Liquid depot precursors, methods of making and pharmaceutical formulations

Abstract

The present application relates to the technical field of pharmaceutical preparations, and in particular to a liquid reservoir precursor, a preparation method thereof and a pharmaceutical preparation. The liquid reservoir precursor comprises alkyl alcohol-terminated cyclic ester oligomers, neutral acyl lipids, phospholipids and a solvent; the amount of the alkyl alcohol-terminated cyclic ester oligomers is 3 wt% to 30 wt% based on 100 wt% of the total amount of the liquid reservoir precursor; the alkyl alcohol-terminated cyclic ester oligomers satisfy the following characteristics: (1) the number of carbon atoms of the alkyl alcohol is 8 to 22; (2) the weight average molecular weight of the alkyl alcohol-terminated cyclic ester oligomers is 500 to 2000 Da. The liquid reservoir precursor of the present application is compounded by using alkyl alcohol-terminated cyclic ester oligomers, neutral acyl lipids and phospholipids, can quickly form a cluster when meeting water, can effectively reduce the burst release, has good long-acting sustained-release performance, and can also maintain good injectability.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a liquid reservoir precursor, its preparation method, and a pharmaceutical formulation thereof. Background Technology

[0002] Long-acting injectables (LAIs) refer to drug delivery systems that can continuously or in a controlled manner release drugs over a relatively long period after injection. LAI formulations are mainly based on technologies such as oil solutions, liposomes, implants, microspheres, and in-situ gels. Among these, in-situ gel technology has broad application prospects due to its relatively simple preparation process.

[0003] In-situ gels are biodegradable liquid or injectable semi-solid formulations that spontaneously form gel-like drug reservoirs at the injection site. They are typically composed of a drug (API), a solvent, and a matrix material that forms the reservoir. The matrix material is usually a water-insoluble, biodegradable material such as poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), polycaprolactone (PCL), sucrose isobutyrate acetate (SAIB), polyorthoester (POE), and lipid liquid crystal precursors. Depending on the formulation composition, in-situ gels can form in-situ reservoirs in vivo through precipitation, organic gelation, or other methods.

[0004] However, the drug release behavior of long-acting injectables based on in-situ gels still faces significant challenges. Firstly, during the phase transition and reservoir formation process of in-situ gels (including lyotropic lipid liquid crystal gels) in vivo, burst release of drugs is common, potentially leading to excessively high blood drug concentrations at the initial administration stage and increasing safety risks. Secondly, once the drug reaches the sustained-release phase, achieving long-term and stable drug release requires extremely stringent performance matching of the sustained-release materials. Currently available material systems are limited, making it difficult to simultaneously meet the dual requirements of burst release inhibition and long-term stable release. Therefore, there is an urgent need to develop an excipient to reduce burst release, lower peak blood drug concentrations, and achieve long-term stable release, thereby meeting the sustained-release performance requirements of long-acting injectables.

[0005] In view of this, the present invention is hereby proposed. Summary of the Invention

[0006] The present invention aims to provide a liquid reservoir precursor, a method for preparing the same, and a pharmaceutical formulation thereof. The liquid reservoir precursor of the present invention can effectively reduce burst release, enhance sustained and controlled release, and also possesses good biocompatibility and injectability.

[0007] To achieve the above-mentioned objectives of the present invention, a first aspect of the present invention provides a liquid reservoir precursor comprising: an alkyl alcohol-terminated cyclic ester oligomer, a neutral acyl ester, a phospholipid, and a solvent; Based on a total amount of 100 wt% of the liquid reservoir precursor, the amount of the alkyl alcohol-terminated cyclic ester oligomer is 3 wt% to 30 wt%; The alkyl alcohol-terminated cyclic ester oligomers satisfy the following characteristics: (1) Alkyl alcohols have 8 to 22 carbon atoms; (2) The weight average molecular weight of the alkyl alcohol-terminated cyclic ester oligomer is 500~2000 Da.

[0008] In a specific embodiment of the present invention, the alkyl alcohol-terminated cyclic ester oligomer is prepared by ring-opening polymerization of an alkyl alcohol and a cyclic ester monomer. Further, the molar ratio of the alkyl alcohol to the cyclic ester monomer is 1:(1~11).

[0009] In a specific embodiment of the present invention, the cyclic ester monomer includes at least one of lactide, glycolide and caprolactone.

[0010] In a specific embodiment of the present invention, the polydispersity index (PDI) of the alkyl alcohol-terminated cyclic ester oligomer is <2.0, preferably 1.0 to 1.8.

[0011] In a specific embodiment of the present invention, the alkyl alcohol-terminated cyclic ester oligomer includes at least one of alkyl alcohol-terminated dextrorotatory lactic acid oligomer, alkyl alcohol-terminated levorotatory lactic acid oligomer, and alkyl alcohol-terminated racemic lactic acid oligomer.

[0012] In a specific embodiment of the present invention, in the alkyl alcohol-terminated dextrorotatory lactic acid oligomer or the alkyl alcohol-terminated levorotatory lactic acid oligomer, the molar ratio of alkyl alcohol to cyclic ester monomer is 1:(1~7).

[0013] In a specific embodiment of the present invention, the alkyl alcohol-terminated cyclic ester oligomer includes an alkyl alcohol-terminated dextrorotatory lactic acid oligomer and an alkyl alcohol-terminated levorotatory lactic acid oligomer. Further, the mass ratio of the alkyl alcohol-terminated dextrorotatory lactic acid oligomer to the alkyl alcohol-terminated levorotatory lactic acid oligomer is 1:(0.5~2).

[0014] In a specific embodiment of the present invention, the neutral acyl ester includes at least one of neutral diacyl ester and neutral monoacyl ester. Further, the neutral diacyl ester includes at least one diacylglycerol ester; the neutral monoacyl ester includes at least one monoacylglycerol ester.

[0015] In a specific embodiment of the present invention, the phospholipid includes at least one of soybean phospholipid, egg yolk phospholipid, dipalmitoyl phospholipid, distearate, dioleoyl phosphatidylethanolamine, dipalmitoyl phosphatidylethanolamine, dioleoyl phosphatidylserine, dioleoyl phosphatidylglycerol, dipalmitoyl phosphatidylglycerol, hydrogenated soybean phospholipid, hydrogenated lecithin, distearate phosphatidylethanolamine-polyethylene glycol, and dimyristoyl phosphatidylethanolamine-polyethylene glycol.

[0016] In a specific embodiment of the present invention, based on a total amount of 100 wt% of the liquid reservoir precursor, the total amount of the neutral acyl ester and the phospholipid is 50 wt% to 90 wt%.

[0017] In a specific embodiment of the present invention, the mass ratio of the neutral acyl ester to the phospholipid is 65:35~40:60.

[0018] In a specific embodiment of the present invention, the solvent includes at least one selected from ethanol, dimethyl sulfoxide, propylene glycol, glycerol, N-methylpyrrolidone, benzyl alcohol, and triacetylglycerol.

[0019] In a specific embodiment of the present invention, with the total amount of the liquid reservoir precursor being 100 wt%, the amount of the solvent used is 5 wt% to 20 wt%.

[0020] The second aspect of the present invention provides a method for preparing the liquid reservoir precursor provided in the first aspect of the present invention, comprising the following steps: mixing an alkyl alcohol-terminated cyclic ester oligomer, a neutral acyl ester, a phospholipid, and a solvent uniformly.

[0021] In a specific embodiment of the present invention, the preparation method includes: mixing a solvent, a neutral acyl ester, and a phospholipid uniformly under heating conditions, then adding an alkyl alcohol-terminated cyclic ester oligomer and mixing uniformly under heating conditions. The heating temperature is 30-80°C.

[0022] A third aspect of the present invention provides a pharmaceutical preparation comprising the liquid reservoir precursor and the drug provided in the first aspect of the present invention.

[0023] In a specific embodiment of the present invention, the drug includes at least one of risperidone, olanzapine, doxycycline hydrochloride, leuprorelin, telbestide, and smegglutide.

[0024] In a specific embodiment of the present invention, the drug loading in the pharmaceutical preparation is 0.1 wt% to 35 wt%.

