CN117582440A - Method for stabilizing pharmaceutical compositions - Google Patents
Method for stabilizing pharmaceutical compositions Download PDFInfo
- Publication number
- CN117582440A CN117582440A CN202311048042.8A CN202311048042A CN117582440A CN 117582440 A CN117582440 A CN 117582440A CN 202311048042 A CN202311048042 A CN 202311048042A CN 117582440 A CN117582440 A CN 117582440A
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- component
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- celebrarphine
- acid
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- 238000000034 method Methods 0.000 title claims abstract description 61
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 56
- 230000000087 stabilizing effect Effects 0.000 title claims abstract description 20
- 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 123
- 238000002360 preparation method Methods 0.000 claims abstract description 65
- 239000003814 drug Substances 0.000 claims abstract description 36
- 239000000203 mixture Substances 0.000 claims description 260
- 238000009472 formulation Methods 0.000 claims description 219
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 99
- 239000003960 organic solvent Substances 0.000 claims description 86
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 84
- 229910052760 oxygen Inorganic materials 0.000 claims description 84
- 239000001301 oxygen Substances 0.000 claims description 84
- 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 58
- 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 58
- 239000002253 acid Substances 0.000 claims description 52
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 51
- 235000010469 Glycine max Nutrition 0.000 claims description 49
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 48
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 44
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 39
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 39
- 239000011976 maleic acid Substances 0.000 claims description 39
- 229940071643 prefilled syringe Drugs 0.000 claims description 38
- 229930182555 Penicillin Natural products 0.000 claims description 31
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 31
- 229940049954 penicillin Drugs 0.000 claims description 31
- 238000002156 mixing Methods 0.000 claims description 29
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 28
- 244000068988 Glycine max Species 0.000 claims description 24
- 208000002193 Pain Diseases 0.000 claims description 24
- 230000009977 dual effect Effects 0.000 claims description 22
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 21
- 238000012377 drug delivery Methods 0.000 claims description 21
- 238000004090 dissolution Methods 0.000 claims description 16
- 230000036407 pain Effects 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 239000003708 ampul Substances 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 13
- 238000003860 storage Methods 0.000 claims description 13
- -1 acyl glycerol Chemical compound 0.000 claims description 12
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 11
- 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 11
- 229960000590 celecoxib Drugs 0.000 claims description 11
- 150000001982 diacylglycerols Chemical class 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 208000000094 Chronic Pain Diseases 0.000 claims description 5
- 239000001530 fumaric acid Substances 0.000 claims description 5
- 102000002322 Egg Proteins Human genes 0.000 claims description 4
- 108010000912 Egg Proteins Proteins 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 4
- 235000013345 egg yolk Nutrition 0.000 claims description 4
- 210000002969 egg yolk Anatomy 0.000 claims description 4
- 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
- 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 4
- 206010058019 Cancer Pain Diseases 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 230000001684 chronic effect Effects 0.000 claims description 3
- 210000004185 liver Anatomy 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
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- 230000003187 abdominal effect Effects 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 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 2
- 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
- 238000010438 heat treatment Methods 0.000 claims description 2
- 208000014617 hemorrhoid Diseases 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
- 125000000403 lignoceroyl 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])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 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 2
- 238000004519 manufacturing process Methods 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
- 230000000399 orthopedic effect Effects 0.000 claims description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 2
- 230000008569 process Effects 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
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims 2
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- 239000007788 liquid Substances 0.000 description 18
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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 14
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- 238000006731 degradation reaction Methods 0.000 description 8
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 8
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- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 5
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- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 4
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- LZPBLUATTGKZBH-UHFFFAOYSA-L fenoprofen calcium Chemical compound O.O.[Ca+2].[O-]C(=O)C(C)C1=CC=CC(OC=2C=CC=CC=2)=C1.[O-]C(=O)C(C)C1=CC=CC(OC=2C=CC=CC=2)=C1 LZPBLUATTGKZBH-UHFFFAOYSA-L 0.000 description 1
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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
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/14—Details; Accessories therefor
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- 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
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Emergency Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pain & Pain Management (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
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- Organic Chemistry (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a method for stabilizing a pharmaceutical composition, and also relates to a preparation method of a celebrazil preformulation. The preparation and the method for stabilizing the pharmaceutical composition provided by the invention can obviously improve the stability of the preparation by taking the prescription containing the acylglycerol and the phosphatidylcholine as one component and storing the prescription and the component containing the celebrazil separately, and the preparation also has the advantages of high drug loading amount, faster onset of action and longer acting time.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a method for stabilizing a pharmaceutical composition, a pre-formulation, a preparation method and application in the pharmaceutical industry.
Background
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 long-acting sustained release preparation of the celebrity is marketed in taiwan at present, so that patients with severe or long-term pain do not need frequent administration of the nalbuphine preparation.
WO2016189393a discloses an oil-miscible preparation for injection, which is prepared by dissolving DNS in a mixed solvent of benzyl benzoate and a plant solvent such as sesame oil, castor oil and the like in a ratio of 0.8-1.2:1, wherein the oil-miscible preparation 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 and are easy to cause muscle caking during clinical intramuscular injection. Benzyl benzoate also has adverse effects including skin irritation and allergic reactions.
Chinese 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, etc. 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 various routes of administration, but with low drug loading, not suitable for sustained release long-term administration and/or for formulations requiring a high 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, in order to increase the drug loading and reduce the viscosity of the injection composition, the composition has a higher surfactant content, and has a certain hemolysis risk for the long-acting slow-release injection preparation. Furthermore, pharmaceutical compositions for administration to the human body should have good storage stability, otherwise it may lead to a change in the mass of the pharmaceutical composition over time, which may be dangerous, if not directly dangerous, to the administered person, and storage instability may cause significant changes in pharmacokinetics and/or efficacy.
In summary, the present long-acting injection of the celebrazil cannot meet clinical requirements, and the provided long-acting injection of the celebrazil can meet clinical requirements and has important significance in one or more aspects of drug loading, stability, safety, onset of action and the like.
Disclosure of Invention
Compared with the injection of the Buddha 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 storage stability of the preparation, improving the medication compliance of patients in pain management, solving the problems of the crystallization suspension stability of the Buddha, the impurity degradation stability and the like.
In a second aspect the invention provides a single use administration device for standard dose prefilling comprising a buprenorphine pre-formulation.
In a third aspect the invention provides a drug delivery device, and a kit comprising a pre-formulation of celebrarphine.
Pre-formulations
In a first aspect, the present invention provides a pre-formulation of celebrarphine, the pre-formulation comprising a first component and a second component, and the first component and the second component being stored separately;
Wherein, scheme a: the first component comprises (a) an acylglycerol, (b) a Phosphatidylcholine (PC) and (c) an oxygen-containing organic solvent; the second component comprises (c) an oxygen-containing organic solvent, (d) at least one acid, and (e) celebrazil; or,
scheme B: the first component comprises (a) an acylglycerol, (b) a Phosphatidylcholine (PC), (c) an oxygen-containing organic solvent, and (d) at least one acid; the second component comprises (e) celecoxib.
Preferably, the celebrazier pre-formulation comprises 5-20 wt% of the celebrazier; the sum of the content of the acyl glycerol and the phosphatidylcholine is 40 to 79 weight percent; the mass ratio of the celebrazil to the acid is 4-15:1, and the content 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).
In one embodiment of the invention, the first component is stored in a first container and the second component is stored in a second container; or the first component and the second component may be stored separately in separate compartments of a dual compartment dispensing device.
In one embodiment of the invention, the first component is stored in a first container and the second component is stored in a second container, the first container and the second container each being independently selected from a penicillin bottle, an ampoule or a prefilled syringe, the prefilled syringe being single-chambered, preferably the prefilled syringe being a prefilled luer lock syringe; for example, the first component and the second component are stored in two separate penicillin bottles, respectively; or the first component and the second component are respectively stored in two independent safety profiles; or one of the first component and the second component is stored in a penicillin bottle, and the other component is stored in an ampoule; or the first component and the second component are stored separately in separate pre-filled syringes, which are single-chambered, preferably pre-filled luer-lock syringes.
In one embodiment of the invention, the celebrarphine pre-formulation may also be stored in a dual chamber pre-filled syringe comprising a front chamber and a back chamber, the first component being stored in the front chamber and the second component being stored in the back chamber, or the first component being stored in the back chamber and the second component being stored in the front chamber; preferably, the second component is stored in the front compartment and the first component is stored in the rear compartment.
The pre-formulation according to the invention is that the injection of the celecoxib is present in the final "ready-to-use" form, also called "single dose" form, or "unit formulation". The pre-formulation provided by the invention is used for the injection of the celebrarphineIt is highly advantageous to store it stably for a long period of time in the form of the final "ready-to-use drug". The pre-formulation of celebrazil may be prepared by mixing the first component with the second component prior to use, by any method known in the art, such as, without limitation, when the first and second components are stored in the first and second containers, respectively, by aspirating the first component through a syringe into the container containing the second component, or aspirating the entire liquid from the container containing the second component (e.g., a penicillin bottle), transferring to the container containing the first component (e.g., a penicillin bottle), shaking, visualizing the liquid to a homogeneous liquid, removing air bubbles in the liquid, aspirating the entire liquid using a syringe (e.g., an 18G needle), replacing the syringe needle with a 23G needle, and injecting into a patient; when the first and second components are stored in a dual chamber prefilled syringe, such mixing is easy, allowing for mixing of the components in the front and rear chambers by movement of the plunger rod; when the first component and the second component are stored in two separate prefilled syringes, such as prefilled luer lock syringes, respectively, the method of mixing the two components is not limited, e.g., the syringes containing the first component and the second component are connected by a connector, e.g., two syringe luer lock connectors are screwed onto threads on both ends of the connector, respectively, and then the mixture is slowly pushed back and forth in the two syringes until the mixture is uniform. The luer lock syringe is commercially available, for example Luer lock syringe->Prefilled luer lock polymer syringe, hypak SCF for bi di medical (BD) TM PRTC glass prefilled syringe, hylok TM Pre-potting systems, and the like.
The double-chamber prefilled syringe according to the present invention is a double-chamber type syringe serving as a container, in which a front plug is usually inserted into the front end of an outer tube, a rear plug is inserted into the rear end of the outer tube, a center plug is inserted into the center portion of the outer tube, and the inner portion of the outer tube is divided into front and rear chambers. The invention is not limited to the specific structure of such dual chamber pre-filled syringes, and dual chamber pre-filled syringes known in the art that meet the pharmaceutical standards are suitable for use in the invention. Similar dual-chamber dual-purpose syringes are disclosed in, for example, japanese patent application laid-open No. 8-112333, CN103228308A, which are incorporated by reference into the present invention.
In one embodiment of the invention, the celebrarphine pre-formulation wherein (a) the acylglycerol comprises a "head group" glycerol moiety and independently 2 to 3 "tail group" acyl group moieties, in the invention the acylglycerol is a diacylglycerol, a triacylglycerol or a mixture of both; in particular, diacylglycerols are preferred.
Further, 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 the present invention, the acyl groups of the acylglycerols are selected from lauroyl (C12:0), myristoyl (C14:0), palmitoyl (C16:0), phytanoyl (C16:0), palmitoyl (C16:1), stearoyl (C18:0), oleoyl (C18:1), elaidoyl (C18:1), linoleoyl (C18:2), linolenoyl (C18:3), arachidonoyl (C20:4), behenoyl (C22:0) and tetracosanoyl (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. However, 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 one embodiment of the invention, the (b) 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 (b) one or more components of phosphatidylcholine, 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 described in the present 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 (a) acylglycerols and (b) phosphatidylcholines is GDO and PC, in particular GDO and soybean PC.
