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US20090281177A1 - Butylphthalide Intravenous Emulsion and Application Thereof - Google Patents

Butylphthalide Intravenous Emulsion and Application Thereof Download PDF

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Publication number
US20090281177A1
US20090281177A1 US12/086,665 US8666506A US2009281177A1 US 20090281177 A1 US20090281177 A1 US 20090281177A1 US 8666506 A US8666506 A US 8666506A US 2009281177 A1 US2009281177 A1 US 2009281177A1
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United States
Prior art keywords
oil
butylphthalide
mixture
emulsion according
amount
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US12/086,665
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English (en)
Inventor
Chunshun Zhao
Zhanqi Niu
Zhen Chen
Haibo Guo
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SHIJIAZHUAN PHARMA GROUP NBP PHARMACEUTICAL Co Ltd
Shijiazhuang Pharma Group NBP Pharmaceutical Co Ltd
Original Assignee
SHIJIAZHUAN PHARMA GROUP NBP PHARMACEUTICAL Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SHIJIAZHUAN PHARMA GROUP NBP PHARMACEUTICAL Co Ltd filed Critical SHIJIAZHUAN PHARMA GROUP NBP PHARMACEUTICAL Co Ltd
Assigned to SHIJIAZHUANG PHARMA GROUP NBP PHARMACEUTICAL CO., LTD. reassignment SHIJIAZHUANG PHARMA GROUP NBP PHARMACEUTICAL CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ZHAO, CHUNSHUN, CHEN, ZHEN, GUO, HAIBO, NIU, ZHANQI
Publication of US20090281177A1 publication Critical patent/US20090281177A1/en
Abandoned legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a butylphthalide preparation, and specifically to a butylphthalide intravenous emulsion and application thereof.
  • NBP dl-3-n-Butylphthalide
  • 1-3-n-Butylphthalid is extracted from celery seeds.
  • NBP acts on multiple steps of cerebral ischemia procedure, such as reducing infarct area after focal cerebral ischemia, increasing cerebral blood flow in ischemic area and improving microcirculation in cerebral ischemic area, protecting mitochondrial function, alleviating damage to nerve function, and improving cerebral energy metabolism after total cerebral ischemia.
  • butylphthalide preparations available in market are only soft capsules. Since butylphthalide is of an oily liquid form, it can be dissolved in an oil phase or directly processed to form an emulsion, then can be packaged in hard capsules or soft capsules, or can be orally administered directly. However, butylphthalide has a relatively apparent first pass effect which leads to a relatively low bioavailability.
  • cerebral ischemia patients usually are integrated with dysphagia or coma, so that capsules cannot meet the clinical requirements for these patients. For cerebral ischemia patients, time is life. Therefore, it is vital to develop a new delivery system suitable for clinical application.
  • butylphthalide is an oily liquid and hardly dissoluble in water
  • a specific manufacture technology is employed in the present invention to process butylphthalide into an emulsion for intravenous administration.
  • the butylphthalide intravenous emulsion of the present invention has the following advantages: the drug directly enters into systemic circulation, thus resulting in quick action; the solubility of butylphthalide is improved, resulting in a reduced dosage; and/or the targeting of butylphthalide to brain tissue is improved, thus reducing its toxic side-effects.
  • the emulsion of the present invention has a particle size of between 10 and 2000 nm, and may be administered via intravenous injection or infusion in order to achieve quick action and brain targeting effect.
  • the butylphthalide intravenous emulsion of the present invention comprises butylphthalide or derivatives thereof as an active ingredient in an amount of 0.01 ⁇ 50 wt %, preferably 0.01 ⁇ 20 wt %, more preferably 0.01 ⁇ 10 wt %, and an excipient in an amount of 50 ⁇ 99.99 wt %, preferably 80 ⁇ 99.9 wt %, more preferably 90 ⁇ 99.5 %, based on the total weight of the emulsion.
  • the excipient comprises an oil phase, an aqueous phase, an emulsifier, a stabilizer and/or an osmoregulation agent.
  • Butylphthalide or derivatives thereof may be either a raceme of butylphthalide or derivatives thereof, or l-butylphthalide or derivatives thereof.
  • the excipient may comprise an oil phase in an amount of 0 ⁇ 50 wt %, preferably 0.1 ⁇ 40 wt %, an aqueous phase in an amount of 50 ⁇ 98 wt %, preferably 60 ⁇ 97 wt %, an emulsifier in an amount of 0.01 ⁇ 50 wt %, preferably 0.5 ⁇ 10 wt %, a stabilizer in an amount of 0 ⁇ 50 wt %, preferably 0 ⁇ 15 wt %, and an osmoregulation agent in an amount of 0 ⁇ 10 wt %, all based on the total weight of the excipient.
  • the process for manufacture of the butylphthalide intravenous emulsion of the present invention comprises the steps of, such as preparing a primary emulsion, homogenizing, sterilizing and quality controlling.
  • the step of preparing the primary emulsion is carried out by utilizing ultrasonic method or high-speed shearing method (FA25 Model High Shear Emulsifying Machine, FLUKO Equipment Shanghai Co., Ltd.).
  • the step of homogenizing is carried out by utilizing a two-stage high pressure emulsifying and homogenizing method (Niro-Soavi NS1001L Model High Pressure Homogenizer and Avestin EmulsiFlex-C5 High Pressure Homogenizer) or microfluidizing technology.
