DE102021127957A1 - Coated drug formulation for controlled in vivo uptake of CO2 - Google Patents

Abstract

The present invention relates to an encapsulated active substance formulation for the controlled in vivo uptake of CO2 and here in particular in the form of microspherules. The invention also relates to a liquid medical composition that contains this active ingredient formulation and its use for the treatment of selected diseases, especially in the respiratory area. Finally, the invention also relates to a method for producing controlled CO2-absorbing microspheres.

Description

The present invention relates to an encapsulated active substance formulation for the controlled in vivo uptake of CO ₂ and here in particular in the form of microspherules. The invention also relates to a liquid medical composition that contains this active ingredient formulation and its use for the treatment of selected diseases, especially in the respiratory area. Finally, the invention also relates to a method for producing controlled CO ₂ absorption microspherules.

Background of the Invention

There are numerous respiratory diseases that are associated with an increased level of CO ₂ in the blood, which is also known as hypercapnia. The cause of hypercapnia is usually a disturbance in the ventilation of the lungs (formerly known as global respiratory insufficiency) which arises from alveolar hypoventilation, pulmonary diffusion disturbances or pulmonary distribution disturbances. Hypercapnic respiratory failure can occur, for example, with worsening chronic obstructive pulmonary disease (COPD). However, hypercapnia is also caused by metabolic alkalosis or by inhaling air with a high concentration of carbon dioxide (carbon dioxide poisoning occurs from 8 to 10 percent by volume). Doctors also speak of hypercapnic respiratory failure, ie carbon dioxide poisoning with simultaneous lack of oxygen in the blood. Typical signs of hypercapnia are shortness of breath, restlessness, but also drowsiness, headaches, confusion, blue discoloration of the skin and an increased heart rate.

To treat hypercapnic respiratory failure, the patient may be given mechanical ventilation, such as pressure-supported noninvasive ventilation, to support the work of breathing. Such a treatment requires a lot of equipment and costs and is associated with numerous risks, such as damage to the lungs due to pressure, pneumonia, increase in pressure in the chest cavity or worsening of cardiac insufficiency.

However, hypercapnia can also occur in the course of intensive medical treatment of children and adults if increased CO ₂ partial pressures are accepted in favor of more gentle ventilation (also referred to as "permissive hypercapnia").

Therefore, there is a need for alternative methods of treating hypercapnia. There are experimental attempts to reduce the CO ₂ content in the blood by the oral _{administration} of CO 2 absorbers using the large inner surface of the human digestive system.

The WO 2020/035163 A1 discloses a composition of a CO ₂ absorbent or adsorbent with a polymeric coating of a silicone rubber made from liquid silicone rubber or with a polymeric coating of a cellulose derivative. To this end, it teaches rubber coating by simple dip coating with liquid silicone rubber and subsequent compression to form tablets. This has the disadvantage that harmful organic solvents have to be used and particles with an uneven coating result, so that the absorption kinetics cannot be predicted. Furthermore, the method is not suitable for large-scale production. In addition, the silicone rubber particles have a sticky surface, which leads to agglomeration and makes it difficult to produce a formulation that can be dosed.

Alternatively, WO'163 teaches the encapsulation of a powdered CO ₂ absorber in a capsule made of regenerated cellulose. Such a capsule has several disadvantages. Regenerated cellulose has only a low CO ₂ permeability and, due to its hygroscopic behavior, leads to swelling and poor flow behavior even in the liquid formulation, which is associated with a short shelf life. Corresponding capsules do not have the strength required to enclose strongly basic absorber substances. A small damage to the capsule shell immediately leads to "dose dumping", ie the sudden and massive release of CO ₂ absorbers into the organism. In addition, the manufacturing process is difficult to scale to the required quantities.

Further prior art can WO 2005/097075 A2 , the U.S. 2015/245999 A1 or the U.S. 2017/319617 A1 be removed.

The object of the present invention is to improve the prior art or to offer an alternative.

Summary of the Invention

• (i) Eine aus einem Wandmaterial bestehende Hülle, wobei die Hülle permeabel für CO₂ und optional auch für Wasserdampf ist;
• (ii) Und einem Kernbereich, der mindestens einem CO₂-aufnehmenden Wirkstoff aufweist.

According to a first aspect of the present invention, the task at hand is an encapsulated active substance formulation for the controlled in vivo uptake of CO ₂ , the encapsulated active substance formulation comprising the following:

• (i) An envelope consisting of a wall material, the envelope being permeable to CO ₂ and optionally also to water vapour;
• (ii) And a core region which has at least one CO ₂ -scavenging agent.

Further embodiments are subject of the further independent and dependent claims.

The following is explained conceptually:

The invention initially relates to an encapsulated active ingredient formulation. A CO ₂ -absorbing active substance is provided as the active substance in the formulation. The mechanism of action consists accordingly in the in vivo uptake of carbon dioxide. Within the scope of the present invention, the in vivo uptake of CO ₂ means an uptake of CO ₂ in the whole living organism, with an extrapulmonary reduction of carbon dioxide occurring. Accordingly, the active ingredient formulation must also be suitable for in vivo application.

Furthermore, the active substance formulation according to the invention achieves a controlled uptake of CO ₂ . This is achieved on the one hand by separating the core area into a CO ₂ -absorbing area and a shell surrounding this core, and on the other hand by designing the shell to be permeable to CO ₂ .

In the case of a basic CO ₂ absorber, the basic CO ₂ absorber is only activated by the water vapor permeability of the shell in connection with the resulting moistening. Here, the carbon dioxide is converted into carbonic acid by the small amount of water, which then reacts with the CO ₂ absorber to form a carbonate compound and water.

The invention has several advantages over the prior art.

The production process within the scope of the invention makes it possible to produce formulations which have an extremely homogeneous particle size distribution. This ensures that the CO ₂ uptake can be controlled in a targeted manner by the active substance.

In addition, the coated active ingredient formulation of the invention, in particular as a microsphere, is amenable to large-scale production. Due to the disparate separation into the core area and the envelope area, the absorption capacity and/or the absorption kinetics can be controlled in a targeted manner.

As a result, active ingredient formulations can be produced which can be easily distributed and/or are stable in storage. The properties you are aiming for in the end formulations can therefore be achieved without any problems.

Due to its enteral administration, the present coated active substance formulation can be widely used for the therapy of respiratory diseases without impairing or burdening the respiratory tract.

The result is an innovative therapy option with few side effects, which can be used in newborns, children or patients at risk.

