Slow-release lipid composition and method for producing same

Abstract

The present invention relates to a sustained release lipid composition and a method for producing the same, specifically to a solid composition containing lipids and a liposome composition obtained therefrom, the liposomes having improved release characteristics.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to Chinese patent applications filed in China on June 28, 2019 and December 30, 2019, with Chinese patent application numbers CN201910571807.3 and CN201911390028.X, respectively, the entire contents of which are incorporated herein by reference.

[0002] (Technical field) The present disclosure is in the pharmaceutical field and relates to sustained release lipid compositions and methods for making same. [Background technology]

[0003] Liposomes, also called lipid vesicles, are completely closed lipid bilayer membranes that contain an internal volume that contains aqueous medium. Lipid bilayers are generally made of phosphatides, such as lecithin, and related materials, such as glycolipids. Lipid bilayer membranes generally function in a manner similar to cell membranes. Thus, they exhibit certain biological properties, such as the ability to be easily accommodated in the living cell environment. Therefore, in recent years, there has been an increasing interest in using liposomes as vectors to deliver compounds with special biological or pharmaceutical properties to patients.

[0004] Liposomes can be divided into unilamellar and multilamellar liposomes according to the number of bilayer phosphatide membrane layers contained in the structure. Vesicles containing unilamellar bilayer phosphatide membranes are called unilamellar liposomes, and vesicles containing multilamellar bilayer phosphatide membranes are called multilamellar vesicles (MLVs). Unilamellar liposomes can also be divided into small unilamellar vesicular (SUVs) and large unilamellar vesicular (LUVs). Multilamellar liposomes are vesicles with an onion-like structure in which bilayer lipid membranes are alternated with water, and generally consist of multiple concentric layers, and can function as a lipid matrix sustained-release drug vector for local or systemic drug delivery. Methods for producing multilamellar liposomes generally include reverse phase evaporation, thin film hydration, freeze-drying, etc.

[0005] In recent years, liposomes have been widely applied in drug development due to their sustained release drug vector properties. However, after liposomes are delivered into the body, the initial therapeutic effect of liposome administration is poor due to a lack of drug released in the early stage. Currently, there are several methods that improve the initial release of liposomes. WO2019046293 discloses a method for producing MLVs that deliver sustained release anesthetic compositions, in which MLVs are produced using a buffer system water such as histidine and highly encapsulated lipid structures (HELS) to obtain partially encapsulated liposome compositions. CN1893926B discloses that MLVs are produced by mixing an organic phase containing fentanyl and lipids with an aqueous phase, with the final formulation containing 30-40% fentanyl as the free acid or free base of the drug and the remainder (70-60%) present in the encapsulation portion. CN104666248A discloses preparing a dual-action immediate-release and sustained-release inhalation ciprofloxacin formulation by mixing liposomes encapsulating ciprofloxacin with a non-encapsulated ciprofloxacin solution. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2019046293 [Patent Document 2] China Patent Publication No. 1893926 [Patent Document 3] China Patent Publication No. 104666248 DISCLOSURE OF THEINVENTION [Problem to be solved by the invention]

[0007] It is an object of the present disclosure to provide improved liposomal drug compositions which improve the release properties of liposomes. [Means for solving the problem]

[0008] According to one aspect of the present disclosure, there is provided a solid composition comprising: (1) a lipid comprising at least one phosphatide; (2) a free acid or free base of a drug; and (3) a pharma- ceutically acceptable salt, complex or chelate of the drug, preferably a pharma- ceutically acceptable salt of the drug.

[0009] The free acid or free base of the drug is the drug active ingredient that exists in bulk form, as opposed to, for example, a salt form of the drug.

[0010] The pharma- ceutically acceptable salt of the drug may be an acid salt or a base salt of the drug. Some free acids of drugs can form acid salts with, for example, organic or inorganic acids. Suitable acid salts of drugs include, but are not limited to, acetate, benzoate, benzenesulfonate, hydrobromide, camphorsulfonate, hydrochloride, citrate, ethylenesulfonate, fumarate, glucoheptonate, gluconate, glucuronate, hydroiodide, isethionate, lactate, galacturonate, dodecyl sulfate, malate, maleate, methanesulfonate, naphthoate, naphthalenesulfonate, nitrate, stearate, oleate, oxalate, pamoate, phosphate, polygalacturonate, succinate, sulfate, sulfosalicylate, tartrate, toluenesulfonate, trifluoroacetate, etc. of the drug. Some drug free bases can form base salts, for example with inorganic bases, organic bases, inorganic or organic salts, etc. Suitable drug base salts include, but are not limited to, benzathine, calcium, choline, diethanolamine, diethylamine, magnesium, meglumine, piperazine, potassium, silver, sodium, trometamol, zinc salts, etc.

[0011] The solid compositions described in this disclosure may be, for example, powders, granules, or cakes or chunks agglomerated together.

[0012] In some embodiments, the solid composition is a dry solid composition. Methods for drying the composition include, but are not limited to, evaporation, freeze drying, or spray drying.

[0013] In some embodiments, the solid composition can form a liposomal composition after hydration, preferably a liposomal composition comprising multilamellar liposomes (MLVs). In some embodiments, other liposomal forms such as SUVs or LUVs can also be present in the liposomal composition. In some embodiments, the liposomal composition is primarily present in the form of MLVs.

[0014] In some embodiments, the solid composition is substantially free of lipid vesicle structures, preferably the solid composition is free of lipid vesicle structures, hi some embodiments, the solid composition does not form liposomes.

[0015] The hydration is generally achieved by mixing the solid composition with water or an aqueous solution. In some embodiments, the aqueous solution includes, but is not limited to, an isotonic solution or a buffer solution. The isotonic solution is a solution having substantially the same osmotic pressure as human blood and can be prepared from an isotonic agent and water. The isotonic agent includes sodium chloride, potassium chloride, magnesium chloride, calcium chloride, glucose, xylitol, and sorbitol. The buffer solution is a buffered solution that prevents changes in pH due to the action of its acid-base conjugate components. In one embodiment, the pH range of the buffer solution of the present disclosure is about 4.5 to about 8.5. Examples of buffer solutions that can control the pH within this range include acetate (e.g., sodium acetate), succinate (e.g., sodium succinate), gluconate, histidine, citrate, carbonate, PBS, HEPES, or other organic acid buffers.

[0016] In some embodiments, the hydration is achieved by mixing the solid composition with water or an isotonic solution.

[0017] In some embodiments, the liposome composition formed after hydration provides a peak concentration of drug (C) within about 3 hours after administration to an individual. max ), e.g., the peak concentration of the drug (C max ), preferably within about 1.5 hours, more preferably within about 1 hour, and most preferably within about 45 minutes.

[0018] In some embodiments, the liposome composition formed after hydration provides a sustained release of drug in an individual for 12 hours or more, preferably for 24 hours or more, more preferably for 48 hours or more, and most preferably for 72 hours or more.

[0019] The lipids described in the present disclosure can include completely neutral or negatively charged phosphatides.The term "phosphatide" refers to a hydrophobic molecule that contains at least one phosphorus group, natural or synthetic.For example, phosphatides can include phosphorus-containing groups and optionally OH, COOH, oxo, amine or substituted or unsubstituted aryl groups, saturated or unsaturated alkyl.Phosphatides differ from each other in terms of the length of their acyclic chain and the degree of unsaturation.

[0020] In some embodiments, the phosphatide comprises one or more of phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidic acid, and phosphatidylinositol. The term "phosphatidylcholine" refers to phosphatidylcholine and its derivatives. Phosphatides suitable for use in the present disclosure include, for example, dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphatidylcholine (PLPC), dioleoylphosphatidylcholine (DOPC), 1,2-dihydrocoil-sn-glycero-3-phosphocholine (DEPC), and 1,2-dihydrocoil-sn-glycero-3-phosphocholine (DEPC). PC), egg yolk phosphatidylcholine (EPC), dilauroyl phosphatidylcholine (DLPC), hydrogenated soy phosphatidylcholine (HSPC), l-myristoyl-2-palmitoyl phosphatidylcholine (MPPC), l-palmitoyl-2-myristoyl phosphatidylcholine (PMPC), l-palmitoyl-2-stearoyl phosphatidylcholine (PSPC), l-stearoyl-2-palmitoyl phosphatidylcholine ( SPPC), palmitoyloleylphosphatidylcholine (POPC), lysophosphatidylcholine, dilinoleoylphosphatidylcholine, distearoylphosphatidylethanolamine (DSPE), dimyristoylphosphatidylethanolamine (DMPE), dipalmitoylphosphatidylethanolamine (DPPE), dioleoylphosphatidylglycerol (DOPG), dimyristoylphosphatidylglycerol (DMPG), distearoylphosphatidylglycerol (DSPG), dipalmitoylglycerol phosphate glycerol (DPPG), dipalmitoylphosphatidylserine (DPPS), 1,2-dioleyl-sn-glycerol-3-phosphatidylserine (DOPS), dimyristoylphosphatidylserine (DMPS), distearoylphosphatidylserine (DSPS), dipalmitoylphosphatidic acid (DPPA), 1,2-dioleyl-sn-glycerol-3-phosphatidic acid (DOPA), dimyristoyl phosphatidic acid (DMPA), distearoyl phosphatidic acid (DSPA), dipalmitoyl phosphatidylinositol (DPPI), 1,2-dioleyl-sn-glycerol-3-phosphatidylinositol (DOPI), dimyristoyl phosphatidylinositol (DMPI), distearoyl phosphatidylinositol (DSPI) or more.

