens. However, hypercapnia can also occur with metabolic alkalosis or when breathing air that is high in carbon dioxide (8 to 10 percent carbon dioxide by volume occurs). Medical professionals also refer to obstructive pulmonary disease, i.e. a lack of oxygen in the blood in addition to carbon dioxide poisoning. Typical signs of hypercapnia are shortness of breath, restlessness but also fatigue, headache, confusion, bluish skin, and increased pulse rate. In the treatment of obstructive pulmonary disease, patients can be mechanically ventilated, for example by pressure-assisted non-invasive ventilation, to assist with the respiratory movement. This type of treatment is equipment- and cost-intensive, and carries many risks, including lung injury from pressure, pneumonia, elevated intrathoracic pressure, and worsening heart failure. However, in the course of intensive care for children and adults, gentler ventilation is preferred over CO 2 Hypercapnia can also occur when increased particle pressure is tolerated (also called "tolerant hypercapnia").

[0003] Therefore, alternative methods to treat hypercapnia are needed, such as taking advantage of the large internal surface area of ​​the human digestive system and pumping CO 2 By administering an absorbent orally, CO 2 There are experimental approaches aimed at reducing the content. In this regard, WO 2020 / 035163 describes a CO 2 ?lm having a polymer coating made of silicone rubber produced from liquid silicone rubber or a polymer coating made from a cellulose derivative. 2 A composition comprising an absorbent or adsorbent is disclosed. For this purpose, a rubber coating by simple dip coating with liquid silicone rubber and subsequent compression to form tablets is taught. This has the disadvantages of having to use organic solvents, which are harmful to health, resulting in particles with non-uniform coating and unpredictable absorption kinetics. Moreover, this method is not suitable for large-scale production. Moreover, silicone rubber particles have a sticky surface, which causes agglomeration, making it difficult to produce administrable formulations.

[0004] Alternatively, WO'163 describes powdered CO in a capsule made of regenerated cellulose. 2 This type of capsule has several drawbacks. Regenerated cellulose has low CO 2 They are only permeable and, due to their hygroscopic behavior, even in liquid formulations they swell and exhibit poor pouring behavior, which leads to a shortened shelf life. The corresponding capsules do not have sufficient strength required for the inclusion of highly basic absorbing substances. In this case, even the slightest damage to the capsule shell immediately leads to "dose dumping", i.e. CO 2 This leads to a sudden, large release of the absorbent into the body. Furthermore, this manufacturing method is difficult to scale up to the required quantities. Further prior art can be found in WO 2005 / 097075, U.S. Patent Application Publication No. 2015 / 245999 or U.S. Patent Application Publication No. 2017 / 319617. The problem that the present invention seeks to solve is to provide an improvement or alternative to the prior art. Summary of the Invention

[0005] According to a first aspect of the present invention, a controlled CO 2 1. A coated active ingredient formulation for in vivo uptake comprising: (i) a coating made of a wall material, 2 a coating that is permeable to water vapor and, optionally, to water vapor; (ii) at least one CO 2 a core region containing a receptive active ingredient; The problem to be solved by the present invention is solved by a coated active ingredient formulation comprising the above. The further independent and dependent claims relate to further embodiments. The terms are explained as follows. The present invention relates primarily to a coated active ingredient formulation. 2 The receptor active ingredient is provided as the active ingredient in the formulation. The mechanism of action corresponds to the in vivo uptake of carbon dioxide. In the context of the present invention, CO 2 In vivo uptake of CO is the total CO uptake in the organism as a whole. 2 This means that the intake of carbon dioxide is restricted to the lungs and the extrapulmonary reduction of carbon dioxide takes place. Accordingly, the active ingredient formulation must also be suitable for in vivo application. Furthermore, the active ingredient formulation according to the present invention 2 This achieves a controlled uptake of CO 2 This is achieved by separating the receptive core region from the coating surrounding the core, while the coating is CO 2 This is achieved by designing the device to be transparent to

[0006] Basic CO 2 In the case of absorbents, the water vapor permeability of the coating allows the basic CO 2The absorbent is only activated in combination with the resulting wetting. In this case, carbon dioxide is converted by a small amount of water into carbon dioxide, which is then converted into CO 2 It reacts with the absorbent to form carbonate compounds and water. The present invention has several advantages over the prior art. The manufacturing process in the context of the present invention makes it possible to produce formulations with a very uniform particle size distribution. This allows for the CO 2 This allows for deliberate control of uptake. Furthermore, the coated active ingredient formulations of the present invention, especially as microspheres, are amenable to large-scale production. The complete separation of the core and coating regions allows the absorption volume and / or absorption kinetics to be purposefully controlled. As a result, easily dispensable and / or storage-stable active ingredient formulations can be produced in this way, so that the selected properties in the final formulation can be achieved without problems. The coated active ingredient preparation of the present invention is enterally administered and therefore can be widely used for the treatment of respiratory diseases without impairing or burdening the airways. This has resulted in revolutionary treatments with few side effects that can be used in newborns, children, and high-risk patients. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] In the case of coated active ingredient formulations according to the invention, it can be advantageously provided that the coating is impermeable to water. This is advantageous both for the preparation of the formulation (e.g. as an aqueous suspension) and for the in vivo application. In one embodiment, the coating is permeable to water vapor, thus allowing a controlled wetting of the active ingredient, while the penetration of water into the core region is thus prevented. Upon reaction with water, the core swells and damages the coating, or at least the reaction with water causes CO 2 may lose its receptive properties. In the context of this application, the term "impermeable to water" is synonymous with the term "watertightness". The so-called watertightness of a coating is measured based on the head of water, at which pressure the material begins to let water through. According to EN343, from values ​​of 1300 mm and above the membrane is watertight. The coated active ingredient formulation may be provided in one of the following four embodiments:

[0008] (Embodiment 1: CO having a membrane envelope for forming liposomes or niosomes 2 (Liquid core containing active ingredient) In one embodiment, the coated active ingredient formulation can be present as a liposome. The advantage of liposomes is the high gas permeability of the membrane envelope, allowing high CO 2 Niosomes are microscopic spheres similar to liposomes, with a bilayer membrane surrounding the interior. Active ingredients can be entrapped within these. Niosomes have a similar structure to liposomes. However, whereas liposomes contain a bilayer membrane formed from phospholipids, the building blocks of the niosome bilayer membrane are derived from sugars and amino acids. (Embodiment 2: CO with single layer coating 2 (solid core containing active ingredient) In this embodiment, the solid core is covered with a single layer coating, thus making it a simple and cost-effective formulation to manufacture. (Embodiment 3: CO with multi-layer coating 2 (solid core containing active ingredient) In this embodiment, the solid core is covered with a multi-layer coating. This is a more complex formulation, where the properties of the coating in terms of permeability, stability or biocompatibility can be purposefully designed or distributed. For example, an inner coating layer can provide the required strength to the formulation, while an outer coating layer can provide a desired permeability.

