Abaparatide preparation

Abstract

The invention discloses an abparatide preparation, the abparatide preparation comprises an abparatide solution and a pre-filling and sealing clamping type bottle, the abparatide solution is filled in the pre-filling and sealing clamping type bottle, the abparatide solution comprises a bacteriostatic agent, and the content of the bacteriostatic agent is not less than 4.75 mg / mL.

Description

Technical Field

[0001] The present application relates to the field of medical technology, and specifically to an abaparatide preparation. Background Art

[0002] Abaloparatide is a synthetic 34-amino acid polypeptide, an analog of parathyroid hormone-related protein, used to treat osteoporosis in postmenopausal women at risk of fracture or who are refractory to other drugs, and in men at risk of fracture or who are refractory to other drugs. Its English name is Abaloparatid, and its peptide sequence is: Ala-Val-Ser-Glu-His-Gln-Leu-Leu-His-Asp-Lys-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Aib-Lys-Leu-His-Thr-Ala-NH2.

[0003] The common dosage form of abaparatide is injection, which is filled in a prefilled cartridge vial and injected subcutaneously using a pen-type syringe. When the applicant conducted a stability study on the abaparatide preparation during the research and development process, it was unexpectedly discovered that after the abaparatide preparation was placed for a period of time, the content of the antibacterial agent in the preparation was significantly reduced, resulting in a decrease in the antibacterial efficacy of the abaparatide preparation itself, thereby affecting the long-term storage stability of the abaparatide preparation. At the same time, when the content of the antibacterial agent is low, the antibacterial efficacy does not meet the pharmacopoeia standards, affecting the safety of the preparation itself.

[0004] In order to solve the problem of reduced antibacterial agent content in abaparatide preparations, the applicant first considered the following two solutions: 1. Increasing the amount of antibacterial agent added to the preparation; 2. Replacing a variety of different packaging containers. However, for the first solution, if too much antibacterial agent is added, it will not meet the requirements of the maximum unit dose in the "US FDA Inactive Ingredient Database", affecting the safety of the drug; for the second solution, if other packaging containers are used, the advantages of multiple doses of pre-filled cartridges for multiple injections will be lost. Summary of the invention

[0005] To solve the above technical problems, the present application provides an abaparatide preparation, which includes an abaparatide solution and a prefilled cartridge, and can inhibit the reduction of the antibacterial agent content in the abaparatide preparation, ensure the antibacterial efficacy, and thus ensure the safety and effectiveness of the abaparatide preparation.

[0006] Specifically, the present application provides an abaparatide preparation, which includes an abaparatide solution and a prefilled cartridge, wherein the abaparatide solution is filled in the prefilled cartridge.

[0007] In some embodiments, the abaparatide solution comprises abaparatide, a bacteriostatic agent, water for injection, and a pH adjuster.

[0008] In some embodiments, the pH adjusting agent includes one or more of acetic acid / sodium hydroxide, acetic acid / sodium acetate, hydrochloric acid / sodium acetate, or sodium acetate / sodium hydroxide / hydrochloric acid. In some embodiments, the pH adjusting agent includes one or more of acetic acid / sodium acetate, hydrochloric acid / sodium acetate. In some embodiments, the pH adjusting agent is acetic acid / sodium acetate.

[0009] In some embodiments, the antibacterial agent is selected from at least one of phenol, cresol, chlorocresol, chlorobutanol, benzyl alcohol, methylparaben, ethylparaben, and propylparaben. In some embodiments, the antibacterial agent is further selected from at least one of phenol, cresol, chlorocresol, and chlorobutanol. In some embodiments, the antibacterial agent is preferably phenol.

[0010] In some embodiments, the content of the antibacterial agent in the abaparatide solution is not less than 4.75 mg / mL. In some embodiments, the content of the antibacterial agent is not less than 5.0 mg / mL. In some embodiments, the content of the antibacterial agent is not less than 5.25 mg / mL.

[0011] In some embodiments, the antibacterial agent content is 4.75-5.5 mg / mL. In some embodiments, the antibacterial agent content is 4.75-5.25 mg / mL. In some embodiments, the antibacterial agent content is 4.75-5.0 mg / mL. In some embodiments, the antibacterial agent content is 5.0-5.5 mg / mL. In some embodiments, the antibacterial agent content is 5.0-5.25 mg / mL. In some embodiments, the antibacterial agent content is 5.25-5.5 mg / mL.

[0012] In some embodiments, the prefilled cartridge used in the present application may be a commercially available prefilled cartridge.

[0013] In some embodiments, the prefilled cartridge used in the present application may be a cartridge that has been self-cleaned, coated, and sterilized.