[0021] In some embodiments, the phosphatides described herein are selected from one or more of dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), 1,2-dihydrocoil-sn-glycero-3-phosphocholine (DEPC), dilauroylphosphatidylcholine (DLPC) and dimyristoylphosphatidylcholine (DMPC).

[0022] The present disclosure may further include other neutral lipids, cationic lipids and / or anionic lipids.

[0023] Other neutral lipids that can be used in the present disclosure include, for example, one or more of steroids, such as cholesterol and its derivatives, lecithin, soy lecithin, cephalin, sphingomyelin, hydrogenated soy lecithin, etc. In some embodiments, the molar percentage of steroids does not exceed 90% by weight of the total lipid mixture.

[0024] In some embodiments, the lipid comprises at least one phosphatide and cholesterol. The molar percentage of cholesterol relative to the amount of the total lipid mixture may be between 0.1% and 90%, preferably between 10% and 80%, and more preferably between 20% and 70%.

[0025] Based on the total moles of the solid composition, the molar content of said lipids may be between 10% and 99%, preferably between 20% and 70%.

[0026] A "drug" as used herein means any compound that can be used to prevent, diagnose, treat or cure disease, relieve pain, or manage or improve any physiological or pathological disorder in any human or animal. Drugs can exist in various forms, such as the free acid or free base form of the drug, pharma- ceutically acceptable salts, complexes or chelates of the drug. Drugs as used herein include all possible forms thereof. Types of drugs include, but are not limited to, antineoplastic drugs, antibiotics, antihypertensive drugs, hypoglycemic drugs, antihyperlipidemic drugs, antiepileptic drugs, antidepressants, antiemetic drugs, antihistamines, antipsychotic drugs, antianxiety drugs, drugs for erectile dysfunction, drugs for migraine headaches, drugs for alcoholism treatment, hemostatic drugs, muscle relaxants, nonsteroidal anti-inflammatory drugs, anesthetic drugs, analgesics, and steroidal anti-inflammatory drugs.

[0027] Antibiotics include, but are not limited to, cefmetazole, cefazolin, cephalosporin, cefoxitin, cephaacetonitrile, cephalosporin III, cephalosporin II, cephalosporin c, cephalothin, cephamycin a, cephamycin b, cephamycin c, cephalosporium, ampicillin, amoxicillin, hetacillin, carfecillin, carindacillin, carbenicillin, penicillin, azidocillin, benzylpenicillin, clometocillin, cloxacillin, cyclacillin, methicillin, nafcillin, 2-pentenepenicillin, penicillin n, penicillin o, penicillin s, penicillin v, chloropenicillin, diflucillin, diphenylpenicillin, heptylpenicillin, and metampicillin, and the like, and combinations thereof.

[0028] Anti-epileptic agents include, but are not limited to, 4-amino-3-hydroxybutanoic acid, ethylene sulfonate esters, gabapentin, and aminohexenoic acid, and the like, and combinations thereof.

[0029] Antidepressants include amitriptyline, amoxapine, benmoxine, butriptyline, clomipramine, desipramine, dosulepin, sinequan, imipramine, lofepramine, medifoxamine, mianserin, maprotiline, mirtazapine, nortriptyline, protriptyline, trimipramine, viloxazine, citalopram, cotinine, duloxetine, fluoxetine, fluvoxamine, milnacipran, nisoxetine, paroxetine, reboxetine, sertraline, tianeptine, acetylperphenazine, binedaline, brofaromine, benzenepropanol, clovoxamine, ipro These include, but are not limited to, niazid, isocarboxazid, moclobemide, phenyhydrazine, phenelzine, selegiline, sibutramine, tranylcypromine, adenosylmethionine, adrafinil, amesergide, amisulpride, amperozide, benactyzine, bupropion, caroxazone, gepirone, idazoxan, metralindole, milnacipran, milnacipran, nefazodone, nomifensine, ritanserin, roxindole, S-adenosylmethionine, tofenacin, trazodone, tryptophan, venlafaxine, and zalospirone, and the like, and combinations thereof.

[0030] Antiemetic agents include, but are not limited to, alizapride, azasetron, benzquinamide, bromopride, buclizine, chlorpromazine, cinnarizine, clebopride, cyclizine, diphenhydramine, diphenidol, dolasetron methanesulfonate, dipyridamole, granisetron, scopolamine, lorazepam, metoclopramide, isonipecotamide, ondansetron, perphenazine, promethazine, prochlorperazine, scopolamine, fosetyl, trifluoperazine, triflupromazine, trimethobenzamide, tropisetron, domperidone, palonosetron, and the like, and combinations thereof.

[0031] Antihistamines include, but are not limited to, azatadine, brompheniramine, chlorpheniramine, clemastine, cyproheptadine, dexmedetomidine, diphenhydramine, doxylamine, hydroxyzine, cetirizine, fexofenadine, loratadine, and promethazine, and the like, and combinations thereof.

[0032] Anti-tremor paralytics include, but are not limited to, amantadine, baclofen, biperiden, benztropine, orphenadrine, procyclidine, trihexyphenidyl, levodopa, carbidopa, selegiline, apomorphine, benserazide, bromocriptine, budipine, cabergoline, dihydroergocryptine, eliprodil, rivastigmine, ergoline, galantamine, lazabemide, lisuride, mazindol, memantine, mofegiline, pergolide, pramipexole, propentofylline, rasagiline, remacemide, terguride, entacapone, and tolcapone, and the like, and combinations thereof.

[0033] Antipsychotics include acetophenazine, alizapride, aripiprazole, amperozide, benperidol, benzquinamide, bromperidol, bramate, butaperazine, carphenazine, carpipramine, chlorpromazine, chlorprothixene, clocapramine, clomacrane, clopenthixol, clospyrazine, clothiapine, cyamemazine, dipyridamole, flupenthixol, fluphenazine, fluspirilene, haloperidol, mesoridazine, metofenazate, penfluridol, and prothiapine. including, but not limited to, lopericyazine, perphenazine, pimozide, pipamperone, piperacetazine, pipotiazine, prochlorperazine, promazine, rimoxipride, sertindol, spiperone, sulpiride, thioridazine, thiothixene, trifluperidol, triflupromazine, trifluoperazine, ziprasidone, zotepine, zuclopenthixol, amisulpride, butaclamol, clozapine, melperone, olanzapine, quetiapine and risperidone, and the like, and combinations thereof.

[0034] Anti-anxiety agents include, but are not limited to, mecloqualone, dexmedetomidine, dexmedetomidine, metomidate, adinazolam, chloridazepoxide, clobenzepam, flurazepam, lorazepam, loprazolam, midazolam, vibegron, aprepitant, alseroxylon, amphenidone, azacyclonol, bromural, buspirone, captodiamine, valeramide, dimethylbisamide, carbromal, chloral betaine, enciprazine, flesinoxan, ixabepilone, lesopitron, laxopine, methaqualone, propranolol, tandospirone, traxanox, zopiclone, and zolpidem, and the like, and combinations thereof.

[0035] Medications for erectile dysfunction include, but are not limited to, tadalafil, sildenafil, vardenafil, apomorphine, apomorphine diacetate, phentolamine, and yohimbine, and the like, and combinations thereof.

[0036] Hemostatic agents include, but are not limited to, thrombin, vitamin K1, protamine sulfate, aminocaproic acid, tranexamic acid, carbazochrome, carbazochrome sodium sulfonate, rutin, hesperidin, and the like, and combinations thereof.

