WO2022152232A1 - 一种缓释制剂组合物 - Google Patents

一种缓释制剂组合物 Download PDF

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WO2022152232A1
WO2022152232A1 PCT/CN2022/071928 CN2022071928W WO2022152232A1 WO 2022152232 A1 WO2022152232 A1 WO 2022152232A1 CN 2022071928 W CN2022071928 W CN 2022071928W WO 2022152232 A1 WO2022152232 A1 WO 2022152232A1
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acid
oil
pharmaceutical composition
alkyl
pharmaceutically acceptable
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PCT/CN2022/071928
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English (en)
French (fr)
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李玲
武曲
嵇元欣
王青松
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南京清普生物科技有限公司
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Priority to EP22739108.3A priority Critical patent/EP4279065A1/en
Priority to KR1020237017771A priority patent/KR20230096056A/ko
Priority to CA3196937A priority patent/CA3196937A1/en
Priority to AU2022208128A priority patent/AU2022208128A1/en
Priority to JP2023526286A priority patent/JP2023547222A/ja
Priority to US18/253,429 priority patent/US20230398089A1/en
Publication of WO2022152232A1 publication Critical patent/WO2022152232A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and in particular relates to a sustained-release preparation composition and a preparation method and application thereof.
  • Postoperative pain is acute pain that occurs immediately after surgery, usually lasting no more than 3 to 7 days, and may develop into chronic pain if it cannot be adequately controlled in the initial state.
  • the commonly used clinical treatment method is to use an analgesic pump for treatment, but the drugs contained in the analgesic pump are mostly opioid analgesics and some auxiliary analgesics such as tramadol, etc.
  • opioid analgesics and some auxiliary analgesics such as tramadol, etc.
  • tramadol tramadol
  • the currently listed long-acting local anesthetic preparations include Bupivacaine Multivesicular Liposome Suspension Injection developed by PACIRA, with the trade name of For the treatment of postoperative pain and nerve block, the analgesic effect can last for 24 hours. Encapsulating bupivacaine in multivesicular liposomes can play a good sustained-release effect, but the preparation process of multivesicular liposomes is complicated and requires high storage conditions.
  • DURECT has developed a long-acting bupivacaine formulation with a small molecule ester as a sustained-release carrier
  • SAIB sucrose acetate isobutyrate
  • benzyl alcohol a pharmaceutical composition containing bupivacaine, sucrose acetate isobutyrate (SAIB) and benzyl alcohol.
  • SAIB sucrose acetate isobutyrate
  • Benzyl alcohol Currently It has entered Phase III clinical trials, but the clinical results showed no statistical difference compared with bupivacaine solution.
  • Dr. Gilbert J. Grant developed the multilamellar liposome (LMVV) of bupivacaine, which has the same structure as Exparel liposome, but the particle size, preparation process and stability are different. There is a risk of leakage when stored at 4°C.
  • Patent CN111655236A discloses a controlled release pharmaceutical composition
  • a biocompatible and bioerodible semi-solid gel comprising castor oil, a gelling agent, bupivacaine and optionally corticosteroids, analgesics or anti-inflammatory agents.
  • the ratio of castor oil and glycerides is 10:1 to 6:3 (w/w). Due to the presence of unsaturated fatty chains in castor oil, there may be a risk of oxidation during storage. In addition, due to the high proportion of castor oil, there may be a risk of oil separation with prolonged storage time.
  • the present invention provides a pharmaceutical composition, comprising the following components:
  • a pharmaceutically acceptable gelling factor selected from one or more of the fatty acid glycerides of formula I:
  • R', R" can be the same or different, independently selected from each other H or RaCO, R"' is selected from RaCO;
  • Each Ra is independently selected from saturated or unsaturated aliphatic hydrocarbon groups;
  • a pharmaceutically acceptable stabilizer selected from one or more of the compounds of formula II or III:
  • each R 3 , R 4 , R 5 is the same or different, that
  • L is selected from alkylene
  • the compound of formula III is wherein R is selected from alkyl
  • At least one pharmaceutically active ingredient At least one pharmaceutically active ingredient.
  • each Ra is independently selected from alkyl, preferably, each Ra is independently selected from C 1-40 alkyl, more preferably, each Ra is independently selected from from C 7-40 alkyl;
  • the b-component pharmaceutically acceptable gelling factor comprises a mixture of glyceryl laurate, glyceryl palmitate, glyceryl myristate, glyceryl stearate, C 8 -C 18 One or more of fatty acid glyceride, glyceryl behenate, glyceryl palmitate stearate, glyceryl cocoate, hydrogenated coconut oil glyceride, hydrogenated palm oil glyceride;
  • the pharmaceutically acceptable gelling factor of the b component includes, for example, glycerol monostearate, glyceryl distearate, glyceryl tristearate, glycerol monobehenate, glyceryl dibehenate
  • glyceride glycerol monopalmitate, glyceryl dipalmitate, glycerol monopalmitate, glyceryl dipalmitate, and glyceryl palmitate.
  • each R 1 and R 2 are the same or different, and are independently selected from C 10-30 saturated or unsaturated aliphatic hydrocarbon groups, such as C 13-21 alkyl groups; each R 3 , R 4 , R 5 are the same or different, and independently of each other are selected from H or C 1-10 alkyl, such as independently from each other, from H, methyl, ethyl; the L is selected from C 1-10 alkylene Alkyl, preferably, L is selected from C 1-6 alkylene, such as methylene, ethylene;
  • R is selected from C 1-10 alkyl, such as C 8-10 alkyl.
  • the c-component pharmaceutically acceptable stabilizer is selected from the group consisting of HSPC (hydrogenated soybean lecithin), DMPC (dimyristoyl phosphatidyl choline), DPPC (dipalmitoyl phosphatidyl choline) , DSPC (distearoyl phosphatidyl choline), DLPC (dilauroyl phosphatidyl choline), SPC soybean phosphatidyl choline (soy phosphatidyl choline), EPC (egg yolk phospholipid), rapeseed phospholipid, sunflower phospholipid, DEPC ( Di-erucyl lecithin), DOPC (dioleoyl lecithin), POPC (palmitoyl oleoyl lecithin), sphingomyelin, distearoyl phosphatidic acid (DSPA), dioleoyl phosphatidyl
  • DSPA dioleo
  • the pharmaceutical composition further comprises e. at least one pharmaceutically acceptable solvent.
  • the pharmaceutical composition may further comprise g. a pharmaceutically acceptable release modifier.
  • the pharmaceutical composition may further comprise f. a pharmaceutically acceptable acid.
  • the liquid oil is selected from castor oil, sesame oil, corn oil, soybean oil, olive oil, safflower oil, cottonseed oil, peanut oil, fish oil, camellia oil, almond oil, babassu oil, black vinegar
  • castor oil sesame oil, corn oil, soybean oil, olive oil, safflower oil, cottonseed oil, peanut oil, fish oil, camellia oil, almond oil, babassu oil, black vinegar
  • borage oil canola oil, palm oil, palm kernel oil, sunflower oil, medium chain triglycerides, glyceryl dioleate, glycerol monooleate.
  • the at least one pharmaceutically active ingredient is not limited to the type of treatment and may be anti-inflammatory, local anesthetic, analgesic, antipsychotic, anxiolytic, sedative-hypnotic, antidepressant , antihypertensive drugs, steroid hormones, antiepileptic drugs, bactericides, anticonvulsants, antiparkinsonian drugs, central nervous system stimulants, antipsychotics, antiarrhythmic drugs, antianginal drugs, antithyroid drugs, antidote , antiemetics, hypoglycemic drugs, anti-tuberculosis drugs, anti-AIDS drugs, anti-hepatitis B drugs, anti-tumor drugs, anti-rejection drugs and mixtures thereof.
  • a suitable pharmaceutically active ingredient may be selected from a combination of one or more of the following compounds: aspirin, acetaminophen, benoxylate, indomethacin, sulindac, diclofenac, Diclofenac potassium, diclofenac sodium, ibuprofen, naproxen, flurbiprofen, flurbiprofen axetil, loxoprofen, nabumetone, ketorolac, phenylbutazone, buprofen, fenox Celebrex, celecoxib, rofecoxib, Polmacoxib, nimesulide, meloxicam, lornoxicam, piroxicam, etodolac, valdecoxib, parecoxib, erecoxib, lu Micoxib.
  • Chlorpromazine Triflupromazine, Mesoridazine, Pecitazine, Thioridazine, Chlorprothixol.
  • Procainamide isoamyl nitrite, nitroglycerin, propranolol, metoprolol, prazosin, phentolamine, imithiophene, captopril, enalapril.
  • Clonidine dexmedetomidine, epinephrine, norepinephrine, tizanidine, alpha-methyldopa, glycopyrrolate.
  • Phenobarbital isopentobarbital, pentobarbital, secobarbital. Carbidopa, Levodopa, Aniracetam, Oxiracetam, Piracetam, Doxapram, Aripiprazole, Olanzapine, Haloperidol, Quetiapine, Risperidone , clozapine, paliperidone, atenolol, bisoprolol, metoprolol.
  • Atenolol amlodipine, nimodipine, isosorbate mononitrate, epoprostenol, treprostinil, iloprost, beraprost. methimazole, propylthiouracil, propranolol, naloxone, lofexidine, flumazenil, amphetamine.
  • Granisetron Granisetron, ondansetron, tropisetron, dolasetron, palonosetron, scopolamine, domperidone, glipizide, glyburide, glimepiride, euglycerol, gliclase Zite, Tolbutamide, Liraglutide, Exelatide, Duraglutide, Semaglutide.
  • the pharmaceutically active ingredient is selected from amide local anesthetics, for example, selected from bupivacaine, ropivacaine, levobupivacaine, mepivacaine, lidocaine and salts thereof.
  • the salts of the amide local anesthetics can be selected from fatty acid salts and water-soluble salts thereof, and the acids forming the salts 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.
  • the pharmaceutically active ingredient further comprises a second active ingredient in addition to the amide local anesthetic, and the pharmaceutically active ingredient may be selected from COX receptor inhibitors, adrenergic receptor agonists and sugars One of the corticosteroids.
  • the COX receptor inhibitors include non-selective COX inhibitors and selective COX-2 inhibitors.
  • NSAIDs represented in these classes include, but are not limited to, the following non-selective COX inhibitors: aspirin, acetaminophen, benoxylate, indomethacin, sulindac, diclofenac, diclofenac potassium, Diclofenac sodium, ibuprofen, naproxen, flurbiprofen, loxoprofen, nabumetone, piroxicam, ketorolac, phenylbutazone, buprofen, fenoprofen; the following optional COX-2 inhibitors: celecoxib, rofecoxib, nimesulide, meloxicam, lornoxicam, etodolac, valdecoxib, parecoxib, erecoxib, luminoxib cloth.
  • the adrenoceptor agonists are mainly ⁇ 2-adrenoceptor agonists, including but not limited to clonidine, dexmedetomidine, epinephrine, norepinephrine, tizanidine, ⁇ -methyl doba.
  • the glucocorticoids include, but are not limited to, cortisone, hydrocortisone, betamethasone, triamcinolone acetonide, dexamethasone, prednisone, prednisolone, methylprednisolone, beclomethasone , Clobetasol.
  • the pharmaceutically active ingredient is selected from one of ropivacaine, bupivacaine, levobupivacaine, meloxicam, celecoxib, ketorolac, and triamcinolone acetonide or a combination of several.