[0014] In some embodiments, the assembly of the prefilled cartridge includes a cartridge and a piston.

[0015] In some embodiments, the assembly of the prefilled cartridge includes a sleeve, a gasket, and an aluminum cap.

[0016] In some embodiments, the assembly of the prefilled cartridge includes a sleeve, a piston, a gasket, and an aluminum cap.

[0017] In some embodiments, the prefilled cartridge is coated with silicone oil.

[0018] In some embodiments, the silicone oil content is no greater than 0.028 mg / cm 2 In some embodiments, the silicone oil content is not higher than 0.019 mg / cm 2 .

[0019] In order to ensure smooth sliding of the piston in the prefilled cartridge, a certain amount of silicone oil needs to be added to the inner surface of the prefilled cartridge to reduce the resistance when moving the piston. In some embodiments, the silicone oil content is not less than 0.005 mg / cm 2 In some embodiments, the silicone oil content is not less than 0.009 mg / cm 2 .

[0020] In some embodiments, the silicone oil content is 0.005-0.028 mg / cm 2 In some embodiments, the silicone oil content is 0.005 to 0.019 mg / cm 2 .

[0021] In some embodiments, the silicone oil content is 0.009-0.028 mg / cm 2 In some embodiments, the silicone oil content is 0.009 to 0.019 mg / cm 2 .

[0022] In some embodiments, the sleeve of the prefilled cartridge in the abaparatide formulation is a glass sleeve.

[0023] In some embodiments, the size of the glass sleeve is 1 mL. In some embodiments, the size of the glass sleeve is 1.5 mL. In some embodiments, the size of the glass sleeve is 1.8 mL. In some embodiments, the size of the glass sleeve is 2 mL. In some embodiments, the size of the glass sleeve is 3 mL.

[0024] In some embodiments, silicone oil is coated on the inner wall of the glass sleeve (or referred to as "inner surface of the glass sleeve") of the prefilled cartridge.

[0025] In some embodiments, the glass sleeve of the prefilled cartridge is a borosilicate glass sleeve. In some embodiments, the borosilicate glass sleeve is a medium borosilicate cartridge.

[0026] In some embodiments, abaloparatide is the only active ingredient in the abaloparatide formulations of the present application.

[0027] The present application provides an abaparatide preparation, which comprises an abaparatide solution and a prefilled cartridge bottle, and has the following beneficial effects: the content of the antibacterial agent in the abaparatide solution is controlled within a range of not less than 4.75 mg / mL and the content of the antibacterial agent is controlled within a range of not less than 0.028 mg / cm2 by coating the prefilled cartridge bottle with an amount not less than 0.028 mg / cm2. 2The amount of silicone oil can effectively inhibit the reduction of the antibacterial agent content in the abaparatide preparation, while ensuring that the antibacterial efficacy of the abaparatide preparation meets the pharmacopoeia standards, ensuring that the product still has an antibacterial efficacy that meets the pharmacopoeia standards even after being stored for a period of time, and better ensuring the safety, effectiveness and clinical applicability of the product. DETAILED DESCRIPTION

[0028] In order to more clearly illustrate the technical solution of the present invention, the technical solution of the present invention will be described using embodiments below. It should be understood that the description of the embodiments is only for the convenience of understanding the technical solution, rather than limiting the present invention to the specific embodiments shown. The titles in this application are provided only for convenience and should not be interpreted as limiting the present invention in any way. The embodiments shown under any title can be combined with the embodiments shown under any other title. For those of ordinary skill in the art, various modifications, improvements and amendments can also be made to these embodiments without paying creative work. So such modifications, improvements and amendments still belong to the spirit and scope of the exemplary embodiments of this specification.

[0029] In the present invention, unless otherwise indicated herein, recitation of ranges of values ​​herein is intended merely to serve as a shorthand method of individually referring to each individual value falling within the range, and each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context.

[0030] Example 1 Prescription Screening Study

[0031] Considering the production cost and product quality of generic drugs, the applicant has conducted a screening study on the prescription of abaparatide solution, mainly for the type and dosage of pH regulators and antibacterial agents, in order to obtain a prescription that can reduce production costs without affecting product quality.

[0032] 1. Types of pH adjusters

[0033] Commonly used pH adjusters include hydrochloric acid, phosphoric acid, acetic acid, citric acid, sodium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium acetate, etc. Considering that the API of abaparatide solution is abaparatide acetate, in order to ensure the stability of the API in abaparatide solution and avoid changes in the API structure, acetic acid and sodium acetate are selected as pH adjusters.

