Reservoir type local anesthetic sustained-release composition as well as preparation method and application thereof

Abstract

The invention belongs to the field of pharmaceutics, and particularly relates to a depot type local anesthetic sustained-release composition as well as a preparation method and application thereof, and the depot type local anesthetic sustained-release composition comprises the following components: a, active pharmaceutical ingredients; b, a slow-release carrier material; c. A phospholipid; d. A pharmaceutically acceptable oil; and e. A pharmaceutically acceptable solvent, the new composition not only can maintain the long-acting slow-release effect of the preparation composition, but also accelerates the corrosion absorption of the preparation composition in the body, on one hand, promotes the complete release of the medicine, on the other hand, accelerates the absorption of the preparation, obviously improves the medication safety and bioavailability, and has the advantages of good slow-release effect, good physical and chemical stability and no toxic or side effect. An in-vivo animal experiment shows that no inflammatory reaction occurs at the administration part, the safety is good, and a wide clinical application prospect is achieved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutics, specifically relating to a reservoir-type sustained-release composition of local anesthetic, 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. Therefore, the clinical demand for long-acting local anesthetics has increased significantly, and the development of long-acting local anesthetics has become a research hotspot for pharmaceutical companies and research institutions both domestically and internationally. To date, no long-acting sustained-release formulations of ropivacaine have been successfully marketed domestically or internationally, while four long-acting sustained-release formulations of bupivacaine have been launched.

[0004] In November 2011, Pacira's bupivacaine multivesicular liposome (MVL) suspension injection was approved for marketing in the United States under the brand name [Brand Name - missing in original text]. Clinically, it is used to treat postoperative pain and nerve blocks, with analgesic effects lasting up to 24 hours. Multi-capsule liposomes can achieve high encapsulation rates of water-soluble drugs, thus offering better application advantages than traditional liposomes. Nevertheless, it still faces challenges such as complex preparation processes, difficulties in industrial production, and stringent requirements for storage and transportation.

[0005] On August 28, 2020, the FDA approved Innocoll's bupivacaine hydrochloride implant, brand name... Used for inguinal hernia repair in adults. Xaracoll uses... The technology uses a high-purity collagen matrix as a carrier, with the drug distributed within the pores of the matrix. As the collagen is slowly absorbed at the surgical site, the drug dissolves and diffuses throughout the body, achieving a slow-release effect. Xaracoll is placed directly into the surgical site during the procedure, releasing the drug immediately and continuously for 24 hours. However, due to the large volume of the corpus cavernosum, swelling at the incision site may occur. Furthermore, the larger surgical wound required limits the scope for future expansion of indications.

[0006] Bupivacaine gel solution (trade name: Posimir) was developed by Durect Inc. in the United States and approved by the FDA on February 2, 2021, for analgesia 72 hours after arthroscopic subacromial decompression surgery. Posimir uses... The formula contains bupivacaine, sucrose acetate isobutyrate (SAIB), and benzyl alcohol. Benzyl alcohol, an excipient used in the formula, is a restricted preservative and is prohibited for use in nerve blocks.

[0007] Bupivacaine / Meloxicam Extended-Release Solution (trade name: Developed by Heron Therapeutics, it was approved by the FDA on May 13, 2021. It is used to provide postoperative analgesia for up to 72 hours by instilling an IV into the soft tissue or around the joint in adult patients after bunion removal, open inguinal hernia repair, or total knee replacement. use This technology uses polyorthoesters (POE) as a sustained-release material to control the diffusion of the active ingredient at the surgical site, thereby regulating the release continuously and stably for 72 hours. However, the use of polyorthoesters as a sustained-release carrier may pose a risk of slow degradation at the administration site, and the clinical application process is relatively cumbersome and inconvenient for medical personnel.

[0008] Patent CN111655236A discloses a controlled-release drug composition comprising a biocompatible and biodegradable semi-solid gel, wherein the semi-solid gel comprises castor oil, a gelling agent, and bupivacaine. Because castor oil contains unsaturated fatty chains, there is a risk of oxidation during storage. Furthermore, due to the high proportion of castor oil, there is a risk of oil separation over extended storage time.

[0009] CN103142458B discloses a ropivacaine oil solution formulation composition, which has a simple formulation process and a certain sustained-release effect. The pharmaceutical composition involved in the examples is ropivacaine dissolved in a system composed of benzyl alcohol, benzyl benzoate, soybean oil, or castor oil. However, investigations have shown that this composition can cause inflammatory reactions at the injection site, potentially leading to neuroinflammatory risks, and also poses a certain risk of local irritation, thus presenting a safety hazard.

[0010] CN109316602A discloses a compound sustained-release drug delivery system composed of a local anesthetic, a nonsteroidal anti-inflammatory drug (NSAID), a solvent, and a sustained-release material. While it possesses certain sustained-release analgesic effects and wound-healing properties, the NSAID exhibits a capping effect and is prone to causing gastrointestinal adverse reactions, as well as neurotoxicity and cardiovascular toxicity. Furthermore, its high proportion of organic solvent (30-40%) can easily cause irritation at the injection site, posing a safety hazard.

[0011] CN108743952A discloses a sustained-release formulation of a local anesthetic with phospholipid-mixed solvent-oil as a carrier and its preparation method. It uses benzyl benzoate, ethanol and benzyl alcohol as solvents, with a total solvent content as high as 40-50%, which can easily cause irritation at the injection site and adverse systemic reactions, posing a safety hazard.

[0012] While currently approved or investigational sustained-release formulations exhibit some sustained-release effects, they suffer from drawbacks such as complex manufacturing processes, injection site irritation, significant safety risks, poor needle penetration, poor stability, and inconvenience in clinical use. There is an urgent clinical need to develop a long-acting sustained-release carrier system for local anesthetics that is simple to manufacture, possesses excellent sustained-release properties, significantly reduces side effects, and exhibits good stability, biocompatibility, and viscosity that can be adjusted according to the clinical route of administration. Summary of the Invention

[0013] During the research, this invention unexpectedly discovered that adding a small amount of a specific oil modifier to the sustained-release composition of a reservoir-type local anesthetic not only maintains the long-lasting sustained-release effect of the formulation composition but also accelerates its dissolution and absorption in vivo. This promotes complete drug release and accelerates absorption, significantly improving drug safety and bioavailability. Furthermore, the new formulation composition exhibits good physicochemical stability, suitable viscosity, and good needle penetration. In vivo pharmacokinetic and degradation studies also show that the in vivo efficacy of the formulation composition described in this invention is consistent with in vitro studies, significantly improving the sustained-release effect in vivo, without any inflammatory reaction at the administration site, demonstrating good safety, a phenomenon not previously reported in this field.

[0014] The composition described in this invention is a novel drug delivery system with high safety and long-lasting sustained-release effect, which has broad clinical application prospects and will surely become a powerful supplement to related formulations of clinical sustained-release drugs, increasing the selectivity of clinical medication.

[0015] More specifically, the present invention provides a sustained-release composition of a reservoir-type local anesthetic, comprising:

[0016] a. Active pharmaceutical ingredient;

[0017] b. Sustained-release carrier material;

[0018] c. Phospholipids;

[0019] d. Pharmaceutically acceptable oils;

[0020] e. Pharmaceutically acceptable solvents.

