Process for preparation of pharmaceutical compositions for delayed release of somatostatin analogs

Abstract

The invention relates to the technical field of medicines, and discloses a preparation method of a pharmaceutical composition for delayed release of somatostatin analogues. The pharmaceutical composition comprises the following main components: lanreotide acetate and an acetic acid aqueous solution, the preparation method comprises the following steps: taking lanreotide acetate, adding an acetic acid aqueous solution to dissolve the lanreotide acetate, filtering and sterilizing after the lanreotide acetate is completely dissolved, and preparing the filled and sterile pre-filled lanreotide acetate sustained-release gel by adopting a one-step vacuum volatilization method. And the concentration of lanreotide in terms of free alkali reaches 23.4-27.1% (w / w). The preparation method has the advantages that the preparation method is simple and easy to implement, and the time cost and the production cost are reduced; sterile operation is performed in the whole process, and sterilization cost is reduced; on the basis of simplifying the operation steps, the prepared lanreotide acetate sustained-release composition has the same release effect as the original lanreotide acetate sustained-release composition.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and particularly relates to a method for preparing a pharmaceutical composition for delayed release of a somatostatin analog, and a pharmaceutical composition prepared by the method. Background Art

[0002] Lanreotide acetate is the acetate compound of Lanreotide, which is a long-acting, sustained-release somatostatin octapeptide analog that can inhibit the secretion of growth hormone, thyroid-stimulating hormone, insulin and glucagon. It was initially used to treat patients with acromegaly and growth hormone-producing pituitary tumors who were ineffective with surgery or radiotherapy, and was later approved by the FDA for the treatment of unresectable, moderately to highly differentiated or metastatic gastroenteropancreatic neuroendocrine tumors.

[0003] Lanreotide is used in Somatuline LP or Depot and other products require a content between 23.4% and 27.1%, and a pH value between 5.8 and 6.4. There are many limitations in the existing market and production applications. Specifically, in the mixing process of its production link, especially in the initial mixing stage, the material has not been completely wetted, and the dry material will make the reciprocating extrusion operation extremely difficult. The force required for the extrusion push rod often exceeds 50MPa, and it is also difficult to ensure uniform mixing. Moreover, this operation process is very cumbersome, especially in large-scale production. If you want to achieve sufficient mixing, you need more operational equipment, which will further increase the production cost significantly. In addition, using this method, the production cycle is relatively long, and the gamma ray irradiation sterilization mode used has high location requirements and high energy consumption.

[0004] US Patent Publication No. 5,595,760 discloses a solid and semisolid pharmaceutical composition for delayed release of peptides, which is composed of a gelling and water-soluble peptide salt, which can be selectively mixed with an appropriate monomer excipient. These compositions will form a gel after being administered to a patient and slowly release the drug for at least 3 days.

[0005] International patent publication WO 1999 / 48519A describes a solid or semisolid pharmaceutical composition containing a gelable and water-soluble peptide salt. Its preparation method includes two cold drying steps, but does not mention the addition of acid to adjust the final pH value. The whole process requires complex drying steps and the introduction of organic solvents, which greatly increases clinical risks.

[0006] China's public patent document CN105456206A provides a simpler method for preparing a composition by a single freeze-drying step, but this method requires more than 60 hours of freeze-drying, and requires difficult mixing methods such as designing special mixing equipment and high energy consumption for mixing, and adjusting pH in the later stage. These existing technologies generally first dissolve lanreotide acetate and freeze-dry it, and then add water to the lyophilized material to make a sustained-release preparation, but this method has many problems. First, the freeze-drying operation process is more cumbersome, and special equipment needs to be equipped, resulting in a significant increase in production costs. Second, after preparing the lyophilized material, it is also necessary to undergo a hydration step, that is, the lyophilized material and water are mixed between two containers by the reciprocating extrusion of a piston, thereby preparing a semi-solid sustained-release preparation with extremely high viscosity.

[0007] China's public patent document CN 119015395 A discloses a vacuum concentration method, which evacuates a sterile weighing material tank to 50Pa and heats it to 40°C for vacuum concentration. During the vacuum concentration process, the weight loss of the sterile material tank is recorded in real time. When the concentration is calculated to be 23% (w / w, based on lanreotide free base) by the weight loss, the vacuum concentration is stopped to obtain the target product. However, this method takes 23 hours and the heating time is long, which is not conducive to the stability of the polypeptide. For such high-viscosity products, subsequent filling and sterilization are difficult.