[0034] 2. Dosage of pH adjuster

[0035] The API in the abaparatide solution is a polypeptide compound, which is extremely sensitive to pH. Different pH values ​​will affect the key quality attributes of the abaparatide solution (such as properties, pH value, visible foreign matter, phenol content, related substances, etc.). In order to explore the optimal pH range of the abaparatide solution, the applicant conducted a pH regulator dosage screening, and the designed experiment is as follows:

[0036] Keeping the sodium acetate dosage at 5.08 mg / mL unchanged, the acetic acid dosage was changed to prepare abaparatide solutions with pH values ​​of 4.5, 4.7, 4.9, 5.1, 5.2, and 5.4, respectively, which were filled into pre-filled cartridge bottles, sealed and stoppered, and placed under accelerated conditions (25°C ± 2°C, 60% RH ± 5% RH) for 6 months. Samples were taken at 0, 3, and 6 months to observe the properties and test the pH value, phenol content, visible foreign matter, and related substances. The relevant test methods for each key quality attribute are as follows:

[0037] Properties: Visual inspection;

[0038] pH value: Calibrate the pH value of the acidometer to a range of 4.01 to 6.86, with a slope not less than 95%. The temperature of the test solution should be around 25°C. After calibration, measure the pH value of the solution.

[0039] Phenol content: The detection steps are as follows:

[0040] 1. Preparation of solvent: Weigh 26.4 g of diammonium hydrogen phosphate, dissolve it in 1000 mL of water, and adjust the pH to 1.5 with perchloric acid.

[0041] 2. Preparation of test solution: Take the abaparatide solution from the pre-filled cartridges in October, March and June respectively.

[0042] 3. Preparation of reference solution: Take an appropriate amount of phenol reference substance, weigh accurately, dissolve it in mobile phase and quantitatively dilute it to make a solution containing about 5 mg per 1 mL.

[0043] 4. Determine according to the high performance liquid chromatography method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512). Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram. The specific parameters are as follows:

[0044]

[0045] Visible foreign matter: Use a clarity detector with the illumination set to 1000-1500lx for detection;

[0046] The quality inspection results of abaparatide solution under different pH conditions are shown in Table 1:

[0047] Table 1 Quality inspection under different pH conditions

[0048]

[0049]

[0050] As shown in Table 1, the properties, pH value, visible foreign matter, and phenol content of the abaparatide solution remained basically unchanged within the pH range of 4.5 to 5.4. However, the total impurity level was relatively high within the pH range of 4.5 to 4.9. In order to ensure the stability and quality of the abaparatide solution, the pH value range of this product was determined to be 5.1 to 5.4.

[0051] 3. Types of antibacterial agents

[0052] The antibacterial agent in the injection mainly plays an antibacterial role to ensure the safety of the injection. However, the antibacterial agent may have compatibility risks with the packaging materials and raw materials, react, and thus affect the quality of the product. Among them, good compatibility means: no extracts with safety risks can be introduced or the level of extracts meets the safety requirements, and the quality, efficacy and safety of the drug will not be affected by the adsorption of active ingredients or functional excipients in the drug. Common types of antibacterial agents include phenol (suggested dosage: 0.25%~0.5%), cresol (suggested dosage: 0.25%~0.3%), chlorocresol (suggested dosage: 0.05%~0.2%), and trichlorobutanol (suggested dosage: 0.25%~0.5%). In order to avoid compatibility risks, the applicant screened the types of antibacterial agents and investigated the effects of different types of antibacterial agents on the key quality attributes of abaparatide solution (properties, pH value, visible foreign matter, related substances). The designed experiment is as follows:

[0053] In order to ensure the antibacterial efficacy, the highest recommended dosage of different antibacterial agents was selected for the test: the maximum dosage of phenol, cresol, chlorocresol and chlorobutanol was 5 mg / mL, 3 mg / mL, 2 mg / mL and 5 mg / mL, respectively, based on the volume of abaparatide solution of 1 mL and the density of the solution of 1.002 g / mL (mass / volume=1.002 g / 1 mL). The dosage of pH adjusters (sodium acetate and acetic acid) was kept constant, the pH value of abaparatide solution was adjusted within the range of 5.1 to 5.4, the type and dosage of antibacterial agents were changed, the solution was prepared, filled into pre-filled cartridge bottles, sealed and stoppered, placed under accelerated conditions (25°C ± 2°C, 60% RH ± 5% RH) for 6 months, and samples were taken at 0, 3 and 6 months to observe the properties and detect the pH value, visible foreign matter and related substances. The results of the investigation are shown in Table 2:

[0054] Table 2 Investigation of the effects of different antimicrobial agents on quality attributes

[0055]

[0056] As shown in Table 2, the properties, pH value, and visible foreign matter of the abaparatide solution with different types of antibacterial agents were basically unchanged. However, compared with other types of antibacterial agents, when the antibacterial agent was phenol, the total impurity level in the abaparatide solution was lower, indicating that phenol had better compatibility with the API in the abaparatide solution. In order to ensure the stability and quality of the abaparatide preparation, phenol was finally determined to be the antibacterial agent of the abaparatide solution.

