WO2020098563A1 - Pharmaceutical composition comprising polypeptide compound, preparation method therefor and use thereof - Google Patents

Abstract

Provided by the present application are a pharmaceutical composition comprising a polypeptide compound and a preparation method therefor, the polypeptide compound having peripheral kappa opioid receptor agonistic activity. Therefore, the present application also relates to the use of the pharmaceutical composition in preparing a drug for the prevention or treatment of kappa opioid receptor-related diseases.

Description

Pharmaceutical composition containing polypeptide compounds, and preparation method and use thereof

This application is based on the application with CN application number 201811357621.X and the application date is November 15, 2018, and claims its priority. The disclosure content of this CN application is hereby incorporated into this application as a whole.

Technical field

The present invention belongs to the technical field of pharmaceutical preparations, and specifically relates to a pharmaceutical composition containing a polypeptide compound and a preparation method thereof, wherein the polypeptide compound has peripheral κ opioid receptor agonistic activity, therefore, the present application also relates to the pharmaceutical composition Use in the preparation of a medicament for the prevention or treatment of diseases associated with kappa opioid receptors.

Background technique

Peripheral kappa opioid receptor agonists can bind to kappa opioid receptors, causing the opioid receptor-coupled Gi / Go protein to be activated, and then reduce cAMP by inhibiting adenylate cyclase activity or by inhibiting calcium channels As a result, Ca ²⁺ influx decreases and K ⁺ efflux increases, causing hyperpolarization of membrane potential, reducing neurotransmitter release, and reducing the excitability of neurons transmitting pain information, thereby inhibiting the transmission of pain signals.

The applicant disclosed in WO 2018/059331 A1 a polypeptide compound having peripheral kappa opioid receptor agonistic activity represented by the following formula, which has a brand-new structure, clear pharmacological effects and important clinical value.

There is an urgent need for the development of pharmaceutical preparations of such compounds with sterility assurance levels and good stability that are compatible with the clinical route of administration.

Summary of the invention

An object of the present application is to provide a pharmaceutical preparation of a polypeptide compound having peripheral kappa opioid receptor agonistic activity, which is compatible with the clinical administration route and can simultaneously ensure the safety of the polypeptide compound in the clinical use process Sex.

Therefore, in one aspect, the present application provides a pharmaceutical composition containing an active ingredient, a buffer, a pH adjuster, and water for injection, and optionally, it further contains a stabilizer; wherein,

The active ingredient is selected from the compounds described in WO2018059331A1, or their stereoisomers, polymorphs, solvates, or their metabolites or pharmaceutically acceptable salts or esters;

The content of the pH adjusting agent is such that the pH of the pharmaceutical composition is 3.5-5.5.

WO2018059331A1 is hereby incorporated by reference in its entirety. Unless otherwise specified, the active ingredient in the pharmaceutical composition described in this application refers to any compound, stereoisomer, polymorph, solvate, or metabolite of WO2018059331A1. Or a pharmaceutically acceptable salt or ester.

In some preferred embodiments, the active ingredient is selected from the following compounds of formula I, or their stereoisomers, polymorphs, solvates, or their metabolites or pharmaceutically acceptable salts or esters:

In some preferred embodiments, the pharmaceutically acceptable salt is an acid addition salt. In some preferred embodiments, the pharmaceutically acceptable salt is selected from formate, acetate, hydrochloride and trifluoroacetate. In some preferred embodiments, the pharmaceutically acceptable salt is acetate or hydrochloride. In some preferred embodiments, the pharmaceutically acceptable salt is an acetate salt. In some preferred embodiments, the molar ratio of the compound of formula I to acid in the pharmaceutically acceptable salt is 1: (0.5-3), for example, 1: (0.5-2.5), 1: (0.5-2), 1: (0.5-1.5) or 1: (0.5-1). In some preferred embodiments, the active ingredient is an acetate salt of the compound of formula I, wherein the molar ratio of the compound of formula I to acetic acid is 1: (0.5-1).

In some preferred embodiments, the content of the pH adjusting agent is such that the pH of the pharmaceutical composition is 3.5-5.0, 4.0-5.5, 4.0-5.0, or 4.3-4.7, such as 4.5. When the pH of the pharmaceutical composition is 4.0-5.0, the impurity content generated at the beginning of storage (for example, 0 days) is less than 0.1%, and the impurity content hardly changes when left at 40 ° C for 10 days, for example, the change in impurity content is less than 0.05%, for example 0.01%, 0.02%, 0.03%, 0.04%.

