Sustained-release preparation composition

Abstract

The present invention relates to a pharmaceutical composition comprising a liquid oil, a pharmaceutically acceptable gelling agent, a pharmaceutically acceptable stabilizer, and a pharmaceutical active ingredient. The pharmaceutical composition is particularly suitable for the development of drug formulations with anesthetic and analgesic activity, and has many advantages over other sustained-release analgesic systems, such as sustained and stable release of the analgesic active ingredient, the ability to be administered by injection, and the ability to be administered stably and conveniently locally, high patient tolerance, and minimal side effects.

Description

Detailed Description of the Invention

[0001] This application claims priority to a prior application, bearing application number 202110051096.4 and entitled "Sustained-release formulation composition," filed with the State Intellectual Property Office of the People's Republic of China on January 14, 2021. The entirety of said prior application is incorporated herein by reference.

[0002] [Technical field] The present invention relates to the field of drug formulations, specifically to a sustained release formulation composition and its preparation method and use.

[0003] [Background technology] Postoperative pain is acute pain that occurs immediately after surgery, usually lasts for 3 to 7 days, and may develop into chronic pain if not properly controlled in the early stages. Currently, the most commonly used clinical treatment is treatment using an analgesic pump, but many of the drugs contained in the analgesic pump are opioid analgesics and some analgesic adjuvants such as tramadol, which have relatively good therapeutic effects but also have a series of side effects such as respiratory depression, nausea and vomiting, hypotension, and the possibility of addiction.

[0004] The use of local anesthetics to treat postoperative pain can avoid the above side effects, but local anesthetics usually have a short duration of action, and the effectiveness lasts for only a few hours after a single dose, which cannot meet the treatment cycle of postoperative pain. Therefore, the development of long-acting local anesthetic formulations has become the focus of current research.

[0005] Currently, the long-acting local anesthetic preparations on the market include pivacaine multivesicular liposome suspension injection under the trade name Exparel® developed by PACIRA, which is used to treat postoperative pain and nerve blocks and can maintain analgesic effect for 24 hours. Encapsulating bupivacaine in multivesicular liposomes can achieve good sustained release effect, but the preparation process of multivesicular liposomes is complicated and requires high storage conditions.

[0006] On August 28, 2020, Innocoll's XARACOLL® bupivacaine hydrochloride implant, which can be used for inguinal hernia repair in adults and provide sustained pain relief at the administration site for up to 24 hours, was approved by the FDA. However, the large size of the XARACOLL® sponge can cause swelling at the incision site, and the larger surgical wound required leaves less room for expansion for later indications.

[0007] Zynrelef® (HTX-011) combined bupivacaine meloxicam solution developed by Heron Therapeutics Inc was approved by the EMA on September 24, 2020, becoming the third long-acting bupivacaine formulation in the world. Zynrelef uses a polymeric material, polyorthoester, as a sustained-release carrier, which carries the risk of degrading too slowly at the administration site.

[0008] In addition, DURECT has developed POSIMIR®, a long-acting bupivacaine formulation that uses a small molecular ester as a sustained release carrier, and the related patent CN101035562 discloses a pharmaceutical composition containing bupivacaine, sucrose acetate isobutyrate (SAIB) and benzyl alcohol. Currently, POSIMIR® is in phase III clinical trials, but the clinical results have not shown statistical differences compared to bupivacaine solution. Dr. Gilbert J. Grant has developed bupivacaine multilamellar liposomes (LMVV), which have the same structure as Exparel liposomes, but have different particle sizes, preparation processes and stability, and there is a risk of leakage when stored at 4°C, and are currently in phase I clinical trials. Hefei Heyuan Pharmaceutical Co., Ltd. has developed bupivacaine pamoate cocrystal HYR-PB21-LA, which has a solubility of only 0.076 mg / mL, allowing for long-term release at the injection site. However, it has disadvantages such as a complicated preparation process.

[0009] Patent CN111655236A discloses a controlled release pharmaceutical composition comprising a biocompatible and bioerodible semi-solid gel, the semi-solid gel comprising castor oil, a gelling agent, bupivacaine and optionally a corticosteroid, an analgesic or an anti-inflammatory agent, wherein the ratio of castor oil to glyceride is 10:1-6:3 (w / w). Castor oil contains unsaturated fatty chains, so there is a risk of oxidation during storage, and the relatively high ratio of castor oil means that there is a risk of oil separation after a long storage period.

[0010] Therefore, there is an urgent need to develop sustained release formulation systems suitable for pharmaceutical use that have improved stability, safety, tolerance and / or sustained release properties.

[0011] Summary of the Invention In order to improve the problems existing in the prior art, the present invention comprises the following components: a. liquid oil; b. a pharma- ceutically acceptable gelling agent selected from one or more fatty acid glycerides of formula I;

[0012] [ka]

[0013] Wherein, R' and R'' may be the same or different and are each independently selected from H or RaCO, R''' is selected from RaCO, and each Ra is independently selected from a saturated or unsaturated aliphatic hydrocarbon group; c. a pharma- ceutically acceptable stabilizer selected from one or more compounds of formula II or formula III; The compound of formula II is

[0014] [ka]

[0015] Of these, Rs is H,

[0016] [ka]

[0017] each R1, R2 is the same or different and is independently selected from a saturated or unsaturated aliphatic hydrocarbon group; each R3, R4, R5 is the same or different and is independently selected from H or an alkyl group; L is an alkylene group; The compound of formula III

[0018] [ka]

[0019] wherein R is selected from alkyl groups; d. at least one pharma- ceutical active ingredient; and The present invention provides a pharmaceutical composition comprising:

[0020] According to an embodiment of the present invention, in the formula I, each Ra is independently selected from an alkyl group, and preferably each Ra is independently selected from C 1-40 More preferably, each Ra is independently selected from the group consisting of C 7-40 selected from alkyl groups, In some embodiments, R', R'' are selected from H and R''' is (C 11-40 alkyl group)C(═O), in some embodiments, R′ is selected from H and R″ is selected from RaCO, and the sum of the carbon atoms of each independently selected Ra alkyl group at R″ and R′″ is greater than 18, and in some embodiments, R′, R″ and R′″ are all selected from RaCO, and the sum of the carbon atoms of each independently selected Ra alkyl group at R′, R″ and R′″ is greater than 17.

[0021] According to an embodiment of the present invention, the pharma- ceutically acceptable gelling factor, which is the component b, is glyceryl laurate, glyceryl palmitate, glyceryl myristate, glyceryl stearate, C8-C 18glyceryl mixed fatty acids, glyceryl behenate, glyceryl palmitate stearate, glyceryl coconutate, hydrogenated cocoglycerides, and hydrogenated palm oil glycerides; Preferably, the pharma- ceutically acceptable gelling factor, component b, includes, for example, one or more of glyceryl monostearate, glyceryl distearate, glyceryl tristearate, glyceryl monobehenate, glyceryl bisbehenate, glyceryl monopalmitin stearate, glyceryl dipalmitin stearate, glyceryl monopalmitate, glyceryl dipalmitate, and glyceryl palmitin stearate.

[0022] According to an embodiment of the present invention, in the formula II, each R1 and R2 is the same or different, and each independently represents C 13-21 C such as alkyl group 10-30 R3, R4, and R5 are the same or different and each independently represent H or C. 1-10 alkyl groups, e.g., independently selected from H, methyl and ethyl groups, and the L's are C 1-10 Preferably, L is selected from the group consisting of C alkylene groups such as methylene and ethylene groups. 1-6 It is selected from alkylene groups.