[0025] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) The liquid reservoir precursor of the present invention is a compound of alkyl alcohol-terminated cyclic ester oligomer, neutral acyl ester and phospholipid. It can quickly agglomerate when it comes into contact with the aqueous phase, which can effectively reduce burst release, has good long-term sustained-release performance, and can also maintain good injectability. (2) When the liquid reservoir precursor of the present invention is mixed with alkyl alcohol-terminated dextrorotatory lactic acid oligomer and alkyl alcohol-terminated levorotatory lactic acid oligomer, it can effectively increase the static viscosity while having good injectability, so that the liquid reservoir precursor is in a non-flowing state when static; when mixed with solid drugs, it can prevent drug sedimentation and help maintain the homogeneity of drug formulation. (3) The liquid reservoir precursor and pharmaceutical preparation of the present invention are easy to prepare and have good controllability. Attached Figure Description

[0026] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0027] Figure 1 The alkyl alcohol-terminated cyclic ester oligomer 10#-Me(CH2) provided as a preparation example of the present invention 11 GPC spectrum of O-PDLLA 1 / 5.4; Figure 2 These are photographs of the liquid reservoir precursors of Examples 1-1 to 1-4 of the present invention forming reservoirs upon contact with water; from left to right, they are Examples 1-1 to 1-4. Figure 3 These are photographs of the liquid reservoir precursors of Examples 1-5, 1-6, 1-9, and 1-10 of the present invention forming reservoirs upon contact with water; from left to right, they are Examples 1-5, 1-6, 1-9, and 1-10. Figure 4 These are photographs of the liquid reservoir precursors of Examples 1-11 to 1-14 of the present invention forming reservoirs upon contact with water; from left to right, they are Examples 1-11 to 1-14. Figure 5 These are photographs of the liquid reservoir precursors of Examples 1-15 to 1-19 of the present invention forming reservoirs upon contact with water; from left to right, they are Examples 1-15 to 1-19. Figure 6 Photographs showing the formation of reservoirs by the liquid reservoir precursors in Examples 1-20 and 1-22 of the present invention upon contact with water; from left to right: Examples 1-20 and 1-22. Figure 7 These are photographs of the liquid reservoir precursors of Examples 1-25 to 1-27 of the present invention forming reservoirs upon contact with water; from left to right, they are Examples 1-25 to 1-27. Figure 8 These are photographs of the liquid reservoir precursors of Examples 1-28 to 1-30 of the present invention forming reservoirs upon contact with water; from left to right, they are Examples 1-28 to 1-30. Figure 9 These are photographs of the liquid reservoir precursors of Examples 1-31 to 1-33 of the present invention forming reservoirs upon contact with water; from left to right, they are Examples 1-31 to 1-33. Figure 10 These are photographs of the liquid reservoir precursors of Examples 2-1 to 2-4 of the present invention forming reservoirs upon contact with water; from left to right, they are Examples 2-1 to 2-4. Figure 11 These are photographs of the liquid reservoir precursors of Examples 2-5 to 2-8 of the present invention forming reservoirs upon contact with water; from left to right, they are Examples 2-5 to 2-8. Figure 12 These are photographs of the liquid reservoir precursors of Examples 2-9 to 2-11 of the present invention forming reservoirs upon contact with water; from left to right, they are Examples 2-9 to 2-11. Figure 13 These are photographs of the liquid reservoir precursors of Examples 2-13 to 2-15 of the present invention forming reservoirs upon contact with water; from left to right, they are Examples 2-13 to 2-15. Figure 14 These are photographs of the liquid reservoir precursors of Examples 2-12, 2-16 to 2-19 of the present invention forming reservoirs upon contact with water; from left to right, they are Examples 2-12, 2-16 to 2-19. Figure 15 These are photographs of the liquid reservoir precursors of Examples 2-20 to 2-23 and Comparative Examples 2-24 to 2-25 of the present invention forming reservoirs upon contact with water; from left to right: Examples 2-20, 2-21, 2-22, 2-23, Comparative Example 2-25, and Comparative Example 2-24. Figure 16 These are photographs of the liquid reservoir precursors of Embodiments 1-12, 1-13 and 1-15 of the present invention in a static state; from top to bottom on the left are Embodiments 1-12 and 1-13, and on the right are Embodiments 1-15. Figure 17These are photographs of the liquid reservoir precursors of Embodiments 1-16, 1-17 and 1-18 of the present invention in a static state; from top to bottom on the left are Embodiments 1-16 and 1-17, and on the right is Embodiment 1-18. Figure 18 These are photographs of the liquid reservoir precursors of Examples 2-9, 2-10, and 2-12 of the present invention in a static state; from top to bottom, they are Examples 2-9, 2-10, and 2-12. Figure 19 These are photographs of the liquid reservoir precursors of Embodiments 2-13, 2-14, and 2-15 of the present invention in a static state; from top to bottom, they are Embodiments 2-13, 2-14, and 2-15. Figure 20 The release curves of Ris-A to Ris-E for the five samples prepared in Example 4 are shown. Figure 21 The release curves of Leu-A to Leu-C of the three samples prepared in Example 7 are shown. Figure 22 The release curves of Leu-D to Leu-G from the four samples prepared in Example 8 are shown. Figure 23 This is a release curve of the long-acting telboreptide in situ gel injection of the present invention; Figure 24 This is a release curve of the long-acting semaglutide in situ gel injection of the present invention. Detailed Implementation

[0028] The technical solution of the present invention will be clearly and completely described below with reference to the accompanying drawings and specific embodiments. However, those skilled in the art will understand that the embodiments described below are some embodiments of the present invention, but not all embodiments, and are only used to illustrate the present invention, and should not be regarded as limiting the scope of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall be followed. Where the manufacturers of reagents or instruments are not specified, they are all conventional products that can be purchased commercially.

[0029] Unless otherwise specified, the molecular weights used in this invention are considered to be weight-average molecular weights; where additional explanations are given, those explanations shall prevail.

[0030] In this invention, unless otherwise specified, all parts and percentages are by weight; where further explanation is required, the explanation shall prevail.

[0031] A first aspect of the present invention provides a liquid reservoir precursor comprising: an alkyl alcohol-terminated cyclic ester oligomer, a neutral acyl ester, a phospholipid, and a solvent; Based on a total amount of 100 wt% of the liquid reservoir precursor, the amount of the alkyl alcohol-terminated cyclic ester oligomer is 3 wt% to 30 wt%; The alkyl alcohol-terminated cyclic ester oligomers satisfy the following characteristics: (1) Alkyl alcohols have 8 to 22 carbon atoms; (2) The weight average molecular weight of the alkyl alcohol-terminated cyclic ester oligomer is 500~2000 Da.

[0032] The liquid reservoir precursor of the present invention is a compound of alkyl alcohol-terminated cyclic ester oligomers, neutral acyl esters, and phospholipids. It can rapidly aggregate in the aqueous phase, effectively reducing burst release, and has good long-lasting sustained-release performance, while also maintaining good injectability.

[0033] In some embodiments, based on a total amount of 100 wt% of the liquid reservoir precursor, the amount of the alkyl alcohol-terminated cyclic ester oligomer is 3 wt% to 30 wt%, specifically within the range of 3 wt%, 5 wt%, 8 wt%, 10 wt%, 12 wt%, 15 wt%, 18 wt%, 20 wt%, 22 wt%, 25 wt%, 30 wt%, or any combination thereof. Controlling the amount of the alkyl alcohol-terminated cyclic ester oligomer in the liquid reservoir precursor within the above range helps improve the compatibility of the alkyl alcohol-terminated cyclic ester oligomer with the lipid liquid crystal component, and ensures the injectability of the liquid reservoir precursor, reduces burst release, and improves sustained-release properties.

[0034] In some embodiments, the alkyl alcohol-terminated cyclic ester oligomer has an alkyl alcohol with 8 to 22 carbon atoms, specifically within the range of 8, 10, 12, 14, 16, 18, 20, 22, or any combination thereof. Here, alkyl alcohol refers to an organic compound having the general formula R-OH, where R is an alkyl group. By using an alkyl alcohol with a certain carbon chain length to terminate the cyclic ester oligomer, it can achieve better compatibility with lipid liquid crystal components while ensuring a certain degree of oil solubility and preventing excessively rapid degradation. When the number of alkyl carbon atoms in the alkyl alcohol is too small or the carbon chain is too short, the compatibility with lipid liquid crystal components deteriorates.

[0035] In some embodiments, the alkyl alcohol includes at least one selected from n-octanol, 1-decyl alcohol, 1-dodecyl alcohol, 1-hexadecyl alcohol, and 1-dienoyl alcohol.

[0036] In some embodiments, the weight-average molecular weight of the alkyl alcohol-terminated cyclic ester oligomer is 500-2000 Da, specifically within the range of 500 Da, 600 Da, 700 Da, 800 Da, 1000 Da, 1200 Da, 1500 Da, 1600 Da, 1800 Da, 2000 Da, or any combination thereof. Using alkyl alcohol-terminated cyclic ester oligomers with a weight-average molecular weight within the above range is beneficial for achieving a balance between the injectability of the liquid reservoir precursor, reducing burst release, and enhancing sustained-release properties.