[0037] Medications for migraine headaches include, but are not limited to, almotriptan, codeine, dihydroergotamine, ergotamine, eletriptan, frovatriptan, isometheptenam, lidocaine, lisuride, metoclopramide, naratriptan, oxycodone, propoxyphene, rizatriptan, sumatriptan, tolfenamic acid, zolmitriptan, amitriptyline, atenolol, clonidine, cyproheptadine, diltiazem, sinequan, fluoxetine, lisinopril, methysergide, metoprolol, nadolol, nortriptyline, paroxetine, pizotifen, propranolol, protriptyline, sertraline, timolol, and verapamil, and the like, and combinations thereof.

[0038] Medications for treating alcoholism include, but are not limited to, acamprosate, naloxone, naltrexone, and disulfiram, and the like, and combinations thereof.

[0039] Muscle relaxants include, but are not limited to, baclofen, cyclobenzaprine, orphenadrine, quinine, atracurium, rocuronium bromide, suxamethonium, tiotropium bromide, rapacuronium bromide, vecuronium bromide, pancuronium, and tizanidine, and the like, and combinations thereof.

[0040] Anesthetics include ambucaine, amoranone, amylocaine, oxybuprocaine, benzocaine, betoxycaine, biphenamine, bupivacaine, butacaine, butambene, butambene picrate, butanilicaine, butethamine, butoxycaine, carticaine, chloroprocaine, cocaethylene, cocaine, cyclomethycaine, dibucaine, dimethisoquin, dimethocaine, diperodone, diphenylhydroxylamine, dyclonine, ecgonidine, ecgonine, chloroethane, etidocaine, β-eucaine, hexylcaine, chloroprocaine, hydroxyprocaine, hydroxytetracaine, isobutane, Examples of suitable anti-inflammatory drugs include, but are not limited to, caine, butyl 4-aminobenzoate, ketocaine, leucinocaine, levoxadrol, mepivacaine, amylocaine, ambucaine, metabutetamine, myrtecaine, octacaine, orthocaine, oxethazin, parethoxycaine, phenacaine, phenol, piperocaine, pyridocaine, lauromacrogol 400, pramocaine, prilocaine, procaine, primacaine, proparacaine, propipocaine, propoxycaine, pseudococaine, pyrrocaine, ropivacaine, saligenin, tetracaine, tricaine, trimecaine, and the like, and combinations thereof.

[0041] Painkillers include alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenophine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, and levofloxacin. including, but not limited to, lorphan, levorphanol, levophenacylmorphan, lofentanil, pethidine, meptazinol, metazocine, methadone, metopon, morphine, mylophine, nalbuphine, nalorphine, narceine, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxycodone, oxymorphone, papavertam, pentazocine, phenadoxone, phenazocine, phenomorphan, phenoperidine, biminodine, piritramide, propeptadine, promedol, properidine, propiram, propyl phenyl ether, sufentanil, tilidine, tramadol, and the like, and combinations thereof.

[0042] Steroidal anti-inflammatory agents include alclometasone, amcinonide, betamethasone, betamethasone 17-pentanoate, curbetasol, clobetasol propionate, clocortolone, cortisone, dehydrotestosterone, desoxycorticosterone, desonide, dexamethasone, dexamethasone 21-isonicotinate, diflorasone, fluocinonide, fluocinolone acetonide, flumetholone, fluocinonide, fluticasone, halocyanide, urobetasol, cortisone hydrogen, cortisone hydrogen acetate, cortisone hydrogen cyclopentanepropanoate, and cortisone hydrogen hemisuccinate. , hydrogenated cortisone 21-lysine ester, hydrogenated cortisone succinate, isoflupredone, isoflurane acetate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, methylprednisolone, mometasone, prednicarbate, prednisolone, prednisolone acetate, prednisolone hemisuccinate, prednisolone sodium phosphate, prednisolone sodium succinate, prednisolone pentanoate-acetate, prednisone, triamcinolone, triamcinolone acetonide, and the like, and combinations thereof.

[0043] Nonsteroidal anti-inflammatory drugs include salicylic acid derivatives (e.g., salicylic acid, acetylsalicylic acid, salicylic acid methyl ester, diflunisal, olsalazine, salsalate, sulfasalazine, etc.), indolyl and indene acetic acids (e.g., indomethacin, etodolac, sulindac, etc.), fenamates (e.g., meclofenamic acid, mefenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, etc.), heteroaryl acetic acids (e.g., acemetacic acid, alclofenac acid, clidanac acid, diclofenac acid, fenclofenac acid, fentiazacic acid, furofenac acid, ibufenac acid, isoxepac acid, ketorolac, tiopinac, tolmetin, zidometacin, zomepirac, etc.), aryl acetic acid and propionic acid derivatives (e.g., aluminoprofen, benoxaprofen, bucloxanic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indolylprofen, ketoprofen, miloprofen, naproxen, naproxen sodium, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, tioxaprofen, etc.), glycinic acids (e.g., xicam derivatives ampiroxicam, cinoxicam, droxicam, lornoxicam, meloxicam, piroxicam, sadoxicam and tenoxicam, and pyrazolone derivatives aminopyrine, antipyrine, apazone, analgin, oxyphenbutazone, phenylbutazone, etc.), para-aminophenol derivatives (e.g., acetaminophen, etc.), alkanones (e.g., nabumetone, etc.), nimesulide, proquinazone, etc., and combinations thereof.

[0044] In some embodiments, the drug may be an anesthetic, a hemostatic agent, an analgesic, or a nonsteroidal anti-inflammatory agent.

[0045] In some embodiments, the drug may be bupivacaine, ropivacaine, butorphanol, dexmedetomidine, tranexamic acid, etc. The free acid or free base of the drug may be bupivacaine free base, ropivacaine free base, butorphanol free base, dexmedetomidine free base, tranexamic acid, etc. The corresponding pharma- ceutically acceptable salts, complexes or chelate complexes may be pharma- ceutically acceptable salts, complexes or chelates of bupivacaine (e.g., bupivacaine hydrochloride), pharma- ceutically acceptable salts, complexes or chelates of ropivacaine (e.g., ropivacaine hydrochloride), pharma- ceutically acceptable salts, complexes or chelates of butorphanol (e.g., butorphanol tartrate), pharma- ceutically acceptable salts, complexes or chelates of dexmedetomidine (e.g., dexmedetomidine hydrochloride), pharma- ceutically acceptable salts, complexes or chelates of tranexamic acid, and the like.

[0046] In some embodiments, suitable drugs of the present disclosure include those with a logP value of greater than about 1.0 (i.e., an octanol / water partition coefficient greater than 10), such as ropivacaine, which reportedly has a logP value of 3.16, bupivacaine, which has a logP value of 3.69, butorphanol, which has a logP value of 3.68, fentanyl, which has a logP value of 4.25, ondansetron, which has a logP value of 2.37, and sumatriptan, which has a logP value of 1.05.

[0047] Based on the total moles of the solid composition, the molar content of the drug (free acid or free base of the drug plus a pharma- ceutically acceptable salt, complex or chelate of the drug) may be 1%-90%, preferably 30%-90%, and more preferably 30%-80%.

[0048] The weight ratio of the free acid or free base of the drug to the pharma- ceutically acceptable salt, complex or chelate of the drug can be adjusted according to the actual therapeutic effect required. In some embodiments, the molar ratio of the free acid or free base of the drug to the pharma- ceutically acceptable salt, complex or chelate of the drug may be 0.01:1 to 100:1, preferably 1:9 to 9:1.

[0049] In some embodiments, the solid composition comprises (1) a lipid comprising at least one phosphatide, (2) ropivacaine free base, and (3) a pharma- ceutically acceptable salt of ropivacaine, preferably ropivacaine hydrochloride.

[0050] In some embodiments, the solid composition comprises (1) a lipid comprising at least one phosphatide, (2) bupivacaine free base, and (3) a pharma- ceutically acceptable salt of bupivacaine, preferably bupivacaine hydrochloride.

[0051] In some embodiments, the solid composition comprises (1) a lipid comprising at least one phosphatide, (2) butorphanol free base, and (3) a pharma- ceutically acceptable salt of butorphanol, preferably butorphanol tartrate.

[0052] In some embodiments, the solid composition comprises (1) a lipid comprising at least one phosphatide, (2) dexmedetomidine free base, and (3) a pharma- ceutically acceptable salt of dexmedetomidine, preferably dexmedetomidine hydrochloride.

[0053] In some embodiments, the solid composition comprises (1) a lipid comprising at least one phosphatide, (2) tranexamic acid free acid or free base, and (3) a pharma- ceutically acceptable salt of tranexamic acid.

