WO2023115311A1 - 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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Publication number
WO2023115311A1
WO2023115311A1 PCT/CN2021/139979 CN2021139979W WO2023115311A1 WO 2023115311 A1 WO2023115311 A1 WO 2023115311A1 CN 2021139979 W CN2021139979 W CN 2021139979W WO 2023115311 A1 WO2023115311 A1 WO 2023115311A1
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polyoxyethylene
oil
acid
stearate
polysorbate
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PCT/CN2021/139979
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English (en)
French (fr)
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王青松
武曲
邹丽敏
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南京清普生物科技有限公司
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Priority to PCT/CN2021/139979 priority Critical patent/WO2023115311A1/zh
Publication of WO2023115311A1 publication Critical patent/WO2023115311A1/zh

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    • 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
    • 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
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and in particular relates to a sustained-release preparation composition, a preparation method and application thereof.
  • Postoperative pain is acute pain that occurs immediately after surgery and usually lasts no more than 3 to 7 days. If it cannot be adequately controlled in the initial state, it may develop into chronic pain.
  • the commonly used clinical treatment method is to use analgesic pump for treatment, but the drugs contained in the analgesic pump are mostly opioid analgesics and some auxiliary analgesics such as tramadol.
  • opioid analgesics and some auxiliary analgesics such as tramadol.
  • tramadol auxiliary analgesics
  • the curative effect is good, it is also accompanied by A series of side effects such as respiratory depression, nausea and vomiting, hypotension and potential addiction.
  • local anesthetics to treat postoperative pain can avoid the above-mentioned adverse reactions, but local anesthetics usually have a short action time, and the drug effect only lasts for several hours after a single administration, which cannot meet the treatment cycle of postoperative pain. Therefore, the development of long-acting local anesthetic preparations is a current research hotspot.
  • bupivacaine polyvesicular liposome suspension injection developed by PACIRA
  • the trade name is It is used to treat postoperative pain and nerve block, and 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.
  • Patent CN103142458 discloses a non-addictive narcotic analgesic sustained-release drug delivery system, which mainly consists of analgesic, drug solvent, and drug sustained-release agent.
  • analgesic is ropivacaine
  • the drug solvent is one or both of benzyl alcohol, ethanol, and benzyl benzoate
  • the drug slow-release agent is one or both of soybean oil and castor oil.
  • the duration is at least 24 hours.
  • ropivacaine long-acting Preparations in vivo plasma concentration can be maintained for 48 hours.
  • the oil sustained-release system is generally liquid at room temperature and can only be administered by injection. There are limitations in the way of administration, and there is uncertainty in the release of the drug at a specific site.
  • the polymer sustained-release system is also one of the means to develop long-acting preparations.
  • Commonly used polymer sustained-release systems include polylactic acid polyglycolic acid copolymer (PLGA) and polyorthoester (POE) systems.
  • FDA approved in 2002 It is a long-acting preparation with PLGA system as the sustained-release matrix.
  • LIQUIDIA has developed a long-acting bupivacaine preparation LIQ865 using PLGA system as a sustained-release matrix, which has entered phase II clinical trials. The safety, pharmacokinetics and pharmacodynamics of the Phase I clinical trials were evaluated, and the results showed that patients at different doses could tolerate it, and the efficacy of the preparation could last for at least 3 days.
  • Heron uses polyorthoester as a slow-release carrier for the development of long-acting local anesthetic preparations.
  • the patent CN106535886 discloses a composition containing amide local anesthetics, enol NSAIDs and polyorthoesters and its preparation method.
  • the long-acting compound preparation HTX011 developed by Heron Company has completed the III clinical research, and the results show that the postoperative analgesic effect can be maintained for 3 days.
  • sustained-release preparations containing polymers there will be a problem of long-term degradation of the polymer in vivo, resulting in local accumulation.
  • the degradation products of PLGA-type sustained-release systems include glycolic acid and lactic acid, and the acidic degradation products may cause inflammation at the administration site React side effects, and not conducive to treatment.
  • DURECT has developed a long-acting bupivacaine formulation with a small molecule ester as a sustained-release carrier
  • the related patent CN101035562 discloses a pharmaceutical composition containing bupivacaine, sucrose acetate isobutyrate (SAIB) and benzyl alcohol. at present It has entered phase III clinical trials, but the clinical results showed no statistical difference compared with bupivacaine solution.
  • the present invention provides a pharmaceutical composition, comprising the following components:
  • At least one pharmaceutically acceptable gelling factor selected from the group consisting of:
  • Fatty acid its structural formula is C n H 2n+1 COOH;
  • Fatty alcohol its structural formula is C n H 2n+1 OH;
  • Poloxamers whose structural formula is HO(C 2 H 4 O) a (C 3 H 6 O) b (C 2 H 4 O) a H;
  • Polyoxyethylene alkyl ether its structural formula is CH 3 (CH 2 ) a (OCH 2 CH 2 ) b OH;
  • the n values are independent of each structural formula of each structural formula of the fatty acid and
  • the pharmaceutical composition further comprises d. at least one pharmaceutically acceptable solvent.
  • the pharmaceutical composition may further comprise a pharmaceutically acceptable release modifier.
  • the liquid oil is 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, black vinegar
  • castor oil sesame oil, corn oil, soybean oil, olive oil, safflower oil, cottonseed oil, peanut oil, fish oil, tea oil, almond oil, babassu oil, black vinegar
  • borage oil canola oil, palm oil, palm kernel oil, sunflower oil, medium chain triglycerides, glyceryl dioleate, glyceryl monooleate.
  • the gelling factor is selected from the group consisting of fatty alcohols, fatty acids, fatty acid glycerides, sterols, sorbitol fatty acid esters, poloxamers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil
  • the gelling factor is selected from lauric acid, palmitic acid, arachidic acid, myristyl alcohol, Cetyl Alcohol, Behenyl Alcohol, Glyceryl Laurate, Glyceryl Palmitate, Glyceryl Monostearate, Glyceryl Distearate, Glyceryl Tristearate, C8-C18 Mixed Fatty Acid Glycerides, Sorbet Alcohol Palmitate, Sorbitan Stearate, Glyceryl Behenate, Glyceryl Palmitostearate, Glyceryl Cocoate, Cholesterol, Poloxamer 124, Poloxamer
  • Polysorbate 40 polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, polysorbate 120, polyoxyethylene stearate , polyoxyethylene tetraester stearate, polyoxyethylene hexaester stearate, polyoxyethylene octaester stearate, polyoxyethylene lauryl stearate, polyoxyethylene eicosyl stearate, stearic acid Polyoxyethylene tricotyl stearate, polyoxyethylene tetrastearyl stearate, polyoxyethylene pentaester stearate, polyoxyethylene one hundred stearate, polyoxyethylene one hundred fifty stearate, Polyoxyethylene tetraester distearate, polyoxyethylene octaester distearate, polyoxyethylene lauryl distearate, polyoxyethylene tridodecyl distearate, polyoxyethylene distearate One or more combinations of one hundred fifty est
  • the at least one pharmaceutically active ingredient is not limited to the type of treatment, and may be anti-inflammatory drugs, local anesthetics, analgesics, antipsychotics, anxiolytics, sedative-hypnotics, antidepressants , antihypertensive drugs, steroid hormones, antiepileptic drugs, bactericides, anticonvulsants, antiparkinsonian drugs, central nervous system stimulants, antipsychotics, antiarrhythmic drugs, antianginal drugs, antithyroid drugs, antidotes , antiemetic drugs, hypoglycemic drugs, anti-tuberculosis drugs, anti-AIDS drugs, anti-hepatitis B drugs, antineoplastic drugs, anti-rejection drugs and their mixtures.
  • suitable pharmaceutically active ingredients may be selected from one or more combinations of the following compounds: aspirin, acetaminophen, benoate, indomethacin, sulindac, diclofenac, Diclofenac potassium, diclofenac sodium, ibuprofen, naproxen, flurbiprofen, flurbiprofen axetil, loxoprofen, nabumetone, ketorolac, phenylbutazone, butadiene hydroxyacid, fenol Profen, Celecoxib, Rofecoxib, Polmacoxib, Nimesulide, Meloxicam, Lornoxicam, Piroxicam, Etodolac, Valdecoxib, Parecoxib, Erecoxib, Lu Micoxib.
  • Caffeine Fentanyl, Sufentanil, Remifentanil, Tramadol, Nortramadol, Tapentadol, Dezocine, Pentazocine, Methadone, Pethidine, Ketamine, Diazepam Panam, Chlormetazepam, Lisdexamphetamine, Dextropropoxyphene, Difelikefalin, Oliceridine.
  • Chlorpromazine triflupromazine, mesoridazine, pecitazine, thioridazine, chlorprothixene.
  • Procainamide isoamyl nitrite, nitroglycerin, propranolol, metoprolol, prazosin, phentolamine, mithiophene, captopril, enalapril.