[0037] In some embodiments, the alkyl alcohol-terminated cyclic ester oligomer is prepared by ring-opening polymerization of an alkyl alcohol and a cyclic ester monomer. Further, the molar ratio of the alkyl alcohol to the cyclic ester monomer is 1:(1~11), specifically within the range of 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:8, 1:10, 1:11, or any combination thereof.

[0038] In some embodiments, the cyclic ester monomer includes at least one of lactide, glycolide, and caprolactone. Further, the lactide includes at least one of meso-lactide, racemic (D,L-)lactide, dextrorotatory (D-)lactide, and levorotatory (L-)lactide.

[0039] In some embodiments, the polydispersity index (PDI) (Mw / Mn) of the alkyl alcohol-terminated cyclic ester oligomer is <2.0, specifically a range of 1.0, 1.05, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8 or any two of these ranges, such as 1.0 to 1.8.

[0040] In some embodiments, the ring-opening polymerization of alkyl alcohols and cyclic ester monomers is carried out in the presence of a catalyst. The catalyst includes, but is not limited to, stannous octoate.

[0041] In some embodiments, a method for preparing the alkyl alcohol-terminated cyclic ester oligomer includes: using stannous octoate as a catalyst, and carrying out a ring-opening polymerization reaction of an alkyl alcohol and a cyclic ester monomer; the ring-opening polymerization reaction is carried out at a temperature of 100~140℃ and for a reaction time of 48~150 h.

[0042] In some embodiments, the catalyst is used in an amount of 0.01 wt% to 0.04 wt% of the total amount of the alkyl alcohol and the cyclic ester monomer, for example, 0.01 wt%, 0.02 wt%, 0.03 wt%, 0.04 wt%, or any combination thereof.

[0043] In some embodiments, the ring-opening polymerization reaction includes: reacting the mixture at 125-135°C for 10-48 hours, followed by cooling to 105-115°C and reacting for 24-72 hours.

[0044] In some embodiments, the stannous octoate is added directly or in the form of a premix; the premix includes stannous octoate and a cyclic ester monomer. Further, the preparation of the premix includes, but is not limited to: mixing a cyclohexane solution of stannous octoate with a cyclic ester monomer in a specific ratio, then removing the cyclohexane under vacuum to obtain the premix; wherein the concentration of stannous octoate in the cyclohexane solution can be 10-120 mg / mL.

[0045] In some embodiments, the ring-opening polymerization reaction is carried out under a vacuum or a protective gas atmosphere. The protective gas atmosphere includes at least one of nitrogen and argon.

[0046] In some embodiments, the alkyl alcohol-terminated cyclic ester oligomer includes at least one of alkyl alcohol-terminated dextrorotatory lactic acid oligomers, alkyl alcohol-terminated levorotatory lactic acid oligomers, and alkyl alcohol-terminated racemic lactic acid oligomers, such as at least one, at least two, etc.

[0047] In some embodiments, in the alkyl alcohol-terminated dextrorotatory lactic acid oligomer or the alkyl alcohol-terminated levorotatory lactic acid oligomer, the molar ratio of alkyl alcohol to cyclic ester monomer is 1:(1~7), specifically 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, or any combination thereof. For crystalline alkyl alcohol-terminated cyclic ester oligomers, such as PLLA or PDLA, the molar amount of cyclic ester monomer does not exceed 7 times that of the alkyl alcohol, thereby ensuring the compatibility of the alkyl alcohol-terminated cyclic ester oligomer with the lipid liquid crystal component. For amorphous alkyl alcohol-terminated cyclic ester oligomers, such as PDLLA, the molar amount of cyclic ester monomer can reach 11 times that of the alkyl alcohol.

[0048] In some embodiments, the alkyl alcohol-terminated cyclic ester oligomer includes alkyl alcohol-terminated dextrorotatory lactic acid oligomers and alkyl alcohol-terminated levorotatory lactic acid oligomers. Further, the mass ratio of the alkyl alcohol-terminated dextrorotatory lactic acid oligomer to the alkyl alcohol-terminated levorotatory lactic acid oligomer is 1:(0.5~2), specifically within the range of 1:0.5, 1:0.8, 1:1, 1:1.5, 1:2, or any combination thereof. The inventors of this invention have discovered that when alkyl alcohol-terminated dextrorotatory lactic acid oligomers and alkyl alcohol-terminated levorotatory lactic acid oligomers are mixed, good injectability is achieved while effectively increasing static viscosity, ensuring the liquid reservoir precursor remains non-flowing in a static state; when mixed with solid drugs, drug sedimentation is prevented, contributing to maintaining the homogeneity of the drug formulation.

[0049] In some embodiments, the neutral acyl ester includes at least one of neutral diacyl esters and neutral monoacyl esters. Specifically, the neutral diacyl ester includes at least one diacylglycerol ester; the two fatty acyl groups of the diacylglycerol ester are each independently selected from oleyl, linoleyl, stearoyl, palmitoyl, myristoyl, lauroyl, decyl, capryloyl, and their corresponding 1,2- and 1,3-position isomers. Examples include dioleoglyceride (GDO), dilinoleoglyceride, distearate, dipalmitoate, dimyristicate, dilaurate, didecanoate, dicaprylate, and glycerides of mixed acids. Glycerides of mixed acids refer to esters formed from two different acids and glycerol, i.e., diacylglycerol esters with two different fatty acyl groups. The neutral monoacyl ester includes at least one monoacylglycerol ester; the fatty acyl group of the neutral monoacyl ester is selected from oleyl, linoleyl, stearoyl, palmitoyl, myristoyl, lauroyl, decyl, capryloyl and the corresponding 1,2-, 1,3-position isomers, specifically including monooleic glycerol, monolinoleic glycerol, monostearate glycerol, monopalmitoate glycerol, monomyristate glycerol, monolaurate glycerol, monodecanoate glycerol, monocaprylic glycerol, etc.

[0050] In some embodiments, the phospholipids include at least one of soybean phospholipids (SPC), egg yolk phospholipids, dipalmitoyl phospholipids, distearate phospholipids, dioleoyl phosphatidylethanolamine, dipalmitoyl phosphatidylethanolamine, dioleoyl phosphatidylserine, dioleoyl phosphatidylglycerol, dipalmitoyl phosphatidylglycerol, hydrogenated soybean phospholipids, hydrogenated lecithin, distearate phosphatidylethanolamine-polyethylene glycol, and dimyristoyl phosphatidylethanolamine-polyethylene glycol.

[0051] The neutral acyl esters and phospholipids listed above in this invention, when combined with alkyl alcohol-terminated cyclic ester oligomers, can all form liquid reservoir precursors. These liquid reservoir precursors rapidly aggregate upon contact with an aqueous phase, effectively reducing burst release and exhibiting excellent long-acting sustained-release properties while maintaining good injectability. It should be noted that the subsequent embodiments, using GDO and SPC as examples, exemplify the preparation method, reservoir formation effect, and drug release behavior of the liquid reservoir precursors of this invention, but the scope of protection of this invention is not limited thereto. Other listed neutral acyl esters and phospholipids, when combined with the alkyl alcohol-terminated cyclic ester oligomers of this invention, can also achieve similar effects.

[0052] In some embodiments, based on a total amount of 100 wt% of the liquid reservoir precursor, the total amount of the neutral acyl ester and the phospholipid is 50 wt% to 90 wt%, specifically 50 wt%, 55 wt%, 60 wt%, 65 wt%, 70 wt%, 75 wt%, 80 wt%, 85 wt%, 90 wt%, or any combination thereof.

[0053] In some embodiments, the mass ratio of the neutral acyl ester to the phospholipid is 65:35 to 40:60, specifically a range of 65:35, 60:40, 55:45, 50:50, 45:55, 40:60, or any combination thereof.

[0054] In some embodiments, the solvent includes at least one selected from ethanol (EtOH), dimethyl sulfoxide (DMSO), propylene glycol, glycerol, N-methylpyrrolidone (NMP), benzyl alcohol, and triacetin. The liquid reservoir precursor of the present invention can ensure compatibility between components with a smaller solvent volume, while the solvent itself has excellent biocompatibility, further meeting the safety requirements for pharmaceutical formulations.