In some preferred embodiments, the content of the active ingredient is 0.01-0.1% (w / v), for example 0.01-0.02% (w / v).

In some preferred embodiments, the buffering agent is selected from the group consisting of carbonate, phosphate, citrate, acetate, barbiturate, trishydroxymethylaminomethane, and borate. In some preferred embodiments, the buffer is selected from phosphate, citrate and acetate, such as sodium dihydrogen phosphate, sodium citrate and sodium acetate. In some preferred embodiments, the buffering agent is sodium acetate or sodium acetate trihydrate. The sodium acetate buffer system has good compatibility with the pharmaceutical composition. For example, the sodium acetate buffer system allows the pharmaceutical composition to produce fewer impurities at the beginning of storage (eg, 0 days), less than the detection limit of the instrument, and the impurities increase less when stored at 60 ° C for 10 days, for example, the amount of impurities changes less than 10 .

In some preferred embodiments, the molar concentration of the buffer is 1-5 mM, such as 1, 2, 3, 4 or 5 mM, preferably 2 mM. When the concentration of the buffering agent (for example, sodium acetate or sodium acetate trihydrate) is 2 mM, the pharmaceutical composition is left at 60 ° C for 15 days or 30 days with less increase in impurities.

In some preferred embodiments, the pH adjusting agent is selected from one or more of hydrochloric acid, phosphoric acid, citric acid, glacial acetic acid, barbituric acid, boric acid, sodium hydroxide, and potassium hydroxide. In some preferred embodiments, the pH adjusting agent is glacial acetic acid, hydrochloric acid or sodium hydroxide.

In some preferred embodiments, the pharmaceutical composition also contains an osmotic regulator.

In some preferred embodiments, the osmotic pressure adjusting agent is selected from one or more of sodium chloride, glucose, glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, and xylitol. In some preferred embodiments, the osmotic pressure adjusting agent is sodium chloride.

In some preferred embodiments, the amount of the osmotic pressure regulator is such that the osmotic pressure of the pharmaceutical composition is 250-350 mOsm / kg, such as 260-330 mOsm / kg, 290-310 mOsm / kg. In some preferred embodiments, the content of the osmotic pressure adjusting agent is 0.80-1.05% (m / v), for example 0.90-0.95% (m / v).

In some preferred embodiments, the stabilizer is an antioxidant or a metal ion chelating agent. In some preferred embodiments, the antioxidant is selected from sodium bisulfite, sodium thiosulfate and sodium metabisulfite. In some preferred embodiments, the metal ion chelating agent is selected from disodium edetate and sodium calcium edetate. In some preferred embodiments, the stabilizer is selected from sodium thiosulfate and sodium calcium edetate. In some preferred embodiments, the stabilizer is calcium sodium edetate.

In some preferred embodiments, the content of the stabilizer is 0.05-0.2% (w / v), preferably 0.05-0.1% (w / v).

In some preferred embodiments, the composition consists of the following ingredients:

Wherein, the pH adjusting agent is selected from hydrochloric acid, sodium acetate and sodium hydroxide;

The stabilizer is selected from sodium thiosulfate and calcium sodium edetate.

In some preferred embodiments, the composition consists of the following ingredients:

Wherein, the pH adjusting agent is selected from hydrochloric acid, sodium acetate and sodium hydroxide;

The stabilizer is selected from sodium thiosulfate and calcium sodium edetate.

In some preferred embodiments, the pharmaceutical composition consists of an active ingredient, sodium acetate or sodium acetate trihydrate, sodium chloride, pH adjuster, water for injection, and optional stabilizer, wherein the stabilizer is selected From sodium thiosulfate and sodium calcium edetate, the pH of the pharmaceutical composition is 4.0-5.5.

In some preferred embodiments, the pharmaceutical composition is selected from formulas (1)-(3):

Recipe (1):

Recipe (2):

Recipe (3):

In some preferred embodiments, the pharmaceutical composition is an injection, emulsion or suspension.