  • the pharmaceutically active ingredient is selected from the group consisting of an amide-type local anesthetic in combination with a non-steroidal anti-inflammatory drug, such as a combination of ropivacaine and meloxicam, and a combination of levobupivacaine and meloxicam , bupivacaine and meloxicam compositions, ropivacaine and celecoxib compositions, levobupivacaine and celecoxib compositions, bupivacaine and celecoxib compositions, and the like.
  • a non-steroidal anti-inflammatory drug such as a combination of ropivacaine and meloxicam, and a combination of levobupivacaine and meloxicam, bupivacaine and meloxicam compositions, ropivacaine and celecoxib compositions, levobupivacaine and celecoxib compositions, bupivacaine and celecoxib compositions, and the like.
  • the pharmaceutically acceptable release modifier is selected from small molecule esters and surfactants.
  • the small molecular esters are triacetin, isopropyl stearate, isopropyl laurate, isopropyl palmitate, isopropyl myristate, and benzyl benzoate.
  • the surfactant is a nonionic surfactant.
  • the surfactant includes polyoxyl 40 stearate, caprylic capric polyglycol glyceride, lauroyl polyoxyethylene glyceride, stearoyl polyoxyethylene glyceride, oleoyl Polyoxyethylene Glycerides, Vitamin E Macrogol Succinate, Egg Lecithin, Soy Lecithin, Hydrogenated Soy Lecithin, Poloxamer, Polysorbate, Macrogol-12-Hydroxystearate, Propylene Glycol Monocaprylate, etc.
  • the poloxamer can be selected from, for example, poloxamer 407, poloxamer 188, and the polysorbate can be selected from, for example, polysorbate 80.
  • the pharmaceutically acceptable acid is selected from the group consisting of 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, etc.
  • 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 systems 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, dibutylated hydroxytoluene, ethylenediaminetetraacetic acid and its sodium salt, citric acid, tartaric acid.
  • the composition may further comprise other excipients conventional in the field of pharmacy, examples of suitable pharmaceutical excipients are in Excipients and their use in injectable products.
  • suitable pharmaceutical excipients are in Excipients and their use in injectable products.
  • the liquid oil comprises from about 20% to about 90% (w/w) of the total composition, such as 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%, 75%, 76%, 77%, 78%, 79%.
  • 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).
  • the gelling factor comprises 2% to 50% (w/w) of the total composition, eg 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%.
  • the gelling factor comprises 2% to 30% (w/w) of the total composition.
  • the stabilizer comprises 1% to 40% (w/w) of the total composition, such as 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%.
  • the stabilizer comprises 5% to 30% (w/w) of the total composition.
  • the pharmaceutically active ingredient accounts for 0.01% to 50.0% (w/w) of the total amount of the composition.
  • the pharmaceutically active ingredient constitutes 0.01% to 15% (w/w) of the total composition, such as 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%.
  • the pharmaceutically active ingredient is present in an amount of 3% (w/w) to 10% (w/w).
  • each pharmaceutically active ingredient may account for 0.01% to 10% (w/w) of the total amount of the composition, such as 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%.
  • the total amount of the solvent accounts for 0% to 50% (w/w) of the total amount of the composition.
  • no solvent may be contained.
  • the total amount of the solvent is The amount may be 0.01-50% of the total composition, preferably 2-50%, such as 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%.
  • the total amount of the solvent is 5%-50% (w/w) of the total amount of the composition, and in some embodiments, the total amount of the solvent is 5%-30% of the total amount of the composition (w/w).
  • each solvent may account for 0% to 30% (w/w) of the total composition, preferably 0.01-30%, such as 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%, 30%.
  • the solvent is a non-aqueous solvent
  • the non-aqueous solvent is selected from one or more combinations of alcohols, N-methylpyrrolidone, benzyl benzoate, and dimethyl sulfoxide.
  • the alcohols are selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, propylene glycol, glycerol, benzyl alcohol, phenethyl alcohol, and polyethylene glycol.
  • the non-aqueous solvent is selected from one or more combinations of benzyl alcohol, N-methylpyrrolidone, dimethyl sulfoxide and absolute ethanol
  • the release modifier comprises 0% to 40% (w/w) of the total composition, preferably 0.1% to 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% of the total composition , 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, when the release modifier is selected from small molecule esters, the amount of the release modifier is 1-35%; in some embodiments, when the release modifier is When the release modifier is When the release modifier is selected from surfactants, the amount of the release modifier is 0.1% to be
  • the pharmaceutically acceptable acid (component f) accounts for 0% to 20% (w/w) of the total composition, in some embodiments, may be free of acid, in some embodiments
  • the acid accounts for 0.01% to 20% of the total composition, preferably 0.05-20%, such as 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 composition.
  • the pharmaceutical composition provided by the present invention is a semi-solid preparation.
  • the pharmaceutically acceptable solvents and release modifiers may act as viscosity modifiers, making the compositions suitable for injection.
  • the composition has a viscosity of less than 20,000 cP at 30°C.
  • the viscosity of the composition is in the range of 5000 to 10000 cP at 30°C.
  • the composition has a viscosity in the range of 3000 to 5000 cP at 30°C.
  • the composition has a viscosity in the range of 1000 to 3000 cP at 30°C.
  • the invention provides a preparation method of the pharmaceutical composition, comprising the following steps:
  • the mixing of the step (a1) further includes adding at least one release modifier, for example, the step (a1) may be a liquid oil, a gelling factor, a pharmaceutical stabilizer, a pharmaceutical
  • the step (a1) may be a liquid oil, a gelling factor, a pharmaceutical stabilizer, a pharmaceutical
  • the above-acceptable solvent is mixed with the release modifier.
  • the method includes:
  • the method includes:
  • the more insoluble active molecules are first dissolved in part of the solvent, and then added to the solution formed by heating and mixing the liquid oil, the gelling factor and the remaining part of the solvent to prepare the compound. desired pharmaceutical composition.
  • the method includes:
  • the insoluble active molecules can be dissolved in part of the solvent first, and then added to the solution formed by heating and mixing the liquid oil, the gelling factor, the part of the solvent and the release modifier. And prepare the desired pharmaceutical composition.
  • the method includes:
  • the mixed solution is naturally cooled to room temperature; in some embodiments, the mixed solution is rapidly cooled and solidified and then placed at room temperature; in some embodiments, the mixed solution is rapidly cooled and solidified After cooling and solidification, the mixed solution is kept at room temperature after being kept at a specific temperature for a certain period of time; in some embodiments, the mixed solution is kept at room temperature after being kept at the melting temperature of the system; in some embodiments, the mixed solution is kept at the melting temperature of the system after being kept solidified Store at room temperature after holding at a specific temperature for a certain period of time.
  • the present invention provides a sustained release formulation comprising the pharmaceutical composition, the formulation being administered as a depot formulation, in one aspect, the formulation is injectable. Alternatively, the formulation can be administered topically.
  • the formulation can be injected subcutaneously, peripherally, intramuscularly, or applied directly to a wound.
  • formulations are suitable for administration on the skin or mucous membranes.
  • the preparation provided by the invention is administered in a single dose, and the contained amount of the drug can achieve the effects of analgesia and nerve block, and can be used to prevent or relieve local pain.
  • the preparation provided by the present invention can form a morphologically stable reservoir at the administration site, can release the drug slowly and continuously, prolong the release time of the local anesthetic, and improve the therapeutic effect.
  • the formulation continues to be effective for treatment for at least 24 hours after administration. In some embodiments, the formulation remains effective for treatment for at least 24 to 48 hours after administration. In some embodiments, the formulation remains effective for treatment for at least 48 to 72 hours after administration. In some embodiments, the formulation continues to be effective for treatment for at least 72 hours after administration.
  • the formulation further comprises a packaging material filled with the formulation, and the packaging material is selected from one or more of the following: vials, prefilled syringes, and cartridges.
  • aliphatic hydrocarbon group includes saturated or unsaturated, straight-chain or branched chain hydrocarbon groups, and the type of the aliphatic hydrocarbon group can be selected from alkyl (saturated aliphatic hydrocarbon group), alkenyl, alkynyl, etc., the aliphatic hydrocarbon group
  • the number of carbon atoms is preferably 1-40, more preferably 1-30 (for example, 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 including but not limited to the following groups: methyl, ethyl, n-propyl, isopropyl, n
  • alkyl is a saturated aliphatic hydrocarbon group, which meets the relevant definitions in the above-mentioned aliphatic hydrocarbon group, for example, the number of carbon atoms of the alkyl group is preferably 1-40, more preferably 1-30, or 1-10 (for example, 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).
  • alkylene can also refer to the relevant definitions in the above-mentioned aliphatic hydrocarbon group, for example, the number of carbon atoms of the alkylene can be C1, C2, C3, C4, C5, C6, C6, C7 , C8, C9, C10.
  • biocompatibility refers to the interaction between the components of the composition and the body.
  • active ingredient refers to a drug used to treat a disease. Therefore, active ingredients, drugs can be used interchangeably.
  • active ingredient or drug as used herein includes, but is not limited to, locally or systemically acting pharmaceutical actives, which may be administered by topical administration 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.
  • oil gel refers to a thermally reversible, semi-solid and viscoelastic dispersion system obtained by adding gelling factors to liquid oil.
  • gelator refers to a class of substances that have lipophilic structures and interactable sites in the molecule, as well as certain surface activity and thermal reversibility.
  • semi-solid refers to a form that is flowable under pressure. More specifically, semi-solids typically have viscosities between 100 and 50,000 cP at 30°C, especially viscosities between 100 and 20,000 cP at 30°C.
  • small molecule esters refers to esters with a molecular weight of less than 500 that are liquid at room temperature.
  • amide type used in the present invention refers to amide or caine-type local anesthetics, such as bupivacaine, levobupivacaine, ropivacaine, mepivacaine, lidocaine and the like.
  • Amide local anesthetics are generally composed of a lipophilic part and a hydrophilic part.
  • the lipophilic part can be aromatic hydrocarbon or aromatic heterocycle, and the benzene ring has the strongest effect.
  • the introduction of electron donating groups such as amino groups on the benzene ring can enhance the activity.
  • the hydrophilic part is generally secondary amine, tertiary amine or pyrrolidine, piperidine, morpholine, etc., tertiary amine is the most common.
  • pKa is generally between 7.5 and 7.9, and it is ionic under physiological conditions.
  • SPC soybean phosphatidyl choline (soy lecithin)
  • EPC egg yolk phosphatidyl choline (egg yolk phospholipid)
  • HSPC hydrogenated soybean phosphatidyl choline
  • DLPC dilauroyl phosphatidyl Choline
  • DMPC dimyristoyl phosphatidyl choline
  • DPPC dipalmitoyl phosphatidyl choline
  • DSPC distearoyl phosphatidyl choline
  • DEPC diperucyl lecithin
  • DOPC dioleoyl phosphatidyl phospholipid Acylcholine (dioleoyl lecithin)
  • POPC palmitoyl oleoyl lecithin
  • DEPC dierucyl lecithin
  • DOPC dioleoyl lecithin
  • POPC palmitoyl oleoyl lecithin
  • the present invention provides a sustained-release preparation composition, which is semi-solid at normal temperature and can be directly used as a drug reservoir at the administration site.