  • Clonidine dexmedetomidine, epinephrine, norepinephrine, tizanidine, alpha-methyldopa, glycopyrrolate. cortisone, hydrocortisone, betamethasone, triamcinolone acetonide, dexamethasone, dexamethasone ester, prednisone, prednisolone, methylprednisolone, beclomethasone, clobetasol, progesterone , Testosterone, Testosterone Enanthate, Testosterone Undecanoate, Testosterone Cypionate, Progesterone, Fulvestrant, Pregnenolone, Ganaxolone, Phenytoin, Ethytoin.
  • Benzalkonium Chloride Benzethonium Chloride, Sulfamethonium Acetate, Mebenzethonium Chloride, Furacilin, Mercury Nicresol.
  • 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.
  • the pharmaceutical active ingredient is selected from amide local anesthetics, for example, from bupivacaine, ropivacaine, levobupivacaine, mepivacaine, lidocaine and salts thereof.
  • the salt of the amide local anesthetic may be selected from fatty acid salts and water-soluble salts thereof, and the acids forming the salt include lauric acid, myristic acid, stearic acid, palmitic acid, behenic acid, arachidic acid, hydrochloric acid, sulfonic acid , phosphoric acid, acetic acid, citric acid, etc.
  • the pharmaceutically active ingredient further includes a second active ingredient in addition to an amide local anesthetic, and the pharmaceutically active ingredient can be selected from COX receptor inhibitors, adrenergic receptor agonists, and sugars.
  • 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, benolate, indomethacin, sulindac, diclofenac, diclofenac potassium, Diclofenac sodium, ibuprofen, naproxen, flurbiprofen, loxoprofen, nabumetone, piroxicam, ketorolac, phenylbutazone, butyrate, fenoprofen; the following optional COX-2 inhibitors: celecoxib, rofecoxib, nimesulide, meloxicam, lornoxicam, etodolac, valdecoxib, parecoxib, erecoxib, lumixide cloth.
  • the adrenergic receptor agonists are mainly ⁇ 2-adrenoceptor agonists, including but not limited to clonidine, dexmedetomidine, epinephrine, norepinephrine, tizanidine, ⁇ -methyl doba.
  • the glucocorticoid drugs include, but are not limited to cortisone, hydrocortisone, betamethasone, triamcinolone acetonide, dexamethasone, prednisone, prednisolone, methylprednisolone, beclomethasone , Clobetasol.
  • the pharmaceutical active ingredient is selected from one of ropivacaine, bupivacaine, levobupivacaine, meloxicam, celecoxib, ketoprofen, and triamcinolone acetonide or a combination of several.
  • the pharmaceutically active ingredient is selected from a combination of an amide local anesthetic and a non-steroidal anti-inflammatory drug, such as a combination of ropivacaine and meloxicam, a combination of levobupivacaine and meloxicam , bupivacaine and meloxicam composition, ropivacaine and celecoxib composition, levobupivacaine and celecoxib composition, bupivacaine and celecoxib composition, etc.
  • a non-steroidal anti-inflammatory drug such as a combination of ropivacaine and meloxicam, a combination of levobupivacaine and meloxicam , bupivacaine and meloxicam composition, ropivacaine and celecoxib composition, levobupivacaine and celecoxib composition, bupivacaine and celecoxib composition, etc.
  • the pharmaceutically acceptable release regulator is selected from small molecule esters and surfactants.
  • the small molecule esters are glyceryl triacetate, isopropyl stearate, isopropyl laurate, isopropyl palmitate, isopropyl myristate and benzyl benzoate.
  • the surfactant is a nonionic surfactant.
  • the surfactant includes soybean lecithin, egg yolk lecithin, dierucoyl lecithin, dioleoyl lecithin, polyoxyl 40 stearate, caprylic capric acid macrogolglyceride, Lauroyl polyoxyethylene glyceride, stearoyl polyoxyethylene glyceride, oleoyl polyoxyethylene glyceride, vitamin E polyethylene glycol succinate, egg yolk lecithin, soybean lecithin, hydrogenated soybean lecithin, poloxamer , polysorbate, polyethylene glycol-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 composition may further comprise one or more antioxidants.
  • Antioxidants can be used to prevent or reduce oxidation of phospholipids or liquid oils in the sustained release drug delivery system of 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 .
  • the composition may further include other conventional excipients in the field of pharmacy.
  • suitable pharmaceutical excipients can be found in Excipients and their use in injectable products. PDA J Pharm Sci Technol. Volume 51 , July-August 1997, pp. 166-171 and described in Excipient Selection In Parenteral Formulation Development, Pharma Times, Vol. 45, No. 3, March 2013, pp. 65-77, which are cited in their entirety and into the present invention.
  • 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%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%.
  • the proportion of liquid oil is about 30 to 90% (w/w) of the total composition, such as about
  • the gel factor accounts for 2% to 50% (w/w) of the total composition, 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 gelling factor comprises 2% to 30% (w/w) of the total composition.
  • the pharmaceutically active ingredient accounts for 0.1% to 50.0% (w/w) of the total composition.
  • the pharmaceutically active ingredient accounts for 0.1% to 15% (w/w) of the total composition, such as 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 pharmaceutical active ingredient may account for 0.1% to 10% (w/w) of the total composition, such as 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 solvent accounts for 0% to 50% (w/w) of the total amount of the composition, and in some embodiments, no solvent is contained in the pharmaceutical composition (the total amount of solvent accounts for the total amount of the composition 0% of the total amount of the composition), in some embodiments, the total amount of the solvent may account for 0.1%, 0.5%, 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 %, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%. In some embodiments, the total amount of the solvent accounts for 10%-50% (w
  • 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 dimethylsulfoxide.
  • the alcohols are selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, propylene glycol, glycerin, benzyl alcohol, phenylethyl alcohol, polyethylene glycol.
  • the release modifier accounts for 0% to 40% (w/w) of the total composition, preferably 0.1% to 40% (w/w).
  • the release modifier can account for 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 dosage of the release modifier is 1-35%; in some embodiments, when the release modifier is selected from surfactants, the dosage of the release modifier is 0.1% to
  • the pharmaceutical composition provided by the invention is a semi-solid preparation.
  • the pharmaceutically acceptable solvent and release modifier can act as a viscosity modifier to make the composition suitable for injection.
  • the composition has a viscosity of less than 20,000 cP at 30°C.
  • the composition has a viscosity in the range of 5,000 to 10,000 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 composition has a viscosity in the range of 100 to 1000 cP at 30°C.
  • the present invention provides a kind of preparation method of described pharmaceutical composition, comprises the steps:
  • the mixing of the step (a1) also includes adding at least one pharmaceutically acceptable solvent and a release regulator, for example, the step (a1) can be liquid oil, gel factor, At least one pharmaceutically active ingredient is mixed with at least one pharmaceutically acceptable solvent; said step (a1) can be liquid oil, gel factor, at least one pharmaceutically active ingredient, release modifier and at least one A pharmaceutically acceptable solvent is mixed.
  • the step (a1) can be liquid oil, gel factor, at least one pharmaceutically active ingredient, release modifier and at least one A pharmaceutically acceptable solvent is mixed.
  • the method includes:
  • the method includes:
  • the method includes:
  • the active molecules that are difficult to dissolve can be dissolved in a part of the solvent first, and then added to the solution formed by heating and mixing liquid oil, gel factor, and the remaining part of the solvent to prepare the drug. desired pharmaceutical composition.
  • the method includes:
  • the less soluble active molecules can be dissolved in part of the solvent first, and then added to the solution formed by heating and mixing liquid oil, gel factor, part of the solvent, and 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 placed at room temperature; in some embodiments, the mixed solution is quickly After cooling and solidifying, keep it at a specific temperature for a certain period of time and then place it at room temperature; in some embodiments, the mixed solution is kept at room temperature after being kept at the melting temperature of the system for solidification; in some embodiments, the mixed solution is kept at the melting temperature of the system. Keep it warm at a specific temperature for a certain period of time and then place it at room temperature.
  • the present invention provides a sustained release formulation comprising said pharmaceutical composition, said formulation being administered as a depot formulation, in one aspect said formulation being injectable. In another aspect, the formulation can be administered topically.
  • the formulation can be injected subcutaneously, perineurally, intramuscularly or directly into a wound.
  • the formulation is suitable for dermal or mucosal administration.
  • the preparation provided by the invention is administered in a single dose, and the amount of the medicine contained therein can achieve the effects of analgesia and nerve block, and can be used for preventing or alleviating local pain.
  • the preparation provided by the present invention can form a stable reservoir at the site of administration, which can release the drug slowly and continuously, prolong the release time of the local anesthetic, and improve the therapeutic effect.
  • the formulation is effective for at least 24 hours after administration. In some embodiments, the formulation is effective for at least 24 to 48 hours after administration. In some embodiments, the formulation is effective for at least 48 to 72 hours after administration. In some embodiments, the formulation is effective for at least 72 hours after administration.
  • the preparation further includes a packaging material filled with the preparation, and the packaging material is selected from one or more of the following: vials, prefilled syringes, and cartridges.
  • the numerical range is defined as a “number” or may include “integer” or “non-integer”, it should be understood that both endpoints of the range, each integer within the range, and each integer within the range are recited. decimal.
