# US 12,599,647 B2 · Peptide amide composition and preparation method therefor

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- Number: US 12,599,647 B2
- Document ID: US12599647B2
- Status: Granted
- Kind: B2
- Application number: 17/637,189
- Filed: 2020-08-24
- Published: 2022-09-29
- Granted: 2026-04-14
- Earliest claimed: 2019-08-23
- Assignees: Xizang Haisco Pharmaceutical Co., Ltd.
- Applicants: Xizang Haisco Pharmaceutical Co., Ltd.
- Inventors: Yi Mo; Honghu Li; Li Zhang; Xiangling Ma; Can Zhao
- Web page: https://patentgrep.com/patent/US12599647B2

## CPC

- A61K 38/07: Tetrapeptides
- 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 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61K 47/183: {Amino acids, e.g. glycine, EDTA or aspartame}
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61P 7/10: Antioedematous agents; Diuretics
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 27/06: Antiglaucoma agents or miotics
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- 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

## Abstract

Disclosed are a peptide amide compound composition, a preparation method therefor and medical use thereof. Specifically, the composition contains a compound of formula (I) and pH regulators, and the pH of the solution thereof is 3-5.5. The composition is stable and requires few excipients, and is stable in clinical use. The composition is used for treating or preventing a disease or condition associated with kappa opioid receptors