[0055] In some embodiments, based on a total amount of 100 wt% of the liquid reservoir precursor, the amount of solvent used is 5 wt% to 20 wt%, specifically a range of 5 wt%, 8 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 18 wt%, 20 wt%, or any combination thereof.

[0056] In some embodiments, the liquid reservoir precursor satisfies the following conditions: when the mass concentration of the alkyl alcohol-terminated cyclic ester oligomer is 5%~15% and the total mass concentration of the neutral acyl ester and phospholipid is 70%~85%, at room temperature (20~25°C), the liquid reservoir precursor is injected using a 1 mL syringe (inner diameter 4.5~4.7 mm) with a 25G, 20 mm needle, with a 20 s injection interval of 1 mL, and the maximum force during injection does not exceed 30 N, preferably not more than 20 N, and more preferably not more than 15 N; the liquid reservoir precursor is injected using a 1 mL syringe (inner diameter 4.5~4.7 mm) with a 26G, 16 mm needle, with a 20 s injection interval of 1 mL, and the maximum force during injection does not exceed 30 N; the liquid reservoir precursor is injected using a 1 mL syringe (inner diameter 4.5~4.7 mm) with a 23G, 25 mm needle, with a 20 s injection interval of 1 mL, and the maximum force during injection does not exceed 30 N; the liquid reservoir precursor is injected using a 1 mL syringe (inner diameter 4.5~4.7 mm) with a 23G, 25 mm needle, with a 20 s injection interval of 1 mL, and the maximum force during injection does not exceed 30 N. mL, and the maximum force during the injection process should not exceed 30 N.

[0057] The second aspect of the present invention provides a method for preparing the liquid reservoir precursor provided in the first aspect of the present invention, comprising the following steps: mixing an alkyl alcohol-terminated cyclic ester oligomer, a neutral acyl ester, a phospholipid, and a solvent uniformly.

[0058] In some embodiments, the preparation method includes: mixing a solvent, a neutral acyl ester, and a phospholipid uniformly under heating conditions, then adding an alkyl alcohol-terminated cyclic ester oligomer and mixing uniformly under heating conditions. The heating temperature is 30-80°C, and the specific heating conditions can be adjusted according to actual conditions to ensure rapid dissolution.

[0059] A third aspect of the present invention provides a pharmaceutical preparation comprising the liquid reservoir precursor and the drug provided in the first aspect of the present invention.

[0060] In some embodiments, the drug includes at least one of risperidone, olanzapine, doxycycline hydrochloride, leuprorelin, telbestide, and smegglutide.

[0061] In some embodiments, the drug loading in the pharmaceutical formulation is 0.1 wt% to 35 wt%, specifically it can be a range of 0.1 wt%, 1 wt%, 2 wt%, 5 wt%, 8 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, or any combination thereof.

[0062] In some embodiments, the preparation method of the pharmaceutical formulation is not limited, and may include, for example, mixing the drug with a liquid reservoir precursor in a specified ratio until homogeneous. The mixing method is not limited, and may include, but is not limited to, using a vortex mixer.

[0063] The Chinese meanings or full names of some of the English abbreviations mentioned in this document are as follows: DLLA: D,L-lactide, racemic lactide; LLA: L-lactide, L-lactide; DLA: D-lactide, dextrorotatory lactide; GA: glycolide; PLLA: poly(L-lactide); PDLA: poly(D-lactide); PDLLA: poly(D,L-lactide); Me(CH2) mentioned later nIn O-PLLA (PDLA, PDLLA, PLGA) X / Y ( / Z), n is the number of carbon atoms in the alkyl alcohol minus 1, i.e., n+1 corresponds to the number of carbon atoms in the alkyl alcohol. X / Y represents the mass ratio of alkyl alcohol to L-lactide (D-lactide, D,L-lactide) in the oligomer. If there is X / Y / Z, X / Y / Z represents the mass ratio of alkyl alcohol to L-lactide (D-lactide, D,L-lactide) and GA in the oligomer.

[0064] Preparation Example Preparation of alkyl alcohol-terminated cyclic ester oligomers A certain amount of alkyl alcohol was added to a clean flask of appropriate volume equipped with a magnetic stirrer (e.g., 500 mL for approximately 200 g, 10 mL for approximately 10 g). (In the preparation of oligomers 24#, 25#, and 28#, due to the volatility of n-propanol and n-octanol, the monomer and catalyst were added at this stage, and no vacuum was applied after the addition. The following heating and cooling polymerization steps were then performed.) The flask was immersed in an oil bath at 110°C, and a vacuum was applied for approximately 0.5 h to remove residual moisture and other volatiles from the alkyl alcohol. The oil bath temperature was raised to 130°C, and a certain amount of monomer and stannous octoate (or a certain amount of stannous octoate / monomer premix) were added. After complete melting, the mixture was stirred at 130°C for 24 h, then cooled to 110°C and stirred for another 48 h to complete the polymerization reaction, yielding the alkyl alcohol-terminated cyclic ester oligomer Me(CH2). n O-PLLA (PDLA, PDLLA) X / Y. After each feeding, a brief evacuation (e.g., 30 minutes) is performed before sealing.

[0065] The preparation of the stannous octoate / monomer premix includes: weighing 181 mg of stannous octoate, adding 2 mL of cyclohexane to dissolve it into a cyclohexane solution of stannous octoate with a concentration of 90.5 mg / mL; taking a certain amount of the cyclohexane solution of stannous octoate and mixing it with all the monomers, and then removing the cyclohexane under vacuum.

[0066] The preparation methods for the alkyl alcohol-terminated cyclic ester oligomers in the preparation examples are the same, the difference lies in the type and / or amount of alkyl alcohol and monomer, as shown in Table 1.

[0067] Table 1. Raw material composition of cyclic ester oligomers with different alkyl alcohols terminated

[0068] Oligomer 29# was prepared by referring to the preparation of alkyl alcohol-terminated cyclic ester oligomers, the difference being that water was used instead of alkyl alcohol. The specific preparation method included: adding 0.318 g of water and 9.768 g of stannous octoate / monomer premix (containing 4 mg of stannous octoate and D,L-lactide as monomer) to a clean flask equipped with a magnetic stirrer. The oil bath temperature was raised to 130℃, and after complete melting, the mixture was stirred at 130℃ for 24 h. Then, the temperature was lowered to 110℃ and stirring continued for 48 h to complete the polymerization reaction, yielding the cyclic ester oligomer PDLLA.

[0069] The weight-average molecular weight and polydispersity index (PDI) of each oligomer were tested by gel permeation chromatography (GPC). The specific test conditions are as follows, and the test results are shown in Table 2. Figure 1 It is oligomer 10#-Me(CH2). 11 GPC spectrum of O-PDLLA 1 / 5.4.

[0070] GPC testing conditions: The chromatographic column was Shodex GPC KF-803L (8.0 mm × 300 mm, 6 μm), the column temperature was 40℃, the injection volume was 20 μL, the detector was a differential refractive index detector, and the analysis time was 15 min. The mobile phase was tetrahydrofuran (THF), with isocratic elution at a flow rate of 1 mL / min, and the standard was polyethylene glycol. Sample preparation included dissolving the test sample in THF to prepare a solution with a concentration of 10 mg / mL, filtering it through a 0.45 µm PTFE membrane into a liquid chromatography vial for detection.

[0071] Table 2 Test results of different oligomers

[0072] Example 1 Group This embodiment provides a method for preparing a liquid reservoir precursor, including the following steps: adding a certain proportion of EtOH to a certain proportion of GDO / SPC, heating to 60°C to fully melt and mix, then adding a certain proportion of oligomer, heating to 60°C to fully melt and mix, and naturally cooling to room temperature to obtain the liquid reservoir precursor.

[0073] The preparation methods of the different liquid reservoir precursors in Example 1 are the same, the difference lies in the amount or type of each component, as shown in Table 3. The amount in the table is the percentage of each component in the total mass of the liquid reservoir precursor.

[0074] Table 3 Raw material composition of the liquid storage precursor in Example 1

[0075] The injectability and semi-solid or solid reservoir formation effect of the liquid reservoir precursors prepared in Example 1 were tested, and the test results are shown in Table 4. The specific test method for injectability included injecting the test sample at room temperature (20~25℃) using a 1 mL syringe (inner diameter 4.5~4.7 mm) with a 25 G / 20 mm (corresponding to superscript 1 for injectability test results), 26 G / 16 mm (corresponding to superscript 2 for injectability test results), or 23 G / 25 mm (corresponding to superscript 3 for injectability test results). 1 mL was injected with a target time of 20 s, and the maximum force (N) during the injection process was measured using a digital dynamometer. In the injectability test results, NT represents: superscript c indicates high resistance and plunger bending; superscript d indicates oligomer incompatibility; and superscript e indicates gel-like structure that was not sampled for testing.

