WO2023016237A1 - 普那布林或其制剂中的杂质及其用途 - Google Patents

普那布林或其制剂中的杂质及其用途 Download PDF

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WO2023016237A1
WO2023016237A1 PCT/CN2022/107702 CN2022107702W WO2023016237A1 WO 2023016237 A1 WO2023016237 A1 WO 2023016237A1 CN 2022107702 W CN2022107702 W CN 2022107702W WO 2023016237 A1 WO2023016237 A1 WO 2023016237A1
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plinabulin
compound
composition
formula
preparation
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PCT/CN2022/107702
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English (en)
French (fr)
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何成江
张丹扬
毛建民
杜丽华
黄岚
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大连万春布林医药有限公司
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Priority to CN202280054900.7A priority Critical patent/CN117940418A/zh
Publication of WO2023016237A1 publication Critical patent/WO2023016237A1/zh

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/86—Signal analysis

Definitions

  • the invention belongs to the field of medicine, and in particular relates to impurities in plinabulin or its preparations and uses thereof.
  • Plinabulin ((3Z,6Z)-3-[(5-tert-butyl-1H-imidazol-4-yl)methylene]-6-(benzylidene)-2,5-piperazine di Keto
  • phenylahistin a synthetic analogue of the diketopiperazine phenylahistin (phenylahistin) found in marine and terrestrial species of Aspergillus, the structure of which is shown below:
  • Plinabulin is structurally distinct from colchicine and its combretastatin-like analogs (eg, compretastatin phosphate) and at the colchicine-binding site on the tubulin monomer or its vicinity.
  • combretastatin-like analogs eg, compretastatin phosphate
  • plinabulin induces tubulin depolymerization and monolayer permeability in vascular endothelial cells at low concentrations compared with colchicine and have shown that plinabulin induces apoptosis in Jurkat leukemia cells Death.
  • Studies of Plinabulin as a single agent in patients with advanced malignancies lung, prostate and colon cancer demonstrated favorable pharmacokinetic, pharmacodynamic and safety profiles.
  • Impurity research is an important part of drug research and development, which runs through the entire process of drug research and development and directly affects the safety, effectiveness and quality controllability of drugs.
  • the quality control of drugs is mainly to control the content of active ingredients and related substances, especially the content of related substances needs to meet the pharmaceutical requirements, and the impurities mainly come from the synthesis process and drug degradation.
  • a high-purity impurity is required to be used as a reference substance to control the quality of the drug that may contain the impurity. Therefore, providing a plinabulin impurity standard is of great significance to the quality control of plinabulin or its pharmaceutical composition.
  • the object of the present invention is to provide a plinabulin impurity, its preparation method, and its application in drug quality control.
  • the first aspect of the present invention provides a compound of formula I
  • the second aspect of the present invention provides a composition, wherein the composition comprises i) plinabulin and ii) the compound of formula I described in the first aspect.
  • the composition comprises: (a) a safe and therapeutically effective amount of plinabulin polymorphs or pharmaceutically acceptable salts thereof, and (b) pharmaceutically acceptable carriers and diluents , an excipient, or a combination thereof.
  • the diluent includes 15-hydroxy polyethylene glycol stearate.
  • the diluent includes propylene glycol.
  • the diluent includes 15-hydroxy polyethylene glycol stearate and propylene glycol.
  • the diluent is 15-hydroxypolyethylene glycol stearate and propylene glycol, wherein, 15-hydroxypolyethylene glycol stearate is about 40% by weight and propylene glycol is about 60% by weight. weight%.
  • the mass ratio of plinabulin to the compound of formula I is 1-10000:10000-1.
  • the content of Plinabulin ranges from 0.01% to 99.99%.
  • the third aspect of the present invention provides a pharmaceutical composition, wherein the pharmaceutical composition comprises i') the composition as described in the second aspect and ii') a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may be injection, tablet, capsule, aerosol, suppository, film, drop pill, external liniment, controlled release or sustained release or nano-preparation.
  • the single dose of the composition is about 1 mg to about 300 mg.
  • the inert solvent is selected from: ethanol, ethylene glycol, DMSO, DMF, or combinations thereof.
  • the acid is HCl, HAc, or a combination thereof.
  • reaction temperature is 40-80°C, preferably 50-60°C.
  • the molar ratio of acid to plinabulin is 200:1-20:1, preferably 100:1-15:1.