  • “the number from 0 to 10” should be understood as not only recording each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least recording each of the integers respectively Sum with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.
  • biocompatibility refers to the interaction between the components of a composition and the body.
  • active ingredient refers to a drug used in the treatment of a disease. Therefore, active ingredients, drugs can be used alternatively.
  • active ingredient or drug as used herein includes, but is not limited to, pharmaceutically active substances of local or systemic action, which may be administered topically or by injection, such as subcutaneous, intradermal, intramuscular and intraarticular injections . 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 a gelling factor to liquid oil.
  • gelling factor refers to a class of substances that have a lipophilic structure and an interactive site in the molecule, and have certain surface activity and thermal reversibility.
  • semi-solid refers to a form that can flow under pressure. More specifically, semi-solids typically have a viscosity between 100 and 50,000 cP at 30°C, especially between 100 and 20,000 cP at 30°C.
  • small molecule esters refers to esters with a molecular weight of less than 500, which are liquid at room temperature.
  • amide type used in the present invention refers to amide or caine 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 an aromatic hydrocarbon or an 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., and tertiary amine is the most common.
  • the pKa is generally between 7.5 and 7.9, and it is ionic under physiological conditions.
  • the present invention provides a sustained-release preparation composition, which is semi-solid at room temperature and can be directly used as a drug reservoir at the site of administration.
  • the gel factor selected in the present invention has good biocompatibility with other ingredients of the preparation, and can form a reverse double-layer nanostructure through self-assembly in liquid oil, and the reverse double-layer structure grows subsequently, and the tissue forms a sheet-like microstructure. structure, finally forming a continuous and stable three-dimensional network structure, and the network structure has good oil holding capacity.
  • the mechanical strength and performance of the entire system can support and satisfy the release performance of active ingredients.
  • the present invention further found that adding a suitable release modifier to the formulation system can further improve the release performance of the active ingredient, reduce the viscosity of the oil gel, etc.;
  • 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 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 formulation system provided by the present invention can enable active pharmaceutical ingredients to achieve good release performance and reduce the possibility of burst 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 drug systems, such as continuous and stable release of analgesic active ingredients, not only can be injected It is suitable for stable and convenient local administration, with good tolerance of patients and few side effects.
  • Figure 1-1 is the pharmacokinetic study of the solution and oil gel composition (R38, see information table 19-1) in rats, and Figure 1-1 is the blood concentration-time curve of bupivacaine .
  • Figures 2-1 and 2-2 are the pharmacokinetic studies in rats of the pharmaceutical compositions prepared by different liquid oil types and gel factor dosages (compositions R36, R38 and R39, see Table 20-1 for details) .
  • Figure 2-1 is the blood concentration-time curve of bupivacaine
  • Figure 2-2 is the blood concentration-time curve of meloxicam.
  • Figures 3-1 and 3-2 show the pharmacokinetic differences between oil preparations and oil gel compositions (compositions R73 and R74, see Table 21-1 for details) in rats.
  • Figure 3-1 is the blood concentration-time curve of bupivacaine
  • Figure 3-2 is the blood concentration-time curve of meloxicam.
  • Figures 4-1 and 4-2 show the pharmacokinetic differences between bupivacaine and ropivacaine compositions (compositions R71, R73, R74, see Table 22-1 for details) in dogs.
  • Figure 4-1 is the blood concentration-time curve of bupivacaine
  • Figure 4-2 is the blood concentration-time curve of meloxicam.
  • Figure 5-1 shows the differences in drug effects of ropivacaine solution, ropivacaine single composition and ropivacaine/celecoxib compound composition in postoperative pain research in rats.
  • Figure 6-1 shows the difference in drug efficacy between the ropivacaine/ropivacaine compound composition and the ropivacaine/celecoxib compound composition in postoperative pain research in rats.
  • the gelling factors tested included fatty acids, fatty alcohols, single fatty acid glycerides and mixed fatty acid glycerides, and sterols, wherein single fatty acid glycerides were esterified from the same fatty acid and glycerol, while mixed fatty acid glycerides were formed from different fatty acids Formed by esterification with glycerol.
  • Oil gel composition containing different proportions of gelling factors
  • compositions containing gelatin factors in different proportions were prepared according to each ingredient shown in the following Table 2-1.
  • meloxicam solution stir while heating until a transparent and uniform solution is formed, and cool to room temperature to form a solid gel-like substance.
  • Example 2 Weigh a certain amount of the pharmaceutical composition from Example 2, place it in a centrifuge tube, and centrifuge at a speed of 9000 rpm for 15 minutes. After centrifugation, turn the centrifuge tube upside down for about 40 minutes, drain the centrifuged oil, and calculate the oil according to the following formula: The oil retention of the gel, the results are shown in Table 3-1.
  • m 1 is the quality (g) of the centrifuge tube
  • m2 is the quality (g) of centrifuge tube and oil gel system
  • m3 is the mass (g) of the centrifuge tube and the precipitate after centrifugation
  • x is the mass fraction of glyceride in the oil gel.
  • Oil retention is one of the indicators for evaluating the structural stability of oil gels. In order to ensure the solidification ability of the gel factor to liquid oil and prevent the phenomenon of liquid oil precipitation during long-term storage, it is necessary to study the oil retention of the preparation. Maximum oil carrying capacity in the gel.
  • glycerol monostearate was taken as an example to compare the oil-carrying capacity of oil gels formed with different proportions of glyceride. The results are shown in Table 3-1. When the proportion of the gelling factor increases, the oil holding capacity of the three-dimensional network structure of the oil gel also increases during centrifugation. When the gelling factor is glyceryl monostearate, the glycerol monostearate When the ester ratio is 12% or more, the oil retention of the oil gel is maintained at 98% or more.
  • Oleo-gel compositions containing different liquid oils Oleo-gel compositions containing different liquid oils
  • compositions containing different liquid oils were prepared according to each ingredient shown in Table 4-1 below.
  • Solution and benzyl alcohol were mixed, stirred while heating until a transparent and uniform solution was formed, and cooled to room temperature to form a solid gel-like substance.
  • This embodiment selects different natural vegetable oils and synthetic oil medium-chain triglycerides to carry out prescription research. Experiments show that all liquid oils and gel factors can obtain clear and transparent solutions under heating conditions, and all solidify after cooling at room temperature. flow.
  • the release of ropivacaine from the composition of Example 4 was determined by adding 100 mg of the oleogel composition from Example 4 into a dialysis bag and placing it in a tube containing 200 mL of phosphate buffer. Shake at 37°C, and take 1 mL of phosphate buffer solution from the tube at 24h, 48h, and 72h respectively.
  • the concentrations of ropivacaine and meloxicam in each sample were determined by HPLC. The results are shown in Table 5-1 below.
  • Oleogel composition containing different non-aqueous solvents
  • Oil gel compositions containing different non-aqueous solvents were prepared according to each ingredient shown in Table 6-1 below.
  • the solution and the non-aqueous solvent are mixed, heated and stirred until a transparent and uniform solution is formed, and cooled to room temperature to form a solid gel-like substance. .
  • the release of ropivacaine from the composition of Example 6 was determined by adding 100 mg of the oleogel composition from Example 6 into a dialysis bag and placing it in a tube containing 200 mL of phosphate buffer. Shake at 37°C, and take 1 mL of phosphate buffer solution from the tube at 24h, 48h, and 72h respectively.
  • the concentrations of ropivacaine and meloxicam in each sample were determined by HPLC. The results are shown in Table 7-1 below.
  • Oleogel compositions containing different release modifiers were prepared according to each ingredient shown in Table 8-1 below.
  • Solution, benzyl alcohol, and release modifier are mixed, stirred while heating until a transparent and uniform solution is formed, and cooled to room temperature to form a solid gel-like substance.
  • the release of ropivacaine from the composition of Example 8 was determined by adding 50 mg of the pharmaceutical composition from Example 8 into a dialysis bag and placing it in a tube containing 200 mL of phosphate buffer. Shake at 37°C, and take 1 mL of phosphate buffer solution from the tube at 24h, 48h, and 72h respectively.
  • the concentrations of ropivacaine and meloxicam in each sample were determined by HPLC.
  • Table 9-1 The results proved that triacetin had a greater effect on the overall properties of the oil gel than benzyl benzoate, and the addition of a small amount of triacetin significantly increased drug release.
  • using benzyl benzoate as a release modifier can better control the release of the drug and reduce the viscosity of the composition.
  • Oleogel compositions containing different concentrations of release modifiers were prepared according to each ingredient shown in Table 10-1 below.
  • Solution, benzyl alcohol, and release modifier are mixed, stirred while heating until a transparent and uniform solution is formed, and cooled to room temperature to form a solid gel-like substance.
  • the release of ropivacaine from the composition of Example 10 was determined by adding 100 mg of the oleogel composition from Example 10 to a dialysis bag and placing it in a tube containing 200 mL of phosphate buffer. Shake at 37°C, and take 1 mL of phosphate buffer solution from the tube at 24h, 48h, and 72h respectively.