[0009] (Embodiment 4: Microcapsules) In this embodiment, the coated active ingredient formulation may also be present as microcapsules. Microcapsules are injectable powders with particle sizes ranging from about 1 μm to about 1000 μm. They are produced using various coating processes of finely dispersed solid or liquid substances. Usually, polymers are used as coating or wall materials. In principle, microcapsules are composed of two distinct regions: a core region and a coating region. For microcapsules to be pourable, it is necessary that no adhesive forces occur between the particles, which also involve adhesion or aggregation ("agglomeration"). According to the DIN standard EN ISO 6186, as also described in the European Pharmacopoeia, Chapter 2.9.1 "Flowability", pourability can be measured. This standard specifies the equipment used to monitor and test the pourability of solids in powder or granular form (e.g. plastic granules). In this case, the material is dispensed using a standardized funnel and the elapsed time is measured using a stopwatch. Information can be obtained about the processability and about the uniform process control during production. Good pourability is important for trouble-free automatic processing. The pourability of a material is greatly influenced by the surface condition of the particles.

[0010] Suitable manufacturing methods for microencapsulation are phase separation methods (simple and complex coacervation), interfacial polymerization methods (polycondensation or polyaddition from dispersions), mechanical / physical methods (fluidized bed, spray drying). A fundamental drawback of conventional microencapsulation is the relatively high production costs. Advantageously, in the case of the present invention, in the coated active ingredient formulation, the microcapsules are microspheres in which CO 2 It may be provided that the receptive active ingredient is incorporated in the form of a solid dispersion or in dissolved form in a polymeric carrier matrix. Microspheres are a system related to microcapsules, which are not strictly divided into a core and a coating region. However, with regard to the size of the microspheres, which are about 1 μm to 1000 μm, they correspond to microcapsules. In microspheres, the embedded active ingredient is present in solid, i.e. dispersed, or dissolved form, incorporated in a carrier matrix. Microspheres are therefore a special type of microcapsule. The carrier matrix usually consists of a polymer.

[0011] CO 2 By embedding the receptive active ingredient in the microsphere, the carrier matrix provides a continuous width in terms of "wall thickness" (defined in this case as the shortest distance from the active ingredient to the outside of the microsphere), thereby allowing the permeated CO 2 The advantage is that the gas impinges on the active ingredient in a time-delayed manner, starting from the active ingredient embedment closest to the surface. 2 In the early onset case, CO 2 The uptake continues for a long period of time. In the present invention, in the case of a coated active ingredient formulation, CO 2 The active ingredient is CO 2 Absorbent material, CO 2 Adsorption materials, CO 2 Dissolved materials, and CO 2 converting enzymes, preferably CO 2 It may be provided that the material is absorbent. The term "absorption" describes the process whereby carbon dioxide is taken up or "dissolved" in another phase. This is not accumulation on a surface (adsorption), but incorporation into the free volume of the absorbing phase. In the case of absorption, a distinction is made between physical and chemical absorption. In the case of physical absorption, carbon dioxide is dissolved as a gas in a solvent. Mixing takes place without chemical reaction. In the case of chemical absorption, the carbon dioxide undergoes a chemical reaction with a "solvent" or absorbent to form a product. In this case, "adsorption" refers to the concentration of carbon dioxide on a solid surface.

[0012] In the present invention, advantageously, in the coated active ingredient formulation, the coating has a concentration of 0.004 to 2,500 × 10 -13 cm 3 cm cm -2 Pa -1 s -1 , preferably 5 to 500×10 -13 cm 3 cm cm -2 Pa -1 s -1 , particularly preferably 10 to 300×10 -13 cm 3 cm cm -2 Pa -1 s -1 CO 2 The coating may be provided having a transmittance of, for example, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, or 275×10 -13 cm 3 cm cm -2 Pa -1 s -1 CO 2 This type of CO 2 The permeable coating has been found to achieve an appropriate profile in terms of absorption kinetics. Preferably, the polymer is CO 2 A material with high permeability to CO is used as the wall material. This allows for the prevention of CO 2 Examples in this respect include the following polymers: polyethylenes, such as high density polyethylene (HD-PE) and low density polyethylene (LD-PE), polylactic acid (PLA), polybutylene adipate terephthalate (PBAT, EcoFlex), and polyhydroxyalkanoates, such as poly[(R)-3-hydroxybutyrate] (PHB).

[0013] CO as defined above 2For permeable coatings, a carrier matrix of microspheres is preferred. In the present invention, advantageously, in the coated active ingredient formulation, the coating has a viscosity of 0.009 to 32,000 × 10 -13 cm 3 cm cm -2 Pa -1 s -1 , preferably 100 to 1500×10 -13 cm 3 cm cm -2 Pa -1 s -1 The coating may be provided having a water vapor transmission rate of, for example, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400 or 1450×10 -13 cm 3 cm cm -2 Pa -1 s -1 It has been found that coatings with water vapor permeability of this kind allow wetting of the absorbent material to about 10% moisture by weight, which means that, precisely in the case of a basic absorbent such as calcium hydroxide, carbon dioxide reacts to form carbonic acid only after the latter has reacted to form carbonic acid, and thus the carbonic acid cannot react with calcium hydroxide to form calcium carbonate and water. 2 It is essential for efficient absorption of

[0014] Advantageously, a material, preferably a polymer, is used as the wall material, which has a sufficiently high permeability to water vapor, so that in the context of an in vivo application, CO 2 , which is generated via carbonic acid as an intermediate, can be prevented. 2Examples in this respect include the following polymers: polyethylene, such as high density polyethylene (HD-PE) or low density polyethylene (LD-PE), polylactic acid (PLA), polybutylene adipate terephthalate (PBAT, EcoFlex), and polyhydroxyalkanoates, such as poly[(R)-3-hydroxybutyrate] (PHB). The water vapor permeable coating as defined above is preferably a carrier matrix of microspheres. In a further possibility, it can be provided that in the case of coated active ingredient formulations, the coating has a mass fraction of 10 to 95% by weight, preferably 40 to 60% by weight, particularly preferably 55 to 65% by weight, based on the weight of the coated active ingredient formulation. The mass fraction of the coating can be, for example, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62 or 64% by weight. In this case, the coating is preferably a microspherical carrier matrix.

[0015] In the case of coated active ingredient formulations, it is furthermore conceivable that the coating has an average layer thickness of 10 to 500 μm, preferably 50 to 250 μm, particularly preferably 100 to 200 μm. As has been found, layer thicknesses of this type still provide sufficient CO 2 It allows for incorporation while being stable enough to prevent undesired release of the core material into the body. In the case of coated active ingredient formulations, the wall material forming the coating is preferably a polymer, particularly preferably selected from the group consisting of poly(organo)siloxanes; polyolefins; polyesters; polybutylene succinate; polybutylene adipate terephthalate (PBAT); polyethylenes, such as high density polyethylene (HDPE) or low density polyethylene (LDPE); polylactides (PLA), poly(glycolic acid) (PGA) and polylactic-co-glycolic acid (PLGA); lipids, such as fatty acids or phospholipids. In this case, the wall material is particularly preferably polyesters. The use of polyesters has the advantage that they exhibit very good resistance to bases and acids and can be processed in a particularly wide process window.