  • the oxidizing agent is selected from: peroxide, oxygen, or a combination thereof.
  • the fifth aspect of the present invention provides a use of the compound of formula I described in the first aspect, wherein the compound is used as a standard for quality control of plinabulin bulk drug or its preparation.
  • control is to measure the content of the compound of formula I in the plinabulin bulk drug or its preparation by high performance liquid chromatography, and calculate it by area normalization method.
  • FIG. 1 shows the HPLC profiles of Plinabulin formulations
  • FIG. 1 shows the HPLC spectrum of Plinabulin bulk drug after acid degradation.
  • FIG. 3 shows the H NMR spectrum of the impurity in Plinabulin.
  • FIG. 4 shows the mass spectrum of Plinabulin impurities.
  • the inventors unexpectedly discovered for the first time a plinabulin preparation impurity, which also produced corresponding impurities in the acid degradation experiment of plinabulin bulk drug.
  • the inventor destroys the plinabulin bulk drug under neutral and acidic conditions in the presence of an oxidant, and separates and purifies it to obtain the plinabulin impurity.
  • the present invention has been accomplished.
  • RT retention time
  • RRT means relative retention time
  • API means a stock solution
  • NPI-2602 The structure of NPI-2602 is shown below
  • the plinabulin composition of the present invention refers to a composition comprising plinabulin and a compound of formula I.
  • the mass ratio of Plinabulin to the compound of formula I is 1-10000:10000-1, preferably 1:1000 to 1000:1; more preferably 1:500 to 500:1; more preferably Earth, 1:100 to 100:1.
  • the content of Plinabulin is in the range of 0.01% to 99.99%, based on the total weight of the composition; preferably 0.1% to 99.9%; more preferably 99.80% to 99.99%; more preferably 99.90% to 99.95% .
  • the content of plinabulin impurities ranges from 0.01% to 99.99%, based on the total weight of the composition; preferably 0.1% to 99.9%; more preferably 0.20% to 0.01%; more preferably 0.1 % to 0.05%.
  • the compositions may also include one or more pharmaceutically acceptable diluents.
  • a pharmaceutically acceptable diluent may include (15-hydroxypolyethylene glycol stearate, kolliphor).
  • the pharmaceutically acceptable diluent may include propylene glycol.
  • pharmaceutically acceptable diluents may include kolliphor and propylene glycol.
  • the pharmaceutically acceptable diluent can include kolliphor and propylene glycol, wherein the kolliphor is about 40% by weight and the propylene glycol is about 60% by weight, based on the total weight of the diluent.
  • the composition may also include one or more other pharmaceutically acceptable excipients.
  • some embodiments include a pharmaceutical composition comprising: (a) a safe and therapeutically effective amount of plinabulin polymorph or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier, diluent , an excipient, or a combination thereof.
  • embodiments include the co-administration of the plinabulin polymorph and the additional therapeutic agent in separate compositions or in the same composition. Accordingly, some embodiments include a first pharmaceutical composition and a second pharmaceutical composition, wherein the first pharmaceutical composition comprises: (a) a safe and therapeutically effective amount of a polymorph of plinabulin or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof; and a second pharmaceutical composition comprising: (a) a safe and therapeutically effective amount of an additional therapeutic agent and (b) a pharmaceutically acceptable carrier , diluent, excipient or combination thereof.
  • Some embodiments include a pharmaceutical composition
  • a pharmaceutical composition comprising: (a) a safe and therapeutically effective amount of a polymorph of plinabulin or a pharmaceutically acceptable salt thereof; (b) a safe and therapeutically effective amount of an additional therapeutic agent; and (c) a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • the dosage form of the pharmaceutical composition of the present invention includes (but not limited to): injection, tablet, capsule, aerosol, suppository, film, drop pill, external liniment, controlled-release or sustained-release or nano-preparation.
  • Administration of the pharmaceutical compositions described herein may be via any acceptable means of administering agents (for similar uses), including, but not limited to, oral, sublingual, buccal, subcutaneous, intravenous, intranasal, topical, Transdermal, intradermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular. Oral and parenteral administration are commonly used in the treatment of indications which are the subject of preferred embodiments.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art.
  • the use of such media or agents in therapeutic compositions is contemplated, except for any conventional media or agents that are incompatible with the active ingredient.