  • the step of sterilizing is carried out by using high pressure sterilizing under rotation.
  • the quality controlling is mainly carried out by measuring particle size.
  • the oil phase generally has an amount in mass of 0 ⁇ 50% (w/v). It is required in the present invention that a therapeutically effective amount of drug should be dissolved in a relatively small amount of oil phase, no drug precipitate occurs or no layer separation occurs under cryogenic storage condition, and in the meantime a stable emulsion is able to be formed with an aqueous phase in the presence of an emulsifier.
  • the oil phase as used in the present invention may be a natural vegetable oil with long chain fatty acid ester groups or a vegetable oil or fatty acid ester being subjected to structure modification and hydrolysis.
  • the examples of those may be one of or a mixture of soybean oil (especially in injection grade), castor oil, tea-seed oil, peanut oil, cottonseed oil, sesame oil, rape oil, safflower oil, olive oil, coconut oil, palm oil and cacao oil; or may be a glyceride with a chain length of C 6 ⁇ C 12 fatty acid, such as but not limited to Arlacel 80, Arlacel 86, Capmul MCM, Captex 200 (oil), Captex 355 (oil), Miglyol 812 (oil), Myvacet (oil), Myverol 18-92, glyceride oleate, glyceride linoleate, macrogol glyceryl laurate, ethyl oleate, ethyl linoleate, caprylocaproyl triglyceride, and a mixture thereof; or may be a mixture of the above long chain fatty acid esters and medium-chain fatty acid est
  • oils may also be used in the present invention:
  • the emulsifier as used in the present invention may be one of or a mixture of nonionic surfactants and anionic surfactants.
  • the preferred emulsifier may be but not limited to one of or a mixture of soybean lecithin or modified soybean lecthin (natural or synthesized), ovolecithin or modified ovolecithin (natural or synthesized), Ophase 31, Poloxamer 108, Poloxamer 188, Poloxamer 407, polyoxyethylene (hydrogenated) castor oil, water soluble VE (TPGS), Solutol HS-15, PEG-400 monostearate, PEG-1750 monostearate, Tween-80, Tween-20, and Span-20.
  • the preferred emulsifier has relatively little haemolysis effect and is refined.
  • the following may also be used in the butylphthalide emulsion of the present invention:
  • Suitable stabilizer as used in the present invention may be but not limited to one of or a mixture of oleic acid, sodium oleate, sodium caprylate, cholesterol, cholic acid, deoxycholic acid and sodium salt thereof, vitamin A, vitamin C, and vitamin E.
  • Suitable osmoregulation agent as used in the present invention may be but not limited to one of or a mixture of sodium chloride, glucose, sorbitol, xylitol, mannitol, and glycerol.
  • the ratio of butylphthalide:oil phase:emulsifier:aqueous phase:stabilizer:osmoregulation agent is any ratio (by weight) within the range of 0.01 ⁇ 50 wt %:0 ⁇ 50 wt %:0.01 ⁇ 50 wt %:50 ⁇ 98 wt %:0 ⁇ 50 wt %:0 ⁇ 10 wt %.
  • the butylphthalide intravenous emulsion of the present invention has the following composition:
  • composition (g) Butylphthalide 10 Soybean lecithin 12 Soybean oil 100 Vitamin E 1 Sorbitol 25 Water for injection Added to 1000 ml
  • the preparation process comprises the steps of: butylphthalide, vitamin E and soybean oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60° C. water bath. Soybean lecithin and sorbitol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60° C. water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min. Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is 100 MPa and the second stage pressure is 10 MPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121° C. for 15 min. Nitrogen gas is fed for protection during the whole process.
  • composition (g) Butylphthalide 15 Castor oil 100 Soybean lecithin 12 Poloxamer 188 6 Glycerol 25 Oleic acid 10 Water for injection Added to 1000 ml
  • the preparation process comprises the steps of: butylphthalide, soybean lecithin, oleic acid and castor oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60° C. water bath. Poloxamer 188 and glycerol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60° C. water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min.
  • the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is 100 MPa and the second stage pressure is 10 MPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121° C. for 15 min. Nitrogen gas is fed for protection during the whole process.
  • composition (g) Butylphthalide 20 Soybean lecithin 12 Olive oil 100 Cholic acid 1 Mannitol 20 Water for injection Added to 1000 ml
  • the preparation process comprises the steps of: butylphthalide, cholic acid and olive oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60° C. water bath. Soybean lecithin and mannitol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60° C. water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was treated with ultrasonic waves for 10 times (10 seconds for each time, power: 400W). Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is 100 MPa and the second stage pressure is 10 MPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121° C. for 15 min. Nitrogen gas is fed for protection during the whole process.
  • composition (g) Butylphthalide 25 Cottonseed oil 100 Ovolecithin 12 Poloxamer 188 20 Glycerol 25 Sodium oleate 10 Water for injection Added to 1000 ml