[0023] According to an embodiment of the present invention, in the compound of formula III, R is C 8-10 C such as alkyl group 1-10 The alkyl group is selected from the group consisting of alkyl groups.

[0024] According to an embodiment of the present invention, the pharma- ceutically acceptable stabilizer which is the component c is selected from the group consisting of HSPC (hydrogenated soy lecithin), DMPC (dimyristoyl phosphatidylcholine), DPPC (dipalmitoyl phosphatidylcholine), DSPC (distearoyl phosphatidylcholine), DLPC (dilauroyl phosphatidylcholine), SPC soy phosphatidylcholine (soybean phospholipid), EPC (egg yolk phospholipid), rapeseed phospholipid, sunflower phospholipid, DEPC ( Diethylcoil phosphatidylcholine), DOPC (dioleoylphosphatidylcholine), POPC (PO phosphatidylcholine), sphingomyelin, distearoylphosphatidic acid (DSPA), dioleoylphosphatidylethanolamine (DOPE), dipalmitoylphosphatidic acid (DPPA), myristoyl lysophosphatidylcholine (M-lysoPC), palmitoyl lysophosphatidylcholine (P-lysoPC), 1-stearoyl-lysophosphatidylcholine (S-lysoPC), dipalmitoylphosphatidylethanolamine (DPPE), distearoylphosphatidic acid (DSPA), The phosphatidyl ester is one or more selected from the group consisting of dioleoylethanolamine (DSPE), dioleoylphosphatidylglycerol (DOPG), dimyristoylphosphatidylethanolamine (DMPE), dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphosphatidylglycerol (DPPG), 1-palmitoyl-2-oleoylphosphatidylglycerol (POPG), distearoylphosphatidylglycerol (DSPG), dipalmitoylphosphatidylserine (DPPS), phosphatidylinositol (PI), and cholesterol (CHO).

[0025] According to an embodiment of the invention, the pharmaceutical composition further comprises: e. at least one pharma- ceutically acceptable solvent.

[0026] According to an embodiment of the present invention, the pharmaceutical composition may further comprise g. a pharma- ceutically acceptable release modifier.

[0027] According to an embodiment of the present invention, the pharmaceutical composition may further comprise: f. a pharma- ceutically acceptable acid.

[0028] According to an embodiment of the present invention, the liquid oil is one or a combination of more selected from castor oil, sesame oil, corn oil, soybean oil, olive oil, safflower oil, cottonseed oil, peanut oil, fish oil, tea oil, almond oil, babassu oil, blackcurrant seed oil, borage oil, canola oil, palm oil, palm kernel oil, sunflower oil, medium chain triglycerides, glyceryl dioleate, glyceryl monooleate.

[0029] According to an embodiment of the present invention, the at least one pharma- ceutical active ingredient is not limited to a type of treatment and may be an anti-inflammatory drug, a local anesthetic, an analgesic, an antipsychotic, an anxiolytic, a sedative-hypnotic, an antidepressant, an antihypertensive, a steroid hormone, an antiepileptic, a bactericide, an anticonvulsant, an antiparkinsonian, a central nervous system stimulant, an antipsychotic, an antiarrhythmic, an antianginal, an antithyroid drug, an antidote, an antiemetic, a hypoglycemic, an antituberculous drug, an anti-AIDS drug, an anti-hepatitis B drug, an antitumor drug, an anti-rejection drug, and mixtures thereof.

[0030] According to an embodiment of the present invention, the suitable pharmacoactive ingredient may be one or more combinations selected from the following compounds: aspirin, acetaminophen, benorylate, indomethacin, sulindac, diclofenac, diclofenac potassium, diclofenac sodium, ibuprofen, naproxen, flurbiprofen, flurbiprofen axetil, loxoprofen, nabumetone, ketorolac, phenylbutazone, bufexamac, fenoprofen, celecoxib, rofecoxib, pormacoxib, nimesulide, meloxicam, lornoxicam, piroxicam, etodolac, valdecoxib, parecoxib, imrecoxib, lumiracoxib, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, lidocaine, procaine, benzocaine, tetracaine, dyclonine. Enkephalin, dynorphin, beta-endorphin, naltrexone, buprenorphine, morphine, dimethylmorphine, codeine, dihydrocodeine, oxycodone, hydrocodone, nalbuphine, fentanyl, sufentanil, remifentanil, tramadol, nortramadol, tapentadol, dezocine, pentazocine, methadone, meperidine, ketamine, diazepam, lormetazepam, lisdexamfetamine, dextropropoxyphene, difelikephalin, oliceridine. Chlorpromazine, triflupromazine, mesoridazine, piperacetazine, thioridazine, chlorprothixene. Diazepam, alprazolam, clonazepam, oxazepam, imipramine, amitriptyline, doxepin, nortriptyline, amoxapine, tranylcypromine, phenelzine. Procainamide, isoamyl nitrite, nitroglycerin, propranolol, metoprolol, prazosin, phentolamine, trimethaphan, captopril, enalapril. Clonidine, dexmedetomidine, adrenaline, noradrenaline, tizanidine, alpha-methyldopa, glycopyrrolate.Cortisone, hydrocortisone, betamethasone, triamcinolone acetonide, dexamethasone, dexamethasone esters, prednisone, prednisolone, methylprednisolone, beclomethasone, clobetasol, progesterone, testosterone, testosterone enanthate, testosterone undecanoate, testosterone cypionate, progesterone, fulvestrant, allopregnenolone, ganaxolone, phenytoin, ethotoin. benzalkonium chloride, benzethonium chloride, mafenide acetate, methylbenzethonium chloride, nitrofurazone, nitrocresol. phenobarbital, amobarbital, pentobarbital, secobarbital. Carbidopa, Levodopa, Aniracetam, Oxiracetam, Piracetam, Doxapram, Aripiprazole, Olanzapine, Haloperidol, Quetiapine, Risperidone, Clozapine, Paliperidone, Atenolol, Bisoprolol, Metoprolol. Atenolol, Amlodipine, Nimodipine, Isosorbide Mononitrate, Epoprostenol, Treprostinil, Iloprost, Beraprost. Methimazole, Propylthiouracil, Propranolol, Naloxone, Lofexidine, Flumazenil, Amphetamine. Granisetron, Ondansetron, Tropisetron, Dolasetron, Palonosetron, Scopolamine, Domperidone, Glipizide, Glibenclamide, Glimepiride, Glibenclamide, Gliclazide, Tolbutamide, Liraglutide, Exenatide, Dulaglutide, Semaglutide. Darunavir, dolutegravir sodium, emtricitabine, raltegravir, ritonavir, stavudine, nevirapine, zidovudine, stavudine, etravirine, adefovir dipivoxil, entecavir, telbivudine, lamivudine, tenofovir disoproxil, tenofovir alafenamide, thioacetazone, pyrazinamide, prothionamide, cyclophosphamide, 5-fluorouracil, carmustine, lomustine, melphalan, chlorambucil, methotrexate, vincristine, bleomycin, doxorubicin, tamoxifen, cyclosporine, tacrolimus, everolimus, sirolimus and pharma- ceutically acceptable salts, stereoisomers and derivatives of said compounds.