  • various adjuvants commonly used in the art for example, may be included. Considerations for including various components in pharmaceutical compositions are described, e.g., in Gilman et al. (eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Edition, Pergamon Press, which is incorporated by reference in its entirety This article.
  • substances that can be used as pharmaceutically acceptable carriers or components thereof are: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethylcellulose Sodium, ethylcellulose, and methylcellulose; powdered gum tragacanth; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil , olive oil, corn oil and cocoa butter; polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifiers such as TWEENS; wetting agents such as sodium lauryl sulfate; Coloring agents; flavoring agents; tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphat
  • compositions described herein are preferably presented in unit dosage form.
  • a "unit dosage form" is a composition containing an amount of a compound or composition suitable for administration in a single dosage to an animal, preferably a mammalian subject, in accordance with good medical practice.
  • a single dosage form or unit dosage form does not mean that the dosage form is administered once per day or once per course of treatment.
  • the dosage form is contemplated to be administered once, twice, three times or more per day, and may be administered as an infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or as a continuous infusion, and may be administered over a course of More than one administration during the period, but a single administration is not specifically excluded.
  • the formulation does not take into account the entire course of treatment and that such determinations should be left to those skilled in the therapeutic art rather than the formulation art.
  • compositions as described above may be in any of a variety of suitable forms for various routes of administration, for example, for oral, sublingual, buccal, nasal, rectal, topical (including transdermal and intradermal ), ocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular or other parental routes of administration.
  • oral and nasal compositions include compositions administered by inhalation and prepared using appropriate techniques.
  • pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, solubilizers, surfactants and encapsulating substances.
  • Optional pharmaceutically active materials may be included which do not substantially interfere with the activity of the compound or composition.
  • the amount of carrier used in conjunction with the compound or composition is sufficient to provide a practical amount of the material for administration per unit dose of the compound.
  • Techniques and compositions for preparing dosage forms suitable for use in the methods described herein are described in the following reference, which is incorporated herein by reference: Modern Pharmaceuticals, 4th Edition, Chapters 9 and 10 (Banker and Rhodes, Ed., 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).
  • oral dosage forms can be used including, for example, solid forms such as tablets, capsules (eg, liquid gel capsules and solid gel capsules), granules and bulk powders. Tablets may be compressed, molded, sugar-coated, film-coated or multiple compressed, containing suitable binders, lubricants, diluents, disintegrants, coloring agents, flavoring agents, flow-inducing agents and fusion aids.
  • Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent formulations reconstituted from effervescent granules, containing suitable solvents, preservatives , emulsifiers, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
  • Pharmaceutically acceptable carriers suitable for preparing unit dosage forms for oral administration are well known in the art.
  • Tablets usually contain conventional pharmaceutically compatible adjuvants as inert diluents, for example: calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders, such as starch, gelatin and sucrose; disintegrants, such as Starch, alginic acid and croscarmellose; lubricants such as magnesium stearate, stearic acid and talc.
  • Glidants such as silicon dioxide can be used to improve the flow characteristics of the powder mixture.
  • colorants such as FD&C dyes can be added.
  • sweetening and flavoring agents such as aspartame, saccharin, menthol, peppermint, sucrose and fruit flavors are useful adjuvants.
  • Capsules generally contain one or more solid diluents disclosed above. The choice of carrier components depends on minor considerations such as taste, cost and storage stability, which are not critical and can be readily accomplished by those skilled in the art.
  • Oral compositions also include liquid solutions, emulsions, suspensions, and the like.
  • Pharmaceutically acceptable carriers suitable for use in preparing such compositions are well known in the art.
  • Typical carrier components for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water.
  • typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICE LRC-591, tragacanth, and sodium alginate;
  • typical wetting agents include lecithin and polysorbate 80; and
  • Typical preservatives include methylparaben and sodium benzoate.
  • Oral liquid compositions may also contain one or more of the ingredients disclosed above, such as sweetening, flavoring and coloring agents.
  • compositions may also be coated by conventional methods, usually with pH-dependent or time-dependent coatings, so that the release of the composition in the gastrointestinal tract is near the desired topical application, or at different times to Prolong desired activity.
  • dosage forms typically include, but are not limited to, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, ethylcellulose, Eudragit coatings, One or more of wax and shellac.
  • compositions described herein may optionally include other pharmaceutical actives.