[0076] The specific test method for semi-solid or solid reservoir formation effect includes: extruding the test sample into PBS buffer at pH 7.4, with an extrusion volume of 0.5 mL, placing it at 37℃, and directly observing whether a reservoir can be formed. In the reservoir formation effect test results, NT means that the superscript d indicates oligomer incompatibility.

[0077] Table 4 Test results of injectability and reservoir formation effect of liquid reservoir precursor in Example 1 group

[0078] Example 2 group This embodiment provides a method for preparing a liquid reservoir precursor, including the following steps: adding a certain proportion of DMSO to a certain proportion of GDO / SPC, heating to 60°C to fully melt and mix, then adding a certain proportion of oligomer, heating to 60°C to fully melt and mix, and naturally cooling to room temperature to obtain the liquid reservoir precursor.

[0079] The preparation methods of the different liquid reservoir precursors in Example 2 are the same, the difference lies in the amount or type of each component, as shown in Table 5. The amount in the table is the percentage of each component in the total mass of the liquid reservoir precursor.

[0080] Table 5 Raw material composition of the liquid storage precursor in Example 2

[0081] The injectability and semi-solid or solid reservoir formation effect of the liquid reservoir precursors prepared in Example 2 were tested, and the test results are shown in Table 6. The specific test method for injectability included injecting the test sample at room temperature (20~25℃) using a 1 mL syringe (inner diameter 4.5~4.7 mm) with a 23 G / 25 mm (corresponding to superscript 1 for injectability test results), 25 G / 20 mm (corresponding to superscript 2 for injectability test results), 26 G / 16 mm (corresponding to superscript 3 for injectability test results), or 21 G / 35 mm (corresponding to superscript 4 for injectability test results). The injection time was 20 s, and the maximum force (N) during the injection process was measured using a digital dynamometer. In the injectability test results, NT means that the superscript 'e' represents a gel-like substance that was not sampled for testing.

[0082] The specific test method for the formation effect of semi-solid or solid reservoirs includes: squeezing the sample to be tested into PBS buffer at pH 7.4, with a squeezing volume of 0.5 mL, placing it at 37°C, and directly observing whether a reservoir can be formed.

[0083] Table 6 Test results of injectability and reservoir formation effect of liquid reservoir precursors in Example 2 group

[0084] In Examples 2-21, 2-22, 2-23, Control Examples 2-24, and Control Examples 2-25, oligomers were mixed with lipid liquid crystal components to obtain opalescent mixtures. However, precipitation occurred after standing at room temperature for about 16 hours, indicating relatively poor compatibility.

[0085] Example 3 Group This embodiment provides a method for preparing a liquid reservoir precursor, including the following steps: adding a certain proportion of EtOH to a certain proportion of GDO / SPC, heating to 60°C to fully melt and mix, then adding a certain proportion of oligomer, heating to 60°C to fully melt and mix, and naturally cooling to room temperature to obtain the liquid reservoir precursor.

[0086] The preparation methods of the different liquid reservoir precursors in Example 3 are the same, the difference lies in the amount or type of each component, as shown in Table 7. In the table, each amount is the percentage of each component in the total mass of the liquid reservoir precursor, and the content in parentheses in the GDO+SPC column is the mass ratio of GDO to SPC.

[0087] Referring further to the reservoir formation effect test method of Example 1, the reservoir formation effect of the liquid reservoir precursor in this example was tested, and the test results are shown in Table 7.

[0088] Table 7. Raw material composition and reservoir formation effect of the liquid reservoir precursor in Example 3

[0089] Example 4 group This set of embodiments provides a method for preparing risperidone in situ gel long-acting injection, including the following steps: a certain amount of risperidone powder and liquid reservoir precursor are mixed evenly with the assistance of a vortex mixer to obtain risperidone in situ gel long-acting injection.

[0090] The preparation method of the liquid reservoir precursor includes: adding a certain amount of EtOH to a certain amount of GDO and SPC, heating to 60°C to fully melt and mix, then adding a certain amount of oligomer, heating to 60°C to fully melt and mix, and naturally cooling to room temperature to obtain the liquid reservoir precursor.

[0091] The dosage information of liquid reservoir precursors and risperidone powder for different risperidone in situ gel long-acting injections is shown in Tables 8 and 9 below.

[0092] Table 8. Composition of liquid reservoir precursors for different risperidone in situ gel long-acting injections in Example 4

[0093] Table 9. Composition of different risperidone in situ gel long-acting injections in Example 4

[0094] Example 5 group This set of embodiments provides a method for preparing olanzapine in-situ gel long-acting injection, including the following steps: after passing olanzapine powder through a 200-mesh sieve, a certain amount of olanzapine powder and liquid reservoir precursor are weighed and mixed evenly with the assistance of a vortex mixer to obtain olanzapine in-situ gel long-acting injection.

[0095] Among them, liquid reservoir precursors A to B are shown in Example 4; the dosage information of liquid reservoir precursors and olanzapine powder for different olanzapine in-situ gel long-acting injections is shown in Table 10 below.

[0096] Table 10 Composition of different olanzapine in-situ gel long-acting injections in Example 5

[0097] Example 6 group This set of embodiments provides a method for preparing doxycycline hydrochloride in situ gel long-acting injection, including the following steps: after passing doxycycline hydrochloride powder through a 200-mesh sieve, a certain amount of doxycycline hydrochloride powder and liquid reservoir precursor are weighed and mixed evenly with the assistance of a vortex mixer to obtain doxycycline hydrochloride in situ gel long-acting injection.

[0098] Among them, liquid reservoir precursors A to C are shown in Example 4; the dosage information of liquid reservoir precursors and doxycycline hydrochloride powder for different doxycycline hydrochloride in situ gel long-acting injections is shown in Table 11 below.

[0099] Table 11 Composition of different long-acting doxycycline hydrochloride in situ gel injections in Example 6

[0100] Example 7 group This set of embodiments provides a method for preparing leuprorelin in situ gel long-acting injection, including the following steps: after passing leuprorelin powder through a 200-mesh sieve, a certain amount of leuprorelin powder and liquid reservoir precursor are weighed and mixed evenly with the assistance of a vortex mixer to obtain leuprorelin in situ gel long-acting injection.

[0101] Among them, liquid reservoir precursors A to C are shown in Example 4; the dosage information of liquid reservoir precursors and leuprorelin powder for different leuprorelin in situ gel long-acting injections is shown in Table 12 below.

[0102] Table 12 Composition of 7 different leuprorelin in situ gel long-acting injections in Example 1

[0103] Example 8 group This set of examples provides a method for preparing leuprorelin in-situ gel long-acting injection, including the following steps: Weigh 0.608g GDO, 0.409g SPC, and 0.218g anhydrous ethanol, and dissolve and mix at 37°C to obtain mother liquor I; Weigh 0.603g GDO, 0.402g SPC, and 0.191g anhydrous ethanol, and dissolve and mix at 37°C to obtain mother liquor II. Pass leuprorelin powder through a 200-mesh sieve for later use.

[0104] Weigh a certain amount of the corresponding mother liquor, add a certain amount of the corresponding oligomer, and mix at 60℃ for 2 h to obtain a liquid reservoir precursor; take a certain amount of the liquid reservoir precursor, add a certain amount of leuprorelin powder, and vortex mix.

[0105] The dosage information of each component in different leuprorelin in situ gel long-acting injections is shown in Table 13 below.

[0106] Table 13 Composition of 8 different leuprorelin in situ gel long-acting injections in Example 1

[0107] Example 9 group This set of embodiments provides a method for preparing telpotide in situ gel long-acting injection, including the following steps: after passing telpotide powder through a 200-mesh sieve, a certain amount of telpotide powder and liquid reservoir precursor are weighed and mixed evenly with the assistance of a vortex mixer to obtain telpotide in situ gel long-acting injection.

[0108] Among them, liquid reservoir precursors A to C are shown in Example 4; the dosage information of liquid reservoir precursors and telpoteptide powder for different telpoteptide in situ gel long-acting injections is shown in Table 14 below.