[0031] According to an embodiment of the present invention, the pharma- ceutical active ingredient is selected from amide type local anesthetics, such as bupivacaine, ropivacaine, levobupivacaine, mepivacaine, lidocaine and salts thereof. The salts of the amide type local anesthetics may be selected from their fatty acid salts and water-soluble salts, and the salt-forming acids include lauric acid, myristic acid, stearic acid, palmitic acid, behenic acid, arachidic acid, hydrochloric acid, sulfonic acid, phosphoric acid, acetic acid, citric acid, maleic acid, methanesulfonic acid, fumaric acid, succinic acid, lactic acid, etc.

[0032] According to an embodiment of the present invention, the pharmacologic active ingredient, in addition to containing an amide-type local anesthetic, further contains a second active ingredient, which may be one selected from COX receptor inhibitors, adrenergic receptor agonists and glucocorticoids. The COX receptor inhibitors include non-selective COX inhibitors and selective COX-2 inhibitors. Representative nonsteroidal anti-inflammatory drugs in these categories include, but are not limited to, non-selective COX inhibitors such as aspirin, acetaminophen, benorylate, indomethacin, sulindac, diclofenac, diclofenac potassium, diclofenac sodium, ibuprofen, naproxen, flurbiprofen, loxoprofen, nabumetan, piroxicam, ketorolac, phenylbutazone, bufexamac, fenoprofen, and the like; selective COX-2 inhibitors such as celecoxib, rofecoxib, nimesulide, meloxicam, lornoxicam, etodolac, valdecoxib, parecoxib, imrecoxib, lumiracoxib, and the like; and pharmaceutically acceptable salts, stereoisomers, and derivatives of the foregoing compounds. The adrenergic receptor agonists are mainly α2-adrenergic receptor agonists, including but not limited to clonidine, dexmedetomidine, adrenaline, noradrenaline, tizanidine, and α-methyldopa.The glucocorticoids include but are not limited to cortisone, hydrocortisone, betamethasone, triamcinolone acetonide, dexamethasone, prednisone, prednisolone, methylprednisolone, beclomethasone, and clobetasol. In some embodiments, the pharma- ceutical active ingredient is a combination of one or more selected from ropivacaine, bupivacaine, levobupivacaine, meloxicam, celecoxib, ketorolac, and triamcinolone acetonide. In some embodiments, the pharma-ceutical active ingredient is a combination selected from an amide type local anesthetic and a nonsteroidal anti-inflammatory drug, such as a composition of ropivacaine and meloxicam, a composition of levobupivacaine and meloxicam, a composition of bupivacaine and meloxicam, a composition of ropivacaine and celecoxib, a composition of levobupivacaine and celecoxib, or a composition of bupivacaine and celecoxib. According to an embodiment of the present invention, the pharma- ceutically acceptable release modifier is selected from small molecule esters and surfactants, the small molecule esters being triacetin, isopropyl stearate, isopropyl laurate, isopropyl palmitate, isopropyl myristate, and benzyl benzoate.

[0033] In some embodiments, the surfactant is a non-ionic surfactant.

[0034] In some embodiments, the surfactants include polyoxyl 40 stearate, caprylic capric macrogolglycerides, lauroyl polyoxyethylene glycol, stearoyl polyoxyethylene glycol, oleoyl polyoxyethylene glycol, vitamin E polyethylene glycol succinate, egg yolk lecithin, soybean phospholipids, hydrogenated soybean lecithin, poloxamers, polysorbates, polyethylene glycol-12-hydroxystearate, propylene glycol monocaprylate, etc. The poloxamers may be selected from, for example, poloxamer 407, poloxamer 188, and the polysorbates may be selected from, for example, polysorbate 80.

[0035] According to an embodiment of the present invention, the pharma- ceutically acceptable acid (ingredient f) is selected from acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, methanesulfonic acid, linoleic acid, sorbic acid, caprylic acid, nonanoic acid, lauric acid, palmitic acid, oleic acid, hydrochloric acid, phthalic acid, capric 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, vitamin E succinic acid, and the like.

[0036] According to an embodiment of the present invention, the composition may further comprise one or more antioxidants. Antioxidants can be used to prevent or reduce the oxidation of phospholipids or liquid oils in the sustained release drug delivery system described in the present invention. Antioxidants provided by the present invention include, but are not limited to, vitamin C (ascorbic acid), cysteine ​​or its hydrochloride, vitamin E (tocopherol), ascorbyl palmitate, glutathione, alpha lipoic acid, thioglycerol, butylated hydroxyanisole, dibutylhydroxytoluene, ethylenediaminetetraacetic acid and its sodium salt, citric acid, and tartaric acid.

[0037] According to an embodiment of the present invention, the composition may further comprise other conventional excipients in the pharmaceutical field, and examples of suitable pharmaceutical excipients are described in Excipients and their use in injectable products. PDA J Pharm Sci Technol. Vol.51, July-August 1997, pp.166-171 and Excipient Selection In Parenteral Formulation Development, Pharma Times, Vol.45, No.3, March 2013, pp.65-77, which are incorporated herein by reference in their entirety.

[0038] According to an embodiment of the present invention, the liquid oil comprises about 20% to about 90% (w / w) of the total amount of the composition, for example about 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74 5%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%. In some embodiments, the liquid oil ratio is about 30% to 90% (w / w). In some embodiments, the liquid oil ratio is about 40% to 79% (w / w).

[0039] According to an embodiment of the invention, the gelling agent comprises 2% to 50% (w / w) of the total amount of the composition, for example 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%. In some embodiments, the gelling agent comprises 2% to 30% (w / w) of the total amount of the composition.

[0040] According to an embodiment of the invention, the stabilizer comprises 1% to 40% (w / w) of the total amount of the composition, for example 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%. In some embodiments, the stabilizer comprises 5% to 30% (w / w) of the total amount of the composition.

[0041] According to an embodiment of the invention, the pharma- ceutical active ingredient comprises 0.01% to 50.0% (w / w) of the total amount of the composition. According to some embodiments, the pharma- ceutical active ingredient comprises 0.01% to 15% (w / w) of the total amount of the composition, for example 0.01%, 0.05%, 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 10.5%, 11.0%, 11.5%, 12.0%, 12.5%, 13.0%, 13.5%, 14.0%, 14.5%, 15.0%. According to some embodiments, the pharma- ceutical active ingredient is present in an amount of 3% (w / w) to 10% (w / w). According to some embodiments, when two or more pharma- ceutical active ingredients are selected, each pharma- ceutical active ingredient may comprise 0.01% to 10% (w / w) of the total amount of the composition, e.g., 0.01%, 0.05%, 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%.

[0042] According to an embodiment of the present invention, the total amount of the solvents comprises 0%-50% (w / w) of the total amount of the composition, and in some embodiments may be solvent-free. In some embodiments, the total amount of the solvent may comprise 0.01% to 50% of the total amount of the composition, preferably 2 to 50%, for example 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50%. In some embodiments, the total amount of the solvents comprises 5%-50% (w / w) of the total composition, and in some embodiments, the total amount of the solvents comprises 5%-30% (w / w) of the total composition. When a combination of two or more solvents is used, each solvent may account for 0% to 30% (w / w) of the total amount of the composition, preferably 0.01% to 30%, for example 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30%.

