Acid-containing sustained-release composition as well as preparation method and application thereof

Abstract

The invention discloses an acid-containing slow-release composition as well as a preparation method and application thereof, and more specifically, through a large amount of research, water-soluble acid of a specific variety and proportion is added into a carrier material based on phospholipid and an oil matrix, and it is unexpectedly found that the water-soluble acid can regulate and control the release speed of a main drug in the slow-release composition, so that the slow-release effect of the main drug in the slow-release composition is improved. Therefore, a better slow-release effect is obtained.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical science, specifically relating to an acid-containing sustained-release composition, its preparation method, and its application. Background Technology

[0002] Pain is a complex physiological and psychological activity, comprising two components: the pain sensation caused by a noxious stimulus acting on the body, and the individual's pain response to the noxious stimulus, accompanied by complex psychological activities. The International Association for the Study of Pain (IASP) defines pain as: an unpleasant sensation and emotional experience of actual, potential tissue damage; or a description of that damage. Pain is an unpleasant physiological experience that occurs widely in the course of various diseases. Pain not only causes physical discomfort but also has varying degrees of impact on the patient's mental, psychological, and physical well-being, directly affecting their quality of life and survival.

[0003] Local anesthetics, by inhibiting sodium ion channels in nerve cells, reversibly block the generation and conduction of nerve impulses at the site of application, and are commonly used clinically for analgesia. Ropivacaine and bupivacaine are currently first-line drugs for local anesthesia in clinical practice, with low toxicity to the central nervous system and cardiovascular system, and are increasingly widely used in anesthesia, postoperative analgesia, and other fields. However, their duration of action is usually less than 6-12 hours, and a single dose is insufficient to meet the needs of prolonged analgesia. Therefore, multiple administrations are required, but multiple administrations result in poor patient compliance, prolonged patient stay in the hospital, and increased treatment costs; secondly, they can easily cause peak-and-trough effects in blood drug concentration, leading to a series of toxic side effects. In recent years, scholars at home and abroad have attempted to increase the duration of action of local anesthetics through various methods, such as intermittent multiple administrations via epidural catheter implantation and the use of microinfusion pumps, but these still have drawbacks such as larger dosages, higher costs, poor patient compliance, and the risk of infection, sepsis, and nerve damage.

[0004] Publicly reported long-acting local anesthetic sustained-release formulations mainly include those based on oil-based sustained-release systems, phospholipid-solvent-oil carrier-based sustained-release systems, polymer-based sustained-release systems, liposomes, and suspension-based sustained-release systems. However, these formulation systems still suffer from drawbacks such as local irritation during administration, difficulty in achieving a sustained-release time of 72 hours, high formulation viscosity, poor injectability, complex preparation processes, and high production costs.

[0005] CN113941004B discloses a sustained-release composition of a high-concentration local anesthetic, comprising a liquid oil, a pharmaceutically acceptable hydrogen bond donor, and an active ingredient, the local anesthetic. In this formulation composition, adding a certain proportion of acid can increase the solubility of the active ingredient, but it will significantly accelerate the drug release rate. US20150297730A1 discloses a formulation composition and related preparation method composed of a biodegradable polyorthoester polymer, organic acid excipients, and a local anesthetic in the form of a free base. Adding different proportions of organic acid to the formulation composition can accelerate the release of the active drug to varying degrees.

[0006] Through extensive research, the inventors unexpectedly discovered that the release rate of local anesthetic formulations can be significantly regulated by using specific types and proportions of water-soluble acids, enabling the formulations to maintain a sustained-release effect for a longer period of time. This has not been reported in the prior art and is contrary to the results reported in published literature, showing an unexpected effect. Summary of the Invention

[0007] During the research of sustained-release formulations, this invention unexpectedly discovered that adding a specific water-soluble acid release modifier to the formulation can significantly regulate the in vivo and in vitro release rate of local anesthetics, achieving a longer sustained-release effect.

[0008] More specifically, the present invention provides an acid-containing sustained-release formulation composition, comprising:

[0009] a. Active pharmaceutical ingredient;

[0010] b. Sustained-release carrier material;

[0011] c. Phospholipids;

[0012] d. Pharmaceutically acceptable acids;

[0013] e. Pharmaceutically acceptable solvents.

[0014] According to an embodiment of the present invention, the active pharmaceutical ingredient includes one or more of bupivacaine, ropivacaine, levobupivacaine, mepivacaine, lidocaine free base, and pharmaceutically acceptable salts thereof.

[0015] According to embodiments of the present invention, pharmaceutically acceptable salts include, but are not limited to, one or more of the following: hydrochloride, mesylate, hydrobromide, hydroiodide, sulfate, citrate, tartrate, lactate, citric acid, maleate, and fumarate.

[0016] According to embodiments of the present invention, the active pharmaceutical ingredient, calculated as a free base of the drug, accounts for 0.01% to 10.0% (w / w) of the total composition; preferably 0.01% to 8%; more preferably 0.01% to 6%; more preferably 0.01% to 4%; and more specifically, the active pharmaceutical ingredient accounts for 0.5%, 1%, 2%, 3%, or 4% of the total composition.

[0017] According to an embodiment of the present invention, the sustained-release carrier material is selected from one or more of natural plant oils or synthetic oils.

[0018] According to an embodiment of the present invention, the natural vegetable oil is selected from one or more of castor oil, sesame oil, soybean oil, sunflower seed oil, peanut oil, corn oil, rapeseed oil, olive oil, and cottonseed oil.

[0019] According to an embodiment of the present invention, the synthetic oil is selected from one or more of medium-chain triglycerides (MCT), long-chain triglycerides, triacetin, ethyl oleate, and trioleic acid ester.

[0020] According to an embodiment of the present invention, the sustained-release carrier material is selected from one or more of medium-chain triglycerides, castor oil, sesame oil, and soybean oil.

[0021] According to embodiments of the present invention, the sustained-release carrier material accounts for about 10% to about 90% (w / w) of the total composition; preferably 20% to 80%; preferably 25% to 70%; preferably 30% to 65%; preferably 35% to 50%; more preferably 30% to 35%.