In another aspect, the present application provides a method for preparing the pharmaceutical composition, which includes the following steps:

(1) Dissolve the buffer, osmotic pressure regulator (if any) and optional stabilizer in water for injection to obtain solution 1;

(2) The active ingredient is dissolved in the solution 1 to obtain a solution 2;

(3) Adjust the pH of the solution 2 to 3.5-5.5 with the pH adjusting agent to obtain the pharmaceutical composition;

Optionally, the preparation method further includes the step of sterilizing the pharmaceutical composition;

Optionally, the step method further includes the step of adjusting the pH value of the solution 1 to 3.5-5.5 with a pH adjusting agent after step (1);

Optionally, after the sterilization step, a step of nitrogen filling is further included;

Optionally, after the nitrogen filling step, a filling step is also included.

In some preferred embodiments, in step (3), the solution 2 is adjusted to pH 3.5-5.0, 4.0-5.5, 4.0-5.0, or 4.3-4.7 with the pH adjusting agent.

In some preferred embodiments, step (1) and step (2) are performed at a temperature of 15-40 ° C. In some preferred embodiments, step (1) and step (2) are performed at a temperature of 15-25 ° C.

In some preferred embodiments, the above-mentioned sterilization refers to filtration sterilization, for example, sterilization through a 0.22 μm filter membrane. In some preferred embodiments, a 0.22 μm polyethersulfone filter is used for filtration and sterilization.

In another aspect, the present application provides an injectable product comprising the above pharmaceutical composition and a closed container containing the pharmaceutical composition, wherein the volume of the pharmaceutical composition is less than or equal to the volume of the closed container, when the When the volume of the pharmaceutical composition is smaller than the volume of the closed container, the remaining space of the closed container is filled with an inert gas.

In some preferred embodiments, the airtight container is a glass or plastic airtight container, such as an ampoule or a vial (such as a medium borosilicate glass controlled injection bottle). In some preferred embodiments, the inert gas is nitrogen.

In another aspect, the present application provides the use of the pharmaceutical composition in the preparation of a medicament for preventing or treating a disease associated with a kappa opioid receptor.

In another aspect, the present application provides the pharmaceutical composition for preventing or treating diseases associated with kappa opioid receptors.

In another aspect, the present application provides a method of preventing or treating a disease associated with a kappa opioid receptor, which includes the step of administering an effective amount of the pharmaceutical composition described herein to a subject in need thereof.

In some preferred embodiments, the disease associated with a kappa opioid receptor is selected from pain, inflammation, itching, edema, hyponatremia, hypokalemia, intestinal obstruction, cough and glaucoma. In some preferred embodiments, the disease associated with kappa opioid receptors is pain. In some preferred embodiments, the pain is selected from neuropathic pain, somatic pain, visceral pain and skin pain. In some preferred embodiments, the pain is selected from arthritis pain, kidney stone pain, uterine cramps, dysmenorrhea, endometriosis, post-surgical pain, post-medical pain, ocular pain, otitis pain , Cancer pain and pain related to gastrointestinal disorders.

In this application, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Meanwhile, in order to better understand the present invention, definitions and explanations of related terms are provided below.

As used herein, "w / v" and "m / v" refer to Kg / L.

The water for injection described herein generally refers to water suitable for in vivo injection, that is, it should meet the requirements of the product for injection for bacterial endotoxin test. The water for injection may be distilled water of pure water.

Beneficial effects of invention

The present application provides a pharmaceutical composition containing a polypeptide compound, a preparation method and use thereof. The pharmaceutical composition of the present application can achieve at least one of the following technical effects:

1. The pharmaceutical composition improves the stability of the polypeptide compound on the premise of ensuring the sterility level, thereby improving the application safety.

2. The pH of the pharmaceutical composition meets the requirements of injectables (pH 4-9), enhancing its exploitability as an intravenous injection preparation.

detailed description

The embodiments of the present invention will be described in detail below in conjunction with examples, but those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. If no specific conditions are indicated in the examples, the conventional conditions or the conditions recommended by the manufacturer shall be followed. The reagents or instruments used do not indicate the manufacturer, are all conventional products that are commercially available.

Unless otherwise specified, the active ingredients used in the following examples and comparative examples are acetate salts of the compound of formula I, wherein the molar ratio of the compound of formula I and acetic acid in the active ingredients used in examples 1-2 and comparative examples 1-2 The ratio was 1: 0.8, and the molar ratio of the compound of formula I to acetic acid in the active ingredients used in Examples 3-6 and Comparative Examples 3-4 was 1: 0.6. Unless otherwise specified, glacial acetic acid, hydrochloric acid and / or sodium hydroxide are used in each embodiment to adjust the pH of the system. Sodium acetate refers specifically to sodium acetate trihydrate.