[0043] According to an embodiment of the present invention, the solvent is a non-aqueous solvent selected from one or more combinations of alcohols, N-methylpyrrolidone, benzyl benzoate, and dimethyl sulfoxide, and the alcohols are selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, propylene glycol, glycerin, benzyl alcohol, phenylethanol, and polyethylene glycol.

[0044] Preferably, the non-aqueous solvent is one or a combination of a plurality of solvents selected from the group consisting of benzyl alcohol, N-methylpyrrolidone, dimethylsulfoxide, and absolute ethanol.

[0045] According to an embodiment of the present invention, the release modifier comprises 0%-40% (w / w) of the total amount of the composition, preferably 0.1%-40% (w / w). In some embodiments, the release modifier may comprise 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40% of the total composition. In some embodiments, when the release modifier is selected from a small molecule ester, the dosage of the release modifier is 1% to 35%. In some embodiments, when the release modifier is selected from a surfactant, the dosage of the release modifier is 0.1% to 5% (w / w).

[0046] According to an embodiment of the present invention, the pharma- ceutically acceptable acid (component f) accounts for 0% to 20% (w / w) of the total amount of the composition, and in some embodiments, may not include an acid. In some embodiments, the acid accounts for 0.01% to 20% of the total amount of the composition, preferably 0.05% to 20%, for example, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%. In some embodiments, the acid accounts for 4% to 20% of the total amount of the composition.

[0047] The pharmaceutical composition provided by the present invention is a semi-solid formulation. In the pharmaceutical composition of the present invention, the pharma- ceutically acceptable solvent and release modifier can be used as viscosity modifiers to make the composition suitable for injection. In some embodiments, the viscosity of the composition is less than 20,000 cP at 30°C. In some embodiments, the viscosity of the composition is in the range of 5,000-10,000 cP at 30°C. In some embodiments, the viscosity of the composition is in the range of 3,000-5,000 cP at 30°C. In some embodiments, the viscosity of the composition is in the range of 1,000-3,000 cP at 30°C.

[0048] The present invention relates to (a1) mixing a liquid oil, a pharma- ceutically acceptable gelling agent, and a pharma-ceutically acceptable stabilizer with a solvent, and stirring under heating conditions until a transparent and homogeneous mixed solution is obtained; (a2) adding at least one pharma- ceutical active ingredient to the mixed solution and stirring until a homogenous mixture is formed; (a3) cooling the homogenous mixture formed in (a2) to room temperature.

[0049] According to an embodiment of the present invention, the mixing in step (a1) further comprises adding at least one release modifier, for example, in step (a1), a liquid oil, a gelling agent, a pharma- ceutically acceptable stabilizer, a pharma- ceutically acceptable solvent and the release modifier may be mixed.

[0050] In some embodiments, the method includes: 1. Mix liquid oil, gelling factor, stabilizer, pharma- ceutical active molecule and pharma- ceutical acceptable solvent at 50℃-70℃ until a clear solution is obtained.

[0051] 2. Sterilize the hot solution through a 0.22 μm filter membrane.

[0052] 3. The filtered mixture is cooled to room temperature.

[0053] In some embodiments, the method includes: 1. Mix liquid oil, gelling factor, pharma- ceutical acceptable stabilizer, pharma- ceutical active molecule, pharma-ceutical acceptable solvent and release modifier at 50℃-70℃ until a clear solution is obtained.

[0054] 2. Sterilize the hot solution through a 0.22 μm filter membrane.

[0055] 3. The filtered mixture is cooled to room temperature.

[0056] In some embodiments, according to the properties of various pharma- ceutical active molecules, the active molecules that are poorly soluble are first dissolved in a part of the solvent, and then added to the liquid oil, the gelling agent, and the remaining solvent to form a solution by heating and mixing to prepare the required pharmaceutical composition.

[0057] In some embodiments, the method includes: 1. Mix liquid oil, gelling agent and stabilizer with some solvent at 50℃~70℃ until a clear solution is obtained.

[0058] 2. The pharma- ceutical active molecule is added to a portion of the solvent until completely dissolved.

[0059] 3. Mix the drug solution with solution 1 uniformly.

[0060] 4. Sterilize the hot solution through a 0.22 μm filter membrane.

[0061] 5. The filtered mixture is cooled to room temperature.

[0062] In some embodiments, according to the properties of various pharma- ceutical active molecules, the active molecules that are poorly soluble are first dissolved in a part of solvent, and then added to the solution formed by heating and mixing liquid oil, gelling agent, a part of solvent, and release modifier to prepare the required pharmaceutical composition. In some embodiments, the method includes: 1. Mix liquid oil, gelling agent, stabilizer, some solvent and release modifier at 50℃~70℃ until a clear solution is obtained.

[0063] 2. The pharma- ceutical active molecule is added to a portion of the solvent until completely dissolved.

[0064] 3. Mix the drug solution with solution 1 uniformly.

[0065] 4. Sterilize the hot solution through a 0.22 μm filter membrane.

[0066] 5. The filtered mixture is cooled to room temperature.

[0067] In some embodiments, the method for preparing the pharmaceutical composition described in the present invention comprises: naturally cooling the mixed solution to room temperature; rapidly cooling and solidifying the mixed solution and then leaving it at room temperature; rapidly cooling and solidifying the mixed solution and then keeping it at a specific temperature for a certain period of time and then leaving it at room temperature; keeping the mixed solution at a system melting temperature to solidify it and then leaving it at room temperature; and keeping the mixed solution at a system melting temperature to solidify it and then keeping it at a specific temperature for a certain period of time and then leaving it at room temperature.

[0068] The present invention provides a sustained release formulation administered as a depot and comprising said pharmaceutical composition, which on the one hand is injectable, and on the other hand may be administered topically.

[0069] Alternatively, the formulation may be injected subcutaneously, into a peripheral nerve, intramuscularly or directly into a wound.

[0070] Alternatively, the formulation is suitable for administration to the skin or mucosa.

[0071] The preparations provided by the present invention are administered in a single dose, and the amount of drug contained therein can achieve the effects of analgesia, nerve block, and prevent or relieve local pain.

[0072] According to some embodiments, the formulations provided by the present invention can form a morphologically stable depot at the administration site, slowly and sustainably release the drug, prolong the release time of the local anesthetic, and enhance the therapeutic effect.

[0073] In some embodiments, the formulation can provide a sustained and effective treatment for at least 24 hours after administration. In some embodiments, the formulation can provide a sustained and effective treatment for at least 24 to 48 hours after administration. In some embodiments, the formulation can provide a sustained and effective treatment for at least 48 to 72 hours after administration. In some embodiments, the formulation can provide a sustained and effective treatment for at least 72 hours after administration. According to an embodiment of the present invention, the formulation further includes a packaging material filled with the formulation, and the packaging material is one or more selected from a vial, a prefilled syringe, and a cartridge.

[0074] [Terms and Abbreviations] Unless otherwise specified, the definitions of groups and terms described in the specification and claims of this application include exemplary definitions, exemplary definitions, preferred definitions, definitions described in the tables, definitions of specific compounds in the examples, etc., and can be combined or linked with each other in any way. The definitions of groups and the structures of compounds after such combination or linkage should be included in the scope described in the specification of this application.