[0021] In some embodiments, the active pharmaceutical ingredient is one or more drugs selected from bupivacaine, ropivacaine, levobupivacaine, mepivacaine, lidocaine free base or pharmaceutically acceptable salts thereof. Preferably, the pharmaceutically acceptable salts include, but are not limited to, one or more of hydrochloride, mesylate, hydrobromide, hydroiodide, sulfate, citrate, tartrate, lactate, citrate, maleate, and fumarate.

[0022] In some embodiments, the active pharmaceutical ingredient accounts for 0.01% to 10.0% (w / w) of the total composition; preferably 0.5% to 8%; more preferably 1% to 5%; and more specifically 1%, 2%, 3%, 4%, and 5%.

[0023] In some embodiments, the sustained-release carrier material is selected from one or more of glyceryl monooleate, glyceryl monolinoleate, glyceryl dioleate, sorbitan monooleate, glyceryl trioleate, sorbitan fatty acid ester, phytanetriol, and oleyl glycerol, preferably one or more of sorbitan monooleate, glyceryl monooleate, and glyceryl dioleate.

[0024] In some embodiments, the sustained-release carrier material accounts for about 10% to about 90% (w / w) of the total composition; preferably 20% to 80%; more preferably 20% to 60%; more preferably 30% to 50%; even more preferably 35% to 45%; more specifically, the sustained-release carrier material accounts for 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of the total composition.

[0025] In some embodiments, the phospholipid is selected from hydrogenated soybean phospholipids, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearyl phosphatidylcholine, dilauryl phosphatidylcholine, soybean phospholipids, egg yolk phospholipids, rapeseed phospholipids, sunflower phospholipids, disqualoyl lecithin, dioleoyl lecithin, palmitoyl oleoyl lecithin, sphingomyelin, distearyl phosphatidic acid, dioleoyl phosphatidylethanolamine, dipalmitoyl phosphatidic acid, myristoyl lysophosphatidyl, and palmitoyl lysophosphatidyl One or more of the following: 1-stearoyl-lysophosphatidylcholine, dipalmitoylphosphatidylethanolamine, distearylphosphatidylethanolamine, dioleoylphosphatidylglycerol, dimyristoylphosphatidylethanolamine, dimyristoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, 1-palmitoyl-2-oleoylphosphatidylglycerol, distearylphosphatidylglycerol, dipalmitoylphosphatidylserine, phosphatidylinositol, and cholesterol, preferably one or more of soybean phospholipids, egg yolk phospholipids, and dioleoyl acyl lecithin.

[0026] In some embodiments, the phospholipids comprise about 10% to about 90% (w / w) of the total composition; preferably 20% to 80%; more preferably 20% to 60%; more preferably 30% to 50%; even more preferably 35% to 45%; and more specifically 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, and 60%.

[0027] In some embodiments, the ratio of the sustained-release carrier material to phospholipid is about 1:9 to 9:1; preferably 1:5 to 5:1; preferably 0.8:1 to 1.8:1, preferably 0.9:1 to 1.6:1; more preferably 1:1 to 1.5:1.

[0028] In some embodiments, the pharmaceutically acceptable oil is selected from soybean oil, castor oil, hydrogenated castor oil, sulfonated castor oil, polyoxyethylene castor oil, sesame oil, peanut oil, cottonseed oil, corn oil, olive oil, sunflower seed oil, cottonseed oil, almond oil, tea oil, palm oil, sea buckthorn oil, fish oil, garlic oil, safflower oil, medium-chain triglycerides, ethyl oleate, triacetin, medium- and long-chain oils, glyceryl monoacetate, benzyl benzoate, isopropyl myristate, and tributyl citrate. The oil is selected from one or more of the following: esters, alkyl (C12-C15) methylbenzyl esters, benzyl phenylacetate, ethyl octanoate, dibutyl gallate, ethyl gallate, propyl gallate, methyl myristate, isopentyl palmitate, ethyl propionate, isopentyl propionate, benzyl propionate, N-methyl-2-pyrrolidone, oleic acid and oleic acid esters, more preferably, pharmaceutically acceptable oils are selected from one or more of castor oil, soybean oil, sesame oil, corn oil, and medium-chain triglycerides.

[0029] In some embodiments, the pharmaceutically acceptable oil comprises about 0.01% to about 20% (w / w) of the total composition, preferably 0.01% to 15%, more preferably 0.01% to 10%, and more specifically, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, and 10%.

[0030] In some embodiments, the pharmaceutically acceptable solvent is 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.

[0031] In some embodiments, 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%, more preferably 0.01% to 15%, more preferably 0.01% to 10%, and more specifically, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, and 10%.

[0032] In some embodiments, when the active pharmaceutical ingredient is ropivacaine hydrochloride and the pharmaceutically acceptable oil is sesame oil, the active pharmaceutical ingredient (calculated as free base) accounts for 0.01% to 2% of the total composition, and the pharmaceutically acceptable oil accounts for 0.01% to 10% of the total composition; when the active pharmaceutical ingredient is ropivacaine hydrochloride, the active pharmaceutical ingredient (calculated as free base) accounts for 0.01% to 2% of the total composition, and the pharmaceutically acceptable oil is soybean oil, medium-chain triglycerides, or castor oil, the pharmaceutically acceptable oil accounts for 0.01% to 5% of the total composition.

[0033] In some embodiments, when the active pharmaceutical ingredient is ropivacaine and the pharmaceutically acceptable oil is soybean oil, medium-chain triglycerides, or sesame oil, the active pharmaceutical ingredient accounts for 0.01% to 2% of the total composition, and the pharmaceutically acceptable oil accounts for 0.01% to 10% of the total composition.

[0034] In some embodiments, when the active pharmaceutical ingredient is ropivacaine mesylate and the pharmaceutically acceptable oil is sesame oil, the active pharmaceutical ingredient (calculated as free base) accounts for 0.01% to 3.5% of the total composition, and the pharmaceutically acceptable oil accounts for 0.01% to 4% of the total composition; when the active pharmaceutical ingredient is ropivacaine mesylate and the pharmaceutically acceptable oil is castor oil, the active pharmaceutical ingredient (calculated as free base) accounts for 0.01% to 3% of the total composition, and the pharmaceutically acceptable oil accounts for 0.01% to 5% of the total composition.

[0035] In some embodiments, when the active pharmaceutical ingredient is bupivacaine and the pharmaceutically acceptable oil is a medium-chain triglyceride or sesame oil, the active pharmaceutical ingredient accounts for 0.01% to 2% of the total composition, and the pharmaceutically acceptable oil accounts for 0.01% to 10% of the total composition.

[0036] In some embodiments, when the active pharmaceutical ingredient is bupivacaine hydrochloride and the pharmaceutically acceptable oil is sesame oil or soybean oil, the active pharmaceutical ingredient (calculated as free base) accounts for 0.01% to 2% of the total composition, and the pharmaceutically acceptable oil accounts for 0.01% to 5% of the total composition.

[0037] In some embodiments, the sustained-release composition further comprises f. a pharmaceutically acceptable acid.

[0038] In some embodiments, 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.

[0039] In some embodiments, the pharmaceutically acceptable acid accounts for about 0.01% to about 10% (w / w) of the total composition, preferably 0.01% to 5%, more preferably 0.01% to 3%, and more specifically 0.5%, 1%, 2%, and 3%.

