CN117999079A - Pharmaceutical composition containing celebrazil - Google Patents
Pharmaceutical composition containing celebrazil Download PDFInfo
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- CN117999079A CN117999079A CN202280056159.8A CN202280056159A CN117999079A CN 117999079 A CN117999079 A CN 117999079A CN 202280056159 A CN202280056159 A CN 202280056159A CN 117999079 A CN117999079 A CN 117999079A
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 106
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims abstract description 60
- 208000002193 Pain Diseases 0.000 claims abstract description 37
- 239000002253 acid Substances 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 24
- 239000003960 organic solvent Substances 0.000 claims abstract description 20
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 16
- 239000001301 oxygen Substances 0.000 claims abstract description 16
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 124
- AFSHUZFNMVJNKX-UHFFFAOYSA-N 1,2-di-(9Z-octadecenoyl)glycerol Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCC=CCCCCCCCC AFSHUZFNMVJNKX-UHFFFAOYSA-N 0.000 claims description 75
- AFSHUZFNMVJNKX-LLWMBOQKSA-N 1,2-dioleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](CO)OC(=O)CCCCCCC\C=C/CCCCCCCC AFSHUZFNMVJNKX-LLWMBOQKSA-N 0.000 claims description 75
- 235000010469 Glycine max Nutrition 0.000 claims description 70
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 63
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 61
- 239000000203 mixture Substances 0.000 claims description 61
- 244000068988 Glycine max Species 0.000 claims description 58
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 56
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 56
- 239000011976 maleic acid Substances 0.000 claims description 56
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 40
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 36
- 238000002360 preparation method Methods 0.000 claims description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- 239000003814 drug Substances 0.000 claims description 23
- 238000003756 stirring Methods 0.000 claims description 21
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 20
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 claims description 17
- 229960000590 celecoxib Drugs 0.000 claims description 17
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 14
- 125000002252 acyl group Chemical group 0.000 claims description 11
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- 239000001530 fumaric acid Substances 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
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- 125000002811 oleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000002714 alpha-linolenoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])/C([H])=C([H])\C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000002669 linoleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
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- 125000002886 arachidonoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])/C([H])=C([H])\C([H])([H])/C([H])=C([H])\C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000003910 behenoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002463 lignoceryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001419 myristoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000005456 alcohol based solvent Substances 0.000 claims 1
- 125000001924 fatty-acyl group Chemical group 0.000 claims 1
- 150000008105 phosphatidylcholines Chemical class 0.000 claims 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 claims 1
- 238000002347 injection Methods 0.000 abstract description 18
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- 206010018910 Haemolysis Diseases 0.000 abstract description 5
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- NETZHAKZCGBWSS-CEDHKZHLSA-N nalbuphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC[C@@H]3O)CN2CC1CCC1 NETZHAKZCGBWSS-CEDHKZHLSA-N 0.000 description 22
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
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- 238000013112 stability test Methods 0.000 description 11
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- 238000004128 high performance liquid chromatography Methods 0.000 description 9
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- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 8
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- 230000002829 reductive effect Effects 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 4
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 4
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 4
- ZQPPMHVWECSIRJ-MDZDMXLPSA-N elaidic acid Chemical compound CCCCCCCC\C=C\CCCCCCCC(O)=O ZQPPMHVWECSIRJ-MDZDMXLPSA-N 0.000 description 4
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 4
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- ALOIOAGKUOQNID-ITCIXCFHSA-N bis[(4r,4as,7s,7ar,12bs)-3-(cyclobutylmethyl)-4a,7-dihydroxy-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-9-yl] decanedioate Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CC[C@@H]5O)O)CC1)OC(=O)CCCCCCCCC(=O)OC1=CC=C2C[C@@H]3[C@]4(O)CC[C@@H]([C@@H]5OC1=C2[C@]45CCN3CC1CCC1)O)CC1CCC1 ALOIOAGKUOQNID-ITCIXCFHSA-N 0.000 description 3
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- 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
- A61K47/26—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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Molecular Biology (AREA)
- Pain & Pain Management (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dispersion Chemistry (AREA)
- Neurology (AREA)
- Biochemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
A pharmaceutical composition comprising celebrity, a method for preparing the same and use thereof. The pharmaceutical composition comprises acylglycerol, phosphatidylcholine, at least one oxygen-containing organic solvent, at least one acid and celebrane, and the obtained pharmaceutical composition has higher stability, faster onset of action and longer action time, and can reduce injection pain and reduce hemolysis.
Description
Cross-reference to related patent applications
The patent application claims the priority of the prior patent application with the application number 202110957327.8 filed by 2021, 8 and 20 to the China national intellectual property agency and the name of "a pharmaceutical composition containing celebrarphine". The entire disclosure of this prior application is incorporated by reference herein.
The invention belongs to the technical field of medicines, and particularly relates to a pharmaceutical composition containing celebrazil, a preparation method thereof and application thereof in the pharmaceutical industry.
Nalbuphine sebacate (dinalbuphine sebacate, DNS), also known as celebrarphine, is a dimer of nalbuphine, the chemical structure of which is shown below,
The Nalbuphine is diester of Nalbuphine (Nalbuphine) linked by a sebacic acid linker, is a prodrug of Nalbuphine and is mainly used for treating moderate to severe postoperative pain. Because nalbuphine must be injected every 4 to 6 hours, DNS as a nalbuphine prodrug can be slowly degraded, and has the potential to be prepared into a sustained release preparation.
Because of the dependency and addiction risk of opioids, the drug concentration of the opioids to be administered needs to achieve the analgesic effect properly but avoid the risk of drug dependency as much as possible. In addition, long-acting sustained-release opioid injection formulations with smooth blood levels have been a focus of development to avoid repeated injections, reduce pain management burden, because postoperative pain, cancer pain, or other relatively severe chronic or acute pain often require longer time periods to apply. The preparation is prepared by dissolving DNS in a mixed solvent of benzyl benzoate, sesame oil, castor oil and other plant solvents in a ratio of 0.8-1.2:1, and the oil solution for injection has the defects of easy oxidation, easy pollution, difficult preservation and the like, and vegetable solvents such as sesame oil, castor oil and the like are easy to cause anaphylactic reaction, so that patients have strong pain feeling and are easy to cause muscle agglomeration during clinical intramuscular injection. In addition, patients still need oral ketorolac to relieve pain after surgery; benzyl benzoate also has adverse effects including skin irritation and allergic reactions.
Patent CN104968338a discloses a controlled release dosage form of sebacoyl nalbuphine-PLGA as a long-acting analgesic, which is prepared into microspheres by using polylactic acid, polylactic acid-polyethylene glycol copolymer and the like as carriers. However, the microsphere preparation process is complex, organic solvent residue, sterility assurance and the like are all great challenges facing industrialization.
Patent CN101014319a discloses a preformulation of a universal low viscosity non-liquid crystalline mixture comprising an acylglycerol and/or at least one tocopherol, at least one phosphatidylglycerol, at least one biocompatible solvent, suitable for a variety of administration routes, but with a low drug loading, the specification states that octreotide drug loading is about 0.5-3% (w/w), chlorhexidine drug loading is about 5% (w/w), the anti-inflammatory/analgesic drug benzydamine drug loading is about 3.2-4.5% (w/w), and valdecolonine drug loading is about 5% (w/w), and thus is not suitable for sustained release long-term administration and/or formulations requiring a large drug loading.
Patent CN101123949a discloses an ionic composition comprising 10-40% of at least one phosphatidylcholine, 30-75% of at least one acylglycerol, at least one tocopherol or a mixture thereof, 5-30% of at least one surfactant having a molecular weight below 8000 daltons. However, the composition can only incorporate up to 20wt% of the active agent. In addition, in order to increase the drug loading and reduce the viscosity of the injection composition, the content of the surfactant used is higher, and a certain hemolysis risk exists for the long-acting slow-release injection preparation.
In view of the above, the present long-acting injection of celebrarphine cannot meet clinical requirements, and for a suitable drug loading, the viscosity of the pharmaceutical composition can be reduced, the stability can be improved, the pain of patients caused by injection can be reduced, and one or more aspects of avoiding hemolysis and anaphylactic reaction, improving the drug onset speed and the like are still in need of improvement.
Disclosure of Invention
Compared with the injection composition of the celebrarphine in the prior art, the invention adopts a non-oily preparation formula, and has the beneficial effects of improving the drug action speed, prolonging the drug action time, reducing the occurrence of vascular irritation and hemolysis risk, improving the medication compliance of patients in pain management, solving the problem of suspension stability caused by the crystallization of the celebrarphine and the like.
First, the present invention provides, in a first aspect, a pharmaceutical composition comprising the following components:
(a) Acyl glycerols;
(b) Phosphatidylcholine;
(c) At least one oxygen-containing organic solvent;
(d) At least one acid;
(e) The preparation method comprises the steps of preparing the celecoxib,
Wherein the content of the component (e) is 5 to 20 wt%, the sum of the contents of the component (a) and the component (b) is 40 to 79 wt%, such as 60 to 79 wt% or 40 wt% to less than 60 wt%, the mass ratio of the component (e) to the component (d) acid is 5 to 15:1, and the content of the component (c) is 15 to 42 wt%, such as 15 to 34 wt% or more than 34 wt% to 42 wt%;
The weight percentages are relative to the total weight of (a), (b), (c), (d) and (e).
Preferably, the content of the component (e) is 5-20 wt%, the sum of the content of the component (a) and the content of the component (b) is 60-79 wt%, the mass ratio of the component (e) to the component (d) acid is 5-15:1, and the content of the component (c) is 15-34 wt%;
The weight percentages are relative to the total weight of (a), (b), (c), (d) and (e).
Further preferably, in some embodiments of the present invention, the content of the celebrazil in the above composition is 7.5 to 10 wt%; the sum of the contents of component (a) and component (b) is 65 to 75% by weight; the mass ratio of the component (e) of the celebrazil to the component (d) of the acid is 6-10:1; the component (c) contains 20 to 25% by weight of an oxygen-containing organic solvent, relative to the total weight of (a), (b), (c), (d) and (e).