In one embodiment of the present invention, the sum of the contents of (a) acylglycerols and (b) phosphatidylcholines 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%, 49 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%, 45 to 60 wt%, 50 to 60 wt%, 55 to 60 wt%, 40 to 55 wt%, 45 to 55 wt%, 50 to 55 wt%, 48 to 72 wt%, 49 to 72 wt%, 48 to 71 wt%, 49 to 74 wt%, 49 to 75 wt%, 54 to 68 wt%, 61 to 62 wt%, 63 to 64 wt%, 61 to 64 wt%, 65 to 74 wt%, 61 to 74 wt%, or 60 to 68 wt%, etc. and all ranges contained therein; preferably 49 to 75 wt%, more preferably 50 to 70 wt%; by way of further illustration, the sum of the contents of (a) acylglycerols and (b) phosphatidylcholines may be present in the pre-formulation 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 63 wt%, about 62 wt%, about 61 wt%, about 60 wt%, about 59 wt%, about 54 wt%, about 53 wt%, about 52 wt%, about 50 wt%, or about 49 wt% and ranges between any two values.
In one embodiment of the invention, the mass ratio of (a) acylglycerols and (b) phosphatidylcholine can be used to formulate a celebrarphine pre-formulation in a wide range, said (a) acylglycerols content being 20 to 60 wt.%; for example, 40 to 60 wt%, 50 to 60 wt%, 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%, 26 to 47 wt%, 29 to 40 wt%, 37 to 41 wt%, or 38 to 39 wt%, etc., and all ranges included therein; further by way of example, the (a) acylglycerols may be present in the pre-formulation in the following amounts: about 20 wt%, about 26 wt%, about 29 wt%, about 30 wt%, about 31 wt%, about 32 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%, about 50 wt%, about 55 wt%, about 56 wt%, or about 60 wt%, etc., and ranges between any two values therein; preferably (a) the content of acylglycerols is from 25 to 50% by weight, more preferably from 30 to 45% by weight; alternatively, (a) the content of the acylglycerol is preferably 40 to 60% by weight, more preferably 50 to 60% by weight; .
In one embodiment of the present invention, the content of the (b) phosphatidylcholine is 4 to 40 wt%, such as 4 to 10 wt%, 4 to 8 wt%, 5 to 6 wt%, 20 to 40 wt%, 25 to 40 wt%, 30 to 40 wt%, 20 to 35 wt%, 25 to 35 wt%, 30 to 35 wt%, 20 to 30 wt%, 20 to 31 wt%, 20 to 25 wt%, 26 to 31 wt%, 26 to 33 wt%, 25 to 33 wt%, 26 to 31 wt%, 23 to 30 wt%, 24 to 30 wt%, 25 to 26 wt%, 25 to 30 wt%, 35 to 40 wt%, etc. and all ranges included therein; by way of further illustration, (b) phosphatidylcholine may be present in the pre-formulation in the following amounts: about 4 wt%, about 5 wt%, about 6 wt%, 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%, or about 40 wt%, etc., and ranges between any two values therein; preferably (b) the content of phosphatidylcholine is 20 to 35 wt%, more preferably 20 to 31 wt%; alternatively, the content of the phosphatidylcholine (b) is 4 to 10 wt%, for example, 4 to 5 wt%, 4 to 8 wt%, 5 to 6 wt%, or 5 to 10 wt%, etc.
In one embodiment of the present invention, the acylglycerol is contained in an amount of 50 to 60% by weight and the phosphatidylcholine is contained in an amount of 4 to 10% by weight. The inventors have unexpectedly found that the onset of action of the celebrazil can be significantly increased when the content of phosphatidylcholine in the pre-formulation of the invention is significantly lower than the content of acylglycerol, in particular in that timely administration can be performed before and/or during surgery; in addition, the combination of acylglycerols and phosphatidylcholine at such levels can also significantly reduce the viscosity of the pre-formulation or the composition after mixing of the two components thereof.
In another embodiment of the invention, the acylglycerol content is 20 to 50 wt%, preferably 25 to 50 wt%; the content of the phosphatidylcholine is 20 to 40 wt%, preferably 20 to 35 wt%.
In embodiments of the invention, the inclusion of an oxygen-containing organic solvent in the first component is advantageous for reducing the viscosity of the composition; the inclusion of an oxygen-containing organic solvent in the second component facilitates thorough mixing of the active ingredient, celebrazil, with the acid, thereby increasing the storage stability of the celebrazil. In one embodiment, (C) the oxygen-containing organic solvent is selected from amides, C 1-3 At least one of alcohols or benzyl alcohol, the amides are selected from at least one of N-methyl pyrrolidone (NMP), dimethylformamide, 2-pyrrolidone and dimethylacetamide (DMAC, also called N, N-dimethylacetamide); the C is 1-3 The alcohol is selected from methanol, ethanol, isopropanol or propanol. The inventors found through research that the stability of the celebrazil in NMP and DMAC is better than that of other oxygen-containing organic solvents, preferably (c) the oxygen-containing organic solvents are N-methylpyrrolidone and/or dimethylacetamide; the dimethylacetamide of the present invention has a larger safety range, and therefore, it is particularly preferable that (c) the oxygen-containing organic solvent is dimethylacetamide.
The total amount of the oxygen-containing organic solvent in the first and second components of the pre-formulation is: 15 to 42 wt%, e.g., 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%, 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%, 17 to 24 wt%, 25 to 26 wt%, 27 to 28 wt%, 25 to 28 wt%, etc., and all ranges contained therein; by way of illustration, the total amount of the oxygen-containing organic solvents of component (c) is: 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%, or about 40 wt%, etc., and ranges between any two values therein; preferably from 20 to 35% by weight, particularly preferably from 25 to 30% by weight; wherein the ratio of the content of the oxygen-containing organic solvent in the first component to the content of the oxygen-containing organic solvent in the second component in the scheme A is (0.5-3) 1, such as (1-3) 1, (1-2) 1, (2-3) 1, (0.5-1) 1, or (0.5-2) 1.
In a specific embodiment, in the above-mentioned pre-formulation, the content of the celebrazil is from 5 to 20% by weight, for example: 7 to 15 wt%, 7 to 8 wt%, 10 to 15 wt%, 7.5 to 12.5 wt%, 7.5 to 10 wt%, 8 to 11 wt%, 9 to 10 wt%, 15 to 18 wt%, 15 to 20 wt%, about 7.5 wt%, about 7.9 wt%, about 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 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, or about 20 wt%, etc., and a range between any two of these values, preferably the content of the celecoxib is 7 to 15 wt%, such as 8 to 15 wt%, 10 to 15 wt%, or 7 to 8 wt%, etc.
In a specific embodiment, the acid of (d) 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 storage stability of the celebrarphine, the increase in stability being demonstrated by: the results of stability studies (15 days in a 40 ℃ +/-5 ℃/RH75% +/-10% stability test box, 1 month in a 25 ℃ +/-5 ℃/RH60% +/-10% stability test box, and 1 month in a 2-8 ℃ refrigerator) after the first component and the second component in the pre-formulation are mixed show that when the acid (especially methanesulfonic acid) disclosed by the invention exists in the pre-formulation, the chemical stability of the acid is obviously improved, the degradation of impurities is less, and the purity results detected by HPLC can be seen; the same increase in stability is also reflected in an increase in physical stability, in particular in that the addition of an acid, in particular methanesulfonic acid, can significantly reduce the problem of crystallization of the celebrarphine in the pre-formulation, and therefore (d) preferably comprises methanesulfonic acid. Further studies have found that the addition of maleic acid is also advantageous for improving the chemical stability of the pre-formulation, and thus, in one embodiment, (d) may also comprise maleic acid. It is advantageous that the mass ratio of the celebuprenorphine to the methanesulfonic acid is 4-15:1, such as 5-15:1, 6-15:1, 7-15:1, 5-11:1, 7-10:1, 7.5-10:1, 9-10:1 or 8-10:1 etc., the maleic acid content is 0-0.2 wt%, such as 0-0.02 wt%, 0-0.01 wt%, etc.
In a preferred embodiment, the present invention provides a pre-formulation of celebrarphine comprising: the first component comprises glycerol dioleate, soybean PC and an oxygen-containing organic solvent; the second component comprises an oxygen-containing organic solvent, methanesulfonic acid, and celebrarphine, optionally comprising maleic acid; or,
the first component comprises glycerol dioleate, soy PC, an oxygen-containing organic solvent, methanesulfonic acid, optionally maleic acid; the second component comprises celebrarphine;
wherein the oxygen-containing organic solvent is N-methyl pyrrolidone or N, N-dimethylacetamide.
In a preferred embodiment, the present invention provides a pre-formulation of celebrarphine comprising: a first component and a second component, and the first component and the second component are stored separately;
wherein, scheme a: the first component comprises (a) glycerol dioleate, (b) soy PC and (c) N-methylpyrrolidone; the second component comprises (c) N-methylpyrrolidone, (d) methanesulfonic acid and/or maleic acid, and (e) celebrazil; or,
scheme B: the first component comprises (a) glycerol dioleate, (b) soy PC, (c) N-methylpyrrolidone, and (d) methanesulfonic acid and/or maleic acid; the second component comprises (e) celebrarphine;
Wherein the total content of N-methylpyrrolidone is 15 to 35 wt%, e.g., 17 to 35 wt%, 15 to 25 wt%, 15 to 30 wt%, 25 to 28 wt%, 20 to 35 wt%, 25 to 35 wt%, 30 to 35 wt%, 20 to 25 wt%, 20 to 30 wt%, 25 to 30 wt%, 17 to 28 wt%, etc., preferably 20 to 30 wt%, e.g., about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, or about 28 wt%, etc., and ranges between any two values therein;
it is further preferable that the ratio of the content of N-methylpyrrolidone in the first component to the content of N-methylpyrrolidone in the second component in the embodiment A is (0.5 to 3) 1, for example, (1 to 3) 1, (1 to 2) 1, (2 to 3) 1, (0.5 to 1) 1, (0.5 to 2) 1, etc.;
further preferably, the content of the celebuprenorphine is from 5 to 20 wt%, preferably from 7 to 15 wt%, more preferably from 7 to 10 wt%, or from 8 to 10 wt%, for example, about 7.5 wt%, about 8 wt%, about 9 wt%, about 10 wt%, or about 15 wt%, and any range therebetween;
further preferably, the sum of the content of glycerol dioleate and soybean PC is 50 to 75% by weight, preferably 60 to 75% by weight, more preferably 61 to 74% by weight;
Wherein the glycerol dioleate content is preferably 30 to 50 wt%, preferably 37 to 41 wt%; the content of the soybean PC is 20 to 35% by weight, preferably 25 to 35% by weight, more preferably 25 to 30% by weight; alternatively, the glycerol dioleate content is preferably 40 to 60 wt%, preferably 50 to 60 wt%, and the soybean PC content is 4 to 10 wt%, preferably 5 to 8 wt%.
Further preferably, the mass ratio of the celebrarphine to the methanesulfonic acid is 5-15:1, preferably 7-10:1, more preferably 9-10: 1, a step of;
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).