[0057] 4. Study on the dosage of phenol

[0058] In order to ensure that the antibacterial efficacy of abaparatide preparations meets the regulations, it is necessary to study the effect of different phenol contents on the antibacterial efficacy of abaparatide solutions, so as to determine the appropriate range of phenol dosage in abaparatide solutions. The experiment is designed as follows:

[0059] Keep the remaining excipients and prescription dosages in the abaparatide solution unchanged, and change the dosage of phenol. In view of the fact that the "US FDA Inactive Ingredient Database" stipulates that the dosage of inactive ingredients for subcutaneous injection shall not exceed 0.55%, based on the volume of the abaparatide solution of 1mL and the density of the solution of 1.002g / mL, the concentration of inactive ingredients in the abaparatide solution should not exceed 5.5mg / mL, that is, the amount of phenol in the abaparatide solution cannot exceed 5.5mg / mL. Therefore, the following phenol dosages are set: 3.0mg / mL, 4.0mg / mL, 4.75mg / mL, 5.0mg / mL, 5.5mg / mL, and the liquid is prepared and filled into prefilled cartridge bottles, sealed and stoppered. The determination of antibacterial efficacy is carried out in accordance with the "Chinese Pharmacopoeia 2020 General Principles 1121 Antibacterial Efficacy Test Method", and the specific operation method is as follows:

[0060] 1. Preparation of bacterial solution: Collect the cultured Pseudomonas aeruginosa, Staphylococcus aureus, and Candida albicans by centrifugation, dilute with 0.9% sterile sodium chloride solution and make the bacterial count per mL to about 10 8 cfu suspension. Take a fresh culture of Aspergillus niger and add an appropriate amount of 0.9% sterile sodium chloride solution containing 0.05% (mL / mL) polysorbate 80 to wash out the spores. Then, aspirate the spore suspension into a sterile test tube and add an appropriate amount of 0.9% sterile sodium chloride solution containing 0.05% (mL / mL) polysorbate 80 to make a suspension containing 10 cfu of spores per 1 mL. 8 cfu of spore suspension. Determine the number of bacteria contained in 1 mL of bacterial suspension.

[0061] 2. Inoculation of test sample: Take 4 portions of abaparatide solution from intact prefilled cartridges and directly inoculate the test bacteria (one test bacteria is inoculated in each container). The inoculation amount is 10 5 ~10 6cfu, the volume of the inoculated solution shall not exceed 1% of the volume of the test sample. After inoculation, mix thoroughly to ensure that the test bacteria in the test sample are evenly distributed, and then store at 20-25℃ away from light.

[0062] 3. Determination of the number of viable bacteria: This product is an injection. According to the specified intervals (as shown in Table 3), take 1 mL of the test sample from each of the above containers and determine the number of bacteria contained in each sample. Trypticase soy peptone agar medium is used for bacteria determination, and Sabouraud dextrose agar medium is used for fungi determination. According to the results of the determination of the number of viable bacteria, calculate the number of bacteria added to 1 mL of the test sample for each test bacteria and the number of bacteria at each interval, and convert it into lg value.

[0063] Table 3 Judgment criteria for antibacterial efficacy of injection preparations

[0064]

[0065] The antibacterial efficacy test results of different phenol contents are shown in Table 4:

[0066] Table 4 Antibacterial efficacy of different phenol contents

[0067]

[0068]

[0069]

Note 1

[0070]

Note 2

[0071] As shown in Table 4, when the phenol content was 3.0 mg / mL, the lg values ​​of Staphylococcus aureus detected at 6h and 24h were 1.5 and 1.1, respectively, which were significantly lower than the lg values ​​that should be reduced in 6h and 24h as defined by the "A standard level" in Table 1; when the phenol content was 4.0 mg / mL, the lg value of Staphylococcus aureus detected at 6h was 1.4, which was significantly lower than the lg value that should be reduced in 6h as defined by the "A standard level" in Table 1; however, when the phenol content was ≥4.75 mg / mL, the lg values ​​of each test bacteria were all greater than the lg values ​​that should be reduced in the corresponding time intervals as defined by the "A standard level" in Table 1. The results in Table 4 show that when the phenol content was ≥4.75 mg / mL, the antibacterial efficacy of the product reached the "A standard level" and met the requirements of the pharmacopoeia.