Further preferably, in other embodiments of the present invention, the content of the celebrazil in the above composition is 7 to 15 wt%, preferably 7.5 to 10 wt%; the sum of the contents of component (a) and component (b) is 50 to 75% by weight; the mass ratio of the component (e) of the celebrazil to the component (d) of the acid is 6-15:1; the content of the oxygen-containing organic solvent of component (c) is 15 to 35% by weight, relative to the total weight of (a), (b), (c), (d) and (e).
In one embodiment of the present invention, the pharmaceutical composition has a viscosity of 100 to 1000cps, preferably 100 to 500cps, more preferably 200 to 400cps at 20 ℃.
In one embodiment of the present invention, the pharmaceutical composition has a viscosity of 30 to 1000cps at 25 ℃, for example, a viscosity of 30 to 500cps, a viscosity of 30 to 400cps, a viscosity of 30 to 300cps, a viscosity of 30 to 200cps, a viscosity of 50 to 300cps, a viscosity of 50 to 400cps, a viscosity of 100 to 500cps, or a viscosity of 200 to 400cps and any range therebetween, preferably has a viscosity of 30 to 500cps, for example, a viscosity of 50 to 300cps, a viscosity of 200 to 400cps, or the like.
In one embodiment of the present invention, the sum of the contents of the component (a) and the component (b) is 40 to 79 wt%, for example, 45 to 79 wt%, 50 to 79 wt%, 55 to 79 wt%, 60 to 79 wt%, 65 to 79 wt%, 70 to 79 wt%, 40 to 75 wt%, 45 to 75 wt%, 50 to 75 wt%, 55 to 75 wt%, 60 to 75 wt%, 65 to 75 wt%, 70 to 75 wt%, 40 to 70 wt%, 45 to 70 wt%, 50 to 70 wt%, 55 to 70 wt%, 60 to 70 wt%, 65 to 70 wt%, 40 to 65 wt%, 45 to 65 wt%, 50 to 65 wt%, 55 to 65 wt%, 60 to 65 wt%, 40 to 60 wt%, 40 to 55 wt%, 45 to 55 wt%, 48 to 72 wt%, 49 to 72 wt%, 48 to 71 wt%, 60 to 68 wt%, 40 to less than 60 wt%, 53 wt%, 50 wt%, and the like, and all ranges thereof are included therein; by way of further illustration, the sum of the amounts of component (a) and component (b) may be present in the composition in the following amounts: about 75 wt%, 74 wt%, about 72 wt%, about 71 wt%, about 70 wt%, about 69 wt%, about 68 wt%, about 67 wt%, about 66 wt%, about 65 wt%, about 64 wt%, about 60 wt%, about 59 wt%, about 54 wt%, about 52 wt%, about 50 wt%, about 49 wt%, and any range between any two thereof.
In one embodiment of the present invention, the mass ratio of component (a) acylglycerol to component (b) phosphatidylcholine may be in a wide range to formulate a precursor composition, component (a) acylglycerol content of 20 to 60 wt%, e.g., 20 to 50 wt%, 25 to 50 wt%, 30 to 50 wt%, 35 to 50 wt%, 40 to 50 wt%, 45 to 50 wt%, 20 to 40 wt%, 25 to 40 wt%, 35 to 40 wt%, 20 to 30 wt%, 25 to 30 wt%, 20 to 45 wt%, 25 to 45 wt%, 30 to 45 wt%, 31 to 40 wt%, 37 to 41 wt%, 35 to 45 wt%, or 20 to less than 30 wt%, etc., and all ranges contained therein; by way of further illustration, component (a) acylglycerols may be present in the composition in the following amounts: about 20 wt%, about 26 wt%, about 29 wt%, about 30 wt%, about 31 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 44 wt%, about 46 wt% or about 50 wt%, etc., and ranges between any two values therein; preferably component (a) has an acylglycerol content of 30 to 50 wt%, more preferably 30 to 45 wt%; the content of the phosphatidylcholine of the component (b) is 15 to 40% by weight, for example, 20 to 40% by weight, 25 to 40% by weight, 30 to 40% by weight, 20 to 35% by weight, 25 to 35% by weight, 30 to 35% by weight, 20 to 30% by weight, 20 to 31% by weight, 20 to 25% by weight, 26 to 31% by weight, 31 to 35% by weight, 25 to 30% by weight, 35 to 40% by weight, or the like, and all ranges included therein; by way of further illustration, component (b) phosphatidylcholine may be present in the composition in the following amounts: about 20 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, about 30 wt%, about 31 wt%, about 33 wt%, about 35 wt%, about 40 wt%, etc., and ranges between any two values therein; the content of the phosphatidylcholine component (b) is preferably 20 to 35% by weight, more preferably 25 to 35% by weight or 20 to 30% by weight.
In one embodiment of the invention, component (a) the acylglycerols comprise a "head group" glycerol moiety and independently 2 to 3 "tail group" acyl group moieties, in the present invention the acylglycerols are diacylglycerols, triacylglycerols or a mixture of both; in particular, diacylglycerols are preferred.
In one embodiment of the invention, component (a) acylglycerol may comprise at least 50% by weight of moieties having such acyl groups.
Further preferred, the acylglycerol comprises at least 50% by weight of moieties having a C 12-C 24 acyl group, the acyl group having from 0 to 9 unsaturations.
More preferably, the acylglycerol comprises at least 50% by weight of moieties having a C 12-C 18 acyl group, the acyl group having from 0 to 2 unsaturations.
Further, the acylglycerol comprises at least 50 wt% of a moiety having a C 16-C 18 acyl group, the acyl group having from 0 to 2 unsaturations.
In one embodiment of the invention, the "tail groups" are selected independently, i.e. the acyl groups may have the same or different carbon atoms and are each independently saturated or unsaturated, in which case the acyl groups of the acylglycerols are selected from lauroyl (C12:0), myristoyl (C14:0), palmitoyl (C16:0), phytantyl (phytanoly) (C16:0), palmitoyl (C16:1), stearoyl (C18:0), oleoyl (C18:1), elaitoyl (elaidoyl) (C18:1), linoleoyl (linoleoyl) (C18:2), linolenoyl (linolenoyl) (C18:3), arachidonoyl (C20:4), behenoyl (C22:0) and tetracosyl (C24:9), preferably oleoyl.
In one embodiment of the invention, the acyl groups are based on natural fatty acids including, but not limited to, lauric acid, myristic acid, palmitic acid, phytanic acid, palmitoleic acid, stearic acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, arachidonic acid, behenic acid, or tetracosanoic acid. Preferred sources of acyl groups are palmitic acid, stearic acid, oleic acid and linolenic acid, in particular oleic acid is preferred.
In one embodiment of the present invention, the acylglycerol comprises at least a portion of a diacylglycerol, which may also be a single diacylglycerol; wherein the diacylglycerol comprises at least 50% by weight of Glycerol Dioleate (GDO), preferably comprises at least 80% by weight of GDO, more preferably diacylglycerols wherein substantially all are GDO.
Typically, GDO and other diacylglycerols are present in proportions of "impurity" lipids, etc. having other chain lengths. Thus, in one aspect, GDO as used herein is intended to mean any commercial grade of GDO (i.e., commercial purity GDO) containing accompanying impurities. These impurities can be isolated and removed by purification, but if the grades are consistent, the purification is rarely necessary. If necessary, the "GDO" may be substantially chemically pure GDO, e.g., GDO that is at least 80% pure, preferably at least 85% pure, more preferably at least 90% pure.
In a preferred embodiment, component (b) the phosphatidylcholine (phospholipid, PC) may be derived from a natural source. Suitable sources of Phospholipids (PC) include egg, heart (e.g., bovine), brain, liver (e.g., bovine) and plant sources including soybean. Such sources may provide one or more ingredients of component (b), which may comprise any mixture of phospholipids. Any single PC or mixture of PCs from these or other sources may be used, but mixtures containing soy PC or egg PC are very suitable, whereby the phosphatidylcholine of component (b) of the invention is selected from at least one of egg PC, heart PC, brain PC, liver PC, egg yolk PC or soy PC, preferably at least one of egg PC, egg yolk PC or soy PC, more preferably soy PC.
In a preferred embodiment, a particularly advantageous combination of components (a) and (b) is GDO and PC, in particular GDO and soybean PC.
The oxygen-containing organic solvent may significantly reduce the viscosity of the composition, and in one embodiment, component (C) is selected from at least one of the amides selected from at least one of the group consisting of N-methylpyrrolidone (NMP), dimethylformamide, 2-pyrrolidone, and dimethylacetamide (DMAC, also known as N, N-dimethylacetamide), alcohols of C 1-C 3 such as methanol, ethanol, isopropanol, or propanol. The inventors found through research that nalbuphine sebacate is superior to other oxygenated organic solvents in NMP and DMAC, preferably component (c) the organic solvent is N-methylpyrrolidone and/or dimethylacetamide.
The oxygen-containing organic solvent may be present in the composition in the following amounts: about 15 to 42 wt%, such as 15 to 40 wt%, 16 to 40 wt%, 20 to 40 wt%, 25 to 40 wt%, 30 to 40 wt%, 35 to 40 wt%, 15 to 35 wt%, 15 to 34 wt%, 34 wt% or more to 42 wt%, 20 to 35 wt%, 25 to 35 wt%, 30 to 35 wt%, 15 to 30 wt%, 20 to 30 wt%, 25 to 30 wt%, 15 to 25 wt%, 20 to 25 wt%, 15 to 20 wt%, 15 to 34 wt%, etc., and all ranges subsumed therein; by way of further illustration, the component (c) oxygen-containing organic solvent may be present in the composition in the following amounts: such as about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, about 30 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 40 wt%, and any range between any two thereof.
In a specific embodiment, the content of the celebrarphine in the above composition is 5 to 20% by weight, for example: 7-15 wt%, 7.5-12.5 wt%, 7.5-10 wt%, about 7.5 wt%, about 7.9 wt%, 8 wt%, about 8.2 wt%, about 9.2 wt%, about 9.5 wt%, about 10 wt%, about 10.5 wt%, about 10.6 wt%, about 11 wt%, about 11.5 wt%, about 12 wt%, about 14 wt%, about 11.5 wt%, and ranges between any two values thereof.