In another preferred embodiment of the present invention there is provided a buprenorphine pre-formulation comprising: a first component and a second component, and the first component and the second component are stored independently;
wherein, scheme a: the first component comprises (a) glycerol dioleate, (b) soy PC and (c) dimethylacetamide; the second component comprises (c) N, N-dimethylacetamide, (d) methanesulfonic acid and/or maleic acid, and (e) celebrarphine; or,
scheme B: the first component comprises (a) glycerol dioleate, (b) soy PC, (c) N, N-dimethylacetamide and (d) methanesulfonic acid and/or maleic acid; the second component comprises (e) celebrarphine;
Wherein the total content of said N, N-dimethylacetamide in the pre-formulation is 15 to 40 wt%, such as 16 to 40 wt%, 20 to 40 wt%, 25 to 40 wt%, 20 to 30 wt%, 20 to 35 wt%, 25 to 35 wt%, preferably 25 to 30 wt%;
it is further preferable that the ratio of the content of N, N-dimethylacetamide in the first component to the content of N, N-dimethylacetamide in the second component in the embodiment A is ((0.5 to 3): 1, such as (1 to 3): 1, (1 to 2): 1, (2 to 3): 1, (0.5 to 1): 1, (0.5 to 2): 1, etc.;
further preferably, the content of the celebrarphine is in the range of 5 to 20 wt%, such as 6 to 15 wt%, 7 to 10 wt%, 10 to 15 wt% or 9 to 11 wt% and any range therebetween; preferably 7 to 15% by weight;
further preferably, the sum of the content of glycerol dioleate and soybean PC is 45 to 75 wt%, such as 50 to 75 wt%, 50 to 70 wt%, 49 to 72 wt%, 53 to 68 wt%, 54 to 68 wt% or 53 to 65 wt% and any range therebetween; preferably 53 to 68% by weight;
wherein the glycerol dioleate content is 20-50 wt%, 25-50 wt%, 26-47 wt%, 29-40 wt%, 25-45 wt%, 25-35 wt%, 30-35 wt%, or 25-30 wt% and any range therebetween, preferably 30-35 wt%; the soybean PC is contained in an amount of 20 to 35% by weight, for example, 20 to 30% by weight, 20 to 35% by weight, 22 to 31% by weight, 24 to 30% by weight, 25 to 33% by weight and any range therebetween; preferably 22 to 31% by weight; or,
The glycerol dioleate content is 40 to 60 wt%, preferably 50 to 60 wt%; the content of the soybean PC is 4 to 10% by weight, preferably 4 to 8% by weight, more preferably 5 to 6% by weight.
Further preferably, the mass ratio of the celebrarphine to the methanesulfonic acid is 4-15:1, for example 5-15:1, 7-15:1, 8-15: 1,4 to 11:1, 8-10: 1,9 to 10:1,5 to 11:1 or 5 to 10:1 and any range therebetween, preferably 5 to 11:1, a step of; more preferably 9 to 10:1, a step of; the maleic acid content is 0 to 0.2 wt%, preferably 0 to 0.01 wt%;
in a specific embodiment of the present invention there is provided a buprenorphine pre-formulation comprising: a first component and a second component, and the first component and the second component are stored independently,
wherein, scheme a: the first component comprises (a) glycerol dioleate, (b) soy PC and (c) N, N-dimethylacetamide; the second component comprises (c) N, N-dimethylacetamide, (d) methanesulfonic acid and/or maleic acid, and (e) celebrarphine; or,
scheme B: the first component comprises (a) glycerol dioleate, (b) soy PC, (c) N, N-dimethylacetamide and (d) methanesulfonic acid and/or maleic acid; the second component comprises (e) celebrarphine;
Wherein the ratio of the content of N, N-dimethylacetamide in the first component to the content of N, N-dimethylacetamide in the second component is (0.5-3): 1;
the content of the selvedge is 7 to 15 wt%, preferably 7 to 8 wt%;
the content of the N, N-dimethylacetamide is 20 to 35 wt%, preferably 25 to 30 wt%;
the content of the glycerol dioleate is 40 to 60 weight percent, preferably 50 to 60 weight percent;
the content of the soybean PC is 4 to 10 wt%, preferably 5 to 10 wt%;
the mass ratio of the celebrarphine to the methanesulfonic acid is 4-15:1, preferably 9-10:1; the content of maleic acid is 0 to 0.01 percent;
the weight percentages are relative to the total weight of (a), (b), (c), (d) and (e).
In another aspect of the invention, the inventors have found that when the content of (b) is lower in the pre-formulation than in (a), it is advantageous to facilitate the release of the active ingredient in vivo of the celebrazil pre-formulation after administration to an individual. Thus, in another preferred embodiment, the present invention provides a pre-formulation of celebrarphine, the pre-formulation comprising a first component and a second component, and the first component and the second component being stored separately;
wherein, scheme a: the first component comprises (a) an acylglycerol, (b) a phosphatidylcholine, and (c) an oxygen-containing organic solvent; the second component comprises (c) an oxygen-containing organic solvent, (d) at least one acid, and (e) celebrazil; or,
Scheme B: the first component comprises (a) an acylglycerol, (b) a phosphatidylcholine, (c) an oxygen-containing organic solvent, and (d) at least one acid; the second component comprises (e) celebrarphine; wherein the ratio of (b) phosphatidylcholine to (a) acylglycerol is about 0.1 to 1, e.g., 0.1 to 0.3,0.4 to 1,0.5 to 0.9,0.6 to 0.8,0.7 to 0.9,0.6 to 0.7, or 07 to 0.8, etc., by weight.
Wherein the (a) acylglycerols, (b) phosphatidylcholines, (c) oxygen-containing organic solvents and (d) at least one acid are as defined above.
In a preferred embodiment, the (a) acylglycerol is selected from glycerol dioleate, the (b) phosphatidylcholine is selected from soy PC, the (c) oxygen-containing organic solvent is selected from N-methylpyrrolidone or dimethylacetamide, and the (d) is selected from methanesulfonic acid, optionally including maleic acid, wherein the ratio of (b) soy PC to (a) glycerol dioleate is about 0.1 to 1, such as 0.1 to 0.3,0.4 to 1,0.5 to 0.9, or 0.6 to 0.8, by weight, etc.
Further preferred, the content of the celebuprenorphine is in the range of from 5 to 20 wt%, preferably from 7 to 15 wt%, such as from 7.5 to 12.5 wt%, such as from 7.5 to 10 wt%, such as about 7.5 wt%, about 7.9 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 10.5 wt%, about 11 wt%, about 11.5 wt%, or about 12 wt% and any range between two values thereof.
The sum of the glycerol dioleate and 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%, or about 50 wt% and any range between two values thereof.
The mass ratio of the celebrity 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, 15:1, or the like, and the preferred mass ratio between any two values 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; the content of the optional maleic acid is 0 to 0.2% by weight, preferably 0 to 0.01%.
Further, the content of the N-methylpyrrolidone is 15 to 35% by weight, for example, 17 to 35% by weight, 15 to 25% by weight, 15 to 30% by weight, 25 to 28% by weight, 20 to 35% by weight, 25 to 35% by weight, 30 to 35% by weight, 20 to 25% by weight, 20 to 30% by weight, 25 to 30% by weight, 17 to 28% by weight, etc., preferably 20 to 30% by weight, for example, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, or about 28% by weight and a range between any two thereof.
Further, the content of the N, N-dimethylacetamide is 15 to 40% by weight, for example, 16 to 40% by weight, 20 to 40% by weight, 25 to 40% by weight, 20 to 30% by weight, 20 to 35% by weight, or 25 to 35% by weight, etc., preferably 25 to 30% by weight;
wherein the weight percentages are relative to the total weight of (a), (b), (c), (d) and (e).
In a specific embodiment, there is provided a pre-formulation of celebrarphine comprising a first component and a second component, and the first component and the second component being stored separately;
wherein, scheme a: the first component comprises (a) glycerol dioleate, (b) soy PC and (c) N, N-dimethylacetamide; the second component comprises (c) N, N-dimethylacetamide, (d) methanesulfonic acid and/or maleic acid, and (e) celebrarphine; or,
scheme B: the first component comprises (a) glycerol dioleate, (b) soy PC, (c) N, N-dimethylacetamide and (d) methanesulfonic acid and/or maleic acid; the second component comprises (e) celebrarphine;
wherein the sum of the content of glycerol dioleate and soybean PC is 40 to 79 wt%, for example 45 to 75 wt%, or 50 to 75 wt%, etc., preferably 55 to 65 wt%;
The content of the celebrazil is 5-20 wt%; preferably 7 to 15 wt%, for example 7 to 8 wt%, 9 to 11 wt%, or 10 to 11 wt%, etc.;
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 maleic acid content is 0 to 0.2 wt.%, preferably 0 to 0.01 wt.%;
the content of N, N-dimethylacetamide is 15 to 40% by weight, for example 15 to 35% by weight, 20 to 35% by weight, 25 to 35% by weight, etc., preferably 25 to 30% by weight;
(b) The ratio of soybean PC to (a) glycerol dioleate is about 0.1 to 1, e.g., 0.1 to 0.3, or 0.4 to 1, or 0.5 to 0.9, etc., by weight percent relative to the total weight of (a), (b), (c), (d), and (e).
In a preferred embodiment, the pre-formulation of celebrazil as described in the context of the present invention, wherein said first component is stored in a first container and the second component is stored in a second container, each independently selected from a penicillin bottle, an ampoul or a pre-filled syringe, said pre-filled syringe being single-chambered, preferably said pre-filled syringe being a pre-filled luer lock syringe; alternatively, the celebrarphine pre-formulation is pre-potted in a dual chamber pre-potted syringe comprising a front chamber and a back chamber, the first component being stored in the front chamber and the second component being stored in the back chamber, or the first component being stored in the back chamber and the second component being stored in the front chamber.
The first component and the second component of the celebrazier pre-formulation provided by the invention have lower viscosity after being uniformly mixed, so that the celebrazier pre-formulation has good needle penetrating property. In one embodiment, the first component and the second component of the pre-formulation, after being mixed into a homogeneous liquid formulation, have a viscosity of no more than 1000cps, such as a viscosity of no more than 500cps, or a viscosity of no more than 300cps, or a viscosity of no more than 200cps, or a viscosity of no more than 100cps, or a viscosity of 10-1000 cps, or a viscosity of 30-500 cps, or a viscosity of 30-400 cps, or a viscosity of 30-300 cps, or a viscosity of 40-500 cps, or a viscosity of 40-400 cps, or a viscosity of 40-300 cps, or a viscosity of 40-200 cps, or a viscosity of 50-500 cps, or a viscosity of 50-400 cps, or a viscosity of 50-300 cps, a viscosity of 7 or 0-300 cps, or a viscosity of 70-250 cps, or a viscosity of 100-300 cps at about 25 ℃; alternatively, the first component of the pre-formulation has a viscosity of no more than 1000cps, such as a viscosity of no more than 500cps, or a viscosity of no more than 300cps, or a viscosity of no more than 200cps, or a viscosity of no more than 100cps, or a viscosity of 10 to 1000cps, or a viscosity of 30 to 500cps, or a viscosity of 30 to 400cps, or a viscosity of 30 to 300cps, or a viscosity of 40 to 500cps, or a viscosity of 40 to 400cps, or a viscosity of 40 to 300cps, or a viscosity of 40 to 200cps, or a viscosity of 50 to 500cps, or a viscosity of 50 to 400cps, or a viscosity of 50 to 300cps, or a viscosity of 70 to 250cps, or a viscosity of 100 to 300cps, preferably has a viscosity of no more than 500cps, more preferably has a viscosity of no more than 100cps at about 25 ℃.
The weight ratio of (b) phosphatidylcholine to (a) acylglycerol described herein can be such that the first component of the pre-formulation, or the first component and the second component, after mixing into a homogeneous medicinal solution, can pass smoothly through an international standard syringe needle, or through various fine needle holes, such as 18G or less needle holes, 23G or less needle holes, 27G or less needle holes.
In the present invention, the international standard syringe needle 18G, 23G, 27G sizes are as follows:
application of
The pre-formulations provided herein are preferably administered parenterally. Administration will be by injection, which refers to any method of passing the formulation through the skin, such as by needle, catheter or needleless injector. In a preferred embodiment of the invention, the pre-formulation of celebrazil is stored in final administration dosage units and is delivered into a mammal (preferably a human) through a needle after mixing the first component and the second component into a homogeneous liquid drug prior to use, preferably by subcutaneous (s.c.) or intramuscular (i.m.) injection. Advantages of the pre-formulations of the present invention include that the first and second components thereof, when mixed, can be administered by intramuscular injection, subcutaneous administration, and other routes without toxic or significant local effects, and that they are also suitable for intraluminal administration, or by deep subcutaneous formation of depot formulations. The inventor observes through experiments that the pre-preparation provided by the invention can slowly release the active ingredient of the celebrity after being applied, and plays a continuous role. Since the pre-formulation of the present invention is capable of forming a gel depot at the injection site after administration in vivo, it allows for an extended period of release, with a longer stable release period desirable for patient comfort and compliance. The rapid onset of action following administration is a particularly significant advantage of the pre-formulation provided by the present invention, which can facilitate immediate pre-operative administration without the need for 1 day or even longer prior administration, greatly improving the convenience of clinical administration.
