# US 11,440,872 B2 · Carbonic acid adducts

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- Number: US 11,440,872 B2
- Document ID: US11440872B2
- Status: Granted
- Kind: B2
- Application number: 16/644,909
- Filed: 2018-09-07
- Published: 2020-07-09
- Granted: 2022-09-13
- Earliest claimed: 2017-09-07
- Assignees: Inflamed Pharma GmbH
- Applicants: Inflamed Pharma GmbH
- Inventors: Beatrice Engert; Susanne Vogelsang
- Web page: https://patentgrep.com/patent/US11440872B2

## CPC

- C07C 233/07: having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
- C07C 237/04: the carbon skeleton being acyclic and saturated
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61K 9/2059: {Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin}
- A61K 9/4866: {Organic macromolecular compounds}
- A61K 31/245: Amino benzoic acid types, e.g. procaine, novocaine (salicylic acid esters A61K31/60)
- A61K 33/00: Medicinal preparations containing inorganic active ingredients
- A61K 47/02: Inorganic compounds
- A61K 47/06: Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61P 11/16: Central respiratory analeptics
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- C04B 24/04: Carboxylic acids; Salts, anhydrides or esters thereof
- C07C 211/63: having quaternised nitrogen atoms bound to acyclic carbon atoms
- C07C 227/14: from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C 229/60: with amino and carboxyl groups bound in meta- or para- positions
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C04B: LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE {(roofing granules E04D7/005)}; CERAMICS (devitrified glass-ceramics C03C10/00); REFRACTORIES; TREATMENT OF NATURAL STONE

## Abstract

The present invention relates to a carbonic acid adduct (CAA) comprising carbonic acid, at least one amine, and optionally at least one salt, said adduct being producible by a method comprising the following steps: a) providing a solution (A) comprising dissolved CO2; optionally b) dissolving a base (BA) not corresponding to the amine (AM) in the solution (A) so as to obtain the solution (A1); c) dissolving the at least one amine (AM) in the solution (A) or (A1) so as to obtain the solution (B); d) freezing the solution obtained after completion of step c); and e) storing the solution frozen in step d) at −100 to 0° C. for no longer than 4 days. The content of CO2 in the solution that is subjected to step c) is at least 6 g/l. The invention also relates to a method for producing the carbonic acid adduct (CAA), a pharmaceutical preparation (PP) comprising the carbonic acid adduct (CAA), and methods for the production thereof and use of the carbonic acid adduct (CAA) or the pharmaceutical preparation (PP) in therapy for a range of indications.

## Claims

### Claim 1

A method for preparing a carbonic acid adduct (CAA), comprising carbonic acid, at least one amine (AM), and optionally at least one salt (S), the method comprising steps of
a) providing a solution (A) which comprises at least one solvent, and CO2 dissolved in the at least one solvent,
optionally b) dissolving a base (BA), which does not correspond to the amine (AM), in the solution (A), thereby obtaining the solution (A1),
c) dissolving the at least one amine (AM) in the solution (A) or (A1), thereby obtaining the solution (B),
d) freezing the solution obtained after completion of step c),
e) maintaining the solution frozen in step d) at −100 to 0° C. for no more than 4 days, wherein the content of CO2 in the solution that undergoes step d) is at least 6 g/l, optionally at least 10 g/l, optionally at least 12 g/l, optionally at least 14 g/l, or optionally at least 15 g/l, optionally the amine (AM) being in the form of a salt.

### Claim 2 (depends on 1)

The method of claim 1 wherein step a) comprises at least one of the following substeps:
a1) cooling the solvent, the solvent optionally being water, to a temperature in the range of 3 to 8° C., or optionally about 5° C.;
a2) introducing CO2 into the solvent, optionally up to a saturation concentration in the range of: 3 to 10 g/L, or optionally 4.5 to 7.5 g/L, and optionally a pH of the solution following saturation with CO2 is in the range of 3.0 to 6.0, or optionally in the range of greater than 4.3 to 4.8;
a3) maintaining the solution (A) at 1 to 10° C., or optionally 3 to 8° C., optionally for: at least 30 min, at least 50 min, at least 60 min; and up to 5 days (120 h); the storage optionally takes place at 3 to 8° C.; or
any combination of substeps a1)-a3), optionally all substeps a1)-a3), and optionally in the sequence whereby a2) follows a1), and a3) follows a2).

### Claim 3 (depends on 1)

The method of claim 1, wherein the base (BA) in step b) is a hydrogen carbonate or a carbonate, or optionally a hydrogen carbonate, or optionally sodium hydrogen carbonate.