The invention in detail

In the case of the coated active substance formulation according to the invention, it can advantageously be provided that the coating is water-impermeable. This is advantageous both for the preparation of the formulation (eg as an aqueous suspension) and for in vivo use. In one embodiment, the shell is permeable to water vapor and thus allows controlled moistening of the active ingredient, but penetration of water into the core area is thus prevented. By reacting with water, the core could swell and damage the shell, or at least lose its CO ₂ -absorbing properties by reacting with the water.

In the context of the present application, the term “water impermeability” is synonymous with the term “watertightness”. The so-called watertightness of the shell is measured by the water column under the pressure of which the material begins to let water through. According to EN 343, a membrane is impermeable to water from a value of 1,300 mm upwards.

• Ausführungsform 1: Flüssiger Kern aufweisend den CO₂-aufnehmenden Wirkstoff mit einer Membranhülle zur Bildung eines Liposoms oder Niosoms.

The coated drug formulation can be provided in one of the following four embodiments:

• Embodiment 1: Liquid core containing the CO ₂ -scavenging agent with a membrane shell to form a liposome or niosome.

In one embodiment, the encapsulated drug formulation may be in the form of a liposome. The advantage of liposomes lies in the high gas permeability of the membrane shell, so that a high level of CO ₂ absorption is possible on the shell side. Niosomes are microscopic spheres similar to liposomes with a double membrane enclosing an interior space. Active ingredients can be incorporated into this interior space. Niosomes are constructed analogously to liposomes. However, liposomes contain double membranes formed from phospholipids, whereas the building blocks of the niosome Double membrane derived from sugars or amino acids.

Embodiment 2: Solid core comprising the CO ₂ -scavenging agent with a single-layer shell.

In this embodiment, the solid core is encased in a single layer shell. Accordingly, it is a simple formulation that is inexpensive to produce.

Embodiment 3: Solid core comprising the CO ₂ -scavenging agent with a multi-layer shell.

In this embodiment, the solid core is encased in a multi-layered shell. It is a complex formulation in which the properties of the shell in terms of permeability, stability or biocompatibility can be adjusted or distributed in a targeted manner. An inner shell layer can give the formulation the necessary strength, and an outer shell layer can achieve the prescribed permeability.

Embodiment 4: Microcapsule.

In this embodiment, the coated active substance formulation can also be in the form of a microcapsule.

Microcapsules are free-flowing powders with particle diameters in the range of approx. 1 µm - 1,000 µm. They are manufactured using various coating processes of finely divided solid or liquid materials. Polymers are usually used as the shell or wall material. Basically, microcapsules consist of two disparate areas, the core area and the envelope area.

In order for the microcapsules to be free-flowing, there must be no adhesive forces between the particles that would result in the particles sticking together or even in agglomeration (“lump formation”). The pourability is based on the DIN standard EN ISO 6186 determinable, as is also described in the European Pharmacopoeia, Chapter 2.9.1 "Flowability". This defines an apparatus that is used to control and test the pourability of solids in powder or granulate form (e.g. plastic granulate). The material is fed through a standardized funnel and the run-off time is determined using a stopwatch. One can derive information regarding workability and steady process control in production. Good pourability is important for trouble-free automatic processing. The pourability of materials is essentially influenced by the surface properties of the grains.

Manufacturing processes suitable for microencapsulation are phase separation processes (simple and complex coacervation), interfacial polymerization processes (polycondensation or polyaddition from dispersions) and mechanical-physical processes (fluidized bed process, spray drying).

The fundamental disadvantage of conventional microencapsulation is the relatively high production cost.

Advantageously, the invention can provide for the microcapsule of the coated active ingredient formulation to be a microspherule in which the CO ₂ -absorbing active ingredient is incorporated in a solid, dispersed form or in dissolved form in a polymeric carrier matrix.

Microspherules are systems related to microcapsules, in which there is no exact separation of the core and shell areas. In their size of approx. 1 µm - 1,000 µm, however, microspherules correspond to microcapsules. In microspheres, the embedded active ingredient is present in a solid, i.e. dispersed, or dissolved form incorporated into the carrier matrix. Microspherules are a special form of microcapsules. The carrier matrix usually consists of a polymer.

It can be provided in the invention that, in the case of the coated active substance formulation, the CO ₂ -absorbing active substance is selected from the group consisting of CO ₂ -absorbing material, CO ₂ -adsorbing material, CO ₂ -dissolving material and CO ₂ -converting enzyme, and preferably is a CO ₂ absorbing material.

The term "absorption" describes the process of absorbing or "dissolving" the carbon dioxide in another phase. This is not an accumulation on the surface (adsorption), but an uptake into the free volume of the absorbent phase. When it comes to absorption, a distinction is made between physical and chemical absorption. In physical absorption, the carbon dioxide is dissolved as a gas in a solvent. Mixing takes place without a chemical reaction.

In chemical absorption, the carbon dioxide undergoes a chemical reaction with the "solvent" or absorbent to form a product substance.

In the present case, “adsorption” refers to the accumulation of carbon dioxide on the surface of a solid.

Advantageously, it can be provided in the invention that, in the case of the coated active substance formulation, the coating has a CO ₂ permeability of 0.004 to 2,500×10 ^-13 cm ³ cm ^-2 Pa ^-1 s ^-1 , preferably from 5 to 500×10 ^-13 cm ³ cm cm ^-2 Pa ^-1 s ^-1 , and more preferably from 10 to 300 x 10 ^-13 cm ³ cm cm ^-2 Pa ^-1 s ^-1 . For example, the envelope may have a CO ₂ permeability of 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 x 10 ^-13 cm ³ cm cm ^-2 Pa ^-1 s ^-1 . It has been found that a shell with such a CO ₂ permeability achieves adequate profiles in terms of absorption kinetics.

A material, which is preferably a polymer, with high permeability for CO ₂ is suitably used as the wall material. This enables efficient CO ₂ uptake in the context of in vivo application. The following polymers may be mentioned as examples: low-density polyethylene (LD-PE), polylactides (PLA), polybutylene adipate terephthalate (PBAT, EcoFlex) and polyhydroxyalkanoates such as poly[(R)-3-hydroxybutyrate] (PHB).

The previously defined CO ₂ -permeable shell is preferably the carrier matrix of a microspherule.

Advantageously, it can be provided in the invention that in the coated active ingredient formulation, the shell has a water vapor permeability of 0.009 to 32,000 × 10 ^-13 cm ³ cm ^-2 Pa ^-1 s ^-1 , and preferably from 100 to 1500 × 10 ^-13 cm ³ cm cm ^-2 Pa ^-1 s ^-1 . For example, the shell can have a water vapor permeability of 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 x 10 ^-13 cm ³ cm cm ^-2 Pa ^{-1 s -1} . It has been found that a shell with such a water vapor permeability enables the absorber material to be moistened by up to _approx of the carbon dioxide to form carbonic acid, this carbonic acid can react with the calcium hydroxide to form calcium carbonate and water.