[0008] In view of the above situation, in order to further improve Lanruifu's production efficiency and reduce corresponding production costs, it is necessary to improve and optimize its production processes and other aspects to overcome the shortcomings of the existing production methods and meet the market demand for efficient and low-cost production. Summary of the invention

[0009] The technical problem to be solved by the present invention is to provide a new method for preparing a pharmaceutical composition for delayed release of somatostatin analogs in view of the deficiencies of the prior art. The method has a simple operation process, low requirements on equipment and short time required.

[0010] The technical problem to be solved by the present invention is to adopt the following technical solution:

[0011] The present invention relates to a method for preparing a pharmaceutical composition for delayed release of somatostatin analogs, the characteristics of which are: the main components of the pharmaceutical composition are lanreotide acetate and acetic acid aqueous solution; the preparation method comprises the following steps: taking lanreotide acetate, adding acetic acid aqueous solution to dissolve it, filtering and sterilizing after it is completely dissolved, and then adopting a vacuum evaporation method to obtain the product lanreotide acetate sustained-release gel.

[0012] The method for preparing the pharmaceutical composition for delayed release of somatostatin analogs described above, a further preferred technical solution thereof is that the specific steps are as follows:

[0013] (1) Dissolve lanreotide acetate in acetic acid aqueous solution, filter it with a 0.22 μm filter membrane, place it in a 5 mL syringe, and press the plunger;

[0014] (2) The syringe is placed upside down in a sterile vacuum drying oven, the air pressure is adjusted to 95-115 μbar, the temperature is 8°C, and it is left to stand for 1-2 hours, then the air pressure is reduced by 15-25 μbar every hour, and finally the vacuum degree is controlled to be 20 μbar until the volume of 6 gels reaches the required 0.25 mL scale line, and lanreotide acetate sustained-release gel is obtained. Subsequently, the syringe piston is pushed up by controlling the vacuum machine to press the lower plate until the gel fills the syringe, and then the upper plate is controlled to press the syringe needle cap, and finally the packaging is completed.

[0015] The above-mentioned method for preparing a pharmaceutical composition for delayed release of somatostatin analogs, and its further preferred technical scheme is that in step (2): the above-mentioned syringe is inverted in a sterile vacuum drying oven, the air pressure is adjusted to 100 μbar, and it is left to stand for 1 hour, and then it is reduced by 20 μbar every 1 hour, and finally the vacuum degree is controlled to be 20 μbar and maintained for 4-6 hours, until the gel volume reaches the required 0.25 mL scale line, and lanreotide acetate sustained-release gel is obtained. Subsequently, the syringe piston is pushed up by controlling the vacuum machine to press the lower plate of the plunger until the gel fills the syringe, and then the upper plate of the plunger is controlled to press the syringe needle cap, and finally the packaging is completed.

[0016] Compared with the prior art, the present invention has the following beneficial effects:

[0017] 1. The present invention adopts a sterile vacuum evaporation technology to prepare lanreotide acetate sustained-release gel in one step. The method has a simple operation process, low equipment requirements, no need for complex mixing equipment, and a short time required for preparing lanreotide acetate sustained-release gel.

[0018] 2. In the present invention, all operations from filling to finished product are carried out under aseptic conditions, and no gamma ray irradiation sterilization is required.

[0019] 3. On the basis of simplifying the operation steps, the pH, content and release effect of the lanreotide acetate sustained-release composition prepared by the method of the present invention are all within the qualified range of the original research.

[0020] 4. Compared with the prior art, the preparation method of the present invention is simple, reducing the risk of polypeptide stability, time cost and production cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 -8 is a release curve diagram of the lanreotide acetate sustained-release gel prepared in Example 1-8;

[0022] Fig. 9 This is a release curve diagram of the lanreotide acetate sustained-release gel prepared in Comparative Example 1.

[0023] Fig.10 This is the release curve of the original formulation. DETAILED DESCRIPTION

[0024] The specific technical solutions of the present invention are further described below to help those skilled in the art further understand the present invention without limiting the rights thereof.

[0025] The reagents or instruments used without indicating the manufacturer are all conventional products that can be purchased from the market.

[0026] Raw materials: Jiangsu Nuotai Ausino Biopharmaceutical Co., Ltd.

[0027] Vacuum drying oven: Dalian Pinhong Pharmaceutical Machinery Co., Ltd.

[0028] The original marketed preparation of lanreotide acetate (trade name: somadulin): IPSEN PHARMA, 60mg / 0.2ml, batch number P22713.