[0054] The size of the liposomes may be the regular size of the multilamellar liposomes. In some embodiments, the size of the liposomes d(0.1) may be greater than 0.5 μm, such as greater than 1 μm. In some embodiments, the size of the liposomes d(0.5) may be greater than 1 μm, such as greater than 5 μm, such as greater than 10 μm. In some embodiments, the size of the liposomes d(0.9) may be greater than 1 μm, such as greater than 10 μm, such as greater than 15 μm, such as greater than 20 μm.

[0055] In some embodiments, the solid composition comprises (1) a lipid comprising at least one phosphatide, (2) ropivacaine free base, and (3) a pharma- ceutically acceptable salt of ropivacaine, preferably ropivacaine hydrochloride.

[0056] In some embodiments, the solid composition, after hydration, is capable of forming liposomal compositions, including multilamellar liposomes (MLVs).

[0057] In some embodiments, the lipid comprises at least one of phosphatidylcholine and cholesterol. The phosphatidylcholine is selected from one or more of dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dierucaphosphatidylcholine (DEPC), dilauroylphosphatidylcholine (DLPC) and dimyristoylphosphatidylcholine (DMPC). The molar ratio of the phosphatidylcholine to cholesterol may be 1000:1 to 1:9, preferably 4:1 to 1:4.

[0058] In some embodiments, the molar content of ropivacaine (free base plus pharma- ceutically acceptable salt of ropivacaine) may be 1%-90%, preferably 30%-90%, more preferably 30%-80%, based on the total moles of the solid composition. The molar ratio of the free base to the pharma- ceutically acceptable salt of ropivacaine may be 1:0.01-0.01:1, preferably 9:1-1:9.

[0059] In some embodiments, the solid composition comprises (1) a lipid comprising at least one of phosphatidylcholine and cholesterol, (2) ropivacaine free base, and (3) a pharma- ceutically acceptable salt of ropivacaine, preferably ropivacaine hydrochloride, of which: the molar ratio of the phosphatidylcholine to the cholesterol is 4:1 to 1:4; the molar ratio of the free base to the pharma- ceutically acceptable salt of ropivacaine is 9:1 to 1:9; Preferably, said solid composition is substantially free of lipid vesicle structures.

[0060] In some embodiments, the solid composition can form a liposome composition, preferably a liposome composition including a multilamellar liposome, after hydration. In some embodiments, the phosphatidylcholine is selected from dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), 1,2-dihydrocoyl-sn-glycero-3-phosphocholine (DEPC), dilauroylphosphatidylcholine (DLPC) and dimyristoylphosphatidylcholine (DMPC).

[0061] In some embodiments, the solid composition comprises (1) a lipid comprising at least one phosphatide, (2) butorphanol free base, and (3) a pharma- ceutically acceptable salt of butorphanol, preferably butorphanol tartrate.

[0062] In some embodiments, the solid composition, after hydration, is capable of forming liposomal compositions, including multilamellar liposomes (MLVs).

[0063] In some embodiments, the lipid comprises at least one phosphatidylcholine and cholesterol. The phosphatidylcholine is selected from one or more of dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dierucaphosphatidylcholine (DEPC), dilauroylphosphatidylcholine (DLPC) and dimyristoylphosphatidylcholine (DMPC), preferably dimyristoylphosphatidylcholine. The molar ratio of the phosphatidylcholine to cholesterol may be 1000:1 to 1:9, preferably 4:1 to 1:4.

[0064] In some embodiments, the molar content of butorphanol (free base plus pharma- ceutically acceptable salt of butorphanol) may be 1%-90%, preferably 30%-90%, and more preferably 30%-80%, based on the total moles of the solid composition. The molar ratio of the free base to the pharma- ceutically acceptable salt of butorphanol may be 1:0.01-0.01:1, and preferably 9:1-1:9.

[0065] The present disclosure further provides a method for preparing a solid composition according to the present disclosure, comprising mixing a lipid, a free acid or free base of the drug, a pharma- ceutically acceptable salt, complex or chelate of the drug, and a liquid medium, and removing the liquid medium.

[0066] The present disclosure further provides a method for making a solid composition according to the present disclosure, comprising mixing a lipid, a free acid or free base of a drug, a salifying agent, a liquid medium, and removing the liquid medium.

[0067] In some embodiments, the mixing step may also include adding a pharma- ceutically acceptable salt, complex, or chelate of the drug.

[0068] The salting agent includes one or more of an inorganic acid, an organic acid, an inorganic base, an organic base, an inorganic salt, and an organic salt, which may correspond to the pharma- ceutically acceptable salt that the free acid or free base of the drug is to form.

[0069] Suitable salification agents include, but are not limited to, acetic acid, benzoic acid, benzenesulfonic acid, hydrobromic acid, camphorsulfonic acid, acid, citric acid, ethylenesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, hydroiodic acid, isethionic acid, lactic acid, galacturonic acid, dodecylsulfuric acid, malic acid, maleic acid, methanesulfonic acid, naphthoic acid, naphthalenesulfonic acid, nitric acid, stearic acid, oleic acid, oxalic acid, pamoic acid, phosphoric acid, polygalacturonic acid, succinic acid, sulfuric acid, sulfosalicylic acid, tartaric acid, toluenesulfonic acid, trifluoroacetic acid, calcium hydroxide, calcium acetate, calcium chloride, choline, diethanolamine, diethylamine, magnesium hydroxide, magnesium chloride, methanolic magnesium, meglumine, piperazine, potassium hydroxide, sodium hydroxide, trometamol, zinc chloride, zinc hydroxide, and the like.

[0070] Possible liquid media include, but are not limited to, water, organic solvents, and water / organic solvent co-solvent systems. The organic solvents include, but are not limited to, methanol, ethanol, propyl alcohol, isopropanol, normal butanol, isobutanol, tert-butanol, acetone, acetonitrile, dichloromethane, dimethylsulfoxide, and the like. Suitable liquid media may be water, ethanol, isopropanol, tert-butanol, water / ethanol, water / isopropanol, water / tert-butanol, and the like. The liquid medium may be removed using known techniques, such as evaporation, freeze-drying, or spray-drying, preferably freeze-drying or spray-drying.

[0071] In some embodiments, the volume ratio of water to organic solvent in the water / organic solvent co-solvent may be from 1000:1 to 1:1000, preferably from 9:1 to 1:1000, and more preferably from 1:4 to 1:1000.

[0072] The present disclosure further provides a liposome composition obtained by hydrating the solid composition described in the present disclosure.

[0073] The hydration is generally achieved by mixing the solid composition with water or an aqueous solution. In some embodiments, the aqueous solution includes, but is not limited to, an isotonic solution or a buffer solution. The isotonic solution is a solution having substantially the same osmotic pressure as human blood and can be prepared from an isotonic agent and water. The isotonic agent includes sodium chloride, potassium chloride, magnesium chloride, calcium chloride, glucose, xylitol, and sorbitol. The buffer solution is a buffered solution that prevents changes in pH due to the action of its acid-base conjugate components. In one embodiment, the pH range of the buffer solution of the present disclosure is about 4.5 to about 8.5. Examples of buffer solutions that can control the pH within this range include acetate (e.g., sodium acetate), succinate (e.g., sodium succinate), gluconate, histidine, citrate, carbonate, PBS, HEPES, or other organic acid buffers.

[0074] In some embodiments, the solid composition can form a liposomal composition after hydration, preferably a liposomal composition comprising multilamellar liposomes (MLVs). In some embodiments, other liposomal forms such as SUVs or LUVs can also be present in the liposomal composition. In some embodiments, the liposomal composition is primarily present in the form of MLVs.

[0075] In some embodiments, the hydration is achieved by mixing the solid composition with water or an isotonic solution.

[0076] In some embodiments, the solid compositions or compositions after hydration described herein can further include other active agents.

[0077] In some embodiments, the liposomal compositions of the present disclosure optionally include a pharma- ceutical compatible vector.

[0078] In some embodiments, the liposome compositions described herein provide a sustained release of drug in an individual for 12 hours or more. In some embodiments, a sustained release of drug is provided for 24 hours or more. In some embodiments, a sustained release of drug is provided for 36 hours or more. In some embodiments, a sustained release of drug is provided for 48 hours or more. In some embodiments, a sustained release of drug is provided for 60 hours or more. In some embodiments, a sustained release of drug is provided for 72 hours or more.

[0079] In some embodiments, the liposome composition can reach a peak drug concentration within about 3 hours, for example within about 2 hours, preferably within about 1.5 hours, more preferably within about 1 hour, and most preferably within about 45 minutes, after administration to an individual.