  • the selected gelling factor of the present invention has good biocompatibility with other components of the preparation, and can solidify the liquid oil to meet the requirement of sustained release of the drug.
  • the present invention also surprisingly finds that adding a suitable stabilizer to the formulation system can improve the discoloration problem of the composition during long-term storage, improve the oil retention of the composition, enhance the gel properties of the composition, and reduce the composition. viscosity, etc.;
  • the sustained-release drug delivery liquid composition of the present invention has suitable viscosity and is easy to administer; the sustained-release drug delivery semi-solid composition of the present invention can be directly applied to the administration site, which is convenient for clinical administration.
  • composition of the present invention is less irritating and has good drug safety and tolerance.
  • the sustained-release preparation system provided by the present invention can enable the active pharmaceutical ingredients to achieve good release performance and reduce the possibility of sudden release.
  • composition of the present invention is especially suitable for the development of pharmaceutical preparations with anesthesia and analgesic activity, and has more advantages compared to other sustained-release analgesic systems, such as continuous and stable release of analgesic active ingredients, not only injection It is suitable for stable and convenient topical administration, with good patient tolerance and few side effects.
  • Figures 1-1 and 1-2 are rheological results of composition 1010 at 2-8°C and 25°C
  • Figures 1-3 and 1-4 are rheological results of composition 1013 at 2-8°C and 25°C
  • Figures 1-5 to 1-7 are the rheological results of compositions 1051 and 1052, 1030, 1031
  • Figures 1-8 are viscosity-temperature profiles of compositions 1010 and 1013
  • Figures 1-9 are viscosity-temperature profiles of compositions 1051 and 1052
  • Figures 1-10 are graphs of viscosity-rotation changes for compositions 1053 and 1054
  • Figures 2-1 and 2-2 are the bupivacaine and meloxicam plasma concentration time curves of composition 1047.
  • Figures 2-3 and 2-4 are the bupivacaine and meloxicam plasma concentration-time profiles for Composition 1048.
  • Figure 3-1 is the effect of compositions 1076, 1077 and 1078 on mechanical hyperalgesia in the rat CFA inflammatory pain model.
  • Pre represents the basic mechanical pain threshold before modeling, and the black solid dots represent the results compared with the model group, and the results are statistically different (p ⁇ 0.05).
  • Figures 4-1 and 4-2 are the ropivacaine and meloxicam plasma concentration-time curves of composition 1079.
  • Figures 5-1 and 5-2 are the ropivacaine and meloxicam plasma concentration-time profiles of Composition 1080.
  • Figures 5-3 and 5-4 are the ropivacaine and meloxicam plasma concentration-time profiles of Composition 1081.
  • Glyceryl Monostearate Cithrol GMS 40, Geleol
  • stearyl Stearyl 36, Stearyl 38, SUPPOCIRE AM, SUPPOCIRE CM, GELUCIRE 43/01, SOFTISAN 378.
  • Glyceryl Behenate COMPRITOL 888 ATO
  • Phospholipids SPC, HSPC, DMPC, DPPC, DSPC, DEPC, EPC, DOPC
  • compositions containing different gelling factors as shown in Table 1-1 to Table 1-3 and place them at room temperature for a long time for 20 months. The change in appearance color of the composition was examined.
  • Table 1-1 Appearance color of the composition with glyceryl monostearate as gelling factor after long-term storage
  • the present invention unexpectedly finds that the color of the oil-gel preparation containing only fatty acid glycerides as a gelling factor darkens to varying degrees during the long-term sample retention process, and the composition added with a stabilizer (such as SPC, HSPC) is placed for a long time for 20 months,
  • a stabilizer such as SPC, HSPC
  • the appearance color number is between Y7-8, 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.
  • compositions containing different ratios of gelling factors were prepared according to each ingredient shown in Tables 2-1 to 2-9 below. 0.5 g of the pharmaceutical composition was weighed, placed in a centrifuge tube, centrifuged at different speeds, and the centrifuge tube was inverted after centrifugation to observe the oil separation of the composition.
  • Oil retention is one of the indicators to evaluate the structural stability of oil gels.
  • the composition containing the stabilizer can significantly improve oil retention, improve physical stability, and effectively reduce the risk of oil separation during storage.
  • compositions containing different amounts of stabilizers and organic solvents were prepared according to Tables 3-1 to 3-3.
  • the viscosity of the pharmaceutical composition was measured by a shaft method using a viscometer equipped with a No. 14 rotor, the detection temperature was 30° C. and the rotation speed was 10 rpm.
  • the viscosity detection results are shown in Tables 3-1 to 3-3 below.
  • the present invention unexpectedly finds that after adding stabilizers (such as SPC, DEPC, CHO, DOPC, etc.), the viscosity of the pharmaceutical composition can be significantly reduced, and the amount of organic solvent also affects the viscosity of the entire system. Therefore, by adjusting the ratio of stabilizer and organic solvent, the viscosity of the pharmaceutical composition can be optimized to make it easier for clinical administration.
  • stabilizers such as SPC, DEPC, CHO, DOPC, etc.
  • the maximum thrust of the needle for clinical administration is not more than 2kg.
  • the influence of the dosage of the organic solvent on the acupuncture is investigated, and the results show that increasing the dosage of the organic solvent can reduce the thrust and is more beneficial to clinical administration.
  • other stabilizers can be added to the oil-gel composition to reduce the thrust.
  • the oleogel compositions were prepared according to Tables 5-1 to 5-4, and rheological studies were carried out.
  • the storage modulus G' and loss modulus G" parameters in rheology can be used to evaluate the gel properties.
  • the larger the storage modulus G' of glycerides the stronger the gel strength and the stronger the gel network structure. Stable.
  • the sample exhibits gel properties.
  • Figures 1-1 to 1-7 are the results of the rheological properties of the oil-gel compositions in Tables 5-1 to 5-3, respectively.
  • the present invention unexpectedly found that the composition containing SPC (1013) G' was greater than G" and had obvious gel properties, while the compositions without SPC (1010, 1030, 1031) did not show gel properties.
  • the stabilizer was added The dosage of 1051 and 1052 can enhance the gel strength of the preparation.
  • Figures 1-8 and 1-9 are the trends of the viscosity of the compositions 1010, 1013, 1051 and 1052 changing with temperature. According to the changing trends, the gelation temperature of the compositions can be inferred. The results are shown in Table 5-5. From Table 5-5 It can be seen that the gelation temperature of the composition can be reduced after adding SPC, which is more conducive to the scale-up production and filling.
  • Fig. 1-10 is the trend that the viscosity of composition 1053 and 1054 changes with rotating speed, according to the changing trend, it can be seen that the oil-gel composition of the present invention has the property of shear thinning, which is more conducive to clinical administration. At the same time, the amount of stabilizer SPC increases, and the viscosity of the composition decreases to a certain extent.
  • the oil gel compositions were prepared according to Tables 6-1 to 6-3, and the solidification temperature of the composition upon cooling after dissolving was observed under a microscope, and the effects of organic solvents and stabilizers on the solidification temperature were investigated.
  • the test results are shown in Tables 6-1 to 6-3 below.
  • the present invention unexpectedly finds that adding an organic solvent and a stabilizer can reduce the solidification temperature of the composition, which is more conducive to production and filling.
  • Oil-gel compositions of different active ingredients are provided.
  • Oil gel compositions containing different main active ingredients were prepared according to each ingredient shown in Table 7-1 below. Mix the raw and auxiliary materials in the table at 70°C, stir while heating until a transparent and homogeneous solution is formed, and cool to room temperature to form a solid gel-like substance.
  • compositions containing various concentrations of active ingredients and antioxidants containing various concentrations of active ingredients and antioxidants
  • Oil gel compositions containing various concentrations of active ingredient and antioxidant were prepared according to each ingredient shown in Table 8 below. Mix the raw and auxiliary materials in the table at 70°C, stir while heating until a transparent and homogeneous solution is formed, and cool to room temperature to form a solid gel-like substance.
  • Oil gel compositions containing different organic solvents were prepared according to each of the ingredients shown in Table 9 below. Mix the raw and auxiliary materials in the table at 70°C, stir while heating until a transparent and homogeneous solution is formed, and cool to room temperature to form a solid gel-like substance.
  • Efficacy studies in rats are as follows. The PWT value of the rats was measured once a day on the first three days of the experiment, and the PWT value was measured once a day before the model establishment on the fourth day as the pre-model basal value. Then all rats were given 100 ⁇ L CFA to the right hind paw respectively, and then 24 hours after the inflammation model was established. The PWT value measured once was the basal value after modeling, and the composition was administered by subcutaneous injection through the sole of the foot. The sample information is shown in Table 11. The model group was not treated with medication, and the rats were stimulated with Von Frey monofilament at different time points after administration.
  • the mechanical paw withdrawal threshold (PWT) was tested as the pain threshold.
  • the detection time was 30min, 1h, 4h, 8h, 12h, 24h, 48h, 72h, 92h after administration, respectively.