[0040] In some embodiments, the sustained-release composition further comprises g. a pharmaceutically acceptable antioxidant or stabilizer.

[0041] In some embodiments, the antioxidant or stabilizer is selected from one or more of vitamin C, cysteine ​​or its hydrochloride, α-tocopherol, α-tocopherol acetate, ascorbyl palmitate, glutathione, alpha-lipoic acid, thioglycerol, N-acetyl-L-cysteine, butylated hydroxyanisole, propyl gallate, tert-butylhydroquinone, and butylated hydroxytoluene, wherein the antioxidant or stabilizer is preferably ascorbyl palmitate.

[0042] In some embodiments, the pharmaceutically acceptable antioxidant accounts for 0.01% to 5% (w / w) of the total composition; preferably 0.05% to 1%; more preferably 0.1% to 0.5%; and more specifically 0.1%, 0.2%, 0.3%, 0.4%, and 0.5%.

[0043] In some embodiments, the pharmaceutically acceptable stabilizer comprises 0.01% to 5% (w / w) of the total composition; preferably 0.05% to 1%; more preferably 0.1% to 0.5%; and more specifically 0.1%, 0.2%, 0.3%, 0.4%, and 0.5%.

[0044] In another aspect, the present invention provides a method for preparing a sustained-release composition of a reservoir-type local anesthetic as described in any one of the above claims, characterized by comprising the following steps:

[0045] (a1) Dissolve the prescribed amount of active pharmaceutical ingredient, sustained-release carrier material, phospholipid, and pharmaceutically acceptable oil in a pharmaceutically acceptable solvent until homogeneous;

[0046] (a2) Remove excess organic solvent from step (a1) by rotary evaporation or vacuum drying process;

[0047] (a3) Add the drug solvent to the prescribed amount as needed, and mix well to obtain the final product;

[0048] Or it may include the following steps:

[0049] (b1) Dissolve the prescribed amount of sustained-release carrier material, phospholipids, and pharmaceutically acceptable oil in a pharmaceutically acceptable solvent under nitrogen protection until fully homogeneous;

[0050] (b2) The prescribed amount of active pharmaceutical ingredient is added to solution b1 and heated and stirred under nitrogen protection until completely dissolved;

[0051] (b3) Cool to room temperature; filter to obtain the final product;

[0052] Preferably, steps (a1) and (b1) may further include the addition of a pharmaceutically acceptable amount of a pharmaceutically acceptable acid, a pharmaceutically acceptable antioxidant, or a stabilizer.

[0053] In some embodiments, the process also includes dispensing, sterilization, or disinfection steps. Preferably, sterilization is performed by filtration, and disinfection is performed by moist heat sterilization.

[0054] In another aspect, the present invention 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 controllably modulates the duration of pain treatment, providing a long-lasting analgesic effect.

[0055] In some embodiments, 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.

[0056] In some embodiments, 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.

[0057] The pharmaceutical composition provided by this invention is a clear, transparent, oily solution. In the pharmaceutical composition of this invention, the pharmaceutically acceptable solvent can act as a viscosity modifier, making the composition suitable for injection or local perfusion administration. In some embodiments, the viscosity of the formulation composition is less than 10,000 mPa·s at 25°C. In some embodiments, the viscosity of the composition at 25°C is in the range of 10 to 5,000 mPa·s. In some embodiments, the viscosity of the composition at 25°C is in the range of 50 to 6,000 mPa·s.

[0058] Terms and Abbreviations

[0059] 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.

[0060] 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.

[0061] 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.

[0062] Unless otherwise stated, all figures used in this specification and claims to indicate content, concentration, proportion, weight, percentage, technical effect, etc., shall in any instance be understood to be modified by the terms “about” or “approximately”. “About” represents a range of ±10% of the value it modifies.

[0063] Therefore, unless otherwise indicated, the numerical parameters listed in the following description and appended claims are approximate values. Unless otherwise stated, the terminology used herein has its common meaning as understood by one of ordinary skill in the art. It will be apparent to those skilled in the art that it may vary depending on the desired properties and effects sought through this disclosure, and each numerical parameter should be interpreted according to the number of significant figures and conventional rounding methods or as understood by one of ordinary skill in the art.

[0064] Although the numerical ranges and parameters illustrating the broad scope of the invention are approximate, the values ​​presented in the specific embodiments are provided as precisely as possible. However, any numerical value will inherently contain some errors, which are necessarily caused by the standard deviation found in its corresponding test measurements. Each numerical range given in this specification will include every narrower numerical range falling within that wider range, as if these narrower numerical ranges were explicitly stated herein.

[0065] Unless otherwise stated, the definitions of excipients recorded in this application specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific excipients in embodiments, can be arbitrarily combined and combined with each other. Such combinations and combinations of excipients shall fall within the scope of this application specification.

[0066] The term "biocompatibility" refers to the interaction between the components of a composition and the body.

[0067] 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; GDO is dioleoglyceride; GMO is monooleoglyceride; GMLO is monolinoleoglyceride; SMO is Span 80; SPC is soybean lecithin; EPC is egg yolk lecithin; DOPC is dioleoyl lecithin; HSPC is hydrogenated soybean lecithin; DMPC is dimyristoyl phosphatidylcholine.

[0068] The antioxidants and stabilizers described in this invention have the same definition and play the same or similar functions in this invention.

[0069] Beneficial effects

[0070] (1) Through extensive research, this invention prepares local anesthetics into in-situ gel injections to prolong the release time and analgesic effect of local anesthetics, providing a novel long-acting in-situ gel precursor solution for local anesthetics.

[0071] (2) The reservoir-type sustained-release composition of the present invention has a significant long-term sustained-release effect, can meet the requirements of long-term analgesia (more than 72 hours), and has a low burst release rate, which can reduce the number of administrations, has good compliance, and can avoid peak and trough phenomena and has few adverse reactions.

[0072] (3) The in-situ gel prepared using the same carrier material as the present invention has slow absorption and metabolism in vivo and long retention time, which poses a significant safety risk. The inventors unexpectedly discovered that by adding a certain proportion of a specific oil regulator to the precursor solution formulation, it can not only maintain the long-lasting sustained-release effect and good stability of the formulation composition, but also accelerate the dissolution and absorption of the formulation in vivo, reduce the body's inflammatory response, and promote complete drug release, thereby improving the safety of medication and the bioavailability of the drug.

[0073] (4) The new formulation composition has good physicochemical stability, suitable viscosity, and good needle penetration. The reservoir-type 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.

[0074] (5) The reservoir-type sustained-release composition of local anesthetic of the present invention can be prepared by simple melting, mixing or rotary evaporation steps. Compared with the existing long-acting formulations of local anesthetics, the preparation method is simple and easy to implement, which is conducive to industrial production. Attached Figure Description

[0075] Figure 1 The morphological observation of different oil-containing formulations after in vitro phase transition under a polarized light microscope.

[0076] Figure 2 This is a polarized light microscope observation of the morphology of different active pharmaceutical ingredients containing sesame oil after in vitro phase transition.

[0077] Figure 3 These are the plasma concentration-time curves of formulation compositions 1033 and 1034 for ropivacaine.

[0078] Figure 4 The results were obtained by anatomical observation 72 hours after subcutaneous injection of formulations 1033 and 1034 into rats.

[0079] Figure 5 These are the plasma concentration-time curves of ropivacaine hydrochloride formulations 1011 and 1012.