[0080] As used herein, the term "individual" includes mammals and humans, and preferably, the individual can include rats. The liposome composition described in the present disclosure can achieve similar effects in humans. For example, the liposome composition described in the present disclosure provides sustained release of a drug for 12 hours or more in humans. In some embodiments, it provides sustained release of a drug for 24 hours or more. In some embodiments, it provides sustained release of a drug for 36 hours or more. In some embodiments, it provides sustained release of a drug for 48 hours or more. In some embodiments, it provides sustained release of a drug for 60 hours or more. In some embodiments, it provides sustained release of a drug for 72 hours or more. In some embodiments, it provides sustained release of a drug for 84 hours or more. In some embodiments, it provides sustained release of a drug for 96 hours or more. In some embodiments, it provides sustained release of a drug for 108 hours or more. In some embodiments, it provides sustained release of a drug for 120 hours or more. In some embodiments, it provides sustained release of a drug for 132 hours or more. In some embodiments, it provides sustained release of a drug for 144 hours or more. In some embodiments, it provides sustained release of a drug for 156 hours or more. In some embodiments, the liposome composition provides a sustained release of drug for 168 hours or more. For example, the liposome composition can reach a peak drug concentration within about 4 hours, in some embodiments within about 3.5 hours, in some embodiments within about 3 hours, in some embodiments within about 2.5 hours, in some embodiments within about 2 hours, in some embodiments within about 1.5 hours, in some embodiments within about 1 hour, in some embodiments within about 45 minutes, in some embodiments within about 30 minutes, in some embodiments within about 15 minutes, and in some embodiments within about 10 minutes after administration to a human.

[0081] In some embodiments, the total concentration of drug in the liposome composition is from about 0.1 mg / mL to about 300 mg / mL, preferably from about 1 mg / mL to about 50 mg / mL, and more preferably from about 2.5 mg / mL to about 40 mg / mL.

[0082] In some embodiments, the unencapsulated drug is about 1% to about 80% of the total molar amount of drug in the drug composition. In some embodiments, the unencapsulated drug is about 5% to about 70% of the total molar amount of drug in the drug composition. In some embodiments, the unencapsulated drug is about 10% to about 60% of the total molar amount of drug in the drug composition. In some embodiments, the unencapsulated drug is about 20% to about 50% of the total molar amount of drug in the drug composition. In some embodiments, the molar ratio of the unencapsulated drug to the encapsulated drug is 1:50 to 10:1. In some embodiments, the molar ratio of the unencapsulated drug to the encapsulated drug is 1:40 to 5:1. In some embodiments, the molar ratio of the unencapsulated drug to the encapsulated drug is 1:30 to 4:1. In some embodiments, the molar ratio of the unencapsulated drug to the encapsulated drug is 1:20 to 2:1. In some embodiments, the molar ratio of unencapsulated drug to encapsulated drug is 1:10 to 1:1. In some embodiments, the molar ratio of unencapsulated drug to encapsulated drug is 1:5 to 1:1.

[0083] In some embodiments, the liposome composition is obtained by hydrating a solid composition comprising (1) a lipid, including at least one phosphatide, (2) ropivacaine free base, and (3) a pharma- ceutically acceptable salt of ropivacaine, preferably ropivacaine hydrochloride.

[0084] In some embodiments, the aqueous medium used in the hydration step is water or an isotonic solution, wherein the isotonic solution is selected from physiological saline or a glucose solution.

[0085] In some embodiments, the total concentration of ropivacaine in the liposome composition is from about 0.1 mg / mL to about 80 mg / mL, preferably from about 1 mg / mL to about 40 mg / mL, and more preferably from about 2.5 mg / mL to about 25 mg / mL.

[0086] In some embodiments, the unencapsulated ropivacaine is about 1% to about 90% of the total molar amount of ropivacaine in the drug composition. In some embodiments, the unencapsulated ropivacaine is about 5% to about 50% of the total molar amount of ropivacaine in the drug composition. In some embodiments, the unencapsulated ropivacaine is about 10% to about 40% of the total molar amount of ropivacaine in the drug composition. In some embodiments, the unencapsulated ropivacaine is about 20% of the total molar amount of ropivacaine in the drug composition. In some embodiments, the molar ratio of unencapsulated ropivacaine to encapsulated ropivacaine is 1:99 to 10:1. In some embodiments, the molar ratio of unencapsulated ropivacaine to encapsulated ropivacaine is 1:40 to 4:1. In some embodiments, the molar ratio of unencapsulated ropivacaine to encapsulated ropivacaine is 1:30 to 4:1. In some embodiments, the molar ratio of unencapsulated ropivacaine to encapsulated ropivacaine is between 1:20 and 2: 1. In some embodiments, the molar ratio of unencapsulated ropivacaine to encapsulated ropivacaine is between 1:10 and 1: 1. In some embodiments, the molar ratio of unencapsulated ropivacaine to encapsulated ropivacaine is between 1:5 and 1:1.

[0087] In some embodiments, the liposome composition, after administration to an individual, is capable of reaching a peak ropivacaine drug concentration within about 3 hours, for example, a peak ropivacaine drug concentration of the drug within about 2 hours, preferably, a peak ropivacaine drug concentration within about 1.5 hours, more preferably, a peak ropivacaine drug concentration within about 1 hour, and most preferably, a peak ropivacaine drug concentration within about 45 minutes.

[0088] In some embodiments, the liposome composition can provide a sustained release of ropivacaine for 12 hours or more, preferably a sustained release of ropivacaine for 48 hours or more, more preferably a sustained release of ropivacaine for 72 hours or more, and most preferably a sustained release of ropivacaine for 120 hours or more.

[0089] In some embodiments, the solid composition comprises (1) a lipid comprising at least one phosphatide, (2) butorphanol free base, and (3) a pharma- ceutically acceptable salt of butorphanol, preferably butorphanol tartrate.

[0090] The liposomal drug compositions of the present disclosure may be administered in a variety of ways, including but not limited to topical administration, parenteral administration, etc. The compositions may include ophthalmic and injectable dosage forms, and may include medical diagnostic products.

[0091] The present disclosure further provides a method for producing a liposomal composition comprising the steps of producing a solid composition as described herein and hydrating said solid composition.

[0092] The present disclosure further provides a method for producing a liposomal composition, comprising the steps of producing a solid composition and hydrating said solid composition, The step of preparing the solid composition may include (1) mixing the lipid, the free acid or free base of the drug, a pharma- ceutically acceptable salt, complex or chelate of the drug, and the liquid medium, and removing the liquid medium; or (2) mixing the lipid, the free acid or free base of the drug, a salifying agent, and the liquid medium, and removing the liquid medium.

[0093] Among these, the lipid, the free acid or free base of the drug, and the pharma- ceutically acceptable salt, complex or chelate of the drug are as described above.

[0094] In some embodiments, the mixing step may also include adding a pharma- ceutically acceptable salt, complex, or chelate of the drug.

[0095] The salifying agent may include one or more of an inorganic acid, an organic acid, an inorganic base, an organic base, an inorganic salt, and an organic salt, which may correspond to the pharma- ceutically acceptable salt that the free acid or free base of the drug is to form.

[0096] Suitable salification agents include, but are not limited to, acetic acid, benzoic acid, benzenesulfonic acid, hydrobromic acid, camphorsulfonic acid, citric acid, ethylenesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, hydroiodic acid, isethionic acid, lactic acid, galacturonic acid, dodecylsulfuric acid, malic acid, maleic acid, methanesulfonic acid, naphthoic acid, naphthalenesulfonic acid, nitric acid, stearic acid, oleic acid, oxalic acid, pamoic acid, phosphoric acid, polygalacturonic acid, succinic acid, sulfuric acid, sulfosalicylic acid, tartaric acid, toluenesulfonic acid, trifluoroacetic acid, calcium hydroxide, calcium acetate, calcium chloride, choline, diethanolamine, diethylamine, magnesium hydroxide, magnesium chloride, magnesium methanol, meglumine, piperazine, potassium hydroxide, sodium hydroxide, trometamol, zinc chloride, zinc hydroxide, and the like.

[0097] Possible liquid media include, but are not limited to, water, organic solvents, and water / organic solvent co-solvent systems. The organic solvents include, but are not limited to, methanol, ethanol, propyl alcohol, isopropanol, normal butanol, isobutanol, tert-butanol, acetone, acetonitrile, dichloromethane, dimethylsulfoxide, and the like. Suitable liquid media may be water, ethanol, isopropanol, tert-butanol, water / ethanol, water / isopropanol, water / tert-butanol, and the like. The liquid medium may be removed using known techniques, such as evaporation, freeze-drying, or spray-drying, preferably freeze-drying or spray-drying.