  • the concentrations of ropivacaine and meloxicam in each sample were determined by HPLC. The results are shown in Table 11-1 below.
  • Example 10 uses Poloxamer 188 as a release modifier, and the HLB value of Poloxamer 188 is 29.
  • Example 11 examines the addition of 0.1% (w/w) to 5% (w/w) effect on drug release. According to the in vitro release results in Table 11-1, it can be known that with the addition of 5% (w/w) poloxamer 188, the release of ropivacaine in 24 hours is close to 100%, indicating that surfactants with high HLB values can significantly affect oil production.
  • the hydrophilicity of the gel accelerates the dissolution rate of the oleogel in the release medium, thereby accelerating the release of the drug.
  • Oleogel compositions containing different release modifiers were prepared according to each ingredient shown in Table 12-1 below.
  • Example 12 100 mg of the pharmaceutical composition from Example 12 was added to a dialysis bag and placed in a tube containing 200 mL of phosphate buffer to measure the release of ropivacaine from the composition of Example 12. Shake at 37°C, and take 1 mL of phosphate buffer solution from the tube at 24h, 48h, and 72h respectively. The concentrations of ropivacaine and meloxicam in each sample were determined by HPLC. The results are shown in Table 13-1 below.
  • Example 12 a series of surfactants with different HLB values were selected as release modifiers for the preparation of pharmaceutical compositions. The results showed that by selecting surfactants with different HLB values and different addition amounts, the oil gel can be adjusted. Hydrophilic, to achieve the desired drug release effect.
  • Oleo-gel compositions containing different main active ingredients.
  • Oil gel compositions containing different main active ingredients were prepared according to each ingredient shown in Table 14-1 below.
  • the release of ropivacaine from the composition of Example 14 was determined by adding 100 mg of the pharmaceutical composition from Example 14 to a dialysis bag and placing it in a tube containing 200 mL of phosphate buffer. Shake at 37°C, and take 1 mL of phosphate buffer solution from the tube at 24h, 48h, and 72h respectively.
  • the concentrations of ropivacaine and meloxicam in each sample were determined by HPLC. The results are shown in Table 15-1 below.
  • Oleo-gel compositions containing different main active ingredients.
  • Oil gel compositions containing different main active ingredients were prepared according to each ingredient shown in Table 16-1 below.
  • meloxicam was dissolved in N-methylpyrrolidone to prepare a 50mg/g meloxicam concentrated solution, and liquid oil, gel factor, different amide local anesthetics, and meloxicam were mixed at 70°C. Mix the concentrated solution and benzyl alcohol, stir while heating until a transparent and uniform solution is formed, and cool to room temperature to form a solid gel-like substance.
  • Example 16 50 mg of the pharmaceutical composition from Example 16 was added to a dialysis bag and placed in a tube containing 200 mL of phosphate buffer to measure the release of ropivacaine from the composition of Example 16. Shake at 37°C, and take 1 mL of phosphate buffer solution from the tube at 24h, 48h, and 72h respectively. The concentrations of ropivacaine and meloxicam in each sample were determined by HPLC. The results are shown in Table 17-1 below.
  • the pharmacokinetics in rats are as follows. SD rats with a weight of about 200 g were given free access to water and food throughout the experiment. Each group was administered by subcutaneous injection, and the sample information is shown in Table 19-1. Every SD rat is given bupivacaine hydrochloride solution by 8 mg/kg, and oil gel composition is given by 40 mg/kg dose, each group of animals is taken 0 hour before administration, after administration, after administration 30min, About 0.3 mL of blood samples were collected at 1, 2, 6, 24, 48, and 72 hours each into EDTA-2K+ anticoagulated blood collection tubes. The whole blood was centrifuged at 8000 rpm for 5 minutes to collect plasma, and then detected by LC-MS/MS in plasma samples. drug concentration.
  • the blood concentration-time curve of bupivacaine within 72 hours after administration of the composition is shown in Fig. 1-1.
  • the pharmacokinetics in rats are as follows. SD rats with a weight of about 200 g were given free access to water and food throughout the experiment. Each group was administered by subcutaneous injection, and the sample information is shown in Table 20-1. Every SD rat is administered by 40mg/kg dose, each group of animals gets 0 hour before administration, after administration, after administration, 30min, 1, 2, 6, 24, 48 and 72 hours respectively collect blood samples about 0.3 mL into EDTA-2K+ anticoagulated blood collection tubes, the whole blood was centrifuged at 8000rpm for 5 minutes to collect plasma, and then the drug concentration in the plasma samples was detected by LC-MS/MS.
  • Fig. 2-1 and Fig. 2-2 The blood concentration-time curves of bupivacaine and meloxicam within 72 hours after administration of the composition are shown in Fig. 2-1 and Fig. 2-2.
  • the solubility of ropivacaine in castor oil is only 24.7mg/mL. If only pure castor oil system is used, the blood concentration of ropivacaine in 72 hours is only 5ng/mL, and it cannot be detected in blood in 96 hours Ropivacaine. Therefore, simply using the oil system cannot meet the 72h sustained release requirement of ropivacaine.
  • the oil gel composition provided by the invention can solve the problem of too fast release of ropivacaine.
  • Embodiment 19 and embodiment 20 have carried out the pharmacokinetic research of ropivacaine pure oil composition and ropivacaine oil gel composition in rat and dog body respectively, and experimental result shows that oil gel composition can Significantly reduce the release rate of ropivacaine to achieve a sustained release effect of more than 72 hours.
  • the pharmacokinetics in rats are as follows. SD rats with a weight of about 200 g were given free access to water and food throughout the experiment. Each group was administered by subcutaneous injection, and the sample information is shown in Table 21-1. Each SD rat was administered at a dose of 30 mg/kg, and the animals in each group were collected 0 hours before administration, 30 minutes after administration, 1, 2, 4, 6, 24, 48 and 72 hours after administration. About 0.3 mL of the blood sample was put into EDTA-2K+ anticoagulated blood collection tubes, and the whole blood was centrifuged at 8000 rpm for 5 minutes to collect the plasma, and then the drug concentration in the plasma sample was detected by LC-MS/MS.
  • bupivacaine or ropivacaine
  • meloxicam The blood drug concentration-time curves of bupivacaine (or ropivacaine) and meloxicam within 96 hours after administration of the composition are shown in Fig. 4-1 and Fig. 4-2.
  • mice All rats were first anesthetized with 3.5-4% isoflurane oxygen, and then maintained anesthesia with 1.5-2% isoflurane. After the operation, 0.5 cc of 400,000 units of penicillin solution was subcutaneously injected into the rat's neck to prevent infection. Under sterile conditions, make a longitudinal incision 1 cm long with a No. 11 scalpel blade at a position 0.5 cm behind the plantar of each rat, separate the fascia and muscle, and make a longitudinal incision along the muscle. After light pressure to stop the bleeding, the wound was closed, and the incision site was sutured with two non-continuous stitches with No. 5 nylon thread to suture the skin.
  • mice All rats were first anesthetized with 3.5-4% isoflurane oxygen, and then maintained anesthesia with 1.5-2% isoflurane. After the operation, 0.5 cc of 400,000 units of penicillin solution was subcutaneously injected into the rat's neck to prevent infection. Under sterile conditions, make a longitudinal incision 1 cm long with a No. 11 scalpel blade at a position 0.5 cm behind the plantar of each rat, separate the fascia and muscle, and make a longitudinal incision along the muscle. After light pressure to stop the bleeding, the wound was closed, and the incision site was sutured with two non-continuous stitches with No. 5 nylon thread to suture the skin.