[0016] Suitably, a pharmacologic harmless material, preferably a polymer, is used as the wall material. This allows in vivo application with little or no side effects. Examples in this respect include the following polymers: polyethylene, such as high density polyethylene (HD-PE) or low density polyethylene (LD-PE), polylactic acid (PLA), polybutylene adipate terephthalate (PBAT, EcoFlex), and polyhydroxyalkanoates, such as poly[(R)-3-hydroxybutyrate] (PHB). Preferably, the wall material used has a content (preferably in the polymer) of what are known as "leachables" or "extractables" below acceptable limits due to the purity of the material, which allows for in vivo application with little or no side effects. In the case of coated active ingredient formulations, the coating is 2 It is preferably inert with respect to the receptive active ingredient, i.e., it is free of basic CO 2 , such as calcium hydroxide. 2 In the case of receptive active ingredients, the coating is stable to base. In the context of the present invention, the term "stable", when used to characterize a coating in base, means that the coating remains almost completely intact after the action of saturated aqueous calcium hydroxide solution at 90° C. for 1 day or at 40° C. for 30 days, the coating preferably remains substantially completely intact under these conditions, and the coating particularly preferably remains virtually completely intact under these conditions. In the context of acid treatment, the terms "largely, substantially completely, and virtually completely" mean that after the action of these conditions, the coating matrix retains at least 90%, at least 95%, and at least 99%, respectively, of its chemical bonds in the polymer scaffold.

[0017] That is, more acidic CO 2 For receptive active ingredients, the coating is acid stable. Acid stability is also required for oral administration or passage through the stomach. In the context of the present invention, the term "stable", when used to characterize a coating in acid, means that the coating remains almost completely intact after the action of a solution of 20% sulfuric acid at 90° C. for 1 day or at 40° C. for 30 days, the coating preferably remains substantially completely intact under these conditions, and the coating particularly preferably remains virtually completely intact under these conditions. In the context of acid treatment, the terms "largely, substantially completely, and virtually completely" mean that after the action of these conditions, the coating matrix retains at least 90%, at least 95%, and at least 99%, respectively, of its chemical bonds in the polymer scaffold. For coated active ingredient formulations, CO 2 Non-polar molecules such as gas molecules pass through the coating and are released into the CO 2It is further advantageous if the coating forms a semi-permeable barrier, insofar as it allows the receptive active ingredient to reach it. However, as a semi-permeable barrier, said coating is impermeable to charged molecules such as salt cations or anions, and accordingly protons and hydroxide anions. The coating therefore represents a selectively permeable coating, which allows the selective permeability of the coating to be selectively permeable to highly basic CO ions, such as calcium hydroxide. 2 In the case of absorbent materials, it is possible to prevent the excretion of hydroxide ions into the body.

[0018] Wall materials that allow the construction of such selectively permeable coatings include, for example, polyethylene, such as high density polyethylene (HD-PE) or low density polyethylene (LD-PE), polylactic acid (PLA), polybutylene adipate terephthalate (PBAT, EcoFlex), and polyhydroxyalkanoates, such as poly[(R)-3-hydroxybutyrate] (PHB). In the present invention, advantageously, 2 The receptive active ingredient is the following material: (a) a CO2 atom selected from the group consisting of inorganic hydroxide compounds, lithium peroxide, and mixtures thereof; 2 The CO absorbing material is preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, and magnesium hydroxide, and mixtures thereof. 2 Absorbent material, or (b) CO selected from the group consisting of activated carbon, molecular sieves, e.g., zeolites, silica, and metal-organic frameworks (MOFs). 2 Adsorbent material, or (c) a CO 2 solution selected from the group consisting of highly eutectic solvents and ionic fluids; 2 Melting material, or (d) CO, such as carbonic anhydrase (EC 4.2.1.1) 2 Converting enzymes, It may be provided that the compound is one of:

[0019] In the present invention, advantageously, 2The receptive active ingredient may be provided to include calcium hydroxide. According to a further embodiment, CO 2 The absorbent material consists essentially of calcium hydroxide, which reacts with carbon dioxide to form pharma- ceutically harmless calcium carbonate. In this case, "substantially" means that the CO 2 It is meant that the absorbent material comprises at most 5% by weight of other components, preferably at most 4% by weight, preferably at most 3% by weight, more preferably at most 1% by weight. In an advantageous embodiment, calcium hydroxide-containing CO 2 It is provided that the absorbing material is substantially free of sodium hydroxide and potassium hydroxide, where "substantially" means that the absorbing material is substantially free of CO 2 It means that the absorbent material contains at most 4% by weight, preferably at most 2% by weight, preferably at most 1% by weight, more preferably at most 0.5% by weight of sodium hydroxide and potassium hydroxide, and very particularly preferably does not contain sodium hydroxide and potassium hydroxide.

[0020] In one embodiment, the calcium hydroxide-containing composition described above contains, as an additional optional ingredient, an effective amount of a hygroscopic or deliquescent wetting agent capable of absorbing carbon dioxide. According to a further embodiment, CO 2 The absorbent material consists essentially of magnesium hydroxide, which has the advantage of being less basic, thus improving tolerability in gastrointestinal applications, and is hygroscopic, thus facilitating the initial wetting of the absorbent material and the release of CO as carbonic acid. 2 Finally, magnesium hydroxide has been found to be a cost-effective material that can be easily processed, especially in the manufacture of microspheres. Magnesium hydroxide reacts with carbon dioxide to form magnesium carbonate, which is pharma- ceutical harmless. In this case, "substantially" means that the CO 2 It is meant that the absorbent material comprises at most 5% by weight of other components, preferably at most 4% by weight, preferably at most 3% by weight, more preferably at most 1% by weight.

[0021] In an advantageous embodiment, magnesium hydroxide-containing CO 2 It is provided that the absorbing material is substantially free of sodium hydroxide and potassium hydroxide, where "substantially" means that the absorbing material is substantially free of CO 2 It means that the absorbent material contains at most 4% by weight, preferably at most 2% by weight, preferably at most 1% by weight, more preferably at most 0.5% by weight of sodium hydroxide and potassium hydroxide, and very particularly preferably does not contain sodium hydroxide and potassium hydroxide. In one embodiment, the magnesium hydroxide-containing composition described above contains, as an additional optional ingredient, an effective amount of a hygroscopic or deliquescent wetting agent capable of absorbing carbon dioxide. In the case of coated active ingredient formulations, it is advantageous to 2 It may be provided that the adsorbent material is selected from the group consisting of activated carbon, molecular sieves, such as zeolites, silica, metal-organic frameworks (MOFs).

[0022] Activated carbon is 300 to 2000 m 2 / g of carbon. In this case, the term "molecular sieve" is a functional designation for natural and synthetic zeolites or other materials that have a high adsorption capacity for carbon dioxide. In addition to zeolites, there are also, for example, carbon molecular sieves or molecular sieve carbons. Molecular sieves have a large internal surface area (600-700 m 2 / g) with uniform pore sizes on the order of the molecular diameter. Metal-organic frameworks (MOFs) are defined in this application as microporous materials composed of what are known as inorganic building blocks (IBUs) and organic molecules as linkers between the inorganic building blocks. MOFs are coordination networks with open frameworks that contain pores. The pores of the three-dimensional structure are usually filled with guest molecules (such as solvent and unreacted linkers) after synthesis. By removing the guest molecules (e.g. by calcination, decompression, or a combination of the two), the pores can be filled again with CO 2 It will be possible to take in gases such as In the context of this application, deep eutectic solvents (DES) refer to multi-component eutectic molten salts whose melting points are close to or below room temperature, similar to the melting points of ionic liquids. Examples of eutectic solvents are based on mixtures of quaternary ammonium compounds with hydrogen bridge donors (such as amines) and carboxylic acids.