[0098] In some embodiments, the volume ratio of water to organic solvent in the water / organic solvent co-solvent may be from 1000:1 to 1:1000, preferably from 9:1 to 1:1000, and more preferably from 1:4 to 1:1000.

[0099] The hydration is generally achieved by mixing the solid composition with water or an aqueous solution. In some embodiments, the aqueous solution includes, but is not limited to, an isotonic solution or a buffer solution. The isotonic solution is a solution having substantially the same osmotic pressure as human blood and can be prepared from an isotonic agent and water. The isotonic agent includes sodium chloride, potassium chloride, magnesium chloride, calcium chloride, glucose, xylitol, and sorbitol. The buffer solution is a buffered solution that prevents changes in pH due to the action of its acid-base conjugate components. In one embodiment, the pH range of the buffer solution of the present disclosure is about 4.5 to about 8.5. Examples of buffer solutions that can control the pH within this range include acetate (e.g., sodium acetate), succinate (e.g., sodium succinate), gluconate, histidine, citrate, carbonate, PBS, HEPES, or other organic acid buffers.

[0100] In some embodiments, the hydration is achieved by mixing the solid composition with water or an isotonic solution.

[0101] Some embodiments of the present disclosure relate to a method of treating, ameliorating, or preventing a disease comprising administering to an individual a liposome composition described herein. In some embodiments, the administration is parenteral administration. In some embodiments, the administration is topical administration. In some embodiments, the administration is parenteral and topical administration. In some embodiments, the parenteral administration is selected from intravenous injection, subcutaneous injection, tissue injection, wound infiltration, or wound instillation.

[0102] Administration of the liposomal compositions of the present disclosure can be accomplished using standard methods and devices, such as pens, syringe systems, needle and injectors, subcutaneous injection port delivery systems, tubes, and the like.

[0103] The term "about" means that quantities, sizes, formulations, parameters, and other quantities and characteristics may be imprecise, and need not be exact, but may be approximate and / or greater or lesser values ​​as desired, thereby reflecting tolerances, conversion factors, rounding, measurement errors, and the like, as well as other factors known to those of skill in the art. Its meaning may include a variation of ±10%, preferably a variation of ±5%.

[0104] The solid composition of the present disclosure can form a liposome composition, such as a multi-layer liposome, after being hydrated. In the liposome composition produced, some of the drugs are encapsulated in liposomes, and some of the drugs are not encapsulated. The ratio of the encapsulated drug to the unencapsulated drug is appropriate so that after the liposome is administered to an individual, the unencapsulated drug is released quickly to obtain a therapeutic effect, and the encapsulated drug is released continuously to maintain a therapeutic effect. The ratio of the encapsulated drug to the unencapsulated drug can be determined by measuring the encapsulation rate of the liposome.

[0105] The "encapsulation percentage" or "encapsulation rate" of each formulation refers to the percentage of the molar amount of all drug forms encapsulated in liposomes relative to the total molar amount of drug in the composition. The encapsulation rate is preferably in the range of about 1% to 99%, more preferably about 60% to 85%. The encapsulation rate can be measured by conventional methods for measuring the encapsulation rate, such as the HPLC method.

[0106] The term "substantially free of lipid vesicle structures" means that the lipids in the solid composition do not form lipid vesicle structures or do not form dry lipid vesicles (e.g., the form formed after lyophilization of lipid vesicles), e.g., substantially no lipid vesicle structures or dry lipid vesicles can be observed in a scanning electron micrograph of the solid composition. In some embodiments, the process of forming the solid composition does not substantially include a process of forming lipid vesicle structures. In some embodiments, the solid composition contains no more than about 10%, or 5%, or 3%, or 1% lipid vesicle structures.

[0107] The term "particle size distribution" or "PSD" refers to a particle size distribution measured using dynamic light scattering techniques known to those skilled in the art, such as the Malvern Mastersizer. TM 2000. In the present disclosure, "d(0.1)" refers to the particle size distribution in the liposome composition measured when the cumulative particle size distribution percentage of a sample reaches 10%. "d(0.5)" refers to the particle size distribution when the cumulative particle size distribution percentage of a sample reaches 50%. "d(0.9)" refers to the particle size distribution when the cumulative particle size distribution percentage of a sample reaches 90%. [Brief description of the drawings]

[0108] [Figure 1] FIG. 2 is a cryo-transmission electron microscope image of the ropivacaine liposome produced in Example 1. [Diagram 2] 1 shows the plasma PK profile of the ropivacaine formulation prepared in Example 1. [Diagram 3] 1 is an in vitro release curve of ropivacaine liposome prepared in Example 1. [Figure 4] 1 is an in vitro release curve of butorphanol liposomes prepared in Example 5. [Diagram 5] 1 is a plasma PK profile of the butorphanol formulation prepared in Example 5. [Figure 6] FIG. 2 is a scanning electron microscope image of the ropivacaine solid composition prepared in Example 1. [Figure 7] FIG. 2 is a frozen scanning electron microscope image of the ropivacaine liposome produced in Example 1. [Figure 8] 1 shows the effect of the ropivacaine liposome prepared in Example 1 on the pain threshold at the administration site of subcutaneous injection in guinea pigs. [Figure 9] 1 shows the effect of the ropivacaine liposome prepared in Example 1 on the pain threshold at the administration site of intradermal injection in guinea pigs. [Figure 10] 1 shows the effect of the ropivacaine liposome prepared in Example 1 on the local pain threshold of rats after plantar surgery. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0109] Example 1: Preparation of Ropivacaine Liposomes

[0110] [Table 1]

[0111] Preparation of solid composition: 5.10 g of DMPC, 1.50 g of cholesterol, 2.40 g of ropivacaine free base, and 0.68 g of ropivacaine hydrochloride were weighed and dissolved in 100 mL of tert-butanol, and dispensed into 50 10 mL vials, each containing 2.0 mL. The samples were placed in a freeze dryer and freeze-dried to prepare the ropivacaine solid composition.

[0112] Liposome preparation: The lyophilized product from the previous step was re-eluted with an appropriate amount of physiological saline and mixed homogeneously. The content and encapsulation rate of liposomes were measured by HPLC, and the content was 17.989mg / mL (calculated based on ropivacaine free base, the same below), and the encapsulation rate was 79.34%. Characterization by cryo-transmission electron microscopy showed that it contained multi-layered liposomes. The liposome particle size measurement results showed that D[4,3] was 15.959μm, d(0.1) was 3.325μm, d(0.5) was 12.964μm, and d(0.9) was 31.674μm.

[0113] Example 2: Pharmacokinetic study of ropivacaine liposomes in rats

[0114] 1. Test drug Ropivacaine liposomes prepared in Example 1, standard 17.99 mg / mL; Commercially available ropivacaine hydrochloride injection, standard 10mL:100mg (calculated based on ropivacaine hydrochloride).

[0115] 2. Test Animals Sprague Dawley rats (SPF grade), male, aged approximately 6-8 weeks, weighing 180-250g. Provided by: Shanghai Xipuer-Bikai Laboratory Animal Co., Ltd. Qualification certificate number 20180006003423, production license number SCXK(Hu)2018-0006.

[0116] 3. Test Procedure The grouping and study design are specifically shown in the following table.

[0117] [Table 2]

[0118] Sample collection time and volume: Group 1: 6 minutes, 18 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 8 hours, 12 hours, and 24 hours after administration. A total of 12 time points. Group 2: Pre-dose and 30 min, 1 h, 2 h, 4 h, 8 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, and 168 h after administration. A total of 12 time points. A 2-minute tolerance was allowed for each blood sampling time point within 30 minutes after administration, a 5-minute tolerance was allowed for each blood sampling time point from 30 minutes to 8 hours after administration, a 10-minute tolerance was allowed for each blood sampling time point from 8 hours to 48 hours after administration, and a 20-minute tolerance was allowed for each blood sampling time point from 48 hours to 168 hours after administration.

[0119] The collected blood samples were placed in heparin anticoagulated blood collection tubes and centrifuged to extract plasma (6800g centrifugal force, 6 minutes, 2-8°C). The plasma samples were stored in a -80°C refrigerator before being sent to the client. The drug concentration in the plasma was measured by HPLC-MS / MS. The test results are shown in Figure 2 and the following table.