In a specific embodiment, component (d) the acid is at least one of methanesulfonic acid, maleic acid, p-toluenesulfonic acid, acetic acid, fumaric acid, citric acid or hydrochloric acid, the addition of which is beneficial for improving the stability of the pharmaceutical composition, the increase in stability being demonstrated by: the chemical stability of the pharmaceutical composition is significantly improved by stability experiments (15 days in a 40 ℃ ± 5 ℃/RH75% ± 10% stability test box, 1 month in a 25 ℃ ± 5 ℃/RH60% ± 10% stability test box, 1 month in a 2-8 ℃ freezer) in the presence of the acid (especially methanesulfonic acid) than in the absence of the acid, as reflected by less degradation of impurities, as can be seen from the purity results of HPLC detection; the same stability increase is also reflected in an increase in physical stability, in particular in that the addition of an acid can reduce the problem of crystal precipitation of the buprofezin in the pharmaceutical composition, and in the course of the study, it has been found that the addition of methanesulfonic acid can significantly solve the problem of suspension caused by crystal precipitation of the buprofezin in the pharmaceutical composition, and therefore, the preferred component (d) is methanesulfonic acid. Further studies have found that the addition of maleic acid is advantageous for improving the chemical stability of the pharmaceutical composition, and therefore, in a more preferred embodiment, component (d) also comprises maleic acid. Advantageously, the mass ratio of the celebrarphine to the methanesulfonic acid is from 5 to 15:1, preferably the mass ratio of the celebrarphine to the methanesulfonic acid is from 6 to 15:1, more preferably from 6 to 10:1; the effect is best when the mass ratio of the celecoxib to the methanesulfonic acid is 6-15:1, preferably 6-10:1, and the maleic acid is 0-0.2 wt%, preferably 0-0.01 wt%.
In a specific embodiment, the present invention provides a pharmaceutical composition comprising:
(a) Glycerol dioleate;
(b) Soybean PC;
(c) N-methylpyrrolidone;
(d) Methanesulfonic acid and maleic acid;
(e) The preparation method comprises the steps of preparing the celecoxib,
Wherein the content of the celecoxib is 5-20 wt%;
the sum of the content of glycerol dioleate and soybean PC is 40 to 79 wt%, preferably 60 to 79 wt%;
The mass ratio of the celebrazil to the methanesulfonic acid is 5-15:1, and the content of the N-methylpyrrolidone is 15-35 wt%, preferably 15-34 wt%; the maleic acid content is 0 to 0.2 wt.%, preferably 0 to 0.02 wt.%;
The weight percentages are relative to the total weight of (a), (b), (c), (d) and (e).
In a specific embodiment, the present invention provides a pharmaceutical composition comprising:
(a) Glycerol dioleate;
(b) Soybean PC;
(c) N-methylpyrrolidone;
(d) Methanesulfonic acid and maleic acid;
(e) Celebrarphine;
wherein the content of the celecoxib is 7-10 wt%, preferably 7.5-10 wt%;
The sum of the content of the glycerol dioleate and the content of the soybean PC is 65-75 wt%;
The mass ratio of the celebrazil to the methanesulfonic acid is 6-10:1, and the content of the N-methylpyrrolidone is 15-35 wt%, preferably 15-34 wt%; the content of maleic acid is 0 to 0.2 wt%, preferably 0 to 0.02 wt%, more preferably 0 to 0.01 wt%;
The weight percentages are relative to the total weight of (a), (b), (c), (d) and (e).
In a specific embodiment of the present invention, the above pharmaceutical composition, wherein the content of glycerol dioleate is 20 to 60 wt%, preferably 25 to 55 wt%, e.g. 30 to 50 wt%, 35 to 50 wt%, 40 to 50 wt%, 45 to 50 wt%, 35 to 45 wt%, 40 to 45 wt%, 30 to 40 wt%, 35 to 40 wt%, 37 to 41 wt%, about 30 wt%, about 35 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 44 wt%, about 50 wt% and a range between any two values;
Wherein the soybean PC is present in an amount of 20 to 40 wt%, e.g., 25 to 40 wt%, 30 to 40 wt%, 35 to 40 wt%, 20 to 35 wt%, 25 to 35 wt%, 30 to 35 wt%, 20 to 30 wt%, 25 to 30 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, about 30 wt%, about 31 wt%, about 33 wt%, and a range between any two values;
Further preferably, the content of glycerol dioleate is 35 to 45% by weight and the content of soybean PC is 25 to 35% by weight.
The content of N-methylpyrrolidone is 15 to 34% by weight, for example, 15 to 30% by weight, 20 to 30% by weight, 25 to 30% by weight, 15 to 25% by weight, 20 to 25% by weight, about 17% by weight, about 21% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, and a range between any two values, preferably 20 to 25% by weight.
In a specific embodiment, the present invention provides a pharmaceutical composition comprising:
(a) Glycerol dioleate;
(b) Soybean PC;
(c) Dimethylacetamide;
(d) Methanesulfonic acid and optionally maleic acid;
(e) Celebrarphine;
wherein the sum of the content of the glycerol dioleate and the content of the soybean PC is 40-79 wt%;
The content of the celebrazil is 5-20 wt%; the mass ratio of the celebrarphine to the methanesulfonic acid is 5-15:1; the content of maleic acid is 0 to 0.2 wt%;
The dimethylacetamide content is 15 to 42 wt%, preferably 16 to 40 wt%;
The weight percentages are relative to the total weight of (a), (b), (c), (d) and (e).
In a specific embodiment, the present invention provides a pharmaceutical composition comprising:
(a) Glycerol dioleate;
(b) Soybean PC;
(c) Dimethylacetamide;
(d) Methanesulfonic acid and optionally maleic acid;
(e) Celebrarphine;
wherein the sum of the content of glycerol dioleate and soybean PC is 45-75 wt%, preferably 50-75 wt%;
The content of the celebrazil is 7.5-15 wt%; the mass ratio of the celebrarphine to the methanesulfonic acid is 6-15: 1, a step of; the content of maleic acid is 0 to 0.01 percent;
the dimethylacetamide content is 15 to 40 wt%, preferably 15 to 35 wt%;
The weight percentages are relative to the total weight of (a), (b), (c), (d) and (e).
Preferably, the pharmaceutical composition wherein the glycerol dioleate is present in an amount of 20 to 50 wt%, e.g., 25 to 50 wt%, 30 to 50 wt%, 35 to 50 wt%, 40 to 50 wt%, 45 to 50 wt%, 25 to 45 wt%, 30 to 45 wt%, 35 to 45 wt%, 40 to 45 wt%, 25 to 40 wt%, 30 to 40 wt%, 35 to 40 wt%, 40 to 45 wt%, 26 to 47 wt%, 29 to 40 wt%, about 26 wt%, about 29 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 40 wt%, about 46 wt%, about 47 wt% and a range between any two values.
Wherein the soybean PC is present in an amount ranging from 20 to 40 wt%, e.g., 25 to 40 wt%, 30 to 40 wt%, 35 to 40 wt%, 20 to 35 wt%, 25 to 35 wt%, 30 to 35 wt%, 20 to 30 wt%, 25 to 30 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 27 wt%, about 28 wt%, about 29 wt%, about 30 wt%, about 31 wt%, and any range between any two numbers;
Wherein the dimethylacetamide is present in an amount of 15 to 42 wt%, e.g., 15 to 40 wt%, 15 to 35 wt%, 15 to 30 wt%, 16 to 40 wt%, 16 to 35 wt%, 16 to 30 wt%, 16 to 25 wt%, 16 to 20 wt%, 20 to 40 wt%, 25 to 40 wt%, 30 to 40 wt%, 35 to 40 wt%, 20 to 35 wt%, 20 to 30 wt%, 20 to 25 wt%, and any value within the range thereof, e.g., about 16 wt%, about 17 wt%, about 20 wt%, about 21 wt%, about 24 wt%, about 25 wt%, about 29 wt%, about 30 wt%, about 34 wt%, about 35 wt%, about 40 wt%, and any range between any two values.
Wherein the content of the celebuprenorphine is in the range of 7.5 to 15 wt%, e.g. 7.5 to 12.5 wt%, 7.5 to 10 wt%, 9 to 10 wt%, 10 to 11 wt%, 9 to 11 wt%, 8 to 12 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 10.3 wt%, about 10.5 wt%, about 10.6 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt% and any range between two values thereof.
In another aspect of the present invention, the inventors have found that when the content of component (b) is lower than the content of component (a) in the pharmaceutical composition, the drug release of the celebrarphine is facilitated, and thus it is advantageous. Thus, for pharmaceutical compositions comprising component (a), component (b), component (c), component (d) and component (e), the ratio of component (a) to component (b) may vary. In one embodiment, the ratio of component (b) to component (a) is from about 0.1 to 1, preferably from 0.4 to 1, more preferably from 0.5 to 0.9, for example from 0.6 to 0.8,0.65 to 0.75, etc., by weight. In yet another embodiment, the composition comprises (a) glycerol dioleate, (b) soy PC, (c) N-methylpyrrolidone, (d) methanesulfonic acid, optionally including maleic acid, (e) celebrarphine, wherein the ratio of (b) soy PC to (a) glycerol dioleate is about 0.1 to 1, preferably 0.4 to 1, more preferably 0.6 to 0.8, e.g. 0.65 to 0.75, by weight. In yet another embodiment, the composition comprises (a) glycerol dioleate, (b) soy PC, (c) dimethylacetamide, (d) methanesulfonic acid, optionally including maleic acid, (e) celebrarphine, wherein the ratio of (b) soy PC to (a) glycerol dioleate is about 0.1 to 1, preferably 0.4 to 1, more preferably 0.5 to 0.9, e.g. 0.7 to 0.9, by weight.
Thus, in another embodiment of the invention, the composition comprises (a) glycerol dioleate, (b) soy PC, (c) N-methylpyrrolidone, (d) methanesulfonic acid and maleic acid, (e) celebrarphine, wherein the ratio of (b) soy PC to (a) glycerol dioleate is about 0.1 to 1, preferably 0.4 to 1, more preferably 0.6 to 0.8, for example 0.65 to 0.75, by weight. In another embodiment of the invention, the composition comprises (a) glycerol dioleate, (b) soy PC, (c) dimethylacetamide, (d) methanesulfonic acid and maleic acid, (e) celebrarphine, wherein the ratio of (b) soy PC to (a) glycerol dioleate is about 0.1 to 1, preferably 0.4 to 1, more preferably 0.5 to 0.9, for example 0.7 to 0.9, by weight.