Example 1

Purpose of the experiment: To investigate the effect of different pH values on the stability of the solution.

Experimental method: according to the prescription in Table 1, weigh the active ingredient and sodium acetate, and prepare a 1 mg / ml drug solution. Use glacial acetic acid or sodium hydroxide solution to adjust the pH to pH 4.0-pH 5.5 respectively, after 0.22 After filtering, the μm filter membrane is filled in ampoules to prepare samples.

Each sample was placed at 40 ° C for 10 days to detect changes in related substances. The results are shown in Table 2.

Table 1 Composition of prescriptions investigated at different pH values

Sample serial number	Active ingredient (mg / ml)	Sodium acetate (mg / ml)	Add water to (ml)	pH value
No.1	1.01	3.40	40	4.00
No. 2	1.01	3.40	40	4.50
No. 3	1.01	3.40	40	5.01
No. 4	1.01	3.40	40	5.51

Table 2 Test results of related substances

Experimental results: The results of the above examples show that the total impurity content of the solution at pH 4.0-pH5.0 is less than 0.1% at 0 days; after being placed at 40 ° C, the total impurity content of the drug solution at pH 4.0-pH5.0 hardly changes. For example, the change in total impurity content is less than 0.05%. Therefore, the drug solution of pH4.0-pH5.0 is relatively stable.

Example 2

Purpose of the experiment: To investigate the effect of the type of buffer system on the stability of the solution.

According to the prescription composition in Table 3, the active ingredient and sodium acetate are weighed into a drug solution with a concentration of 1 mg / ml. The pH value is adjusted to 4.5 with glacial acetic acid, filtered through a 0.22 μm filter membrane and filled into ampoules to obtain sample.

Each sample was placed at a high temperature of 60 ° C for 10 days to detect changes in related substances.

Table 3 The prescription composition of the buffer system

Experimental results: The maximum single impurity in the sample is only 0.17%, the total impurity is only 0.58%, and the number of impurities is 10 under the condition of being placed at 60 ° C for 10 days. It shows that the active ingredients in the sample have good compatibility with the sodium acetate buffer system.

Example 3

Purpose of the experiment: To investigate the effect of the stabilizer and nitrogen on the stability of the solution.

Experimental content: According to the prescription composition of samples 1-4 (see Table 4), weigh the prescribed amount of sodium acetate, sodium chloride, sodium thiosulfate and calcium edetate sodium into the water, stir and dissolve, Use hydrochloric acid to adjust the pH to 4.3, add the active ingredient to prepare a drug solution with a concentration of 0.1mg / ml, use hydrochloric acid to adjust the pH to 4.5, filter it through a 0.22μm filter membrane and fill it in a medium borosilicate glass control injection bottle. Samples 1-3 were prepared. In the same way, a drug solution with an active ingredient concentration of 0.1 mg / ml without stabilizer was prepared, and the headspace was filled with nitrogen before filling to prepare sample 4.

Place the above samples at 60 ℃ to detect the changes of related substances. The test results are shown in Table 5.

Table 4 Examine the composition of prescriptions with different stabilizers

Sample serial number	1	2	3	4
Sodium acetate (mg)	27	27	27	27
Sodium chloride (mg)	900	900	900	900
Active ingredient (mg)	10	10	10	10
Sodium thiosulfate (mg)	/	200	/	/
Calcium sodium edetate (mg)	/	/	50	/
Nitrogen (N 2 )	/	/	/	Nitrogen filling
Water to (ml)	100	100	100	100

Note: "/" means that the material is not added.

Table 5 Test results of related substances added with different stabilizers

Note: "/" means not detected.

Experimental results: Compared with the drug solution without antioxidants and stabilizers, after adding sodium thiosulfate or calcium edetate, the drug solution was stored at 60 ℃ for 15 days. The total impurity content was less than 0.9% for 30 days. The total impurity content is less than 1.1%; the drug solution using the nitrogen filling process has the smallest change in total impurity content when stored at 60 ° C for 15 days compared with the non-nitrogen filled solution, and the drug solutions of samples 2-4 can achieve good stability .

Example 4

The purpose of the experiment: to investigate the effect of different preparation temperature and preparation time on the stability of the solution.