[0022] According to embodiments of the present invention, the phospholipids are selected from hydrogenated soybean phospholipids, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearyl phosphatidylcholine, dilauroyl phosphatidylcholine, soybean lecithin (SPC), egg yolk lecithin (EPC), rapeseed phospholipids, sunflower phospholipids, disqualoyl lecithin, disqualoyl lecithin (DOPC), palmitoyl oleoyl lecithin, sphingomyelin, distearyl phosphatidic acid, dioleoyl phosphatidylethanolamine, dipalmitoyl phosphatidic acid, and myristoyl lysophosphophosphate. One or more of the following: lipids, palmitoyl lysophosphatidyl, 1-stearoyl-lysophosphatidylcholine, dipalmitoyl phosphatidylethanolamine, distearyl phosphatidylethanolamine, dioleoyl phosphatidylglycerol, dimyristoyl phosphatidylethanolamine, dimyristoyl phosphatidylglycerol, dipalmitoyl phosphatidylglycerol, 1-palmitoyl-2-oleoyl phosphatidylglycerol, distearyl phosphatidylglycerol, dipalmitoyl phosphatidylserine, phosphatidylinositol, and cholesterol; preferably one or more of the following: soybean phosphatidyl, egg yolk phosphatidyl, and dioleoyl acyl lecithin.

[0023] According to embodiments of the present invention, phospholipids account for about 10% to about 90% (w / w) of the total composition; preferably 20% to 80%; preferably 30% to 70%; preferably 30% to 65%; preferably 35% to 55%; more preferably 40% to 50%.

[0024] According to embodiments of the present invention, the pharmaceutically acceptable acid is a pharmaceutically acceptable water-soluble acid with a molecular weight of less than 300 amu, more preferably less than 200 amu; the pharmaceutically acceptable water-soluble acid release modifier typically has a pKa of less than 5, preferably less than 4.7, most preferably less than 4.5, and the acid must also be suitable for dissolving at a desired level in the selected oily matrix system.

[0025] According to embodiments of the present invention, the pharmaceutically acceptable acid is selected from one or more of acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, methanesulfonic acid, benzoic acid, caprylic acid, alanine, carbonic acid, sorbic acid, caprylic acid, nonanoic acid, lauric acid, palmitic acid, oleic acid, hydrochloric acid, phosphoric acid, phthalic acid, decanoic acid, myristic acid, propionic acid, butyric acid, heptanoic acid, valeric acid, malic acid, tartaric acid, oxalic acid, citric acid, ascorbic acid, salicylic acid, caffeic acid, glycolic acid, aspartic acid, glutamic acid, and vitamin E succinic acid; preferably one or more of lactic acid, citric acid, and maleic acid.

[0026] According to embodiments of the present invention, the pharmaceutically acceptable acid accounts for about 0.01% to about 10% (w / w) of the total amount of the formulation composition; preferably 0.01% to 8%; more preferably 0.01% to 6%; even more preferably 0.01% to 5%; more specifically, the pharmaceutically acceptable acid accounts for 0.5%, 1%, 2%, 3%, 4%, and 5% of the total amount of the formulation composition.

[0027] According to embodiments of the present invention, a pharmaceutically acceptable solvent is selected from one or more of alcohols, N-methylpyrrolidone, benzyl benzoate, dimethyl sulfoxide, and water for injection.

[0028] According to an embodiment of the present invention, the alcohol is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, propylene glycol, glycerol, benzyl alcohol, phenethyl alcohol, and polyethylene glycol.

[0029] According to embodiments of the present invention, a pharmaceutically acceptable solvent is selected from one or more of ethanol, N-methylpyrrolidone, and dimethyl sulfoxide.

[0030] According to embodiments of the present invention, the pharmaceutically acceptable solvent accounts for about 0.01% to about 30% (w / w) of the total composition; preferably 0.01% to 25%; more preferably 0.01% to 20%; preferably 0.01% to 15%; more preferably 0.01% to 10%; even more preferably, the pharmaceutically acceptable solvent accounts for about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of the total composition.

[0031] According to embodiments of the present invention, when the active pharmaceutical ingredient is bupivacaine free base and the pharmaceutically acceptable acids are lactic acid and citric acid, the active pharmaceutical ingredient accounts for 0.01% to 8% of the total composition, the pharmaceutically acceptable lactic acid accounts for 0.01% to 10% of the total composition, and the citric acid accounts for 0.01% to 3% of the total composition. When the active pharmaceutical ingredient is bupivacaine hydrochloride and the pharmaceutically acceptable acids are lactic acid, citric acid, and maleic acid, the active pharmaceutical ingredient (calculated as free base) accounts for 0.01% to 2% of the total composition, the pharmaceutically acceptable lactic acid and citric acid account for 0.01% to 3% of the total composition, and the maleic acid accounts for 0.01% to 6% of the total composition.

[0032] According to an embodiment of the present invention, when the active pharmaceutical ingredient is ropivacaine and the pharmaceutically acceptable acids are lactic acid and citric acid, the active pharmaceutical ingredient accounts for 0.01% to 4% of the total composition, the pharmaceutically acceptable lactic acid accounts for 0.01% to 10% of the total composition, and the citric acid accounts for 0.01% to 3% of the total composition. When the active pharmaceutical ingredient is ropivacaine hydrochloride, and the pharmaceutically acceptable acid is lactic acid or citric acid, the active pharmaceutical ingredient (calculated as free base) accounts for 0.01% to 2% of the total composition, the pharmaceutically acceptable lactic acid accounts for 0.01% to 10% of the total composition, and the citric acid accounts for 0.01% to 3% of the total composition. When the active pharmaceutical ingredient is ropivacaine mesylate, and the pharmaceutically acceptable acid is maleic acid or citric acid, the active pharmaceutical ingredient accounts for 0.01% to 4% of the total composition, the pharmaceutically acceptable citric acid accounts for 0.01% to 6% of the total composition, and the maleic acid accounts for 0.01% to 3% of the total composition. Furthermore, the present invention also provides a method for preparing the sustained-release composition described in any of the above claims, comprising:

[0033] (a1) Dissolve the prescribed amount of active pharmaceutical ingredient, sustained-release carrier material, phospholipid, and pharmaceutically acceptable acid in a pharmaceutically acceptable solvent until homogeneous;

[0034] (a2) Remove excess organic solvent from step (a1) by rotary evaporation or vacuum drying process;

[0035] (a3) Add the drug solvent to the prescribed amount as needed, and mix well to obtain the final product;

[0036] Or it may include the following steps:

[0037] (b1) Dissolve the prescribed amount of sustained-release carrier material, phospholipids, and pharmaceutically acceptable acid in a pharmaceutically acceptable solvent under nitrogen protection until fully homogeneous;

[0038] (b2) The prescribed amount of active pharmaceutical ingredient is added to solution b1 and heated and stirred under nitrogen protection until completely dissolved;

[0039] (b3) Cool to room temperature; filter to obtain.

[0040] According to embodiments of the present invention, the process further includes dispensing, sterilization, or disinfection steps.

[0041] According to an embodiment of the present invention, sterilization is performed by filtration, and sterilization is performed by moist heat sterilization.

[0042] The present invention also provides the use of the sustained-release composition described in any of the above claims in the preparation of a pain-relieving medicament, preferably wherein the sustained-release composition can controllably regulate the duration of pain treatment to provide a long-lasting analgesic effect.

[0043] The present invention also provides a sustained-release composition comprising any one of the above claims, characterized in that the sustained-release composition is administered as a reservoir formulation, preferably, the formulation is administered by subcutaneous or intramuscular injection, incision infusion, incision infiltration, nerve plexus administration, or intra-articular injection.

[0044] According to an embodiment of the present invention, the formulation further includes packaging material filled with the formulation, the packaging material being selected from one or more of the following: vials, pre-filled syringes, and cartridges.

[0045] Terms and Abbreviations

[0046] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures shall fall within the scope of this application specification.

[0047] The numerical ranges described in this application specification and claims, when defined as such or as being limited to "integers", should be understood to include the two endpoints of the range and every integer within that range. For example, "integers from 0 to 10" should be understood to include every integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0048] When a range of values ​​is defined as a "number" or may include "integer" or "non-integer", it should be understood as recording the two endpoints of the range, every integer within the range, and every decimal within the range. For example, "numbers from 0 to 10" should be understood as not only recording every integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also recording at least the sum of each of these integers with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9.

[0049] The abbreviations used in this invention have the following definitions: Rop is ropivacaine; Rop.HCl is ropivacaine hydrochloride or ropivacaine hydrochloride; Rop.Mes is ropivacaine mesylate or ropivacaine mesylate; Bup is bupivacaine; Bup.HCl is bupivacaine hydrochloride or bupivacaine hydrochloride; EtOH is ethanol; NMP is N-methylpyrrolidone; DMSO is dimethyl sulfoxide; MCT is medium-chain triglyceride; SPC is soybean lecithin; EPC is egg yolk lecithin; HSPC is hydrogenated soybean lecithin; DMPC is myristoylphosphatidylcholine.

[0050] Beneficial effects

[0051] (1) Through extensive research, the present invention has unexpectedly discovered that adding specific types and proportions of water-soluble acids to phospholipid and oil-based carrier materials can regulate the release rate of the active pharmaceutical ingredient in the sustained-release composition of the present invention, thereby achieving a better sustained-release effect. This is contrary to the conventional understanding in the field: that is, adding acid to an oil-based drug delivery system generally has no effect on the release behavior of the active pharmaceutical ingredient or accelerates its release.

[0052] (2) The present invention has unexpectedly discovered that certain solvents help to improve the release rate of the active pharmaceutical ingredient in the sustained-release composition of the present invention.

[0053] (3) The sustained-release composition of the present invention has adjustable viscosity, is easy to administer, facilitates clinical administration, and can meet the needs of different clinical administration routes.

[0054] (4) The sustained-release composition of the present invention has a significant long-term sustained-release effect, can meet the requirements of long-term analgesia, and has no obvious burst release, which can reduce the number of administrations, has good compliance, and can avoid peak and trough phenomena and has few adverse reactions.

[0055] (5) The sustained-release composition of the present invention can be prepared by simple melting, mixing or rotary evaporation steps. Compared with the long-acting formulations of existing local anesthetics, the preparation method is simple and easy to carry out, which is conducive to industrial production.

[0056] (6) The sustained-release composition of the present invention, wherein the carrier material used has good biocompatibility and safety, no local irritation, and good drug safety and tolerability. Attached Figure Description

[0057] Figure 1 It is a morphological observation under a polarizing microscope after the in vitro phase transition of an acid-containing preparation composition.

[0058] Figure 2 The figures show the plasma concentration-time curves of ropivacaine for Comparative Example-1, formulation compositions 1033 and 1034.

[0059] Figure 3 These are the plasma concentration-time curves of formulation compositions 1033 and 1034 for ropivacaine.

[0060] Figure 4 This is the plasma concentration-time curve of ropivacaine mesylate in Comparative Example-2 and formulation compositions 1047 and 1048.

[0061] Figure 5 These are the plasma concentration-time curves of formulation compositions 1047 and 1048, ropivacaine mesylate. Detailed Implementation

[0062] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0063] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0064] Example 1: Investigation of the solubility of acid in oily systems and aqueous media

[0065] According to Table 1-1, take about 2g of blank oily sustained-release composition, add 3% by mass of acid and sonicate to dissolve, observe the solubility of acid in blank oily sustained-release composition, and the results are shown in Table 1-1.

[0066] Table 1-1 Solubility of Acids in Blank Oily Sustained-Release Compositions

[0067]

[0068] According to Table 1-2, take about 1g of purified water or pH 7.4 buffer medium, add an appropriate amount of acid and sonicate to dissolve, and observe the maximum solubility of different types of acid. The results are shown in Table 1-2.