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Abstract

一种油凝胶药物组合物，包含液体油、药学上可接受的凝胶因子、稳定剂和活性成分。所述药物组合物尤其适用于具有麻醉、镇痛活性的药物制剂，具有良好的释放持续稳定性，可用于注射、局部给药，患者耐受性好，副作用少。

Description

一种缓释制剂组合物
本申请要求2021年1月14日向中国国家知识产权局提交的，专利申请号为202110051096.4，发明名称为“一种缓释制剂组合物”的在先申请的优先权。所述在先申请的全文通过引用的方式结合于本申请中。
技术领域
本发明属于药物制剂领域，具体涉及一种缓释制剂组合物及其制备方法和用途。
背景技术
手术后疼痛是手术后即刻发生的急性疼痛，通常持续不超过3～7天，如果不能在初始状态下被充分控制，则可能发展为慢性疼痛。目前常用的临床治疗手段是采用镇痛泵进行治疗，但是镇痛泵里含有的药物多为阿片类镇痛药和一些辅助镇痛药如曲马多等，尽管疗效较好，但也伴随着一系列副作用如呼吸抑制、恶心呕吐、低血压及潜在成瘾性等。
采用局麻药治疗术后疼痛可以避免上述不良反应，但是局麻药通常作用时间较短，单次给药后药效仅维持数小时，无法满足术后疼痛的治疗周期。因此开发长效局麻药制剂是目前的研究热点。
目前上市的长效局麻药制剂有PACIRA开发的布比卡因多囊脂质体混悬注射液，商品名为
Figure PCTCN2022071928-appb-000001
用于治疗术后疼痛及神经阻滞，镇痛效果可持续24小时。将布比卡因包裹在多囊脂质体中能起到良好的缓释作用，但是多囊脂质体制备工艺复杂，且对储藏条件要求高。
2020年8月28日，FDA批准Innocoll公司
Figure PCTCN2022071928-appb-000002
盐酸布比卡因植入剂，用于成人腹股沟疝修补术，在给药部位可持续24小时镇痛。但由于
Figure PCTCN2022071928-appb-000003
海绵体积较大，可能导致切口部位肿胀，此外由于所需手术创面较大，后期适应症拓展空间较小。
Heron Therapeutics Inc开发的
Figure PCTCN2022071928-appb-000004
(HTX-011)复方布比卡因美洛昔康溶液已于2020年9月24日被EMA批准，成为全球第三个长效布比卡因制剂。Zynrelef采用高分子材料聚原酸酯作为缓释载体，可能存在给药部位降解过慢的风险。
此外，DURECT公司开发了一种以小分子酯作为缓释载体的长效布比卡因制剂
Figure PCTCN2022071928-appb-000005
相关专利CN101035562公开了一种含有布比卡因、蔗糖醋酸异丁酸酯(SAIB)和苯甲醇的药物组合物。目前
Figure PCTCN2022071928-appb-000006
已进入III期临床，但临床结果与布比卡因溶液相比未表现出统计 学差异。Gilbert J.Grant博士开发了布比卡因的大多室脂质体(LMVV)，与Exparel脂质体结构相同，但粒径、制备工艺和稳定性有差异，4℃储存有泄漏风险，目前进入临床I期。合肥合源药业有限公司开发了帕莫酸布比卡因共晶HYR-PB21-LA，由于溶解度仅为0.076mg/mL，在注射部位可实现长效释放。但存在制备工艺较为复杂等缺点。
专利CN111655236A公开了一种控释药物组合物，其包含生物相容性和可生物蚀解的半固体凝胶，所述半固体凝胶包含蓖麻油、胶凝剂、布比卡因和任选的皮质类固醇、镇痛剂或抗炎剂。其中蓖麻油和甘油酯的比例为10:1至6:3(w/w)。由于蓖麻油中含有不饱和脂肪链，在储存过程中可能存在被氧化的风险，此外由于蓖麻油比例较高，随着放置时间的延长，可能存在析油风险。
因此，亟需开发一种适于药用，稳定性、安全性、耐受性和/或缓释性能得到改善的缓释制剂系统。
发明内容
为改善现有技术中存在的问题，本发明提供一种药物组合物，包括如下组分：
a.液体油
b.药学上可接受的凝胶因子，所述凝胶因子选自如式I的脂肪酸甘油酯中的一种或多种：
Figure PCTCN2022071928-appb-000007
其中，R’、R”可以相同或不同，彼此独立地选自H或RaCO，R”’选自RaCO；每个Ra彼此独立地选自饱和或不饱和脂肪烃基；
c.药学上可接受的稳定剂，所述稳定剂选自式II或式III化合物中的一种或多种：
所述式II化合物为
Figure PCTCN2022071928-appb-000008
其中，Rs选自H，
Figure PCTCN2022071928-appb-000009
每个R 1、R 2
相同或不同，彼此独立地选自饱和或不饱和脂肪烃基；每个R 3、R 4、R 5相同或不同，彼
此独立地选自H或烷基；L选自亚烷基；
所述式III化合物为
Figure PCTCN2022071928-appb-000010
其中，R选自烷基；
d.至少一种药学上的活性成分。
根据本发明的实施方案，所述式I中，每个Ra独立地选自烷基，优选的，每个Ra独立地选自C 1-40烷基，更优选的，每个Ra独立地选自C 7-40烷基；
在一些实施方案中，R’、R”选自H，R”’选自(C 11-40烷基)C(＝O)；在一些实施方案中，R’选自H，R”选自RaCO，且R”、R”’中各自独立所选Ra烷基的碳数总和大于18；在一些实施方案中，R’、R”、R”’均选自RaCO，且R’、R”、R”’中各自独立所选Ra烷基的碳数总和大于17。
根据本发明的实施方案，所述b组分药学上可接受的凝胶因子包括月桂酸甘油酯、棕榈酸甘油酯、肉豆蔻酸甘油酯、硬脂酸甘油酯、C 8-C 18的混合脂肪酸甘油酯、山嵛酸甘油酯、棕榈酸硬脂酸甘油酯、椰油酸甘油酯、氢化椰子油甘油酯、氢化棕榈油甘油酯中的一种或多种；
优选的，所述b组分药学上可接受的凝胶因子包括例如单硬脂酸甘油酯，双硬脂酸甘油酯、三硬脂酸甘油酯、单山嵛酸甘油酯、双山嵛酸甘油酯、单棕榈酸硬脂酸甘油酯、双棕榈酸硬脂酸甘油酯、单棕榈酸甘油酯、双棕榈酸甘油酯、棕榈酸硬脂酸甘油酯中的一种或多种。
根据本发明的实施方案，所述式II中，每个R 1、R 2相同或不同，彼此独立地选自C 10-30饱和或不饱和脂肪烃基，例如C 13-21烷基；每个R 3、R 4、R 5相同或不同，彼此独立地选自H或C 1-10烷基，例如彼此独立地选自H，甲基，乙基；所述L选自C 1-10亚烷基，优选的，L选自C 1-6亚烷基，例如为亚甲基，亚乙基；
根据本发明的实施方案，式III所示化合物中，R选自C 1-10烷基，例如C 8-10烷基。
根据本发明的实施方案，所述c组分药学上可接受的稳定剂选自HSPC(氢化大豆磷脂)、DMPC(二肉豆蔻酰基磷脂酰胆碱)、DPPC(二棕榈酰基磷脂酰胆碱)、DSPC(二硬脂酰基磷脂酰胆碱)、DLPC(二月桂酰磷脂酰胆碱)、SPC大豆磷脂酰胆碱(大豆磷脂)，EPC(蛋黄磷脂)，油菜籽磷脂，向日葵磷脂，DEPC(二芥酰基卵磷脂)，DOPC(二油酸酰基卵磷脂)，POPC(棕榈酰基油酰基卵磷脂)、鞘磷脂、二硬脂酰磷脂酸(DSPA)、二油酰磷脂酰乙醇胺(DOPE)、二棕榈酰磷脂酸(DPPA)、肉豆蔻酰溶血磷脂(M-lysoPC)、棕榈酰溶血磷脂(P-lysoPC)、1-硬脂酰-溶血磷脂酰胆碱(S-lysoPC)、二棕榈酰磷脂酰乙醇胺(DPPE)、二硬脂酰磷脂酰乙醇胺(DSPE)、二油酰磷脂酰甘油(DOPG)、二肉豆蔻酰磷脂酰乙醇胺(DMPE)、二肉豆蔻酰磷脂酰甘油(DMPG)、二棕榈酰磷脂酰甘油(DPPG)、1-棕榈酰-2-油酰磷脂酰甘油(POPG)、二硬脂酰酰磷脂酰甘油(DSPG)、二棕榈酰磷酯酰丝氨酸(DPPS)、磷脂酰肌醇(PI)、胆固醇(CHO)中的一种或多种。
根据本发明的实施方案，所述药物组合物还包含e.至少一种药学上可接受的溶剂。
根据本发明的实施方案，所述药物组合物可以进一步包含g.药学上可接受的释放调节剂。
根据本发明的实施方案，所述药物组合物可以进一步包含f.药学上可接受的酸。
根据本发明的实施方案，所述液体油选自蓖麻油、芝麻油、玉米油、大豆油、橄榄油、红花油、棉籽油、花生油、鱼油、茶油、杏仁油、巴巴苏油、黑醋栗种子油、琉璃苣油、卡诺拉油、棕榈油、棕榈仁油、向日葵油、中链甘油三酯、二油酸甘油酯、单油酸甘油酯中的一种或多种组合。
根据本发明的实施方案，所述至少一种药学活性成分不限于治疗类型，并可为抗炎药、局麻药、镇痛药、抗精神失常药、抗焦虑药、镇静催眠药、抗抑郁药、抗高血压药、类固醇激素、抗癫痫药、杀菌剂、抗惊厥药、抗帕金森病药、中枢神经兴奋药、抗精神病药、抗心律失常药、抗心绞痛药、抗甲状腺药、解毒药、止吐药、降糖药、抗结核病药、抗艾滋病药、抗乙肝药、抗肿瘤药、抗排斥药及其混合物。
根据本发明的实施方案，合适的药学活性成分可选自下述化合物中的一种或多种的组合：阿司匹林，对乙酰氨基酚，贝诺酯，吲哚美辛，舒林酸，双氯芬酸，双氯芬酸钾，双氯芬酸钠，布洛芬，萘普生，氟比洛芬，氟比洛芬酯、洛索洛芬，萘丁美酮，酮咯酸，保泰松，丁苯羟酸，非诺洛芬，塞来昔布，罗非昔布，Polmacoxib，尼美舒利，美洛昔康，氯诺昔康，吡罗昔康，依托度酸，伐地考昔，帕瑞昔布，艾瑞昔布，卢米昔布。布比卡因，左旋布比卡因，罗哌卡因，甲哌卡因，利多卡因，普鲁卡因，苯佐卡因，丁卡因，达克罗宁。脑啡肽，强啡肽，β-内啡肽，纳曲酮，丁丙诺啡，吗啡，二甲基吗啡，可待因，双氢可待因，羟考酮、氢可酮、 纳布啡，芬太尼，舒芬太尼，瑞芬太尼，曲马多，去甲曲马多，他喷他多，地佐辛，喷他佐辛，美沙酮，哌替啶，氯胺酮，地西泮，氯甲西泮，赖右苯丙胺，右丙氧芬，Difelikefalin，Oliceridine。氯丙嗪，三氟丙嗪，美索哒嗪，哌西他嗪，硫利达嗪，氯普噻吨。地西泮，阿普唑仑，氯硝西泮，奥沙西泮，丙咪嗪，阿密曲替林，多虑平，去甲替林，阿莫沙平，反苯环丙胺，苯乙肼。普鲁卡因胺，亚硝酸异戊酯，硝酸甘油，心得安，美托洛尔，哌唑嗪，酚妥拉明，咪噻吩，卡托普利，依那普利。可乐定，右美托咪定，肾上腺素，去甲肾上腺素，替扎尼定，α-甲基多巴，格隆溴铵。可的松，氢化可的松，倍他米松，曲安奈德，地塞米松，地塞米松酯，泼尼松，泼尼松龙，甲泼尼龙，倍氯米松，氯倍他索，黄体酮，睾酮，庚酸睾酮，十一烷酸睾酮，环戊丙酸睾酮，孕酮，氟维司群，别孕烯醇酮，Ganaxolone，苯妥英，乙妥英。苯扎氯铵，苄索氯铵，醋酸磺胺米隆，甲苄索氯铵，呋喃西林，硝甲酚汞。苯巴比妥、异戊巴比妥、戊巴比妥、司可巴比妥。卡比多巴，左旋多巴，阿尼西坦，奥拉西坦，吡拉西坦，多沙普仑，阿立哌唑，奥氮平，氟哌啶醇，喹硫平，利培酮，氯氮平，帕利哌酮，阿替洛尔，比索洛尔，美托洛尔。阿替洛尔，氨氯地平，尼莫地平，单硝酸异山梨酸酯，依前列醇，曲前列尼尔，伊洛前列素，贝前列素。甲巯咪唑，丙巯氧嘧啶，普萘洛尔，纳洛酮，洛非西定，氟马西尼，苯丙胺。格拉司琼，昂丹司琼，托烷司琼，多拉司琼，帕洛诺司琼，东莨菪碱，多潘立酮，格列吡嗪，格列本脲，格列美脲，优降糖，格列齐特，甲苯磺丁脲，利拉鲁肽，艾塞拉肽，度拉鲁肽，索马鲁肽。达芦那韦，多替拉韦钠，恩曲他滨，拉替拉韦，利托那韦，司他夫定，奈韦拉平，齐多夫定，司他夫定，依曲韦林，阿德福韦酯，恩替卡韦，替比夫定，拉米夫定，替诺福韦二吡呋酯，磷丙替诺福韦，氨硫脲，吡嗪酰胺，丙硫异烟胺，环磷酰胺，5-氟尿嘧啶，卡莫司汀，洛莫司汀，马法兰，苯丁酸氮芥，甲氨蝶呤，长春新碱，博来霉素，阿霉素，他莫昔芬，环孢素，他克莫司，依维莫司，西罗莫司以及所述化合物的药学可接受的盐，立体异构体，衍生物。