Experimental content: according to the prescription composition in Table 6, weigh sodium chloride and sodium acetate in water, stir and dissolve, adjust the pH to 4.3 with hydrochloric acid, add active ingredients, prepare a drug solution with a concentration of 0.1 mg / ml, use hydrochloric acid Adjust the pH value to 4.5, stir at 25 ℃, 30 ℃, and 40 ℃ for 0h, 2h, 5h, and 8h, and then take samples to observe the properties of the solution. At the same time, detect the related substances and pH. The test results are shown in Table 7.

Table 6 Composition of prescriptions with different preparation temperature and preparation time

ingredient	Dosage
Sodium acetate (mg)	27
Sodium chloride (mg)	900
Active ingredient (mg)	10
Water to (ml)	100

Table 7 Test results of pH and related substances of each sample

Experimental results: The results of the above examples show that in the temperature range of 25 ° C to 40 ° C, the stability of the solution prepared within 8 hours is good.

Example 5

Purpose of the experiment: To investigate the effect of different molar concentrations of buffer salts on the stability of the solution.

Experimental content: According to the prescription composition in Table 8, weigh sodium chloride and sodium acetate trihydrate (final concentrations are 1 mM and 2 mM respectively) in water, stir and dissolve, adjust the pH to 4.3 with hydrochloric acid, add active ingredients, and prepare the concentration It is a 0.1mg / ml drug solution, adjusted to pH 4.5 with hydrochloric acid, filtered through a 0.22μm filter membrane and filled in a medium borosilicate glass control injection bottle, stoppered, capped, and placed at 60 ° C for 15 days and 30 days. Test related substances and pH value. The test results are shown in Table 9.

Table 8 Prescription composition of buffer salts with different molar concentrations

ingredient	1mM group	2mM group
Sodium acetate trihydrate (mg)	14	27
Sodium chloride (mg)	900	900
Active ingredient (mg)	10	10
Add water to (ml)	100	100

Table 9 Test results of samples of buffer salts with different molar concentrations and related substances

Experimental results: The results of the above examples show that the pH value of the samples with sodium acetate solution of 1 mM and 2 mM remains basically unchanged after being placed at 60 ° C for 30 days, while the total impurity content of the sample with sodium acetate solution of 2 mM has a small change Good stability.

Example 6

Purpose of the experiment: To investigate the effect of different amounts of sodium chloride on the osmotic pressure of the solution.

Experimental content: According to the prescription composition in Table 10, weigh sodium chloride and sodium acetate in water, stir and dissolve, adjust the pH to 4.3 with hydrochloric acid, add active ingredients, and prepare a drug solution with a concentration of 0.1 mg / ml, using hydrochloric acid Adjust the pH value to 4.5, filter it through a 0.22μm filter membrane, and fill it in a medium borosilicate glass controlled injection bottle, stopper it, and check the osmotic pressure. The test results are shown in Table 11.

Table 10 Prescription composition of different sodium chloride dosage

Sample serial number	1	2	3	4	5
Sodium acetate (mg)	27	27	27	27	27
Sodium chloride (mg)	850	900	950	1000	1050
Active ingredient (mg)	10	10	10	10	10
Water to (ml)	100	100	100	100	100

Table 11 Osmotic pressure test results

Sample serial number	1	2	3	4	5
Sodium chloride dosage (w / v)	0.85%	0.90%	0.95%	1.00%	1.05%
Osmotic pressure (mOsmol / kg)	277	297	310	326	340

Experimental results: When the amount of sodium chloride is 0.90% -0.95%, the osmotic pressure of the composition for injection is isotonic or slightly hypertonic, which is the most suitable osmotic pressure of the injection.

Example 7

The purpose of the experiment: To investigate the feasibility of filtering sterilization.

Experimental method: According to the prescription in Table 12, weigh sodium acetate and glacial acetic acid into a 100mL glass bottle, add water to 100mL, stir and dissolve, add active ingredients, and prepare a 0.1mg / ml drug solution with pH 4.5. Filter through 0.22μm * 13mm polyethersulfone filter membrane. The solutions before and after continuous filtration for 15 minutes and 30 minutes were taken as samples to detect the changes of related substances. The results are shown in Table 13.