It is further preferred that the content of the celecoxib in the above composition is 5-20 wt%, preferably 7.5-15 wt%, such as 7.5-12.5 wt%, such as 7.5-10 wt%, for example about 7.5 wt%, about 7.9 wt%, about 8.0 wt%, about 8.2 wt%, about 9.2 wt%, about 10 wt%, about 10.5 wt%, about 10.6 wt%, about 11 wt%, about 11.5 wt%, about 12 wt%, thereby representing a range of, for example, 7.5-15 wt%, or 7.5-12.5 wt%, or 7.5-10 wt%.
The sum of the glycerol dioleate and the soybean PC content is 40 to 79 wt%, e.g., 50 to 75 wt%, 50 to 70 wt%, 60 to 79 wt%, 60 to 70 wt%, or 65 to 75 wt%, etc., e.g., about 70 wt%, about 71 wt%, about 72 wt%, about 75 wt%, about 68 wt%, about 64 wt%, about 60 wt%, about 59 wt%, about 53 wt%, about 50 wt%, etc.
The mass ratio of the celecoxib to the methanesulfonic acid is 5-15:1, such as 6:1,7.5:1,8:1,9:1,9.3:1,9.5:1, 10:1, 11:1, 12:1, or 15:1, etc., preferably the mass ratio is 6-10:1, such as 6.5:1,7.5:1,8.3:1,9.3:1,9.4:1,9.5:1, or 10:1, etc.
Further, the content of the N-methylpyrrolidone is 15 to 34% by weight, for example, 15 to 25% by weight, 20 to 25% by weight, etc., preferably 15 to 30% by weight, for example, about 17.5% by weight, about 18.5% by weight, about 21% by weight, about 25% by weight, about 27% by weight, etc., thereby exhibiting a range of 15 to 30% by weight; more preferably, the content of the N-methylpyrrolidone is 20 to 25% by weight.
Further, the dimethylacetamide is contained in an amount of 15 to 42% by weight, for example, 16 to 40% by weight, preferably 15 to 35% by weight, for example, about 17% by weight, about 20% by weight, about 21% by weight, about 25% by weight, about 29% by weight, about 35% by weight, or the like.
The optional maleic acid content is 0 to 0.2% by weight.
Wherein the weight percentages are relative to the total weight of (a), (b), (c), (d) and (e).
In another embodiment of the invention, the pharmaceutical composition of the invention consists of the following components:
(a) Acyl glycerols;
(b) Phosphatidylcholine;
(c) At least one oxygen-containing organic solvent;
(d) At least one acid;
(e) The preparation method comprises the steps of preparing the celecoxib,
Wherein the contents of components (a), (b), (c), (d) and (e) are as described above.
In another embodiment of the invention, the pharmaceutical composition is composed of the following components:
(a) Glycerol dioleate;
(b) Soybean PC;
(c) N-methylpyrrolidone;
(d) Methanesulfonic acid and maleic acid;
(e) Celebrarphine;
Wherein the ratio of component (b) to component (a) is from about 0.1 to 1, preferably from 0.4 to 1, more preferably from 0.6 to 0.8, most preferably from 0.65 to 0.75, by weight.
In one embodiment of the invention, the sum of the glycerol dioleate and soybean PC content is 45 to 79 wt%, preferably 60 to 79 wt%, more preferably 65 to 75 wt%;
In one embodiment of the invention, the mass ratio of the celebrarphine to the methanesulfonic acid is 5-15:1, preferably 6-10: 1, a step of;
In one embodiment of the invention, the content of N-methylpyrrolidone is 15 to 35% by weight, preferably 15 to 34% by weight, more preferably 20 to 25% by weight;
In one embodiment of the present invention, the maleic acid content is 0 to 0.2 wt%, preferably 0 to 0.02 wt%, more preferably 0 to 0.01 wt%.
In another embodiment of the invention, the pharmaceutical composition of the invention consists of the following components:
(a) Glycerol dioleate;
(b) Soybean PC;
(c) N-methylpyrrolidone;
(d) Methanesulfonic acid and maleic acid;
(e) Celebrarphine;
Wherein the content of the celecoxib is 7.5-10 wt%;
The sum of the content of the glycerol dioleate and the content of the soybean PC is 65-75 wt%;
The mass ratio of the celebrazil to the methanesulfonic acid is 6-10:1, and the content of the N-methylpyrrolidone is 20-25 wt%; the content of maleic acid is 0 to 0.01 wt%;
The weight percentages are relative to the total weight of (a), (b), (c), (d) and (e).
It is further preferred that the ratio of component (b) to component (a) is from about 0.1 to 1, preferably from 0.4 to 1, more preferably from 0.6 to 0.8, most preferably from 0.65 to 0.75 by weight.
In another embodiment of the invention, the pharmaceutical composition is composed of the following components:
(a) Glycerol dioleate;
(b) Soybean PC;
(c) Dimethylacetamide;
(d) Methanesulfonic acid and optionally maleic acid;
(e) Celebrarphine;
Wherein the ratio of component (b) to component (a) is from about 0.1 to 1, preferably from 0.4 to 1, more preferably from 0.5 to 0.9, by weight.
In one embodiment of the invention, the sum of the glycerol dioleate and soybean PC content is 40 to 79% by weight, preferably 50 to 75% by weight.
In one embodiment of the invention, the mass ratio of the celebrarphine to the methanesulfonic acid is 5-15:1, such as 6-15:1, 7.5-15:1, 9-15:1, 6-10:1 or 6-15:1, etc.; more specifically, for example, 6:1,7.5:1,8:1,9:1,9.3:1,9.4:1,9.5:1, 10:1, 11:1, 12:1, or 15:1, etc.
In one embodiment of the present invention, the dimethylacetamide content is 15 to 42% by weight, preferably 15 to 35% by weight.
In one embodiment of the invention, the maleic acid content is from 0 to 0.2% by weight, preferably from 0 to 0.02% by weight, preferably from 0 to 0.01% by weight.
In another embodiment of the invention, the pharmaceutical composition is composed of the following components:
(a) Glycerol dioleate;
(b) Soybean PC;
(c) Dimethylacetamide;
(d) Methanesulfonic acid and optionally maleic acid;
(e) Celebrarphine;
Wherein the sum of the content of glycerol dioleate and soybean PC is 40-79 wt%, preferably 50-75 wt%;
The content of the celebrazil is 5-20 wt%; preferably 7.5 to 15 wt%, for example 10 to 11 wt%;
The mass ratio of the celebrarphine to the methanesulfonic acid is 5-15:1, such as 6-15:1, 7.5-15:1, 9:15-1, 6-10:1 or 6-15:1, etc.; more specifically, for example, 6:1,7.5:1,8:1,9:1,9.3:1,9.4:1,9.5:1, 10:1, 11:1, 12:1, or 15:1, etc.;
the dimethylacetamide content is 15 to 42 wt%, preferably 15 to 35 wt%;
the maleic acid content is 0 to 0.2 wt.%, preferably 0 to 0.01 wt.%;
the weight percentages are relative to the total weight of (a), (b), (c), (d) and (e);
it is further preferred that the ratio of component (b) to component (a) is from about 0.1 to 1, preferably from 0.4 to 1, more preferably from 0.5 to 0.9 by weight.
In one embodiment, the weight ratio of component (b) to component (a) is such that the pharmaceutical composition can pass smoothly through an international standard syringe needle, but also through various fine needle openings, such as 18G or less needle openings, 23G or less needle openings, 27G or less needle openings.
Further, the pharmaceutical composition has a viscosity of 100 to 1000cps at 20 ℃, preferably 100 to 500cps, more preferably 200 to 400 cps.
Further, the pharmaceutical composition has a viscosity of 30 to 1000cps at 25 ℃, for example, a viscosity of 30 to 500cps, a viscosity of 30 to 400cps, a viscosity of 30 to 300cps, a viscosity of 30 to 200cps, a viscosity of 50 to 300cps, a viscosity of 50 to 400cps, a viscosity of 100 to 500cps, or a viscosity of 200 to 400cps and any range therebetween, preferably has a viscosity of 30 to 500cps, for example, a viscosity of 50 to 300cps or a viscosity of 200 to 400cps, etc.
In the present invention, the parameter range selection includes the end values, for example, 5 to 20 wt% includes the end values "5%" and "20%"; the ratio range of 6 to 10:1 includes "6:1" and "10:1". In particular, when referring to a given numerical value, the term "about" is meant to include plus or minus 5% deviation, preferably plus or minus 3% deviation, plus or minus 2% deviation, plus or minus 1% deviation, plus or minus 0.5% deviation.
"Optional," "optional," or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
The term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects. It should be understood that the term "comprising" may cover the closed meaning, i.e. "consisting of …".
The pharmaceutical compositions provided herein are preferably administered parenterally. In certain embodiments, the composition is formulated for delivery through a needle into a host, the administration typically being by subcutaneous or intramuscular injection.
The key of the pharmaceutical composition provided by the invention is to provide a pharmaceutical composition for injection of the celebrazil, the composition has good stability and low viscosity, and particularly the composition can be injected by using a needle with the specification of 18G to 23G. On the other hand, compared with the injection composition of the celebrarphine in the prior art, the non-oily preparation formula is adopted, so that the pain at the injection site can be reduced, the allergic reaction is reduced, and the medication compliance of patients in pain management is improved.
In addition, the pharmaceutical composition provided by the invention avoids the use of surfactants and reduces vascular irritation and hemolysis risk. In a more preferred embodiment, the problem of crystalline suspension of the buprenorphine in the formulation composition is solved by adding an acid, particularly methanesulfonic acid, thereby significantly improving the stability and the needle-punching property of the pharmaceutical composition of the buprenorphine.
The pharmaceutical compositions provided by the present invention also preferably have an injection volume of no more than 3 mL/administration per administration, more preferably no more than 2 mL/administration per administration, because of the unique high drug loading property. In one embodiment, the pharmaceutical composition comprises at least 100 to 180mg, e.g. 100mg,120mg,150mg,180mg, etc., preferably 150mg of celebrazil in a unit formulation.