[0023] According to a further advantage, in the case of the active ingredient formulation according to the invention, CO 2 The absorbent material is 10 mg CO 2 / g active ingredient formulation, preferably 40mgCO 2 More than 50 mg / g active ingredient formulation, particularly preferred 2 / g active ingredient formulation, especially 75mgCO 2 / g active ingredient formulation, CO 2 It may be provided that the patient has the capacity to receive CO 2 The higher the capacity, the lower the dosage of the active ingredient formulation that is required to obtain a therapeutically adequate effect. In a second aspect, the present invention relates to a medical liquid composition comprising, as a dispersion, the coated active ingredient formulation according to the invention and a pharma-ceutically harmless aqueous carrier liquid. A "medical composition" as used herein is a composition that can be used for the prevention, diagnosis, treatment, or alleviation of a disease. Thus, a medical composition includes both a pharmaceutical composition for preparing a drug and a composition for preparing a pharmaceutical product. Furthermore, a medical composition also includes a non-medical composition, so long as it is suitable for application to a mammal, particularly a human. A dispersion is defined in the context of this application as a heterogeneous mixture of two substances that are insoluble or poorly soluble in each other or do not chemically bond to each other, in which the active ingredient formulation is present as a dispersed phase dispersed in a carrier liquid as a dispersion medium.

[0024] When the coated active ingredient formulation or medical liquid composition is used according to the present invention for the treatment of respiratory diseases such as acute or chronic respiratory or pulmonary diseases, cardiovascular diseases, or infectious diseases, or respiratory diseases following the course of a severe disease, these diseases may occur both as the main disease or as an associated disease. Furthermore, the coated active ingredient formulation or a medical liquid composition produced therefrom can also be used in the step of returning a patient from medical artificial ventilation to spontaneous breathing, i.e., returning a patient who has been artificially ventilated from a ventilator to spontaneous breathing. In a further aspect, the present invention relates to the use of the liquid medical composition according to the invention in intraperitoneal or enteral application, for example oral, rectal or via a tube. Controlled and efficient CO 2 The advantageous properties of the coated active ingredient formulation of the present invention with regard to uptake allow the formulation to be used in a wide range of application forms. Enteral application, i.e. application that obtains its effect via the digestive tract, is preferred here. In this case, enteral application may be orally, or perorally, for example, to the distal part of the oral cavity via a tube or stoma, or rectally. Depending on the degree of hypercapnia, it may be necessary to apply a large amount of the preparation according to the invention, so enteral application is advantageous, and CO 2 After uptake is complete, the active ingredient formulation can be easily replaced with a new one by a rinsing step.

[0025] Furthermore, the active ingredient formulation can also be administered intraperitoneally. In a preferred embodiment, oral application is excluded from the application forms, so that the active ingredient formulation is not taken up precisely via the oral cavity, but rather delivered to the organism in another way (eg rectal application). The present invention further relates to a coated active ingredient formulation or a medical liquid composition produced using the same for use in the prevention or treatment of diseases of the respiratory system such as acute or chronic respiratory or pulmonary diseases, cardiovascular diseases, metabolic disorders accompanied by acidosis (e.g., ketoacidosis), or infectious diseases, or respiratory diseases following the course of severe diseases. In this case, the disease of the respiratory system is preferably (a) Chronic obstructive pulmonary disease (b) Asthma (c) Cystic fibrosis (d) Acute respiratory distress syndrome (e) Hypercapnia (f) Pneumonia (g) Lung cancer (h) Pulmonary fibrosis (i) Respiratory diseases according to medical definitions in accordance with ICD-10 J95 (j) Respiratory failure according to ICD-10 J96 (i) Other respiratory diseases according to ICD-10 J97 (l) Respiratory diseases classified elsewhere according to ICD-10 J99 (m) immature lungs The selected item is selected from the list consisting of:

[0026] The present invention further relates to a coated active ingredient formulation or a medical liquid composition produced therewith for use in inducing hypocapnia in a patient. 2 This includes the possibility of applications requiring extrapulmonary reduction of the active ingredient content. 2 The reduction in particle pressure has a vasoactive effect, allowing intracranial pressure to be actively or passively reduced without hyperventilation. In this case, the coated active ingredient formulation is preferably present in the form of microspheres. In a further aspect, the present invention relates to the use of the coated active ingredient formulation according to the present invention or the medical liquid composition according to the present invention for increasing performance during physical exercise or shortening recovery time after physical exercise in mammals and preferably humans. This use comprises the step of applying the coated active ingredient formulation according to the present invention or the medical liquid composition according to the present invention to a mammal and preferably humans. In this case, the application can be performed before, during or after physical exercise. It is preferably performed before physical exercise. The use claimed here is considered to be performed from a non-pathological normal state, and therefore is a non-therapeutic performance improvement without the promotion of recovery. In contrast, the aim of treatment is always the return of a pathological state to a normal state or the prevention of a pathological state.

[0027] In an alternative aspect, the present invention now relates to a coated active ingredient formulation according to the invention or a liquid medical composition according to the invention in use for increasing performance during physical exercise or shortening recovery time after physical exercise in a mammal and preferably a human. This use comprises a step of applying a coated active ingredient formulation according to the invention or a liquid medical composition according to the invention to a mammal and preferably a human. In this case, the application can be performed before, during or after physical exercise. Preferably, it is performed before physical exercise.

[0028] In a further aspect, the present invention relates to a method for the preparation of a coated active ingredient formulation according to the invention in the form of microspheres, comprising the following steps: (A) CO in solid or liquid form 2 Providing a receptive active ingredient, 2 The receptive active ingredient is advantageously CO 2 Absorbing material, CO 2 Providing a receptive active ingredient; (B) providing at least one polymer as a carrier plastic; (C)CO 2Feeding the receptive active ingredient, at least one polymer from step (B) to an extruder, and optionally additives such as dispersing aids, to the extruder, preferably a screw extruder; (D) The polymer is melted in the extruder and CO is added to the molten polymer stream. 2 A powerful mix of receptive active ingredients 2 Dispersing a receptive active ingredient in a polymer; (E) extruding the molten mixture from (D) through one or more shaping openings, such as a nozzle or multiple nozzles; (F) cooling the extruded plastic strands; (G) pelletizing the extruded plastic strands, particularly preferably in a liquid bath immediately after the forming opening; (H) optionally, grinding the plastic granules from step (G), preferably by cryogenic grinding; (I) CO exposed on the particle surface 2 surface treating the surface to neutralize or remove the receptive active ingredient; The present invention relates to a method comprising the steps of:

[0029] In a further aspect, the present invention relates to an alternative method for the preparation of a coated active ingredient formulation according to the invention in the form of microspheres, comprising the following steps: (A) CO in solid or liquid form 2 Providing a receptive active ingredient, 2 The receptive active ingredient is advantageously CO 2 Absorbing material, CO 2 Providing a receptive active ingredient; (B) providing at least one polymer as a carrier plastic; (C)CO 2Feeding the receptive active ingredient, at least one polymer from step (B) to an extruder, and optionally additives such as dispersing aids, to the extruder, preferably a screw extruder; (D) The polymer is melted in the extruder and CO is added to the molten polymer stream. 2 A powerful mix of receptive active ingredients 2 Dispersing a receptive active ingredient in a polymer; (E1) Extruding the molten mixture from(D) through one or more shaping openings, such as a nozzle or nozzles, into an aqueous medium, with direct cooling and underwater microgranulation of the extruded strands; (I) Optionally, CO exposed on the particle surface 2 surface treating the surface to neutralize or remove the receptive active ingredient; The present invention relates to an alternative method, including

[0030] In step (A) of the above two methods, 2 The receptive active ingredient is provided in solid or liquid form. The core region of the active ingredient formulation is intended to be formed from this. Preferably, 2 The receptive active ingredient is calcium hydroxide, 2 It is an absorbent material. In step (B) of the above two methods, at least one polymer is provided as a carrier plastic. The polymer is preferably provided as a solid polymer, which is preferably provided as a granule. This polymer is preferably a thermoplastic polymer, which is melted in an extruder, thereby allowing the active ingredient to be embedded in the polymer carrier matrix. In step (C), the components provided in accordance with steps (A) and (B), i.e., CO 2 The receptive active ingredient and at least one polymer are fed into the extruder. Optionally, one or more additives can be added here. Examples of possible additives include dispersing agents. In the extruder, the plastically deformable to viscous mass is continuously extruded under pressure through a forming opening (also called a nozzle).

[0031] The extruder is preferably a screw extruder and can be designed as a single or twin screw extruder. In this design, the pressure is generated by the extrusion screw, also called "screw" for short. The screw is inserted in what is known as the screw cylinder, the nominal diameter of which is practically identical to the external diameter of the screw. The nozzle, which is the shaping outlet opening, is located at the front end of the screw cylinder. The drive, which ensures the rotation of the screw, is located at the rear end of the cylinder. The materials are thoroughly mixed by the extruder screw, the thermoplastic polymer is melted by the pressure and, optionally, by the additional supply of heat by the heated screw and / or the heated extruder housing, and the CO is extruded into the polymer carrier matrix. 2 A homogeneous distribution of the receptive active ingredient particles results. The screw also conveys the material further towards the nozzle. In a further advantageous embodiment, the extruder is a planetary roller extruder, which has the advantage that it allows a particularly uniform mixing of the fed components.

[0032] By processing the components in the extruder, step (D) melts the polymer in the extruder and introduces CO into the molten polymer stream. 2 A powerful mix of receptive active ingredients 2 The receptive active ingredient is dispersed in the polymer. This process typically takes place in a section of the extruder known as the compression zone, where the reduction in the flight depth of the screw further compresses the material, increasing the pressure required for ejection in the die. The ingredients can be rapidly degassed in the extruder. Finally, a discharge or metering zone ensures uniform material flow towards the die so that in step (E) the molten mixture from (D) is extruded through one or more forming openings, such as a nozzle or multiple nozzles. Alternatively, in the last-mentioned method, in step (E1), the molten mixture from (D) is subjected to underwater granulation (also called underwater microgranulation) dissipating through one or more shaping openings, such as a nozzle or nozzles, so that microgranules with a uniform microdistribution are produced in one step. 2 It has the added advantage that uniform particles are initially obtained that are completely loaded with the receptive active ingredient. Any basic absorbent material (such as calcium hydroxide or magnesium hydroxide) that is unintentionally present on the surface is immediately washed away by spraying the particles into an aqueous liquid.

[0033] The extruded and cut particles, aided by the rheology of the melt, facilitated by the general temperature in water and non-contact suspension in the liquid, can be substantially more advantageously designed after cutting. This method has many advantages: 1. Reduced surface roughness (smoother surface). 2. Fewer absorbent particles are located on the surface (i.e., still surrounded by the polymer matrix after cutting). 3. Improved particle shape (i.e., typically spherical particles, resulting in improved injectability and more uniform uptake kinetics). 4. Smaller particle sizes can be achieved compared to other manufacturing methods. Methods and equipment for underwater microgranulation are well known to those skilled in the art and will be selected and used by them according to specific requirements (eg based on the type of plastic and particle size). The resulting extrudate as plastic strands is then heated to 100°C until the thermoplastic polymer hardens accordingly and the CO 2 The mixture is cooled in step (F) so as to tightly surround the receptive active ingredient.

[0034] In step (G), the extruded plastic strand is granulated. This is preferably carried out immediately after the forming opening, and in this case, particularly preferably in the liquid bath used for cooling. The plastic strand can be divided into individual parts here using a scoring or cutting device. Step (H) is an optional step, providing for grinding the plastic granules from step (G) produced in step (G), which grinding is preferably carried out by cryogenic grinding. In step (I), the surface of the plastic particles or microparticles is treated to remove CO 2 The pH neutralization or removal of the receptive active ingredient occurs. This step reduces CO 2 The receptive material, which is provided in a free state on the particle surface due to an incomplete coating and which may therefore directly interact with the surrounding environment, is subjected to a surface treatment, which advantageously comprises the following steps: (i) washing the microspheres with an acid and then neutralizing the pH; (ii) CO exposed to the surface 2 temporarily melting the microspheres to entrap the receptive active ingredient; (iii) further coating the microspheres; This is carried out by one or more of the following:

[0035] Basic CO such as calcium hydroxide 2 In the case of absorbents, according to step (i), the basic absorbent exposed at the surface can be neutralised by washing the microspheres with an acid. The acid-base reaction converts the absorbent into a (preferably soluble) salt, which may then be removed, optionally, by a subsequent washing step. According to step (ii), the microspheres may be temporarily melted. This is particularly possible in the case of thermoplastic polymers. As the inventors have found, this temporary melting can be achieved by dissolving the CO 2This thermal step does not require any chemical treatment and results in the sealing of the absorbent. 2 The advantage is that the total amount of absorbent is maintained.To prevent particle agglomeration, temporary melting of the microspheres is performed in liquid suspension and / or the microspheres are vigorously mixed. According to step (iii), the microspheres can be provided with an additional coating, so that the CO 2 The absorbent can be coated and thus sealed. By such coating, the microspheres can be further purposefully modified with respect to further properties such as hydrophobicity, hydrophilicity or biocompatibility.

[0036] In another embodiment, a polymer forming a carrier matrix can be used for the coating, thereby achieving a uniform structure of the microspheres. In the process according to the invention, it is also conceivable to further add excipients and / or additives to the above-mentioned components.For example, surface-active substances, fillers, further flame retardants, nucleating agents, oxidation stabilizers, sliding and demolding aids, dyes and pigments, optionally stabilizers, such as stabilizers against hydrolysis, light, heat or discoloration, inorganic and / or organic fillers, reinforcing agents and plasticizers.Suitable excipients and additives are described, for example, in Kunststoffhandbuch [Plastics compendium], Volume VIII "Polyester", Gerhard W. Becker and Dietrich Braun, Carl Hanser Verlag, Munich, Vienna, 1993. Furthermore, bicomponent fibers produced by extrusion can be provided. These bicomponent fibers consist of two polymers that are strongly but separably bonded to each other and have different chemical and / or physical structures. Although there are several geometrical arrangements of the polymers, the following four fiber cross sections are particularly advantageous: a) side-by-side (SS), b) shell / core (MK), c) matrix / fibril (MF), and d) cake slice (also called orange slice).