Table 12 The composition of the prescription for investigation of the compatibility between the filter membrane and the solution

Prescription composition	Prescription / mg
Active ingredient	10

Sodium acetate	60
glacial acetic acid	35
water	100mL

Table 13 Investigation results of the compatibility between the filter membrane and the solution

sample	Maximum single impurity%	Total miscellaneous%	Number of impurities
Before filtering	0.19	0.46	6
-15min after filtration	0.11	0.32	6
-30min after filtration	0.11	0.34	6

Experimental results: Before and after the drug solution was filtered through the polyethersulfone filter membrane, there was no significant change in the content and quantity of impurities, indicating that the drug solution and the polyethersulfone filter membrane have good compatibility. The filter sterilization process is suitable for the production of this product.

Comparative Example 1

Purpose of the experiment: To investigate the effect of different pH values on the stability of the solution.

Experimental method: according to the prescription composition in Table 14, weigh the active ingredient and sodium acetate into a 1 mg / ml drug solution, and adjust the pH to pH 3.5-pH 8.5 using glacial acetic acid or sodium hydroxide solution, after 0.22 After filtering, the μm filter membrane is filled in ampoules to prepare samples.

Each sample was placed at 40 ° C for 10 days to detect changes in related substances. The results are shown in Table 15.

Table 14 The composition of prescriptions investigated at different pH values

Sample serial number	Active ingredient (mg / ml)	Sodium acetate (mg / ml)	Water to (ml)	pH value
No.1	1.01	3.40	40	3.51
No. 2	1.02	3.40	30	6.01

No. 3	0.98	3.40	30	6.90
No. 4	1.03	3.40	30	7.52
No. 5	1.04	3.40	30	8.09
No. 6	1.00	3.40	30	8.41

Table 15 Relevant substance test results

Experimental results: At pH 0, there are few impurities in the solution at pH 3.5, but when left for 10 days, the amount of impurities and the change in impurity content increase significantly; the impurities at pH 6.0-8.5 are relatively large. Therefore, the above-mentioned pH drug solutions are not the most preferable range.

Comparative Example 2

Purpose of the experiment: To investigate the effect of different types of buffer systems on the stability of the solution.

According to the prescription composition in Table 16, the active ingredients, sodium citrate and sodium dihydrogen phosphate monohydrate (calculated based on the weight of sodium dihydrogen phosphate) are weighed into a drug solution with a concentration of 1 mg / ml. Phosphoric acid was adjusted to pH 4.5, filtered through a 0.22 μm filter membrane and filled in ampoules to prepare samples.

Each sample was placed at a high temperature of 60 ° C for 10 days to detect changes in related substances. The results are shown in Table 17.

Table 16 Prescription composition of different buffer systems

Note: "/" means that the material is not added.

Table 17 Test results of related substances

Experimental results: The drug solution prepared with the sodium citrate system has a rapid growth of impurities under high temperature conditions, while the drug solution prepared with the sodium dihydrogen phosphate system has a relatively rapid growth of impurities under high temperature conditions, which are significantly inferior to the acetate salt of Example 2 Buffer system.

Comparative Example 3

Purpose of the experiment: To investigate the effect of adding stabilizers on the stability of the solution.

Experimental content: According to the prescription composition of samples 1-2 (see Table 18), weigh the prescribed amounts of sodium acetate, sodium chloride, cysteine (if any) and sodium bisulfite (if any), and add After stirring and dissolving in water, adjust the pH to 4.3 with hydrochloric acid, add the active ingredient to prepare a drug solution with a concentration of 0.1mg / ml, adjust the pH to 4.5 with hydrochloric acid, filter it through a 0.22μm filter membrane and fill it in medium Samples 1-2 were prepared in silica glass controlled injection bottles.

Place the above sample at 60 ℃ to detect the changes of related substances. The test results are shown in Table 19.

Table 18 Examine the composition of prescriptions with different stabilizers

Sample serial number	1	2
Sodium acetate (mg)	27	27
Sodium chloride (mg)	900	900
Active ingredient (mg)	10	10

Cysteine (mg)	200	/
Sodium bisulfite (mg)	/	200
Water to (ml)	100	100

Note: "/" means that the material is not added.

Table 19 Test results of related substances added with different stabilizers

Experimental results: Compared with the prescription of adding sodium thiosulfate or calcium edetate stabilizer in Example 3, after adding cysteine and sodium bisulfite, the drug solution was stored at 60 ° C for 15 days and 30 days for impurities The growth is more obvious.

Comparative Example 4

Purpose of the experiment: To investigate the effect of terminal sterilization methods on the stability of the solution.