Further, it is preferred that the pharmaceutical composition of the present invention has a unit volume of 1.0 to 2.0ml, for example 1.0ml to 1.5ml,1.5 to 2.0ml, or 1.8 to 2.0ml, more preferably 1.0ml to 1.5ml, per unit formulation volume, wherein at least the content of the celebrarphine is 150 mg. The unit preparation of the invention has the conventional meaning in the art, and refers to a detachable minimum administration unit or minimum packaging unit in a medicine, for example, a tablet unit preparation is one tablet, a capsule unit preparation is one granule, a powder unit preparation is one bottle, a bag unit preparation is one box, and an injection unit preparation is one piece.
The invention has the remarkable advantages that the medicinal composition has quick response and can be released for a long time to continuously take effect; compared with the prior art, the problem that the pain relieving needs to be carried out before operation for one day of administration is solved; the pharmaceutical composition provided by the invention can also solve the problem of drug abuse.
The pharmaceutical composition provided by the invention is generally filled in a prefilled device for clinical application, such as a prefilled syringe, or is canned by a penicillin bottle. In one embodiment, the pharmaceutical composition provided by the invention has low viscosity and thus good needle penetration. The pharmaceutical compositions of the present invention may be passed smoothly through an international standard syringe needle, or through a variety of fine needle openings, such as 18G or less, 23G or less, 27G or less.
In the present invention, the international standard syringe needle 18G, 23G, 27G sizes are as follows:
As used herein, an "acid" of component (d) is typically a low molecular weight compound that forms an acidic solution in an aqueous medium (i.e., water). These acids typically have a pKa of less than 6, or less than 5, preferably less than 4.7, most preferably less than 4.5. Since the acid is administered as part of a parenteral drug delivery system, biocompatibility in the relevant amounts is also necessary. Suitable acids are preferably methanesulfonic acid, maleic acid, p-toluenesulfonic acid, acetic acid, fumaric acid, citric acid, sodium dihydrogen phosphate or hydrochloric acid in this context. Particularly preferred are organic acids selected from methanesulfonic acid, maleic acid, acetic acid, fumaric acid, citric acid. The most preferred acid is at least one of methanesulfonic acid and maleic acid.
The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps:
dissolving the celebrarphine and the acid in a prescription proportion in an oxygen-containing organic solvent, then adding acyl glycerol, and finally adding phosphatidylcholine, and dissolving to obtain the preparation; or alternatively
Adding the acid with the prescription proportion into the organic solvent, sequentially adding the acylglycerol and the phosphatidylcholine, stirring and dissolving, and finally adding the celebrarphine, stirring and dissolving to obtain the product.
In the first and second preparation methods of the present invention, the acid, the oxygen-containing organic solvent, the acylglycerol and the phosphatidylcholine are as defined above.
In a specific embodiment, the method for preparing the pharmaceutical composition comprises the following steps:
Dissolving the celebrine, the methanesulfonic acid and the maleic acid in the prescription proportion in N-methylpyrrolidone, then adding glycerol dioleate, stirring, finally adding soybean PC, and dissolving to obtain the product; or alternatively
According to the prescription proportion, firstly, methanesulfonic acid and maleic acid are dissolved in N-methyl pyrrolidone, then glycerol dioleate is added for stirring, soybean PC is added for stirring and dissolving, and finally, the celebrane is added for stirring and dissolving, thus obtaining the compound.
In another embodiment, the method of preparing the pharmaceutical composition comprises the steps of:
Dissolving the celebrine, the methanesulfonic acid and the maleic acid which are optionally further contained in the prescription proportion into dimethylacetamide, then adding glycerol dioleate, stirring, finally adding soybean PC, and dissolving to obtain the product; or alternatively
According to the prescription proportion, firstly, the methanesulfonic acid and the maleic acid which is optionally further contained are dissolved in the dimethylacetamide, then the glycerol dioleate is added for stirring, then the soybean PC is added for stirring and dissolving, and finally the celebrazil is added for stirring and dissolving, thus obtaining the product.
Preferably, the above method is to heat the mixture to no more than 45 ℃, preferably to 40 ℃, before adding phosphatidylcholine for dissolution, so as to significantly accelerate the dissolution rate.
In some embodiments of the invention, the method of preparation of the invention further comprises filter sterilization of the prepared composition by means of a 0.22 μm sterile filtration membrane.
In a third aspect the invention also provides the use of said pharmaceutical composition in the manufacture of a medicament for the treatment of pain.
The invention also provides a method of treating pain comprising administering to a subject (e.g., a mammalian subject, such as a human) in need thereof a pharmaceutical composition of the invention.
The pain according to the invention is selected from surgical pain or chronic pain in the long term. The surgical operation includes, but is not limited to, common surgical operations of a common type such as hernia operation, hemorrhoid operation, abdominal operation, plastic surgery, orthopedic operation, otorhinolaryngological operation, and the like; such chronic pain includes, but is not limited to, cancer pain, chronic back pain, chronic joint pain, and the like. All percentages herein are by weight unless otherwise indicated. The pharmaceutical composition may consist essentially of, and in one aspect consist entirely of, these components.
FIG. 1 is a graph comparing the dissolution curves of the nanosolution pain, prescription 1 and prescription 2 tested in example 5;
fig. 2 is a dissolution profile obtained by performing a dissolution test on pharmaceutical compositions of different formulations in example 5.
FIG. 3 is a graph comparing analgesic strength of nano-analgesic, prescription 1; wherein, the ordinate is the mechanical tenderness and foot reduction threshold (MWT); SC means that the formulation 1 celebrazil pharmaceutical composition of the invention is administered by subcutaneous injection; IM is the administration of the natto by intramuscular injection; model refers to a model group; control refers to blank group; the pharmaceutical composition of the celebrazier in the prescription 1 is injected Subcutaneously (SC) and the pain relieving is injected Intramuscularly (IM), so that the 100mpk analgesic effect of the pharmaceutical composition of the celebrazier (prescription 1) provided by the invention is superior to the 100mpk pain relieving effect; wherein the unit mpk refers to milligrams per kilogram (MILLIGRAMS PER Kilograms).
Fig. 4 is a graph of the pharmacokinetic study of a pharmaceutical composition of celebrarphine provided by the invention in vivo.
Fig. 5 is a graph of the in vivo pharmacokinetics of a pharmaceutical composition of formula C03 in DMAC as a solvent.
Fig. 6 is a photograph of a record of the skin condition of a pharmaceutical composition of celebrarphine provided by the present invention after subcutaneous administration on the outside of the rat thigh.
Fig. 7 is a dissolution graph of pharmaceutical compositions of prescription C01, prescription C02, prescription C04, and prescription C05 in example 8.
Embodiments of the present invention are described in detail below. The following examples are illustrative only and are not to be construed as limiting the invention. Unless otherwise indicated, the proportions, percentages, etc., referred to herein are by weight.
Reagent(s)
Celebrarphine (source: homemade); nalbuphine (source: minofeine); soybean PC (source: shenyang Tianfeng biopharmaceutical Co., ltd.); glycerol dioleate (source: croda, uk); nalgesic solution (source: shuntian medical technology Co., ltd.);
Apparatus and method for controlling the operation of a device
A viscometer: SNB-1, shanghai Tianmei;
Dissolution instrument: a Logan 850DL full-automatic dissolution sampling system;
high performance liquid chromatography: agilent 1260 Infinity liquid chromatograph;
pH meter: mettler Toledo FiveEasy Plus;
Example 1 solubility test
In the invention, research shows that (referring to the method for measuring solubility of four < guide to the use > parts of Chinese pharmacopoeia 2015 edition), the active ingredient of the pharmaceutical composition is greatly different from the metabolite nalbuphine, the solubility of the active ingredient of the pharmaceutical composition is different from that of the metabolite nalbuphine, and the specific solubility difference is shown in the following table 1.
TABLE 1 solubility Difference of nalbuphine and nalbuphine
Results
From the above table 1 it is clear that nalbuphine and celecoxib have a large difference in solubility in the simulated human buffer, whereas the solubility of the active ingredient is of great significance in formulation prescription studies, so that the significance of referencing nalbuphine in the study of the prescription of celecoxib is not great.
EXAMPLE 2 Effect of solvent on stability of celebrarphine
An appropriate amount of celebrazil was weighed, formulated to about 3. Mu.g/mL with acetate buffer at pH3.8, and 2% (v/v) ethanol or NMP was added for HPLC detection at 0min, 10min, 30min, 60min, respectively, as follows.
Liquid chromatography detection (Agilent 1260), column ZORBAX SB-Aq, 4.6X106, 5 μm. Chromatographic conditions: phase A (3.85 g of ammonium acetate is weighed and added into 1000mL of ultrapure water, dissolved by ultrasonic, 3mL of acetic acid is added, and the mixture is filtered through a 0.45 mu m filter membrane and is used after ultrasonic treatment for 15 min): phase B (acetonitrile) =40%: 60% (v/v); column incubator: 40 ℃; sample injector: 25 ℃; flow rate: 1.5mL/min; wavelength: 278nm. And the sample injection amount is 10 mu L, and the content of the celebrazil at different time points is calculated according to the peak area percentage of the peak area at different sampling time points relative to the peak area percentage of 0min by an external standard method. The results are shown in tables 2 and 3 below.
Table 2 variation of the content of celebrarphine in NMP
| Time of | Area of the Saunabuprenorphine peak (NMP) | Percent peak area |
| 0min | 917.312 | 100.0％ |
| 10min | 910.237 | 99.2％ |
| 30min | 923.139 | 100.6％ |
| 60min | 915.091 | 99.8％ |
TABLE 3 variation of content of celebrazil in ethanol
| Time of | Area of the Sai Naburphine peak (ethanol) | Percent peak area |
| 0min | 919.367 | 100.0％ |
| 10min | 910.123 | 99.0％ |
| 30min | 891.659 | 97.0％ |
| 60min | 844.870 | 91.9％ |
Results
From the results of tables 2 and 3, it is evident that the celebrazil is unstable in ethanol, and the content of the celebrazil is significantly reduced after 60 minutes, namely, the content of the celebrazil is only 91.9%, which indicates that the celebrazil is easily degraded in ethanol to generate impurities; whereas the content of the celebrine in NMP was stable, the measurement at 60 minutes was almost unchanged from the initial measurement (at 0 minutes), indicating that the celebrine was stable in NMP, which was the solvent for the appropriate celebrine.