[0080] Figure 6 The results were obtained by anatomical observation 72 hours after subcutaneous injection of formulations 1011 and 1012 into rats.

[0081] Figure 7 These are the plasma concentration-time curves of formulation compositions 1045 and 1046, ropivacaine mesylate.

[0082] Figure 8 The results were obtained by anatomical observation 72 hours after subcutaneous injection of formulations 1045 and 1046 into rats. Detailed Implementation

[0083] 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.

[0084] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0085] Example 1: Investigation of Oil Type and Dosage

[0086] Using ropivacaine hydrochloride as a model drug, the effects of the type and amount of commonly used pharmaceutical excipient-grade oil on the performance of ropivacaine hydrochloride formulation compositions were investigated. According to the formulation composition in Table 1-1, the prescribed amounts of sustained-release material, phospholipids, pharmaceutical-grade oil, acid, and solvent were completely dissolved by magnetic stirring at 70–80°C. Then, the prescribed amount of the active pharmaceutical ingredient was added, and stirring continued until a clear, homogeneous solution was formed. The final formulation composition was obtained by cooling to room temperature.

[0087] Table 1-1 Evaluation of Formulation Compositions Using Different Types of Oils and Dosages

[0088]

[0089] Take about 0.2g of the formulation composition in Table 1-1 and place it in a 50ml centrifuge tube containing 30ml of phosphate buffer (pH=6.5). Shake at 100rpm at 37℃. Take samples at 24h and 72h to detect the cumulative drug release content. The results are shown in Table 1-2.

[0090] Table 1-2 In vitro release results of compositions containing different types of oil preparations

[0091] Composition Number 24h(％) 72h(％) endpoint gel softness Remark 1001 3.49 5.06 firm gel / 1002 1.64 4.31 Soft gel No significant effect on release 1003 3.29 5.24 Soft gel No significant effect on release 1004 17.62 41.22 Soft gel Significantly accelerate release 1005 3.55 8.28 Soft gel No significant effect on release 1006 7.30 17.68 Soft gel Significantly accelerate release 1007 5.24 11.44 Soft gel No significant effect on release 1008 2.76 4.51 Soft gel No significant effect on release 1009 6.45 10.35 Soft gel No significant effect on release 1010 29.17 64.57 Soft gel Significantly accelerate release 1011 5.45 10.35 firm gel / 1012 1.98 2.92 Soft gel No significant effect on release 1013 1.98 4.13 Soft gel No significant effect on release

[0092] The results showed that when the mass percentages of soybean oil, MCT, and castor oil were in the range of 0–5%, the hardness of the gel formed after the formulation composition came into contact with the release medium was significantly reduced, while the in vitro release rate of ropivacaine hydrochloride was not significantly affected. When the oil content in the formulation exceeded 5%, although the gel hardness of the formulation decreased, the in vitro release of the active pharmaceutical ingredient was significantly accelerated. When the mass percentage of sesame oil was in the range of 0–10%, it had no significant effect on the in vitro release of ropivacaine hydrochloride and could significantly reduce the hardness of the gel formed after the formulation composition came into contact with the release medium. When the mass percentage exceeded 10%, the in vitro release of the formulation was significantly accelerated.

[0093] Example 2: Investigation of different types of sustained-release material compositions

[0094] Using ropivacaine hydrochloride as a model drug, the effects of different types of sustained-release materials on the performance of ropivacaine formulation compositions were investigated. According to Tables 2-1 and 2-3, the prescribed amounts of sustained-release materials, phospholipids, feed-grade oil, acid, and solvent 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.

[0095] Approximately 0.2 g of the formulation compositions listed in Tables 2-1 and 2-3 were placed in 50 ml centrifuge tubes containing 30 ml of phosphate buffer (pH = 6.5) and shaken at 100 rpm at 37 °C. Samples were taken at 24 h and 72 h to detect the cumulative drug release content. The results are shown in Tables 2-2 and 2-4.

[0096] (1) Investigation of Phospholipid Types

[0097] Table 2-1 Evaluation of different types of phospholipid formulations

[0098]

[0099]

[0100] Table 2-2 In vitro cumulative release results of compositions containing different types of phospholipids

[0101] Composition Number 24h(％) 72h(％) 1009 6.45 10.35 1015 34.71 48.71 1016 6.97 15.92 1018 73.48 92.32

[0102] The results showed that replacing the phospholipid SPC in the formulation composition with DOPC had no significant effect on the in vitro release of ropivacaine hydrochloride; replacing it with EPC or DMPC significantly accelerated the in vitro release of ropivacaine hydrochloride; and replacing it with HSPC failed to yield a homogeneous formulation composition.

[0103] (2) Investigation of oil-oil sustained-release materials

[0104] Table 2-3 Evaluation of Formulation Compositions Using Different Types of Oil-Release Materials

[0105]

[0106] Table 2-4 In vitro release results of different types of oil-release material formulations

[0107] Composition Number 24h(％) 72h(％) 1019 4.30 5.89 1020 1.98 4.13 1021 8.50 12.77 1022 6.09 10.81

[0108] The results showed that when the sustained-release material SMO in the formulation was replaced with GDO, GMO, or GMLO, there was no significant effect on the in vitro release of ropivacaine hydrochloride.

[0109] Example 3: Investigation of compositions containing different proportions of sustained-release materials

[0110] Using ropivacaine hydrochloride as a model drug, SPC and SMO were selected as sustained-release materials to investigate the effect of different proportions of sustained-release materials on the performance of the formulation composition. According to Table 3-1, the prescribed amounts of sustained-release materials, phospholipids, pharmaceutical excipient-grade oil, acid, and solvent 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.

[0111] Take about 0.2g of the formulation composition in Table 3-1 and place it in a 50ml centrifuge tube containing 30ml of phosphate buffer (pH=6.5). Shake at 100rpm at 37℃. Take samples at 24h and 72h to detect the cumulative drug release content. The results are shown in Table 3-2.

[0112] Table 3-1 Evaluation of the proportion of different sustained-release materials in the formulation composition

[0113]

[0114] Table 3-2 In vitro release results of different types of oil-based sustained-release material formulations

[0115] Composition Number 24h(％) 72h(％) 1009 6.45 10.35 1023 90.23 90.89 1024 81.48 87.23 1025 8.21 15.23 1026 19.44 36.14

[0116] The results showed that when the mass ratio of sustained-release material to phospholipid was in the range of 1:1 to 1.5:1, ropivacaine hydrochloride had the best in vitro release effect, and there was no significant difference in the gel formed after the formulation composition came into contact with the release medium.

[0117] Example 4: Investigation of Compositions with Different Solvents

[0118] Using ropivacaine hydrochloride as a model drug, the effects of different types of solvents on the performance of the formulation composition were investigated. According to Table 4-1, the prescribed amounts of sustained-release material, pharmaceutical excipient-grade oil, acid, and solvent 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.

[0119] Table 4-1 Evaluation of formulation compositions using different solvents

[0120]

[0121] Take about 0.2g of the formulation composition in Table 4-1 and place it in a 50ml centrifuge tube containing 30ml of phosphate buffer (pH=6.5). Shake at 100rpm at 37℃. Take samples at 24h and 72h to detect the cumulative drug release content. The results are shown in Table 4-2.