根据本发明的实施方案，所述药学活性成分选自酰胺类局麻药，例如选自布比卡因、罗哌卡因、左旋布比卡因、甲哌卡因、利多卡因及其盐。所述酰胺类局麻药的盐可以选自其脂肪酸盐和水溶性盐，形成盐的酸包括月桂酸、肉豆蔻酸、硬脂酸、棕榈酸、山嵛酸、花生酸、盐酸、磺酸、磷酸、醋酸、枸橼酸、马来酸、甲磺酸、富马酸、琥珀酸、乳酸等。
根据本发明的实施方案，所述药学活性成分除了包含酰胺类局麻药，还进一步包含第二种活性成分，所述药学活性成分可选自COX受体抑制药、肾上腺素受体激动药和糖皮质激素类药中的一种。所述COX受体抑制药包括非选择性COX抑制药和选择性COX-2抑制药。这些类别中代表的非甾体抗炎药包括，但不限于，下列非选择性COX抑制药：阿司匹林，对乙 酰氨基酚，贝诺酯，吲哚美辛，舒林酸，双氯芬酸，双氯芬酸钾，双氯芬酸钠，布洛芬，萘普生，氟比洛芬，洛索洛芬，萘丁美酮，吡罗昔康，酮咯酸，保泰松，丁苯羟酸，非诺洛芬；下列选择性COX-2抑制药：塞来昔布，罗非昔布，尼美舒利，美洛昔康，氯诺昔康，依托度酸，伐地考昔，帕瑞昔布，艾瑞昔布，卢米昔布。以及所述化合物的药学可接受的盐，立体异构体，衍生物。所述的肾上腺素受体激动药主要是α2-肾上腺素受体激动药，包括但不限于可乐定，右美托咪定，肾上腺素，去甲肾上腺素，替扎尼定，α-甲基多巴。所述的糖皮质激素类药包括，但不限于可的松，氢化可的松，倍他米松，曲安奈德，地塞米松，泼尼松，泼尼松龙，甲泼尼龙，倍氯米松，氯倍他索。
在一些实施方式中，所述药学活性成分选自罗哌卡因、布比卡因、左旋布比卡因、美洛昔康、塞来昔布、酮咯酸、曲安奈德中的一种或几种的组合。在一些实施方式中，所述药学活性成分选自酰胺类局麻药与非甾体抗炎药的组合，例如罗哌卡因和美洛昔康组合物、左旋布比卡因和美洛昔康组合物、布比卡因和美洛昔康组合物、罗哌卡因和塞来昔布组合物、左旋布比卡因和塞来昔布组合物、布比卡因和塞来昔布组合物等。
根据本发明的实施方案，所述药学上可接受的释放调节剂选自小分子酯类和表面活性剂。所述小分子酯类为三醋酸甘油酯、硬脂酸异丙酯、月桂酸异丙酯、棕榈酸异丙酯、肉豆蔻酸异丙酯、苯甲酸苄酯。
在一些实施方式中，所述表面活性剂为非离子型表面活性剂。
在一些实施方式中，所述表面活性剂包括硬脂酸聚烃氧40酯、辛酸癸酸聚乙二醇甘油酯、月桂酰聚氧乙烯甘油酯、硬脂酰聚氧乙烯甘油酯、油酰聚氧乙烯甘油酯、维生素E聚乙二醇琥珀酸酯、蛋黄卵磷脂、大豆磷脂、氢化大豆磷脂，泊洛沙姆，聚山梨酯，聚乙二醇-12-羟基硬脂酸酯、丙二醇单辛酸酯等。所述泊洛沙姆可选自例如泊洛沙姆407、泊洛沙姆188，所述聚山梨酯可选自例如聚山梨酯80。
根据本发明的实施方案，所述药学上可接受的酸(f组分)选自醋酸、乳酸、琥珀酸、富马酸、马来酸、甲磺酸、亚油酸、山梨酸、辛酸、壬酸、月桂酸、棕榈酸、油酸、盐酸、邻苯二甲酸、癸酸、肉豆蔻酸、丙酸、丁酸、庚酸、戊酸、苹果酸、酒石酸、草酸、柠檬酸、抗坏血酸、水杨酸、咖啡酸、维生素E琥珀酸等。
根据本发明的实施方案，所述组合物还可以进一步包括一种或多种抗氧化剂。抗氧化剂可用于防止或减少本发明中所述缓释递药系统中磷脂或液体油的氧化。本发明提供的抗氧化剂包括但不限于维生素C(抗坏血酸)，半胱氨酸或其盐酸盐，维生素E(生育酚)，抗坏血酸棕榈酸酯，谷胱甘肽，α硫辛酸，硫代甘油，丁基羟基茴香醚，二丁基羟基甲苯，乙二胺四乙酸 及其钠盐、柠檬酸、酒石酸。
根据本发明的实施方案，所述组合物还可以进一步包括其他药学领域常规的赋形剂，合适的药物赋形剂的实例在Excipients and their use in injectable products.PDA J Pharm Sci Technol.第51卷，1997年7-8月，第166-171页和Excipient Selection In Parenteral Formulation Development，Pharma Times，第45卷，第3期，2013年3月，第65-77页中描述，他们通过引用整体并入本发明中。
根据本发明的实施方案，所述液体油占组合物总量的约20％至约90％(w/w)，例如约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％、75％、76％、77％、78％、79％。在一些实施方案中，所述液体油比例约为30至90％(w/w)。在一些实施方案中，所述液体油比例约为40％至79％(w/w)。
根据本发明的实施方案，所述凝胶因子占组合物总量的2％至50％(w/w)，例如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％。在一些实施方案中，所述凝胶因子占组合物总量2％至30％(w/w)。
根据本发明的实施方案，所述稳定剂占组合物总量的1％至40％(w/w)，例如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％。在一些实施方案中，所述稳定剂占组合物总量5％至30％(w/w)。
根据本发明的实施方案，所述药学活性成分占组合物总量的0.01％至50.0％(w/w)。根据一些实施方案，药学活性成分占组合物总量的0.01％至15％(w/w)，例如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％。根据一些实施方式，药学活性成分以3％(w/w)至10％(w/w)的量存在。根据一些实施方式，当药学活性成分选自两种以上时，每种药学活性成分可以占组合物总量的0.01％至10％(w/w)，例如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％。
根据本发明的实施方案，所述溶剂总量占组合物总量的0％至50％(w/w)，在一些实施方案中，可以不含有溶剂，在一些实施方案中，所述溶剂总量可以占组合物总量的0.01-50％，优选为2-50％，例如为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％。在一些实施方案中，所述溶剂总量占组合物总量的5％-50％(w/w)，在一些实施方案中，所述溶剂总量占组合物总量的5％-30％(w/w)。当溶剂选自两种以上的组合时，每种溶剂可以占组合物总量的0％至30％(w/w)，优选为0.01-30％，例如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％、30％。
根据本发明的实施方案，所述溶剂为非水溶剂，所述非水溶剂选自醇类、N-甲基吡咯烷酮、苯甲酸苄酯、二甲亚砜中的一种或多种组合。所述醇类选自甲醇、乙醇、正丙醇，异丙醇，正丁醇，异丁醇、叔丁醇、乙二醇、丙二醇、甘油、苯甲醇、苯乙醇、聚乙二醇。
优选的，所述非水溶剂选自苯甲醇、N-甲基吡咯烷酮、二甲亚砜、无水乙醇中的一种或多种组合
根据本发明的实施方案，所述释放调节剂占组合物总量的0％至40％(w/w)，优选的，为0.1％至40％(w/w)，在一些实施方式中，所述释放调节剂可以占组合物总量的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％，在一些实施方式中，当所述释放调节剂选自小分子酯类时，所述释放调节剂用量为1～35％；在一些实施方式中，当所述释放调节剂选自表面活性剂时，所述释放调节剂用量为0.1％至5％(w/w)。
根据本发明实施方案，所述药学上可接受的酸(f组分)占组合物总量的0％至20％(w/w)，在一些实施方案中，可以不含酸，在一些实施方案中，所述酸占组合物总量的0.01％至20％，优选为0.05-20％，例如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％，在一些实施方式中， 所述酸占组合物总量的4％至20％。
本发明提供的药物组合物为半固体制剂。在本发明的药物组合物中，所述药学上可接受的溶剂和释放调节剂可以作为粘度调节剂，使所述组合物适于注射。在一些实施方式中，在30℃时，所述组合物的粘度小于20000cP。在一些实施方式中，在30℃时所述组合物的粘度在5000至10000cP的范围内。在一些实施方式中，在30℃时，所述组合物的粘度在3000至5000cP的范围内。在一些实施方式中，在30℃时，所述组合物的粘度在1000至3000cP的范围内。
本发明提供了一种所述药物组合物的制备方法，包括如下步骤：
(a1)将液体油、药学上可接受的凝胶因子、药学上的稳定剂和溶剂混合，在加热条件下搅拌至澄清均一的混合溶液；
(a2)将至少一种药学上的活性成分添加到所述混合溶液中，搅拌至形成均一混合物；
(a3)将(a2)形成的均一混合物冷却至室温。
根据本发明的实施方案，所述步骤(a1)的混合还包括加入至少一种释放调节剂，例如，所述步骤(a1)可以为将液体油、凝胶因子、药学上的稳定剂、药学上可接受的溶剂与释放调节剂混合。
在一些实施方式中，所述方法包括：
1.在50～70℃下将液体油、凝胶因子、稳定剂、药学上的活性分子和药学上的溶剂混合，直至得到澄清透明溶液。
2.将热溶液过0.22μm滤膜除菌。
3.将所述过滤后的混合溶液冷却至室温。
在一些实施方式中，所述方法包括：
1.在50～70℃下将液体油、凝胶因子、药学上的稳定剂、药学上的活性分子、药学上的溶剂和释放调节剂混合，直至得到澄清透明溶液。
2.将热溶液过0.22μm滤膜除菌。
3.将所述过滤后的混合溶液冷却至室温。
在一些实施方式中，可以根据不同药学活性分子的性质，将较难溶解的活性分子先溶于部分溶剂，再加入由液体油、凝胶因子、剩余部分溶剂加热混合形成的溶液中而制备所需的药物组合物。
在一些实施方式中，所述方法包括：
1.在50～70℃下将液体油、凝胶因子和稳定剂与部分溶剂混合，直至得到澄清透明溶液。
2.将药学上的活性分子加入部分溶剂中，直至完全溶解。
3.将药物溶液与1中的溶液混合均匀。
4.将热溶液过0.22μm滤膜除菌。
5.将所述过滤后的混合溶液冷却至室温。
在一些实施方式中，可以根据不同药学活性分子的性质，将较难溶解的活性分子先溶于部分溶剂，再加入由液体油、凝胶因子、部分溶剂、释放调节剂加热混合形成的溶液中而制备所需的药物组合物。
在一些实施方式中，所述方法包括：
1.在50～70℃下将液体油、凝胶因子，稳定剂，部分溶剂和释放调节剂混合，直至得到澄清透明溶液。
2.将药学上的活性分子加入部分溶剂中，直至完全溶解。
3.将药物溶液与1中的溶液混合均匀。
4.将热溶液过0.22μm滤膜除菌。
5.将所述过滤后的混合溶液冷却至室温。
本发明所述的药物组合物的制备方法，在一些实施方式中，混合溶液自然冷却至室温；在一些实施方式中，混合溶液迅速冷却凝固后于室温放置；在一些实施方式中，混合溶液迅速冷却凝固后于特定温度保温一定时间后于室温放置；在一些实施方式中，混合溶液在体系熔融温度下保温凝固后于室温放置；在一些实施方式中，混合溶液在体系熔融温度下保温凝固后于特定温度保温一定时间后于室温放置。