[0069] Table 1-2 Solubility of acids in different aqueous media

[0070]

[0071] Table 1-3 Summary of common acidic physicochemical properties

[0072]

[0073] The results showed that lactic acid, citric acid, and maleic acid all had good solubility in both aqueous and oil-based matrices.

[0074] Example 2: Investigation of different types of acids

[0075] Using bupivacaine hydrochloride as a model drug and phospholipids and sesame oil as sustained-release carriers, the effects of different types of acids on the in vitro release performance of bupivacaine hydrochloride were preliminarily investigated. According to the formulation composition in Table 2-1, the prescribed amounts of phospholipids, sustained-release materials, acid release modifiers, and organic solvents were magnetically stirred and completely dissolved at 70–80°C. Then, the prescribed amount of the active pharmaceutical ingredient was added, and the mixture was stirred until a clear and homogeneous solution was formed. The solution was then cooled to room temperature to obtain the final formulation composition.

[0076] Table 2-1 Evaluation of different acid formulations

[0077]

[0078]

[0079] Take about 0.2g of the formulation composition in Table 2-1 and place it in a centrifuge tube containing 30ml of phosphate buffer (pH 6.5). Shake at 100rpm at 37℃. Take samples at 4h and 24h to detect the cumulative drug release content. The results are shown in Table 2-2.

[0080] Table 2-2 In vitro release of formulations containing different types of acids

[0081] Composition Number 4h(％) 24h(％) 1001 8.45 60.17 1002 4.79 54.45 1003 2.05 11.20 1004 26.49 59.40 1005 47.94 70.42 1006 5.46 42.87 1007 25.61 56.68

[0082] The results showed that, compared with the non-acid formulation, lactic acid, citric acid and maleic acid could significantly reduce the early in vitro release of bupivacaine hydrochloride; benzoic acid, octanoic acid and oleic acid not only failed to reduce the in vitro release of the active ingredient, but also significantly accelerated the in vitro release of the active ingredient in the first 4 hours.

[0083] Example 3: Investigation of Acid Dosage

[0084] Using bupivacaine hydrochloride as a model drug, the effects of different proportions of lactic acid, citric acid, and maleic acid on the performance of the formulation composition were investigated. According to Table 3-1, the prescribed amounts of phospholipids, sustained-release materials, acids, and solvents were completely dissolved by magnetic stirring at 70–80°C. Then, the prescribed amount of the active pharmaceutical ingredient was added, and the mixture was stirred until a clear, homogeneous solution was formed. The final formulation composition was obtained by cooling to room temperature.

[0085] Take an appropriate amount of the formulation composition in Table 3-1 and place it in a centrifuge tube containing 30 ml of release medium. Shake at 100 rpm at 37°C. Take samples at 4 h and 24 h respectively to detect the cumulative drug release content. The results are shown in Table 3-2.

[0086] Table 3-1 Bupivacaine hydrochloride sustained-release compositions containing different proportions of acid

[0087]

[0088]

[0089] Table 3-2 In vitro cumulative release results of bupivacaine hydrochloride sustained-release compositions containing different proportions of acid.

[0090] Composition Number 4h(％) 24h(％) 1001 8.45 60.17 1002 4.79 54.45 1008 15.96 66.24 1009 75.09 91.26 1003 2.05 11.20 1006 5.46 42.87 1011 8.33 40.64

[0091] The results showed that lactic acid mass percentage in the range of 0-3% could reduce the in vitro release of the active ingredient, and the in vitro release of the active ingredient accelerated with the continued increase of lactic acid dosage; citric acid and maleic acid mass percentage in the ranges of 0-3% and 0-6% respectively could significantly reduce the in vitro release of the active ingredient.

[0092] Example 4: Investigation of compositions containing different types of phospholipids and sustained-release materials

[0093] Using bupivacaine hydrochloride as a model drug, lactic acid was selected as a release modifier to investigate the effects of different types of sustained-release materials on the performance of the formulation composition. According to Tables 4-1 and 4-3, the prescribed amounts of phospholipids, sustained-release materials, acids, and solvents were completely dissolved by magnetic stirring at 70–80°C. Then, the prescribed amount of the active pharmaceutical ingredient was added, and the mixture was stirred until a clear, homogeneous solution was formed. The final formulation composition was obtained by cooling to room temperature.

[0094] Take an appropriate amount of the formulation composition in Tables 4-1 and 4-3 and place it in a centrifuge tube containing 30 ml of release medium. Shake at 100 rpm at 37°C. Take samples at 4 h and 24 h time points to detect the cumulative drug release content. The results are shown in Tables 4-2 and 4-4.

[0095] (1) Investigation of Phospholipid Types

[0096] Table 4-1 Compositions containing different types of phospholipid sustained-release compounds

[0097]

[0098]

[0099] Table 4-2 In vitro cumulative release results of different types of phospholipid sustained-release compositions

[0100] Composition Number 4h(％) 24h(％) 1002 4.79 54.45 1012 5.79 58.45

[0101] The results showed that when the sustained-release material SPC in the formulation was replaced with EPC, it had no significant effect on the in vitro release of the active pharmaceutical ingredient; however, when replaced with HSPC or DMPC, a homogeneous formulation could not be obtained.

[0102] (2) Investigation of sustained-release materials

[0103] Table 4-3 Sustained-release compositions containing different types of sustained-release materials

[0104]

[0105] Table 4-4 Cumulative in vitro release results of different types of sustained-release material formulations

[0106] Composition Number 4h(％) 24h(％) 1002 4.79 54.45 1015 4.56 56.34 1016 5.29 58.15 1017 5.67 59.48

[0107] The results showed that after replacing sesame oil in the formulation with castor oil, MCT and soybean oil, the formulation was a loose mixture of phospholipids and oils in the release medium. The in vitro release trends of the active ingredient were basically the same at 4h and 24h, and the cumulative release rate in vitro was lower than that of the formulation without acid. This indicates that adding acid to the formulation containing different oils also has an inhibitory effect on the in vitro release of the active ingredient.