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Abstract

一种药物组合物，包含a.液体油，b.至少一种药学上可接受的凝胶因子，凝胶因子选自：脂肪酸，脂肪醇，脂肪酸甘油酯，甾醇，山梨醇脂肪酸酯，泊洛沙姆，聚氧乙烯烷基醚，聚氧乙烯蓖麻油衍生物，聚山梨酸酯，和硬脂酸聚氧乙烯酯，c.至少一种药学上的活性成分。药物组合物在常温下呈现半固体，在给药部位可作为药物储库，便于临床给药，刺激性小。药物组合物适用于具有麻醉、镇痛活性的药物制剂，活性成分释放持续稳定，可以注射给药，局部给药。

Description

一种缓释制剂组合物 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。
迄今位为止，上市的长效局麻药制剂仅有PACIRA开发的布比卡因多囊脂质体混悬注射液，商品名为
Figure PCTCN2021139979-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。
油缓释体系是开发长效制剂最简单的手段之一，目前已上市多种药用油制剂，缓释作用从1至2天到2至4周不等。专利CN103142458公开了一种无成瘾性麻醉镇痛缓释递药系统，主要由镇痛剂、药物溶媒、药物缓释剂组成。其中镇痛剂为罗哌卡因，药物溶媒为苯甲醇、乙醇、苯甲酸苄酯中的一种或两种，药物缓释剂为大豆油和蓖麻油中的一种或两种，镇痛持续时间至少为24小时。另外，Min-Quan Hui等制备了以大豆油为缓释体系的罗哌卡因长效制剂，并进行了犬药动学研究，与罗哌卡因溶液剂相比，罗哌卡因长效制剂在体内血药浓度可维持48小时。此外，油缓释体系在室温下一般为液体，只能进行注射给药，给药方式存在局限性，在特定部位释药存在不确定性。
聚合物缓释体系也是开发长效制剂的手段之一，常用的聚合物缓释体系包括聚乳酸聚乙醇酸共聚物(PLGA)和聚原酸酯(POE)体系等。其中2002年FDA批准的
Figure PCTCN2021139979-appb-000002
是以PLGA体系作为缓释基质的长效制剂。另外，LIQUIDIA开发了一种以PLGA体系作为缓释基质的长效布比卡因制剂LIQ865，目前已进入II期临床。I期临床进行了安全性、药动学和药效学 评价，结果显示不同剂量下患者均可耐受，且制剂疗效可持续至少3天。此外，Heron以聚原酸酯为缓释载体用于开发长效局麻药制剂，在专利CN106535886中公开了含有酰胺类局麻药，烯醇类非甾体抗炎药和聚原酸酯的组合物及其制备方法。目前Heron公司开发的长效复方制剂HTX011已完成Ⅲ临床研究，结果显示术后镇痛疗效可维持3天。针对含有聚合物的缓释制剂，会存在聚合物体内降解周期长而造成局部蓄积的问题，另外，PLGA类缓释体系的降解产物包含羟基乙酸和乳酸，酸性降解产物可能会引起给药部位炎症反应副作用，且不利于治疗。
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 PCTCN2021139979-appb-000003
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 PCTCN2021139979-appb-000004
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。
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.至少一种药学上可接受的凝胶因子，所述凝胶因子选自：
脂肪酸，其结构式为C nH 2n+1COOH；
脂肪醇，其结构式为C nH 2n+1OH；
脂肪酸甘油酯，其结构式为(C nH 2n-1O) 2(CH 2) 2CHOC mH 2m-1
甾醇，其结构式为
Figure PCTCN2021139979-appb-000005
其中，R＝C nH 2n+1；
山梨醇脂肪酸酯，其结构式为
Figure PCTCN2021139979-appb-000006
其中R’＝R”，且R’和R”选自H或C nH 2n-1O，R”’＝C nH 2n-1O；
泊洛沙姆，其结构式为HO(C 2H 4O) a(C 3H 6O) b(C 2H 4O) aH；
聚氧乙烯烷基醚，其结构式为CH 3(CH 2) a(OCH 2CH 2) bOH；
聚氧乙烯蓖麻油衍生物；
聚山梨酸酯，其结构式为
Figure PCTCN2021139979-appb-000007
其中R＝C nH 2n+1；
硬脂酸聚氧乙烯酯，其结构式为RCO(OCH 2CH 2) xOH,RCO(OCH 2CH 2) xOOCR，其中R＝CH 3(CH 2) 16；
c.至少一种药学上的活性成分
根据本发明的实施方案，所述脂肪酸和脂肪醇的结构式中n＝12～22；脂肪酸甘油酯的结构式中n＝8～22，m＝8～22，且n+m＞20；甾醇结构式中取代基为R＝C nH 2n+1，其中n＝8～10；山梨醇脂肪酸酯结构式中，取代基R’和R”选自H或C nH 2n-1O，R”’＝C nH 2n-1O，其中n＝12～18；泊洛沙姆结构式中a＝10～110；b＝15～60；聚氧乙烯烷基醚结构式中a＝8～19；b＝10～60；聚山梨酸酯结构式中，a+b+c+d＝4～20，n＝8～22；硬脂酸聚氧乙烯酯结构式中x＝10～150；例如，所述各结构式中的n值彼此独立，各自可在取值范围内独立的选自8，9，10，11，12，13，14，15，16，17，18，19，20，21，22；所述各结构式中的m值彼此独立，各自可在取值范围内独立的选自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。
根据本发明的实施方案，所述药物组合物还包含d.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药学上可接受的释放调节剂。
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，所述凝胶因子选自所述脂肪醇、脂肪酸、脂肪酸甘油酯、甾醇、山梨醇脂肪酸酯、泊洛沙姆、聚氧乙烯烷基醚、聚氧乙烯蓖麻油衍生物、聚山梨酸酯、硬脂酸聚氧乙烯酯中的一种或多种组合，在一些实施方式中，所述凝胶因子选自月桂酸、棕榈酸、花生酸、十四醇、十六醇、二十二醇、月桂酸甘油酯、棕榈酸甘油酯、单硬脂酸甘油酯，双 硬脂酸甘油酯、三硬脂酸甘油酯、C8-C18的混合脂肪酸甘油酯、山梨醇棕榈酸酯、山梨醇硬脂酸酯、山嵛酸甘油酯、棕榈酸硬脂酸甘油酯、椰油酸甘油酯、胆固醇、泊洛沙姆124、泊洛沙姆188、泊洛沙姆237、泊洛沙姆338、泊洛沙姆407、聚氧乙烯5蓖麻油、聚氧乙烯9蓖麻油、聚氧乙烯15蓖麻油、聚氧乙烯35蓖麻油、聚氧乙烯40蓖麻油、聚氧乙烯40氢化蓖麻油、聚氧乙烯60氢化蓖麻油、聚氧乙烯20十六烷基硬脂酰醚、聚氧乙烯2鲸蜡基醚、聚氧乙烯10鲸蜡基醚、聚氧乙烯20鲸蜡基醚、聚氧乙烯4月桂基醚、聚氧乙烯9月桂基醚、聚氧乙烯23月桂基醚、聚氧乙烯2肉豆蔻基醚、聚氧乙烯10肉豆蔻基醚、聚氧乙烯20肉豆蔻基醚、聚氧乙烯2硬脂基醚、聚氧乙烯10硬脂基醚、聚氧乙烯20硬脂基醚、聚氧乙烯100硬脂基醚、聚山梨酯20、聚山梨酯21、聚山梨酯40、聚山梨酯60、聚山梨酯61、聚山梨酯65、聚山梨酯80、聚山梨酯81、聚山梨酯85、聚山梨酯120、硬脂酸聚氧乙烯二酯、硬脂酸聚氧乙烯四酯、硬脂酸聚氧乙烯六酯、硬脂酸聚氧乙烯八酯、硬脂酸聚氧乙烯十二酯、硬脂酸聚氧乙烯二十酯、硬脂酸聚氧乙烯三十酯、硬脂酸聚氧乙烯四十酯、硬脂酸聚氧乙烯五十酯、硬脂酸聚氧乙烯一百酯、硬脂酸聚氧乙烯一百五十酯、二硬脂酸聚氧乙烯四酯、二硬脂酸聚氧乙烯八酯、二硬脂酸聚氧乙烯十二酯、二硬脂酸聚氧乙烯三十二酯、二硬脂酸聚氧乙烯一百五十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、酮洛芬、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大豆磷脂、蛋黄磷脂、二芥酰基卵磷脂、二油酸酰基卵磷脂、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。
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％、80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％。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85％(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，所述药学活性成分占组合物总量的0.1％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0.1％至15％(w/w)，例如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0.1％至10％(w/w)，例如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，所述药物组合物中不含有溶剂(溶剂总量占组合物总量的0％)，在一些实施方案中，所述溶剂总量可以占组合物总量的0.1％、0.5％、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％、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10％-50％(w/w)，在一些实施方案中，所述溶剂总量占组合物总量的10％-30％(w/w)。
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。
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)。