[0075] When a numerical range is described in the specification and claims of this application, and the numerical range is defined as an "integer" or may be only an "integer", it should be understood that the two endpoints of the range and each integer within the range are described. For example, "an integer from 0 to 10" should be understood to describe the integers 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0076] When this numerical range is defined as a "number" or may include an "integers" or a "non-integer," it is to be understood that the two endpoints of the range, each integer within the range, and each decimal point within the range are described. For example, "numbers from 0 to 10" is to be understood to describe not only each of the integers 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also each of the integers plus at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9.

[0077] The term "aliphatic hydrocarbon group" includes chain-like hydrocarbon groups having saturated or unsaturated, straight or branched chains, and the type of the aliphatic hydrocarbon group may be selected from an alkyl group (saturated aliphatic hydrocarbon group), an alkenyl group, an alkynyl group, etc., and the number of carbon atoms of the aliphatic hydrocarbon group is preferably 1 to 40, more preferably 1 to 30 (e.g., C1, C2, C3, C4, C5, C6, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C30, C40), specifically, methyl group, ethyl group, n-propyl group, The "aliphatic hydrocarbon group" may include, but is not limited to, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a neopentyl group, an n-hexyl group, a vinyl group, a 1-propenyl group, a 2-propenyl group, a 1-methylvinyl group, a 1-butenyl group, a 1-ethylvinyl group, a 1-methyl-2-propenyl group, a 2-butenyl group, a 3-butenyl group, a 2-methyl-1-propenyl group, a 2-methyl-2-propenyl group, a 1-pentenyl group, a 1-hexenyl group, an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 1-methyl-2-propynyl group, a 3-butynyl group, a 1-pentynyl group, and a 1-hexynyl group, and some of the "aliphatic hydrocarbon groups" contained in other groups are the same as defined above.

[0078] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group as defined above for an aliphatic hydrocarbon group, for example, the alkyl group preferably has 1 to 40, more preferably 1 to 30, or 1 to 10 carbon atoms (e.g., C1, C2, C3, C4, C5, C6, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C30, C40). Those skilled in the art should also understand that the term "alkylene group" can also refer to the relevant definition of the above aliphatic hydrocarbon group, for example, the number of carbon atoms of the alkylene group can be C1, C2, C3, C4, C5, C6, C6, C7, C8, C9, or C10.

[0079] The term "biocompatibility" refers to the interaction between the components of a composition and the body.

[0080] The term "active ingredient" refers to a drug used to treat a disease. Thus, active ingredient and drug can be used interchangeably. The term "active ingredient" or "drug" as used herein includes, but is not limited to, drug active substances with local or systemic action that can be administered topically or by injection, such as subcutaneous, intradermal, intramuscular and intraarticular injection. At least one active ingredient is present in the sustained release drug delivery system of the present invention.

[0081] The term "oil gel" refers to a thermoreversible, semi-solid, dispersed system with a certain viscoelasticity obtained by adding a gelling agent to a liquid oil.

[0082] The term "gelling agent" refers to a substance that has sites within its molecule capable of interacting with lipophilic structures and that has a certain surface activity and thermal reversibility.

[0083] The term "semi-solid" refers to a form that is flowable under a certain pressure. More specifically, semi-solids typically have a viscosity of 100 to 50,000 cP at 30°C, and more particularly, a viscosity of 100 to 20,000 cP at 30°C.

[0084] The term "small molecule ester" refers to esters with a molecular weight of less than 500 that are liquid at room temperature.

[0085] The term "amide type" as used in the present invention refers to amide or caine type local anesthetics such as bupivacaine, levobupivacaine, ropivacaine, mepivacaine, and lidocaine. Amide type local anesthetics are generally composed of a lipophilic portion and a hydrophilic portion, the lipophilic portion may be an aromatic hydrocarbon or an aromatic heterocycle, and the effect of the benzene ring is the strongest. The activity can be increased by introducing an electron donating group such as an amino group into the benzene ring. The hydrophilic portion is generally a secondary amine, a tertiary amine, or pyrrolidine, piperidine, morpholine, etc., and tertiary amines are the most common. The pKa is generally between 7.5 and 7.9, and is an ionic form under physiological conditions.

[0086] The abbreviations used in the present invention are defined as follows: SPC is soybean phosphatidylcholine (soybean phospholipid), EPC is egg yolk phosphatidylcholine (egg yolk phospholipid), HSPC is hydrogenated soybean phosphatidylcholine, DLPC is dilauroylphosphatidylcholine, DMPC is dimyristoylphosphatidylcholine, DPPC is dipalmitoylphosphatidylcholine, DSPC is distearoylphosphatidylcholine, DEPC is Diethylcoil phosphatidylcholine , DOPC is dioleoylphosphatidylcholine (dioleoylphosphatidylcholine), POPC is PO phosphatidylcholine, and DEPC is Diethylcoil phosphatidylcholine, DOPC is dioleoylphosphatidylcholine, POPC is PO phosphatidylcholine, DSPA is distearoylphosphatidic acid, DOPE is dioleoylphosphatidylethanolamine, DPPA is dipalmitoylphosphatidic acid, M-lysoPC is myristoyl lysophosphatidylcholine, P-lysoPC is palmitoyl lysophosphatidylcholine, S-lysoPC is 1-stearoyl-lysophosphatidylcholine, DPPE is dipalmitoylphosphatidylethanolamine, DSPE is distearoylphosphatidylethanolamine, DOPG is dioleoylphosphatidylglycerol, DMPE is dimyristoylphosphatidylethanolamine, DMPG is dimyristoylphosphatidylglycerol, DPPG is dioleoylphosphatidylglycerol, Palmitoyl phosphatidylglycerol, POPG is 1-palmitoyl-2-oleoyl phosphatidylglycerol, DSPG is distearoyl phosphatidylglycerol, DPPS is dipalmitoyl phosphatidylserine, PI is phosphatidylinositol, BA is benzyl alcohol, NMP is N-methylpyrrolidone, DMSO is dimethyl sulfoxide, BHA is butylated hydroxyanisole, BHT is dibutylhydroxytoluene, BUP is bupivacaine, ROP is ropivacaine, MLX is meloxicam, CHO is cholesterol, PRX is piroxicam, LBUP is levobupivacaine, TAC is triamcinolone acetonide, KTL is ketorolac, VE is vitamin E, and VES is vitamin E succinate.

[0087] [Beneficial Effects] 1) The present invention provides a sustained-release formulation composition that is semi-solid at room temperature and can be directly used as a drug depot at the administration site. The gelling factor selected in the present invention has good biocompatibility with other components of the formulation, can solidify liquid oil, and can meet the requirements for sustained drug release.

[0088] 2) The present invention also surprisingly found that by adding an appropriate stabilizer to the formulation system, it is possible to improve the color change problem of the composition during long-term storage, improve the oil retention of the composition, enhance the gel properties of the composition, reduce the viscosity of the composition, and the like.

[0089] 3) The sustained release drug delivery liquid composition of the present invention has a suitable viscosity and is easy to administer. The sustained release drug delivery semi-solid composition of the present invention can be administered directly to the administration site, facilitating clinical administration.

[0090] 4) The composition of the present invention is less irritating and has good administration safety and tolerance.

[0091] 5) The sustained release formulation system provided by the present invention allows the active drug ingredient to achieve good release performance and reduce the possibility of burst release.

[0092] 6) The composition of the present invention is particularly suitable for the development of drug formulations with anesthetic and analgesic activity. Compared with other sustained-release analgesic systems, for example, the release of analgesic active ingredients is sustained and stable, and it is not only suitable for injection administration but also suitable for stable and convenient local administration, and has high patient tolerance and few side effects.