本发明提供一种包含所述药物组合物的缓释制剂，所述制剂作为储库制剂施用，一方面，所述制剂为可注射的。另一方面，所述制剂可以局部给药。
另一方面，所述制剂可皮下注射，周围神经注射，肌内注射或向伤口直接施用。
另一方面，所述制剂适合在皮肤或粘膜给药。
本发明提供的制剂以单次剂量施用，所含药量可以达到止痛、神经阻滞的效果，可用于防止或减轻局部疼痛。
根据一些实施方式，本发明提供的制剂可在给药部位形成形态稳定的储库，可缓慢持续地释放药物，延长局麻药释放时间，提高治疗效果。
在一些实施方式中，所述制剂施用后可持续有效治疗至少24小时。在一些实施方式中，所述制剂施用后可持续有效治疗至少24至48小时。在一些实施方式中，所述制剂施用后可持续有效治疗至少48至72小时。在一些实施方式中，所述制剂施用后可持续有效治疗至少 72小时。根据本发明的实施方案，所述制剂进一步包括填充了所述制剂的包材，所述包材选自以下一种或多种：西林瓶、预灌封注射器、卡式瓶。
术语与缩写
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。
本申请说明书和权利要求书记载的数值范围，当该数值范围被定义或其仅可为“整数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如，“0～10的整数”应当理解为记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数。
当该数值范围被定义为“数”或可以包括“整数”或“非整数”时，应当理解为记载了该范围的两个端点、该范围内的每一个整数以及该范围内的每一个小数。例如，“0～10的数”应当理解为不仅记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数，还至少记载了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和。
术语“脂肪烃基”包括饱和或不饱和，直链或具有支链的链状烃基，所述脂肪烃基的类型可选自烷基(饱和脂肪烃基)、烯基、炔基等，所述脂肪烃基的碳原子数优选为1-40，进一步优选为1-30(例如为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)，具体可包括但不限于如下基团：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、乙烯基、1-丙烯基、2-丙烯基、1-甲基乙烯基、1-丁烯基、1-乙基乙烯基、1-甲基-2-丙烯基、2-丁烯基、3-丁烯基、2-甲基-1-丙烯基、2-甲基-2-丙烯基、1-戊烯基、1-己烯基、乙炔基，1-丙炔基，2-丙炔基，1-丁炔基，1-甲基-2-丙炔基，3-丁炔基，1-戊炔基和1-己炔基；其他基团中所含“脂肪烃基”部分同上述解释。
术语“烷基”为饱和脂肪烃基，符合上述脂肪烃基中的相关定义，例如所述烷基的碳原子数优选为1-40，进一步优选为1-30，或1-10(例如为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)。且本领域技术人员可以理解“亚烷基”亦可参照上述脂肪烃基中的相关定义，例如所述亚烷基的碳原子数可以为C1，C2，C3，C4，C5，C6，C6，C7，C8，C9，C10。
术语“生物相容性”是指组合物成分与机体之间的相互作用。
术语“活性成分”是指用于治疗疾病的药物。因此，活性成分、药物可替换使用。此处使用的术语“活性成分”或“药物”包括但不限于局部或全身作用的药物活性物质，其可以通过局部给药或通过注射，如皮下、皮内、肌内及关节内注射进行施用。至少一种活性成分存在于本发明的缓释递药系统中。
术语“油凝胶”是指在液态油中添加凝胶因子而得到的一种热可逆、半固体状且具有一定粘弹性的分散体系。
术语“凝胶因子”是指分子中具有亲脂结构和可相互作用位点，并且具有一定表面活性以及热可逆性的一类物质。
术语“半固体”是指在一定压力下可流动的形态。更具体地，半固体通常在30℃下粘度在100至50000cP之间的粘度，特别是在30℃下100至20000cP的之间粘度。
术语“小分子酯类”是指分子量小于500的酯类，室温下为液体。
本发明所用的术语“酰胺型”是指酰胺或卡因类局部麻醉剂，如布比卡因，左旋布比卡因，罗哌卡因，甲哌卡因，利多卡因等。酰胺类局麻药一般由亲脂部分和亲水部分组成，亲脂性部分，可为芳烃或芳杂环，而以苯环作用最强。苯环上引入给电子基团例如氨基等可使活性增强。亲水部分一般为仲胺、叔胺或吡咯烷、哌啶、吗啉等，以叔胺最为常见。pKa一般在7.5～7.9之间，生理条件下为离子型。
本发明使用的缩写词具有如下定义：SPC为大豆磷脂酰胆碱(大豆磷脂)，EPC为蛋黄磷脂酰胆碱(蛋黄磷脂)，HSPC为氢化大豆磷脂酰胆碱，DLPC为二月桂酰磷脂酰胆碱，DMPC为二肉豆蔻酰基磷脂酰胆碱，DPPC为二棕榈酰基磷脂酰胆碱，DSPC为二硬脂酰基磷脂酰胆碱，DEPC为二芥酰基卵磷脂，DOPC为二油酸酰基磷脂酰胆碱(二油酸酰基卵磷脂)，POPC为棕榈酰基油酰基卵磷脂，DEPC为二芥酰基卵磷脂，DOPC为二油酸酰基卵磷脂，POPC为棕榈酰基油酰基卵磷脂，DSPA为二硬脂酰磷脂酸，DOPE为二油酰磷脂酰乙醇胺，DPPA为二棕榈酰磷脂酸，M-lysoPC为肉豆蔻酰溶血磷脂，P-lysoPC为棕榈酰溶血磷脂，S-lysoPC为1-硬脂酰-溶血磷脂酰胆碱，DPPE为二棕榈酰磷脂酰乙醇胺，DSPE为二硬脂酰磷脂酰乙醇胺，DOPG为二油酰磷脂酰甘油，DMPE为二肉豆蔻酰磷脂酰乙醇胺，DMPG为二肉豆蔻酰磷脂酰甘油，DPPG为二棕榈酰磷脂酰甘油，POPG为1-棕榈酰-2-油酰磷脂酰甘油，DSPG为二硬脂酰酰磷脂酰甘油，DPPS为二棕榈酰磷酯酰丝氨酸，PI为磷脂酰肌醇，BA为苯甲醇，NMP为N-甲基吡咯烷酮，DMSO为二甲基亚砜，BHA代表丁基羟基茴香醚，BHT代表二丁基羟基甲苯，BUP为布比卡因，ROP为罗哌卡因，MLX为美洛昔康，CHO代表胆 固醇，PRX为吡罗昔康，LBUP为左旋布比卡因，TAC为曲安奈德，KTL为酮咯酸，VE代表维生素E，VES代表维生素E琥珀酸。
有益效果
1)本发明提供了一种缓释制剂组合物，该组合物制剂在常温下呈现半固体，在给药部位可直接作为药物储库。本发明所选用的凝胶因子，与制剂其他成分具有良好的生物相容性，可使液体油固化，满足药物缓释释放需求。
2)本发明还惊奇地发现，在制剂体系中加入合适的稳定剂，可以改善组合物在长期放置过程中出现的变色问题，提高组合物的持油性，增强组合物的凝胶特性，降低组合物粘度等；
3)本发明的缓释递药液体组合物具有合适的粘度，易于给药；本发明的缓释递药半固体组合物可直接施用于给药部位，便于临床给药。
4)本发明组合物刺激性小，具有良好的用药安全性及耐受性。
5)本发明提供的缓释制剂系统，能够使得活性药物成分实现良好的释放性能，降低突释的可能性。
6)本发明的组合物尤其适用于具有麻醉、镇痛活性的药物制剂开发，相对于其他缓释镇痛药体系具有更多的优势，例如对于镇痛活性成分的释放持续稳定，不仅可以注射给药，而且适用于稳定便捷的局部给药，患者耐受性好，副作用少。
附图说明
图1-1和图1-2是组合物1010在2-8℃和25℃的流变学结果
图1-3和图1-4是组合物1013在2-8℃和25℃的流变学结果
图1-5～1-7是组合物1051和1052、1030、1031的流变学结果
图1-8是组合物1010和1013的粘度-温度变化图谱
图1-9是组合物1051和1052的粘度-温度变化图谱
图1-10是组合物1053和1054的粘度-转速变化图谱
图2-1和2-2是组合物1047的布比卡因和美洛昔康血药浓度时间曲线。
图2-3和2-4是组合物1048的布比卡因和美洛昔康血药浓度时间曲线。
图3-1是组合物1076、1077和1078对大鼠CFA炎症痛模型的机械痛觉敏感的影响。Pre表示造模前基础机械痛阈值，黑色实心点表示与模型组相比，结果具有统计学差异(p<0.05)。
图4-1和4-2是组合物1079的罗哌卡因和美洛昔康血药浓度时间曲线。
图5-1和5-2是组合物1080的罗哌卡因和美洛昔康血药浓度时间曲线。
图5-3和5-4是组合物1081的罗哌卡因和美洛昔康血药浓度时间曲线。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
实验材料：
蓖麻油：CO；
单硬脂酸甘油酯：
Figure PCTCN2022071928-appb-000011
Cithrol GMS 40、Geleol
混合脂肪酸甘油酯(硬脂)：硬脂36型，硬脂38型，SUPPOCIRE AM，SUPPOCIRE CM，GELUCIRE 43/01，SOFTISAN 378。
双硬脂酸甘油酯：Precirol ATO5
山嵛酸甘油酯：COMPRITOL 888 ATO
磷脂：SPC，HSPC、DMPC、DPPC、DSPC、DEPC、EPC、DOPC
实施例1
稳定剂对组合物外观的影响
按照表1-1至表1-3中所示配制含有不同凝胶因子的组合物，并于室温长期放置20个月，将组合物与标准比色液Y(黄色)1～10号对比，考察组合物外观颜色的变化。
表1-1单硬脂酸甘油酯作为凝胶因子的组合物长期放置后的外观颜色
Figure PCTCN2022071928-appb-000012
表1-2硬脂作为凝胶因子的组合物长期放置后的外观颜色
Figure PCTCN2022071928-appb-000013
表1-3山嵛酸甘油酯作为凝胶因子的组合物长期放置后的外观颜色
Figure PCTCN2022071928-appb-000014
本发明意外发现只含有脂肪酸甘油酯作为凝胶因子的油凝胶制剂在长期留样过程中颜色均发生不同程度变深，加入稳定剂(例如SPC、HSPC)的组合物长期放置20个月，外观色号在Y7～8号之间，颜色变化明显小于其他油凝胶组合物，能够明显提高油凝胶组合物的外观稳定性。
实施例2
组合物的持油性研究
按照下表2-1～2-9中所示的每种成分制备含有不同比例凝胶因子的药物组合物。称取0.5g药物组合物，置于离心管中，以不同转速离心，离心后将离心管倒置，观察组合物析油情况。
表2-1不含稳定剂的油凝胶组合物持油性研究
Figure PCTCN2022071928-appb-000015
表2-2加入稳定剂后油凝胶组合物的持油性对比
Figure PCTCN2022071928-appb-000016
表2-3稳定剂用量对油凝胶组合物的持油性研究
Figure PCTCN2022071928-appb-000017
表2-4稳定剂用量对油凝胶组合物的持油性研究
Figure PCTCN2022071928-appb-000018
Figure PCTCN2022071928-appb-000019
表2-5稳定剂用量对油凝胶组合物的持油性研究
Figure PCTCN2022071928-appb-000020
表2-6含有稳定剂油凝胶组合物的持油性研究
Figure PCTCN2022071928-appb-000021
表2-7含有稳定剂油凝胶组合物的持油性研究