[0120] [Table 3]

[0121] After subcutaneous injection of ropivacaine liposomes in rats, the time to peak (t max ) was 0.6 hours, and the peak time (t max = 1.15 hours), which explains that ropivacaine liposomes exert their effects quickly in the body and that their onset time in the body is similar to that of commercially available ropivacaine injections. 1 / 2 ) was approximately 18 times that of the commercially available ropivacaine injection, proving that ropivacaine liposomes have an ideal sustained release effect. The dose of ropivacaine liposomes was approximately six times that of the commercially available formulation, but the peak concentration (C max ) are similar, proving that the safety of ropivacaine liposomes is relatively good, and the clinical single dose can reach at least six times that of the commercially available formulation. Thus, the rat PK data of ropivacaine liposomes suggests that this type can exert its effect rapidly while maintaining a relatively long sustained release effect, and has a high tolerated dose, which is favorable for improving patient compliance.

[0122] Example 3: Preparation of liposomes without initial addition of ropivacaine hydrochloride

[0123] [Table 4]

[0124] Liposomes were prepared without adding ropivacaine hydrochloride initially according to the method of Example 1. The content and encapsulation rate of liposomes were determined by HPLC, and the content was 18.558 mg / mL and the encapsulation rate was 97.24%.

[0125] Example 4: In vitro release of ropivacaine liposomes

[0126] 1. Cleaning the dialysis bag: 10g of sodium bicarbonate and 0.168g of EDTA-2Na were weighed into 500mL of water and mixed uniformly. The dialysis bag was cut into 10cm pieces and boiled in a 1L beaker with cleaning solution for 10 minutes. The dialysis bag was then washed 10 times with 200mL of purified water, and another 500mL of purified water was added and boiled for 10 minutes. Dialysis bags that are not used for a long time can be stored in 10% ethanol and washed 10 times with 200mL of purified water each time before use.

[0127] 2. Preparation of release medium: 2.3 g of potassium dihydrogen phosphate, 7.6 g of dipotassium hydrogen phosphate trihydrate, 5.6 g of sodium chloride, and 132 mg of ammonium sulfate were weighed into a 1000 mL volumetric flask, and water was added to the volume, and the mixture was mixed uniformly to obtain a release medium.

[0128] 3. Lofting and sampling measurement of released samples: Using a pipette gun, 1.0 mL of the liposome solution to be measured was accurately weighed and added to a 10 cm dialysis bag, 1 mL of release medium was added, and both ends of the dialysis bag were clamped with clips, and then placed in a 150 mL tall beaker containing 99 mL of release medium. The sample was incubated on a shaker at 37°C and 10 rpm, and 1 mL was sampled at each set time point and assayed by HPLC.

[0129] The test results are shown in FIG. 3 and the following table.

[0130] [Table 5]

[0131] It was found that the liposomes of Example 3 have a relatively high encapsulation rate, and therefore their in vitro release within 0 to 4 hours is slower, and the 4-hour release rate is close to the 1-hour release rate of the liposomes of Example 1. The above results reveal that too high an encapsulation rate affects the release of the drug at the initial stage, which is disadvantageous to the rapid exertion of the analgesic effect of the local analgesic drug.

[0132] Example 5: Preparation of butorphanol liposomes

[0133] [Table 6]

[0134] According to the methods of Examples 1 and 3, butorphanol liposomes were prepared.

[0135] Example 6: In vitro release of butorphanol liposomes The in vitro release of butorphanol liposomes was measured using the test method of Example 4. The test results are shown in Figure 4 and the following table.

[0136] [Table 7]

[0137] Within 0-4 hours, the in vitro release of liposomes of formulation 2 was relatively slow, and its 4-hour release rate was close to that of liposomes of formulation 1 at 0.5 hours. It was proved that too high an encapsulation rate would affect the initial release of the drug, which was unfavorable to the rapid exertion of the analgesic effect of butorphanol.

[0138] Example 7: Pharmacokinetic study of butorphanol liposomes in rats

[0139] 1. Test drug Butorphanol liposome formulation 1 prepared in Example 5, standard: 14.96 mg / mL; Butorphanol tartrate injection available commercially, standard size 2mL:4mg.

[0140] 2. The test animals and methods were the same as in Example 2.

[0141] 3. Test Results: The test results are shown in FIG. 5 and the following table.

[0142] [Table 8]

[0143] Rats were subcutaneously injected with butorphanol liposomes and butorphanol tartrate injection, and the time to peak (t max ) was within 0.5 hours in both cases, which explains the rapid effect of butorphanol liposomes in the body. 1 / 2 ) was about 15 times that of the commercially available butorphanol tartrate injection, proving that butorphanol liposomes have an ideal sustained-release effect. The dosage of butorphanol liposomes was about four times that of the commercially available formulation, but the peak concentration (C max ) is the peak concentration (C max ), proving that butorphanol liposomes have relatively good safety and that the clinical single dose can reach at least four times or more than that of the commercially available formulation. Thus, the rat PK data of butorphanol liposomes suggests that this variety can exert its effect quickly while maintaining a relatively long sustained release effect, and has a high tolerable dose, which is favorable for improving patient compliance.

[0144] Example 8: Analgesic test using subcutaneous injection of ropivacaine liposomes in guinea pigs

[0145] 1. Test drug Ropivacaine liposome prepared in Example 1, Over-the-counter ropivacaine hydrochloride injection.

[0146] 2. Test Method Guinea pigs were divided into low, medium, and high dose ropivacaine liposome groups and ropivacaine hydrochloride injection groups, with 10 animals in each group, half of which were male and half of which were female. Guinea pigs in each group were subcutaneously injected with ropivacaine liposome at doses of 0.4, 0.885, and 1.9 mg / animal (equivalent to approximately 1.3, 2.9, and 6.3 mg / kg, calculated based on ropivacaine free base; the same applies below) and ropivacaine hydrochloride injection at doses of 0.885 mg / animal (equivalent to approximately 2.9 mg / kg), respectively, into the upper left hind leg, and pain thresholds at the injection site were measured by the needling method 0.5, 1, 2, 4, 6, 8, 10, and 24 hours after administration.

[0147] The test results are shown in Figure 8. The pain threshold at the injection site at the first detection point (0.5 hours) after injection was significantly higher than that before injection (P<0.001). The pain threshold peaked at about 1 hour after injection, and the percentage increase in the peak pain threshold was 875.70%, 863.35%, and 964.28%, respectively. Thereafter, the pain threshold slowly decreased, and the pain threshold at 24 hours was still higher than that before injection (P<0.05 or P<0.01), and the duration of the drug effect was about 24 hours. Guinea pigs were subcutaneously injected with ropivacaine hydrochloride injection solution at 0.885 mg / animal, and the pain threshold after injection was significantly higher than that before injection (P<0.001), and the pain threshold peaked at the first detection point (0.5 hours), and the percentage increase in the peak pain threshold was 961.23%. The pain threshold rapidly decreased from 4 hours after administration, and 4 hours after administration, the pain threshold was about 45% of the peak pain threshold, and the 24-hour pain threshold was not significantly different from the pain threshold before administration (P>0.05), and the analgesic effect lasted for about 10 hours. From 4 to 10 hours after administration, the pain threshold of the guinea pigs in the ropivacaine hydrochloride injection group rapidly decreased, and the percentage increase in pain threshold of the guinea pigs in the ropivacaine liposome group at a dose of 0.885 mg / animal was significantly higher than that of the ropivacaine hydrochloride injection group at 0.885 mg / animal (P<0.01 or P<0.001).

[0148] Example 9: Analgesic test using subcutaneous injection of ropivacaine liposomes in guinea pigs

[0149] 1. Test drug Ropivacaine liposome prepared in Example 1, Over-the-counter ropivacaine hydrochloride injection.

[0150] 2. Test Method After the subcutaneous injection administration in Example 8, the guinea pigs were subjected to a 7-day washout period and then an intradermal injection analgesia test was conducted. Each administration group (10 animals per group, half male and half female) was intradermally injected into the upper right hind leg with ropivacaine liposome at doses of 0.2, 0.443, and 0.95 mg / animal (equivalent to approximately 0.7, 1.5, and 3.1 mg / kg) and ropivacaine hydrochloride injection at a dose of 0.443 mg / animal (equivalent to approximately 1.5 mg / kg). The pain threshold at the administration site was measured by the needling method 0.5, 1, 2, 4, 6, 8, 10, and 24 hours after administration.