## Claims

### Claim 1

A pharmaceutical composition consisting of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pH regulator, wherein the composition has a pH value of 3-5.5, and the pH regulator is a buffer consisting of acids and corresponding salts thereof and has a pH value of 3-5.5,
wherein
R1 is selected from
m1 and m2 are each independently selected from 1, 2, 3 or 4;
m3 and m4 are each independently selected from 0, 1, 2, 3 or 4, provided that m3 and m4 are not both 0;
n1 and n2 are each independently selected from 0, 1, 2, 3 or 4;
Z is selected from CRz1Rz2 or NRz3;
Rz1 and Rz2 are each independently selected from H, F, Cl, Br, I, OH, CF3, nitro, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, —C(═O)—C1-6alkyl, —(CH2)q—C(═O)O—C1-6alkyl, —(CH2)q—NR1eR1f, —(CH2)q—COOH, —(CH2)q—CONH2, C3-8carbocyclyl, or 3- to 8-membered heterocyclyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally further substituted with 0-5 substituents selected from F, Cl, Br, I, OH, CF3, ═O, carboxyl, nitro, cyano, amino, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-8carbocyclyl or 3- to 8-membered heterocyclyl, the heterocyclyl contains 1 to 3 heteroatoms optionally selected from N, O or S, and when the heteroatom is S, the heterocyclyl can optionally contain S, S═O or S(═O)2;
R1e and R1f are each independently selected from H, C1-6alkyl, —C(═O)O—C1-6alkyl, —C(═O)O—(CH2)q—C3-8carbocyclyl, or —C(═O)O—(CH2)q-3- to 8-membered heterocyclyl, wherein the alkyl, carbocyclyl or heterocyclyl is optionally further substituted with 0-5 substituents selected from F, Cl, Br, I, OH, CF3, cyano, nitro, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-8carbocyclyl or 3- to 8-membered heterocyclyl, and the heterocyclyl contains 1 to 3 heteroatoms selected from N, O or S;
or Rz1 and Rz2 together with the carbon atoms to which they are attached form a 3- to 10-membered nitrogen-containing heterocyclic ring, wherein the ring is optionally further substituted with a substituent selected from F, Cl, Br, I, OH, CF3, cyano, nitro, ═O, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-8carbocyclyl or 3- to 8-membered heterocyclyl;
R1a and R1b are each independently selected from F, CF3, C1-6alkyl, C2-6alkenyl, C2-6alkynyl or 3- to 8-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl or heterocyclyl is optionally further substituted with 0-5 substituents selected from F, Cl, Br, I, OH, CF3, nitro, cyano, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-8carbocyclyl or 3- to 8-membered heterocyclyl, and the heterocyclyl contains 1 to 3 heteroatoms optionally selected from N, O or S;
Rz3 is independently selected from H, —C(═O)—C1-6alkyl, —C(═O)O—C1-6alkyl, —C(═O)—C3-8carbocyclyl, —C(═O)O—C3-8carbocyclyl, —C(═O)O-(3- to 8-membered heterocyclyl), —S(═O)p—C1-6alkyl, —S(═O)p—C3-8carbocyclyl, —S(═O)p-(3- to 8-membered heterocyclyl), —C(═O)NR1gR1h, —S(═O)p—NR1iR1j or 3- to 8-membered heterocyclyl, wherein the alkyl, carbocyclyl or heterocyclyl is optionally further substituted with 0-5 substituents selected from F, Cl, Br, I, OH, CF3, nitro, cyano, amino, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-8carbocyclyl or 3- to 8-membered heterocyclyl, and the heterocyclyl contains 1 to 3 heteroatoms optionally selected from N, O or S;
R1g, R1h, R1i, and R1j are each independently selected from H or C1-6alkyl;
or R1g and R1h together with the nitrogen atoms to which they are attached form a 3- to 10-membered heterocyclic ring, wherein the ring is optionally further substituted with a substituent selected from F, Cl, Br, I, OH, CF3, cyano, nitro, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl or —S(═O)p—C1-6alkyl, and the heterocyclic ring contains 1 to 3 heteroatoms selected from N, O or S;
q is selected from 0, 1, 2, 3 or 4;
p is selected from 0, 1 or 2;
a is selected from 0, 1, 2 or 3;
R4 is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl or —(CH2)q—C3-8carbocyclyl, wherein the alkyl, alkenyl, alkynyl or carbocyclyl is optionally further substituted with 0-5 substituents selected from F, Cl, Br, I, OH, CN, CF3, NO2, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-8carbocyclyl or 3- to 8-membered heterocyclyl, and the heterocyclyl contains 1 to 3 heteroatoms selected from N, O or S;
R2, R3, R7 and R8 are each independently selected from H, C1-6alkyl, —C(═O)O—C1-4alkyl, —C(═O)O—(CH2)q—C3-8carbocyclyl, —C(═O)O—(CH2)q-3- to 8-membered heterocyclyl or
wherein the alkyl, carbocyclyl or heterocyclyl is optionally further substituted with 0-5 substituents selected from F, Cl, Br, I, OH, CF3, nitro, cyano, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-8carbocyclyl or 3- to 8-membered heterocyclyl, and the heterocyclyl contains 1 to 3 heteroatoms optionally selected from N, O or S;
b is selected from 0, 1, 2, 3, 4 or 5;
c is selected from 0, 1, 2, 3, 4 or 5;
R5 and R6 are each independently selected from F, Cl, Br, I, CF3, cyano, nitro, C1-4alkyl, —OR5a, —C(O)OR5b, —SR5c, —S(O)R5d, +S(O)2R5e or —NR5fR5g;
R5a, R5b, R5c, R5d, R5e, R5f and R5g are each independently selected from H or C1-4alkyl;
or R5f and R5g together with the nitrogen atoms to which they are attached form a 5- to 6-membered heterocyclic ring, wherein the heterocyclic ring contains 1 to 3 heteroatoms optionally selected from N, O or S.

### Claim 2 (depends on 1)

The composition according to claim 1, wherein the compound of formula (I) has a structure of formula (II):

### Claim 3 (depends on 1)

The composition according to claim 1, wherein the acid is selected from acetic acid, phosphoric acid, tartaric acid, or benzoic acid.

### Claim 4 (depends on 1)

The composition according to claim 1, wherein the acid and corresponding salt is selected from an acetic acid-sodium acetate buffer, a tartaric acid-sodium hydrogen tartarate buffer, or a tartaric acid-sodium hydrogen tartarate-sodium tartrate concomitant buffer.

### Claim 5 (depends on 4)

The composition according to claim 4, wherein the pH regulator is at a concentration of 1 mmol/L-500 mmol/L.

### Claim 6 (depends on 3)

The composition according to claim 3, wherein the tartaric acid is selected from D-tartaric acid, L-tartaric acid or a racemate thereof.