Figure PCTCN2022071928-appb-000022
表2-8含有稳定剂的油凝胶组合物的持油性研究
Figure PCTCN2022071928-appb-000023
表2-9含有稳定剂的油凝胶组合物的持油性研究
Figure PCTCN2022071928-appb-000024
持油性是评价油凝胶结构稳定性的指标之一，为了保证凝胶因子对液体油的固化能力，防止在长期放置过程中液体油析出的现象，需对制剂的持油性进行研究，考察油凝胶中最大载油能力。本发明意外的发现含有稳定剂的组合物能显著提高持油性，提高物理稳定性，有效降低储存期间析油风险。
实施例3
油凝胶组合物的粘度测量
按表3-1至3-3制备含有不同稳定剂和有机溶剂用量的药物组合物。在70℃下将表中原辅料混合，边加热边搅拌直至形成透明均一的溶液，冷却至室温形成固态凝胶状物质。随后使用配备14号转子的粘度计通过轴方法测量药物组合物的粘度，检测温度为30℃转速为10rpm，粘度检测结果见下表3-1至3-3。
表3-1不含稳定剂的药物组合物的粘度结果
Figure PCTCN2022071928-appb-000025
表3-2含有不同稳定剂的药物组合物的粘度结果
Figure PCTCN2022071928-appb-000026
3-3含有不同有机溶剂用量的药物组合物的粘度结果
Figure PCTCN2022071928-appb-000027
本发明意外的发现加入稳定剂后(如SPC、DEPC、CHO、DOPC等)，能够显著降低药物组合物的粘度，同时有机溶剂的用量也影响整个体系的粘度。因此可以通过调整稳定剂和有机溶剂的比例，对药物组合物的粘度进行优化，使其更易于临床给药。
实施例4
通针性考察
按照表4-1至4-4配制含有不同有机溶剂和不同稳定剂的油凝胶组合物，对表中组合物进行通针性检测，考察最大推力。检测结果见下表4-1至4-4。
表4-1通针性考察
Figure PCTCN2022071928-appb-000028
表4-2不同有机溶剂用量的通针性考察
Figure PCTCN2022071928-appb-000029
表4-3不同稳定剂的通针性考察
Figure PCTCN2022071928-appb-000030
表4-4含有不同稳定剂用量的药物组合物的通针性结果
Figure PCTCN2022071928-appb-000031
通常为了医生给药方便，临床给药通针性要求最大推力不大于2kg。
本发明考察了有机溶剂用量对通针性的影响，结果表明提高有机溶剂用量，可以降低推力，更有利于临床给药。同时，在油凝胶组合物中加入其他稳定剂均可以达到降低推力的作用。
实施例5
组合物的流变学研究
按表5-1至5-4制备油凝胶组合物，进行流变学研究。流变仪型号：TA DHR-1样品量：1mL。测定模式：振荡模式：时间扫描，固定Strain 0.5％，频率1Hz；振荡模式：频率扫描，固定Strain 0.5％，频率扫描范围为0.1-100rad/s；流动模式：粘度扫描，剪切速率范围为0.01-100 1/s；流动模式：粘度变温扫描，温度变化范围20℃-60℃，固定剪切速率0.11/s
表5-1组合物成分
Figure PCTCN2022071928-appb-000032
表5-2组合物成分
Figure PCTCN2022071928-appb-000033
表5-3组合物成分
Figure PCTCN2022071928-appb-000034
表5-4组合物成分
Figure PCTCN2022071928-appb-000035
流变学中的储能模量G’和损耗模量G”参数可用于评价凝胶特性。理论上甘油酯的储能模量G’越大，凝胶强度越强，凝胶网络结构越稳定。当储能模量(G’)大于损耗模量(G”)时，样品呈现凝胶特性。图1-1至1-7分别为表5-1～5-3油凝胶组合物的流变性质结果。本发明意外发现含有SPC的组合物(1013)G’大于G”，具有明显的凝胶特性，而不含有SPC的组合物(1010、1030、1031)未表现出凝胶性质。同时增加稳定剂的用量(1051和1052)，可增强制剂的凝胶强度。
图1-8和图1-9为组合物1010、1013、1051和1052粘度随温度变化的趋势，根据变化趋势可推断组合物的胶凝温度，结果见表5-5，由表5-5可知，加入SPC后能降低组合物的胶凝温度，更有利于放大生产及灌装。
表5-5组合物胶凝温度
编号 胶凝温度(℃)
1010 49.1
1013 45.2
1051 40.2
1052 40.2
图1-10为组合物1053和1054粘度随转速变化的趋势，根据变化趋势可以看出本发明的 油凝胶组合物存在剪切稀化的性质，更有利于临床给药。同时稳定剂SPC的用量增加，组合物粘度有一定程度的降低。
实施例6
凝固温度研究
按表6-1至6-3制备油凝胶组合物，在显微镜下观察组合物溶解后冷却时的凝固温度，考察有机溶剂和稳定剂对凝固温度的影响。检测结果见下表6-1至6-3。
表6-1不含稳定剂的组合物的凝固温度
Figure PCTCN2022071928-appb-000036
表6-2含有不同有机溶剂的组合物的凝固温度
Figure PCTCN2022071928-appb-000037
表6-3含有不同稳定剂的组合物的凝固温度
Figure PCTCN2022071928-appb-000038
本发明意外发现加入有机溶剂和稳定剂可以降低组合物的凝固温度，更有利于生产灌装。
实施例7
不同活性成分的油凝胶组合物
按照下表7-1中所示的每种成分制备含有不同主要活性成分的油凝胶组合物。在70℃下将表中原辅料混合，边加热边搅拌直至形成透明均一的溶液，冷却至室温均可形成固态凝胶状物质。
表7-1不同活性成分的组合物
Figure PCTCN2022071928-appb-000039
表7-2不同活性成分组合物
Figure PCTCN2022071928-appb-000040
实施例8
含有不同浓度活性成分和抗氧化剂的药物组合物
按照下表8中所示的每种成分制备含有不同浓度活性成分和抗氧化剂的油凝胶组合物。在70℃下将表中原辅料混合，边加热边搅拌直至形成透明均一的溶液，冷却至室温均可形成固态凝胶状物质。
表8含有不同浓度和抗氧化剂的药物组合物
Figure PCTCN2022071928-appb-000041
实施例9不含有机溶剂或含有不同有机溶剂的药物组合物
按照下表9中所示的每种成分制备含有不同有机溶剂的油凝胶组合物。在70℃下将表中原辅料混合，边加热边搅拌直至形成透明均一的溶液，冷却至室温均可形成固态凝胶状物质。
表9不含有机溶剂或含有不同有机溶剂的药物组合物
Figure PCTCN2022071928-appb-000042
实施例10
油凝胶组合物的体内施用。
犬体内药代动力学研究如下。重量约10kg的比格犬实验前禁食12小时(取下喂食的食盒)以上，自由饮水，给药后4小时给食。各组按皮下注射6mg/kg进行给药，样品信息见表10。各组动物于给药前取0小时、于给药后0.5、1、2、3、6、8、12、24、36、48、60、72 和96小时各采集血样约0.5mL至EDTA-2K+抗凝的采血管中，全血经8000rpm离心5min后收集血浆，随后通过LC-MS/MS检测血浆样品中的药物浓度。
表10组合物处方信息
Figure PCTCN2022071928-appb-000043
组合物给药后96小时内的BUP和MLX的血药浓度-时间曲线见图2-1至2-4。
实施例11
油凝胶组合物的体内施用
大鼠药效研究如下。大鼠于实验前三天每天测定一次PWT值，并于第四天造模前测定一次PWT为造模前基础值，随即所有大鼠的右后爪分别给予100μL CFA，炎症造模后24h再测定一次PWT值即为造模后基础值，经足底皮下注射给予组合物，样品信息见表11，模型组不做给药处理，在给药后不同时间点用Von Frey单丝刺激大鼠后肢足底中部，测试其机械性缩爪阈值(paw withdrawal threshold，PWT)作为疼痛阈值。检测时间分别为给药后30min、1h、4h、8h、12h、24h、48h、72h、92h。
表11样品信息
Figure PCTCN2022071928-appb-000044
结果如图3-1所示，造模前，各组大鼠的机械痛阈值(PWT)均保持在21-24g左右；造模后24h，机械痛阈值(PWT)下降到4-6g，可见CFA造模后大鼠的机械性痛觉过敏十分明显。组合物1076在给药后30min即显著提高了大鼠的PWT值(p<0.05)，并且效应可持续到96h，差异具有统计学意义(p＜0.05)。组合物1078在给药后4h出现镇痛效应(p＜0.05)，持续到12h后镇痛效应消失(p＞0.05)，说明其效应维持时间在12h到24h之间。组合物1077直到8h才出现镇痛效应(p＜0.05)，并维持到12h，之后镇痛效果出现波动，在48h处再次显示出镇痛效应(p＜0.05)。
实施例12
油凝胶组合物的体内施用。
犬体内药代动力学研究如下。重量约10kg的比格犬实验前禁食12小时(取下喂食的食盒)以上，自由饮水，给药后4小时给食。各组按皮下注射6mg/kg进行给药，样品信息见表12。各组动物于给药前取0小时、于给药后0.5、1、2、3、6、8、12、24、36、48、60、72 和96小时各采集血样约0.5mL至EDTA-2K+抗凝的采血管中，全血经8000rpm离心5min后收集血浆，随后通过LC-MS/MS检测血浆样品中的药物浓度。
表12组合物处方信息
Figure PCTCN2022071928-appb-000045
组合物给药后96小时内的ROP和MLX的血药浓度-时间曲线见图4-1至4-2。
实施例13
油凝胶组合物的体内施用。
犬体内药代动力学研究如下。重量约10kg的比格犬实验前禁食12小时(取下喂食的食盒)以上，自由饮水，给药后4小时给食。各组按皮下注射6mg/kg进行给药，样品信息见表13。各组动物于给药前取0小时、于给药后0.5、1、2、3、6、8、12、24、36、48、60、72和96小时各采集血样约0.5mL至EDTA-2K+抗凝的采血管中，全血经8000rpm离心5min后收集血浆，随后通过LC-MS/MS检测血浆样品中的药物浓度。
表13组合物处方信息
Figure PCTCN2022071928-appb-000046
组合物给药后96小时内的ROP和MLX的血药浓度-时间曲线见图5-1至5-4。
以上，对本发明示例性的实施方式进行了说明。但是，本发明的保护范围不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种药物组合物，包括如下组分：
    a.液体油
    b.药学上可接受的凝胶因子，所述凝胶因子选自如式I的脂肪酸甘油酯中的一种或多种：
    Figure PCTCN2022071928-appb-100001
    其中，R’、R”可以相同或不同，彼此独立地选自H或RaCO，R”’选自RaCO；每个Ra彼此独立地选自饱和或不饱和脂肪烃基；
    c.药学上可接受的稳定剂，所述稳定剂选自式II或式III化合物中的一种或多种：
    所述式II化合物为