[0122] Table 4-2 In vitro release results of formulation compositions under different solvents

[0123] Composition Number 24h(％) 72h(％) 1027 3.56 6.88 1028 3.89 7.69 1009 6.45 10.35 1029 6.31 10.73 1030 6.93 12.41 1031 3.80 5.97 1032 3.88 5.68

[0124] The results showed that the proportion of ethanol in the formulation had no significant effect on the release of ropivacaine hydrochloride in the range of 0-20%. With the increase of the proportion of ethanol in the formulation, the dissolution rate of the formulation was significantly accelerated during preparation. Replacing ethanol in the formulation with DMSO and NMP had no effect on the release of ropivacaine hydrochloride, but the dissolution rate of the formulation was slowed down during preparation.

[0125] Example 5: Investigation on the preparation of ropivacaine sustained-release composition

[0126] According to the formulation composition in Table 5-1, the prescribed amounts of sustained-release material, phospholipids, pharmaceutical excipient-grade oil, acid and solvent 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.

[0127] Table 5-1 Ropivacaine Free Base Formulation Compositions

[0128]

[0129]

[0130] Take about 0.2g of the formulation composition in Table 5-1 and place it in a 50ml centrifuge tube containing 30ml of phosphate buffer (pH=6.5). Shake at 100rpm at 37℃. Take samples at 24h and 72h to detect the cumulative drug release content. The results are shown in Table 5-2.

[0131] Table 5-2 In vitro release results of ropivacaine free base formulations

[0132]

[0133] The results showed that in acid-containing compositions, when the mass percentages of soybean oil, MCT, and sesame oil were in the range of 0–10%, they had no significant effect on the in vitro release of ropivacaine free base and could significantly reduce the hardness of the gel formed by the formulation composition. When the mass percentage of oil in the formulation was >10%, although the hardness of the formulation gel decreased, the in vitro release of the active ingredient was significantly accelerated. The sustained-release effect of the same mass percentage of castor oil formulation was poor. Increasing the drug loading of the active ingredient significantly accelerated the in vitro release.

[0134] Example 6: Investigation on the preparation of ropivacaine mesylate sustained-release composition

[0135] According to the formulation composition in Table 6-1, the prescribed amounts of sustained-release material, phospholipids, 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.

[0136] Table 6-1 Ropivacaine Mesylate Preparations and Compositions

[0137]

[0138]

[0139] 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 24h and 72h to detect the cumulative drug release content. The results are shown in Table 6-2.

[0140] Table 6-2 In vitro release results of ropivacaine mesylate formulations

[0141]

[0142] The results showed that when the sustained-release material was GDO, the mass percentages of sesame oil and castor oil were in the ranges of 0–4% and 0–5%, respectively, which had no significant effect on the in vitro release of ropivacaine mesylate, while the gel hardness of the formulation decreased. When the mass percentages of sesame oil and castor oil were >4% and >5%, respectively, although the gel hardness of the formulation decreased significantly, the in vitro release of the active pharmaceutical ingredient was significantly accelerated, resulting in poor sustained-release effect. When the sustained-release material was SMO, the mass percentage of sesame oil was in the range of 0–10%, which had no significant effect on the in vitro release of ropivacaine mesylate, while the gel hardness of the formulation decreased.

[0143] Example 7: Investigation on the preparation of bupivacaine sustained-release composition

[0144] According to the formulation composition in Table 7-1, the prescribed amounts of sustained-release material, phospholipids, pharmaceutical excipient-grade oil, acid and solvent are completely dissolved by magnetic stirring at 70-80°C. Then, the prescribed amount of bupivacaine is added and stirred until a clear and homogeneous solution is formed. The final formulation composition is obtained by cooling to room temperature.

[0145] Table 7-1 Bupivacaine Formulation Compositions

[0146]

[0147] 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 24h and 72h to detect the cumulative drug release content. The results are shown in Table 7-2.

[0148] Table 7-2 In vitro release results of bupivacaine formulations

[0149]

[0150] The results showed that in acid-containing compositions, when the mass percentage of sesame oil and MCT was in the range of 0-10%, it had no significant effect on the in vitro release of bupivacaine free base, while significantly reducing the hardness of the gel formed after the formulation composition came into contact with the medium; increasing the drug loading of the active ingredient; and significantly accelerating the in vitro release.

[0151] Example 8: Investigation on the preparation of bupivacaine hydrochloride sustained-release composition

[0152] According to the formulation composition in Table 8-1, the prescribed amounts of bupivacaine hydrochloride, sustained-release material, phospholipid, oil, acid and organic solvent are stirred and dissolved completely under high temperature conditions. Then, the prescribed amount of bupivacaine hydrochloride is added and stirred to form a transparent and homogeneous solution. The solution is then cooled to room temperature to obtain the final formulation composition.

[0153] Table 8-1 Bupivacaine Hydrochloride Formulation Compositions

[0154]

[0155] 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 24h and 72h to detect the cumulative drug release content. The results are shown in Table 8-2.

[0156] Table 8-2 In vitro release results of bupivacaine hydrochloride formulations

[0157]

[0158] The results showed that when the mass percentage of sesame oil and soybean oil was in the range of 0-5%, it had no significant effect on the in vitro release of bupivacaine hydrochloride and reduced the gel hardness of the formulation. When the mass percentage of oil in the formulation was >5%, although the gel hardness of the formulation was significantly reduced, the in vitro release of the active ingredient was significantly accelerated and the sustained-release effect was poor.

[0159] Example 9: In vitro phase transition performance of the drug sustained-release composition

[0160] The sustained-release drug composition prepared in this invention undergoes a phase transition to form a gel upon contact with a small amount of water; therefore, an in vitro phase transition study was conducted. Following the formulation composition in Table 9-1, using ropivacaine hydrochloride as the active ingredient, the effects of different types and amounts of oil on the in vitro phase transition properties of the formulation composition were investigated. The specific process is as follows: the prescribed amounts of sustained-release material, phospholipids, pharmaceutical-grade oil, acid, and solvent were stirred and completely dissolved at 75–80°C. Then, the prescribed amount of the active ingredient was added, and the mixture was stirred until a clear, homogeneous solution was formed. The solution was then cooled to room temperature to obtain the final formulation composition.

[0161] 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 the liquid crystal gel sample formed after the complete phase transition, spread it on a glass slide, press it with a coverslip, observe and photograph it under a polarizing microscope, with a magnification of 10x.

[0162] Table 9-1 In vitro phase transition studies of compositions containing different oil preparations

[0163]

[0164] Depend on Figure 1It can be seen that compositions 1001, 1003, and 1007 exhibit obvious polarization textures, anisotropy, and typical liquid crystal structures, indicating that the addition of 5% by mass of soybean oil and castor oil did not alter the liquid crystal properties of the formulation. Compositions 1005, 1008, and 1009 show a small amount of polarization textures, indicating that the addition of 5% by mass of MCT and 5-10% by mass of sesame oil has a certain impact on the overall liquid crystal structure. When the sesame oil content reaches 15%, the liquid crystal structure of the entire formulation is disrupted, and a large amount of oily substance is visible. Different types of oil have different effects on the phase transition properties of the formulation, presumably related to differences in oil chain length, saturation / unsaturation, and viscosity.