[0072] Therefore, when the phenol content in the abaparatide solution is controlled at 4.75-5.5 mg / mL, the antibacterial efficacy meets the pharmacopoeia standard and meets the safety requirements. Based on this study, it was determined that the abaparatide solution with the same phenol content (e.g., 5.0 mg / mL) was used in subsequent experiments.

[0073] Example 2 Preparation Stability Study

[0074] After confirming the type and dosage of the prescription, the applicant investigated the stability of the abaparatide preparation at different stages of product research. The preparation stability investigation experiment is as follows:

[0075] The dosage of phenol was kept at 5.0 mg / mL and the pH was kept within the range of 5.1 to 5.4, the pharmaceutical solution was prepared, the abaparatide solution was filled into prefilled cartridge bottles, sealed and stoppered, and placed under accelerated conditions (25°C ± 2°C, 60% RH ± 5% RH) for 6 months, and samples were taken at 0, 3, and 6 months to observe the properties and test the pH value, phenol content, visible foreign matter, and antibacterial efficacy.

[0076] After different stages of preparation stability inspection, the applicant found that the antibacterial efficacy of a batch of abaparatide preparations deteriorated. After research, it was found that this was due to the low phenol content of the abaparatide preparations during storage, which led to the unqualified stability quality of the batch. The stability inspection results of the unqualified batch are shown in Tables 5 and 6:

[0077] Table 5 Physical and chemical quality inspection results

[0078]

[0079] As shown in Table 5, the properties, pH value, and visible foreign matter of the abaparatide preparation did not change with the increase in the observation time. However, in the samples accelerated for 3 months and 6 months, the phenol content was significantly reduced to 4.70 mg / mL and 4.68 mg / mL, respectively, which was lower than the minimum phenol content (4.75 mg / mL) that could effectively inhibit bacteria determined in the investigation in Example 1.

[0080] Table 6 Antibacterial efficacy experimental results

[0081]

[0082]

[0083] As shown in Table 6, with the increase of the observation time, when the samples in March and June were cultured for 6 hours, the lg values ​​of Staphylococcus aureus reduction (1.9 and 1.8 respectively) were smaller than the lg values ​​of bacteria reduced after 6 hours of culture in Table 1 (the lg value of reduction should be greater than 2), and the antibacterial efficacy could not reach the "A standard level", which did not meet the requirements of the pharmacopoeia.

[0084] Example 3 Investigation of factors affecting the reduction of phenol content

[0085] As mentioned above, the applicant found in the stability test of abaparatide preparation that the content of phenol as an antibacterial agent in one batch of abaparatide preparation was significantly reduced, and the antibacterial efficacy obviously did not meet the requirements of the pharmacopoeia. In response to this, the applicant conducted a series of studies. Considering that the containers and pistons used in different research stages may be different, it is very likely that the content of phenol in the abaparatide solution was affected. Therefore, the applicant investigated the containers, pistons, etc. involved, including: different types of tube bottles, tube bottles of different materials, different types of pistons, and cartridge bottles with different silicone oil coating amounts.

[0086] 1. Effects of different types of tube bottles on phenol content

[0087] In order to investigate whether different types of tube bottles affect the phenol content in abaparatide solution, the experiment was designed as follows:

[0088] The abaparatide solution was filled into different types of controlled bottles (boron silica cartridges, borosilicate vials, borosilicate ampoules), sealed and stoppered, and placed under accelerated conditions (25°C ± 2°C, 60% RH ± 5% RH) for 6 months. Samples were taken at 0, 3, and 6 months to observe the properties and test the pH value, phenol content, and visible foreign matter. The results are shown in Table 7:

[0089] Table 7 Effect of different types of tube bottles on phenol content

[0090]

[0091] As shown in Table 7, as the inspection time increased, the properties, pH value, and visible foreign matter of the samples in different types of controlled bottles did not change. In the samples inspected in 3 and 6 months, the phenol content remained basically unchanged. The results in Table 7 show that different types of controlled bottles have no effect on the phenol content in the abaparatide solution.