[0108] Example 5: Investigation of compositions containing different amounts of sustained-release materials

[0109] Using bupivacaine hydrochloride as a model drug, lactic acid was selected as a release modifier to investigate the effect of different types of sustained-release materials on the performance of the formulation composition. According to Table 5-1, the prescribed amounts of phospholipids, sustained-release materials, acids, and solvents were completely dissolved by magnetic stirring at 70-80°C. Then, the prescribed amount of the active pharmaceutical ingredient was added, and the mixture was stirred until a clear and homogeneous solution was formed. The final formulation composition was obtained by cooling to room temperature.

[0110] Take an appropriate amount of the formulation composition in Table 5-1 and place it in a centrifuge tube containing 30 ml of release medium. Shake at 100 rpm at 37°C. Take samples at 4 h and 24 h to detect the cumulative drug release content. The results are shown in Table 5-2.

[0111] Table 5-1 Formulation compositions containing different proportions of sustained-release materials

[0112]

[0113] Table 5-2 In vitro cumulative release results of formulations containing different proportions of sustained-release materials

[0114] Composition Number 4h(％) 24h(％) 1018 5.79 56.45 1019 5.65 54.84 1002 4.79 54.45 1020 4.34 46.23 1021 3.67 43.25

[0115] The results showed that formulations containing different proportions of sustained-release materials had no effect on the in vitro release of bupivacaine hydrochloride. However, when the mass percentage of SPC in the formulation was <30%, physical precipitation occurred during storage; or when it was >70%, a homogeneous formulation could not be obtained due to the excessively high proportion of phospholipids.

[0116] Example 6: Investigation of Compositions with Different Solvents

[0117] Using bupivacaine hydrochloride as a model drug, the effects of different types of solvents on the performance of the formulation composition were investigated. According to the formulation composition in Table 6-1, the prescribed amounts of phospholipids, sustained-release materials, acids, and solvents were completely dissolved by magnetic stirring at 70–80°C. Then, the prescribed amount of the active pharmaceutical ingredient was added, and the mixture was stirred until a clear and homogeneous solution was formed. The final formulation composition was obtained by cooling to room temperature.

[0118] Table 6-1 Compositions containing sustained-release formulations with different solvents

[0119]

[0120]

[0121] Take about 0.2g of the formulation composition in Table 6-1 and place it in a 50ml centrifuge tube containing 30ml of phosphate buffer (pH=6.5). Shake at 100rpm at 37℃. Take samples at 4h and 24h to detect the cumulative drug release content. The results are shown in Table 6-2.

[0122] Table 6-2 In vitro cumulative release results of compositions containing different solvents

[0123] Composition Number 4h(％) 24h(％) 1002 4.79 54.45 1022 3.95 53.48 1023 8.70 73.48 1024 50.98 78.18

[0124] The results showed that the percentage of ethanol in the formulation had no significant effect on the in vitro release of the active pharmaceutical ingredient (API), but when the percentage was greater than 15%, the release of the API was significantly accelerated. Homogeneous formulations could not be obtained with the same percentage of DMSO. In formulations containing the same percentage of NMP, the API was released significantly faster in vitro in the first 24 hours than with ethanol. Ethanol, DMSO, and NMP are all commonly used hydrophilic solvents for injection administration. This study unexpectedly found that the specific solvent ethanol helps improve the sustained-release effect of the API in the composition.

[0125] Example 7: Investigation on the preparation of acid-containing bupivacaine sustained-release compositions

[0126] According to the formulation composition in Table 7-1, the prescribed amounts of phospholipids, sustained-release materials, acids and solvents are completely dissolved by magnetic stirring at 70-80°C. Then, the prescribed amount of bupivacaine free base is added and stirred until a clear and homogeneous solution is formed. The final formulation composition is obtained by cooling to room temperature.

[0127] Table 7-1 Bupivacaine Free Base Formulation Compositions

[0128]

[0129] Take about 0.2g of the formulation composition in Table 7-1 and place it in a 50ml centrifuge tube containing 30ml of phosphate buffer (pH=6.5). Shake at 100rpm at 37℃. Take samples at 4h and 24h to detect the cumulative drug release content. The results are shown in Table 7-2.

[0130] Table 7-2 In vitro cumulative release results of bupivacaine free base formulations

[0131]

[0132]

[0133] The results showed that, compared with acid-free formulations, the addition of 0-10% lactic acid and 0-3% citric acid by mass percentage to formulations with a drug loading of 0-8% significantly reduced the cumulative in vitro release of the active pharmaceutical ingredient in the first 4 hours or 24 hours.

[0134] Example 8: Investigation on the preparation of acid-containing ropivacaine sustained-release compositions

[0135] According to the formulation composition in Table 8-1, the prescribed amounts of phospholipids, sustained-release materials, acids and solvents are completely dissolved by magnetic stirring at 70-80°C. Then, the prescribed amount of free ropivacaine base is added and stirred until a clear and homogeneous solution is formed. The final formulation composition is obtained by cooling to room temperature.

[0136] Table 8-1 Ropivacaine Free Base Formulation Compositions

[0137]

[0138] Take about 0.2g of the formulation composition in Table 8-1 and place it in a 50ml centrifuge tube containing 30ml of phosphate buffer (pH=6.5). Shake at 100rpm at 37℃. Take samples at 4h and 24h to detect the cumulative drug release content. The results are shown in Table 8-2.

[0139] Table 8-2 In vitro cumulative release results of ropivacaine free base formulations

[0140] Composition Number 4h(％) 24h(％) 1033 15.43 79.19 1034 7.07 19.87 1035 92.40 / 1036 61.69 / 1037 52.40 / 1038 33.96 / 1039 48.55 /

[0141] The results showed that, compared with the acid-free formulation, the addition of 0-10% lactic acid and 0-3% citric acid by mass percentage to the formulation with a drug loading of 0-4% significantly reduced the cumulative release of the active pharmaceutical ingredient in vitro in the first 4 hours.