[0109] Table 14 Composition of different long-acting telboreptide in situ gels in Example 9

[0110] Example 10 This embodiment provides a method for preparing Tir-D, a long-acting in-situ gel injection of telboreptide, comprising the following steps: Weigh 2.807 g of SPC, 4.215 g of GDO, and 1.508 g of anhydrous ethanol, heat at 40°C for 1 h to mix evenly, add 1.508 g of oligomer 17#, stir at 80°C to dissolve, and then naturally cool to room temperature to obtain a liquid reservoir precursor. Take 0.778 g of the liquid reservoir precursor, add 32.59 mg of telboreptide powder that has passed through a 200-mesh sieve, and vortex mix evenly.

[0111] Example 11 group This set of examples provides a method for preparing semaglutide in situ gel long-acting injection, including the following steps: Weigh semaglutide (purity 98.63%, polypeptide content 89.5%, based on polypeptide content) and excipients (mannitol) into a glass bottle according to Table 15 below, add an appropriate amount of water, dissolve, clarify and transparent, dispense 2 mL into a freeze-drying bottle and freeze-dry, and then pass through a 200-mesh sieve for later use.

[0112] Table 15 Smegglutide Formulation

[0113] The preparation of Smegglutide in situ gel long-acting injection S-1 includes: weighing 0.4 g SPC and 0.6 g GDO, adding 0.176 g ethanol, incubating in a 37°C oven until completely dissolved, taking 0.47 g of the mixture and adding 30 mg Smegglutide@mannitol lyophilized powder, and mixing well to obtain the product.

[0114] The preparation of Smegglutide in situ gel long-acting injection S-2 includes: weighing 0.4 g SPC and 0.6 g GDO, adding 0.2 g ethanol and 0.133 g oligomer 10#, incubating in a 37°C oven until completely dissolved, taking 0.47 g of the mixture and adding 30 mg of Smegglutide@mannitol lyophilized powder, and mixing well to obtain the final product.

[0115] Example 12 group This set of examples provides a method for preparing a long-acting in-situ gel injection of semaglutide, comprising the following steps: Weighing 2.926 g of oligomer 10#, adding 5.852 g of ethanol, heating at 60°C for 2 h and vortexing to obtain liquid A; Weighing 1.024 g of oligomer 10#, adding 1.362 g of ethanol, heating at 60°C for 2 h and vortexing to obtain liquid B; Weighing 1.804 g of oligomer 17#, adding 3.607 g of ethanol, heating at 60°C for 2 h and vortexing to obtain liquid C. All drug powders were sieved through a 200-mesh sieve before addition.

[0116] The preparation of Smegglutide in situ gel long-acting injection S-3 includes: weighing 0.393 g SPC and 0.262 g GDO, adding 0.116 g liquid A, heating at 60℃ for 1 h, then adding 36.96 mg Smegglutide powder, and vortexing to mix.

[0117] The preparation of Smegglutide in situ gel long-acting injection S-4 includes: weighing 0.326 g SPC and 0.324 g GDO, adding 0.119 g liquid A, heating at 60℃ for 1 h, then adding 37.05 mg Smegglutide powder, and vortexing to mix.

[0118] The preparation of Smegglutide in situ gel long-acting injection S-5 includes: weighing 0.263 g SPC and 0.391 g GDO, adding 0.120 g liquid A, heating at 60℃ for 1 h, then adding 36.89 mg Smegglutide powder, and vortexing to mix.

[0119] The preparation of Smegglutide in situ gel long-acting injection S-6 includes: weighing 0.230 g SPC and 0.427 g GDO, adding 0.116 g liquid A, heating at 60℃ for 1 h, then adding 36.36 mg Smegglutide powder, and vortexing to mix.

[0120] The preparation of Smegglutide in situ gel long-acting injection S-7 includes: weighing 0.238 g SPC and 0.357 g GDO, adding 0.102 g liquid A, heating at 60℃ for 1 h, then adding 101.34 mg Smegglutide@mannitol lyophilized powder (equivalent to approximately 33.78 mg Smegglutide), and vortexing to mix.

[0121] The preparation of Smegglutide in situ gel long-acting injection S-8 includes: weighing 0.254 g SPC and 0.380 g GDO, adding 0.140 g liquid B, heating at 60℃ for 1 h, then adding 36.31 mg Smegglutide powder, and vortexing to mix.

[0122] The preparation of Smegglutide in situ gel long-acting injection S-9 includes: weighing 0.263 g SPC and 0.390 g GDO, adding 0.113 g liquid C, heating at 60℃ for 1 h, then adding 36.41 mg Smegglutide powder, and vortexing to mix.

[0123] One copy of each sample group was prepared in parallel.

[0124] Example 13 group This set of examples provides a method for preparing a long-acting in-situ gel injection of semaglutide, including the following steps: Weigh 3.398 g of SPC, 5.107 g of GDO, and 0.999 g of anhydrous ethanol, heat at 60°C for 2 h and vortex mix to obtain mother liquor I; Weigh 2.807 g of SPC, 4.215 g of GDO, and 1.508 g of anhydrous ethanol, heat at 60°C for 2 h and vortex mix to obtain mother liquor II. Semaglutide powder is passed through a 200-mesh sieve for later use.

[0125] Weigh a certain amount of the corresponding mother liquor, add a certain amount of the corresponding oligomer, and mix at 60℃ for 2 h to obtain the liquid reservoir precursor; take a certain amount of the liquid reservoir precursor, add a certain amount of semaglutide powder, and vortex mix. For semaglutide in-situ gel long-acting injection S-10, which does not contain oligomers, simply vortex mix the mother liquor and semaglutide powder directly.

[0126] The dosage information of each component of different semaglutide in situ gel long-acting injections is shown in Table 16 below.

[0127] Table 16 Composition of different long-acting semaglutide in situ gel injections in Example 13

[0128] Example 14 This embodiment provides a method for preparing S-18, a long-acting in-situ gel injection of semaglutide, comprising the following steps: weighing 1.696 g of SPC, 2.551 g of GDO, and 0.500 g of anhydrous ethanol, heating at 40°C for 1 h to mix completely, and obtaining a mixed solution; taking 0.951 g of the mixed solution, adding 0.052 g of oligomer 14#, magnetically stirring at 80°C to dissolve it, cooling to room temperature, adding 46 mg of semaglutide powder that has passed through a 200-mesh sieve, and vortexing to mix.

[0129] Experimental Example 1 Storage Formative Validation The reservoir-forming properties of different liquid reservoir precursors in Examples 1 and 2 were verified upon contact with water. The specific method included: adding an appropriate amount (approximately half or more of the volume of the aliquot bottle) of pH 7.4 PBS buffer to a 10 mL aliquot bottle, and then adding 0.5 mL of the test liquid reservoir precursor to the aliquot bottle using a syringe. When the liquid reservoir precursor came into contact with the surface of the buffer solution, it quickly formed a gel reservoir that floated on the surface. After being placed at 37°C and shaken, the reservoir morphology was observed. No significant overall change was observed within approximately 30 days. Images of some of the liquid reservoir precursors from Examples 1 and 2 forming reservoirs upon contact with water are shown below. Figures 2-15 .

[0130] Figure 16 These are photographs of the liquid reservoir precursors of Examples 1-12, 1-13, and 1-15 of the present invention in a static state; Figure 17 These are photographs of the liquid reservoir precursors of Examples 1-16, 1-17, and 1-18 of the present invention in a static state; Figure 18 These are photographs of the liquid reservoir precursors of Examples 2-9, 2-10, and 2-12 of the present invention in a static state; from top to bottom, they are Examples 2-9, 2-10, and 2-12. Figure 19 These are photographs of the liquid reservoir precursors of Examples 2-13, 2-14, and 2-15 of the present invention in a static state; from top to bottom, they are Examples 2-13, 2-14, and 2-15. As can be seen from the figures, the liquid reservoir precursors obtained by mixing alkyl alcohol-terminated dextrorotatory lactic acid oligomers and alkyl alcohol-terminated levorotatory lactic acid oligomers are in a non-flowing state in a static state; when mixed with solid drugs, they can prevent drug sedimentation and help maintain the homogeneity of the drug formulation.

[0131] Experiment Example 2 Validation of sustained-release effect 1. Risperidone in situ gel long-acting injection The corresponding masses of the five groups of samples Ris-A~Ris-E prepared in Example 4 were weighed into #000 gelatin capsules, added to the dissolution medium, and placed in a 37°C incubator with horizontal shaking at 50 rpm to release the drug. 2 mL of dissolution medium was taken each time and replenished. The drug dissolution was detected by HPLC.

[0132] The dissolution medium was 1X, pH 6.0 phosphate buffer; the volume of the medium was 150 mL.