Experimental content: Prepare a drug solution containing 0.2% cysteine, 0.2% sodium thiosulfate, 0.2% sodium bisulfite, 0.05% calcium edetate active ingredient concentration of 1mg / ml, adjust the pH value After 7.5, it is filled in medium borosilicate glass controlled injection bottles to prepare samples 1-4. In the same way, a drug solution with an active ingredient concentration of 1 mg / ml without stabilizer was prepared, and the headspace was filled with nitrogen before filling to prepare sample 5.

The above samples were sterilized at 121 ° C for 8 minutes to detect changes in related substances. The test results are shown in Table 20.

Table 20 Test results of related substances in terminal sterilization research

Experimental results: After the above samples were sterilized, the impurity levels increased significantly compared with before. Adding antioxidants, stabilizers and nitrogen filling can not improve the stability of the active ingredients after sterilization, so the terminal sterilization process is not applicable, and the sterilization filtration process should be selected.

Although the specific embodiments of the present invention have been described in detail, based on all the teachings disclosed, those skilled in the art can make various modifications and replacements to the details of the technical solutions of the present invention, and these changes are within the protection scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.

Claims (15)

1. A pharmaceutical composition, which contains an active ingredient, a buffer, a pH adjuster, and water for injection, and optionally, it also contains a stabilizer; wherein,

   The active ingredient is selected from the following compounds of formula I, or their stereoisomers, polymorphs, solvates, or their metabolites or pharmaceutically acceptable salts or esters;

   The content of the pH adjusting agent is such that the pH of the pharmaceutical composition is 3.5-5.5 (for example, 3.5-5.0, 4.0-5.5, 4.0-5.0, or 4.3-4.7);

   
2. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt is selected from formate, acetate, hydrochloride and trifluoroacetate; preferably, the pharmaceutically acceptable salt is vinegar Acid salt or hydrochloride salt; preferably, the pharmaceutically acceptable salt is acetate;

   Preferably, the molar ratio of the compound of formula I to the acid in the pharmaceutically acceptable salt is 1: (0.5-3), 1: (0.5-2.5), 1: (0.5-2), 1: (0.5-1.5 ) Or 1: (0.5-1).
3. The pharmaceutical composition according to claim 1 or 2, wherein the content of the active ingredient is 0.01-0.1% (w / v), for example 0.01-0.02% (w / v).
4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the buffering agent is selected from the group consisting of carbonate, phosphate, citrate, acetate, barbiturate, trishydroxymethylaminomethane and boron Acid salt; preferably, the buffer is selected from phosphate, citrate and acetate, such as sodium dihydrogen phosphate, sodium citrate, sodium acetate or sodium acetate trihydrate;

   Preferably, wherein the molar concentration of the buffer is 1-5 mM, such as 1, 2, 3, 4 or 5 mM, preferably 2 mM.
5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pH adjusting agent is selected from one of hydrochloric acid, phosphoric acid, citric acid, glacial acetic acid, barbituric acid, boric acid, sodium hydroxide and potassium hydroxide Or more.
6. The pharmaceutical composition according to any one of claims 1 to 5, further comprising an osmotic pressure adjusting agent; preferably, the osmotic pressure adjusting agent is selected from sodium chloride, glucose, glycerin, propylene glycol, polyethylene glycol, sorbitol, One or more of mannitol and xylitol; preferably, the osmotic pressure adjusting agent is sodium chloride;

   Preferably, the amount of the osmotic pressure adjusting agent is such that the osmotic pressure of the pharmaceutical composition is 250-350 mOsm / kg, such as 260-330 mOsm / kg, 290-310 mOsm / kg; preferably, the osmotic pressure adjusting agent The content is 0.80-1.05% (m / v), for example 0.90-0.95% (m / v).
7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the stabilizer is an antioxidant or a metal ion chelating agent; preferably, the antioxidant is selected from sodium thiosulfate, sodium bisulfite and sodium metabisulfite ; Preferably, the metal ion chelating agent is selected from disodium edetate and sodium calcium edetate; preferably, the stabilizer is selected from sodium thiosulfate and sodium calcium edetate; preferably, the stabilizer The agent is calcium edetate;