EXAMPLE 3 preparation method of pharmaceutical composition of celebrarphine
The method comprises the following steps: dissolving the celebrarphine in the prescription proportion in NMP with acid stirring, adding GDO and stirring, and finally adding soybean PC for dissolving to prepare the celebrarphine pharmaceutical composition.
The second method is as follows: stirring and dissolving acid in the proportion of the prescription in NMP, adding GDO, stirring and dissolving soybean PC, and finally adding the celebrazil and stirring and dissolving to prepare the celebrazil pharmaceutical composition.
The soybean PC can be properly heated to 40 ℃ when dissolved in the steps, so that the dissolution speed can be obviously increased.
The formulations are shown in tables 4.1 and 4.2 below.
Table 4.1: single dose prescription of selbuprenorphine pharmaceutical composition formulated according to method one
| Material name | Prescription 1 | Prescription 2 | Prescription 3 | Prescription 4 | Prescription 5 | Prescription 6 |
| Saibuprorphine/mg | 150 | 150 | 150 | 150 | 150 | 150 |
| NMP/mg | 450 | 350 | 400 | 400 | 400 | 400 |
| GDO/mg | 840 | 300 | 964 | 844 | 750 | 675 |
| Soybean PC/mg | 560 | 200 | 385 | 506 | 600 | 675 |
| Soybean PC/GDO | 0.7 | 0.7 | 0.4 | 0.6 | 0.8 | 1 |
| Methanesulfonic acid/mg | 15 | 15 | 20 | 20 | 20 | 20 |
| Maleic acid/mg | 0.3 | 0.2 | / | / | / | / |
| Drug loading rate | 7.4％ | 14.8％ | 7.8％ | 7.8％ | 7.8％ | 7.8％ |
| Total/mg | 2015.3 | 1015.2 | 1919 | 1920 | 1920 | 1920 |
Table 4.2: single dose prescription of selbuprenorphine pharmaceutical composition prepared according to method two
EXAMPLE 4 through-needle and viscosity testing
A portion of the formulation prepared in example 3 was measured for its viscosity at room temperature (25 ℃) using a digital viscometer, with rotor number 4 being chosen and the rotational speed being chosen to be 60rpm. And each prescription was determined to pass through an international standard syringe needle 18G, 23G, 27G. The test results are shown in table 5 below.
TABLE 5 penetration and viscosity test results
And v indicates that the prescription can pass through the corresponding syringe needle, x indicates that it is difficult to pass through the needle.
The results show that: the prepared pharmaceutical composition of celebuprenorphine in example 3 has a viscosity in the range of 200 to 400cps and can pass both 18G and 23G international standard universal syringe needles, part of the prescription passing 27G needles.
EXAMPLE 5 dissolution testing of different prescriptions
The dissolution rate of the prescription 1 and the prescription 2 provided by the invention is examined, the dissolution method adopts a USP 2 method, namely a paddle method, the rotating speed is 200rpm, the dissolution medium is an acetate buffer solution with the pH value of 3.8 (the dissolution medium is 900 mL), 5mL is sampled respectively at 5min, 30min, 60min, 120min, 240min and 360min, the subsequent filtrate is filtered and subjected to HPLC detection, and the dissolution rate is calculated. The test results are shown in fig. 1, and illustrate that the pharmaceutical composition provided by the invention has a dissolution curve equivalent or similar to that of the nano-pain.
The dissolution test was conducted on the prescription 3, the prescription 4, the prescription 5 and the prescription 6 prepared in the example 3, the dissolution method adopts a USP 1 method, namely a spin basket method, the rotation speed is 50rpm, 0.5% SDS is added into the dissolution medium, 5mL is sampled at 5min, 10min, 30min, 60min, 120min, 180min, 240min and 360min respectively, and the subsequent filtrate is filtered, subjected to HPLC detection and the dissolution is calculated.
HPLC detection conditions: liquid chromatography detection (agilent 1260), column: island body fluid ODS-3,4.6X 250,5 μm. Chromatographic conditions: phase A (3.85 g of ammonium acetate is weighed and added into 1000mL of ultrapure water, dissolved by ultrasonic, 3mL of acetic acid is added, and the mixture is filtered through a 0.45 mu m filter membrane and is used after ultrasonic treatment for 15 min): phase B (acetonitrile) =40%: 60% (v/v); column incubator: 40 ℃; sample injector: 25 ℃; flow rate: 1.5mL/min; wavelength: 278nm. The sample injection amount is 60 mu L, and the content of the celebrazil at different time points is calculated according to an external standard method through the peak area.
As a result (as shown in FIG. 2), the dissolution release effect was good when the ratio of phosphatidylcholine to glyceryl oleate in the formulation was 0.4 to 1, and the dissolution release effect was optimal when the ratio was 0.6 to 0.8.
Example 6 one-factor control test
In this example, a single factor control experiment was designed to prepare a pharmaceutical composition of celebrarphine containing different acids (the prescription is shown in table 6) using method two, and the composition was allowed to stand for 48 hours to check its appearance and needle penetration. The needle penetration test is specifically carried out by placing a syringe on a syringe support, applying pressure to the syringe plunger via a cylindrical probe connected to a force sensing element, pushing the solution through the syringe and needle until the solution is pushed out of the needle, and calculating the average force of the solution flowing out of the needle. The passable person is marked "v" and the failed person is marked "x".
Table 6: prescription, appearance and needle-penetrating property of 4 batches of celebrity pharmaceutical composition
From the above results, it can be seen that, in the pharmaceutical composition of the present invention, when the acid is citric acid, methanesulfonic acid, fumaric acid, or acetic acid, the crystallization of the celebrarphine from the preparation can be inhibited to different degrees, and the crystallization can be realized through 18G pinholes: compared with acetic acid, citric acid and fumaric acid, the methanesulfonic acid has better effect of inhibiting the crystallization of the celebrazil from the preparation, and meanwhile, the appearance of the preparation is clear, the needle penetrating property is better, and 18G and 23G pinholes can be formed. The fumaric acid and citric acid groups have relatively weak inhibition effect on the crystallization of the celebrazil in the composition, and the preparation contains part of crystallization particles with larger particle size, so that the needle penetration is relatively poorer than that of the methanesulfonic acid group.
Further study the high temperature 60 ℃ stability of the samples of recipe a01, recipe a02, recipe a 04; the 3 batches of samples were simultaneously placed in a stability test chamber at a high temperature of 60 ℃ and were sampled at 0W, 1W, 2W and 4W to detect the appearance and purity of the samples. Wherein purity is determined by HPLC, liquid chromatography (agilent 1260), column: shim-PACK CIST C, 4.6X 250,3 μm. Chromatographic conditions: phase A (1L of ultrapure water is measured and introduced into a beaker, 1.0795g of sodium octane sulfonate is weighed and stirred uniformly, the pH is regulated to 2 by phosphoric acid, and the solution is filtered and used after ultrasonic treatment); phase B (acetonitrile), gradient elution (MPA: 90%. Fwdarw.10%v/v); column incubator: 40 ℃; sample injector: 25 ℃; flow rate: 1.5mL/min; wavelength: 220nm. The sample injection amount was 3. Mu.L. The detection results are shown in the following table 7.
Table 7: results of stability study on 3 samples
From the test results in Table 7, it can be seen that the methanesulfonic acid group sample had better stability at a high temperature of 60℃than the citric acid group and the acetic acid group.
Example 7 stability test
Two batches of samples were prepared for this example, the recipe of which is shown in Table 8 below; the preparation method adopts the first method.
Table 8: prescription B01 and prescription B02 sample prescriptions
| Material name | Prescription B01 | Prescription B02 |
| Saibuprorphine/mg | 150 | 150 |
| NMP/mg | 400 | 400 |
| GDO/mg | 600 | 600 |
| Soybean PC/mg | 400 | 400 |
| Methanesulfonic acid/mg | 15 | 15 |
| Maleic acid/mg | 0.3 | 0 |
The two samples were simultaneously placed in a stability test chamber at a high temperature of 60℃and were sampled at 1 week (1W), 2 weeks (2W) and 4 weeks (4W) to determine their appearance and purity, respectively, wherein the purity was determined by HPLC and the chromatographic conditions were the same as in example 6.
The results are shown in Table 9 below:
Table 9: stability test results of samples of recipe B01 and recipe B02
The results show that the stability of the celebrazil can be improved to a certain extent by adding a small amount of maleic acid into the prescription at the high temperature of 60 ℃ and the generation of related impurities can be slowed down.
EXAMPLE 8 investigation of pharmaceutical compositions in DMAC (dimethylacetamide) as solvent
8.1: The present example formulated 6-prescription pharmaceutical compositions, the prescriptions being shown in table 8.1 below; the preparation method adopts the first method. The viscosity and needle penetration test method were the same as in example 4.
Table 8.1: prescription C01-prescription C06 pharmaceutical composition prescription and viscosity, stability and needle penetration detection result
The pharmaceutical composition has no crystallization phenomenon after being placed for 3 days at the temperature of 2-8 ℃, and has good needle penetrating property of 18G and 23G injection needles.
8.2 Stability
The 6 prescription samples are respectively placed in a stability test box with the temperature of 40+/-5 ℃ and the RH of 75+/-10 percent for 15 days, a stability test box with the temperature of 25+/-5 ℃ and the RH of 60+/-10 percent for 1 month, and a refrigerating box with the temperature of 2-8 ℃ for 1 month, so that the properties and the purity are detected. Wherein the purity is detected by HPLC method. The test results are shown in Table 8.2 below:
table 8.2: stability test results of prescription C01-prescription C06 samples
The purity of the sample is not obviously changed after the sample is placed for 15 days at 40 ℃; the purity is unchanged after being placed for 1 month at 25 ℃ and 2-8 ℃, which indicates that the sample has good stability.