[0037] Advantageously, in the method according to the invention it can be provided that the microspheres are dispersed in a carrier solution in a further step. In a second aspect, the present invention relates to microspheres which can be produced or are produced by the extrusion process according to the invention described above. Microspheres can be produced by extrusion processes with extremely uniform particle size distribution, allowing for CO 2 Uptake can be deliberately controlled. Moreover, the extrusion process allows for the mass production of microspheres. The intensive mixing in the extruder allows for the CO 2 A uniform distribution of the absorbent is obtained, which allows for CO 2 The uptake kinetics of Due to their embedding in a polymer matrix, the resulting microspheres are easily dispersible and / or storage stable. Selection of their properties in the final formulation can thus be achieved without problems. As a further possibility it can be provided that the microspheres have a round, elliptical, irregular or elongated shape.

[0038] The elongated shape can be defined by an aspect ratio, which is defined as the ratio of the length of the microsphere to its maximum lateral extension, in which case the elongated shape has an aspect ratio of 4:1, preferably 3:1, particularly preferably 2.5:1. According to a further advantage, it can be provided that the microspheres according to the invention have an outer surface consisting exclusively of polymeric material. In the present invention, it can be advantageously provided that the microspheres, when spherical, have a particle size of 50 to 1000 μm, preferably 100 to 500 μm. Particles with a size of less than 500 μm have the advantage of passing through the stomach quickly. Liquids leave the stomach relatively quickly (half-life of fasting water: 10 to 20 minutes), which also applies to particles with a small particle size of less than 500 μm. The particle size of the microspheres can be, for example, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450 or 475 μm. For elongated particles, preferably having a circular, trilobal or square cross section, the particle diameter is preferably 50-800 μm and the length is preferably 4 mm.

[0039] (definition) In this specification, the term "polymer" includes a collection of chemically homogeneous macromolecules that differ in terms of degree of polymerization, molar mass and chain length, which have been produced by polyreaction (polymerization, polyaddition, polycondensation). Furthermore, the term also includes derivatives from polyreactions of such collections of macromolecules, i.e. compounds obtained by reaction, for example addition or substitution, of functional groups on a particular macromolecule, which may be chemically homogeneous or chemically heterogeneous. The term also includes copolymers and what are known as prepolymers, i.e. pre-adducts of reactive oligomers whose functional groups participate in the construction of the macromolecule. As used herein, the term "copolymer" refers to a polymer made up of two or more different types of monomer units. Copolymers are therefore distinct from homopolymers, which are made up of only one type of monomer (real or fictitious) and correspondingly one type of repeat unit. Specifically, copolymers are divided into five classes: 1.) Statistical copolymers: the distribution of the two monomers in the chain follows a statistical distribution. 2.) Gradient Copolymers: Similar in principle to statistical copolymers, but the proportion of one monomer increases and the proportion of the other decreases as the chain advances. 3.) Alternating Copolymer: Two monomers occur alternately. 4.) Block and segmented copolymers: consist of longer sequences or blocks of each monomer. 5.) Graft Copolymers: Blocks of one monomer are grafted onto a scaffold (backbone) of another monomer.

[0040] In the present specification, "molecular weight" is understood to mean the molar mass of a molecule (grams / mole or Daltons). In the present specification, "average molecular weight" always refers to the number average M n (number average). In this case, the term "number average molar mass" is also used as a synonym for "average molecular weight". In the present specification, the term "solvent" refers to compounds described as organic solvents in CD Rompp Chemie Lexikon [Chemistry Lexicon], 9th edition, Version 1.0, Georg Thieme Verlag, Stuttgart 1995. The polyols used according to the invention are not included in this definition, although they act as solvents for the monomers and also for the low molecular weight polymers resulting from the radical polymerization. In the present specification, "solid" is understood to mean a substance that does not change its shape without external action or that is difficult to deform, but in particular is not flowable. Correspondingly, "liquid" is understood to mean a deformable and flowable substance, including highly viscous and pasty substances.

[0041] It is expressly noted that in the context of the patent application presented herein, indefinite articles and indefinite numbers such as "one ...", "two ..." are generally to be understood as minimum specifications, i.e. "at least one ...", "at least two ...", etc., unless there is a specific indication to that effect, e.g. from the context or concrete text, that only "exactly one ...", "exactly two ...", etc. should be meant. Furthermore, all numerical values ​​and specifications relating to method parameters and / or apparatus parameters should be understood in a technical sense, i.e. with conventional tolerances. Nor should it be concluded that "exactly one" is meant simply because a limitation such as "at least" is explicitly stated, i.e. in the absence of a designation such as "at least". Unless otherwise specified, in this specification, % is expressed by mass %. The embodiments shown herein are merely illustrative of the present invention and should not be understood as limiting the present invention. Alternative embodiments considered by those skilled in the art are also encompassed within the scope of protection of the present invention.

[0042] (Embodiment) 1. Production of Microspheres According to the Invention LD-PE with a melting temperature of 242 degrees Celsius is introduced into the main stream of the sidestream extruder at 8 g / min. The main shaft speed is 175 rpm. The extruder contains six heating zones with temperatures set at 220, 230, 240, 250, 250 and 250 degrees Celsius respectively. The sidestream extruder is fed with powdered Ca(OH) 2 is added at 7.4 g / min. The strands are spun into deionized water through a 6 mm nozzle with circular cross section. In a subsequent granulator, the strands are cut into spheres 2 mm long. Further grinding is performed in a cryogenic grinder of the Fritsch Pulverisette 14 type at a speed of 20,000 rpm and grinding disk 2.0, with a continuous supply of liquid nitrogen, to obtain microspheres. The fraction with the desired particle size of 100-600 μm is sieved. Microspheres with a particle size of 100 to 600 μm are suspended at a concentration of 25% by mass in a 0.2% agar solution. By adding 30% hydrochloric acid, open-cell Ca(OH) 2 The particles are neutralized and the pH of the suspension is set to 7.40.

[0043] (2. In Vitro CO 2 Import) CO of the produced suspension 2 To analyze the uptake, 1 ml of the suspension was 2 9000ppm of CO 2 Every 60 seconds, add CO 2 By measuring the concentration, the absorption capacity and absorption kinetics can be determined. The results are shown in Figure 2A. Saturation of the microspheres according to the invention was confirmed after a period of 90 minutes, and the permeability properties of the LDPE allowed the CO 2A delayed effect on uptake is achieved. In this embodiment, 3±0.82 mg CO 2 / g microsphere CO 2 Acceptance capacity was measured. (3. In vivo CO 2 Import) To test the formulations according to the invention in vivo, Aachen minipigs were used as an animal model. The animals were deeply anesthetized, artificially ventilated, and CO was pumped from the lungs. 2 After application of 50 g of microspheres prepared according to Example 1, the CO 2 The contents were measured at 15 min intervals using a duodenal tube. Arterial CO as a function of time 2 The contents are shown in Figure 2B. After application, arterial CO 2 The content decreased from 25 mmol / L to 21 mmol / L, and then the arterial CO 2 The content increased slowly to the starting value. These animal tests made it possible to confirm the efficacy of the formulation according to the present invention in mammals.