[0133] The HPLC detection conditions were as follows: Elite LC3100 was used for liquid chromatography; mobile phase A was triethylamine aqueous solution at pH 3.04, and mobile phase B was methanol (v / v). Isocratic elution was performed with mobile phase A and mobile phase B at a v / v ratio of 50:50 for 10 min; the column was Supersil AQ-C18 (5 μm, 4.6 mm × 250 mm); the flow rate was 1.0 mL / min, the column temperature was 40℃, and the wavelength was 280 nm.

[0134] Table 17 shows the drug release (representing burst release) and the time required for 50% release (representing sustained-release characteristics) of the risperidone in-situ gel long-acting injection provided in Example 4 group at 24 h. The results indicate that the drug formulation prepared using the liquid reservoir pretreatment of the present invention significantly reduces burst release and effectively promotes sustained-release of the drug.

[0135] Table 17. Sustained-release effect of risperidone in situ gel long-acting injection

[0136] Figure 20 The figures show the release curves of Ris-A to Ris-E for the five samples prepared in Example 4. As can be seen from the figures, the cumulative release curves of the risperidone in-situ gel long-acting injection in the in vitro release medium over the first 8 days exhibit a rapid initial release followed by a gradual decrease, consistent with the typical release behavior of long-acting injections. Specifically, Group A, without the addition of oligomers, showed approximately 28.37% release on the first day and a cumulative release of 65.74% over 8 days; Group B showed approximately 20.51% release on the first day and a cumulative release of 73.27% over 8 days; and Group C showed approximately 19.32% release on the first day and a cumulative release of 62.45% over 8 days. The addition of oligomers significantly reduced the 24-hour burst release of the drug.

[0137] 2. Olanzapine Plain Injectable Gel Long-Acting Injection The corresponding masses of the three samples Ola-A~Ola-B prepared in Example 5 were weighed into #000 gelatin capsules, added to the dissolution medium, and placed in a 37°C incubator with horizontal shaking at 50 rpm for release. Samples were taken on days 1, 2, 5, and 7. The medium was replenished after each sampling, and the drug dissolution was detected by HPLC.

[0138] The dissolution medium was a pH 4.0 citrate-sodium citrate buffer solution containing 1 wt% SDS 0.1 M; the medium volume was 150 mL.

[0139] The HPLC detection conditions were as follows: Agilent LC1260 was used for liquid chromatography; mobile phase A was 0.057 mol / L phosphate buffer, and mobile phase B was methanol and acetonitrile in a volume ratio of 1:1. Isocratic elution was performed for 15 min with mobile phases A and B in a volume ratio of 25:75; the column was Supersil AQ-C18 (5 μm, 4.6 mm × 250 mm); the flow rate was 1 mL / min, the column temperature was 35℃, the wavelength was 254 nm, and the injection volume was 20 μL.

[0140] Table 18 shows the drug release and the time required for 50% release of the olanzapine in-situ gel long-acting injection provided in Example 5 group within 24 hours. The results indicate that the drug formulation prepared using the liquid reservoir pretreatment method of this invention significantly reduces the burst release of the drug and effectively promotes sustained drug release.

[0141] Table 18. Sustained-release and controlled-release effects of olanzapine in-situ gel long-acting injection

[0142] The test results above show that using the liquid reservoir precursor of the present invention reduces the burst release of olanzapine.

[0143] 3. Doxycycline hydrochloride in situ gel long-acting injection Three samples of Doxy-A to Doxy-C of the corresponding mass obtained in Example 6 were taken and squeezed into the dissolution medium through a syringe with a 26 G needle. The samples were placed in a 37°C incubator and shaken horizontally at 50 rpm for release. Samples were taken at 2 h, 5 h, 24 h, 96 h, 120 h, 144 h, 168 h, and 264 h. The medium was changed after each sampling, and the drug dissolution was detected by HPLC.

[0144] The dissolution medium was 1X, pH 7.4 phosphate buffer; the volume of the medium was 20 mL.

[0145] The HPLC detection conditions were as follows: Agilent LC1260 was used for liquid chromatography; mobile phase A was 0.05% (v / v) trifluoroacetic acid aqueous solution, and mobile phase B was acetonitrile. Isocratic elution was performed for 10 min with mobile phases A and B in a v / v ratio of 60:40; the column was Supersil AQ-C18 (5 μm, 4.6 mm × 250 mm); the flow rate was 1.0 mL / min, the column temperature was 35℃, and the wavelength was 270 nm.

[0146] Table 19 shows the drug release and the time required for 50% release of the doxycycline hydrochloride in situ gel long-acting injection provided in Example 6 at 24 h. The results indicate that the drug formulation prepared using the liquid reservoir pretreatment method of this invention significantly reduces the burst release of the drug and effectively promotes sustained drug release.

[0147] Table 19. Sustained-release and controlled-release effects of doxycycline hydrochloride in situ gel long-acting injection

[0148] 4. Leuprorelin in situ gel long-acting injection Three samples (Leu-A to Leu-C) of the corresponding mass prepared in Example 7 were taken and extruded into the dissolution medium through a syringe with a 26 G needle. The samples were then placed in a 37°C incubator and shaken to release the drug. The medium was changed after each sampling, and the drug dissolution was detected by HPLC. Four samples (Leu-D to Leu-G) of Example 8, 150 mg each, were filled into size 0 HPMC capsules and placed in the dissolution medium. The capsules were then placed in a 37°C incubator and shaken horizontally at 50 rpm to release the drug. The medium was changed after each sampling, and the drug dissolution was detected by HPLC.

[0149] The dissolution medium was 10 mM PBS buffer at pH 7.4 containing 0.06 wt% PS80; the medium volume was 20 mL.

[0150] The HPLC detection conditions were as follows: Elite LC3100 was used for liquid chromatography; mobile phase A was triethylamine aqueous solution at pH 3.04, and mobile phase B was n-propanol and acetonitrile in a volume ratio of 2:3. Isocratic elution was performed for 10 min with mobile phases A and B in a volume ratio of 70:30; the column was Supersil AQ-C18 (5 μm, 4.6 mm × 250 mm); the flow rate was 0.9 mL / min, the column temperature was 40℃, and the wavelength was 220 nm.

[0151] Table 20 shows the drug release and the time required for 50% release of the leuprorelin in-situ gel long-acting injection provided in Examples 7 and 8 at 24 h. The results indicate that the drug formulation prepared using the liquid reservoir pretreatment method of this invention is effective for sustained drug release.

[0152] Table 20. Sustained-release and controlled-release effects of leuprorelin in situ gel long-acting injection.

[0153] Figure 21 The release curves of Leu-A to Leu-C of the three samples prepared in Example 7 are shown. Figure 22The figure shows the release curves of the four samples Leu-D to Leu-G prepared in Example 8. As can be seen from the figure, at 24 h, sample A released approximately 13.33%, sample B released approximately 11.94%, and sample C released approximately 13.38%. No significant burst release was observed in samples D to G. Release detection was conducted on day 21, with release rates of 76.9%, 88.31%, 81.44%, and 86.25%, respectively. Groups with lower oligomer content showed higher release rates.

[0154] 5. Thilbeptide in situ gel long-acting injection Samples Tir-A to Tir-D, prepared in Examples 9 and 10 respectively, were taken in appropriate quantities. 200 mg of each sample was extruded into the dissolution medium via a syringe through a 26 G needle. The medium was then placed in a 37°C incubator and shaken horizontally at 50 rpm for release. The medium was replaced after each sampling. HPLC was used to detect drug dissolution. Sampling time points were 2 h, 1 d, 4 d, 7 d, 14 d, 21 d, and 28 d.

[0155] The dissolution medium was a 10 mM phosphate buffer solution with pH 7.4 containing 0.06 wt% Tween 80, in a volume of 20 mL.

[0156] The HPLC detection conditions were as follows: Agilent LC1260 was used for liquid chromatography; mobile phase A was a 0.1% (v / v) aqueous solution of trifluoroacetic acid, and mobile phase B was a 0.1% (v / v) trifluoroacetic acid acetonitrile solution. Isocratic elution was performed for 10 min with mobile phases A and B in a v / v ratio of 45:55; the column was a Supersil AQ-C18 (5 μm, 4.6 mm × 250 mm); the flow rate was 1.0 mL / min, the column temperature was 35 °C, and the wavelength was 280 nm.

[0157] Table 21 shows the drug release and the time required for 50% release of the telbeptide in situ gel long-acting injection provided in Example 9 and Example 10 within 24 hours. Figure 23 The image shows the release curve of the long-acting gel-based injection of telbeptide. The results indicate that the drug formulation prepared using the liquid reservoir pretreatment method of this invention significantly reduces the burst release of the drug, effectively promoting sustained drug release.