The present invention provides for a pre-formulation of celebrarphine, because of the unique high drug loading characteristics, the injection volume preferably does not exceed 3 mL/per administration, more preferably does not exceed 2 mL/per administration, e.g. 0.5 mL/per administration, 1 mL/per administration, 1.5 mL/per administration, 1.8 mL/per administration, 2 mL/per administration, etc. The pre-formulation of the celebrazil provided by the invention is preferably a unit preparation for final administration, namely a standard dose pre-formulation, wherein the single pre-formulation at least comprises 50-200 mg, preferably 100-200 mg, such as 100mg,120mg,150mg,180mg,200mg and the like, and preferably the single pre-formulation comprises 120-150 mg, particularly 150mg of the celebrazil; further preferably, the volume of the single pre-formulation is about 3 mL/count, about 2 mL/count, about 1.9 mL/count, about 1.8 mL/count, about 1.5 mL/count, about 1.4 mL/count, about 1 mL/count, or about 0.5 mL/count and any number therebetween.
Further preferably, the total volume of the preformulation first component after mixing with the second component is from 0.5 to 3ml, for example from 0.5ml to 1.0ml, from 0.5ml to 1.5ml, from 1.0ml to 1.5ml, from 1 to 2ml, from 1.5 to 2.0ml, from 1.8 to 2.0ml, from 2.0ml to 3.0ml, about 0.5ml, about 1.0ml, about 1.5ml, about 1.8ml, about 2.0ml, etc.; more preferably 0.5ml to 1.5ml, or 1.5 to 2.0ml, wherein the content of the celebrarphine is about 50mg, or about 100mg, or about 150mg, or about 180mg, or about 200mg, etc. The "unit preparation" as used herein has a meaning conventional in the art and refers to a minimum administration unit or minimum packaging unit which can be split in a medicine, and for an injection, the unit preparation is a single dose.
The key point of the pre-formulation of the celebrazil provided by the invention is to provide a unit formulation for injection of the celebrazil, wherein the pre-formulation has good stability and low viscosity, and particularly, one or more of needles with the specification of 18G to 25G can be used for injection after the first component and the second component of the pre-formulation are mixed.
In addition, the pre-formulation provided by the invention avoids the use of surfactants and reduces vascular irritation and risk of hemolysis. In a more preferred embodiment, the problem of crystalline suspension of the celebrazil in the formulation composition is solved by adding an acid, particularly methanesulfonic acid, and the generation of degradation impurities in the pre-formulation is inhibited, thereby remarkably improving the stability, the needle-punching property and the safety of the celebrazil pre-formulation.
One significant advantage of the pre-formulation provided by the present invention is also that the pre-formulation has the advantage of having a fast onset of action after administration to an individual, and being able to be released over a longer period of time, with a sustained onset of action; compared with the prior art, the pre-preparation provided by the invention can be instantly administered before or during operation, so that the problem that the pain relieving needs to be administered at least 12-24 hours before operation is solved; and the pre-formulation according to scheme a provided by the present invention also solves the problem of drug abuse.
Therapeutic use
In a further aspect the invention provides the use of said pre-formulation of celebrarphine 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 pre-formulation of celebrarphine according to 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 pre-formulation may consist essentially of only these components, and in one aspect consist entirely of these components.
Disposable drug delivery device
In another aspect, the present invention provides a disposable drug delivery device (optionally, further comprising a device assembly) preloaded with standard dose pre-formulations. Such devices will typically contain a single dose ready for administration and are typically packaged aseptically, such that the pre-formulation is stored within the device until administration. Disposable drug delivery devices suitable for use in the present invention include, for example, cartridges, ampoules and/or penicillin bottles, and in particular syringes, such as needles with integral needles or with dual chamber pre-filled syringes suitable for use, single chamber pre-filled syringes and luer lock fittings and the like. Similar devices include needleless syringes, multiple use or single use syringes in combination with dual chamber pre-filled syringes, cartridges, or vials, or penicillin bottles, or ampoule and syringe and/or injection needle and fittings therefor.
In a specific embodiment, the present invention provides a disposable drug delivery device comprising a standard dose pre-filled, pre-formulation of the invention of the celebrarphine as described herein before, the pre-formulation being a single dose ready for administration. The single-use drug delivery device of the present invention may contain up to 3mL, for example, 0.1 to 2mL,0.5 to 3mL,0.5 to 1mL,0.5mL to 1.5mL,1 to 1.5mL,1.5 to 1.8mL,1.8 to 2mL,1 to 2mL,1.5 to 2mL,1.8 to 2mL,2mL to 3mL, about 0.5mL, about 1.0mL, about 1.5mL, about 1.8mL, or about 2.0mL of the total administration volume of the pre-formulation; preferably up to a total administration volume of not more than 2ml, such as 2ml,1.5ml,1ml or 0.5ml etc., wherein the content of the celebrazil is 100mg,120mg,150mg,180mg or 200mg, preferably 150mg.
Further preferably, the single use drug delivery device comprises two separate containers of a size and shape not limited as long as they meet sterility requirements and meet the requirements of the relevant quality of the pharmaceutical excipient package, e.g. the container size may be determined according to the volume size of the first and second components of the pre-formulation, the preferred dosage and volume of the pre-formulation according to the present invention, the container size preferably being 0.5-5 ml, e.g. about 0.5ml, about 1ml, about 1.5ml, about 2ml, about 2.5ml, about 3ml, about 3.5ml, about 4ml or about 5ml, etc. In a preferred embodiment of the invention, the container is a vial, such as a penicillin and/or ampoule, or the container is a pre-filled syringe, which is single-chambered, preferably a pre-filled luer lock syringe. The first and second components of the celebrazil pre-formulation are placed in two vials, e.g. a penicillin and/or ampoule, respectively, i.e. the first component may be stored in one penicillin vial, the second component in another penicillin vial or ampoule, or the first component may be stored in one ampoule, and the second component in another ampoule or penicillin vial; the administration device further comprises a barrel, a syringe and a syringe barrel, and optionally an injection needle, such as an 18G needle and/or a 23G needle, the administration device comprising means for at least one injection administration, e.g. the pre-formulation is administered by means of a syringe, which is required to transfer one of the components into the other component for even mixing and then to be administered to the individual by means of the syringe, and in a preferred embodiment, the first component is transferred into the container in which the second component is located before administration, or the second component is transferred into the container in which the first component is located for mixing and then to be administered to the individual by means of the syringe.
In a specific embodiment, for example, the pre-formulation is composed of two parts, a first part and a second part, each part being stored in a 2ml penicillin bottle. The method of use of the pre-formulation according to the invention can be adjusted by the person skilled in the art according to the results of the needle penetration, the convenience of clinical use and the acceptability of the patient, as well as according to the difficulty of aspiration and injection of the components. For example, using a 2ml 18G syringe, the whole of the drug solution is sucked from the first component, transferred to a vial (e.g., penicillin bottle) in which the second component is located, shaken for 1 to 3 minutes, visually changed into a homogeneous drug solution, allowed to stand for about 5 minutes to remove air bubbles in the drug solution, sucked by using a 2ml 18G syringe, replaced with a 23G syringe needle, and injected into a patient.
In another preferred embodiment, the disposable drug delivery device comprises a dual chamber pre-filled syringe, wherein the first component and the second component of the pre-formulation of the celebrarphine are placed in two different chambers of the dual chamber pre-filled syringe, respectively, preferably the second component is located in the front chamber and the first component is located in the rear chamber of the dual chamber pre-filled syringe, and optionally the drug delivery device further has a standard fitting adapted for disposable injection using a dual chamber syringe.
The dual chamber prefilled syringe of the present invention is consistent with the general understanding of those skilled in the art, such as for example, dual chamber syringes for Abilify Maintena prefilling, for which commercial products have been available in the art for clinical use, and in addition any similar dual chamber prefilled syringe that has been disclosed by the date of this application is suitable for use in the present invention, such as the dual compartment products for sterile mixing substances disclosed in CN102482023A, and the like.
In another embodiment, the disposable drug delivery device comprises a prefilled syringe, the prefilled syringe is a single-chamber, preferably the prefilled syringe is a prefilled luer lock syringe, the first component and the second component are respectively prefilled in the prefilled syringe such as the prefilled luer lock syringe, the drug delivery device further comprises a connector matched with the luer lock screw thread of the prefilled luer lock syringe, both ends of the connector are provided with screw threads, the prefilled luer lock syringe filled with the first component and the prefilled luer lock syringe filled with the second component can be connected through the connector, and then the first component and the second component are uniformly mixed in the two syringes, and the drug delivery device further comprises a needle and other accessories matched with the prefilled luer lock syringe, so that the drug delivery device can at least meet the requirement of disposable injection drug delivery.
The medicine box comprises:
the present invention provides a kit for administration of a pre-formulation of a celebrazil of the invention, said kit comprising a pre-filled disposable drug delivery device of the invention and/or a pre-formulation of a celebrazil of the invention. Preferably, the pre-formulation is contained within a disposable drug delivery device according to the present invention, making it suitable for intramuscular or subcutaneous injection, or for postoperative infusion. The kit may include additional administration components such as needles (e.g., 2 18G needles, 1 23G needles, etc.), syringes, containers (e.g., penicillin bottles, ampoules, or pre-filled syringes), etc., and optionally and preferably contains instructions for administration. The description will generally relate to indications of a pre-formulation of celebrarphine by the route as described in the present invention and/or as described hereinbefore.
In a preferred embodiment, the present invention provides a kit comprising a pre-formulation of celebrazil as described hereinbefore and a disposable drug delivery device, preferably further comprising a needle having a needle opening of 18G or less and/or a needle having a needle opening of 23G or less, optionally further comprising instructions for administration and/or timing of administration, route of administration, indication of treatment of disease, etc. depending on factors such as the weight and/or dose of the subject, concentration of celebrazil, etc.
In a preferred embodiment, the kit comprises a single dose of 50 to 200mg, preferably 100 to 180mg, more preferably 100 to 150mg of celecoxib.
The preparation method of the pre-formulation comprises the following steps:
in another aspect, the present invention provides a method of preparing the celebrazil pre-formulation comprising the steps of:
method Aa: adding (a) acylglycerols in a prescribed proportion into (c) an oxygen-containing organic solvent, and then adding (b) phosphatidylcholine, and stirring and dissolving to obtain a first component;
adding the (d) acid in the prescription proportion into the (c) oxygen-containing organic solvent, stirring and mixing uniformly, and then adding the (e) celebrazil to dissolve and mix uniformly to obtain the second component.
Method Ba: adding (d) acid in a prescription proportion into (c) an oxygen-containing organic solvent, stirring and mixing uniformly, and then adding (a) acylglycerol and (b) phosphatidylcholine, stirring and dissolving to obtain a first component;
taking the prescribed proportion of (e) celebrazil as a second component;
storing the first component and the second component separately, e.g., storing the first component and the second component separately in a first container and a second container, each independently selected from a vial, such as a xilin bottle or an ampoule, or storing the first component and the second component separately in a prefilled syringe, which is a single chamber, preferably a prefilled luer-lock glass syringe; or the first component and the second component are stored in the front and back chambers of a dual chamber pre-filled syringe, respectively.
In the preparation methods Aa and Ba according to the present invention, the acid, the oxygen-containing organic solvent, the acylglycerol and the phosphatidylcholine, the container, the prefilled luer-lock glass syringe, and the two-chamber prefilled syringe are defined as described above.
In a specific embodiment, the method of preparing the pre-formulation comprises the steps of:
method Aa01: adding GDO in a prescription proportion into N, N-dimethylacetamide, adding soybean phospholipid, and stirring to dissolve to obtain a first component;
adding methanesulfonic acid, optionally containing maleic acid, into N, N-dimethylacetamide according to a prescription proportion, stirring and mixing uniformly, and adding the celebrazil to dissolve and mix uniformly to obtain a second component.