[0092] 2. Effect of different material tube bottles on phenol content

[0093] In order to investigate whether the tube bottles of different materials affect the phenol content in the abaparatide solution, the experiment was designed as follows:

[0094] The abaparatide solution was filled into control bottles of different materials (low borosilicate vials, medium borosilicate vials, and sodium calcium vials), sealed and stoppered, and placed under accelerated conditions (25°C ± 2°C, 60% RH ± 5% RH) for 6 months. The properties were observed and the pH value, phenol content, and visible foreign matter were tested at 0, 3, and 6 months. The results are shown in Table 8:

[0095] Table 8 Effect of tube bottles of different materials on phenol content

[0096]

[0097] As shown in Table 8, as the inspection time increased, the properties and visible foreign matter of the samples in the vials made of different materials did not change. In the samples of the accelerated inspection in March and June, the phenol content remained basically unchanged. Among them, the pH value of the samples in the sodium-calcium bottles increased slightly, but it was still within the appropriate pH range. The results in Table 8 show that the vials made of different materials had no effect on the phenol content in the abaparatide solution.

[0098] 3. Effect of different types of pistons on phenol content

[0099] In order to investigate whether different types of pistons affect the phenol content in abaparatide solution, the experiment was designed as follows:

[0100] The abaparatide solution was filled into a borosilicate cartridge, sealed and stoppered with different types of pistons (butyl bromide piston, butyl chloride piston, and film-coated butyl bromide piston), and placed under accelerated conditions (25°C ± 2°C, 60% RH ± 5% RH) for 6 months. The properties were observed and the pH value, phenol content, and visible foreign matter were tested at 0, 3, and 6 months. The results are shown in Table 9:

[0101] Table 9 Effect of different types of pistons on phenol content

[0102]

[0103] As shown in Table 9, as the investigation time increased, the properties, pH value, and visible foreign matter of the samples in the borosilicate cartridges with different types of pistons did not change. In the samples of the accelerated investigation in March and June, the phenol content remained basically unchanged. The results in Table 9 show that different types of pistons have no effect on the phenol content in the abaparatide solution.

[0104] 4. Effect of different cartridges on phenol content

[0105] After investigating different types and materials of tube bottles and different types of pistons, it was found that these three factors would not lead to a decrease in the phenol content during the preparation stability investigation. The applicant consulted the supplier of the container and found that in order to meet the mechanical sliding properties of the prefilled cartridge bottle, silicone oil needs to be applied inside the prefilled cartridge bottle, and the amount of silicone oil applied on the inner surface of cartridge bottles from different sources and batches may be different. Therefore, the applicant further investigated the effect of cartridge bottles with different silicone oil coating amounts on the phenol content in the abaparatide solution, and designed the experiment as follows:

[0106] The abaparatide solution was filled into different cartridges (medium borosilicate cartridge, prefilled cartridge 1, prefilled cartridge 2), sealed and stoppered, and placed under accelerated conditions (25°C ± 2°C, 60% RH ± 5% RH) for 6 months. The properties were observed and the pH value, phenol content, and visible foreign matter were tested at 0, 3, and 6 months. The results are shown in Table 10:

[0107] Table 10 Effect of different cartridges on phenol content

[0108]

[0109] As shown in Table 10, as the inspection time increases, the properties, pH values, and visible foreign matter of the samples in different cartridges do not change. Among them, after the accelerated inspection for 6 months, the phenol content in the sample of prefilled cartridge 1 is basically unchanged. However, after the accelerated inspection for 3 months and 6 months, the phenol content in the sample of prefilled cartridge 2 is significantly reduced. The results in Table 10 show that the amount of silicone oil applied in the prefilled cartridge has an effect on the phenol content in the abaparatide solution, and different amounts of silicone oil applied in the prefilled cartridge have different effects on the phenol content.

[0110] It can be seen that the decrease in phenol content in the abaparatide solution during the preparation stability study was caused by the silicone oil coated in the prefilled cartridge.

[0111] Example 4 Effect of different silicone oil coating amounts on phenol content

[0112] Through the above-mentioned study on the effect of different cartridges on the phenol content in the abaparatide solution, the applicant unexpectedly found that the silicone oil coated in the pre-filled cartridge would cause the phenol content of the abaparatide solution to decrease during long-term storage, thereby reducing the antibacterial efficacy of the abaparatide preparation and affecting safety. In addition, the applicant found that pre-filled cartridges with different silicone oil coating amounts had different effects on the phenol content in the abaparatide solution.