### Claim 4 (depends on 1)

The method of claim 1, wherein step c) comprises at least one of the following substeps:
c1) dissolving the at least one amine (AM) in the solution (A) or (A1), thereby obtaining the solution (B);
c2) adding solution (A) to solution (B), thereby obtaining the solution (B1);
c3) enriching solution (B) or (B1) with CO2;
c4) storing the solution (B) or (B1) at a temperature in the range of 1 to 10° C., optionally 3 to 8° C., for at least 1 h, optionally 24 h to 120 h, or optionally 24 to 72 h;
c5) enriching the solution (B) or (B1) with CO2 to a total concentration of at least 6 g/L, optionally: at least 10 g/L, at least 12 g/L, at least 14 g/L, or at least 15 g/L;
or any combination of c1) c5);
wherein optionally:
i) the concentration of the amine (AM) in solution (B) or, if substep c2) is carried out then in solution (B1), is in the range of 0.01 to 0.25 g/mL, optionally in the range of: 0.03 to 0.20 g/mL, or 0.08 to 0.15 g/mL;
ii) after carrying out step c5), the pH of the solution (B) or (B1) is less than or equal to 7.0;
iii) when step b) is carried out, the ratio of the amine (AM) to the base (BA) in solution (B) is in the range of 2:1 to 5:1, optionally in the range of: 3:1 to 4:1, or 3.23:1 to 3.26:1 [g/g];
iv) when step b) is carried out, the molar ratio of the amine (AM) to the base equivalents of the base (BA) in solution (B) is in the range of 0.8:1 to 1.5:1, or optionally in the range of 1.2:1, or about 1:1;
v) in step c1), the at least one amine (AM) comprises an acid addition salt, optionally as a hydrohalide, hydrogen sulfate, hydrogen sulfite, hydrogen phosphate, hydromesylate, hydrotosylate, hydroacetate, hydroformiate, hydropropanoate, hydromalonate, hydrosuccinate, hydrofumarate, hydroxalate, hydrotartrate, hydrocitrate, hydromaleate, hydrochloride, or hydrobromide;
or any combination of c1)-c5);
optionally step c) comprises all substeps c1), c2), c3), c4) and c5); optionally wherein substeps c1), c2), c3), c4) and c5) are carried out in the sequence whereby c2) follows c1), c3) follows c2), c4) follows c3), and c5) follows c4).

### Claim 5 (depends on 1)

The method of claim 1, where, in step d):
i) the solution (B) or (B1) is frozen at a temperature in the range of: −100° C. to −20° C., optionally −90° C. to −30° C., optionally −80 to −40° C., or optionally −70 to −50° C.;
ii) the solution (B) or (B1) is frozen within 0.3 to 60 minutes, optionally within 1 to 30 minutes, optionally within 1.1 to 10 minutes, or optionally within 1.5 to 5 minutes;
iii) the container in which the solution (B) or (B1) is located during the freezing process is optionally rotated in the coolant at a rate in the range of: 10 to 1000 rpm, optionally 50 to 600 rpm, optionally 100 to 400 rpm, or optionally 200 to 300 rpm;
iv) the solution (B) or (B1) is frozen at a cooling rate in the range of: 10 to 100 K/min, optionally 20 to 80 K/min, optionally 30 to 70 K/min, or optionally 40 to 60 K/min; or
any combination of i)-iv).

### Claim 6 (depends on 1)

The method of claim 1, where, in step e):
i) the frozen solution (B) or (B1) is maintained for a period of time in the range of: 1.5 to 4 days, optionally 2.5 to 4 days;
ii) the frozen solution (B) or (B1) is optionally maintained at a temperature in the range of: −50° C. to 0° C., optionally −30° C. to −5° C., optionally −25 to −10° C., or optionally −20 to −15° C.;
or both i) and ii).

### Claim 7 (depends on 1)

The method of claim 1 comprising a further step f) which is carried out after step e), of
f) drying the solution stored in step e), thereby obtaining dried carbonic acid adduct (CAA), wherein, in step f), optionally
i) the water is removed from the solution (B) or (B1) until a residual content of less than 0.8 wt. %, optionally less than 0.1 wt. % is achieved, based on the total weight of the drying product (C);
ii) CO2 that is not bound in the carbonic acid adduct (CAA) is removed from the solution (B) or (B1) until a residual content of less than 0.8 wt. %, optionally less than 0.1 wt. % is achieved, based on the total weight of the drying product (C);
iii) the drying is carried out by means of lyophilization;
iv) during the drying, the pressure is in the range of: 0.01 to 30 mbar, optionally 0.02 to 20 mbar, optionally 0.03 to 10 mbar, optionally 0.03 to 0.5 mbar, optionally 0.05 to 0.1 mbar, said pressure optionally maintained throughout the entire drying process;
v) the pressure during the drying according to iv) is reached within 10 h, optionally within 7 h, optionally within 5 h, and optionally within 4 h of the start of the evacuation process, and/or
vi) the temperature during the entire drying process in step f) is in the range of: 0 to 20° C., optionally 4 to 18° C., or optionally 8 to 16° C.;
vii) the total drying time is in the range of: 10 to 60 h, optionally 30 to 55 h, or optionally 41 to 52 h; or
any combination of i)-vii).