[0165] Based on the prescriptions in Table 9-1, sesame oil was used as an oil regulator to further investigate the in vitro phase transition properties of formulations containing different active pharmaceutical ingredients. The corresponding prescriptions are shown in Table 9-2.

[0166] Table 9-2 In vitro phase transition studies of different active pharmaceutical preparations containing sesame oil

[0167]

[0168] from Figure 2 It can be seen that the oil-free formulations 1033, 1011, and 1064 have obvious polarization textures, exhibit anisotropy, and have typical liquid crystal structures. When observed under a polarizing microscope, compositions 1034, 1012, 1013, and 1045 show a small amount of polarization textures, indicating that the addition of 4-10% by weight of sesame oil has a certain influence on the internal structure arrangement of the liquid crystal in the formulations, but does not destroy the properties of the liquid crystal.

[0169] Example 10: In vitro corrosion study of the sustained-release drug composition

[0170] The key properties of reservoir formulations are related to the degree of gel tolerance to erosion / fragmentation caused by endogenous surfactants and / or lipid-degrading enzymes. An indicator for evaluating the in vitro erosion resistance of a formulation can be the difference in gel weight after the lipid gel has been eroded in a surfactant-rich aqueous environment.

[0171] According to the formulation composition in Table 10-1, with ropivacaine hydrochloride as the main drug, the effects of different types and amounts of oil on the in vitro dissolution behavior of the formulation composition were investigated. The specific process is as follows: The prescribed amount of sustained-release material, phospholipid, pharmaceutical excipient grade oil, acid and solvent were stirred and dissolved completely at 75-80℃. Then, the prescribed amount of the main drug was added and stirred until a transparent and homogeneous solution was formed. The final formulation composition was obtained by cooling to room temperature.

[0172] Take about 0.20g of the formulation composition and inject it into a 50ml centrifuge tube containing 30mL of 0.5% Tween-80PBS buffer solution using a syringe. Shake at 100rpm at 37°C for 24 hours. Take out the residual formulation from the centrifuge tube and weigh it. Calculate the percentage of residual formulation by comparing it with the initial formulation weight.

[0173] Table 10-1 In vitro corrosion investigation of different types of oils and dosage formulations

[0174]

[0175] The results showed that, in oil-free formulations, the addition of 5% by weight of soybean oil and castor oil, respectively, resulted in good in vitro sustained-release effects, but the in vitro dissolution was relatively slow. Unexpectedly, the addition of 5% by weight of MCT and 5-10% by weight of sesame oil not only maintained good in vitro sustained-release effects but also significantly accelerated in vitro dissolution. When the sesame oil content reached 15%, the formulation dissolved rapidly, but the sustained-release effect was poor. These in vitro dissolution results were largely consistent with the observed structures related to in vitro phase transitions, suggesting that differences in oil chain length, saturation / unsaturation, and viscosity among different types of oil affect the liquid crystal gel structure in different ways, leading to performance differences among different formulations.

[0176] Based on the prescriptions in Table 10-1, sesame oil was used as an oil regulator to further investigate the in vitro dissolution behavior of different active pharmaceutical ingredients. The corresponding prescriptions are shown in Table 10-2.

[0177] Table 10-2 In vitro corrosion investigation of different active pharmaceutical preparations containing sesame oil

[0178]

[0179] The results showed that adding 10% by weight of sesame oil to the ropivacaine and ropivacaine hydrochloride formulations not only maintained good in vitro sustained-release effects but also significantly accelerated in vitro dissolution. Adding 4% sesame oil to the mesylate formulations resulted in rapid dissolution and good sustained-release effects. When the sesame oil content in the formulation was greater than 5% by weight, although the formulations dissolved rapidly, the sustained-release effect was poor. These in vitro dissolution results were largely consistent with the observed structures from in vitro phase transitions, indicating that the addition of sesame oil altered the liquid crystal gel structure of the formulations.

[0180] Example 11 Viscosity determination of drug sustained-release composition

[0181] The formulation compositions containing different active pharmaceutical ingredients, different sustained-release materials, phospholipids, different proportions of oil, and different amounts of solvent were prepared according to the formulation composition in Table 11-1. The specific process is as follows: The raw materials and excipients in the prescribed amounts were mixed and stirred at 75-80℃ until a transparent and homogeneous solution was formed. The solution was then cooled to room temperature to obtain the final formulation composition. The viscosity of the formulation composition was measured using a viscometer equipped with a No. 14 rotor at a temperature of 25℃ and a rotation speed of 40 rpm. The viscosity test results are shown in Table 11-1 below.

[0182] Table 11-1 Results of viscosity determination for different formulation compositions

[0183]

[0184] The results showed that adding a certain proportion of pharmaceutical oil to the formulation composition could significantly reduce the viscosity of the formulation; adjusting the proportion of organic solvents in the formulation composition could significantly regulate the viscosity of the formulation. Formulation compositions with different viscosity ranges can meet the clinical requirements for both injection and perfusion administration routes.

[0185] Example 12: Investigation of the push-pull force and needle penetration properties of the drug sustained-release composition

[0186] According to the formulation composition in Table 12-1, formulation compositions containing different active pharmaceutical ingredients, different sustained-release materials, phospholipids, different proportions of oil, and different amounts of solvent were prepared. The specific process is as follows: Under conditions of 75-80℃, the prescribed amounts of raw materials and excipients were mixed and stirred until a transparent and homogeneous solution was formed, and then cooled to room temperature to obtain the final formulation composition.

[0187] Approximately 1 g of the formulation composition described in Table 12-1 was injected into a 1 ml syringe, and the maximum push-pull force was measured using a digital push-pull force gauge (model: SF-50). Another approximately 0.2 g of the formulation composition was injected into a 1 ml syringe, and needle penetration was assessed by manual injection. The results of the maximum push-pull force and needle penetration tests for the formulation composition are shown in Table 12-1.

[0188] Table 12-1 Results of the investigation on maximum push-pull force and needle penetration of different formulation compositions

[0189]

[0190]

[0191] For the convenience of doctors administering medication, the maximum thrust for clinical administration of medication via needles is usually not greater than 2 kg.

[0192] The results showed that adding a certain proportion of pharmaceutical oil to the formulation composition could significantly reduce the push-pull force of the formulation; increasing the proportion of organic solvents in the formulation composition could also significantly reduce the push-pull force. By adjusting the proportions of the components in the formulation composition, the clinical requirements for injection and perfusion administration routes can be met.

[0193] Example 13 Comparison of physical stability of oil-containing and oil-free systems

[0194] The formulation composition was prepared according to the formulation in Table 13-1. The specific process is as follows: The prescribed amounts of raw materials and excipients were mixed and stirred at 75–80°C until a clear, homogeneous solution was formed. The solution was then cooled to room temperature to obtain the final formulation composition. The obtained formulation composition was stored at 5°C, and its appearance was observed periodically. The results of the physical stability study are shown in Table 13-1.

[0195] Table 13-1 Oil-containing and oil-free formulation compositions for evaluation

[0196]

[0197]

[0198] The results showed that the excipient GDO would physically precipitate out during low-temperature storage in the oil-free formulation; unexpectedly, adding a certain proportion of oil to the formulation significantly improved the physical stability of the formulation composition.

[0199] Example 14: In vivo pharmacokinetics and degradation study of the drug sustained-release composition.