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。在一些实施方式中，在30℃时，所述组合物的粘度在100至1000cP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药学上可接受的溶剂和释放调节剂，例如，所述步骤(a1)可以为将液体油、凝胶因子、至少一种药学上的活性成分与至少一种药学上可接受的溶剂混合；所述步骤(a1)可以为将液体油、凝胶因子、至少一种药学上的活性成分、释放调节剂与至少一种药学上可接受的溶剂混合。
在一些实施方式中，所述方法包括：
1.在50～70℃下将液体油、凝胶因子和药学上的活性分子混合，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，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“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。
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，在液体油中可通过自组装形成反向双层纳米结构，反向双层结构随后生长、组织形成片状微结构，最终形成连续、稳定的三维网络结构，且所述网络结构具有良好的持油性。整个体系的机械强度与性能能够支撑与满足活性成分的释放性能。2)本发明还进一步发现，在制剂体系中加入合适的释放调节剂，可以进一步改良活性成分的释放性能，减少油凝胶粘度等；
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是溶液剂和油凝胶组合物(R38，详见信息表19-1)在大鼠体内的药代动力学研究，图1-1是布比卡因血药浓度-时间曲线。
图2-1和2-2是不同液体油种类和凝胶因子用量(组合物R36、R38和R39，详细信息见表20-1)制备的药物组合物在大鼠体内的药代动力学研究。其中图2-1是布比卡因血药浓度-时间曲线，图2-2是美洛昔康血药浓度-时间曲线。
图3-1和3-2是油制剂和油凝胶组合物(组合物R73、R74，详细信息见表21-1)在大鼠体内的药代动力学差异。其中图3-1是布比卡因血药浓度-时间曲线，图3-2是美洛昔康血药浓度-时间曲线。
图4-1和4-2是布比卡因和罗哌卡因组合物(组合物R71、R73、R74，详细信息见表22-1)在犬体内的药代动力学差异。其中图4-1是布比卡因血药浓度-时间曲线，图4-2是美洛昔康血药浓度-时间曲线。
图5-1是罗哌卡因溶液、罗哌卡因单方组合物和罗哌卡因/塞来昔布复方组合物在大鼠手术后疼痛研究的药效差异。
图6-1是罗哌卡因/罗哌卡因复方组合物和罗哌卡因/塞来昔布复方组合物在大鼠手术后疼痛研究的药效差异。
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。
实验动物来源：
比格犬：江苏亚东实验动物研究院有限公司
大鼠：南通大学动物实验中心
实施例1
几种凝胶因子的临界凝胶浓度
分别配制含有不同比例凝胶因子的处方，在室温下静置12h，将西林瓶倒置，观察西林瓶中制剂的流动情况，筛选成胶的临界凝胶浓度，结果见表1-1、表1-2和表1-3。所测试的凝胶因子包括脂肪酸、脂肪醇、单一的脂肪酸甘油酯和混合脂肪酸甘油酯以及甾醇，其中，单一脂肪酸甘油酯是相同的脂肪酸与甘油酯化而成，而混合脂肪酸则由不同的脂肪酸与甘油酯化形成。本发明在实施过程中意外的发现，当脂肪酸碳链小于12个碳原子时，凝胶因子相互聚集的能力较弱，无法形成三维网络结构使液体油固化，但是当凝胶因子的脂肪酸碳链部分大于12个碳原子时，则可以形成三维网络结构使液体油凝胶化。如下表1-1所示，当选用含有10个碳原子的癸酸作为凝胶因子时，增加癸酸用量至40％(w/w)，仍无法形成油凝胶，又如下表1-2和1-3所示，当选用辛酸甘油酯和辛酸癸酸单双甘油酯作为凝胶因子时，用量为30％(w/w)时，无法形成油凝胶，而当选用的凝胶因子为含有18个碳原子的硬脂酸作为凝胶因子时，在小于10％(w/w)的用量下可以使液体油凝胶化；此外，发明人还意外的发现，当选用混合脂肪酸甘油酯(碳链一般为C8～C18脂肪酸)，在10％(w/w)的用量下可以使液体油凝胶化。
表1-1脂肪酸类临界凝胶浓度
Figure PCTCN2021139979-appb-000008
√：倒置流动；×：倒置不流动
表1-2脂肪醇类临界凝胶浓度
Figure PCTCN2021139979-appb-000009
Figure PCTCN2021139979-appb-000010
√：倒置流动；×：倒置不流动
表1-3脂肪酸甘油酯类临界凝胶浓度
Figure PCTCN2021139979-appb-000011
√：倒置流动；×：倒置不流动
表1-4混合脂肪酸甘油酯类临界凝胶浓度
Figure PCTCN2021139979-appb-000012
表1-5山梨醇脂肪酸酯类临界凝胶浓度
Figure PCTCN2021139979-appb-000013
√：倒置流动；×：倒置不流动
表1-6甾醇类临界凝胶浓度
凝胶因子浓度 倒置流动情况
％(w/w) 胆固醇
5 √
6 √
8 ×
10 ×
√：倒置流动；×：倒置不流动
实施例2
含有不同比例凝胶因子的油凝胶组合物
按照下表2-1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。首先将美洛昔康溶于N-甲基吡咯烷酮中，配制成50mg/g的美洛昔康浓溶液，在70℃下将罗哌卡因、凝胶因子加入液体油、苯甲醇、美洛昔康溶液中，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。
表2-1
Figure PCTCN2021139979-appb-000014
实施例3
油凝胶的持油性研究
称取一定量来自实施例2的药物组合物，置于离心管中，以转速9000rpm进行离心，时间为15min，离心后将离心管倒置约40min，沥干离心出来的油，按照以下公式计算油凝胶的持油性，结果显示于表3-1中。
Figure PCTCN2021139979-appb-000015
m 1为离心管的质量(g)；
m 2为离心管与油凝胶系统的质量(g)；
m 3为离心后离心管与沉淀的质量(g)；
x为甘油酯占油凝胶的质量分数。
表3-1
Figure PCTCN2021139979-appb-000016
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。实施例2和实施例3以单硬脂酸甘油酯为例，对比了不同比例甘油酯形成的油凝胶的载油能力。结果见表3-1，当凝胶因子所占比例增大，离心时油凝胶三维网络结构的持油能力也增强，当凝胶因子为单硬脂酸甘油酯时，单硬脂酸甘油酯比例为12％以上时，油凝胶的持油性维持在98％以上。
实施例4
含有不同液体油的油凝胶组合物
按照下表4-1中所示的每种成分制备含有不同液体油药物组合物。首先将美洛昔康溶于N-甲基吡咯烷酮中，配制成50mg/g的美洛昔康浓溶液，在70℃下将液体油、凝胶因子、罗哌卡因、美洛昔康浓溶液、苯甲醇混合，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。该实施例选用不同天然植物油和合成油中链甘油三酯进行了处方研究，实验表明所有液体油和凝胶因子在加热条件下能得到澄清透明的溶液，室温冷却后均呈固态化，倒置不流动。
表4-1
Figure PCTCN2021139979-appb-000017
实施例5
罗哌卡因和美洛昔康从油凝胶中的体外释放
将100mg来自实施例4的油凝胶组合物加入透析袋中，置于装有200mL的磷酸盐缓冲液的管中来测定罗哌卡因从实施例4组合物中的释放。在37℃下振摇，分别于24h、48h、72h从管中取1mL磷酸盐缓冲液。通过HPLC检测每份样品中罗哌卡因和美洛昔康的浓度。结果显示于下表5-1中。本发明在实施过程中意外的发现，与其他液体油相比，药物在采用蓖麻油制备的油凝胶中释放更加缓慢，缓释效果最好，而选用中链甘油三酯制备的油凝胶制剂缓释效果较弱。
表5-1罗哌卡因和美洛昔康在不同油凝胶中的体外释放
Figure PCTCN2021139979-appb-000018
Figure PCTCN2021139979-appb-000019
实施例6
含有不同非水溶剂的油凝胶组合物
按照下表6-1中所示的每种成分制备含有不同不同非水溶剂的油凝胶组合物。首先将美洛昔康溶于N-甲基吡咯烷酮中，配制成50mg/g的美洛昔康浓溶液，在70℃下将液体油、凝胶因子、罗哌卡因、美洛昔康浓溶液、非水溶剂混合，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。。
表6-1
Figure PCTCN2021139979-appb-000020
实施例7
罗哌卡因和美洛昔康从油凝胶中的体外释放
将100mg来自实施例6的油凝胶组合物加入透析袋中，置于装有200mL的磷酸盐缓冲液的管中来测定罗哌卡因从实施例6组合物中的释放。在37℃下振摇，分别于24h、48h、72h从管中取1mL磷酸盐缓冲液。通过HPLC检测每份样品中罗哌卡因和美洛昔康的浓度。结果显示于下表7-1中。
表7-1罗哌卡因和美洛昔康在不同油凝胶中的体外释放
Figure PCTCN2021139979-appb-000021
实施例8
含有不同释放调节剂的油凝胶组合物
按照下表8-1中所示的每种成分制备含有不同释放调节剂的油凝胶组合物。首先将美洛昔康溶于N-甲基吡咯烷酮中，配制成50mg/g的美洛昔康浓溶液，在70℃下将液体油、凝胶因子、罗哌卡因、美洛昔康浓溶液、苯甲醇、释放调节剂混合，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。
表8-1
Figure PCTCN2021139979-appb-000022
实施例9
罗哌卡因和美洛昔康从油凝胶中的体外释放
将50mg来自实施例8的药物组合物加入透析袋中，置于装有200mL的磷酸盐缓冲液的管中来测定罗哌卡因从实施例8组合物中的释放。在37℃下振摇，分别于24h、48h、72h从管中取1mL磷酸盐缓冲液。通过HPLC检测每份样品中罗哌卡因和美洛昔康的浓度。结果显示于下表9-1中。结果证明，与苯甲酸苄酯相比，三醋酸甘油酯对油凝胶整体特性的影响更大，加入少量的三醋酸甘油酯会明显增加药物的释放。相比之下，用苯甲酸苄酯作为释放调节剂，可以更好的控制药物的释放，并降低组合物的粘度。