Method Ba01: dissolving methanesulfonic acid, optionally containing maleic acid, in N, N-dimethylacetamide, then adding glycerol dioleate, stirring, adding soybean PC, stirring and dissolving to obtain a first component;
the prescribed proportion of (e) celebrazil is taken as the second component.
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 a specific embodiment, the method further comprises separately storing the first component and the second component, e.g., the first component and the second component are stored separately from each other, respectively, in different container devices (e.g., vials, e.g., penicillin bottles, ampules, etc., or pre-filled syringes, e.g., pre-filled luer lock glass syringes); or the first component and the second component may be separately loaded into different compartments of a dual compartment dispensing device (dual-compartment pre-filled syringe), as described in the context of the present invention, and so forth.
In some embodiments of the invention, the method of preparation of the invention further comprises filter sterilization of the prepared first component and/or second component by passing through a 0.22 μm sterile filtration membrane.
Method for stabilizing pharmaceutical compositions of celebrarphine
In another aspect, the present invention provides a method of stabilizing a pharmaceutical composition of celebrarphine, wherein the pharmaceutical composition comprises:
(a) An acylglycerol is used as a starting material for the preparation of a pharmaceutical composition,
(b) Phosphatidylcholine (PC),
(c) At least one kind of oxygen-containing organic solvent,
(d) At least one of the acids is selected from the group consisting of,
(e) The preparation method comprises the steps of preparing the celecoxib,
the method comprises taking acylglycerol, phosphatidylcholine and part of oxygen-containing organic solvent in the pharmaceutical composition as a first component, and taking the rest of oxygen-containing organic solvent, acid and celebrarphine in the pharmaceutical composition as a second component; alternatively, the acylglycerol, phosphatidylcholine, oxygen-containing organic solvent and acid in the pharmaceutical composition are taken as a first component, and the celecoxib in the pharmaceutical composition is taken as a second component;
the first component and the second component are stored separately and the pharmaceutical composition is mixed with the first component and the second component prior to use.
Further, the content of the celebrazil is 5 to 20 wt%, for example 6 to 15 wt%, 7 to 15 wt%, 8 to 11 wt%, 8 to 10 wt%, 9 to 11 wt% or 10 to 15 wt% and any range therebetween; preferably 7 to 15% by weight.
Further, the sum of the contents of the acylglycerols and the phosphatidylcholines is 40 to 79 wt%, for example, 45 to 75 wt%, 50 to 70 wt%, 49 to 72 wt%, 53 to 68 wt% or 65 to 75 wt% and any range therebetween; preferably 50 to 70% by weight.
Further, the mass ratio of the celebrarphine to the acid is 4-15:1, such as 5-15:1, 7-10:1, 7.5-10:1, 9-10:1, 8-15: 1,4 to 11:1,5 to 11:1 or 5-10:1 and any range therebetween, preferably 7-10:1; the maleic acid content is 0 to 0.2 wt.%, preferably 0 to 0.01 wt.%.
Further, the content of the oxygen-containing organic solvent is 15 to 42 wt%, for example 15 to 40 wt%, 20 to 40 wt%, 25 to 40 wt%, 20 to 30 wt%, 20 to 35 wt%, or 25 to 35 wt% and any range therebetween; by way of illustration, the total amount of the oxygen-containing organic solvents of component (c) is: 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%, or about 40 wt%, etc., and ranges between any two values therein; preferably from 20 to 35% by weight, particularly preferably from 25 to 30% by weight.
Further preferably, when the first component and the second component each contain an oxygen-containing organic solvent, the ratio of the content of the oxygen-containing organic solvent in the first component to the content of the oxygen-containing organic solvent in the second component is (0.5 to 3): 1, such as (1 to 3): 1, (1 to 2): 1, (2 to 3): 1, (0.5 to 1): 1, (0.5 to 2): 1, etc.;
the above weight percentages are relative to the total weight of (a), (b), (c), (d) and (e).
In a specific embodiment, the method of stabilizing a pharmaceutical composition of celebrarphine wherein the acylglycerol content is from 20 to 60 weight percent; for example, 40 to 60 wt%, 50 to 60 wt%, 20 to 50 wt%, 25 to 50 wt%, 30 to 50 wt%, 26 to 47 wt%, 29 to 40 wt%, 25 to 45 wt%, 25 to 35 wt%, 30 to 35 wt%, 25 to 30 wt% or 35 to 40 wt%, etc., and all ranges subsumed therein; further by way of example, the (a) acylglycerols may be present in the pre-formulation in the following amounts: about 20 wt%, about 26 wt%, about 29 wt%, about 30 wt%, about 31 wt%, about 32 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%, about 50 wt%, about 55 wt%, about 56 wt%, or about 60 wt%, etc., and ranges between any two values therein; preferably (a) the content of acylglycerols is from 25 to 50% by weight, more preferably from 30 to 45% by weight; alternatively, (a) the content of the acylglycerol is preferably 40 to 60% by weight, more preferably 50 to 60% by weight; .
In a specific embodiment, the phosphatidylcholine is present in an amount of 4 to 40 wt%, e.g., 4 to 10 wt%, 4 to 8 wt%, 5 to 6 wt%, 20 to 40 wt%, 20 to 35 wt%, 20 to 30 wt%, 22 to 31 wt%, 24 to 30 wt%, 25 to 30 wt%, or 25 to 33 wt% and any range therebetween. By way of further illustration, (b) phosphatidylcholine may be present in the pre-formulation in the following amounts: about 4 wt%, about 5 wt%, about 6 wt%, 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%, or about 40 wt%, etc., and ranges between any two values therein; preferably (b) the content of phosphatidylcholine is 20 to 35 wt%, more preferably 20 to 31 wt%; alternatively, the content of the phosphatidylcholine (b) is 4 to 10 wt%, for example, 4 to 5 wt%, 4 to 8 wt%, 5 to 6 wt%, or 5 to 10 wt%, etc.
In a specific embodiment, the method of stabilizing a pharmaceutical composition of celebrarphine wherein the content of the acylglycerol is 50 to 60 weight percent; the content of the phosphatidylcholine is 4-10 wt%. In another embodiment of the invention, the acylglycerol content is 20 to 50 wt%, preferably 25 to 50 wt%; the content of the phosphatidylcholine is 20 to 40 wt%, preferably 20 to 35 wt%.
In a specific embodiment, the method of stabilizing a pharmaceutical composition of celebrarphine wherein the acylglycerol is selected from glycerol dioleate, the phosphatidylcholine is selected from soy PC, the oxygen-containing organic solvent is N-methylpyrrolidone or N, N-dimethylacetamide, and the acid is selected from at least one of methanesulfonic acid, maleic acid.
In a specific embodiment, a method of stabilizing a pharmaceutical composition of celebrarphine is provided, wherein the pharmaceutical composition comprises:
(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,
the method comprises taking acylglycerol, phosphatidylcholine and part of oxygen-containing organic solvent in the pharmaceutical composition as a first component, and taking the rest of oxygen-containing organic solvent, acid and celebrarphine in the pharmaceutical composition as a second component; or the acylglycerol, the phosphatidylcholine, the oxygen-containing organic solvent and the acid in the pharmaceutical composition are taken as a first component, and the celebrazil in the pharmaceutical composition is taken as a second component;
and the first component and the second component are stored independently, and the first component and the second component are mixed before the pharmaceutical composition is used;
Further, the content of the celebrazil is 5 to 20 wt%, preferably 7 to 15 wt%;
further, the content of the oxygen-containing organic solvent is 15 to 42 wt%, preferably 20 to 35 wt%;
further, the content of the acylglycerol is 50 to 60 weight percent;
further, the content of the phosphatidylcholine is 4-10 wt%;
further, the mass ratio of the celebrarphine to the acid is 4-15:1;
the weight percentages are relative to the total weight of (a), (b), (c), (d) and (e)
Further, when the first component and the second component each contain an oxygen-containing organic solvent, the ratio of the content of the oxygen-containing organic solvent in the first component to the content of the oxygen-containing organic solvent in the second component may be (0.5 to 3): 1, for example, (1 to 3): 1, (1 to 2): 1, (2 to 3): 1, (0.5 to 1): 1, (0.5 to 2): 1, or the like.
In a specific embodiment, the method of stabilizing a pharmaceutical composition of celebrarphine wherein the acylglycerol is selected from glycerol dioleate, the phosphatidylcholine is selected from soy PC, the oxygen-containing organic solvent is N-methylpyrrolidone or N, N-dimethylacetamide, and the acid is selected from at least one of citric acid, methanesulfonic acid or maleic acid.
In a specific embodiment, the method of stabilizing a pharmaceutical composition of celebrarphine wherein the means for separately storing the first component and the second component comprises: storing the first component in a first container and the second component in a second container; preferably, the first container and the second container are each independently selected from a penicillin bottle, an ampoule or a prefilled syringe, the prefilled syringe being single-chambered, further preferably the prefilled syringe being a prefilled luer lock syringe; or the first component and the second component may be stored separately in separate compartments of a dual compartment dispensing device.
In a specific embodiment, the method of stabilizing a pharmaceutical composition of celebrarphine wherein the first component and the second component are stored separately from each other in a penicillin bottle, respectively; or storing the composition in a dual chamber pre-filled syringe comprising a front chamber and a back chamber, storing the first component in the front chamber, storing the second component in the back chamber, or storing the first component in the back chamber, storing the second component in the front chamber; or the first component and the second component are stored separately in a pre-filled syringe, which is a single chamber, preferably a pre-filled luer-lock syringe.
In a specific embodiment, the method of stabilizing a pharmaceutical composition of celebrazil wherein the sum of the contents of (b) phosphatidylcholine and (a) acylglycerol is 45 to 75 wt%, preferably 50 to 70 wt%; the ratio of (b) phosphatidylcholine to (a) acylglycerol is about 0.1 to 1, e.g., 0.1 to 0.3, or 0.4 to 1, or 0.5 to 0.9, or 0.6 to 0.8, or 0.7 to 0.9, or 0.65 to 0.75, etc., by weight.
In a preferred embodiment, the method of stabilizing a pharmaceutical composition of celecoxib wherein the composition after the first component and the second component are uniformly mixed has a viscosity of not higher than 1000cps, preferably not higher than 500cps, or not higher than 400cps, or not higher than 300cps, or not higher than 200cps, or not higher than 100cps at 25 ℃; alternatively, the first component has a viscosity of no more than 1000cps, preferably no more than 500cps, or no more than 400cps, or no more than 300cps, or no more than 200cps, or no more than 100cps at 25 ℃;
Alternatively, the composition of the method after the first component and the second component are mixed uniformly can be injected using one or more needles of the 18G to 25G gauge.
The method for stabilizing the celebrarphine pharmaceutical composition provided by the invention can effectively improve the long-term storage stability of the celebrarphine pharmaceutical composition, has more remarkable advantages on the aspects of chemical stability and physical stability of the celebrarphine pharmaceutical composition in long-term storage, has more remarkable advantages on the aspects of appearance, physical stability, impurity degradation reduction and the like when being placed for 24 hours at room temperature compared with a direct preparation, and has better stability after being placed for 1 month under the condition of accelerating test ((40+/-2 ℃/RH75% +/-5%) and less impurity degradation).