[0200] (1) Comparative preparation

[0201] Comparative Example-1: Ropivacaine Hydrochloride Injection

[0202] Weigh the prescribed amounts of ropivacaine hydrochloride and sodium chloride into a vial according to Table 14-1, 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.

[0203] Table 14-1 Ropivacaine Hydrochloride Injection

[0204] prescription Quality percentage (%) Ropivacaine Hydrochloride 2.38 Sodium chloride 0.9 Water for Injection Appropriate amount

[0205] Comparative Example-2: CN104427977B Predrug Liposome Formulation

[0206] According to Table 14-2, 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 vials and store at room temperature for later use.

[0207] Table 14-2 Precursor liposome formulations of patent CN104427977B

[0208] prescription Quality percentage (%) Ropivacaine hydrochloride monohydrate 4.78 Lecithin PL-90G 53.91 castor oil 35.21 Anhydrous ethanol 6.0 Cysteine ​​hydrochloride 0.1

[0209] (2) In vivo administration of ropivacaine sustained-release composition

[0210] The pharmacokinetic study in rats was conducted as follows: Animals weighing approximately 200–230 g were randomly grouped and uniquely identified by tail number. 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.

[0211] Animals were euthanized 72 hours after administration, and the subcutaneous tissue at the administration site was exposed to observe for possible adverse reactions. All residual formulations were then collected, weighed, and the amount of active pharmaceutical ingredient residue was determined.

[0212] Information on the dosage and administration of the drug is shown in Table 14-3.

[0213] Table 14-3 In vivo experimental dosage information for pharmaceutical compositions

[0214] Composition Number Dosage (mg / kg) Comparative Example 1 20 Composition 1033 20 Composition 1034 20

[0215] The pharmacokinetic (PK) parameters of the composition were calculated, and the results are shown in Table 14-4; the blood concentration-time curve is shown in Figure 3.

[0216] Table 14-4 PK parameters of pharmaceutical compositions

[0217] Composition Number Comparative Example 1 Composition 1033 Composition 1034 Cmax(ng / mL) 8928±8655 125.2±50.98 217.8±172.6 AUClast(h*ng / mL) 5365±1532 3051±523.3 4670±1529 AUCinf(h*ng / mL) 5379±1545 3894±243.5 4803±1564

[0218] The in vivo anatomical results of the formulation composition are shown in Table 14-5.

[0219] Table 14-5 In vivo anatomical residues of drug compositions

[0220]

[0221] Figure 4 shows that the sesame oil-free formulation (composition 1033) showed significant hardened formulation residues at the endpoint, affecting digestion and absorption in animals and even wound healing at the administration site. Compared to the oil-free formulation, the addition of a certain proportion of sesame oil to the formulation composition (composition 1034) significantly promoted its biodegradation in animals, consistent with in vitro dissolution results. No inflammatory reaction was observed at the administration site in animals, indicating good safety. Figure 3 The results show that the formulation of this invention, with the addition of a certain proportion of sesame oil, ensures complete and sufficient release of ropivacaine while still exhibiting a significant sustained-release effect in vivo, with a sustained-release time exceeding 72 hours. Compared with Comparative Example-1 (ropivacaine hydrochloride injection) at the same dosage, C max The value is significantly reduced, which can meet the clinical need for long-term postoperative analgesia.

[0222] (3) In vivo administration of ropivacaine hydrochloride sustained-release composition

[0223] The pharmacokinetic study in rats was conducted as follows: Animals weighing approximately 200–230 g were randomly grouped and uniquely identified by tail number. 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.

[0224] Animals were euthanized 72 hours after administration, and the subcutaneous tissue at the administration site was exposed to observe for possible adverse reactions. All residual formulations were then collected, weighed, and the amount of active pharmaceutical ingredient residue was determined.

[0225] Information on the dosage and administration of the drug is shown in Table 14-6.

[0226] Table 14-6 In vivo experimental dosage information for pharmaceutical compositions

[0227] Composition Number Dosage (mg / kg) Comparative Example 2 20 Composition 1011 20 Composition 1012 20

[0228] The pharmacokinetic (PK) parameters of the composition were calculated, and the results are shown in Table 14-7; the blood concentration-time curve is shown in Figure 5.

[0229] Table 14-7 PK Parameters of Pharmaceutical Compositions

[0230] Composition Number Comparative Example 2 Composition 1011 Composition 1012 <![CDATA[C max( ng / mL ) ]]> 2696±2315 74.12±23.78 275.2±249.2 <![CDATA[AUC last( h*ng / mL ) ]]> 6253±2226 2142±575.2 2987±1327 <![CDATA[AUC inf( h*ng / mL ) ]]> 6293±2218 2457±724.6 3181±1398

[0231] The in vivo anatomical results of the formulation composition are shown in Table 14-8.

[0232] Table 14-8 In vivo anatomical residues of drug compositions

[0233]

[0234] Figure 6 shows that the formulation without sesame oil (composition 1011) had significant hardened formulation residue at the final administration site, affecting digestion and absorption in animals; the addition of a certain proportion of sesame oil to the formulation (composition 1012) significantly promoted its biodegradation in animals, consistent with the in vitro dissolution results, and no inflammatory reaction was observed at the administration site in animals, indicating good safety; Figure 5 The results showed that C in rats containing the sesame oil preparation composition was... max The value was significantly lower than that of the comparative 2 (prodrug liposome formulation) at the same dosage, and it had a significant in vivo sustained-release effect with a sustained-release time of more than 72 hours.

[0235] (4) In vivo administration of the ropivacaine mesylate sustained-release composition

[0236] 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 number. 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, 72 h, and 96 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.

[0237] Animals were euthanized 72 hours after administration, and the subcutaneous tissue at the administration site was exposed to observe for possible adverse reactions. All residual formulations were then collected and weighed.

[0238] Information on the dosage and administration of the drug is shown in Table 14-9.

[0239] Table 14-9 In vivo experimental dosage information for pharmaceutical compositions

[0240] Composition Number Dosage (mg / kg) Zynrelef 20 Composition 1045 20 Composition 1046 20

[0241] The pharmacokinetic (PK) parameters of the composition were calculated, and the results are shown in Table 14-10; the blood concentration-time curve is shown in Figure 7.

[0242] Table 14-10 PK Parameters of Pharmaceutical Compositions

[0243] Composition Number Zynrelef Composition 1045 Composition 1046 <![CDATA[C max( ng / mL ) ]]> 1435±376.3 300.5±224.4 861.8±309.2 <![CDATA[AUC last( h*ng / mL ) ]]> 7025±3106 4676±1754 8887±2661 <![CDATA[AUC inf( h*ng / mL ) ]]> 7409±3200 4737±1780 8945±2671

[0244] The in vivo anatomical results of the formulation composition are shown in Table 14-11.

[0245] Table 14-11 In vivo anatomical residues of drug compositions

[0246]

[0247] Figure 8 shows that the addition of a certain proportion of sesame oil to the formulations (compositions 1045 and 1046) significantly promoted their biodegradation in animals. While the in vivo biodegradation accelerated with increasing sesame oil dosage, the sustained-release effect worsened, consistent with the results of in vitro release and in vitro erosion tests. No inflammatory reactions were observed at the administration sites in animals with formulations containing different proportions of sesame oil, indicating good safety. Figure 7 The results showed that C in rats containing the sesame oil preparation composition was... max The value is significantly lower than that of the marketed formulation Zynrelef (bupivacaine / meroxetine formulation) at the same dosage, and it has a significant sustained-release effect in vivo with a sustained-release time of more than 72 hours.