[0093] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1-1] and [Figure 1-2] are the rheology results of composition 1010 at 2-8°C and 25°C. [Figure 1-3] and [Figure 1-4] show the rheology results of composition 1013 at 2-8°C and 25°C. [Figure 1-5] to [Figure 1-7] Rheology results of compositions 1051, 1052, 1030, and 1031. [Figure 1-8] Viscosity-temperature change graph of compositions 1010 and 1013. [Figure 1-9] Viscosity-temperature change graph of compositions 1051 and 1052. [Figure 1-10] Viscosity-rotation speed change graph for compositions 1053 and 1054. [Figure 2-1] and [Figure 2-2] are the blood drug concentration time curves of bupivacaine and meloxicam in composition 1047. [Figure 2-3] and [Figure 2-4] are blood drug concentration time curves of bupivacaine and meloxicam in composition 1048. [Figure 3-1] Effects of compositions 1076, 1077 and 1078 on mechanical hyperalgesia in a rat CFA inflammatory pain model. Pre indicates the basic mechanical pain threshold before model creation, and solid black dots indicate statistical differences compared to the model group (p<0.05). [Figure 4-1] and [Figure 4-2] are the blood drug concentration-time curves of ropivacaine and meloxicam in composition 1079. [Figure 5-1] and [Figure 5-2] are the blood drug concentration time curves of ropivacaine and meloxicam in Composition 1080. [Figure 5-3] and [Figure 5-4] are the blood drug concentration-time curves of ropivacaine and meloxicam in composition 1081.

[0094] [Mode for carrying out the invention] The technical solution of the present invention will be described in more detail below with reference to specific examples. It should be understood that the following examples are merely illustrative and explanatory of the present invention, and do not limit the scope of the claims of the present invention. Any technology realized based on the above content of the present invention is included in the scope of the claims of the present invention.

[0095] Unless otherwise stated, all materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0096] Test materials: Castor oil:CO Glyceryl Monostearate: IMWITOR® 900K, Cithrol GMS 40, Geleol Mixed fatty acid glyceryl (stearyl): Stearyl 36 type, Stearyl 38 type, SUPPOCIRE AM, SUPPOCIRE CM, GELUCIRE 43 / 01, SOFTISAN 378 Glyceryl distearate: Precirol ATO5 Glyceryl Behenate: COMPRITOL 888 ATO Phospholipids: SPC, HSPC, DMPC, DPPC, DSPC, DEPC, EPC, DOPC Example 1 Effect of stabilizers on the appearance of the composition As shown in Tables 1-1 to 1-3, compositions containing different gelling factors were prepared and left at room temperature for a long period of 20 months. The compositions were then compared with standard colorimetric solution Y (yellow) numbers 1 to 10 to observe the change in the appearance of the compositions.

[0097] [Table 1]

[0098] [Table 2]

[0099] [Table 3]

[0100] In the present invention, it was unexpectedly discovered that the color of the oil gel preparation containing only fatty acid glyceryl as a gelling factor darkens to various degrees during long-term storage of the sample, and the composition to which a stabilizer (e.g. SPC, HSPC) was added has an appearance color number between Y7-8 after long-term storage for 20 months, and the color change is obviously smaller than that of other oil gel compositions, which can obviously improve the appearance stability of the oil gel composition.

[0101] Example 2 Study on oil retention of the composition Pharmaceutical compositions containing different ratios of gelling factors were prepared according to the components shown in Tables 2-1 to 2-9 below. 0.5 g of the pharmaceutical composition was weighed out, placed in a centrifuge tube, and centrifuged at various speeds. After centrifugation, the centrifuge tube was inverted to observe the oil separation state of the composition.

[0102] [Table 4]

[0103] [Table 5]

[0104] [Table 6]

[0105] [Table 7]

[0106] [Table 8]

[0107] [Table 9]

[0108] [Table 10]

[0109] [Table 11]

[0110] [Table 12]

[0111] Oil retention is one of the indicators for evaluating the stability of oil gel structure. In order to guarantee the hardening ability of gelling agent for liquid oil and prevent the phenomenon of liquid oil separation during long-term storage, it is necessary to study the oil retention of the formulation and investigate the maximum oil-carrying capacity in the oil gel. In the present invention, it is unexpectedly found that the composition containing stabilizer can significantly improve oil retention, improve physical stability, and effectively reduce the risk of oil separation during storage.

[0112] Example 3 Measurement of viscosity of oil gel compositions Pharmaceutical compositions containing different stabilizers and different amounts of organic solvents were prepared according to Tables 3-1 to 3-3. The raw materials and auxiliary materials in the table were mixed at 70°C, stirred while heating until a transparent and homogeneous solution was formed, and cooled to room temperature to form a solid gel-like substance. Then, the viscosity of the pharmaceutical composition was measured by the spindle method using a viscometer equipped with a No. 14 rotor, the detection temperature was 30°C, the rotation speed was 10 rpm, and the viscosity detection results were shown in Tables 3-1 to 3-3.

[0113] [Table 13]

[0114] [Table 14]

[0115] [Table 15]

[0116] The present invention unexpectedly discovered that after adding a stabilizer (SPC, DEPC, CHO, DOPC, etc.), the viscosity of the pharmaceutical composition can be significantly reduced, and at the same time, the amount of organic solvent used also affects the viscosity of the entire system. Therefore, by adjusting the ratio of the stabilizer and the organic solvent, the viscosity of the pharmaceutical composition can be optimized, making clinical administration easier.

[0117] Example 4 Investigating needle permeability According to Tables 4-1 to 4-4, oil gel compositions containing different organic solvents and different stabilizers were prepared, and the needle permeability of the compositions in the table was detected and the maximum thrust was investigated. The detection results are shown in the following Tables 4-1 to 4-4.

[0118] [Table 16]

[0119] [Table 17]

[0120] [Table 18]

[0121] [Table 19]

[0122] Typically, to make it easier for doctors to administer, the needle penetration for clinical administration required a maximum thrust of 2 kg or less.

[0123] The present invention has investigated the effect of the amount of organic solvent used on the needle permeability, and has shown that increasing the amount of organic solvent used can reduce the thrust, making clinical administration easier. At the same time, adding other stabilizers to the oil gel composition can also play a role in reducing the thrust.

[0124] Example 5 Research on the rheology of compositions Oil gel compositions were prepared according to Tables 5-1 to 5-4, and rheological studies were conducted. Rheometer model: TA DHR-1 Sample volume: 1 mL Measurement modes: Oscillation mode: time scan, fixed strain 0.5%, frequency 1 Hz; Oscillation mode: frequency scan, fixed strain 0.5%, frequency scan range 0.1-100 rad / s; Flow mode: viscosity scan, shear rate range 0.01-100 1 / s; Flow mode: viscosity temperature change scan, temperature change range 20℃-60℃, fixed shear rate 0.1 1 / s

[0125] [Table 20]

[0126] [Table 21]

[0127] [Table 22]

[0128] [Table 23]

[0129] The storage modulus G' and loss modulus G'' parameters of rheology can be used to evaluate the gel properties. In theory, the larger the storage modulus G' of glyceryl, the higher the gel strength and the more stable the gel network structure. When the storage modulus (G') is greater than the loss modulus (G''), the sample exhibited gel properties. Figures 1-1 to 1-7 were the rheological property results of the oil gel compositions in Tables 5-1 to 5-3, respectively. The present invention unexpectedly discovered that the composition containing SPC (1013) had G' greater than G'' and had obvious gel properties, while the compositions not containing SPC (1010, 1030, 1031) did not exhibit gel properties. At the same time, the gel strength of the formulation can be increased by increasing the amount of stabilizer used (1051 and 1052).