  • the preparation process comprises the steps of: butylphthalide, ovolecithin, sodium oleate and cottonseed oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60° C. water bath. Poloxamer 188 and glycerol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60° C. water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min.
  • the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is 100 MPa and the second stage pressure is 10 MPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121° C. for 15 min. Nitrogen gas is fed for protection during the whole process.
  • composition (g) Butylphthalide 30 Soybean lecithin 12 Soybean oil 200 Tween 80 6 Vitamin E 8 Xylitol 100 Water for injection Added to 1000 ml
  • the preparation process comprises the steps of: butylphthalide, Tween 80, vitamin E and soybean oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60° C. water bath. Soybean lecithin and xylitol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60° C. water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min. Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is 100 MPa and the second stage pressure is 10 MPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121° C. for 15 min. Nitrogen gas is fed for protection during the whole process.
  • composition (g) Butylphthalide 40 Caprylocaproyl triglyceride 200 Soybean lecithin 12 Poloxamer 188 20 Glycerol 25 Oleic acid 10 Water for injection Added to 1000 ml
  • the preparation process comprises the steps of: butylphthalide, soybean lecithin, oleic acid and caprylocaproyl triglyceride were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60° C. water bath. Poloxamer 188 and glycerol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60° C. water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min.
  • the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is 100 MPa and the second stage pressure is 10 MPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121° C. for 15 min. Nitrogen gas is fed for protection during the whole process.
  • composition (g) Butylphthalide 50 Soybean lecithin 15 Sesame oil 100 Vitamin E 8 Glycerol 22.5 Water for injection Added to 1000 ml
  • the preparation process comprises the steps of butylphthalide, vitamin E and sesame oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60° C. water bath. Soybean lecithin and glycerol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60° C. water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min. Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is 100 MPa and the second stage pressure is 10 MPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121° C. for 15 min. Nitrogen gas is fed for protection during the whole process.
  • composition (g) Butylphthalide 20 Soybean oil 100 Ovolecithin 12 Poloxamer 188 20 Glycerol 25 Sodium oleate 10 Water for injection Added to 1000 ml
  • the preparation process comprises the steps of butylphthalide, ovolecithin, sodium oleate and soybean oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60° C. water bath. Poloxamer 188 and glycerol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60° C. water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min.
  • the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is 100 MPa and the second stage pressure is 10 MPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121° C. for 15 min. Nitrogen gas is fed for protection during the whole process.
  • composition (g) Butylphthalide 100 Ovolecithin 20 Poloxamer 188 20 Glycerol 25 Sodium oleate 30 Water for injection Added to 1000 ml
  • the preparation process comprises the steps of: butylphthalide, ovolecithin and sodium oleate were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60° C. water bath. Poloxamer 188 and glycerol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60° C. water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min. Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is 100 MPa and the second stage pressure is 10 MPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121° C. for 15 min. Nitrogen gas is fed for protection during the whole process.
  • composition (g) Butylphthalide 0.1 Soybean oil 100 Ovolecithin 19 Poloxamer 188 25 Glycerol 25 Water for injection Added to 1000 ml
  • the preparation process comprises the steps of butylphthalide, ovolecithin and soybean oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60° C. water bath. Poloxamer 188 and glycerol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60° C. water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min. Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is 100 MPa and the second stage pressure is 10 MPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121° C. for 15 min. Nitrogen gas is fed for protection during the whole process.
  • composition (g) Butylphthalide 5 Soybean oil 100 Ovolecithin 12 Poloxamer 188 20 Sodium oleate 3 Water for injection Added to 1000 ml
  • the preparation process comprises the steps of: butylphthalide, ovolecithin, sodium oleate and soybean oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60° C. water bath. Poloxamer 188 was weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60° C. water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min. Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is 100 MPa and the second stage pressure is 10 MPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121° C. for 15 min. Nitrogen gas is fed for protection during the whole process.