A material, which is preferably a polymer, with a sufficiently high permeability for water vapor is suitably used as the wall material. This enables CO ₂ absorption, which occurs via intermediate carbonic acid, within the scope of in vivo application. The following polymers may be mentioned as examples: low-density polyethylene (LD-PE), polylactides (PLA), polybutylene adipate terephthalate (PBAT, EcoFlex) and polyhydroxyalkanoates such as poly[(R)-3-hydroxybutyrate] (PHB).

The previously defined water vapor-permeable shell is preferably the carrier matrix of a microspherule.

In a further possibility it can be provided that in the coated active substance formulation the coating has a mass fraction of 10 to 95% by weight, preferably 40 to 60% by weight and particularly preferably 55 to 65% by weight, based on the weight of the coated drug formulation. The mass fraction of the shell can be, for example, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62 or 64% by weight. In this case, the shell is preferably the carrier matrix of a microspherule.

It is also conceivable that, in the case of the coated active substance formulation, the coating has an average layer thickness of 10 to 500 μm, preferably 50 to 250 μm and particularly preferably 100 to 200 μm. As has been shown, layer thicknesses of this type still allow sufficient CO ₂ absorption on the one hand, but are stable enough on the other hand to prevent the undesired release of the core material into the organism.

In the case of the encapsulated active substance formulation, the wall material making up the encapsulation is preferably a polymer and particularly preferably selected from the group consisting of poly(organo)siloxane; polyolefin; Polyester; polybutylene succinate; polybutylene adipate terephthalate (PBAT); polyethylene such as high-density polyethylene (HDPE) or low-density polyethylene (LDPE); polylactide (PLA), polyhydroxyacetic acid (PGA) and poly(lactide-coglycolide) (PLGA); Lipids such as fatty acids or phospholipids. In this case, the wall material is particularly preferably a polyester. The use of a polyester has the advantage that it has very good resistance to bases and acids and can be processed in a particularly wide process window.

A pharmaceutically acceptable material, which is preferably a polymer, is suitably used as the wall material. This enables an in vivo application with few or no side effects. The following polymers may be mentioned by way of example: low-density polyethylene (LD-PE), polylactides (PLA), polybutylene adipate terephthalate (PBAT; EcoFlex) and polyhydroxyalkanoates such as poly[(R)-3-hydroxybutyrate] (PHB).

A material (preferably in polymer) is suitably used as the wall material which, due to its material purity, has a content of so-called “leachables” or “extractables”. which is below the permissible limit values.

This enables an in vivo application with few or no side effects.

In the case of the coated drug formulation, the shell is suitably inert to the CO ₂ -scavenging drug. This means that with a basic CO ₂ -absorbing agent, such as calcium hydroxide, the shell is base-stable.

The term "stable" in the context of the present invention, when used to characterize the shell in base, means that the shell remains largely intact after a solution of saturated calcium hydroxide solution either at 90 ° C. for one day or 30 days at 40°C, preferably the shell remains substantially completely intact under these conditions, and more preferably the shell remains substantially completely intact under these conditions. In the context of the acid treatment, the terms "broadly, substantially completely and substantially completely" mean that the shell matrix retains at least 90%, at least 95% and at least 99% of its chemical bonds in the polymer backbone after exposure to these conditions, respectively.

This also means that in the case of an acidic CO ₂ -absorbing active ingredient, the shell is acid-stable. Acid stability is also required for oral administration or passage through the stomach.

The term "stable" in the context of the present invention when used to characterize the shell in acid means that the shell remains largely intact after either a solution of 20% sulfuric acid at 90°C for one day or 30 days at 40°C, preferably the shell remains substantially completely intact under these conditions, and more preferably the shell remains substantially completely intact under these conditions. In the context of the acid treatment, the terms "broadly, substantially completely and substantially completely" mean that the shell matrix retains at least 90%, at least 95% and at least 99% of its chemical bonds in the polymer backbone after exposure to these conditions, respectively.

It is also advantageous if the shell of the coated active ingredient formulation forms a semipermeable barrier so that non-polar molecules such as CO ₂ gas molecules can pass through the shell in order to reach the core area of the CO ₂ -absorbing active ingredient. However, as a semipermeable barrier, this shell is impermeable to charged molecules such as salt cations or anions and accordingly also to protons and hydroxide anions. The shell thus represents a selectively permeable shell. This selective permeability can prevent hydroxide ions from being released into the organism, for example in the case of a strongly basic CO ₂ -absorbing material such as calcium hydroxide.

Wall materials that allow the construction of such a selectively permeable shell as described above are, for example, low-density polyethylene (LD-PE), polylactides (PLA), polybutylene adipate terephthalate (PBAT; EcoFlex) and polyhydroxyalkanoates such as poly[(R)- 3-hydroxybutyrate] (PHB).

1. (a) CO₂-absorbierendes Material ausgewählt aus der Gruppe bestehend aus anorganische Hydroxidverbindung, Lithiumperoxid und Mischungen hiervon, wobei Lithiumhydroxid, Natriumhydroxid, Kaliumhydroxid, Calciumhydroxid und Magnesiumhydroxid, und Mischungen hiervon, bevorzugt sind; oder
2. (b) CO₂-adsorbierendes Material ausgewählt aus der Gruppe bestehend aus Aktivkohle, Molekularsieb wie Zeolith, Silika, metallorganische Gerüstverbindungen (MOFs); oder
3. (c) CO₂-lösendes Material ausgewählt aus der Gruppe bestehend aus stark eutektischem Lösungsmittel und ionischer Flüssigkeit; oder
4. (d) CO₂-umsetzendes Enzym wie Carboanhydrase (EC 4.2.1.1).

Advantageously, the invention can provide that the CO ₂ -absorbing agent is one of the following materials:

1. (a) CO ₂ -absorbing material selected from the group consisting of inorganic hydroxide compound, lithium peroxide, and mixtures thereof, with lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, and magnesium hydroxide, and mixtures thereof being preferred; or
2. (b) CO ₂ -adsorbing material selected from the group consisting of activated carbon, molecular sieves such as zeolite, silica, metal-organic frameworks (MOFs); or
3. (c) CO ₂ -dissolving material selected from the group consisting of strong eutectic solvent and ionic liquid; or
4. (d) CO ₂ -converting enzyme such as carbonic anhydrase (EC 4.2.1.1).

In the case of the invention, it can advantageously be provided that the CO ₂ -absorbing material comprises calcium hydroxide.