[0130] Figure 1-8 and Figure 1-9 show the viscosity trends of compositions 1010, 1013, 1051 and 1052 with the change of temperature, and the gelling temperature of the compositions can be estimated based on the change trends, and the results are shown in Table 5-5. As can be seen from Table 5-5, after adding SPC, the gelling temperature of the compositions can be reduced, which is more favorable for production expansion and filling.

[0131] [Table 24]

[0132] Figure 1-10 shows the viscosity trend of compositions 1053 and 1054 with the change of rotation speed. Based on the change trend, it can be seen that the oil gel composition of the present invention has shear thinning properties, which is more advantageous for clinical administration. At the same time, with the increase in the amount of stabilizer SPC, the viscosity of the composition is reduced to a certain extent.

[0133] Example 6 Research on freezing temperature The oil gel compositions were prepared according to Tables 6-1 to 6-3, and the solidification temperature of the compositions was observed when cooled after dissolving under a microscope to investigate the effects of organic solvents and stabilizers on the solidification temperature. The detection results are shown in Tables 6-1 to 6-3 below.

[0134] [Table 25]

[0135] [Table 26]

[0136] [Table 27]

[0137] The present inventors have unexpectedly discovered that by adding an organic solvent and a stabilizer, the freezing temperature of the composition can be reduced, which is more advantageous for production and packaging.

[0138] Example 7 Oil gel compositions containing different active ingredients Oil gel compositions containing different main active ingredients were prepared according to the ingredients shown in Table 7-1 below. The raw materials and auxiliary materials in the table were mixed at 70°C, heated and stirred until a transparent and homogeneous solution was formed, and cooled to room temperature to form a solid gel-like material.

[0139] [Table 28]

[0140] [Table 29]

[0141] Example 8 Pharmaceutical compositions containing different concentrations of active ingredient and antioxidant Oil gel compositions containing different concentrations of active ingredients and antioxidants were prepared according to the ingredients shown in Table 8 below. The raw materials and auxiliary materials in the table were mixed at 70°C, heated and stirred until a transparent and homogenous solution was formed, and cooled to room temperature to form a solid gel-like material.

[0142] [Table 30]

[0143] Example 9 Pharmaceutical compositions containing no organic solvent or different organic solvents Oil gel compositions containing different organic solvents were prepared according to the components shown in Table 9 below. The raw materials and auxiliary materials in the table were mixed at 70°C, heated and stirred until a transparent and homogeneous solution was formed, and cooled to room temperature to form a solid gel-like material.

[0144] [Table 31]

[0145] Example 10 In vivo administration of oil gel compositions.

[0146] The study on in vivo pharmacokinetics in dogs was as follows. Beagle dogs weighing about 10 kg were fasted for more than 12 hours before the experiment (feeding box was removed), allowed to drink water ad libitum, and fed for 4 hours after administration. Each group was administered with 6 mg / kg subcutaneous injection, and the sample information is shown in Table 10. For animals in each group, about 0.5 mL of blood samples were collected in EDTA-2K+anticoagulant blood collection tubes at 0 hours before administration, and at 0.5, 1, 2, 3, 6, 8, 12, 24, 36, 48, 60, 72, and 96 hours after administration. The whole blood was centrifuged at 8000 rpm for 5 min, and then the plasma was collected, and the drug concentration in the plasma sample was detected by LC-MS / MS.

[0147] [Table 32]

[0148] See Figures 2-1 to 2-4 for the blood drug concentration-time curves of BUP and MLX within 96 hours after administration of the composition.

[0149] Example 11 In vivo administration of oil gel compositions The efficacy study using rats was as follows. Three days before the experiment, the rats' PWT values ​​were measured once a day, and on the fourth day before the model was made, the PWT was measured once as the baseline value before the model was made. Then, 100 μL of CFA was administered to the right hind paw of all rats, and the PWT value was measured again 24 h after the inflammation model was made as the baseline value after the model was made, and the composition was administered by subcutaneous injection to the plantar, and the sample information is shown in Table 11. The model group was not administered, and the rats' hind paws were stimulated in the mid-plantar area with Von Frey monofilament at various times after administration, and their mechanical paw withdrawal threshold (PWT) was measured as the pain threshold. The detection times were 30 min, 1 h, 4 h, 8 h, 12 h, 24 h, 48 h, 72 h, and 92 h after administration, respectively.

[0150] [Table 33]

[0151] As shown in FIG. 3-1, the mechanical pain threshold (PWT) of each group of rats was maintained at about 21-24 g before the model was created, and 24 h after the model was created, the mechanical pain threshold (PWT) decreased to 4-6 g, indicating that the mechanical hyperalgesia of the rats was very obvious after the CFA model was created. Composition 1076 significantly increased the PWT value of the rats 30 min after administration (p<0.05), and the effect was sustained for 96 h, and the difference was statistically significant (p<0.05). Composition 1078 showed an analgesic effect 4 h after administration (p<0.05), which persisted for up to 12 h and then disappeared (p>0.05), indicating that the effect was maintained for 12 h to 24 h. Composition 1077 showed an analgesic effect from 8 h (p<0.05), which continued until 12 h, then fluctuated, and again showed an analgesic effect at 48 h (p<0.05).

[0152] Example 12 In vivo administration of oil gel compositions.

[0153] The study on in vivo pharmacokinetics in dogs was as follows. Beagle dogs weighing about 10 kg were fasted for more than 12 hours before the experiment (feeding box was removed), allowed to drink water ad libitum, and fed for 4 hours after administration. Each group was administered with 6 mg / kg subcutaneous injection, and the sample information is shown in Table 12. For animals in each group, about 0.5 mL of blood samples were collected in EDTA-2K+anticoagulant blood collection tubes at 0 hours before administration, and at 0.5, 1, 2, 3, 6, 8, 12, 24, 36, 48, 60, 72, and 96 hours after administration. The whole blood was centrifuged at 8000 rpm for 5 min, and then the plasma was collected, and the drug concentration in the plasma sample was detected by LC-MS / MS.

[0154] [Table 34]

[0155] See Figures 4-1 and 4-2 for the blood drug concentration-time curves of ROP and MLX within 96 hours after administration of the composition.

[0156] Example 13 In vivo administration of oil gel compositions.

[0157] The study on in vivo pharmacokinetics in dogs was as follows. Beagle dogs weighing about 10 kg were fasted for more than 12 hours before the experiment (feeding box was removed), allowed to drink water ad libitum, and fed for 4 hours after administration. Each group was administered with 6 mg / kg subcutaneous injection, and the sample information is shown in Table 13. For animals in each group, about 0.5 mL of blood samples were collected in EDTA-2K+anticoagulant blood collection tubes at 0 hours before administration, and at 0.5, 1, 2, 3, 6, 8, 12, 24, 36, 48, 60, 72, and 96 hours after administration, and the whole blood was centrifuged at 8000 rpm for 5 min, after which the plasma was collected, and then the drug concentration in the plasma sample was detected by LC-MS / MS.