[0029] Embodiment 1:

[0030] 60 mg of lanreotide acetate was dissolved in 4 mL of acetic acid aqueous solution at pH 2, and then filtered through a 0.22 μm filter membrane into a 5 mL syringe, and the plunger was pressed. The above syringe was inverted in a sterile vacuum drying oven, and the air pressure was adjusted to 100 μbar, the temperature was 8 ° C, and the temperature was adjusted to 1 hour, and then the pressure was reduced by 20 μbar every 1 hour, and the vacuum degree was controlled to be 20 μbar for 5 hours. The gel volume reached the required 0.25 mL scale line to obtain a uniformly mixed lanreotide sustained-release gel. Subsequently, the syringe piston was pushed up by controlling the vacuum machine to press the lower plate until the gel filled the syringe, and then the upper plate of the press was controlled to press the syringe needle cap, and finally the encapsulation was completed. pH 5.1 content 27.3%, RSD% 0.34.

[0031] Embodiment 2:

[0032] 60 mg of lanreotide acetate was dissolved in 4 mL of acetic acid aqueous solution at pH 2.5, and then filtered through a 0.22 μm filter membrane into a 5 mL syringe, and the plunger was pressed. The above syringe was inverted in a sterile vacuum drying oven, and the air pressure was adjusted to 100 μbar, the temperature was 8 ° C, and the temperature was adjusted to 1 hour, and then the pressure was reduced by 20 μbar every 1 hour, and the vacuum degree was controlled to be 20 μbar for 5 hours. The gel volume reached the required 0.25 mL scale line to obtain a uniformly mixed lanreotide sustained-release gel. Subsequently, the syringe piston was pushed up by controlling the vacuum machine to press the lower plate until the gel filled the syringe, and then the upper plate of the press was controlled to press the syringe needle cap, and finally the encapsulation was completed. pH 5.5 content 25.2%, RSD% 0.46.

[0033] Embodiment 3:

[0034] 60 mg of lanreotide acetate was dissolved in 4 mL of acetic acid aqueous solution at pH 3, and then filtered through a 0.22 μm filter membrane into a 5 mL syringe, and the plunger was pressed. The above syringe was inverted in a sterile vacuum drying oven, and the air pressure was adjusted to 100 μbar, the temperature was 8 ° C, and the temperature was adjusted to 1 hour, and then the pressure was reduced by 20 μbar every 1 hour, and the vacuum degree was controlled to be 20 μbar for 5 hours. The gel volume reached the required 0.25 mL scale line to obtain a uniformly mixed lanreotide sustained-release gel. Subsequently, the syringe piston was pushed up by controlling the vacuum machine to press the lower plate of the plunger until the gel filled the syringe, and then the upper plate of the plunger was controlled to press the syringe needle cap, and finally the encapsulation was completed, pH 6.0 content 24.1%, RSD% 0.36.

[0035] Embodiment 4:

[0036] 60 mg of lanreotide acetate was dissolved in 4 mL of acetic acid aqueous solution at pH 3.5, and then filtered through a 0.22 μm filter membrane into a 5 mL syringe, and the plunger was pressed. The above syringe was inverted in a sterile vacuum drying oven, and the air pressure was adjusted to 100 μbar, the temperature was 8 ° C, and the temperature was adjusted to 1 hour, and then the pressure was reduced by 20 μbar every 1 hour, and the vacuum degree was controlled to be 20 μbar for 5 hours. The gel volume reached the required 0.25 mL scale line to obtain a uniformly mixed lanreotide sustained-release gel. Subsequently, the syringe piston was pushed up by controlling the vacuum machine to press the lower plate of the plunger until the gel filled the syringe, and then the upper plate of the plunger was controlled to press the syringe needle cap, and finally the encapsulation was completed, pH 6.4 content 23.4%, RSD% 0.55.

[0037] Embodiment 5:

[0038] 60 mg of lanreotide acetate was dissolved in 4 mL of acetic acid aqueous solution at pH 4, and then filtered through a 0.22 μm filter membrane into a 5 mL syringe, and the plunger was pressed. The above syringe was inverted in a sterile vacuum drying oven, and the air pressure was adjusted to 100 μbar, the temperature was 8 ° C, and the temperature was adjusted to 1 hour, and then the pressure was reduced by 20 μbar every 1 hour, and the vacuum degree was controlled to be 20 μbar for 5 hours. The gel volume reached the required 0.25 mL scale line to obtain a uniformly mixed lanreotide sustained-release gel. Subsequently, the syringe piston was pushed up by controlling the vacuum machine to press the lower plate of the plunger until the gel filled the syringe, and then the upper plate of the plunger was controlled to press the syringe needle cap, and finally the encapsulation was completed, pH 6.5 content 23.1%, RSD% 0.56.