According to a further embodiment, the CO ₂ -absorbing material consists essentially of calcium hydroxide. The calcium hydroxide reacts with the carbon dioxide to form pharmaceutically acceptable calcium carbonate. Here, “substantially” means that the CO ₂ -absorbing material contains at most 5% by weight, preferably at most 4% by weight, preferably at most 3% by weight, more preferably at most 1% by weight of other components. According to another embodiment, the CO ₂ -absorbing material consists of calcium hydroxide.

In an advantageous embodiment it is provided that the calcium hydroxide-containing, CO ₂ -absorbing material is essentially free of sodium and potassium hydroxide. Here means "Substantially" that the CO ₂ -absorbing material contains at most 4 wt.%, preferably at most 2 wt.%, preferably at most 1 wt.%, more preferably 0.5 wt.% sodium and potassium hydroxide, and most preferably none Contains sodium and potassium hydroxide.

The calcium hydroxide-containing compositions described above contain, in one embodiment, as an additional optional ingredient, an effective amount of a hygroscopic or deliquescent humectant capable of absorbing carbon dioxide.

In the case of the coated active substance formulation, it can advantageously be provided that the CO ₂ -adsorbing material is selected from the group consisting of activated carbon, a molecular sieve such as zeolite, silica and metal-organic frameworks (MOFs).

Activated carbon is a fine-grained carbon with a large internal surface area, which can be between 300 and 2000 m ² /g of carbon. The term "molecular sieve" is the functional designation for natural and synthetic zeolites or other substances that have a high adsorption capacity for carbon dioxide gas. In addition to zeolites, there are also carbon molecular sieves, for example. The molecular sieves have a large internal surface area (600-700 m ² /g) and have uniform pore diameters that are of the order of the diameters of molecules. According to the present application, metal-organic frameworks (MOFs) are defined as microporous materials consisting of inorganic building units, the so-called inorganic building units (IBUs, English for "inorganic building units") and organic molecules as connecting elements (English linkers) between the inorganic structural units are constructed. MOFs are open-framework coordination networks containing pores. After synthesis, the pores of the three-dimensional structures are usually filled with guest molecules (e.g. solvents or unreacted linkers). By removing the guest molecules (e.g. by heating, in a vacuum or by a combination of both), the pores can be made accessible again for the uptake of gases such as CO ₂ .

In the context of the present application, deep eutectic solvents (DES) refer to multi-component, eutectic molten salts whose melting point, like that of ionic liquids, is close to or below room temperature. Examples of eutectic solvents are based on a mixture of quaternary ammonium compound with hydrogen bond donors (e.g. amines) and carboxylic acid.

According to a further advantage it can be provided that in the active substance formulation according to the invention the CO ₂ -absorbing material has a CO ₂ absorption capacity of more than 10 mg CO ₂ / g active substance formulation, preferably more than 40 mg CO ₂ / g active substance formulation, particularly preferably of more than 50 mg CO ₂ / g active ingredient formulation, and in particular more than 75 mg CO ₂ / g active ingredient formulation. The higher the CO ₂ absorption capacity, the smaller the amounts of active ingredient formulation applied are necessary in order to achieve a therapeutically relevant effect.

In a second aspect, the invention relates to a liquid medical composition which, as a dispersion, comprises the coated active ingredient formulation according to the invention and a pharmaceutically acceptable aqueous carrier liquid.

A "medicinal composition" within the meaning of the invention is a composition that can be used for the prevention, diagnosis, treatment or alleviation of diseases. It thus includes both pharmaceutical compositions for the manufacture of a medicament and compositions for the manufacture of a medicinal product.

In the context of the application, a dispersion is defined as a heterogeneous mixture of two substances that do not or hardly dissolve in one another or chemically combine with one another. The active ingredient formulation is distributed as a disperse phase in the carrier liquid as the dispersion medium.

When using the coated active substance formulation or the liquid medical composition according to the invention for the treatment of diseases of the respiratory system such as acute or chronic respiratory diseases or lung diseases; Cardiovascular diseases, or infectious diseases or respiratory disorders after severe disease progression, these diseases can occur both as main diseases and as comorbidities.

In addition, the coated active ingredient formulation or the liquid medical composition produced from it can also be used for weaning from ventilation (also referred to as “weaning”), i.e. in the phase of weaning a ventilated patient from the ventilator.

In a further aspect, the invention relates to the use of the liquid medicinal composition according to the invention in intraperitoneal or enteral administration, such as, for example, orally, rectally or through a tube.

The advantageous properties of the present coated active ingredient formulation with regard to controlled and efficient CO ₂ uptake allow this formulation to be used in a wide range of application forms.

Enteral application is preferred here, ie an application that achieves the effect via the digestive tract. The enteral administration can take place orally, but also perorally, for example distal to the oral cavity via a probe, via a stoma, or rectally. Since, depending on the extent of the hypercapnia, sometimes large amounts of the formulation according to the invention have to be administered, enteral administration is advantageous, which allows simple replacement for a new active ingredient formulation even after CO ₂ absorption has taken place by flushing processes.

In addition, the active ingredient formulation can also be used as an intraperitoneal application.

In a preferred embodiment, oral administration is excluded from the forms of administration, ie the active substance formulation is not ingested through the mouth, but rather supplied to the organism in other ways (such as, for example, by rectal administration).

The invention further relates to the coated active ingredient formulation or the liquid medical composition produced therewith for use in the prophylaxis or treatment of diseases of the respiratory system such as acute or chronic respiratory diseases or lung diseases; Cardiovascular diseases, metabolic imbalances associated with acidosis (e.g. ketoacidosis) or infectious diseases or respiratory disorders following severe disease progression.

• (a) Chronische obstruktive Lungenerkrankung;
• (b) Asthma;
• (c) Mukoviszidose;
• (d) Akutes Lungenversagen;
• (e) Hyperkapnie;
• (f) Lungenentzündung;
• (g) Lungencarcinom;
• (h) Lungenfibrose;
• (i) Krankheiten der Atemwege nach medizinischen Maßnahmen gemäß ICD-10 J95;
• (j) Respiratorische Insuffizienz gemäß ICD-10 J96;
• (k) Sonstige Krankheiten der Atemwege gemäß ICD-10 J97;
• (l) Krankheiten der Atemwege bei anderenorts klassifizierten Krankheiten gemäß ICD-10, J99;
• (m) Unreife Lunge.

Here, the disease of the respiratory system is preferably selected from the list consisting of:

• (a) Chronic obstructive pulmonary disease;
• (b) asthma;
• (c) cystic fibrosis;
• (d) acute respiratory failure;
• (e) hypercapnia;
• (f) pneumonia;
• (g) lung carcinoma;
• (h) pulmonary fibrosis;
• (i) post-procedure respiratory diseases as defined in ICD-10 J95;
• (j) Respiratory failure according to ICD-10 J96;
• (k) other respiratory diseases as per ICD-10 J97;
• (l) respiratory diseases in diseases classified elsewhere under ICD-10, J99;
• (m) Immature lung.