The conventional storage temperature of the pharmaceutical composition of the present invention is 2-8 ℃, and the stability test (especially the high temperature stability test) in the above examples 6, 7 and 8 fully proves that the pharmaceutical composition of the present invention (especially NMP and/or DMAC as solvents, containing methanesulfonic acid and optionally further containing maleic acid) has good stability, and can meet the long-term stability requirement under the conventional storage temperature condition.
8.3 Dissolution detection:
The dissolution test was conducted on 4 samples of the prescriptions C01, C02, C04, and C05 prepared in example 8.1, and the dissolution method was USP1 method (the USP1 method described in example 5); the results (shown in figure 7) show that the pharmaceutical compositions with DMAC as a solvent, the mass ratio of PC to GDO being 0.5-0.9 and the mass ratio of the celebrarphine to the acid being 5-15:1 have good dissolution and release degrees and slow release effects.
Biological test example 1: analgesic Strength test
The method comprises the following steps:
Animals: 70 male rats with qualified male SPF grade SD are taken, and the weight is 180-220, and the male rats are adaptively kept for 4 days.
And (3) basic value detection: primary screening of rats, testing basic values (testing at least twice, testing for the third time if the difference between the results of the two times is too large, taking an average value), and eliminating sensitive animals;
And (3) performing operation molding: except for the blank control group, the other groups were operated with 7% chloral hydrate as anesthetic, 6.3ml/kg of gavage volume was administered, the rat plantar surgical site was surface sterilized with iodophor, a 1cm longitudinal incision was made forward from the 0.5cm heel margin, including skin, fascia and plantar muscle, two needles of skin were sutured, hemostasis was pressed and the wound was cleaned.
Postoperative grouping: the basic values are tested again 24 hours after operation, and grouping is carried out evenly, so that the basic values of each group are kept consistent as much as possible; rats were divided into 7 groups of 8: blank, model, prescription 1 composition (100 mpk), prescription 1 composition (75 mpk), prescription 1 composition (50 mpk), and nato pain (100 mpk), nato pain (75 mpk) groups.
Administration: the next day after molding, solutions with different concentrations are respectively prepared for administration according to different doses of each group, and the blank group, the model group and the prescription 1 are subcutaneously administered at the back, and the pain relieving is administered at the right thigh muscle. The vehicle of the blank group and the model group is normal saline.
Mechanical tenderness foot reduction threshold (MWT) test: the software automatically records mechanical tenderness and footshrink thresholds (MWT) at 30min, 4h, 28h, 76h and 124h after molding, and statistical analysis is performed by using Mann-WHITNEY TEST. The calculation formula of the MWT improvement rate (%) is as follows:
MWT increase rate (%) = (dosing group MWT value-model group MWT value)/model group MWT value x 100
The test results are shown in Table 10.
Table 10: prescription 1 and pain relieving strength test result
As shown in fig. 3 and table 10, 100mpk of the celebrazier composition group shows remarkable analgesic effect at 30min, 4h and 28h (1 d), and the pain relieving solutions 100mpk and 75mpk show remarkable analgesic effect at 28h (1 d), which indicates that compared with the pain relieving group, the celebrazier composition group provided by the invention has the advantages of quick acting time, small dosage and remarkable analgesic effect. And the 100mpk group analgesic effect time of the celebrarphine composition is obviously better than that of the 100mpk group analgesic effect time of the naltrexone composition.
The composition of prescription 1 measured at 76h and 124h was not significantly different from the pain relief group in terms of pain relief, probably due to the initial disappearance of pain in the rats in the model after 76 hours. From the wound healing of rats observed during the course of the experiment, it was seen from literature report (Pain, 64 (1996) 493-501) that after 76 hours the Pain of rats began to disappear in the model.
Biological test example 2: pharmacokinetic studies
Animals and groupings: 20 male SPF-grade SD male rats with qualified weight are taken, and after being subjected to adaptive feeding for 4 days, the male SPF-grade SD male rats with qualified weight are randomly divided into 5 groups, namely, a celebrazil group (a prescription 13 administration group, a prescription 18 administration group, a prescription 42 administration group and a prescription 46 administration group) and a pain relieving group, wherein each group comprises 4 animals.
Administration: the nalbuphine composition group was administered subcutaneously (75 mpk per nalbuphine) to each rat and the pain relieving group was administered to the right thigh muscle (75 mpk per nalbuphine) to each rat.
Sampling and detecting: the blood is collected from the eye sockets of rats 0min,30min,2h,4h,6h,8h,12h,24h,48h,72h,96h,120h,144h and 168h after administration, and the blood sample is centrifuged to obtain blood plasma within 20min after collection, and the blood sample is placed on crushed ice before centrifugation. The plasma samples obtained by centrifugation were stored in a-80 ℃ freezer until detection and analysis. Centrifugation conditions: 4-10deg.C, 6000rpm,5 minutes. The concentration of nalbuphine in the blood sample was measured by LCMSMS and PK parameters were calculated.
The effective blood concentration of nalbuphine in a mouse is about 25ng/mL, as shown in fig. 4, and test results show that the active time of the nalbuphine pharmaceutical composition provided by the scheme of the invention is less than 30min, the nalbuphine pharmaceutical composition can be timely administered after operation, the active time of naloxone is 12-24 h, and the naloxone pharmaceutical composition needs to be administered 1 day before operation.
The pharmaceutical composition of the aforementioned formulation C03 was tested in the same manner, and the test results are shown in FIG. 5. The effective blood concentration of nalbuphine in mice is about 25ng/mL, and pharmacokinetic study shows that the prescription C03 can reach the blood concentration higher than 200ng/mL within 30min and maintain the blood concentration higher than 25ng/mL within 168h after administration, which indicates that the prescription using DMAC as solvent can be effective within 30min after administration, can be timely administered after operation, has long duration of drug effect and can reduce administration frequency.
Test example 3 administration irritation test
The pharmaceutical composition prepared according to the present invention was subcutaneously administered to the outer thigh of a rat using a 2.5ml syringe at a dose of 75mpk, and the skin condition at the administration site was observed. After administration, the medicine forms a block gel at the administration site, the administration site is free from ulceration and inflammation, and the block at the administration site is slowly reduced along with the extension of the administration time. The results are shown in FIG. 6.
It will be apparent to those skilled in the art that many modifications and variations of the present invention can be made without departing from its spirit and scope. The specific embodiments described herein are offered by way of example only and are not meant to be limiting in any way. The true scope and spirit of the invention is indicated by the following claims, which are exemplary only.
Claims (24)
- A pharmaceutical composition comprising the following components:(a) Acyl glycerols;(b) Phosphatidylcholine (PC);(c) At least one oxygen-containing organic solvent;(d) At least one acid;(e) The preparation method comprises the steps of preparing the celecoxib,Wherein the component (e) comprises 5 to 20 weight percent of the celecoxib; the sum of the contents of the component (a) of the acylglycerol and the component (b) of the phosphatidylcholine is 40 to 79 weight percent; the mass ratio of the component (e) of the celebrity to the component (d) of the acid is 5-15:1, and the content of the component (c) of the oxygen-containing organic solvent is 15-42 wt%;The weight percentages are relative to the total weight of (a), (b), (c), (d) and (e).
- The pharmaceutical composition according to claim 1, wherein the sum of the content of component (a) acylglycerols and component (b) phosphatidylcholines is 60 to 79% by weight or 50 to 75% by weight, preferably 65 to 75% by weight;preferably, the content of the component (a) is 20 to 60 wt% of the acylglycerol, and the content of the component (b) is 15 to 40 wt% of the phosphatidylcholine;Further preferably, wherein the content of the component (a) is 30 to 50% by weight and the content of the component (b) is 20 to 40% by weight;more preferably, the content of the component (a) is 35 to 45% by weight, and the content of the component (b) is 25 to 35% by weight.
- The pharmaceutical composition according to any one of claims 1-2, wherein the content of the oxygen-containing organic solvent of component (c) is 15-40 wt%, preferably 15-35 wt%, more preferably 20-25 wt%.
- A pharmaceutical composition according to any one of claims 1 to 3 wherein the mass ratio of component (e) celebrazil to component (d) is from 6 to 10:1.
- Pharmaceutical composition according to any of claims 1-4, wherein the content of the celebrity is 7-15 wt%, preferably 7.5-10 wt%.
- The pharmaceutical composition according to any one of claims 1 to 5, wherein component (a) acylglycerol is diacylglycerol, triacylglycerol or a mixture of both, more preferably diacylglycerol; the acyl groups of the acylglycerols are each independently selected from C 12-C 18 fatty acyl groups having 0 to 2 unsaturated bonds, preferably lauroyl, myristoyl, palmitoyl, phytantoyl, palmitoyl, stearoyl, oleoyl, elaitoyl, linoleoyl, linolenoyl, arachidonoyl, behenoyl or tetracosyl, more preferably oleoyl; it is further preferred that the acylglycerol of component (a) is glycerol dioleate.
- The pharmaceutical composition according to any one of claims 1 to 5, wherein component (b) the phosphatidylcholine is selected from at least one of egg PC, heart PC, brain PC, liver PC, egg yolk PC or soybean PC, preferably at least one of egg PC, egg yolk PC or soybean PC, more preferably soybean PC.
- The pharmaceutical composition according to any one of claims 1 to 5, wherein component (C) the oxygen-containing organic solvent is selected from at least one of amides, alcohol solvents of C 1-C 3, selected from at least one of N-methylpyrrolidone, dimethylformamide, 2-pyrrolidone and dimethylacetamide, preferably N-methylpyrrolidone and/or dimethylacetamide.
- The pharmaceutical composition according to any one of claims 1 to 5, wherein component (d) the acid is at least one of methanesulfonic acid, maleic acid, p-toluenesulfonic acid, acetic acid, fumaric acid, citric acid, or hydrochloric acid, preferably component (d) is a combination of methanesulfonic acid and maleic acid.
- A pharmaceutical composition according to any one of claims 1 to 5, wherein component (d) is methanesulfonic acid, optionally comprising maleic acid, and the mass ratio of celebrarphine to methanesulfonic acid is from 6 to 15:1, preferably from 6 to 10:1, a step of; maleic acid is 0 to 0.2 wt%, preferably 0 to 0.02 wt%.