[0039] Embodiment 6:

[0040] 60 mg of lanreotide acetate was dissolved in 4 mL of acetic acid aqueous solution at pH 4.5, and then filtered through a 0.22 μm filter membrane into a 5 mL syringe, and the plunger was pressed. The syringe was inverted in a sterile vacuum drying oven, and the air pressure was adjusted to 100 μbar, the temperature was 8 ° C, and the temperature was adjusted to 1 hour, and then the pressure was reduced by 20 μbar every 1 hour, and the vacuum degree was controlled to be 20 μbar for 5 hours. The gel volume reached the required 0.25 mL scale line to obtain a uniformly mixed lanreotide sustained-release gel. Subsequently, the syringe piston was pushed up by controlling the vacuum machine to press the lower plate until the gel filled the syringe, and then the upper plate of the press was controlled to press the syringe needle cap, and finally the encapsulation was completed, pH 6.4 content 22.9%, RSD% 0.26.

[0041] Embodiment 7:

[0042] 60 mg of lanreotide acetate was dissolved in 4 mL of acetic acid aqueous solution at pH 5, and then filtered through a 0.22 μm filter membrane into a 5 mL syringe, and the plunger was pressed. The above syringe was inverted in a sterile vacuum drying oven, and the air pressure was adjusted to 100 μbar, the temperature was 8 ° C, and the temperature was adjusted to 1 hour, and then the pressure was reduced by 20 μbar every 1 hour, and the vacuum degree was controlled to be 20 μbar for 5 hours. The gel volume reached the required 0.25 mL scale line to obtain a uniformly mixed lanreotide sustained-release gel. Subsequently, the syringe piston was pushed up by controlling the vacuum machine to press the lower plate of the plunger until the gel filled the syringe, and then the upper plate of the plunger was controlled to press the syringe needle cap, and finally the encapsulation was completed, pH 6.5 content 22.8%, RSD% 0.56.

[0043] Embodiment 8:

[0044] 60 mg of lanreotide acetate was dissolved in 4 mL of acetic acid aqueous solution at pH 5.5, and then filtered through a 0.22 μm filter membrane into a 5 mL syringe, and the plunger was pressed. The above syringe was inverted in a sterile vacuum drying oven, and the air pressure was adjusted to 100 μbar, the temperature was 8 ° C, and the temperature was adjusted to 1 hour, and then the pressure was reduced by 20 μbar every 1 hour, and the vacuum degree was controlled to be 20 μbar for 5 hours. The gel volume reached the required 0.25 mL scale line to obtain a uniformly mixed lanreotide sustained-release gel. Subsequently, the syringe piston was pushed up by controlling the vacuum machine to press the lower plate of the plunger until the gel filled the syringe, and then the upper plate of the plunger was controlled to press the syringe needle cap, and finally the encapsulation was completed, pH 6.6 content 22.2%, RSD% 0.27.

[0045] Comparative Example 1:

[0046] 60 mg of lanreotide acetate was dissolved in 4 mL of acetic acid aqueous solution, and the freeze drying machine was used. The temperature was initially lowered for 30 minutes and maintained for 3 hours; then the temperature was lowered for 15 minutes, not more than 10 minutes, and maintained for 3.5 hours; then the temperature was raised for 20 hours, and then maintained for 40 hours; and the temperature was further raised for 1 hour, and then maintained for 16 hours. After the temperature of the mixture was lowered, the air pressure was reduced to 20±5 μbar and the air pressure was kept constant during the temperature increase of the mixture. After the final pH was obtained, the acetic acid aqueous solution was added and placed in a 5 ml syringe, and then the two syringes were connected with a three-way valve, vacuumed, statically hydrated overnight, and dynamically hydrated for 2 hours to obtain a uniformly mixed lanreotide sustained-release gel. The lanreotide sustained-release gel was measured to have a pH value of 6.2, a content of 24.5%, and an RSD% of 3.1.

[0047] Verification example:

[0048] pH value: Take this product, dissolve it in water and dilute it to make a solution containing approximately 6.7 mg of lanreotide per 1 ml. Determine it according to the law (General Rules of Part IV of the 2020 Edition of the Chinese Pharmacopoeia 0631), the pH should be 5.8-6.4.