For the method of preformulation of the celebrarphine or stabilization of the pharmaceutical composition of the celebrarphine, the inventors have also studied the option of mixing together the acid with the acylglycerol and the phosphatidylcholine and the oxygen-containing organic solvent as a first component, the remaining oxygen-containing organic solvent with the celebrarphine as a second component, or the acid as a third component, separately; however, the inventors have found that both of these schemes are not optimal, the former running the risk of generating mesylate genotoxic impurities during storage, and the latter not significantly improving the stability of the celebrazil; in the embodiment provided by the invention, the storage of the acid (such as methanesulfonic acid and/or maleic acid) and the celebrane in the same component not only can improve the stability of the celebrane, but also can avoid the problem of the generation of the genotoxic impurities of the methanesulfonate caused by the storage of the acid mixed with the acyl glycerol (such as glycerol dioleate) and the phosphatidylcholine (such as soybean phospholipid), and is also beneficial to improving the stability of the soybean phospholipid; in addition, in the method for stabilizing the celebrazil pre-formulation and the celebrazil pharmaceutical composition provided by the invention, particularly the method for stabilizing the celebrazil pharmaceutical composition by taking the acylglycerol, the phosphatidylcholine and part of the oxygen-containing organic solvent in the pharmaceutical composition as a first component and the rest of the oxygen-containing organic solvent, the acid and the celebrazil in the pharmaceutical composition as a second component, the content of the acid (preferably at least one of methanesulfonic acid and maleic acid) in the composition is allowed to fluctuate within a larger range, and in addition, the pre-formulation of the scheme A or B can also obviously improve the drug loading of the celebrazil, for example, the drug loading is improved to 10-15 wt%, and the pre-formulation can still have good comprehensive performance.
In the present invention, the parameter range selection includes the end values, for example, 5 to 20 wt% includes the end values of "5 wt%" and "20 wt%"; the ratio range of 6 to 10:1 includes "6:1" and "10:1". In particular, when referring to a given numerical value, the terms "about" and "about" indicate that the specified quantity is the primary example, but the actual quantity should not vary significantly from the specified quantity, as judged by one of ordinary skill in the art. Unless the context prohibits, this will typically be + -10%, + -5%, + -3%, + -2%, + -1%, + -0.5% or + -0.05% of the specified value, etc.
"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 …".
"directly formulated formulation" or "direct formulation" in the context of the present invention is to be distinguished from "pre-formulated formulation" in the context of the present invention, which means that all excipients in the formulation are directly mixed together for storage and use at the time of formulation.
Unless otherwise indicated, the weight percentages indicated in the context of the present invention for acylglycerols (e.g., GDO), phosphatidylcholines (e.g., soy PC), oxygenated organic solvents (e.g., NMP or DMAC), acids (e.g., maleic acid, methanesulfonic acid, etc.), and celebrarphines are relative to the total weight of (a), (b), (c), (d), and (e).
When a pre-formulation or pharmaceutical composition is denoted herein as "consisting essentially of certain components", the specified components provide the basic properties of the pre-formulation, such as when the specified components constitute at least 95%, preferably at least 98% of the pre-formulation.
Unless the context prohibits, when the active ingredient, celebuprenorphine, is indicated herein, also disclosed is celebrarphine in the form of any pharmaceutically acceptable salt. Suitable pharmaceutically acceptable salts are well known in the art, such as the salts of halides (especially chlorides), acetates, pamoate, and the like.
Drawings
FIG. 1 shows dissolution profiles of the pre-formulations of celebrazil for prescription 3, prescription 4, prescription 5 and prescription 6 in Table 1;
FIG. 2 shows dissolution profiles of the pre-formulations of celebrazil for prescriptions D801, D802, D804 and D805 in Table 4;
fig. 3: a dissolution profile comparison of the formulation after mixing the first component and the second component of the pre-formulation prescribed as D803 with the directly formulated formulation prescribed as D803L is shown;
Fig. 4: the pharmacokinetic profile of the pre-formulation first component and second component of formulation prescription D803 in table 5.2, directly formulated formulation of prescription D803L in table 5.1, and after administration of a nalyzing solution in SD rats is shown, wherein ordinate Conc (ng/mL) represents nalbuphine blood concentration in: ng/mL;
fig. 5: the pharmacokinetic profiles of prescriptions a06, a07, a08 and the naltrexone in SD rats following administration in table 2 are shown, wherein the ordinate Conc (ng/mL) represents nalbuphine blood concentration in units of: ng/mL;
fig. 6: the pharmacokinetic profile in dogs following administration of the nalbuphine formulation and the naltrexone solution shown in table 8.1, which was formulated as prescription B22, is shown.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
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: nalbuphine (source: minofeine); soybean PC (source: shenyang Tianfeng biopharmaceutical Co., ltd.); glycerol dioleate (source: croda, uk); nalgesic solution (source: shuntian medical technology Co., ltd.);
DMAC refers to N, N-dimethylacetamide, NMP refers to N, N-dimethylpyrrolidone; GDO refers to glycerol dioleate.
Apparatus and method for controlling the operation of a device
A viscometer: SNB-1, shanghai Tianmei;
dissolution instrument: agilent 708-DS;
high performance liquid chromatography: shimadzu LC-20AD liquid chromatograph;
pH meter: mettler Toledo FE-28.
Preparation example 1: a process for the preparation of a pre-formulation of celebuprenorphine:
a first component: adding GDO with a prescribed amount into an oxygen-containing organic solvent (such as N, N-dimethylacetamide or N, N-dimethylpyrrolidone), adding soybean phospholipid (soybean PC), stirring for dissolving, and heating to 40deg.C to speed up the dissolution;
and a second component: adding acid (such as methanesulfonic acid) with a prescription amount into an oxygen-containing organic solvent (such as N, N-dimethylacetamide or N, N-dimethylpyrrolidone), stirring and mixing uniformly, and then adding the celebrazil to dissolve and mix uniformly;
the first and second components were separately stored in 2ml penicillin bottles.
Preparation example 2: method for directly preparing preparation of celebrarphine
Adding acid (such as methanesulfonic acid) with a prescription amount into an oxygen-containing organic solvent (such as N, N-dimethylacetamide or N, N-dimethylpyrrolidone), stirring and mixing uniformly, adding the celebrarphine, dissolving and mixing uniformly, then adding GDO and soybean phospholipid (soybean PC), and stirring to completely dissolve the auxiliary materials.
Example 1: inebrile preformulation prescription and preparation
The preparation of the formulations of celebrarphine was carried out as described in preparation example 1, following the formulation of table 1, and the first and second components of each of the prepared formulations were stored in 2ml penicillin bottles, respectively. Then, the needle penetration and appearance were examined.
The needle-penetrating property and appearance detection method comprises the following steps: the first component and the second component in the celebrazil pre-formulation were mixed uniformly and then allowed to stand for 48 hours, and the appearance and the needle penetration were examined. 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". The test results are shown in Table 1.
Table 1: formulation composition, stability and needle-penetrating properties of a pre-formulation of celebuprofezin
The in vitro dissolution of the pre-formulation of celebuprenorphine prepared in example 1 was further examined. After the first component and the second component in the pre-formulation prepared in example 1 were uniformly mixed, in vitro dissolution test was performed.
The dissolution method comprises the following steps: the USPI method, namely the spin basket method, is adopted, a stainless steel chassis with the diameter of 15mm and the height of 6mm is placed in the right central position of the middle bottom of the basket, the rotating speed is 50rpm, the dissolution medium is phosphate buffer solution with the pH of 6.0 and is added with 0.5 percent SDS, the volume of the dissolution medium is 900mL, 1mL is automatically sampled by filtration respectively 15min, 30min, 60min, 120min, 240min and 300min, and the dissolution curve is calculated by HPLC detection.
The test results are shown in fig. 1, and show that the pre-formulations of the prescription 3, the prescription 4, the prescription 5 and the prescription 6 have good dissolution and release effects.
EXAMPLE 2 preparation of a Inebrile Pre-formulation prescription
The preparation of the pre-formulation of celebrarphine was carried out as described in preparation example 1, following the formulation of table 2, and the first and second components of each pre-formulation prepared were stored separately in 2ml penicillin bottles. Then, needle penetration and viscosity were measured. The method for detecting the needle penetration was the same as in example 1.
The viscosity detection method comprises the following steps: after uniformly mixing the first component and the second component in the celebrazil pre-formulation, the viscosity was measured at normal temperature (25 ℃) using a digital viscometer, wherein the spindle was chosen from spindle number 4 and the rotational speed was chosen from 60rpm. The test results are shown in Table 2.
Table 2: formulation composition, viscosity and needle-penetrating properties of a pre-formulation of celebuprofezin
From the test results in Table 2, it can be seen that the prepared pre-formulations of celebrarphine of the present invention have a viscosity in the range of no more than 400cps and can pass both 18G and 23G internationally standard universal syringe needles, part of the prescription passing through the 27G needle.
Example 3: inebrile preformulation prescription and preparation
The preparation of the pre-formulation of celebrarphine was carried out as described in preparation example 1, following the prescription composition of table 3.1, and the first and second components of each pre-formulation prepared were stored separately in 2ml penicillin bottles. Then, the needle penetration and appearance were measured (the measurement method was the same as in example 1), and the measurement results are shown in Table 3.1.
Table 3.1: needle-penetrating and appearance of the formulation of the pre-formulation of celebrarphine
As can be seen from the detection results in table 3.1, the preparation of the present invention can inhibit the crystallization of the celebrarphine from the preparation to different degrees when the acid is citric acid, methanesulfonic acid, fumaric acid or acetic acid, and can pass 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 comparative study of the crystallization inhibition effect of the fumaric acid and the citric acid on the celebrazil in the pre-formulation shows that the fumaric acid group is relatively weak, and the preparation contains part of crystal particles with larger particle size, so that the needle penetrating property is relatively poorer than that of the methanesulfonic acid group.
Further investigating the effect of methanesulfonic acid and citric acid (anhydrous) on the stability of the celebrazil pre-formulation, the pre-formulations of the respective formulations were prepared according to the formulations listed in table 3.2, with reference to the method described in preparation example 1, and then the first and second components of the N707 and N708 pre-formulations were mixed uniformly and simultaneously placed in an accelerated (40 ℃ ±2 ℃,75% rh±5%) stability test box, stored in a sealed condition, sampled at 1M (1 month) to detect their purity, the purity being determined by HPLC method, and the results are shown in table 3.2 below.
Table 3.2: inebrile preformulation prescription composition and stability detection result
The above results further demonstrate that methanesulfonic acid is more chemically stable to the pre-formulation than citric acid.
The inventors further studied the pre-formulations of 6 prescriptions in table 3.1, and after mixing the first component and the second component, the appearance and HPLC purity of the samples were tested in a stability test box at high temperature of 60 ℃ by sampling at 0W, 1W, 2W and 4W, respectively, and the test results showed that the stability of the formulations N702, N705 and N706 containing methanesulfonic acid was significantly better than the other formulations, in particular in being able to significantly inhibit the generation of degradation impurities, and the HPLC purity was less than the other formulations; in addition, the chemical stability of the formulation comprising citric acid is better than the formulation comprising acetic acid.
Example 4: inebrile preformulation prescription and preparation
The preparation of the formulations of celebrarphine according to the prescription composition of table 4 was carried out as described in preparation example 1, the first and second components of each of the prepared formulations being stored in 2ml penicillin bottles, respectively. Then, the needle penetration and appearance were measured (the measurement method was the same as in example 1), the viscosity was measured (the measurement method was the same as in example 2), and the measurement results were shown in Table 4.
Table 4: formulation composition of pre-formulation of celebrarphine and needle-penetrating property, appearance and viscosity
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As can be seen from the results of the test items in Table 4, the prepared celebrazier pre-formulation has a viscosity of less than 300cps at 25 ℃ by using DMAC as a solvent, and has good physical stability and needle penetration.
Part of the pre-formulations prepared in table 4 were subjected to dissolution investigation, dissolution method: the USPI method, namely the spin basket method, is adopted, a stainless steel chassis with the diameter of 15mm and the height of 6mm is placed in the right central position of the middle bottom of the basket, the rotating speed is 50rpm, the dissolution medium is phosphate buffer solution with the pH value of 7.0 and is added with 0.25 percent SDS, the volume of the dissolution medium is 900mL, 1mL is automatically sampled by filtration respectively 15min, 30min, 60min, 120min, 240min and 300min, and the dissolution curve is calculated by HPLC detection.
The detection result (shown in figure 2) shows that the pre-formulation with DMAC as a solvent and the mass ratio of soybean PC to GDO of 0.5-0.9 and the mass ratio of the celebrarphine to the acid of 5-15:1 has good dissolution and release degrees and has slow release effects.