[0158] [Table 35]

[0159] See Figures 5-1 to 5-4 for the blood drug concentration-time curves of ROP and MLX within 96 hours after administration of the composition.

[0160] The exemplary embodiments of the present invention have been described above. However, the scope of the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention should be included in the scope of the present invention. [Brief description of the drawings]

[0161] [Figure 1-1] 4 is a rheology result of composition 1010 at 2-8° C. [Figure 1-2] 1 is the rheology result of composition 1010 at 25° C. [Figure 1-3]4 is a rheology result of composition 1013 at 2-8° C. [Figure 1-4] 1 is a rheology result of composition 1013 at 25° C. [Figure 1-5] 4 shows the rheology results of compositions 1051 and 1052. [Figure 1-6] Rheology results for 1030. [Figure 1-7] Rheology results of 1031. [Figure 1-8] 1 is a viscosity-temperature profile of compositions 1010 and 1013. [Figure 1-9] 1 is a viscosity-temperature change graph of compositions 1051 and 1052. [Figure 1-10] 1 is a graph showing viscosity versus rotational speed change for compositions 1053 and 1054. [Figure 2-1] 1 is a blood drug concentration time curve of bupivacaine of composition 1047. [Figure 2-2] This is the blood drug concentration time curve of meloxicam of composition 1047. [Figure 2-3] 1 is a blood drug concentration time curve of bupivacaine of composition 1048. [Figure 2-4] 1 is a blood drug concentration time curve of meloxicam of composition 1048. [Figure 3-1] The effect of compositions 1076, 1077 and 1078 on mechanical hyperalgesia in a rat CFA inflammatory pain model. Pre indicates the basic mechanical pain threshold before model creation, and solid black dots indicate statistical differences compared to the model group (p<0.05). [Figure 4-1] This is the blood drug concentration time curve of ropivacaine of composition 1079. [Figure 4-2] This is the blood drug concentration time curve of meloxicam of composition 1079. [Figure 5-1] This is the blood drug concentration time curve of ropivacaine of composition 1080. [Figure 5-2] 1 is a blood drug concentration time curve of meloxicam of composition 1080. [Figure 5-3]This is the blood drug concentration time curve of ropivacaine of composition 1081. [Figure 5-4] This is the blood drug concentration time curve of meloxicam of composition 1081.

Claims

1. The following ingredients: Castor oil, b. a pharma- ceutically acceptable gelling agent selected from one or more of glyceryl monostearate and glyceryl distearate; c. a pharma- ceutically acceptable stabilizer selected from one or more of SPC soy phosphatidylcholine (soybean phospholipid), POPC (PO phosphatidylcholine), DEPC (dierucoyl phosphatidylcholine), EPC (egg yolk phospholipid), and DOPC (dioleoyl phosphatidylcholine); d. A pharma- ceutical active ingredient selected from a combination of ropivacaine and meloxicam, or a combination of bupivacaine and meloxicam; e. a non-aqueous solvent selected from the group consisting of benzyl alcohol, absolute ethanol, N-methylpyrrolidone, benzyl benzoate, and dimethyl sulfoxide, and a combination of one or more of the following: the amount of said castor oil relative to the total amount of said composition is 50 w / w% to 70 w / w%; the amount of said gelling factor relative to the total amount of said composition is 5 w / w% to 20 w / w%; the amount of said stabilizer relative to the total amount of said composition is 4 w / w% to 12 w / w%, the amount of said pharma- ceutical active ingredient relative to the total amount of said composition is 2.0 w / w% to 12.0 w / w%, A pharmaceutical composition, wherein the total amount of the non-aqueous solvent is 5 w / w% to 20 w / w% relative to the total amount of the composition.

2. The pharmaceutical composition of claim 1, wherein the amount of castor oil is 50 w / w%, 51 w / w%, 52 w / w%, 53 w / w%, 54 w / w%, 55 w / w%, 56 w / w%, 57 w / w%, 58 w / w%, 59 w / w%, 60 w / w%, 61 w / w%, 62 w / w%, 63 w / w%, 64 w / w%, 65 w / w%, 66 w / w%, 67 w / w%, 68 w / w%, 69 w / w%, or 70 w / w%.

3. The pharmaceutical composition described in claim 1, wherein the amount of the gelling factor relative to the total amount of the composition is 6 w / w% to 20 w / w%.

4. The pharmaceutical composition of claim 1, wherein the amount of the gelling factor relative to the total amount of the composition is 6 w / w%, 7 w / w%, 8 w / w%, 9 w / w%, 10 w / w%, 11 w / w%, 12 w / w%, 13 w / w%, 14 w / w%, 15 w / w%, 16 w / w%, 17 w / w%, 18 w / w%, 19 w / w%, or 20 w / w%.

5. The pharmaceutical composition of claim 1, wherein the amount of the stabilizer relative to the total amount of the composition is 4 w / w% to 10 w / w%.

6. The pharmaceutical composition of claim 1, wherein the amount of the stabilizer relative to the total amount of the composition is 4 w / w%, 5 w / w%, 6 w / w%, 7 w / w%, 8 w / w%, 9 w / w%, or 10 w / w%.

7. The pharmaceutical composition of claim 1, wherein the amount of the pharma- ceutical active ingredient relative to the total amount of the composition is 3.0 w / w% to 12.0 w / w%.

8. The pharmaceutical composition of claim 1, wherein the amount of the pharma- ceutical active ingredient relative to the total amount of the composition is 3.0 w / w%, 3.5 w / w%, 4.0 w / w%, 4.5 w / w%, 5.0 w / w%, 5.5 w / w%, 6.0 w / w%, 6.5 w / w%, 7.0 w / w%, 7.5 w / w%, 8.0 w / w%, 8.5 w / w%, 9.0 w / w%, 9.5 w / w%, 10.0 w / w%, 10.5 w / w%, 11.0 w / w%, 11.5 w / w%, or 12.0 w / w%.

9. The pharmaceutical composition described in claim 1, wherein the total amount of the non-aqueous solvent relative to the total amount of the composition is 5 w / w% to 15 w / w%.

10. The pharmaceutical composition of claim 1, wherein the total amount of the non-aqueous solvent relative to the total amount of the composition is 5 w / w%, 6 w / w%, 7 w / w%, 8 w / w%, 9 w / w%, 10 w / w%, 11 w / w%, 12 w / w%, 13 w / w%, 14 w / w%, or 15 w / w%.

11. (a1) mixing castor oil, a pharma- ceutically acceptable gelling agent, and a pharma-ceutically acceptable stabilizer with a non-aqueous solvent, and stirring under heating conditions until a transparent and homogeneous mixed solution is obtained; (a2) adding a pharma- ceutical active ingredient to the mixed solution and stirring until a homogenous mixture is formed; (a3) cooling the homogenous mixture formed in (a2) to room temperature. A process for preparing the pharmaceutical composition according to any one of claims 1 to 10.

12. A sustained release formulation comprising the pharmaceutical composition according to any one of claims 1 to 10, The formulation is administered as a depot formulation. A sustained release formulation characterized by:

13. The formulation further comprises a packaging material filled therein, the packaging material being one or more selected from a vial, a prefilled syringe, and a cartridge; 13. The sustained release formulation according to claim 12.

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