[0151] The test results are shown in Figure 9. The pain threshold at the injection site at the first detection point (0.5 hours) after injection was significantly higher than before injection (P<0.001). The pain threshold reached its peak at about 1-2 hours after injection, and the percentage increase in the peak pain threshold was 1006.41%, 922.63%, and 1266.74%, respectively. After that, the pain threshold slowly decreased, and 10 hours after injection, the pain threshold of the guinea pigs in the ropivacaine liposome group with a dose of 0.2 and 0.443 mg / animal was still significantly higher than before injection (P<0.001), and the pain threshold of the guinea pigs in the ropivacaine liposome group with a dose of 0.95 mg / animal was still significantly higher than before injection (P<0.001) at 24 hours after injection. The duration of analgesic effect of ropivacaine liposomes injected intradermally into guinea pigs at doses of 0.2 and 0.443 mg / animal was approximately 10 hours, and the duration of analgesic effect of ropivacaine liposomes injected intradermally into guinea pigs at doses of 0.95 mg / animal was approximately 24 hours. Guinea pigs were intradermally injected with ropivacaine hydrochloride injection solution at 0.443 mg / animal, and the pain threshold at the injection site at the first detection point (0.5 hours) after administration was significantly higher than before administration (P<0.001). The pain threshold peaked around 1 hour after administration, with the percentage increase in the peak pain threshold being 1100.20%. The pain threshold rapidly decreased from 8 hours after administration to approximately 23% of the peak pain threshold. The 10-hour pain threshold was significantly higher than the pain threshold before administration, but there was no clear difference between the 24-hour pain threshold and the pain threshold before administration, and the duration of analgesic effect was approximately 10 hours. From 6 to 10 hours after administration, the percentage increase in pain threshold of guinea pigs in the group administered intradermal injection of ropivacaine liposome (0.443 mg / animal) was significantly higher than that of the group administered ropivacaine hydrochloride injection (0.443 mg / animal) (P<0.01 or P<0.001). From 2 to 24 hours after administration, the percentage increase in pain threshold of guinea pigs in the group administered ropivacaine liposome at a dose of 0.95 mg / animal was significantly higher than that of the group administered ropivacaine injection 0.443 mg / animal (P<0.05, P<0.01 or P<0.001).

[0152] Example 10: Rat plantar surgical incision analgesia test

[0153] 1. Test drug Ropivacaine liposome prepared in Example 1, Over-the-counter ropivacaine hydrochloride injection.

[0154] 2. Test Method The rats were randomly divided according to body weight into a surgery group, low, medium, and high dose ropivacaine liposome groups, and a ropivacaine hydrochloride injection group, with 10 rats in each group, half male and half female. A longitudinal incision was made in the skin of the right hind paw of each group with a scalpel, the incision length was approximately 0.5 cm, the depth was approximately 0.2 cm, and the incision was then sutured. The day after surgery, animals in each group were administered a ropivacaine liposome blank formulation, ropivacaine liposome (0.2, 0.443, and 0.95 mg / rat, equivalent to approximately 0.9, 1.9, and 4.2 mg / kg), and ropivacaine hydrochloride injection 0.443 mg / rat (equivalent to approximately 1.9 mg / kg) via plantar injection. The pain threshold at the injection site was measured by the needling method at 0.5, 1, 2, 4, 6, 8, 10, and 24 hours after administration.

[0155] The results are shown in Figure 10. After the rat plantar surgery, the plantar pain threshold was obviously lowered, and the percentage of decrease in the pain threshold was about 60%. Within 0.5 to 10 hours after the rat plantar injection, the rat pain thresholds of the low, medium, and high dose ropivacaine liposome groups (0.2, 0.443, and 0.95 mg / rat) were significantly higher than the operation control group (P<0.05, P<0.01, or P<0.001), and each time point showed dose-dependence. The analgesic effect of ropivacaine liposome lasted for about 10 hours. Rats were given a plantar injection of 0.443 mg / rat of ropivacaine hydrochloride injection, and within 0.5 to 2 hours after the injection, the pain threshold was significantly higher than the operation control group (P<0.01 or P<0.001), and the analgesic effect lasted for about 2 hours. In the group of rats that received 0.443 mg / rat of ropivacaine liposome by intraplantar injection, the percentage increase in pain threshold was significantly higher than that of the group that received 0.443 mg / rat of ropivacaine hydrochloride injection for 6 to 8 hours after administration (P<0.05 or P<0.01). In the group of rats that received 0.95 mg / rat of ropivacaine liposome by intraplantar injection, the percentage increase in pain threshold was significantly higher than that of the group that received 0.443 mg / rat of ropivacaine hydrochloride injection for 1 to 10 hours (P<0.05, P<0.01 or P<0.001).

[0156] Example 11: Ropivacaine liposomes

[0157] [Table 9]

[0158] Phosphatide, cholesterol, ropivacaine free base, and ropivacaine hydrochloride were weighed and dissolved in 100mL of tert-butanol-water mixed solvent, and dispensed into 20mL vials, each containing 5mL. The samples were placed in a freeze dryer and lyophilized. The freeze-dried product was re-eluted with an appropriate amount of saline and mixed uniformly to obtain the target liposomes, and the active substance content and encapsulation rate were measured.

[0159] Example 12 The in vitro release of ropivacaine liposomes L2-L4 was measured using the test method of Example 4. The test results are shown in the following table.

[0160] [Table 10]

[0161] Although specific embodiments of the present invention have been described above, those skilled in the art will understand that these are merely examples, and that various changes or modifications can be made to these embodiments without departing from the principles and spirit of the present invention, and therefore the scope of protection of the present invention is limited by the claims.

Claims

1. A liposome composition obtained by hydrating a dry solid composition, comprising: The operation of hydration comprises mixing the solid composition with water or an aqueous solution; The solid composition comprises: (1) a lipid comprising at least one phosphatide; (2) a free acid or free base of a drug; and (3) a pharma- ceutically acceptable salt, complex, or chelate of the drug; A liposomal composition, wherein the solid composition is substantially free of lipid vesicle structures.

2. The liposome composition of claim 1 , wherein the phosphatide comprises one or more of phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidic acid, and phosphatidylinositol.

3. The liposome composition of claim 1 , wherein the lipid further comprises a steroid.

4. The liposome composition of claim 3, wherein the steroid is cholesterol and the molar percentage of the cholesterol relative to the total molar amount of the lipids is between 0.1% and 90%.

5. 2. The liposome composition according to claim 1, wherein the total content of the free acid or free base of the drug and the pharma- ceutically acceptable salt, complex or chelate of the drug is 1% to 90%, based on the total molar amount of the solid composition.

6. 2. The liposome composition of claim 1, wherein the molar ratio of the free acid or free base of the drug to the pharma- ceutically acceptable salt, complex or chelate of the drug is 0.01:1 to 100:

1.

7. The liposome composition of claim 1 , wherein the drug is selected from the group consisting of anesthetics, hemostatic agents, analgesics, and nonsteroidal anti-inflammatory agents.

8. The solid composition comprising:

8. The liposome composition of claim 1, comprising: (1) a lipid comprising at least one phosphatide; (2) ropivacaine free base; and (3) a pharma- ceutically acceptable salt of ropivacaine.

9. The solid composition comprising: (1) a lipid comprising at least one of phosphatidylcholine and cholesterol; (2) ropivacaine free base; and (3) a pharma- ceutically acceptable salt of ropivacaine, the molar ratio of said phosphatidylcholine to cholesterol is 4:1 to 1:4; the molar ratio of the free base to the pharma- ceutically acceptable salt of ropivacaine is 9:1 to 1:9; The liposome composition of claim 1 , wherein the solid composition is substantially free of lipid vesicle structures.

10. The liposome composition of claim 1, wherein the solid composition forms a liposome composition after hydration.

11. The liposome composition of claim 10, wherein the hydration operation is achieved by mixing the solid composition with water or an aqueous solution.

12. 11. The liposomal composition of claim 10, wherein the liposomal composition reaches a peak drug concentration within about 3 hours after administration to an individual.

13. The liposome composition of claim 10 , wherein the liposome composition provides a sustained release of the drug in an individual for 12 hours or more.

14. A method for producing a liposomal composition according to any one of claims 1 to 13, comprising the steps of producing a solid composition and hydrating said solid composition, The step of preparing the solid composition includes: (1) mixing a lipid, a free acid or free base of a drug, a pharma- ceutically acceptable salt, complex or chelate of the drug, and a liquid medium, and removing the liquid medium; or (2) mixing the lipid, a free acid or free base of a drug, a salifying agent, and a liquid medium, and removing the liquid medium; The method for producing a liposome composition, wherein the solid composition is substantially free of lipid vesicle structures.

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