The invention further relates to the coated drug formulation or the liquid medicinal composition made therewith for use in inducing hypocapnia in a patient. This includes uses that require extrapulmonary reduction of CO ₂ levels in the body. Thus, with the coated active ingredient formulation, the intracranial pressure can be actively or passively reduced without hyperventilation, since a reduced CO ₂₃ partial pressure has a vasoactive effect.

It is preferred here if the coated active ingredient formulation is in the form of microspherules.

• (A) Bereitstellen eines CO₂-aufnehmenden Wirkstoffs in fester oder flüssiger Form, wobei der CO₂-aufnehmende Wirkstoff vorteilhafterweise ein CO₂-absorbierendes Material ist;
• (B) Bereitstellen von mindestens einem Polymer als Trägerkunstoff;
• (C) Zuführen des CO₂-aufnehmenden Wirkstoffs, dem mindestens einem Polymer aus Schritt (B) zu einem Extruder und optional von Additiven wie Dispergier-Hilfsmittel zu dem Extruder, der bevorzugt ein Schneckenextruder ist;
• (D) Dispergieren des CO₂-aufnehmenden Wirkstoffs in dem Polymer durch Aufschmelzen des Polymers im Extruder und intensive Einmischung des CO₂-aufnehmenden Wirkstoffs in dem aufgeschmolzenen Polymerstrom;
• (E) Extrusion der aufgeschmolzenen Mischung aus (D) durch eine oder mehrere formgebende Öffnungen wie eine Düse oder mehrere Düsen;
• (F) Abkühlen des extrudierten Kunststoffstrangs;
• (G) Granulierung des extrudierten Kunststoffstrangs; besonders bevorzugt direkt hinter der formgebenden Öffnung in einem Flüssigkeitsbad;
• (H) Optional eine Vermahlung der Kunststoffgranulats aus Schritt (G), bevorzugt mittels kryogenem Vermahlen;
• (l) Oberflächenbehandlung zur pH-Neutralisierung oder Entfernung des an der Partikeloberfläche freiliegenden CO₂-aufnehmenden Wirkstoffs.

In a further aspect, the invention relates to a method for producing the coated active substance formulation according to the invention in the form of microspherules, comprising the following steps:

• (A) providing a CO ₂ -scavenging agent in solid or liquid form, wherein the CO ₂ -scavenging agent is advantageously a CO ₂ -absorbing material;
• (B) providing at least one polymer as carrier plastic;
• (C) feeding the CO ₂ scavenging agent, the at least one polymer from step (B) to an extruder and optionally additives such as dispersing aids to the extruder, which is preferably a screw extruder;
• (D) dispersing the CO ₂ -absorbing active substance in the polymer by melting the polymer in the extruder and intensive mixing of the CO ₂ -absorbing active substance in the molten polymer stream;
• (E) extrusion of the melted mixture from (D) through one or more shaping orifices such as a die or dies;
• (F) cooling the extruded plastic strand;
• (G) granulation of the extruded plastic strand; particularly preferably directly behind the shaping opening in a liquid bath;
• (H) optional grinding of the plastic granules from step (G), preferably by means of cryogenic grinding;
• (l) Surface treatment for pH neutralization or removal of the CO ₂ scavenging agent exposed on the particle surface.

In step (A) of the method, the CO ₂ -scavenging agent is provided in solid or liquid form. The core area of the active ingredient formulation is to be formed from it. Preferably, the CO ₂ scavenging agent is a CO ₂ absorbing material such as calcium hydroxide.

In step (B) of the method, at least one polymer is provided as the carrier plastic. This polymer is suitably in the form of a solid polymer, which is preferably in the form of granules. The polymer is suitably a thermoplastic polymer which is melted in the extruder and thus enables the active ingredient to be embedded in the polymeric carrier matrix.

In step (C), the components provided according to step (A) and step (B), ie the CO ₂ -absorbing active substance and the at least one polymer, are fed to an extruder. One or more additives can optionally be added here. An example of a possible additive is a dispersing aid. With an extruder, plastically deformable to viscous masses are continuously pressed out of a shaping opening (also known as a nozzle) under pressure.

The extruder is preferably a screw extruder, which can be designed as a single-screw or twin-screw extruder. With this design, the pressure is generated by means of an extruder screw, also called "screw" for short. It is in the so-called screw cylinder, whose nominal diameter is almost the same as the outer diameter of the screw. The nozzle is located at the front end of the screw cylinder as a shaping outlet opening. At the rear end of the cylinder is the drive that rotates the auger. The material is mixed by the extruder screw and the thermoplastic polymer is melted by the pressure and optionally by additional heat supply by means of a heated screw and/or a heated extruder housing, so that the CO ₂ -absorbing active substance particles are distributed homogeneously in the polymeric carrier matrix. The material is also transported further in the direction of the nozzle by the auger.

In a further advantageous embodiment, the extruder is a planetary roller extruder. This has the advantage that it allows a particularly homogeneous mixing of the supplied components.

By processing the components in the extruder, the CO ₂ -absorbing active substance is dispersed in the polymer in step (D) by melting the polymer in the extruder and intensive mixing of the CO ₂ -absorbing active substance in the molten polymer stream. This happens primarily in the so-called compression zone of the extruder, in which the material is further compressed by the reduced flight depth of the screw and the pressure required for discharge in the tool is built up.

The components can expediently be subjected to devolatilization in the extruder.

Finally, the discharge zone or metering zone ensures a homogeneous flow of material to the tool, so that in step (E) the melted mixture from (D) is extruded through one or more shaping openings such as a nozzle or nozzles.

The extrudate obtained as a plastic strand is cooled in step (F), so that the thermoplastic polymer hardens accordingly and thus firmly encloses the CO ₂ -absorbing active ingredient.

In step (G), the extruded plastic strand is granulated. This preferably takes place directly behind the shaping opening and here particularly preferably in a liquid bath used for cooling. The plastic strand can be divided into individual portions by a separating or cutting device.

Step (H) is an optional step and provides for grinding of the plastic granules generated in step (G) from step (G). This grinding is preferably carried out by means of cryogenic grinding.

In step (l), the surface of the plastic granulate is treated, which serves to neutralize the pH or remove the CO ₂ -absorbing active ingredient that is exposed on the particle surface.

This step serves to absorb the CO ₂ material due to incomplete Coating is free on the surface of the particles and could thus interact directly with the surrounding environment to undergo a surface treatment. In advantageous

• (i) Waschen der Mikrosphärulen mit Säure und anschließender pH-Neutralisierung;
• (ii) temporäres Aufschmelzen der Mikrosphärulen zum Verschluss des an der Oberfläche exponierten, CO₂-aufnehmenden Wirkstoffs; oder
• (iii) Zusätzliche Beschichtung der Mikrosphärulen.