    Figure PCTCN2022071928-appb-100002
    其中，Rs选自H，
    Figure PCTCN2022071928-appb-100003
    每个R 1、R 2相同或不同，彼此独立地选自饱和或不饱和脂肪烃基；每个R 3、R 4、R 5相同或不同，彼此独立地选自H或烷基；L选自亚烷基；
    所述式III化合物为
    Figure PCTCN2022071928-appb-100004
    其中，R选自烷基；
    d.至少一种药学上的活性成分。
  2. 根据权利要求1的药物组合物，其特征在于，所述式I中，每个Ra独立地选自烷基，优选的，每个Ra独立地选自C 1-40烷基，更优选的，每个Ra独立地选自C 7-40烷基；
    优选的，R’、R”选自H，R”’选自(C 11-40烷基)C(＝O)；或R’选自H，R”选自RaCO，且R”、R”’中各自独立所选Ra烷基的碳数总和大于18；或R’、R”、R”’均选自RaCO，且R’、R”、R”’中各自独立所选Ra烷基的碳数总和大于17；
    优选的，所述式II中，每个R 1、R 2相同或不同，彼此独立地选自C 10-30饱和或不饱和脂肪烃基，例如C 13-21烷基；每个R 3、R 4、R 5相同或不同，彼此独立地选自H或C 1-10烷基，例如彼此独立地选自H，甲基，乙基；所述L选自C 1-10亚烷基，优选的，L选自C 1-6亚烷基，例如为亚甲基，亚乙基；式III所示化合物中，R选自C 1-10烷基，例如C 8-10烷基。
  3. 根据权利要求1或2的药物组合物，其特征在于，
    所述b组分药学上可接受的凝胶因子包括例如单硬脂酸甘油酯，双硬脂酸甘油酯、三硬脂酸甘油酯、单山嵛酸甘油酯、双山嵛酸甘油酯、单棕榈酸硬脂酸甘油酯、双棕榈酸硬脂酸甘油酯、单棕榈酸甘油酯、双棕榈酸甘油酯、棕榈酸硬脂酸甘油酯中的一种或多种；
    所述c组分药学上可接受的稳定剂选自HSPC(氢化大豆磷脂)、DMPC(二肉豆蔻酰基磷脂酰胆碱)、DPPC(二棕榈酰基磷脂酰胆碱)、DSPC(二硬脂酰基磷脂酰胆碱)、DLPC(二月桂酰磷脂酰胆碱)、SPC大豆磷脂酰胆碱(大豆磷脂)，EPC(蛋黄磷脂)，油菜籽磷脂，向日葵磷脂，DEPC(二芥酰基卵磷脂)，DOPC(二油酸酰基卵磷脂)，POPC(棕榈酰基油酰基卵磷脂)、鞘磷脂、二硬脂酰磷脂酸(DSPA)、二油酰磷脂酰乙醇胺(DOPE)、二棕榈酰磷脂酸(DPPA)、肉豆蔻酰溶血磷脂(M-lysoPC)、棕榈酰溶血磷脂(P-lysoPC)、1-硬脂酰-溶血磷脂酰胆碱(S-lysoPC)、二棕榈酰磷脂酰乙醇胺(DPPE)、二硬脂酰磷脂酰乙醇胺(DSPE)、二油酰磷脂酰甘油(DOPG)、二肉豆蔻酰磷脂酰乙醇胺(DMPE)、二肉豆蔻酰磷脂酰甘油(DMPG)、二棕榈酰磷脂酰甘油(DPPG)、1-棕榈酰-2-油酰磷脂酰甘油(POPG)、二硬脂酰酰磷脂酰甘油(DSPG)、二棕榈酰磷酯酰丝氨酸(DPPS)、磷脂酰肌醇(PI)、胆固醇(CHO)中的一种或多种。
  4. 根据权利要求1-3任一项所述的药物组合物，其特征在于，所述药物组合物还包含e.至少一种药学上可接受的溶剂；
    和/或所述药物组合物可以进一步包含g.药学上可接受的释放调节剂；
    和/或所述药物组合物可以进一步包含f.药学上可接受的酸。
  5. 根据权利要求1-3任一项所述的药物组合物，其特征在于，所述液体油选自蓖麻油、芝麻油、玉米油、大豆油、橄榄油、红花油、棉籽油、花生油、鱼油、茶油、杏仁油、巴巴苏 油、黑醋栗种子油、琉璃苣油、卡诺拉油、棕榈油、棕榈仁油、向日葵油、中链甘油三酯、二油酸甘油酯、单油酸甘油酯中的一种或多种组合；所述至少一种药学活性成分不限于治疗类型，并可为抗炎药、局麻药、镇痛药、抗精神失常药、抗焦虑药、镇静催眠药、抗抑郁药、抗高血压药、类固醇激素、抗癫痫药、杀菌剂、抗惊厥药、抗帕金森病药、中枢神经兴奋药、抗精神病药、抗心律失常药、抗心绞痛药、抗甲状腺药、解毒药、止吐药、降糖药、抗结核病药、抗艾滋病药、抗乙肝药、抗肿瘤药、抗排斥药及其混合物。
  6. 根据权利要求4所述的药物组合物，其特征在于，所述药学上可接受的释放调节剂选自小分子酯类和表面活性剂；所述小分子酯类为三醋酸甘油酯、硬脂酸异丙酯、月桂酸异丙酯、棕榈酸异丙酯、肉豆蔻酸异丙酯、苯甲酸苄酯；所述药学上可接受的酸选自醋酸、乳酸、琥珀酸、富马酸、马来酸、甲磺酸、亚油酸、山梨酸、辛酸、壬酸、月桂酸、棕榈酸、油酸、盐酸、邻苯二甲酸、癸酸、肉豆蔻酸、丙酸、丁酸、庚酸、戊酸、苹果酸、酒石酸、草酸、柠檬酸、抗坏血酸、水杨酸、咖啡酸、维生素E琥珀酸。
  7. 根据权利要求1-6任一项所述的药物组合物，其特征在于，所述液体油占组合物总量的约20％至约90％(w/w)；所述凝胶因子占组合物总量的2％至50％(w/w)；所述稳定剂占组合物总量的1％至40％(w/w)；所述药学活性成分占组合物总量的0.01％至50.0％(w/w)；所述溶剂总量占组合物总量的0％至50％(w/w)。
  8. 根据权利要求1-7任一项所述的药物组合物的制备方法，其特征在于，包括如下步骤：
    (a1)将液体油、药学上可接受的凝胶因子、药学上的稳定剂和溶剂混合，在加热条件下搅拌至澄清均一的混合溶液；
    (a2)将至少一种药学上的活性成分添加到所述混合溶液中，搅拌至形成均一混合物；
    (a3)将(a2)形成的均一混合物冷却至室温。
    根据本发明的实施方案，所述步骤(a1)的混合还包括加入至少一种释放调节剂，例如，所述步骤(a1)可以为将液体油、凝胶因子、药学上的稳定剂、药学上可接受的溶剂与释放调节剂混合。
  9. 一种包含权利要求1-7任一项所述的药物组合物的缓释制剂，其特征在于，所述制剂作为储库制剂施用，优选的，所述制剂为可注射的或所述制剂可以局部给药。
  10. 根据权利要求9所述的制剂，其特征在于，所述制剂进一步包括填充了所述制剂的包材，所述包材选自以下一种或多种：西林瓶、预灌封注射器、卡式瓶。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11992483B2 (en) 2021-07-07 2024-05-28 Cali Biosciences Us, Llc Emulsions for local anesthetics

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116041342B (zh) * 2022-12-30 2024-02-20 加立(深圳)生物科技有限公司 罗哌卡因/美洛昔康盐的一水合物i晶型、药物组合物及其制备方法和应用

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101035562A (zh) 2004-09-17 2007-09-12 杜雷科特公司 优选含有如蔗糖醋酸异丁酸酯等糖酯的持续局部麻醉组合物
CN108743952A (zh) * 2018-06-11 2018-11-06 西安力邦医药科技有限责任公司 局部麻醉药的磷脂-混溶剂-油缓释递药系统组方与制备方法
CN109316602A (zh) * 2018-11-13 2019-02-12 西安力邦医药科技有限责任公司 一种长效镇痛并促进伤口愈合的复方缓释递药系统的组方与应用
WO2019108602A1 (en) * 2017-11-28 2019-06-06 University Of Florida Research Foundation Methods and compositions for retinal drug delivery
CN111655236A (zh) 2017-12-06 2020-09-11 湖州惠中济世生物科技有限公司 可注射长效局麻药半固体凝胶制剂
CN113018248A (zh) * 2019-12-23 2021-06-25 南京清普生物科技有限公司 一种缓释递药系统
CN113827547A (zh) * 2020-06-23 2021-12-24 南京清普生物科技有限公司 一种缓释制剂组合物

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6093B2 (ja) * 1982-10-26 1985-01-05 光雄 松本 油性ゲルの製造方法
US11426418B2 (en) * 2017-12-06 2022-08-30 Mira Pharma Corporation Injectable long-acting semi-solid gel formulations

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101035562A (zh) 2004-09-17 2007-09-12 杜雷科特公司 优选含有如蔗糖醋酸异丁酸酯等糖酯的持续局部麻醉组合物
WO2019108602A1 (en) * 2017-11-28 2019-06-06 University Of Florida Research Foundation Methods and compositions for retinal drug delivery
CN111655236A (zh) 2017-12-06 2020-09-11 湖州惠中济世生物科技有限公司 可注射长效局麻药半固体凝胶制剂
CN108743952A (zh) * 2018-06-11 2018-11-06 西安力邦医药科技有限责任公司 局部麻醉药的磷脂-混溶剂-油缓释递药系统组方与制备方法
CN109316602A (zh) * 2018-11-13 2019-02-12 西安力邦医药科技有限责任公司 一种长效镇痛并促进伤口愈合的复方缓释递药系统的组方与应用
CN113018248A (zh) * 2019-12-23 2021-06-25 南京清普生物科技有限公司 一种缓释递药系统
CN113827547A (zh) * 2020-06-23 2021-12-24 南京清普生物科技有限公司 一种缓释制剂组合物

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Excipient Selection In Parenteral Formulation Development", PHARMA TIMES, vol. 45, no. 3, March 2013 (2013-03-01), pages 65 - 77
PDA JPHARM SET TECHNOL., vol. 51, 1997, pages 166 - 171

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11992483B2 (en) 2021-07-07 2024-05-28 Cali Biosciences Us, Llc Emulsions for local anesthetics

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