[0113] In order to avoid the effect of the amount of silicone oil applied in the prefilled cartridge on the quality of the abaparatide preparation, the applicant investigated the change in the phenol content in the abaparatide solution when different amounts of silicone oil were applied in the prefilled cartridge, thereby determining the optimal range of the amount of silicone oil applied in the prefilled cartridge. The experiment was designed as follows:

[0114] Take silicone oil, dilute it to different concentrations with an appropriate amount of diluent (such as ethanol), and take several borosilicate cartridges and spray different amounts of silicone oil (0.003 mg / cm 2 , 0.005mg / cm 2 , 0.009mg / cm 2 , 0.019mg / cm 2 , 0.028mg / cm2 , 0.037mg / cm 2 , 0.056mg / cm 2 ) in borosilicate cartridges to prepare pre-filled cartridges with different silicone oil coating amounts.

[0115] Abaparatide solution was filled into different silicone oil coating amounts (0.003 mg / cm 2 , 0.005mg / cm 2 , 0.009mg / cm 2 , 0.019mg / cm 2 , 0.028mg / cm 2 , 0.037mg / cm 2 , 0.056mg / cm 2 ) in a pre-filled cartridge, sealed and stoppered, placed under accelerated conditions (25°C ± 2°C, 60% RH ± 5% RH) for 6 months, and the phenol content in the abaparatide solution was tested at 0, 3, and 6 months, respectively. The results are shown in Table 11:

[0116] Table 11 Effect of different silicone oil coating amounts on phenol content

[0117]

[0118] As shown in Table 11, when the amount of silicone oil applied in the prefilled cartridge is ≤ 0.028 mg / cm 2 At the time of the accelerated investigation for 6 months, the phenol content in the abaparatide solution was 4.78 mg / mL (>4.75 mg / mL), which can ensure that the antibacterial efficacy of the product reaches the "A standard level" required by the pharmacopoeia. Furthermore, when the coating amount of silicone oil in the prefilled cartridge bottle is ≤0.019 mg / cm 2 When the amount of silicone oil in the prefilled cartridge is greater than 0.028 mg / cm 2 When examined under accelerated conditions in March and June, the phenol content in the abaparatide solution was significantly reduced, both <4.75 mg / mL, which will result in the product's antibacterial efficacy failing to reach the "A standard level" required by the pharmacopoeia.

[0119] The results in Table 11 show that when the coating amount of silicone oil in the prefilled cartridge is high, the excess silicone oil will reduce the phenol content in the abaparatide solution, affecting the antibacterial efficacy and thus the safety of the product.

[0120] Therefore, in abaparatide preparations, the amount of silicone oil applied in prefilled cartridges should not exceed 0.028 mg / cm 2, preferably not higher than 0.019mg / cm 2 .

[0121] Example 5 Effect of different silicone oil coating amounts on the sliding properties of prefilled cartridge bottles

[0122] Since a small amount of silicone oil needs to be applied to the prefilled cartridge to reduce the friction between the piston and the glass sleeve to avoid affecting the patient's experience and drug delivery accuracy, the applicant investigated the effect of different silicone oil coating amounts on the sliding performance of the prefilled cartridge to determine the minimum amount of silicone oil applied in the prefilled cartridge. The experiment was designed as follows:

[0123] Take silicone oil, dilute it to different concentrations with an appropriate amount of diluent (such as ethanol), and take several borosilicate cartridges and spray different amounts of silicone oil (0.003 mg / cm 2 , 0.005mg / cm 2 , 0.009mg / cm 2 , 0.019mg / cm 2 , 0.028mg / cm 2 , 0.037mg / cm 2 , 0.056mg / cm 2 ) in borosilicate cartridges to prepare pre-filled cartridges with different silicone oil coating amounts.

[0124] Abaparatide solution was filled into different silicone oil coating amounts (0.003 mg / cm 2 , 0.005mg / cm 2 , 0.009mg / cm 2 , 0.019mg / cm 2 , 0.028mg / cm 2 , 0.037mg / cm 2 , 0.056mg / cm 2 ) in a pre-filled cartridge bottle, seal and stopper it. Prepare 3 pre-filled cartridge bottle samples for each test, insert a 5mm31G hypodermic needle, and fix the treated samples on the test stand of the TSL-1002 electronic tensile testing machine. In the "Test Item List" of the operation interface, select "Sliding Test", set the test parameters test speed: 40.0mm / min, return speed: 300.0mm / min, pause time: 5 seconds, and other parameters are default. After the parameters are set, click the "Test" button to measure the sample starting force, continuous thrust and restart force respectively. The results of the sliding performance inspection are shown in Table 12:

[0125] Table 12 Effect of different silicone oil coating amounts on the sliding properties of prefilled cartridge bottles

[0126]

[0127]

[0128] As shown in Table 12, when the amount of silicone oil applied in the prefilled cartridge is ≤ 0.003 mg / cm 2 When the amount of silicone oil applied in the prefilled cartridge is ≥0.005mg / cm 2 When the starting force, continuous push force and restart force of the prefilled cartridge are all below the acceptable standard, the sliding performance of the prefilled cartridge meets the standard requirements.