This surface treatment is carried out by one or more of the following steps:

• (i) washing the microspheres with acid followed by pH neutralization;
• (ii) temporary melting of the microspheres to occlude the surface-exposed CO ₂ -scavenging agent; or
• (iii) Additional coating of the microspheres.

In the case of a basic CO ₂ absorber such as calcium hydroxide, according to step (i) the surface exposed basic absorber can be neutralized by washing the microspheres with acid. The acid-base reaction converts the absorber into a (preferably soluble) salt, which can then be removed by optional subsequent washing steps.

According to step (ii), the microspheres can be subjected to temporary melting. This is particularly possible with thermoplastic polymers. As the inventors found out, this temporary melting causes the CO ₂ absorbers exposed on the surface to be sealed. This thermal step has the advantage that it does not require any chemical treatment and the total amount of CO ₂ absorber contained is retained. To prevent particle agglomeration, the microspheres are temporarily melted in a liquid suspension and/or the microspheres are vigorously mixed.

According to step (iii), the microspheres can be provided with an additional coating. As a result, the CO ₂ absorbers exposed on the surface can be coated and thus sealed. Such a coating can also be used to specifically modify the microspheres with regard to other properties such as hydrophobicity, hydrophilicity or biocompatibility.

In an alternative embodiment, the polymer building up the carrier matrix can be used for the coating in order to achieve a homogeneous structure of the microspherule.

It is also conceivable that an auxiliary substance and/or an additive is additionally added to the aforementioned components in the method according to the invention. Mention may be made, for example, of surface-active substances, fillers, other flame retardants, nucleating agents, oxidation stabilizers, lubricants and mold release aids, dyes and pigments, optionally stabilizers, e.g. against hydrolysis, light, heat or discoloration, inorganic and/or organic fillers, reinforcing agents and plasticizers. Suitable auxiliaries and additives can be found, for example, in the Plastics Handbook, Volume VIII “Polyester”, Gerhard W. Becker and Dietrich Braun, Carl Hanser Verlag, Munich, Vienna, 1993.

Furthermore, it can be provided that a bicomponent fiber is produced in the extrusion process. Such a bi-component fiber consists of two polymers which are firmly but separably connected to one another and have a different chemical and/or physical structure. A variety of geometric configurations of the polymers exist, but the following four fiber cross-section types are particularly advantageous: a) side-by-side (S/S type); b) sheath/core (M/K type); c) matrix/fibrils (M/F type); d) Pie slices (also called orange slice type).

Advantageously, in the method according to the invention, provision can be made for the microspheres to be dispersed in a carrier solution in a further step.

In a second aspect, the invention relates to microspherules which can be produced or are produced by the extrusion method according to the invention described above.

The extrusion process can be used to produce microspheres that have an extremely homogeneous particle size distribution. This ensures that the CO ₂ uptake can be controlled in a targeted manner by the active substance.

In addition, the extrusion process allows large-scale production of the microspheres. The intensive mixing in the extruder results in a homogeneous distribution of the CO ₂ absorber in the polymer matrix, which is associated with advantageous CO ₂ uptake kinetics in in vivo use.

By embedding them in a polymer matrix, the resulting microspherules can be easily distributed and/or are stable in storage. The properties you are aiming for in the end formulations can therefore be achieved without any problems.

In a further possibility it can be provided that the microspheres have a round, ellipsoidal, irregular or elongated shape.

An elongated shape can be defined via the aspect ratio, which is defined as the ratio of the length of the microspherule to the greatest lateral extent. An elongated form has an aspect ratio of 4:1, preferably 3:1 and 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 entirely of polymer material.

Advantageously, it can be provided in the invention that the microspherules have a spherical shape with a particle size of between 50 and 1000 μm and preferably of between 100 and 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.

In the case of elongated particles, which preferably have a circular, trilobal or square cross-section, it is preferred that the particles have a diameter of 50 to 800 μm and a length of up to 4 mm.

definitions

In the present document, the term "polymer" includes, on the one hand, a group of macromolecules that are chemically uniform but differ in terms of degree of polymerization, molecular weight and chain length, and which were produced by a polyreaction (polymerization, polyaddition, polycondensation). On the other hand, the term also includes derivatives of such a collective of macromolecules from polyreactions, ie compounds which were obtained by reactions, such as additions or substitutions, of functional groups on given macromolecules and which can be chemically homogeneous or chemically heterogeneous. The term also includes copolymers and so-called prepolymers, ie reactive oligomeric pre-adducts whose functional groups are involved in the construction of macromolecules.

• 1.) statistische Copolymere, in denen die Verteilung der beiden Monomeren in der Kette einer statistischen Verteilung folgt,
• 2.) Gradientcopolymere, die prinzipiell den statistischen Copolymeren ähnlich sind, in denen jedoch der Anteil des einen Monomers im Verlauf der Kette zu- und des anderen abnimmt,
• 3.) Alternierende Copolymere, in denen sich die beiden Monomere abwechseln,
• 4.) Blockcopolymere und Segmentcopolymere, die aus längeren Sequenzen oder Blöcken jedes Monomers besteht, und
• 5.) Pfropfcopolymere (engl.: graft copolymers), bei denen Blöcke eines Monomers auf das Gerüst (Rückgrat) eines anderen Monomers aufgepfropft sind.

In the present document, the term “copolymer” refers to a polymer composed of two or more different types of monomer units. This distinguishes the copolymer from a homopolymer, which is made up of only one (real or imaginary) type of monomer and accordingly only has one repeating unit. Copolymers can be divided into five classes viz

• 1.) statistical copolymers, in which the distribution of the two monomers in the chain follows a statistical distribution,
• 2.) Gradient copolymers, which in principle are similar to statistical copolymers, but in which the proportion of one monomer increases and the other decreases in the course of the chain,
• 3.) Alternating copolymers, in which the two monomers alternate,
• 4.) block copolymers and segmented copolymers consisting of longer sequences or blocks of each monomer, and
• 5.) Graft copolymers, in which blocks of one monomer are grafted onto the backbone of another monomer.

As used herein, “molecular weight” means the molar mass (in grams per mole or in daltons) of a molecule. In the present document, “average molecular weight” always means the number average of the molecular weight distribution M _n (number average). The term “number-average molar mass” is also used here as a synonym for “average molecular weight”.

In the present document, the term “solvent” refers to compounds as listed as organic solvents in CD Rompp Chemie Lexikon, 9th edition, version 1.0, Georg Thieme Verlag, Stuttgart 1995. The polyols used according to the invention are not covered by this definition , although they act as solvents for the monomers and also the low molecular weight polymer formed by radical polymerization.