[0142] Example 9: Investigation on the preparation of acid-containing ropivacaine hydrochloride sustained-release composition

[0143] According to the formulation composition in Table 9-1, the prescribed amounts of phospholipids, sustained-release materials, acids and solvents are completely dissolved by magnetic stirring at 70-80°C. Then, the prescribed amount of ropivacaine hydrochloride is added and stirred until a clear and homogeneous solution is formed. The final formulation composition is obtained by cooling to room temperature.

[0144] Table 9-1 Ropivacaine Hydrochloride Formulation Compositions

[0145]

[0146] Take about 0.2g of the formulation composition in Table 9-1 and place it in a 50ml centrifuge tube containing 30ml of phosphate buffer (pH=6.5). Shake at 100rpm at 37℃. Take samples at 4h and 24h to detect the cumulative drug release content. The results are shown in Table 9-2.

[0147] Table 9-2 In vitro cumulative release results of ropivacaine hydrochloride formulations

[0148] Composition Number 4h(％) 24h(％) 1040 89.06 98.36 1041 64.06 103.36 1042 73.40 115.67 1043 46.38 89.10 1045 11.07 25.29 1046 46.23 79.40

[0149] The results showed that, compared with acid-free formulations, the addition of 0–10% lactic acid and 0–3% citric acid by mass percentage to ropivacaine hydrochloride formulations significantly reduced the cumulative in vitro release of the active ingredient in the first 4 hours or 24 hours.

[0150] Example 10: Investigation on the preparation of acid-containing ropivacaine mesylate sustained-release composition

[0151] According to the formulation composition in Table 10-1, the prescribed amounts of sustained-release material, pharmaceutical excipient-grade oil, acid and solvent are completely dissolved by magnetic stirring at 70-80°C. Then, the prescribed amount of ropivacaine mesylate is added and stirred until a clear and homogeneous solution is formed. The final formulation composition is obtained by cooling to room temperature.

[0152] Table 10-1 Ropivacaine Mesylate Formulations

[0153]

[0154]

[0155] Take about 0.2g of the formulation composition in Table 10-1 and place it in a 50ml centrifuge tube containing 30ml of phosphate buffer (pH=6.5). Shake at 100rpm at 37℃. Take samples at 4h and 24h to detect the cumulative drug release content. The results are shown in Table 10-2.

[0156] Table 10-2 In vitro cumulative release results of ropivacaine mesylate formulations

[0157] Composition Number 4h(％) 24h(％) 1047 17.73 66.74 1048 2.93 12.27 1049 0.95 2.31 1051 5.01 13.25 1052 15.55 50.97 1053 12.41 62.00

[0158] The results showed that, compared with acid-free formulations, the addition of 0–6% citric acid and 0–3% maleic acid by mass percentage in ropivacaine mesylate formulations significantly reduced the cumulative in vitro release of the active pharmaceutical ingredient in the first 4 hours or 24 hours.

[0159] Example 11 In vitro performance evaluation of drug sustained-release composition

[0160] The sustained-release drug composition prepared in this invention undergoes a phase transition to form a gel or self-emulsifies to form micelles or emulsions upon contact with a small amount of water. In vitro performance studies of the formulation composition were conducted to compare and examine the effect of adding acid to the system on the microstructure of the formulation composition.

[0161] According to the formulation composition in Table 11-1, the prescribed amounts of sustained-release material, pharmaceutical excipient-grade oil, acid and solvent are stirred and dissolved completely at 75-80°C. Then, the prescribed amount of active pharmaceutical ingredient is added and stirred until a transparent and homogeneous solution is formed. The final formulation composition is obtained by cooling to room temperature.

[0162] Weigh an appropriate amount of the sustained-release composition precursor and slowly add it to pH 7.4 phosphate buffered saline (PBS). Observe the in vitro phase transition. After standing at room temperature, take an appropriate amount of sample, spread it on a glass slide, press it with a coverslip, observe and photograph it under a polarizing microscope, with a magnification of 10x.

[0163] Table 11-1 In vitro performance evaluation of different active pharmaceutical ingredient combinations

[0164]

[0165]

[0166] Depend on Figure 1 It was found that formulation compositions 1033, 1034, 1047, and 1048 all formed droplet or vesicle structures upon contact with the medium, and all exhibited lamellar liquid crystal properties under a polarizing microscope. The addition of acid to the formulation compositions did not alter their structural characteristics. The addition of acid to this formulation system significantly reduced the release of the active pharmaceutical ingredient, presumably due to changes in the interaction between the active pharmaceutical ingredient and the hydrophilic groups of the phospholipids after acid addition.

[0167] Example 12: In vivo pharmacokinetic study of the formulation composition

[0168] (1) Comparative preparation

[0169] Comparative Example-1: Ropivacaine Hydrochloride Injection

[0170] Weigh the prescribed amounts of ropivacaine hydrochloride and sodium chloride into a vial according to Table 12-1, add an appropriate amount of purified water, vortex and sonicate, dissolve and clarify to obtain a homogeneous solution, adjust the pH value to 4.0-6.0, and obtain ropivacaine hydrochloride injection.

[0171] Table 12-1 Ropivacaine Hydrochloride Injection

[0172] prescription Ratio (w / w) Ropivacaine Hydrochloride 2.38％ Sodium chloride 0.9％ Water for Injection Appropriate amount

[0173] Comparative Example-2: CN104427977B Predrug Liposome Formulation

[0174] According to Table 12-2, add the prescribed amounts of ropivacaine hydrochloride, lecithin (PL-90G), castor oil, and cysteine ​​hydrochloride to a pre-weighed round-bottom flask, weigh it, add excess anhydrous ethanol, and place the flask in a rotary evaporator water bath to heat until all components are completely dissolved, ensuring that the amount of anhydrous ethanol exceeds the final amount of the formulation; then evaporate under reduced pressure until the amount of anhydrous ethanol in the final formulation is approximately 6%. Transfer the contents of the flask to a vial and store at room temperature for later use.