表9-1罗哌卡因和美洛昔康在不同油凝胶中的体外释放
Figure PCTCN2021139979-appb-000023
实施例10
含有不同浓度的释放调节剂的油凝胶组合物
按照下表10-1中所示的每种成分制备含有不同浓度的释放调节剂的油凝胶组合物。首先将美洛昔康溶于N-甲基吡咯烷酮中，配制成50mg/g的美洛昔康浓溶液，在70℃下将液体油、凝胶因子、罗哌卡因、美洛昔康浓溶液、苯甲醇、释放调节剂混合，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。
表10-1
Figure PCTCN2021139979-appb-000024
实施例11
罗哌卡因和美洛昔康从油凝胶中的体外释放
将100mg来自实施例10的油凝胶组合物加入透析袋中，置于装有200mL的磷酸盐缓冲液的管中来测定罗哌卡因从实施例10组合物中的释放。在37℃下振摇，分别于24h、48h、72h从管中取1mL磷酸盐缓冲液。通过HPLC检测每份样品中罗哌卡因和美洛昔康的浓度。结果显示于下表11-1中。
表11-1罗哌卡因和美洛昔康在不同油凝胶中的体外释放
Figure PCTCN2021139979-appb-000025
实施例10的组合物采用泊洛沙姆188作为释放调节剂，泊洛沙姆188的HLB值为29，实施例11考察了0.1％(w/w)至5％(w/w)的添加量对药物释放的影响。根据表11-1的体外释放结果可以得知，加入5％(w/w)的泊洛沙姆188，24h罗哌卡因释放接近100％，说明 高HLB值的表面活性剂可显著影响油凝胶的亲水性，加快油凝胶在释放介质中的溶解速率，进而加快药物的释放。
实施例12
含有不同释放调节剂的油凝胶组合物
按照下表12-1中所示的每种成分制备含有不同释放调节剂的油凝胶组合物。首先将美洛昔康溶于N-甲基吡咯烷酮中，配制成50mg/g的美洛昔康浓溶液，在70℃下将液体油、凝胶因子、罗哌卡因、美洛昔康浓溶液、苯甲醇、表面活性剂混合，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。
表12-1
Figure PCTCN2021139979-appb-000026
实施例13
罗哌卡因和美洛昔康从油凝胶中的体外释放
将100mg来自实施例12的药物组合物加入透析袋中，置于装有200mL的磷酸盐缓冲液的管中来测定罗哌卡因从实施例12组合物中的释放。在37℃下振摇，分别于24h、48h、72h从管中取1mL磷酸盐缓冲液。通过HPLC检测每份样品中罗哌卡因和美洛昔康的浓度。结果显示于下表13-1中。
表13-1罗哌卡因和美洛昔康在不同油凝胶中的体外释放
Figure PCTCN2021139979-appb-000027
实施例12中选择了一系列具有不同HLB值的表面活性剂作为释放调节剂进行药物组合物的制备，结果表明通过选择不同HLB值的表面活性剂、不同的加入量，可以调节油凝胶的亲水性，达到期望的药物释放效果。
实施例14
含有不同主要活性成分的油凝胶组合物。
按照下表14-1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。首先将美洛昔康溶于N-甲基吡咯烷酮中，配制成50mg/g的美洛昔康浓溶液，在70℃下将液体油、凝胶因子、罗哌卡因或罗哌卡因硬脂酸盐、美洛昔康浓溶液、苯甲醇混合，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。
表14-1
Figure PCTCN2021139979-appb-000028
Figure PCTCN2021139979-appb-000029
实施例15
药物从油凝胶中的体外释放
将100mg来自实施例14的药物组合物加入透析袋中，置于装有200mL的磷酸盐缓冲液的管中来测定罗哌卡因从实施例14组合物中的释放。在37℃下振摇，分别于24h、48h、72h从管中取1mL磷酸盐缓冲液。通过HPLC检测每份样品中罗哌卡因和美洛昔康的浓度。结果显示于下表15-1中。
表15-1药物在不同油凝胶中的体外释放
Figure PCTCN2021139979-appb-000030
实施例16
含有不同主要活性成分的油凝胶组合物。
按照下表16-1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。首先将美洛昔康溶于N-甲基吡咯烷酮中，配制成50mg/g的美洛昔康浓溶液，在70℃下将液体油、凝胶因子、不同酰胺类局麻药、美洛昔康浓溶液、苯甲醇混合，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。
表16-1
Figure PCTCN2021139979-appb-000031
实施例17
药物从油凝胶中的体外释放
将50mg来自实施例16的药物组合物加入透析袋中，置于装有200mL的磷酸盐缓冲液的 管中来测定罗哌卡因从实施例16组合物中的释放。在37℃下振摇，分别于24h、48h、72h从管中取1mL磷酸盐缓冲液。通过HPLC检测每份样品中罗哌卡因和美洛昔康的浓度。结果显示于下表17-1中。
表17-1药物在不同油凝胶中的体外释放
Figure PCTCN2021139979-appb-000032
实施例18
油凝胶组合物的粘度测量
按表18-1制备含有10％至22.2％(w/w)凝胶因子，0％至20％(w/w)释放调节剂，2.5％至5％(w/w)罗哌卡因，0.19％美洛昔康的药物组合物。在在70℃下将液体油、凝胶因子、不同酰胺类局麻药、美洛昔康浓溶液、非水溶剂混合，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64号转子的粘度计(博勒飞DVⅢ)通过轴方法测量药物组合物的粘度，检测温度为30℃转速为40rpm，粘度检测结果见下表18-1。
表18-1
Figure PCTCN2021139979-appb-000033
实施例19
油凝胶组合物的体内施用。
大鼠体内药代动力学如下。重量约200g的SD大鼠整个实验过程自由饮水、给食。各组 按皮下注射进行给药，样品信息见表19-1。每只SD大鼠按8mg/kg给予盐酸布比卡因溶液剂，按40mg/kg剂量给予油凝胶组合物，各组动物于给药前取0小时、于给药后给药后30min、1、2、6、24、48和72小时各采集血样约0.3mL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19-1组合物处方信息
Figure PCTCN2021139979-appb-000034
组合物给药后72小时内的布比卡因的血药浓度-时间曲线见图1-1。
实施例20
油凝胶组合物的体内施用。
大鼠体内药代动力学如下。重量约200g的SD大鼠整个实验过程自由饮水、给食。各组按皮下注射进行给药，样品信息见表20-1。每只SD大鼠按40mg/kg剂量进行给药，各组动物于给药前取0小时、于给药后给药后30min、1、2、6、24、48和72小时各采集血样约0.3mL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20-1各组组合物处方信息
Figure PCTCN2021139979-appb-000035
组合物给药后72小时内的布比卡因和美洛昔康的血药浓度-时间曲线见图2-1和图2-2。
罗哌卡因在蓖麻油中的溶解度仅为24.7mg/mL，若仅使用纯蓖麻油体系，罗哌卡因72小时的血药浓度仅为5ng/mL，96小时在血液中已检测不到罗哌卡因。因此，单纯使用油体系无法满足罗哌卡因的72h缓释要求。本发明提供的油凝胶组合物可以解决罗哌卡因释放过快的问题。实施例19和实施例20分别进行了罗哌卡因纯油组合物和罗哌卡因油凝胶组合物在大鼠和犬体内的药代动力学研究，实验结果表明油凝胶组合物可以明显降低罗哌卡因的释放速度，达到72小时以上的缓释效果。
实施例21
油凝胶组合物的体内施用。
大鼠体内药代动力学如下。重量约200g的SD大鼠整个实验过程自由饮水、给食。各组按皮下注射进行给药，样品信息见表21-1。每只SD大鼠按30mg/kg剂量进行给药，各组动物于给药前取0小时、于给药后给药后30min、1、2、4、6、24、48和72小时各采集血样约0.3mL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21-1各组组合物处方信息
Figure PCTCN2021139979-appb-000036
组合物给药后72小时内的罗哌卡因和美洛昔康的血药浓度-时间曲线见图3-1和图3-2。
实施例22
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。各组按皮下注射进行给药，样品信息见表22-1。每只比格犬分两次接受注射，每次0.5mL，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22-1各组组合物处方信息
Figure PCTCN2021139979-appb-000037
组合物给药96小时后的药代动力学参数见表22-2和表22-3。
表22-2布比卡因或罗哌卡因的药代动力学参数
参数 R71 R73 R74
Tmax 20.0 1.3 0.5
Cmax 174.4 433.6 274.4
AUClast 7154.5 8446.2 3731.8
AUCINF_obs 7230.0 8718.3 5653.0
Vz_F_obs 121069.5 185675.7 807648.3
Cl_F_obs 7297.1 7590.9 9709.1
表22-3美洛昔康的药代动力学参数
参数 R71 R73 R74
Tmax 3.0 3.0 15.0
Cmax 1729.0 1806.7 550.7
AUClast 45765.4 51218.4 29230.9
AUCINF_obs 55718.2 60665.4 122482.1
Vz_F_obs 4882.0 3098.7 9982.8
Cl_F_obs 70.8 59.9 40.8