Stability investigation: after uniformly mixing the first component and the second component of the pre-formulation prepared in table 4, the pre-formulation was placed in a 40 ℃ ± 2 ℃/RH75% ± 5% stability test box for 15 days, 25 ℃ ± 2 ℃/RH60% ± 5% stability test box for 1 month, and in a 2-8 ℃ refrigerator for 1 month, and the properties and purity were measured. Wherein the purity is detected by HPLC method. The detection result shows that after 15 days in a stability test box with the temperature of 40+/-2 ℃ and the RH of 75+/-5%, the color of the pre-preparation is changed from light yellow to be slightly deepened, and the HPLC purity change is less than or equal to 0.5%; after 1 month in a 25 ℃ +/-5 ℃/RH60% +/-10% stability test box and 1 month in a 2-8 ℃ refrigerator, the color of the pre-formulation is not changed visually, the HPLC purity is not changed, and no degradation impurity is generated.
Example 5: comparison of dissolution of directly formulated formulations after mixing with the preformulation
Pharmaceutical compositions of the formulations described in table 5.1 were formulated following the procedure of preparation 2.
Table 5.1: prescription composition of directly prepared preparation
| Material name | D803L | M301L | M302L |
| Saibuprorphine/mg | 150 | 150 | 150 |
| DMAC/mg | 370 | 448 | 440 |
| GDO/mg | 507 | 470 | 470 |
| Soybean PC/mg | 457 | 424 | 424 |
| Methanesulfonic acid/mg | 16 | 8 | 16 |
| Total amount/mg | 1500 | 1500 | 1500 |
The second components of the recipe composition M103 and M105, respectively, and the first component of the recipe composition M108, shown in Table 5.2, were each prepared and stored in 2ml penicillin bottles, respectively, according to the method described in preparation example 1.
TABLE 5.2 preformulation recipe composition
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"/" indicates none.
The formulations prepared in table 5.1 and having the recipe compositions of M301L and M302L, and the second component prepared in table 5.1 and having the recipe composition of M103 and M105, respectively, and the first component sample having the recipe composition of M108 were simultaneously placed in an accelerated (40 ℃ ±2 ℃/RH75% ±5%) stability test chamber, stored under nitrogen-filled and sealed conditions, and sampled and tested for purity on 15 days and 30 days, respectively, and the purity was measured by HPLC, wherein the second component having the recipe composition of M103 and the first component sample having the recipe composition of M108 were uniformly mixed on 15 th and 30 th days, respectively, and then tested for purity, and the test results are shown in table 5.3 below.
Table 5.3: HPLC purity detection result
The first component and the second component of the pre-formulation with the prescription composition D803 in table 4 are uniformly mixed, and the dissolution test is performed on the pre-formulation with the prescription composition D803L directly in table 5.1, the dissolution test method is the same as that of example 4, the test result is shown in fig. 3, and the result shows that the preparation directly prepared from the celebrazier preparation with the same auxiliary materials and content has almost the same drug dissolution curve as the preparation prepared from the pre-formulation (i.e. the first component and the second component are stored separately) and then uniformly mixed, i.e. the preparation directly prepared from the preparation has the same in vitro release behavior and has a slow release effect.
Example 6: needle penetration of pre-formulations and methods of use
Taking the pre-formulation with the prescription composition of D803 as an example, the viscosity of the second component of the pre-formulation and the full prescription after mixing were examined, wherein the viscosity was measured by a micro-viscometer (the measurement method is the same as in example 2), and the needle passing property was measured by passing through the international standard syringe needles 18G, 21G, 23G, 25G, and the time required for sucking 1ml of the liquid medicine and the time required for discharging 1ml of the liquid medicine were examined, respectively. The test results are shown in table 6 below. TABLE 6 full prescription viscosity and needle penetration results after mixing of the second component in the preformulation
The medicine liquid consists of a first component and a second component, each of which is respectively stored in a 2ml penicillin bottle, and the using method of the medicine is designed according to the needle penetration result, the clinical use convenience and the acceptable degree of a patient and the sucking and injecting difficulty of each component as follows:
using a 2ml 18G syringe to suck all the liquid medicine from the second component, transferring the liquid medicine into a penicillin bottle where the first component is located, shaking for 1min, visually observing that the liquid medicine becomes homogeneous liquid medicine, standing for 5min to remove bubbles in the liquid medicine, using a 2ml 18G syringe to suck all the liquid medicine, replacing a syringe needle with a 23G needle, and injecting the liquid medicine into a patient.
Example 7: compatibility stability study of two-component prescriptions in preformulation
The first and second components of the pre-formulation of formulation D803 were mixed and then left to stand at room temperature for 24 hours with the direct formulation of formulation D803L, respectively, to observe the appearance, physical stability and purity, and the purity was measured by HPLC, and the measurement results are shown in table 7.
Table 7: preformulation of prescription D803 and direct formulation test results of D803L
The above results indicate that the appearance, physical stability and degradation of the two components in the pre-formulation within 24 hours after compatibility are nearly identical to those of the direct formulation recipe.
Example 8: prescription and detection result of celebrarphine preparation
Formulations with recipe composition of table 8.1 were prepared as in example 1, respectively. And the prepared straight preparation of the celebrazil is subjected to property, viscosity, needle penetration and crystallization stability detection, and the detection results are respectively shown in the data under the detection items of table 8.1.
Table 8.1: inebrile straight formulation prescription and test item
Test example 1: pharmacokinetic studies
Male SPF-grade SD male rats weighing about 220g were selected and randomly grouped after 4 days of adaptive feeding: the formulations were divided into test pre-formulation (D803, first and second components mixed prior to use) administration groups, direct formulation (D803L) administration groups, and pain relieving administration groups, 2 each. Rats were given subcutaneously (75 mpk per celebrarphine).
Blood is collected from the orbits of rats at 0h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 24h (1 d), 48h (2 d), 72h (3 d), 120h (5 d), 168h (7 d), 216h (9 d), 264h (11 d) and 336h (14 d) respectively, blood samples are centrifuged within 20min after collection to obtain plasma, and the blood samples are 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℃at 6000rpm for 10 minutes. The concentration of nalbuphine in the blood sample was measured by LCMS and PK parameters were calculated. The detection results are shown in FIG. 4. As can be seen from fig. 4, the blood concentration of the pre-formulation and the directly-formulated formulation prepared by the invention is higher than that of the nano-pain solution within 275h, which indicates that the pre-formulation provided by the invention has good analgesic effect and short onset time compared with the nano-pain solution.
Following the same procedure, the pre-formulations of prescription a06, a07 and a08, and the administration of the natto solutions, were tested for pharmacokinetic profiles in rats and the test results are shown in fig. 5. The pharmacokinetic results further show that the preparation provided by the scheme of the invention has immediate effect after administration, can be timely administered after or during operation, has long duration of drug effect, and can reduce administration frequency.
Test example 2: analgesic Effect study
Male SPF-grade SD male rats weighing 180-220 were harvested and adaptively bred for 4 days. 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 base values were again tested 24h post-operatively, with an average grouping such that each set of base values remained as consistent as possible: blank, model, celebrazil pre-formulation (100 mpk), celebrazil pre-formulation (75 mpk), celebrazil pre-formulation (50 mpk), and nalyzed (100 mpk), nalyzed (75 mpk) groups; where the unit mpk refers to milligrams per kilogram (Milligrams Per Kilograms).
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 preparation of the celebrane are subcutaneously administered at the back and the pain relieving solution 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 the mechanical tenderness and footage thresholds (MWT) at 30min, 4h, and 28h after molding, and statistical analysis was performed using a Mann-whisney 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 result shows that 100mpk of the preparation of the invention shows remarkable analgesic effect in 30min, 4h and 28h, and has the advantages of quick acting time and remarkable analgesic effect.
Test example 3: pharmacokinetic studies
Animals and groupings: the male beagle dogs were randomly divided into 2 groups, one group for formulation B22 and one group for pain relief, 3 for each group.
Administration: the hind legs of beagle were given subcutaneously (5 mpk per celebrity).
Sampling and detecting: 0h, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 10h, 24h (1 d), 48h (2 d), 72h (3 d), 96h (4 d), 120h (5 d), 144h (6 d), 168h (7 d), respectively, after administration. Blood is collected from the anterior leg of beagle, blood sample should be 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 assay 5 was performed. The concentration of nalbuphine in the blood sample was measured by LCMS and PK parameters were calculated.
The pharmacokinetic data is shown in fig. 5, and the formulation of prescription B22 has significantly lower peak time (Tmax) of blood concentration after administration compared to the nalyzed formulation, indicating that the formulation of prescription B22 has a faster release rate of heavy drug; the overall exposure of prescription B22 (AUC 0-168) was similar to the pain relief, and the short-term exposure after administration (AUC 0-6) and T1/2 were significantly higher, indicating that the formulation of prescription B22 was faster to interpret than the pain relief, and was able to meet the demand for more premature analgesia.
Claims (23)
1. A pre-formulation of celebrarphine, wherein the pre-formulation comprises a first component and a second component and the first component and the second component are stored separately;
wherein, scheme a: the first component comprises (a) an acylglycerol, (b) a phosphatidylcholine, and (c) an oxygen-containing organic solvent; the second component comprises (c) an oxygen-containing organic solvent, (d) at least one acid, and (e) celebrazil; or,
scheme B: the first component comprises (a) an acylglycerol, (b) a phosphatidylcholine, (c) an oxygen-containing organic solvent, and (d) at least one acid; the second component comprises (e) celebrarphine;
further preferably, the content of the celebrarphine is 5-20 wt%; the sum of the content of the acyl glycerol and the phosphatidylcholine is 40 to 79 weight percent; the mass ratio of the celebrazil to the acid is 4-15:1, and the content 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).
2. A pre-formulation of celebuprenorphine according to claim 1, wherein the sum of the content of acylglycerols and phosphatidylcholine is 49-75 wt%, preferably 50-70 wt%.
3. A pre-formulation of celebuprenorphine according to claim 1, wherein the acylglycerol content is 20 to 60 wt.%; the content of the phosphatidylcholine is 4-40 wt%;
further preferably, the acylglycerol content is 20 to 50 wt%, more preferably 25 to 50 wt%; the content of the phosphatidylcholine is 20 to 40 wt%, more preferably 20 to 35 wt%; or,
further preferably, the content of the acylglycerol is 50 to 60 wt%; the content of the phosphatidylcholine is 4-10 wt%.
4. A pre-formulation of celebrarphine according to claim 1, wherein the content of the celebrarphine is 7-15 wt%;
preferably, the mass ratio of the celebrarphine to the acid is 5-11:1, more preferably 7-10:1;
preferably, the total amount of oxygen-containing organic solvent in the pre-formulation is 15 to 40 wt%, more preferably 20 to 35 wt%;
preferably, the ratio of the content of the oxygen-containing organic solvent in the first component to the content of the oxygen-containing organic solvent in the second component in the embodiment A is (0.5 to 3): 1.
5. A pre-formulation of celebrarphine according to any one of claims 1 to 4, wherein (a) the acylglycerol is a diacylglycerol, a triacylglycerol or a mixture of both, more preferably a diacylglycerol; the acyl groups of the acylglycerols are each independently selected from lauroyl, myristoyl, palmitoyl, phytanoyl, palmitoyl, stearoyl, oleoyl, elaitoyl, linoleoyl, linolenoyl, arachidonoyl, behenoyl or tetracosanoyl, preferably oleoyl;
more preferably (a) the acylglycerol is glycerol dioleate.
6. A pre-formulation of celebuprenorphine according to any one of claims 1 to 5, wherein the phosphatidylcholine of component (b) 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.
7. A pre-formulation of celebrarphine 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, C1-C3 alcohols or benzyl alcohol, selected from at least one of N-methylpyrrolidone, dimethylformamide, 2-pyrrolidone and N, N-dimethylacetamide, preferably N-methylpyrrolidone and/or N, N-dimethylacetamide;
Preferably, 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, more preferably component (d) the acid is at least one of methanesulfonic acid or maleic acid.