In the present document, "solid" is understood to mean substances which do not change their shape without external influences or which can only be deformed with difficulty, but in particular they are not flowable. “Liquid” means substances that can be deformed and flow, which also includes highly viscous and pasty substances.

It is expressly pointed out that in the context of the present patent application, indefinite articles and indefinite numbers such as "one...", "two..." etc. should generally be understood as at least information, i.e. as "at least one ...", "at least two..." etc., unless it follows from the context or the specific text of a specific passage that there is only "exactly one...", "exactly two..." etc. Furthermore, all numerical data and information on process parameters and/or device parameters are to be understood in the technical sense, i.e. as provided with the usual tolerances. Also from the explicit specification of the restriction "at least" or "at least". or similar, it must not be concluded that the simple use of "one", i.e. without the specification of "at least" or similar, means "exactly one".

Unless otherwise stated, the percentages given in this document are percentages by weight.

The embodiments shown here only represent examples of the present invention and should therefore not be understood to be limiting. Alternative embodiments contemplated by those skilled in the art are equally encompassed within the scope of the present invention.

exemplary embodiments

1. Production of the microspheres according to the invention

8 g/min of LD-PE with a melting temperature of 242 degrees Celsius are introduced in the main stream into a side stream extruder. The main spindle speed is 175 rpm. The extruder has six heating zones in which the temperatures of 220, 230, 240, 250, 250 and 250 degrees Celsius can be set. The side stream extruder adds 7.4 g/min of powdered Ca(OH) ₂ at a speed of 170 rpm. The strand is spun into demineralized water via a 6 mm nozzle with a circular cross-section. In the downstream granulator, the strand is cut into spherules 2 mm in length. A further comminution takes place in a Fritsch Pulverisette 14 cryo-grinder with a speed of 20,000 rpm and grinding disk 2.0, with the constant supply of liquid nitrogen, so that microspherules are obtained. The fraction with the desired grain size of 100 to 600 µm is isolated by sieving.

The microspheres with a particle size of 100 to 600 μm are suspended in a 0.2% by weight agar-agar solution at a concentration of 25% by weight. Exposed Ca(OH) ₂ particles are neutralized by adding 30% hydrochloric acid and the pH of the suspension is adjusted to 7.40.

2. In vitro CO2 uptake by the formulation according to the invention

To analyze the CO ₂ uptake of the suspension produced, 1 ml of this is placed in a vessel with a volume of 700 ml which contains 9,000 ppm of CO ₂ in N ₂ . The absorption capacity and the absorption kinetics can be determined by measuring the CO ₂ concentration in the gas mixture every 60 seconds.

The results are in the 2 A shown. The microspheres according to the invention are saturated after a period of 90 minutes, so that the permeability properties of LDPE result in a delayed effect in terms of CO ₂ uptake.

A CO ₂ absorption capacity of 3 ± 0.82 mg CO ₂ / g microspheres was determined for the present embodiment.

3. In vivo CO ₂ uptake by the formulation according to the invention

The Aachen Mini-Pig was used as an animal model to test the formulation according to the invention in vivo. The animals were ventilated under deep anesthesia with constant CO ₂ elimination via the lungs. After application of 50 g of the microspheres produced according to Example 1 using a duodenal probe, the CO ₂ content of the arterial blood was determined at intervals of 15 minutes.

The content of arterial CO ₂ as a function of time is in 2 B shown. After application, the arterial CO ₂ content fell from 25 mmol/L to 21 mmol/L for a period of 3 hours, followed by a slow increase in the CO ₂ content in the arterial blood to the initial value.

The effectiveness of the formulation according to the invention in mammals could be confirmed by this animal experiment.

• 1 die schematische Darstellung eines erfindungsgemäßen Mikrosphäruls.
• 2A Ergebnisse zur in vitro-Aufnahme von CO₂ durch die erfindungsgemäßen Mikrosphärulen.
• 2B Ergebnisse zur in vivo-Aufnahme von CO₂ durch die erfindungsgemäßen Mikrosphärulen

Various embodiments of the invention are described below with reference to the figures. It shows:

• 1 the schematic representation of a microspherule according to the invention.
• 2A Results of the in vitro uptake of CO ₂ by the microspherules according to the invention.
• 2 B Results of the in vivo uptake of CO ₂ by the microspherules according to the invention

The 1 shows a microspherule 1 according to the invention in a schematic representation. In this embodiment, the microsphere 1 assumes a spherical shape and thus has a particularly advantageous ratio of volume to surface area. It consists of a polymer matrix 2 in which individual particles of CO ₂ absorber 3 are enclosed in a homogeneously distributed form. The CO ₂ absorbers on the surface were removed by acid treatment with subsequent washing steps, so that only cavities 4 remained and thus there is no longer any CO ₂ absorber on the surface. The microsphere 1 is in the form of particles in a liquid dispersion medium 5 .

Reference List

1

microspherule

2

polymer matrix

3

CO ₂ absorber

4

Surface cavity created by washed out CO ₂ absorber

5

dispersion medium

QUOTES INCLUDED IN DESCRIPTION

This list of documents cited by the applicant was generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Patent Literature Cited

• WO 2020/035163 A1 [0006]
• WO 2005/097075 A2 [0008]
• US2015245999A1 [0008]
• US2017319617A1 [0008]

Non-patent Literature Cited

• DIN standard EN ISO 6186 [0032]

Claims (25)