[0044] (4. Preparation of Galen Sample A) 48% by weight of calcium hydroxide was mixed with 52% by weight of low density polyethylene (LD-PE) and extruded into a water bath to form a 1 cm 3 The particles were granulated into cylindrical shapes of 0.01 mm in diameter. They were then freeze-ground to a diameter of approximately 0.5 mm. The particles thus obtained were stirred in ultrapure water, and hydrochloric acid was added to adjust the pH to 7.40. After sieving, 150 g of the particles were suspended in 1 liter of a solution of 0.2% by weight of agar in ultrapure water, and hydrochloric acid was added to set the pH to 7.40. Suspension CO 2 The amount of absorption was measured by mixing the suspension with carbonated water and stirring it in a closed container for 24 hours. 1 g of particles of Galen A absorbed 0.03 g of CO 2 was absorbed. (5. Preparation of Galen Sample B) 30% by mass of calcium hydroxide was mixed into 70% by mass of high density polyethylene (HD-PE) and further processed by underwater microgranulation to obtain particles with a diameter of approximately 0.5 mm. The particles were stirred in a solution of a commercially available scale remover for 24 hours and washed with ultrapure water. After sieving, 150 g of the particles were suspended in 1 liter of a solution of 0.2% by mass of agar dissolved in ultrapure water, and hydrochloric acid was added to set the pH to 7.40. Suspension CO 2 The absorption was evaluated by mixing the suspension with carbonated water and stirring in a closed container for 24 hours. 1 g of particles of Galen B absorbs 0.02 g of CO 2 was absorbed. Considering the results of the in vivo experiments (see point 8 and FIG. 6), 2 The absorption kinetics was tested in carbonated water. The results are shown in Figure 3. 2 Absorption of CO in solution 2 A continuous decrease in concentration was observed, which continued until the final measurement time of 240 min, where it reached approximately 30 mmHg. Furthermore, the uniformity of the particles was evidenced by micrographs (see Figure 4).

[0045] (6. Preparation of Galen Sample C) 30% by mass of magnesium hydroxide was kneaded into 70% by mass of low-density polyethylene (LD-PE), extruded into a water bath, and continuously extruded into a 1.4 cm 3 The particles were stirred in a solution of a commercially available scale remover for 48 hours and washed with ultrapure water. After sieving, the suspension was mixed with carbonated water in a closed vessel and stirred to extract the CO2 from the particles. 2 The absorption was evaluated. 1 g of Galen C particles absorbed 0.02 g of CO 2 Galen sample C absorbed CO 2 The absorption kinetics was tested in carbonated water. The results are shown in Figure 5. 2 Absorption of CO in solution 2 A continuous decrease in the concentration was observed, whereby already after 120 min, CO 2 The concentration is essentially reduced by 50% (from 60mmHg to 30mmHg). (7. Preparation of comparison samples (placebos)) High density polyethylene was extruded by underwater microgranulation to obtain particles with a diameter of approximately 0.5 mm. The particles were stirred in a solution of a commercial descaling agent for 24 hours and washed with ultrapure water. After sieving, 150 g of particles were suspended in 1 liter of a solution of 0.2% by weight agar in ultrapure water, and the pH was set to 7.40 by adding hydrochloric acid. The placebo sample was treated with CO2 from carbonated water. 2 No absorption was observed.

[0046] 8. In Vivo Testing of Samples Galenic samples A and B and the placebo sample were tested in pigs. The pigs were placed under general anesthesia. Arterial pCO 2 After setting the arterial pCO2 value at approximately 50 mmHg, the ventilator settings were kept constant throughout the study. The above suspensions, consisting of 150 mg of each galenoid in 1 liter of ultrapure water thickened with agar, were administered rectally. 2 Values ​​were measured every 15 minutes throughout the study period. The results are shown in Figure 6. Placebo reduced pCO 2 Both Galen preparations did not affect arterial pCO values. 2 The kinetics of Galenic Acid Sample B in vivo 2 This is evaluated as being particularly advantageous since it results in a rapid drop in the concentration (a drop of 10 mmHg within 45 minutes). For Galen sample B, the pH of the large intestine was measured periodically during the experiment. The results are shown in Figure 7. If particles leaked, the pH of the colon would rise significantly. As the measurements show, the pH remained constant throughout the test, which is due to the presence of basic CO 2 This indicates a reliable and consistent absorption of the absorbent. In this case, the pH is in the physiological range of 7.13 to 7.42. Different embodiments of the present invention will now be described with reference to the drawings. [Brief description of the drawings]

[0047] [Figure 1] FIG. 1 is a schematic diagram of a microsphere according to the present invention. [Figure 2A] FIG. 1 shows the results of in vitro uptake of CO2 by microspheres according to the present invention. [Figure 2B] FIG. 1 shows the results of in vivo uptake of CO2 by microspheres according to the present invention. [Diagram 3] FIG. 1 shows the kinetics of in vitro CO2 absorption for Galenic sample B. [Figure 4] A is a micrograph of Galenic specimen B, showing an enlarged detail of B. [Diagram 5] FIG. 1 shows the kinetics of in vitro CO2 absorption for Galen sample C. [Figure 6] FIG. 1 shows an in vivo test of galenic preparations A and B compared to placebo by measuring arterial pCO2 values ​​after rectal application of the preparations in pigs. [Figure 7] FIG. 2 shows an in vivo study of the tolerability of galenic preparation sample B by measuring the colonic pH after rectal application of sample B in pigs.

[0048] Figure 1 is a schematic diagram of a microsphere 1 according to the invention. In this embodiment, the microsphere 1 is spherical and therefore has a particularly advantageous volume to surface area ratio. It consists of a polymer matrix 2, in which CO 2 The individual particles of the absorbent 3 are uniformly dispersed. 2 The sorbent is removed by an acid treatment and subsequent washing step, leaving only the cavity 4 and the CO 2 The absorbent is no longer present. The microspheres 1 are present as particles in the liquid dispersion medium 5. [Explanation of symbols]

[0049] 1 microsphere 2. Polymer matrix 3 CO 2 Absorbent 4. Washed-out CO 2 Surface cavities caused by absorbent material 5 Dispersion medium

Claims

1. Controlled CO 2 A coated active ingredient formulation for in vivo uptake comprising: (i) a coating made of a wall material, 2 a coating that is permeable to water vapor and optionally also to water vapor; (ii) at least one CO 2 A core region containing the receptive active ingredient; The coated active ingredient formulation comprising:

2. 2. A coated active ingredient formulation according to claim 1, characterized in that the coating is impermeable to water.

3. The coated active ingredient formulation is CO with a membrane envelope to form liposomes or niosomes 2 Liquid core containing receptive active ingredients CO with single layer coating 2 Solid core containing receptive active ingredient CO with multi-layer coating 2 Solid core containing receptive active ingredient ・Microcapsules 2. The coated active ingredient formulation according to claim 1, characterized in that it is selected from the group consisting of:

4. The microcapsules are microspheres and CO 2 4. The coated active ingredient formulation according to claim 3, characterized in that the receptive active ingredient is incorporated in the polymer carrier matrix in solid dispersion or dissolved form.