### Claim 8 (depends on 1)

The method of claim 1 comprising, wherein at least one amine (AM) according to one of the following formulae (I) or (II) is used,
wherein, in formula (I) R1 is H, C1-10 alkyl, C2-10 alkenyl, aryl or heteroaryl, optionally H or C1-10 alkyl, optionally H or C1-4 alkyl; R2 is H, C1-10 alkyl, C2-10 alkenyl, aryl or heteroaryl, optionally H or C1-10 alkyl, optionally H or C1-4 alkyl; R3 is H, C1-10 alkyl, C2-10 alkenyl, aryl or heteroaryl, optionally H or C1-10 alkyl, optionally H or C1-4 alkyl; wherein it is optionally possible for R1 and R3 to be linked together and to form a saturated or unsaturated, optionally a saturated ring, together with the nitrogen atom to which R3 is bound and the carbon atom to which R1 is bound, and the ring is optionally 4-, 5- or 6-membered, optionally 5- or 6-membered; R4 is H, halogen, C1-10 alkyl, C2-10 alkenyl, aryl or heteroaryl, optionally H or methyl; R5 is H, halogen, C1-10 alkyl, C2-10 alkenyl, aryl or heteroaryl, optionally H, methyl or halogen;
wherein, in formula (II)
R1 is H, C1-10 alkyl, C2-10 alkenyl, aryl or heteroaryl, optionally H or C1-10 alkyl, optionally H; R2 is H, C1-10 alkyl, C2-10 alkenyl, aryl or heteroaryl, optionally H or C1-10 alkyl, optionally H; R3 is H, C1-10 alkyl, C2-10 alkenyl, aryl, heteroaryl or —(CH2)nNR8R9, optionally —(CH2)nNR8R9, n is 1 to 5, optionally 1 to 3, optionally 1 to 2, R8 is C1-10 alkyl, optionally C1-2 alkyl, R9 is C1-10 alkyl, optionally C1-2 alkyl; R4 is H, halogen, C1-10 alkyl, C2-10 alkenyl, aryl, heteroaryl or alkyl, optionally H, halogen, C1-10 alkyl or —O—C1-10 alkyl, optionally H or halogen; R5 is H, halogen, C1-10 alkyl, C2-10 alkenyl, aryl, heteroaryl or —O—C1-10 alkyl, optionally H, halogen, C1-10 alkyl or —O—C1-10 alkyl, more optionally H or halogen; R6 is H, halogen, C1-10 alkyl, C2-10 alkenyl, aryl, heteroaryl or —O—C1-10 alkyl, optionally H, halogen, C1-10 alkyl or —O—C1-10 alkyl, optionally H or alkyl; R7 is H, halogen, C1-10 alkyl, C2-10 alkenyl, aryl, heteroaryl or —O—C1-10 alkyl, optionally H, halogen, C1-10 alkyl or —O—C1-10 alkyl, optionally H or —O—C1-10 alkyl; wherein the at least one amine according to formula (I) and (II) can optionally also be used in the form of a salt.

### Claim 9 (depends on 1)

The method of claim 1, wherein at least one amine (AM) is used that is selected from the group consisting of 4-aminobenzoic acid-2-(N,N-diethylamino-)ethylester (procaine), 4-aminobenzoic acid ethyl ester (benzocaine), 2-(diethylamino)ethyl-4-amino-2-chlorobenzoate (chloroprocaine), 4-amino-3-butoxybenzoic acid-2-diethylaminoethylester (oxybuprocaine), (2-(dimethylamino)ethyl)-4-(butylamino)benzoate (tetracaine), N-[3-(4-phenoxymethylphenyl)propyl]morpholine (fomocaine), 2-diethylamino-N-(2,6-dimethylphenyl)acetamide (lidocaine), (RS)—N-(2,6-dimethylphenyl)-1-methylpiperidin-2-carboxamide (mepivacaine), (RS)—N-(2-methylphenyl)-2-(propylamino)-propanamide (prilocaine), (RS)-4-methyl-3-[2-(propylamino)-propanamido]thiophene-2-carboxylic acid methyl ester (articaine), (±)-1-Butyl-N-(2,6-dimethylphenyl)-2-piperidincarboxamide (bupivacaine), (S)-1-propyl-2′,6′-dimethyl-2-piperidylcarboxyanilide (ropivacaine), 2-(ethylpropylamino)-2′,6′-butyroxylidide (etidocaine) and 1-(4-butoxyphenyl)-3-piperidin-1-ylpropan-1-one (dyclonine), optionally 4-aminobenzoic acid-2-(N,N-diethylamino-)ethylester (procaine) and 2-diethylamino-N-(2,6-dimethylphenyl)acetamide (lidocaine), (2-(dimethylamino)ethyl)-4-(butylamino)benzoate (tetracaine), and/or the salts of said compounds.