Coated drug formulation for controlled in vivo uptake of CO ₂ , comprising: (i) a shell consisting of a wall material, wherein the shell is permeable to CO ₂ and optionally also to water vapour; (ii) and a core region which has at least one CO ₂ -scavenging agent. Coated drug formulation according to claim 1 , characterized in that the cover is impermeable to water. Coated drug formulation according to claim 1 or 2 , characterized in that the coated drug formulation is selected from the group consisting of: • liquid core containing the CO ₂ -scavenging drug with a membrane shell to form a liposome or niosome; • Solid core containing the CO ₂ -scavenging agent with a single-layer shell; • Solid core containing the CO ₂ -scavenging agent with a multi-layer shell; • Microcapsule. Coated drug formulation according to claim 3 , characterized in that the microcapsule is a microspherule in which the CO ₂ -scavenging agent is incorporated in a solid, dispersed form or in a dissolved form in a polymeric carrier matrix. Coated active ingredient formulation according to any one of the preceding claims, characterized in that the CO ₂ -absorbing active ingredient is selected from the group consisting of CO ₂ -absorbing material, CO ₂ -adsorbing material, CO ₂ -dissolving material and CO ₂ -converting enzyme, and is preferably a CO ₂ -absorbing material. Coated active ingredient formulation according to one of the preceding claims, characterized in that the shell, which is preferably the carrier matrix of a microspherule, has a CO ₂ permeability of 0.004 to 2,500 × 10 ^-13 cm ³ cm cm ^-2 Pa s ^-1 , preferably 5 to 500 x 10 ^-13 cm ³ cm cm ^-2 Pa s ^-1 and more preferably from 10 to 300 x 10 ^-13 cm ³ cm cm ^-2 Pa ^-1 s ^-1 . Coated active ingredient formulation according to one of the preceding claims, characterized in that the shell, which is preferably the carrier matrix of a microspherule, has a water vapor permeability of 0.009 to 32,000 × 10 ^-13 cm ³ cm cm ^-2 Pa s ^-1 , and preferably 100 to 1500 × 10 ^-13 cm ³ cm cm ^-2 Pa s ^-1 . Coated active substance formulation according to one of the preceding claims, characterized in that the coating, which is preferably the carrier matrix of a microspherule, has a mass fraction of 10 to 95% by weight, preferably 40 to 60% by weight and particularly preferably 55 to 65% by weight. %, based on the weight of the coated active ingredient formulation. Coated active ingredient formulation according to one of the preceding claims, characterized in that the coating has an average layer thickness of 10 to 500 µm, preferably 50 to 250 µm and particularly preferably 100 to 200 µm. Coated active ingredient formulation according to one of the preceding claims, characterized in that the wall material is selected from the group consisting of poly(organo)siloxane; polyolefin; Polyester; polybutylene succinate; polybutylene adipate terephthalate (PBAT); polyethylene such as high-density polyethylene (HDPE) or low-density polyethylene (LDPE); polylactide (PLA), polyhydroxyacetic acid (PGA) and poly(lactide-co-glycolide) (PLGA); lipids such as fatty acids or phospholipids, and preferably a polyester. An encapsulated drug formulation according to any one of the preceding claims, characterized in that the CO ₂ -scavenging drug is one of the following materials: (a) CO ₂ -absorbing material selected from the group consisting of inorganic hydroxide compound, lithium peroxide and mixtures thereof, wherein lithium hydroxide, sodium hydroxide , potassium hydroxide, calcium hydroxide and magnesium hydroxide and mixtures thereof are preferred; or (b) CO ₂ -adsorbing material selected from the group consisting of activated carbon, molecular sieves such as zeolite, silica, metal-organic frameworks (MOFs); or (c) CO ₂ -dissolving material selected from the group consisting of strong eutectic solvent and ionic liquid; or (d) CO ₂ -converting enzyme such as carbonic anhydrase (EC 4.2.1.1). Coated drug formulation according to claim 11 characterized in that the CO ₂ -absorbing material comprises calcium hydroxide and optionally an effective amount of a hygroscopic or deliquescent humectant capable of absorbing carbon dioxide, the calcium hydroxide being substantially free of sodium and potassium hydroxide. Coated active ingredient formulation according to one of the preceding claims, characterized characterized in that the CO ₂ -absorbing material has a CO ₂ absorption capacity of more than 10 mg CO ₂ / g active ingredient formulation, preferably more than 40 mg CO ₂ / g active ingredient formulation, particularly preferably more than 50 mg CO ₂ / g active ingredient formulation, and in particular more than 100 mg CO ₂ / g active ingredient formulation. Liquid medicinal composition as a dispersion comprising an encapsulated active ingredient formulation according to one of Claims 1 until 13 and a pharmaceutically acceptable aqueous carrier liquid. Liquid medicinal composition according to Claim 14 for intraperitoneal or enteral administration such as oral or rectal administration through a tube; or for peritoneal application. Coated drug formulation according to a Claims 1 until 13 or a liquid medicinal composition Claim 14 or 15 for use in the prophylaxis or treatment of diseases of the respiratory system such as acute or chronic respiratory diseases or lung diseases; cardiovascular diseases, metabolic imbalances such as ketoacidosis, or infectious diseases or respiratory disorders following severe disease progression. Coated drug formulation or liquid medical composition Claim 16 characterized in that the respiratory system disease is selected from the list consisting of: (a) chronic obstructive pulmonary disease; (b) asthma; (c) cystic fibrosis; (d) acute respiratory failure; (e) hypercapnia; (f) pneumonia; (g) lung carcinoma; (h) pulmonary fibrosis; (i) post-procedure respiratory diseases as defined in ICD-10 J95; (j) Respiratory failure according to ICD-10 J96; (k) other respiratory diseases as per ICD-10 J97; (l) respiratory diseases in diseases classified elsewhere under ICD-10, J99; (m) Immature lung. Coated drug formulation according to a Claims 1 until 13 or liquid medicinal composition Claim 14 or 15 for use in inducing hypocapnia in a patient. Process for the production of microspherules according to one of Claims 4 until 13 , comprising the following steps: (A) providing a CO ₂ -scavenging agent in solid or liquid form, wherein the CO ₂ -scavenging agent is preferably a CO ₂ -absorbing material; (B) providing at least one polymer as carrier plastic; (C) feeding the CO ₂ -scavenging agent, the at least one polymer from step (B) to an extruder and optionally additives such as dispersing aids to the extruder, which is preferably a screw extruder; (D) dispersing the CO ₂ -absorbing active substance in the polymer by melting the polymer in the extruder and intensive mixing of the CO ₂ -absorbing active substance in the molten polymer stream; (E) extrusion of the melted mixture from (D) through one or more shaping orifices such as a die or dies; (F) cooling the extruded plastic strand; (G) granulation of the extruded plastic strand; particularly preferably directly behind the shaping opening in a liquid bath; (H) optional grinding of the plastic granules from step (G), preferably by means of cryogenic grinding; (l) Surface treatment to neutralize or remove the CO ₂ scavenging agent exposed on the particle surface. procedure according to claim 19 , characterized in that the surface treatment of the microspheres for pH neutralization of the exposed CO2 absorbers is carried out by one or more of the following steps: (i) washing the microspheres with acid and subsequent pH neutralization; (ii) Temporarily melting the microspheres to seal the surface-exposed CO ₂ -scavenging agent; (iii) Additional coating of the microspheres. procedure according to claim 19 or 20 , characterized in that the microspherules are dispersed in a carrier solution in a further step. Microspheres produced by a method according to claim 19 until 21 . according to microspheres Claim 22 , characterized in that they have a round, ellipsoidal, irregular or elongated shape. according to microspheres Claim 22 or 23 , characterized in that they have a full always have an outer surface made of polymeric material. according to microspheres Claim 22 until 24 , characterized in that they have a particle size of between 50 and 1000 µm and preferably between 100 and 500 µm.

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