   Preferably, the content of the stabilizer is 0.05-0.2% (w / v), preferably 0.05-0.1% (w / v).
8. The pharmaceutical composition according to any one of claims 1 to 7, which is composed of an active ingredient, sodium chloride, sodium acetate or sodium acetate trihydrate, a pH adjusting agent, water for injection and an optional stabilizer selected from the group consisting of Sodium thiosulfate and calcium sodium edetate, the pH of the pharmaceutical composition is 4.0-5.5;

   Preferably, the pharmaceutical composition is selected from formulas (1)-(3):

   Recipe (1):

   

   Recipe (2):

   

   Recipe (3):

   

   
9. The pharmaceutical composition according to any one of claims 1 to 8, which is an injection, an emulsion or a suspension.
10. The preparation method of the pharmaceutical composition according to any one of claims 1-9, which comprises the following steps:

    (1) Dissolve the buffer, osmotic pressure regulator (if any) and optional stabilizer in water for injection to obtain solution 1;

    (2) The active ingredient is dissolved in the solution 1 to obtain a solution 2;

    (3) Adjust the pH of the solution 2 with the pH adjusting agent to 3.5-5.5 (for example, 3.5-5.0, 4.0-5.5, 4.0-5.0, or 4.3-4.7) to obtain the pharmaceutical composition;

    Optionally, the preparation method further includes the step of sterilizing the pharmaceutical composition;

    Optionally, the step method further includes the step of adjusting the pH value of the solution 1 to 3.5-5.5 with a pH adjusting agent after step (1);

    Optionally, after the sterilization step, a step of nitrogen filling is further included;

    Optionally, after the nitrogen filling step, a filling step is also included.
11. The production method according to claim 10, wherein step (1) and step (2) are carried out at a temperature of 15-40 ° C, preferably 15-25 ° C;

    Further preferably, the sterilization refers to filtration sterilization, for example, sterilization through a 0.22 μm filter membrane, preferably 0.22 μm polyethersulfone filter membrane.
12. Use of the pharmaceutical composition according to any one of claims 1 to 9 in the preparation of a medicament for the prevention or treatment of diseases associated with κ opioid receptors; preferably, the diseases associated with κ opioid receptors are selected from Pain, inflammation, itching, edema, hyponatremia, hypokalemia, intestinal obstruction, cough, and glaucoma; preferably, the pain is selected from neuropathic pain, somatic pain, visceral pain, and skin pain; preferably, The pain is selected from arthritis pain, kidney stone pain, uterine cramps, dysmenorrhea, endometriosis, post-surgical pain, pain after medical treatment, eye pain, otitis pain, cancer pain, and gastrointestinal disorders. Pain.
13. The pharmaceutical composition according to any one of claims 1-9, which is used to prevent or treat a disease associated with a kappa opioid receptor; preferably, the disease associated with a kappa opioid receptor is selected from pain and inflammation , Itching, edema, hyponatremia, hypokalemia, intestinal obstruction, cough, and glaucoma; preferably, the pain is selected from neuropathic pain, somatic pain, visceral pain, and skin pain; preferably, the pain is selected Pain associated with arthritis pain, kidney stone pain, uterine cramps, dysmenorrhea, endometriosis, post-surgical pain, post-medical pain, eye pain, otitis pain, cancer pain, and gastrointestinal disorders.
14. A method for preventing or treating a disease associated with a kappa opioid receptor, which comprises the step of administering to a subject in need thereof an effective amount of the pharmaceutical composition of any one of claims 1-9; preferably, The disease associated with the κ opioid receptor is selected from pain, inflammation, itching, edema, hyponatremia, hypokalemia, intestinal obstruction, cough, and glaucoma; preferably, the pain is selected from neuropathic pain , Body pain, visceral pain and skin pain; preferably, the pain is selected from arthritis pain, kidney stone pain, uterine cramps, dysmenorrhea, endometriosis, post-surgical pain, pain after medical treatment, ocular Pain, otitis pain, cancer pain, and gastrointestinal disorders related pain.
15. An injection product comprising a pharmaceutical composition according to any one of claims 1-9 and a closed container containing the pharmaceutical composition, wherein the volume of the pharmaceutical composition is less than or equal to the volume of the closed container, when the When the volume of the pharmaceutical composition is smaller than the volume of the closed container, the remaining space of the closed container is filled with an inert gas; preferably, the closed container is a glass or plastic closed container, such as an ampoule or a vial (such as Borosilicate glass controlled injection bottle); preferably, the inert gas is nitrogen.