Claims

1. A sustained-release composition of a reservoir-type local anesthetic, comprising: a. Active pharmaceutical ingredient; b. Sustained-release carrier material; c. Phospholipids; d. Pharmaceutically acceptable oils; e. Pharmaceutically acceptable solvents.

2. The sustained-release composition according to claim 1, characterized in that: The active pharmaceutical ingredient is one or more drugs selected from bupivacaine, ropivacaine, levobupivacaine, mepivacaine, lidocaine free base, or pharmaceutically acceptable salts thereof. Preferably, the pharmaceutically acceptable salts include, but are not limited to, one or more of hydrochloride, mesylate, hydrobromide, hydroiodide, sulfate, citrate, tartrate, lactate, citrate, maleate, and fumarate. Preferably, the active pharmaceutical ingredient accounts for 0.01% to 10.0% (w / w) of the total composition; more preferably, 0.5% to 8%; more preferably, 1% to 5%; and more specifically, 1%, 2%, 3%, 4%, and 5%.

3. The sustained-release composition according to claim 1, characterized in that: The sustained-release carrier material is selected from one or more of glyceryl monooleate, glyceryl monolinoleate, glyceryl dioleate, sorbitan monooleate, glyceryl trioleate, sorbitan fatty acid ester, phytanetriol, and oleyl glycerol, preferably one or more of sorbitan monooleate, glyceryl monooleate, and glyceryl dioleate; 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 20% to 60%; more preferably 30% to 50%; more preferably 35% to 45%; more specifically, the sustained-release carrier material accounts for 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, and 60% of the total composition.

4. The sustained-release composition according to claim 1, characterized in that: The phospholipids are selected from hydrogenated soybean phospholipids, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearyl phosphatidylcholine, dilauryl phosphatidylcholine, soybean phospholipids, egg yolk phospholipids, rapeseed phospholipids, sunflower phospholipids, disqualoyl lecithin, dioleoyl lecithin, palmitoyl oleoyl lecithin, sphingomyelin, distearyl phosphatidyl acid, dioleoyl phosphatidylethanolamine, dipalmitoyl phosphatidyl acid, myristoyl lysophosphatidyl, palmitoyl lysophosphatidylcholine, 1-stearoyl-lysophosphatidylcholine, dipalmitoyl phosphatidylethanolamine, distearyl phosphatidylethanolamine, dioleoyl phosphatidylglycerol, dimyristoyl phosphatidylethanolamine, dimyristoyl phosphatidylethanolamine, dimyristoyl phosphatidyl ... The composition comprises one or more of the following: myristoyl phosphatidylglycerol, dipalmitoyl phosphatidylglycerol, 1-palmitoyl-2-oleoyl phosphatidylglycerol, distearyl phosphatidylglycerol, dipalmitoyl phosphatidylserine, phosphatidylinositol, and cholesterol; preferably one or more of the following: soybean phosphatidylglycerol, egg yolk phosphatidylglycerol, and dioleoyl phosphatidylglycerol; preferably, the phosphatidylglycerol accounts for about 10% to about 90% (w / w) of the total composition; preferably 20% to 80%; preferably 20% to 60%; more preferably 30% to 50%; more preferably 35% to 45%; and more specifically 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, and 60%.

5. The sustained-release composition according to claim 1, characterized in that: The ratio of the sustained-release carrier material to phospholipid is approximately 1:9 to 9:1; preferably 1:5 to 5:1; more preferably 0.8:1 to 1.8:1, even more preferably 0.9:1 to 1.6:1; and more preferably 1:1 to 1.5:

1.

6. The sustained-release composition according to claim 1, characterized in that: Pharmaceutically acceptable oils are selected from soybean oil, castor oil, hydrogenated castor oil, sulfonated castor oil, polyoxyethylene castor oil, sesame oil, peanut oil, cottonseed oil, corn oil, olive oil, sunflower seed oil, cottonseed oil, almond oil, tea oil, palm oil, sea buckthorn oil, fish oil, garlic oil, safflower oil, medium-chain triglycerides, ethyl oleate, triacetin, medium- and long-chain oils, glyceryl monoacetate, benzyl benzoate, isopropyl myristate, tributyl citrate, alkyl (C12-C15) methyl benzoate, benzyl phenylacetate, ethyl caprylate, dibutyl gallate, ethyl gallate, propyl gallate, and methyl myristate. The oil comprises one or more of isopentyl palmitate, ethyl propionate, isopentyl propionate, benzyl propionate, N-methyl-2-pyrrolidone, oleic acid and oleate esters; more preferably, the pharmaceutically acceptable oil is selected from one or more of castor oil, soybean oil, sesame oil, corn oil and medium-chain triglycerides; preferably, the pharmaceutically acceptable oil accounts for about 0.01% to about 20% (w / w) of the total composition, more preferably 0.01% to 15%, more preferably 0.01% to 10%, and more specifically, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, and 10%.

7. The sustained-release composition according to claim 1, characterized in that: The pharmaceutically acceptable solvent is 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, dimethyl sulfoxide, glycerol, and water for injection. Preferably, 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%, more preferably 0.01% to 15%, more preferably 0.01% to 10%, and more specifically, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, and 10%.

8. The sustained-release composition according to claim 1, characterized in that: The sustained-release composition further comprises f. a pharmaceutically acceptable acid; preferably, 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; preferably, the pharmaceutically acceptable acid accounts for about 0.01% to about 10% (w / w) of the total composition, preferably 0.01% to 5%, more preferably 0.01% to 3%, and more specifically 0.5%, 1%, 2%, and 3%.

9. The sustained-release composition according to claim 1, characterized in that: The sustained-release composition further comprises a pharmaceutically acceptable antioxidant or stabilizer; preferably, the antioxidant or stabilizer is selected from one or more of vitamin C, cysteine ​​or its hydrochloride, α-tocopherol, α-tocopherol acetate, ascorbyl palmitate, glutathione, alpha-lipoic acid, thioglycerol, N-acetyl-L-cysteine, butylated hydroxyanisole, propyl gallate, tert-butylhydroquinone, and butylated hydroxytoluene, with ascorbyl palmitate being the preferred antioxidant or stabilizer; preferably, the pharmaceutically acceptable antioxidant or stabilizer accounts for 0.01% to 5% (w / w) of the total composition; more preferably 0.05% to 1%; more preferably 0.1% to 0.5%; and more specifically 0.1%, 0.2%, 0.3%, 0.4%, and 0.5%.

10. A method for preparing a reservoir-type sustained-release composition of a local anesthetic according to any one of claims 1-9, characterized in that, Includes the following steps: (a1) Dissolve the prescribed amount of active pharmaceutical ingredient, sustained-release carrier material, phospholipid, and pharmaceutically acceptable oil 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 oil 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, steps (a1) and (b1) may further include the addition of a pharmaceutically acceptable amount of a pharmaceutically acceptable acid, a pharmaceutically acceptable antioxidant, or a stabilizer. Preferably, the process also includes dispensing, sterilization or disinfection steps. Preferably, sterilization is performed by filtration sterilization, and disinfection is performed by moist heat sterilization.

11. Use of the sustained-release composition according to any one of claims 1-9 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.

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