[0129] Therefore, in order to ensure normal injection operation and accurate injection accuracy, the amount of silicone oil applied in the pre-filled cartridge should not be less than 0.005 mg / cm 2 .

[0130] In summary, when the phenol content in the abaparatide solution is not less than 4.75 mg / mL and not more than 5.5 mg / mL, the coating amount of silicone oil in the prefilled cartridge bottle is not less than 0.005 mg / cm 2 And not higher than 0.028mg / cm 2 When the lubrication performance of the prefilled cartridge bottle meets the standard requirements, the phenol content in the abaparatide solution is still higher than 4.75 mg / mL, so as to ensure that the antibacterial efficacy of the abaparatide preparation meets the pharmacopoeia standards. Furthermore, the product safety, effectiveness and clinical applicability can be better guaranteed.

[0131] The use of any and all examples or exemplary language provided herein is intended merely to illustrate certain materials and methods and is not intended to limit the scope. No language in the specification should be construed as indicating any non-claimed element as essential to practice the disclosed materials and methods.

[0132] As shown in this application and claims, unless the context clearly indicates an exception, the words "a", "an", "an" and / or "the" do not refer to the singular and may also include the plural. Generally speaking, the terms "include" and "comprise" only indicate the inclusion of the steps and elements that have been clearly identified, and these steps and elements do not constitute an exclusive list. The method or composition may also include other steps or elements.

[0133] At the same time, this specification uses specific words to describe the embodiments of this specification. For example, "in some embodiments", "in various embodiments", "one embodiment", "an embodiment", and / or "some embodiments" refer to a certain feature, structure or characteristic related to at least one embodiment of this specification. Therefore, it should be emphasized and noted that "in some embodiments", "in various embodiments", "one embodiment", "an embodiment", and / or "some embodiments" mentioned twice or more in different positions in this specification do not necessarily refer to the same embodiment. In addition, some features, structures or characteristics in one or more embodiments of this specification can be appropriately combined.

[0134] Although the above disclosure discusses some of the invention embodiments currently considered useful through various examples, it should be understood that such details are only for illustrative purposes, and the appended claims are not limited to the disclosed embodiments. On the contrary, the claims are intended to cover all modifications and equivalent combinations that are consistent with the essence and scope of the embodiments of this specification.

[0135] Similarly, it should be noted that in order to simplify the description disclosed in this specification and thus help understand one or more embodiments of the invention, in the description of the embodiments of this specification, multiple features are sometimes combined into one embodiment. However, this disclosure method does not mean that the features required by the subject matter of this specification are more than the features mentioned in the claims.

[0136] Finally, it should be understood that the embodiments described in this specification are only used to illustrate the principles of the embodiments of this specification. Other variations may also fall within the scope of this specification. Therefore, as an example and not a limitation, alternative compositions of the embodiments of this specification may be considered consistent with the teachings of this specification. Accordingly, the embodiments of this specification are not limited to the embodiments explicitly introduced and described in this specification.

Claims

1. An abaparatide preparation, comprising an abaparatide solution and a prefilled cartridge, wherein the abaparatide solution is filled in the prefilled cartridge, characterized in that: The abaparatide solution includes an antibacterial agent, and the content of the antibacterial agent is not less than 4.75 mg / mL.

2. The abaparatide preparation according to claim 1, characterized in that The antibacterial agent is selected from at least one of phenol, cresol, chlorocresol, chlorobutanol, benzyl alcohol, methylparaben, ethylparaben and propylparaben.

3. The abaparatide preparation as claimed in claim 2, characterized in that The antibacterial agent is selected from at least one of phenol, cresol, chlorocresol and chlorobutanol.

4. The abaparatide preparation as claimed in claim 3, characterized in that The antibacterial agent is phenol.

5. The abaparatide preparation according to claim 1, characterized in that The content of the antibacterial agent is 4.75-5.5 mg / mL.

6. The abaparatide preparation according to claim 1, characterized in that The pre-filled cartridge bottle is coated with silicone oil, and the content of the silicone oil is not higher than 0.028 mg / cm 2 .

7. The abaparatide preparation according to claim 6, characterized in that The silicone oil content is not higher than 0.019 mg / cm 2 .

8. The abaparatide preparation according to claim 6, characterized in that The silicone oil content is 0.005-0.028 mg / cm 2 .

9. The abaparatide preparation according to claim 7, characterized in that The silicone oil content is 0.005-0.019 mg / cm 2 .

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