5. CO 2 The receptor active ingredient is CO 2 Absorbent material, CO 2 Adsorbent material, CO 2 Dissolved materials, and CO 2 converting enzymes, preferably CO 2 A coated active ingredient formulation according to any one of claims 1 to 4, characterized in that it is an absorbent material.

6. The coating, which is preferably a carrier matrix of microspheres, has a particle size of 0.004 to 2,500×10 -13 cm 3 cm cm -2 Pas -1 , preferably 5 to 500×10 -13 cm 3 cm cm -2 Pas -1 , particularly preferably 10 to 300×10 -13 cm 3 cm cm -2 P -1 s -1 CO 2 The coated active ingredient formulation according to any one of claims 1 to 4, characterized in that it has a permeability.

7. The coating, which is preferably a carrier matrix of microspheres, has a particle size of 0.009 to 32,000×10 -13 cm 3 cm cm -2 Pas -1 , preferably 100 to 1500×10 -13 cm 3 cm cm -2 Pas -1 5. The coated active ingredient formulation according to claim 1, characterized in that it has a water vapor permeability of 0.1 to 0.5%.

8. 5. Coated active ingredient formulation according to claim 1, characterized in that the coating, which is preferably a microspherical carrier matrix, has a mass fraction of 10 to 95% by weight, preferably 40 to 60% by weight, particularly preferably 55 to 65% by weight, based on the weight of the coated active ingredient formulation.

9. 5. Coated active ingredient formulation according to claim 1, characterized in that the coating has an average layer thickness of 10 to 500 μm, preferably 50 to 250 μm, particularly preferably 100 to 200 μm.

10. 5. A coated active ingredient formulation according to any one of claims 1 to 4, characterized in that the wall material is selected from the group consisting of poly(organo)siloxanes; polyolefins; polyesters; polybutylene succinate; polybutylene adipate terephthalate (PBAT); polyethylenes such as high density polyethylene (HDPE) or low density polyethylene (LDPE); polylactides (PLA), poly(glycolic acid) (PGA) and polylactic-co-glycolic acid (PLGA); lipids such as fatty acids or phospholipids, preferably polyesters.

11. CO 2 The receptive active ingredient is the following material: (a) a CO2 gas selected from the group consisting of inorganic hydroxide compounds, lithium peroxide, and mixtures thereof; 2 The CO absorbing material is preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, and magnesium hydroxide, and mixtures thereof. 2 Absorbent material, or (b) a CO2 carrier selected from the group consisting of activated carbon, molecular sieves, e.g., zeolites, silica, and metal-organic frameworks (MOFs); 2 Adsorbent material, or (c) a CO 2 -containing solvent selected from the group consisting of highly eutectic solvents and ionic fluids; 2 Melting material, or (d) CO, such as carbonic anhydrase (EC 4.2.1.1) 2 Converting enzymes, The coated active ingredient formulation according to any one of claims 1 to 4, characterized in that the active ingredient formulation is one of the following:

12. CO 2 12. The coated active ingredient formulation of claim 11, wherein the absorbent material comprises calcium hydroxide and, optionally, an effective amount of a hygroscopic or deliquescent wetting agent capable of absorbing carbon dioxide, the calcium hydroxide being substantially free of sodium hydroxide and potassium hydroxide.

13. CO 2 The absorbent material is 10 mg CO 2 / g active ingredient formulation, preferably 40 mg CO 2 / g active ingredient formulation, particularly preferably 50 mg CO 2 / g active ingredient formulation, especially 100 mg CO 2 / g active ingredient formulation, CO 2 The coated active ingredient formulation according to claim 12, characterized in that it has receptive capacity.

14. A medical liquid composition as a dispersion comprising the coated active ingredient formulation according to any one of claims 1 to 4 and a pharma-ceutical safe aqueous carrier liquid.

15. 15. The medical liquid composition according to claim 14, for intraperitoneal or enteral application, for example oral or rectal application via a tube, or for peritoneal application.

16. The coated active ingredient formulation according to any one of claims 1 to 4 for use in the prevention or treatment of diseases of the respiratory system such as acute or chronic respiratory or pulmonary diseases, cardiovascular diseases, metabolic disorders such as ketoacidosis, or infectious diseases, or respiratory diseases following the course of severe diseases.

17. Respiratory system diseases, (a) Chronic obstructive pulmonary disease (b) Asthma (c) Cystic fibrosis (d) Acute respiratory distress syndrome (e) Hypercapnia (f) Pneumonia (g) Lung cancer (h) pulmonary fibrosis (i) Respiratory diseases according to medical definitions equivalent to ICD-10 J95 (j) Respiratory failure according to ICD-10 J96 (i) Other respiratory diseases according to ICD-10 J97 (l) Respiratory diseases classified elsewhere according to ICD-10 J99 (m) Immature lungs 17. The coated active ingredient formulation or medical liquid composition according to claim 16, characterized in that it is selected from the list consisting of:

18. A coated formulation of an active ingredient according to any one of claims 1 to 4 for use in inducing hypocapnia in a patient.

19. A coated active ingredient formulation according to any of claims 1 to 4 for increasing performance during physical exercise or shortening recovery time after physical exercise in a mammal, preferably in a human.

20. 5. A method for producing the microspheres of claim 4, comprising the steps of: (A) CO in solid or liquid form 2 Providing a receptive active ingredient, 2 The receptor active ingredient is preferably CO 2 The CO absorbing material 2 Providing a receptive active ingredient; (B) providing at least one polymer as a carrier plastic; (C) CO 2 feeding the receptive active ingredient, the at least one polymer from step (B) to an extruder, and optionally feeding additives such as dispersing aids to the extruder, preferably a screw extruder; (D) Melting the polymer in an extruder and injecting CO into the molten polymer stream. 2 By intensively mixing the active ingredients, 2 Dispersing a receptive active ingredient in a polymer; (E) extruding the molten mixture from (D) through one or more shaping openings, such as a nozzle or multiple nozzles; (F) cooling the extruded plastic strands; (G) pelletizing the extruded plastic strands, particularly preferably in a liquid bath immediately after the forming opening; (H) optionally grinding the plastic granules from step (G), preferably by cryogenic grinding; (I) CO exposed on the particle surface 2 surface treatment to neutralize or remove receptive active ingredients; A method comprising:

21. Exposed CO 2 The surface treatment of the microspheres for pH neutralization of the absorbent comprises the steps of: (i) washing the microspheres with acid followed by neutralization of the pH; (ii) CO exposed on the surface 2 temporarily melting the microspheres to entrap the receptive active ingredient; (iii) further coating the microspheres; 21. The method of claim 20, wherein the method is performed by one or more of the following:

22. 22. The method of claim 21, characterized in that the microspheres are dispersed in a carrier solution in a further step.

23. Microspheres produced by the method according to any one of claims 20 to 22.

24. 24. The microspheres of claim 23, characterized in that the microspheres have a circular, elliptical, irregular or elongated shape.

25. 25. Microspheres according to claim 24, characterized in that the microspheres have a surface consisting entirely of polymeric material.

26. Microspheres according to claim 25, characterised in that the microspheres have a particle size of 50 to 1000 μm, preferably 100 to 500 μm.

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