[0158] Table 21. Sustained-release and controlled-release effects of telpotetide in situ gel long-acting injection.

[0159] 6. Smegglutide in situ gel long-acting injection The semaglutide in situ gel long-acting injection prepared in Example 11 was squeezed into a 20 mL glass bottle for release assay. The dosage of the preparation was about 500 mg. The bottle was placed in a 37°C incubator and shaken horizontally at 50 rpm for release. The medium was changed after each sampling. The sampling time points were 2, 24, 48, 120, 168, 336, 504, 552, and 696 h. Approximately 250 mg of the long-acting semaglutide in situ gel prepared in Example 12 was placed in a No. 0 HPMC capsule cap and then added to a 20 mL glass bottle for release assay. The bottle was placed in a 37°C incubator and shaken horizontally at 50 rpm for release. The medium was changed after each sampling. The sampling time points were 2, 24, 48, 120, 168, and 360 h. Take about 250 mg of the long-acting semaglutide in situ gel prepared in Example 13, put it into a No. 0 HPMC capsule cap and then put it into a 20 mL glass bottle for release determination; place it in a 37℃ incubator and shake horizontally at 50 rpm for release. Change the medium after each sampling. The sampling time points are 2, 24, 48 and 216 h. Take about 250 mg of the long-acting semaglutide in situ gel prepared in Example 14, put it into a No. 0 HPMC capsule cap, and then put it into a 20 mL glass bottle for release determination; place it in a 37℃ incubator and shake horizontally at 50 rpm for release. Change the medium after each sampling. The sampling time points are 2, 24, 48, and 216 h. The dissolution medium was a 10 mM phosphate buffer solution with pH 7.4 containing 0.06 wt% Tween 80; the medium volume was 10 mL. The HPLC detection conditions were as follows: Agilent LC1260 was used for liquid chromatography; mobile phase A was a 0.1% (v / v) aqueous solution of trifluoroacetic acid, and mobile phase B was a 0.1% (v / v) trifluoroacetic acid acetonitrile solution. Isocratic elution was performed with mobile phases A and B in a 50:50 (v / v) ratio for 20 min; Supersil AQ-C18 column (5 μm, 4.6 mm × 250 mm); flow rate 1.0 mL / min; column temperature 35 °C; wavelength 280 nm.

[0160] Table 22 shows the drug release and the time required for 50% release of the semaglutide in situ gel long-acting injection within 24 hours. The results indicate that the drug formulation prepared using the liquid reservoir pretreatment method of this invention significantly reduces the burst release of the drug and effectively promotes sustained drug release.

[0161] Table 22. Sustained-release and controlled-release effects of smegglutide in situ gel long-acting injection

[0162] Note: If the release time is less than 50% within the 50% release time, record the release value and the corresponding time.

[0163] Figure 24 Release curves of Smegglutide in situ gel long-acting injections S-10, S-12, S-14, and S-16 are shown. The graphs reveal the cumulative release curves of the Smegglutide in situ gel long-acting injections in the in vitro release medium over the first 9 days. The overall release curves exhibit a rapid initial release followed by a gradual decrease, consistent with the typical release behavior of long-acting injections. Specifically, S-10 and S-14, without oligomers, showed release rates of 14.01% and 53.15% on the first day, respectively. The increase in ethanol content significantly accelerated drug release, with S-10 achieving a cumulative release of 63.22% after 9 days, and S-16 achieving a cumulative release of 99.93% after 9 days. S-12 and S-16, with the addition of oligomers, showed release rates of 5.75% and 5.92% on the first day, respectively. S-12 achieved a cumulative release of 17.60% after 9 days, and S-16 achieved a cumulative release of 26.89% after 9 days. These results indicate that the addition of oligomers significantly reduced the 24-hour burst release and delayed the overall drug release.

[0164] The test results above show that the liquid reservoir precursor of the present invention is a compound of alkyl alcohol-terminated cyclic ester oligomers, neutral acyl esters, and phospholipids. It can quickly aggregate in the aqueous phase, effectively reduce burst release, has good long-lasting sustained-release performance, and can also maintain good injectability.

[0165] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A liquid storage precursor, characterized in that, include: Alkyl alcohol-terminated cyclic ester oligomers, neutral acyl esters, phospholipids, and solvents; Based on a total amount of 100 wt% of the liquid reservoir precursor, the amount of the alkyl alcohol-terminated cyclic ester oligomer is 3 wt% to 30 wt%; The alkyl alcohol-terminated cyclic ester oligomers satisfy the following characteristics: (1) Alkyl alcohols have 8 to 22 carbon atoms; (2) The weight average molecular weight of the alkyl alcohol-terminated cyclic ester oligomer is 500~2000 Da.

2. The liquid storage precursor according to claim 1, characterized in that, The alkyl alcohol-terminated cyclic ester oligomers are prepared by ring-opening polymerization of alkyl alcohols and cyclic ester monomers. Preferably, the molar ratio of the alkyl alcohol to the cyclic ester monomer is 1:(1~11). Preferably, the cyclic ester monomer includes at least one of lactide, glycolide, and caprolactone; Preferably, the polydispersity index (PDI) of the alkyl alcohol-terminated cyclic ester oligomer is <2.

0.

3. The liquid storage precursor according to claim 1, characterized in that, The alkyl alcohol-terminated cyclic ester oligomers include at least one of alkyl alcohol-terminated dextrorotatory lactic acid oligomers, alkyl alcohol-terminated levorotatory lactic acid oligomers, and alkyl alcohol-terminated racemic lactic acid oligomers. Preferably, in the alkyl alcohol-terminated dextrorotatory lactic acid oligomer or the alkyl alcohol-terminated levorotatory lactic acid oligomer, the molar ratio of alkyl alcohol to cyclic ester monomer is 1:(1~7).

4. The liquid storage precursor according to claim 1, characterized in that, The alkyl alcohol-terminated cyclic ester oligomers include alkyl alcohol-terminated dextrorotatory lactic acid oligomers and alkyl alcohol-terminated levorotatory lactic acid oligomers. Preferably, the mass ratio of the alkyl alcohol-terminated dextrorotatory lactic acid oligomer to the alkyl alcohol-terminated levorotatory lactic acid oligomer is 1:(0.5~2).

5. The liquid storage precursor according to claim 1, characterized in that, It has at least one of the following characteristics: (1) The neutral acyl ester includes at least one of neutral diacyl ester and neutral monoacyl ester; The neutral diacyl ester includes at least one diacylglycerol ester; The neutral monoacyl ester includes at least one monoacylglycerol ester; (2) The phospholipids include at least one of soybean phospholipids, egg yolk phospholipids, dipalmitoyl phospholipids, distearate phospholipids, dioleoyl phosphatidyl ethanolamine, dioleoyl phosphatidyl ethanolamine, dioleoyl phosphatidyl serine, dioleoyl phosphatidyl glycerol, dioleoyl phosphatidyl glycerol, hydrogenated soybean phospholipids, hydrogenated lecithin, distearate phosphatidyl ethanolamine-polyethylene glycol, and dimyristoyl phosphatidyl ethanolamine-polyethylene glycol.

6. The liquid storage precursor according to claim 1, characterized in that, Based on a total amount of 100 wt% for the liquid reservoir precursor, the total amount of the neutral acyl ester and the phospholipid is 50 wt% to 90 wt%. Preferably, the mass ratio of the neutral acyl ester to the phospholipid is 65:35~40:

60.

7. The liquid storage precursor according to claim 1, characterized in that, The solvent includes at least one of ethanol, dimethyl sulfoxide, propylene glycol, glycerol, N-methylpyrrolidone, benzyl alcohol, and triacetylglycerol; Preferably, based on a total amount of 100 wt% of the liquid reservoir precursor, the amount of solvent used is 5 wt% to 20 wt%.

8. The method for preparing the liquid reservoir precursor according to any one of claims 1 to 7, characterized in that, The process includes the following steps: mixing alkyl alcohol-terminated cyclic ester oligomers, neutral acyl esters, phospholipids, and solvents until homogeneous.

9. A pharmaceutical preparation, characterized in that, Includes the liquid reservoir precursor and drug as described in any one of claims 1 to 7.

10. The pharmaceutical preparation according to claim 9, characterized in that, The drug includes at least one of risperidone, olanzapine, doxycycline hydrochloride, leuprorelin, telbestide, and smegglutide; Preferably, the drug loading in the pharmaceutical preparation is 0.1 wt% to 35 wt%.

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