8. A pre-formulation of celebuprenorphine according to any one of claims 1 to 5, wherein the first component comprises glycerol dioleate, soy PC and an oxygen-containing organic solvent; the second component comprises an oxygen-containing organic solvent, methanesulfonic acid, and celebrarphine, optionally comprising maleic acid; or,
the first component comprises glycerol dioleate, soy PC, an oxygen-containing organic solvent, methanesulfonic acid, optionally maleic acid; the second component comprises celebrarphine;
wherein the oxygen-containing organic solvent is N-methyl pyrrolidone or N, N-dimethylacetamide.
9. A pre-formulation of celebuprenorphine according to claim 1, wherein the first component comprises glycerol dioleate, soy PC and N, N-dimethylacetamide; the second component comprises N, N-dimethylacetamide, methanesulfonic acid and celebrarphine, optionally comprising maleic acid; or,
the first component comprises glycerol dioleate, soy PC, N-dimethylacetamide and methanesulfonic acid, optionally comprising maleic acid; the second component comprises celebrarphine;
Wherein when the first component and the second component both contain N, N-dimethylacetamide, the ratio of the content of the N, N-dimethylacetamide in the first component to the content of the N, N-dimethylacetamide in the second component is (0.5-3): 1;
the content of the selvedge is 7-15 wt%;
the mass ratio of the celebrarphine to the methanesulfonic acid is 4-15:1; the content of maleic acid is 0 to 0.01 percent;
the content of the N, N-dimethylacetamide is 15-40 wt%;
the content of the glycerol dioleate is 25-50 wt%;
the content of the soybean PC is 20-35 wt%.
10. A pre-formulation of celebuprenorphine according to claim 1, wherein the first component comprises glycerol dioleate, soy PC and N, N-dimethylacetamide; the second component comprises N, N-dimethylacetamide, methanesulfonic acid and celebrarphine, optionally comprising maleic acid; or,
the first component comprises glycerol dioleate, soy PC, N-dimethylacetamide and methanesulfonic acid, optionally comprising maleic acid; the second component comprises celebrarphine;
wherein when the first component and the second component both contain N, N-dimethylacetamide, the ratio of the content of the N, N-dimethylacetamide in the first component to the content of the N, N-dimethylacetamide in the second component is (0.5-3): 1;
The content of the selvedge is 7-15 wt%;
the content of the N, N-dimethylacetamide is 20-35 wt%;
the content of the glycerol dioleate is 50-60 wt%;
the content of the soybean PC is 4-10 wt%;
the mass ratio of the celebrarphine to the methanesulfonic acid is 4-15:1; the content of the maleic acid is 0 to 0.01 percent.
11. A pre-formulation of celebrarphine according to any one of claims 1 to 10, wherein the ratio of (b) phosphatidylcholine to (a) acylglycerol is about 0.1 to 1 by weight.
12. A pre-formulation of celebuprenorphine according to any one of claims 1 to 10, wherein the first component is stored in a first container and the second component is stored in a second container; or the first component and the second component are respectively filled into different compartments of the dual-compartment dispensing device for storage;
further preferably, the first component is stored in a first container and the second component is stored in a second container, each of the first and second containers being independently selected from a penicillin bottle, an ampoule or a prefilled syringe, preferably a prefilled luer lock syringe;
alternatively, the celebrarphine pre-formulation is stored in a dual chamber pre-filled syringe comprising a front chamber and a back chamber, the first component is stored in the front chamber, the second component is stored in the back chamber, or the first component is stored in the back chamber, the second component is stored in the front chamber;
Preferably, the pre-formulation of the celebrarphine is mixed homogeneously with the first component and the second component before use.
13. A pre-formulation of celebrarphine according to any one of claims 1 to 12, wherein the composition of the pre-formulation after homogeneous mixing of the first component and the second component has a viscosity of not higher than 1000cps, such as a viscosity of 10 to 1000cps, or a viscosity of 30 to 500cps, or a viscosity of 40 to 400cps at 25 ℃; alternatively, the first component of the pre-formulation has a viscosity of no more than 1000cps at 25 ℃, for example, a viscosity of 10 to 1000cps, or a viscosity of 30 to 500 cps;
alternatively, the composition of the pre-formulation after the first component and the second component are mixed uniformly can be injected using one or more needles of the 18G to 27G gauge.
14. A pre-formulation of celebrarphine according to any one of claims 1 to 13, wherein the total volume of the pre-formulation after mixing of the first component and the second component is 0.1 to 3ml, preferably 0.5 to 2ml; it is further preferred that the pre-formulation contains 100 to 200mg, more preferably 150mg of celebrarphine.
15. Use of a pre-formulation of celebrarphine according to any one of claims 1 to 14 for the manufacture of a medicament for the treatment of pain, preferably selected from surgical pain or chronic pain; further preferably, the surgical operation includes hernia operation, hemorrhoid operation, abdominal operation, plastic operation, orthopedic operation, otorhinolaryngological operation; the chronic pain includes cancer pain, chronic back pain, and chronic joint pain.
16. A disposable drug delivery device, characterized in that it comprises a standard dose pre-filled pre-formulation of celebrarphine according to any one of claims 1 to 14;
further preferably, the drug delivery device comprises a first container and a second container, wherein the first component of the celebrazil pre-formulation is stored in the first container and the second component is stored in the second container, preferably the first container and the second container are each independently selected from a penicillin bottle, an ampoule or a prefilled syringe, said prefilled syringe being single-chambered, preferably said prefilled syringe being a prefilled luer lock syringe;
or the drug delivery device comprises a double-chamber pre-filled and sealed injector, wherein the first component and the second component in the pre-formulation of the celebrazil are respectively arranged in two same chambers of the double-chamber pre-filled and sealed injector.
17. A kit for administration of a celebrazil pre-formulation, said kit comprising a celebrazil pre-formulation according to any one of claims 1 to 14; or the kit comprises the drug delivery device of claim 16;
further preferably, the kit further comprises a needle having a needle opening of 18G and/or less, one or more of the needles having a needle opening of 23G and/or less, optionally together with instructions for use.
18. The pre-formulation of celebrarphine according to any one of claims 1 to 14, or the administration device according to claim 16, or the kit according to claim 17, wherein the pre-formulation is a single dose; preferably, 50 to 200mg, more preferably 100 to 150mg of celebrarphine are included.
19. A method of stabilizing a pharmaceutical composition of celebrarphine, said pharmaceutical composition comprising:
(a) An acylglycerol is used as a starting material for the preparation of a pharmaceutical composition,
(b) A phosphatidylcholine group, which is a compound of phosphatidylcholine,
(c) At least one kind of oxygen-containing organic solvent,
(d) At least one of the acids is selected from the group consisting of,
(e) The preparation method comprises the steps of preparing the celecoxib,
the method comprises taking acylglycerol, phosphatidylcholine and part of oxygen-containing organic solvent in the pharmaceutical composition as a first component, and taking the rest of oxygen-containing organic solvent, acid and celebrarphine in the pharmaceutical composition as a second component; alternatively, the acylglycerol, phosphatidylcholine, oxygen-containing organic solvent and acid in the pharmaceutical composition are taken as a first component, and the celecoxib in the pharmaceutical composition is taken as a second component;
the first component and the second component are respectively and independently stored, and the first component and the second component are mixed before the pharmaceutical composition is used;
further, the content of the celebrazil is 5 to 20 wt%, preferably 7 to 15 wt%;
Further, the sum of the content of the acylglycerol and the content of the phosphatidylcholine is 40 to 79 weight percent;
further, the mass ratio of the celebrarphine to the acid is 4-15:1;
further, the content of the oxygen-containing organic solvent is 15 to 42 wt%, preferably 20 to 35 wt%;
further, when the first component and the second component both contain an oxygen-containing organic solvent, the ratio of the content of the oxygen-containing organic solvent in the first component to the content of the oxygen-containing organic solvent in the second component is (0.5-3): 1;
further, the content of the acylglycerol is 50 to 60 weight percent, and the content of the phosphatidylcholine is 4 to 10 weight percent; or the content of the acyl glycerol is 25-50 wt%, and the content of the phosphatidylcholine is 20-35 wt%;
the weight percentages are relative to the total weight of (a), (b), (c), (d) and (e).
20. The method of claim 19, wherein the pharmaceutical composition comprises:
(a) An acylglycerol is used as a starting material for the preparation of a pharmaceutical composition,
(b) A phosphatidylcholine group, which is a compound of phosphatidylcholine,
(c) At least one kind of oxygen-containing organic solvent,
(d) At least one of the acids is selected from the group consisting of,
(e) The preparation method comprises the steps of preparing the celecoxib,
the method comprises taking acylglycerol, phosphatidylcholine and part of oxygen-containing organic solvent in the pharmaceutical composition as a first component, and taking the rest of oxygen-containing organic solvent, acid and celebrarphine in the pharmaceutical composition as a second component; or the acylglycerol, the phosphatidylcholine, the oxygen-containing organic solvent and the acid in the pharmaceutical composition are taken as a first component, and the celebrazil in the pharmaceutical composition is taken as a second component;
And the first component and the second component are stored independently, and the first component and the second component are mixed before the pharmaceutical composition is used;
the content of the celebrarphine is 7-15 wt%;
the content of the oxygen-containing organic solvent is 20 to 35 weight percent;
the content of the acyl glycerol is 50-60 wt%;
the content of the phosphatidylcholine is 4-10 wt%;
the mass ratio of the celebrarphine to the acid is 7-10:1;
the weight percentages are relative to the total weight of (a), (b), (c), (d) and (e);
further, when the first component and the second component each contain an oxygen-containing organic solvent, the ratio of the content of the oxygen-containing organic solvent in the first component to the content of the oxygen-containing organic solvent in the second component is (0.5 to 3): 1.
21. The method according to any one of claims 19 to 20, wherein the acylglycerol is selected from glycerol dioleate, the phosphatidylcholine is selected from soy PC, the oxygen-containing organic solvent is N-methylpyrrolidone or N, N-dimethylacetamide, and the acid is selected from at least one of citric acid, methanesulfonic acid or maleic acid.
22. The method of any one of claims 19 to 20, wherein the first component is stored in a first container and the second component is stored in a second container; or the first component and the second component are respectively filled into different compartments of the dual-compartment dispensing device for storage;
Further preferably, the first component is stored in a first container and the second component is stored in a second container, the first container and the second container being each independently selected from a penicillin bottle, an ampoule or a pre-filled syringe, the pre-filled syringe being single-chambered, preferably the pre-filled syringe being a pre-filled luer lock syringe; the composition is stored either in a dual chamber pre-filled syringe comprising a front chamber and a back chamber, the first component is stored in the front chamber, the second component is stored in the back chamber, or the first component is stored in the back chamber, the second component is stored in the front chamber.
23. A process for the preparation of a pre-formulation of celebrarphine as defined in any one of claims 1 to 14, comprising the steps of:
a first component: adding the acyl glycerol with the prescription amount into an oxygen-containing organic solvent, adding phosphatidylcholine, stirring for dissolution, and optionally heating to 40+/-5 ℃;
and a second component: adding the acid with the prescription amount into the oxygen-containing organic solvent, stirring and mixing uniformly, and then adding the celebrazil to dissolve and mix uniformly; storing the first component and the second component separately; preferably, the first component and the second component are stored separately in penicillin bottles.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210996175 | 2022-08-19 | ||
| CN2022109961757 | 2022-08-19 | ||
| CN2023100306980 | 2023-01-10 | ||
| CN202310030698 | 2023-01-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117582440A true CN117582440A (en) | 2024-02-23 |
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ID=89915626
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311048042.8A Pending CN117582440A (en) | 2022-08-19 | 2023-08-18 | Method for stabilizing pharmaceutical compositions |
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| Country | Link |
|---|---|
| CN (1) | CN117582440A (en) |
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2023
- 2023-08-18 CN CN202311048042.8A patent/CN117582440A/en active Pending
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