### Claim 7 (depends on 1)

The composition according to claim 1, wherein the compound of formula (I) has a weight/volume, w/v, of 0.001%-1%.

### Claim 8 (depends on 1)

The composition according to claim 1, wherein the composition is a solution for injection or a sterile lyophilized powder for injection obtained by lyophilizing the solution.

### Claim 9 (depends on 1)

A method for preparing the composition according to claim 1, the method comprising the following steps:
(1) dissolving ingredients, other than an active substance, in water for injection;
(2) adding the active substance to the solution obtained in step (1), wherein the active substance is the compound of formula (I) or a pharmaceutically acceptable salt thereof, to obtain a solution preparation; and
(3) adding water to a constant volume to the solution preparation, carrying out sterilizing filtration of the solution preparation through a 0.22 μm filter, and filling and sealing the solution preparation in a pyrogen-free vial.

### Claim 10 (depends on 1)

A method for preparing the composition according to claim 1, the method comprising the following steps the following steps:
(1) dissolving the pH regulator to water for injection;
(2) adding the active substance to the solution obtained in step (1) to obtain a solution preparation, wherein the active substance is the compound of formula (I) or a pharmaceutically acceptable salt thereof;
(3) adjusting the pH value with the pH regulator to a range of 3.0-5.5; and
(4) adding water to a constant volume to the solution preparation, carrying out sterilizing filtration of the solution preparation through a 0.22 μm filter, and filling and sealing the solution preparation in a pyrogen-free vial.

### Claim 11 (depends on 10)

The method according to claim 10, further comprising a lyophilizing step.

### Claim 12 (depends on 11)

The method according to claim 11, wherein the lyophilizing step comprises:
(1) pre-freezing;
(2) cooling partition boards to −35° C. or lower and maintaining for 1-2 h; then cooling a chamber to −50° C. or lower and vacuuming to 20 Pa or lower; opening a limited leakage valve; raising the temperature to −5° C. over 3-5 h and maintaining for another 1-3 h; raising the temperature to 10° C. over 2-4 h and maintaining until the temperature of the preparation reaches 0° C. or higher; raising the temperature to 35° C. over 2-3 h and maintaining until the temperature of the preparation reaches 25° C. or higher; and then closing the limited leakage valve and maintaining the temperature for 1-3 h; and
(3) vacuuming or charging nitrogen, completely stoppering, and then taking out from the chamber and capping.

### Claim 13 (depends on 1)

A method for treating or preventing a disease or condition associated with kappa opioid receptors in a mammal, wherein the method comprises administering the composition according to claim 1.

### Claim 14 (depends on 13)

The method according to claim 13, wherein the disease or condition associated with kappa opioid receptors is selected from the group consisting of pain, inflammation, itching, edema, hyponatremia, hypokalemia, intestinal obstruction, cough and glaucoma.

### Claim 15 (depends on 14)

The method according to claim 14, wherein the pain is selected from neuropathic pain, somatic pain, visceral pain and skin pain.

### Claim 16 (depends on 4)

The composition according to claim 4, wherein the pH regulator is at a concentration of 10 mmol/L-50 mmol/L.

### Claim 17 (depends on 1)

The composition according to claim 1, wherein the compound of formula (I) has a weight/volume, w/v, of 0.002%-0.05%.

### Claim 18 (depends on 9)

The method according to claim 9, further comprising a lyophilizing step.

### Claim 19 (depends on 18)

The method according to claim 18, wherein the lyophilizing step comprises:
(1) pre-freezing;
(2) cooling partition boards to −35° C. or lower and maintaining for 1-2 h; then cooling a chamber to −50° C. or lower and vacuuming to 20 Pa or lower; opening a limited leakage valve; raising the temperature to −5° C. over 3-5 h and maintaining for another 1-3 h; raising the temperature to 10° C. over 2-4 h and maintaining until the temperature of the preparation reaches 0° C. or higher; raising the temperature to 35° C. over 2-3 h and maintaining until the temperature of the preparation reaches 25° C. or higher; and then closing the limited leakage valve and maintaining the temperature for 1-3 h; and
(3) vacuuming or charging nitrogen, completely stoppering, and then taking out from the chamber and capping.