[0049] Average concentration of lanreotide: Take the contents of each sample under the content determination item, weigh it, and calculate the ratio of the lanreotide content of each sample to the weight of the contents. The average value of 10 samples should be 23.4%-27.1%.

[0050] Release rate: Take one sample each prepared according to the methods of Examples 1 to 8 and Comparative Example 1 and the original marketed preparation of lanreotide acetate (trade name: somadulin) and perform dissolution and release rate determination according to the method (Appendix 1 of the United States Pharmacopoeia 41) <711> Method 4), using 0.9% sodium chloride solution as the release medium, flow rate: 8ml / min; sampling volume: 100μL; the circulation cell uses a standard cell with an inner diameter of 22.6mm, a ruby ​​with a diameter of 5mm is installed at the bottom of the circulation cell cone, covered with about 5g of glass beads with a diameter of 1mm, and the top cover of the circulation cell is equipped with a GF / F ultrafine glass fiber filter membrane with a pore size of 0.7μm. Inject the contents onto the 1mm glass beads and accurately weigh the amount of sample added. Calculate the weight of the lanreotide test sample in the circulation cell, and calculate the amount of lanreotide in the circulation cell according to the following formula:

[0051]

[0052] In the above formula:

[0053] Mi: amount of lanreotide free base in the flow cell (mg);

[0054] T: average concentration of lanreotide free base (%);

[0055] Wi: weight of the test sample in the flow cell (mg);

[0056] Take an appropriate amount of lanreotide acetate reference substance, dissolve and dilute it with 0.9% sodium chloride aqueous solution to prepare a series of reference substance solutions containing approximately 3ug, 9ug, 15ug, 30ug, 60ug, 90ug, and 120ug of lanreotide free base per 1ml. Preparation of dissolution samples: The absorbance was measured at a wavelength of 278nm using a conventional quartz cuvette using an off-line measurement method according to the UV-visible spectrophotometry (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0401). The sampling time points were: 2min, 5min, 10min, 60min, 120min, 180min, 240min, 360min, 480min, 1440min, 2880min;

[0057] The dissolution samples at the above-mentioned time points were directly measured, and the cumulative release amount of lanreotide free base at each time point was calculated according to the following formula:

[0058]

[0059] In the above formula:

[0060] Qi(t): cumulative release percentage (%) of lanreotide free base at each sampling time point (t);

[0061] Ai(t): absorbance of each flow cell (i) at each sampling time point (t)

[0062] Ai(t): (At-A0) sample - (At-A0) blank

[0063] A0: absorbance of dissolution medium;

[0064] A11: is the absorption coefficient value (g / L) obtained from the calibration curve.

[0065] Pi(t): Percentage of lanreotide free base removed from the flow cell (i) at each sampling time point (t):

[0066]

[0067] The results are shown in the attached figure.

[0068] From the above experimental examples and comparative examples, it can be seen that:

[0069] It is known that the smaller the RSD value of the concentration among 10 samples, the more uniform the sample mixing. The RSD of the concentration among 10 samples of the products prepared by the methods of Examples 1, 2, and 3 of the present invention is less than 1%; while the RSD of the concentration among 10 samples of the products prepared by the method of Comparative Example 1 is about 2%, indicating that the product prepared by the method of the present invention is more uniform than that prepared by the prior art.

[0070] The preferred embodiment of this product has a pH of 2.5-4, and the release amounts of the comparative example and the original preparation at 10 minutes, 240 minutes and 480 minutes are all 9%-29%, 40%-64% and 80% higher, indicating that the product prepared by the method of the present invention has a similar release effect to the original preparation.

[0071] Example 9, a method for preparing a pharmaceutical composition for delayed release of a somatostatin analog, the specific steps of which are as follows:

[0072] (1) Dissolve lanreotide acetate in an acetic acid aqueous solution, filter the solution with a 0.22 μm filter membrane, place the solution in a 5 mL syringe, and press the plunger; the pH value of the acetic acid aqueous solution is 2.5.

[0073] (2) First, the syringe is inverted in a sterile vacuum drying oven, the air pressure is adjusted to 95 μbar, and the syringe is left to stand for 1 hour, and then the air pressure is reduced by 25 μbar every 1 hour until the vacuum degree is finally controlled at 20 μbar and maintained until the gel volume reaches the required 0.25 mL mark, at which time the lanreotide acetate sustained-release gel is obtained. Subsequently, the syringe piston is pushed up by controlling the vacuum machine to press the lower plate until the gel fills the syringe, and then the upper plate is controlled to press the syringe needle cap to complete the encapsulation.