- The pharmaceutical composition according to claim 1, comprising:(a) Glycerol dioleate;(b) Soybean PC;(c) N-methylpyrrolidone;(d) Methanesulfonic acid and maleic acid;(e) The preparation method comprises the steps of preparing the celecoxib,Wherein the content of the celecoxib is 5-20 wt%;The sum of the content of the glycerol dioleate and the content of the soybean PC is 40-79 wt%;The mass ratio of the celebrazil to the methanesulfonic acid is 5-15:1, and the content of the N-methylpyrrolidone is 15-35 wt%; the maleic acid content is 0 to 0.2 wt.%, preferably 0 to 0.02 wt.%;The weight percentages are relative to the total weight of (a), (b), (c), (d) and (e).
- The pharmaceutical composition according to claim 1, comprising:(a) Glycerol dioleate;(b) Soybean PC;(c) N-methylpyrrolidone;(d) Methanesulfonic acid and maleic acid;(e) Celebrarphine;wherein the content of the celecoxib is 7-10 wt%;The sum of the content of the glycerol dioleate and the content of the soybean PC is 65-75 wt%;The mass ratio of the celebrazil to the methanesulfonic acid is 6-10:1, and the content of the N-methylpyrrolidone is 15-35 wt%; the content of maleic acid is 0 to 0.02 wt%;The weight percentages are relative to the total weight of (a), (b), (c), (d) and (e).
- The pharmaceutical composition according to any one of claims 11 to 12, wherein the glycerol dioleate is present in an amount of 25 to 55% by weight and the soybean PC is present in an amount of 15 to 40% by weight; the preferred content of glycerol dioleate is 35 to 45% by weight and the content of soybean PC is 20 to 35% by weight.
- The pharmaceutical composition according to claim 1, comprising:(a) Glycerol dioleate;(b) Soybean PC;(c) Dimethylacetamide;(d) Methanesulfonic acid and optionally maleic acid;(e) Celebrarphine;wherein the sum of the content of the glycerol dioleate and the content of the soybean PC is 40-79 wt%;The content of the celebrazil is 5-20 wt%; the mass ratio of the celebrarphine to the methanesulfonic acid is 5-15:1; the content of maleic acid is 0 to 0.2 wt%;The dimethylacetamide content is 15 to 42 wt%, preferably 16 to 40 wt%;The weight percentages are relative to the total weight of (a), (b), (c), (d) and (e).
- The pharmaceutical composition according to claim 1, comprising:(a) Glycerol dioleate;(b) Soybean PC;(c) Dimethylacetamide;(d) Methanesulfonic acid and optionally maleic acid;(e) Celebrarphine;Wherein the sum of the content of the glycerol dioleate and the content of the soybean PC is 45-75 wt%;The content of the celebrazil is 7.5-15 wt%; the mass ratio of the celebrarphine to the methanesulfonic acid is 6-15: 1, a step of; the content of the maleic acid is 0 to 0.01 percent;The content of dimethylacetamide is 15-40 wt%;The weight percentages are relative to the total weight of (a), (b), (c), (d) and (e).
- The pharmaceutical composition according to any one of claims 14 to 15, wherein the glycerol dioleate is present in an amount of 20 to 50% by weight and the soybean PC is present in an amount of 20 to 40% by weight; the preferred content of glycerol dioleate is 25 to 50% by weight and the content of soybean PC is 20 to 31% by weight.
- The pharmaceutical composition according to any one of claims 1 to 16, wherein the ratio of component (b) to component (a) is about 0.1 to 1, preferably 0.4 to 1, more preferably 0.5 to 0.9, even more preferably 0.6 to 0.8 by weight.
- The pharmaceutical composition according to claim 1, comprising:(a) Glycerol dioleate;(b) Soybean PC;(c) N-methylpyrrolidone;(d) Methanesulfonic acid, optionally and maleic acid;(e) Celebrarphine;Wherein the ratio of (b) soybean PC to (a) glycerol dioleate is from about 0.1 to 1, preferably from 0.4 to 1, more preferably from 0.6 to 0.8, for example from 0.65 to 0.75, by weight;Preferably, the content of the selvedge is 5-20 wt%; the sum of the content of the glycerol dioleate and the content of the soybean PC is 45-79 wt%; the mass ratio of the celebrazil to the methanesulfonic acid is 5-15:1, and the content of the N-methylpyrrolidone is 15-35 wt%; the optional maleic acid content is 0 to 0.2 wt.%;Further preferably, the content of the celebrazil is 7.5-10 wt%; the sum of the content of the glycerol dioleate and the content of the soybean PC is 65-75 wt%; the mass ratio of the celebrazil to the methanesulfonic acid is 6-10:1, and the content of the N-methylpyrrolidone is 15-25 wt%; the optional maleic acid content is 0 to 0.02 wt.%;Wherein the weight percentages are relative to the total weight of (a), (b), (c), (d) and (e).
- The pharmaceutical composition according to claim 1, comprising:(a) Glycerol dioleate;(b) Soybean PC;(c) Dimethylacetamide;(d) Methanesulfonic acid and optionally maleic acid;(e) Celebrarphine;Wherein the ratio of (b) soybean PC to (a) glycerol dioleate is from about 0.1 to about 1, preferably from about 0.4 to about 1, more preferably from about 0.5 to about 0.9 by weight;Preferably, the content of the selvedge is 5-20 wt%; the sum of the content of the glycerol dioleate and the content of the soybean PC is 40-79 wt%; the mass ratio of the celebrarphine to the methanesulfonic acid is 5-15:1, and the content of the dimethylacetamide is 15-42 wt%; the optional maleic acid content is 0 to 0.2 wt.%;Further preferably, the content of the celebrazil is 7.5-15 wt%; the sum of the content of the glycerol dioleate and the content of the soybean PC is 50-75 wt%; the mass ratio of the celebrarphine to the methanesulfonic acid is 6-15:1, and the content of the dimethylacetamide is 15-35 wt%; optionally maleic acid in an amount of 0 to 0.02% by weight;Wherein the weight percentages are relative to the total weight of (a), (b), (c), (d) and (e).
- The pharmaceutical composition according to any one of claims 1 to 19, wherein the composition has a viscosity of 30 to 1000cps, preferably 30 to 500cps, more preferably 50 to 400cps at 25 ℃; or the composition may be injected using a needle of 18G to 23G gauge.
- The pharmaceutical composition according to any one of claims 1 to 16, wherein the unit dosage volume is 1.0 to 2.0ml, preferably 1.0ml to 1.5ml or 1.5 to 2.0ml or 1.8 to 2.0ml, wherein the unit dosage contains 150mg of celecoxib.
- A process for preparing a pharmaceutical composition according to any one of claims 1 to 10, comprising the steps of:Dissolving the celebrarphine and the acid in an oxygen-containing organic solvent, then adding the acylglycerol, finally adding the phosphatidylcholine, and dissolving to obtain the preparation; or alternativelyFirstly adding acid into an oxygen-containing organic solvent, then sequentially adding acylglycerol and phosphatidylcholine, stirring and dissolving, and finally adding the celebrazil, stirring and dissolving to obtain the preparation;Preferably, when phosphatidylcholine is added, the mixture is first heated to no more than 45 ℃.
- A process for the preparation of a pharmaceutical composition as claimed in any one of claims 11 to 21 comprising the steps of:Dissolving the celebuprofezin, the methanesulfonic acid and the maleic acid which are optionally contained in the N-methylpyrrolidone or the dimethylacetamide according to the weight percentage, then adding the glycerol dioleate, stirring, finally adding the soybean PC, and dissolving to obtain the product; or alternativelyDissolving methanesulfonic acid and optionally maleic acid in N-methylpyrrolidone or dimethylacetamide according to weight percentage, then adding glycerol dioleate, stirring, adding soybean PC, stirring and dissolving, and finally adding celebrarphine, stirring and dissolving to obtain the product;Preferably, when phosphatidylcholine is added, the mixture is first heated to no more than 45 ℃.
- Use of a pharmaceutical composition according to any one of claims 1-21 in the manufacture of a medicament for the treatment of pain selected from surgical pain or chronic pain over time.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110957327 | 2021-08-20 | ||
| CN2021109573278 | 2021-08-20 | ||
| PCT/CN2022/113527 WO2023020608A1 (en) | 2021-08-20 | 2022-08-19 | Pharmaceutical composition containing dinalbuphine sebacate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117999079A true CN117999079A (en) | 2024-05-07 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202280056159.8A Pending CN117999079A (en) | 2021-08-20 | 2022-08-19 | Pharmaceutical composition containing celebrazil |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN117999079A (en) |
| TW (1) | TWI819756B (en) |
| WO (1) | WO2023020608A1 (en) |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2254852C1 (en) * | 2004-01-23 | 2005-06-27 | Ефим Давыдович Нежинский | Injection solution with expressed analgesic effect and method for its preparing |
| NZ551990A (en) * | 2004-06-04 | 2011-01-28 | Camurus Ab | Liquid depot formulations |
| EA034855B1 (en) * | 2012-07-26 | 2020-03-30 | Камурус Аб | Depot precursor formulation comprising buprenorphine and method of treatment by administration thereof |
| GB201419091D0 (en) * | 2014-10-27 | 2014-12-10 | Camurus Ab | Formulations |
| RU2718900C2 (en) * | 2015-05-28 | 2020-04-15 | Лумоса Терапьютикс Ко., Лтд. | Pharmaceutical compositions for prolonged release of sebacoyl-dinalbuphine ester |
| US10183018B2 (en) * | 2015-05-28 | 2019-01-22 | Lumosa Therapeutics Co., Ltd. | Pharmaceutical formulations for sustained release of sebacoyl dinalbuphine ester |
| WO2019214726A1 (en) * | 2018-05-11 | 2019-11-14 | Alar Pharmaceuticals Inc. | Long-acting injectable formulations and crystalline forms of buprenorphine derivatives |
-
2022
- 2022-08-19 CN CN202280056159.8A patent/CN117999079A/en active Pending
- 2022-08-19 TW TW111131408A patent/TWI819756B/en active
- 2022-08-19 WO PCT/CN2022/113527 patent/WO2023020608A1/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| TW202308628A (en) | 2023-03-01 |
| TWI819756B (en) | 2023-10-21 |
| WO2023020608A1 (en) | 2023-02-23 |
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