组合物给药后96小时内的布比卡因(或罗哌卡因)和美洛昔康的血药浓度-时间曲线见图4-1和图4-2中。
实施例23
油凝胶组合物的体内施用
所有大鼠先用3.5～4％异氟烷氧气进行诱导麻醉，然后以1.5～2％异氟烷维持麻醉。手术后在大鼠颈部皮下注射0.5cc的40万单位青霉素溶液预防感染。在无菌条件下，将每只大鼠距跖后0.5cm处向前用11号手术刀片作1cm长的纵向切口，分离筋膜和肌肉，沿肌肉纵向切口。轻压止血后，闭合创口，用5号尼龙线在切口部位不连续缝合两针，缝合皮肤。然后围绕切口周围皮下注射罗哌卡因溶液以及油凝胶组合物(见表23-1)，给药体积均为0.1mL，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10min、30min、1h、1.5h、2h、4h、6h、8h、10h、12h、24h、48h、72h。实验结束，打开给药部位观察药物吸收情况及给药部位组织炎症情况。
表23-1
Figure PCTCN2021139979-appb-000038
每个测试组中的动物Von Frey反应显示于图5-1中。
实施例24
油凝胶组合物的体内施用
所有大鼠先用3.5～4％异氟烷氧气进行诱导麻醉，然后以1.5～2％异氟烷维持麻醉。手术后在大鼠颈部皮下注射0.5cc的40万单位青霉素溶液预防感染。在无菌条件下，将每只大鼠距跖后0.5cm处向前用11号手术刀片作1cm长的纵向切口，分离筋膜和肌肉，沿肌肉纵向切口。轻压止血后，闭合创口，用5号尼龙线在切口部位不连续缝合两针，缝合皮肤。然后围绕切口周围皮下注射油凝胶组合物复方(见表24-1)，给药体积均为0.1mL，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10min、30min、1h、1.5h、2h、4h、6h、8h、10h、12h、24h、48h、72h。实验结束，打开给药部位观察药物吸收情况及给药部位组织炎症情况。
表24-1
Figure PCTCN2021139979-appb-000039
每个测试组中的动物Von Frey反应显示于图6-1中。
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.至少一种药学上可接受的凝胶因子，所述凝胶因子选自：
    脂肪酸，其结构式为C nH 2n+1COOH；
    脂肪醇，其结构式为C nH 2n+1OH；
    脂肪酸甘油酯，其结构式为(C nH 2n-1O) 2(CH 2) 2CHOC mH 2m-1
    甾醇，其结构式为
    Figure PCTCN2021139979-appb-100001
    其中，R＝C nH 2n+1；
    山梨醇脂肪酸酯，其结构式为
    Figure PCTCN2021139979-appb-100002
    其中R’＝R”，且R’和R”选自H或C nH 2n-1O，R”’＝C nH 2n-1O；
    泊洛沙姆，其结构式为HO(C 2H 4O) a(C 3H 6O) b(C 2H 4O) aH；
    聚氧乙烯烷基醚，其结构式为CH 3(CH 2) a(OCH 2CH 2) bOH；
    聚氧乙烯蓖麻油衍生物；
    聚山梨酸酯，其结构式为
    Figure PCTCN2021139979-appb-100003
    其中R＝C nH 2n+1；
    硬脂酸聚氧乙烯酯，其结构式为RCO(OCH 2CH 2) xOH,RCO(OCH 2CH 2) xOOCR，其中R＝CH 3(CH 2) 16；
    c.至少一种药学上的活性成分；
    优选的，
    所述脂肪酸和脂肪醇的结构式中n＝12～22；脂肪酸甘油酯的结构式中n＝8～22，m＝8～22，且n+m＞20；甾醇结构式中取代基为R＝C nH 2n+1，其中n＝8～10；山梨醇脂肪酸酯结构式中，取代基R’和R”选自H或C nH 2n-1O，R”’＝C nH 2n-1O，其中n＝12～18；泊洛沙姆结构式中a＝10～110；b＝15～60；聚氧乙烯烷基醚结构式中a＝8～19；b＝10～60；聚山梨酸酯结构式中，a+b+c+d＝4～20，n＝8～22；硬脂酸聚氧乙烯酯结构式中x＝10～150；例如，所述各结构式中的n值彼此独立，各自可在取值范围内独立的选自8，9，10，11，12，13，14，15，16，17，18，19，20，21，22；所述各结构式中的m值彼此独立，各自可在取值范围内独立的选自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。
  2. 根据权利要求1的药物组合物，其特征在于，所述药物组合物还包含d.至少一种药学上可接受的溶剂。
  3. 根据权利要求1或2的药物组合物，其特征在于，所述药物组合物可以进一步包含药学上可接受的释放调节剂；优选的，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；更优选的，所述表面活性剂为非离子型表面活性剂，包括大豆磷脂、蛋黄磷脂、二芥酰基卵磷脂、二油酸酰基卵磷脂、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。
  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。
  5. 根据权利1-4任一项所述的药物组合物，其特征在于，
    所述凝胶因子选自所述脂肪醇、脂肪酸、脂肪酸甘油酯、甾醇、山梨醇脂肪酸酯、泊洛沙姆、聚氧乙烯烷基醚、聚氧乙烯蓖麻油衍生物、聚山梨酸酯、硬脂酸聚氧乙烯酯中的一种 或多种组合，在一些实施方式中，所述凝胶因子选自月桂酸、棕榈酸、花生酸、十四醇、十六醇、二十二醇、月桂酸甘油酯、棕榈酸甘油酯、单硬脂酸甘油酯，双硬脂酸甘油酯、三硬脂酸甘油酯、C8-C18的混合脂肪酸甘油酯、山梨醇棕榈酸酯、山梨醇硬脂酸酯、山嵛酸甘油酯、棕榈酸硬脂酸甘油酯、椰油酸甘油酯、胆固醇、泊洛沙姆124、泊洛沙姆188、泊洛沙姆237、泊洛沙姆338、泊洛沙姆407、聚氧乙烯5蓖麻油、聚氧乙烯9蓖麻油、聚氧乙烯15蓖麻油、聚氧乙烯35蓖麻油、聚氧乙烯40蓖麻油、聚氧乙烯40氢化蓖麻油、聚氧乙烯60氢化蓖麻油、聚氧乙烯20十六烷基硬脂酰醚、聚氧乙烯2鲸蜡基醚、聚氧乙烯10鲸蜡基醚、聚氧乙烯20鲸蜡基醚、聚氧乙烯4月桂基醚、聚氧乙烯9月桂基醚、聚氧乙烯23月桂基醚、聚氧乙烯2肉豆蔻基醚、聚氧乙烯10肉豆蔻基醚、聚氧乙烯20肉豆蔻基醚、聚氧乙烯2硬脂基醚、聚氧乙烯10硬脂基醚、聚氧乙烯20硬脂基醚、聚氧乙烯100硬脂基醚、聚山梨酯20、聚山梨酯21、聚山梨酯40、聚山梨酯60、聚山梨酯61、聚山梨酯65、聚山梨酯80、聚山梨酯81、聚山梨酯85、聚山梨酯120、硬脂酸聚氧乙烯二酯、硬脂酸聚氧乙烯四酯、硬脂酸聚氧乙烯六酯、硬脂酸聚氧乙烯八酯、硬脂酸聚氧乙烯十二酯、硬脂酸聚氧乙烯二十酯、硬脂酸聚氧乙烯三十酯、硬脂酸聚氧乙烯四十酯、硬脂酸聚氧乙烯五十酯、硬脂酸聚氧乙烯一百酯、硬脂酸聚氧乙烯一百五十酯、二硬脂酸聚氧乙烯四酯、二硬脂酸聚氧乙烯八酯、二硬脂酸聚氧乙烯十二酯、二硬脂酸聚氧乙烯三十二酯、二硬脂酸聚氧乙烯一百五十酯中的一种或多种组合。
  6. 根据权利1-5任一项所述的药物组合物，其特征在于，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；优选的，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；优选的，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；更优选的，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、酮洛芬、曲安奈德中的一种或几种的组合，或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。
  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)，优选的，所述液体油比例约为30至90％(w/w)，更优选的，所述液体油比例约为40％至85％(w/w)；所述凝胶因子占组合物总量的2％至50％(w/w)，优选的，所述凝胶因子占组合物总量2％至30％(w/w)；所述药学活性成分占组合物总量的0.1％至50.0％(w/w)，优选的，所述药学活性成分占组合物总量的0.1％至15％(w/w)，更优选的，所述药学活性成分以3％(w/w)至10％(w/w)的量存在；所述溶剂总量占组合物总量的0％至50％(w/w)；优选的，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；所述释放调节剂占组合物总量的0％至40％(w/w)，优选的，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％，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)。
  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)形成的均一混合物自然冷却至室温或经过一定温度循环后放至室温，包括但不限于迅速冷却凝固后于室温放置或迅速冷却凝固后于特定温度保温一定时间后于室温放置或在体系熔融温度下保温凝固后于室温放置或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。优选的，所述步骤(a1)的混合还包括加入至少一种药学上可接受的溶剂和释放调节剂，例如，所述步骤(a1)可以为将液体油、凝胶因子、至少一种药学上的活性成分与至少一种药学上可接受的溶剂混合；所述步骤(a1)可以为将液体油、凝胶因子、至少一种药学上的活性成分、释放调节剂与至少一种药学上可接受的溶剂混合。
  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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