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US12/086,665 2005-12-16 2006-12-15 Butylphthalide Intravenous Emulsion and Application Thereof Abandoned US20090281177A1 (en)

Applications Claiming Priority (3)

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CN200510102355.2 2005-12-16
CNB2005101023552A CN100367951C (zh) 2005-12-16 2005-12-16 丁苯酞静脉乳剂及其应用
PCT/CN2006/003434 WO2007068212A1 (fr) 2005-12-16 2006-12-15 Emulsion intraveineuse de butylbenzene phtaleine et son application

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US9504751B2 (en) 2014-04-24 2016-11-29 Everfront Biotech Inc. Stable pharmaceutical composition
CN114886848A (zh) * 2022-05-20 2022-08-12 山东泰合医药科技有限公司 一种纳米胶束组合物制备方法及制备的纳米胶束组合物
CN115177614A (zh) * 2021-04-01 2022-10-14 长春藤生物科技股份有限公司 正丁基苯酞的应用
CN116459224A (zh) * 2023-05-15 2023-07-21 济南大学 一种丁苯酞纳米脂质体冻干粉针剂及其制备方法
WO2024250546A1 (zh) * 2023-06-08 2024-12-12 华北制药集团新药研究开发有限责任公司 7-羟基-丁苯酞纳米乳制剂、其制备方法及应用

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ES2609640T3 (es) * 2009-08-14 2017-04-21 Opko Health, Inc Formulaciones intravenosas de rolapitant
CN102178643B (zh) * 2011-04-29 2014-05-14 石药集团恩必普药业有限公司 一种丁苯酞或其衍生物的微乳透皮凝胶剂及其制备方法
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CN103505409B (zh) * 2012-06-27 2017-12-26 石药集团中奇制药技术（石家庄）有限公司 一种丁苯酞注射液及其制备方法
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