[0074] Example 10, a method for preparing a pharmaceutical composition for delayed release of a somatostatin analog, the specific steps of which are as follows:

[0075] (1) Dissolve lanreotide acetate in an acetic acid aqueous solution, filter the solution through a 0.22 μm filter membrane, place the solution in a 5 mL syringe, and press the plunger; the pH value of the acetic acid aqueous solution is 3.

[0076] (2) First, the syringe is inverted in a sterile vacuum drying oven, the air pressure is adjusted to 110 μbar, and the syringe is left to stand for 2 hours. Then, the air pressure is reduced by 15 or 25 μbar every hour until the vacuum degree is finally controlled at 20 μbar and maintained until the gel volume reaches the required 0.25 mL mark. At this time, the lanreotide acetate sustained-release gel is obtained. Subsequently, the syringe piston is pushed up by controlling the vacuum machine to press the lower plate until the gel fills the syringe, and then the upper plate is controlled to press the syringe needle cap to complete the encapsulation.

[0077] Example 11, a method for preparing a pharmaceutical composition for delayed release of a somatostatin analog, the specific steps of which are as follows:

[0078] (1) Dissolve lanreotide acetate in an acetic acid aqueous solution, filter the solution through a 0.22 μm filter membrane, place the solution in a 5 mL syringe, and press the plunger; the pH value of the acetic acid aqueous solution is 4.

[0079] (2) First, the syringe is inverted in a sterile vacuum drying oven, the air pressure is adjusted to 115 μbar, and the syringe is left to stand for 1.5 hours. Then, the air pressure is reduced by 20 or 25 μbar every hour until the vacuum degree is finally controlled at 20 μbar and maintained until the gel volume reaches the required 0.25 mL mark. At this time, the lanreotide acetate sustained-release gel is obtained. Subsequently, the syringe piston is pushed up by controlling the vacuum machine to press the lower plate until the gel fills the syringe, and then the upper plate is controlled to press the syringe needle cap to complete the encapsulation.

[0080] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of equivalent transformations, and these equivalent transformations all belong to the protection scope of the present invention. It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further explain various possible combinations. In addition, the various different embodiments of the present invention can also be arbitrarily combined, as long as they do not violate the concept of the present invention, they should also be regarded as the contents disclosed by the present invention.

Claims

1. A method for preparing a pharmaceutical composition for delayed release of a somatostatin analog, characterized in that: The main components of the pharmaceutical composition are lanreotide acetate and acetic acid aqueous solution; the preparation method comprises the following steps: taking lanreotide acetate, adding acetic acid aqueous solution to dissolve it, filtering and sterilizing after it is completely dissolved, and then adopting a one-step vacuum evaporation method to prepare a filled and sterile prefilled lanreotide acetate sustained-release gel.

2. The preparation method according to claim 1, characterized in that: The specific steps are as follows: Lanreotide acetate was dissolved in acetic acid aqueous solution, then filtered through a 0.22 μm filter membrane and placed in a 5 mL syringe, and the plunger was pressed; First, the syringe is inverted in a sterile vacuum drying oven, the air pressure is adjusted between 95 and 115 μbar, and it is left to stand for 1 to 2 hours, and then the air pressure is reduced by 15 to 25 μbar every 1 hour until the vacuum degree is finally controlled at 20 μbar and maintained until the gel volume reaches the required 0.25 mL scale line, at which time the lanreotide acetate sustained-release gel is obtained. Subsequently, the syringe piston is pushed up by controlling the vacuum machine to press the lower plate until the gel fills the syringe, and then the upper plate is controlled to press the syringe needle cap to complete the encapsulation.

3. The preparation method according to claim 2, characterized in that: In step (2): the syringe is inverted in a sterile vacuum drying oven, the air pressure is adjusted to 100 μbar, and the mixture is allowed to stand for 1 hour, then the pressure is reduced by 20 μbar every hour, and finally the vacuum is controlled to be 20 μbar for 4-6 hours until the gel volume reaches the desired 0.25 mL mark, thereby obtaining a pre-filled lanreotide acetate sustained-release gel.

4. The preparation method according to claim 1, characterized in that: The pH value of acetic acid aqueous solution is 2.5-4.

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