[0175] Table 12-2 Precursor liposome formulations of patent CN104427977B

[0176] prescription Ratio (w / w) Ropivacaine hydrochloride monohydrate 4.78％ Lecithin PL-90G 53.91％ castor oil 35.21％ Anhydrous ethanol 6.0％ Cysteine ​​hydrochloride 0.1％

[0177] (2) In vivo administration of ropivacaine sustained-release composition

[0178] The pharmacokinetic study in rats was conducted as follows: Animals weighing approximately 200–230 g were randomly assigned to groups and uniquely identified by tail numbers. The drug was administered subcutaneously via injection into the neck and back of the rats. Blood samples were collected from the fundus venous plexus at 0 h before administration and at 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 10 h, 24 h, 32 h, 48 h, 56 h, and 72 h after administration into K2EDTA anticoagulant tubes and temporarily stored on ice until centrifugation. Plasma was centrifuged within 60 min after collection (at 8000 rpm for 5 min at 2–8°C). After centrifugation, the plasma was transferred to 96-well plates or centrifuge tubes, transported on wet ice, and stored at ≤-15°C for LC-MS / MS analysis. After blood collection, the animals were euthanized, and the subcutaneous tissue at the administration site was exposed to observe for possible adverse reactions.

[0179] Table 12-3 In vivo experimental dosage information for pharmaceutical compositions

[0180] Composition Number Dosage (mg / kg) Comparative Example 1 20 Composition 1033 20 Composition 1034 20

[0181] The pharmacokinetic (PK) parameters of the composition were calculated, and the results are shown in Table 12-4; the plasma concentration-time curves are shown in [Table 12-4]. Figure 2 and Figure 3 .

[0182] Table 12-4 PK parameters of pharmaceutical compositions

[0183] Composition Number Comparative Example 1 Composition 1033 Composition 1034 <![CDATA[C max (ng / mL)]]> 8928±8655 1526±631.5 95.06±28.20 <![CDATA[AUC last (mg / mL)]]> 5365±1532 6913±1512 2741±89.02 <![CDATA[AUC inf (mg / mL)]]> 5379±1545 6975±1508 3375±80.56

[0184] Depend on Figure 2 and Figure 3 The results showed that when a certain proportion of acid was added to the ropivacaine free base formulation, the C in animals was reduced. max The value was significantly reduced, consistent with the results of the in vitro release study; the acid-containing ropivacaine free base formulation exhibited a significant in vivo sustained-release effect, with an in vivo sustained-release time of over 72 hours, compared to only 48 hours for the non-acid-containing formulation; compared to Comparative Example-1 (ropivacaine hydrochloride injection) at the same dosage, the acid-containing formulation showed a significantly lower C value. max The value was only 1 / 94 of that. Furthermore, the acid-containing composition showed no inflammatory response in the animals after administration, indicating good safety.

[0185] (3) In vivo administration of the ropivacaine mesylate sustained-release composition

[0186] The pharmacokinetic study in rats was conducted as follows: Animals weighing approximately 200–230 g were randomly assigned to groups and uniquely identified by tail numbers. The drug was administered subcutaneously via the neck and back of the rats. Blood samples were collected from the fundus venous plexus at 0 h before administration and at 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 10 h, 24 h, 32 h, 48 h, 56 h, and 72 h after administration into K2EDTA anticoagulant tubes and temporarily stored on ice until centrifugation. Plasma was centrifuged within 60 min after collection (at 8000 rpm for 5 min at 2–8°C). After centrifugation, the plasma was transferred to 96-well plates or centrifuge tubes, transported on wet ice, and stored at ≤-15°C for LC-MS / MS analysis. After blood collection, the animals were euthanized, and the subcutaneous tissue at the administration site was exposed to observe for possible adverse reactions.

[0187] Table 12-5 In vivo experimental dosage information for pharmaceutical compositions

[0188] Composition Number Dosage (mg / kg) Comparative Example 2 20 Composition 1047 20 Composition 1048 20

[0189] The pharmacokinetic (PK) parameters of the composition were calculated, and the results are shown in Table 12-6; the plasma concentration-time curves are shown in [Table 12-6]. Figure 4 and Figure 5.

[0190] Table 12-6 PK parameters of pharmaceutical compositions

[0191] Composition Number Comparative Example 2 Composition 1047 Composition 1048 <![CDATA[C max (ng / mL)]]> 2696±2315 535.8±106.4 75.07±5.999 <![CDATA[AUC las t(h*ng / mL)]]> 6253±2226 4718±841.9 2198±950.5 <![CDATA[AUC inf (mg / mL)]]> 6293±2218 4782±852.7 2914±1896

[0192] Depend on Figure 4 and Figure 5 The results showed that after adding a certain proportion of acid to the ropivacaine mesylate formulation, the C in animals was reduced. max The value was significantly reduced, consistent with the results of the in vitro release study; the acid-containing composition exhibited a significant in vivo sustained-release effect, with an in vivo sustained-release time of over 72 hours. Compared with Comparative Example-2 (ropivacaine hydrochloride prodrug liposomes) at the same dosage, the acid-containing composition C max The value is only 1 / 36 of that. The formulation composition of the present invention has good safety and can meet the clinical need for long-acting postoperative analgesia.

Claims

1. An acid-containing sustained-release composition, comprising: a. Active pharmaceutical ingredient; b. Sustained-release carrier material; c. Phospholipids; d. Pharmaceutically acceptable acids; e. Pharmaceutically acceptable solvents.

2. The sustained-release composition according to claim 1, wherein: The active pharmaceutical ingredient includes one or more of bupivacaine, ropivacaine, levobupivacaine, mepivacaine, lidocaine free base, and pharmaceutically acceptable salts thereof; Preferred, pharmaceutically acceptable salts include, but are not limited to, one or more of the following: hydrochloride, mesylate, hydrobromide, hydroiodide, sulfate, citrate, tartrate, lactate, citrate, maleate, and fumarate. Preferably, the active pharmaceutical ingredient, calculated as the free base of the drug, accounts for 0.01% to 10.0% (w / w) of the total composition; more preferably 0.01% to 8%; more preferably 0.01% to 6%; and even more preferably 0.01% to 4%.

3. The sustained-release composition according to claim 1, wherein: The sustained-release carrier material is selected from one or more natural plant oils; Preferably, the natural vegetable oil is selected from one or more of castor oil, sesame oil, soybean oil, sunflower seed oil, peanut oil, corn oil, rapeseed oil, olive oil, and cottonseed oil; Preferably, the sustained-release carrier material is selected from one or more of medium-chain triglycerides, castor oil, sesame oil, and soybean oil; Preferably, the sustained-release carrier material accounts for about 10% to about 90% (w / w) of the total composition; more preferably 20% to 80%; more preferably 25% to 70%; more preferably 30% to 65%; more preferably 35% to 50%; and even more preferably 30% to 35%.

4. The sustained-release composition according to claim 1, wherein: Phospholipids are selected from hydrogenated soybean phospholipids, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearyl phosphatidylcholine, dilauroyl phosphatidylcholine, soybean lecithin (SPC), egg yolk phospholipid (EPC), rapeseed phospholipids, sunflower phospholipids, disqualyl lecithin, dioleoyl lecithin (DOPC), palmitoyl oleoyl lecithin, sphingomyelin, distearyl phosphatidic acid, dioleoyl phosphatidylethanolamine, dipalmitoyl phosphatidic acid, myristoyl lysophosphatidyl, palmitoyl lysophosphatidyl One or more of the following: phospholipids, 1-stearoyl-lysophosphatidylcholine, dipalmitoylphosphatidylethanolamine, distearylphosphatidylethanolamine, dioleoylphosphatidylglycerol, dimyristoylphosphatidylethanolamine, dimyristoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, 1-palmitoyl-2-oleoylphosphatidylglycerol, distearylphosphatidylglycerol, dipalmitoylphosphatidylserine, phosphatidylinositol, and cholesterol; preferably one or more of the following: soybean phospholipids, egg yolk phospholipids, and dioleoyl acyl lecithin. Preferably, the phospholipids account for about 10% to about 90% (w / w) of the total composition; more preferably 20% to 80%; more preferably 30% to 70%; more preferably 30% to 65%; more preferably 35% to 55%; and even more preferably 40% to 50%.

5. The sustained-release composition according to claim 1, wherein: Pharmaceutically acceptable acids are selected from one or more of acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, methanesulfonic acid, benzoic acid, caprylic acid, alanine, carbonic acid, sorbic acid, caprylic acid, nonanoic acid, lauric acid, palmitic acid, oleic acid, hydrochloric acid, phosphoric acid, phthalic acid, decanoic acid, myristic acid, propionic acid, butyric acid, heptanoic acid, valeric acid, malic acid, tartaric acid, oxalic acid, citric acid, ascorbic acid, salicylic acid, caffeic acid, glycolic acid, aspartic acid, glutamic acid, and vitamin E succinic acid; preferably one or more of lactic acid, citric acid, and maleic acid. Preferably, the pharmaceutically acceptable acid accounts for about 0.01% to about 10% (w / w) of the total amount of the formulation composition; more preferably 0.01% to 8%; more preferably 0.01% to 6%; even more preferably 0.01% to 5%.

6. The sustained-release composition according to claim 1, wherein: Pharmaceutically acceptable solvents are selected from one or more of alcohols, N-methylpyrrolidone, benzyl benzoate, dimethyl sulfoxide, and water for injection; Preferably, the alcohol is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, propylene glycol, glycerol, benzyl alcohol, phenethyl alcohol, and polyethylene glycol; Preferably, the pharmaceutically acceptable solvent is selected from one or more of ethanol, N-methylpyrrolidone, and dimethyl sulfoxide; Preferably, the pharmaceutically acceptable solvent accounts for about 0.01% to about 30% (w / w) of the total composition; more preferably 0.01% to 25%; more preferably 0.01% to 20%; more preferably 0.01% to 15%; and even more preferably 0.01% to 10%.

7. A method for preparing the sustained-release composition according to any one of claims 1-6, comprising: (a1) Dissolve the prescribed amount of active pharmaceutical ingredient, sustained-release carrier material, phospholipid, and pharmaceutically acceptable acid in a pharmaceutically acceptable solvent until homogeneous; (a2) Remove excess organic solvent from step (a1) by rotary evaporation or vacuum drying process; (a3) Add the drug solvent to the prescribed amount as needed, and mix well to obtain the final product; Or it may include the following steps: (b1) Dissolve the prescribed amount of sustained-release carrier material, phospholipids, and pharmaceutically acceptable acid in a pharmaceutically acceptable solvent under nitrogen protection until fully homogeneous; (b2) The prescribed amount of active pharmaceutical ingredient is added to solution b1 and heated and stirred under nitrogen protection until completely dissolved; (b3) Cool to room temperature; filter to obtain the final product; Preferably, it also includes dispensing, sterilization or sterilization steps; Preferably, sterilization is performed by filtration, and sterilization is performed by moist heat sterilization.

8. Use of the sustained-release composition according to any one of claims 1-6 in the preparation of a pain-relieving medicament, preferably, the sustained-release composition controllably modulates the duration of pain treatment to provide a long-lasting analgesic effect.

9. A sustained-release composition comprising any one of claims 1-6, characterized in that, The sustained-release composition is administered as a reservoir formulation, preferably by subcutaneous or intramuscular injection, incision infusion, incision infiltration, nerve plexus administration, or intra-articular injection.

10. The sustained-release composition of claim 9, wherein the formulation further comprises a packaging material filled with the formulation, the packaging material being selected from one or more of the following: vials, pre-filled syringes, and cartridges.

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