  • compositions useful for achieving systemic delivery of the compounds of the present application include sublingual, buccal and nasal dosage forms.
  • Such compositions typically contain one or more of: soluble filler substances, such as sucrose, sorbitol, and mannitol; and binders, such as acacia, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropyl base methylcellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
  • Liquid compositions for topical ophthalmic use will be formulated such that they can be applied topically to the eye. Comfort can be maximized wherever possible, but sometimes formulation considerations (eg, drug stability) may not allow optimum comfort. Where comfort cannot be maximized, liquids can be formulated such that they are tolerated by the patient for topical ophthalmic use.
  • ophthalmically acceptable fluids may be packaged for single use, or contain a preservative to prevent contamination during multiple uses.
  • solutions or drugs are usually prepared using saline solution as the main carrier.
  • Ophthalmic solutions preferably can be maintained at a comfortable pH with suitable buffer systems.
  • the formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
  • Preservatives that can be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate.
  • a useful surfactant is, for example, Tween 80.
  • a variety of useful carriers can be used in the ophthalmic formulations disclosed herein. These carriers include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamers, carboxymethylcellulose, hydroxyethylcellulose and purified water.
  • Tonicity adjusting agents can be added as desired or convenient. These include, but are not limited to, salts (especially sodium chloride, potassium chloride), mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjusting agent.
  • buffers include acetate buffers, citrate buffered saline, phosphate buffers and borate buffers. Acids or bases can be used to adjust the pH of these formulations as necessary.
  • Ophthalmologically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.
  • excipient components that may be included in ophthalmic formulations are chelating agents.
  • a useful chelating agent is disodium ethylenediaminetetraacetic acid (EDTA), but other chelating agents may be used instead or in combination.
  • EDTA disodium ethylenediaminetetraacetic acid
  • topical formulations may consist of pharmaceutical carriers, co-solvents, emulsifiers, penetration enhancers, preservative systems and emollients.
  • the composition described herein can be dissolved or dispersed in a pharmaceutically acceptable diluent, such as physiological saline or dextrose solution.
  • a pharmaceutically acceptable diluent such as physiological saline or dextrose solution.
  • Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HCl and citric acid.
  • the pH of the final composition is between 2 and 8, or preferably between 4 and 7.
  • Antioxidant excipients may include sodium bisulfite, sodium acetone bisulfite, sodium formaldehyde sulfoxylate, thiourea, and EDTA.
  • excipients present in the final intravenous composition may include sodium or potassium phosphate, citric acid, tartaric acid, gelatin and carbohydrates such as dextrose, mannitol and dextran. Further acceptable excipients are described in Powell et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are hereby incorporated by reference in their entirety.
  • Antimicrobial agents including, but not limited to, phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol may also be included to obtain a bacteriostatic or fungicidal solution.
  • compositions for intravenous administration may be provided to the caregiver in the form of one or more solids which are diluted with a suitable diluent (eg sterile water, normal saline or aqueous dextrose) immediately prior to administration. Do the refactoring.
  • a suitable diluent eg sterile water, normal saline or aqueous dextrose
  • the compositions are provided in solutions that are amenable to parenteral administration.
  • the composition is provided as a further diluted solution prior to administration.
  • the combination may be provided to the caregiver as a mixture, or the caregiver may mix the two agents prior to administration, or the two agents may be administered separately. reagent.
  • a single dose of the composition or other therapeutic agent may be from about 5 mg/m 2 to about 150 mg/m 2 body surface area, from about 5 mg/m 2 to about 100 mg/m 2 body surface area, from about 10 mg/m 2 to about 100 mg/ m2 body surface area, about 10 mg/ m2 to about 80 mg/ m2 body surface area, about 10 mg/ m2 to about 50 mg/ m2 body surface area, about 10 mg/ m2 to about 40 mg/ m2 body surface area , about 10 mg/m 2 to about 30 mg/m 2 body surface area, about 13.5 mg/m 2 to about 100 mg/m 2 body surface area, about 13.5 mg/m 2 to about 80 mg/m 2 body surface area, about 13.5 mg/m 2 2 to about 50 mg/ m2 body surface area, about 13.5 mg/ m2 to about 40 mg/ m2 body surface area, about 13.5 mg/ m2 to about 30 mg/ m2 body surface area, about 15 mg/ m2 to about 80 mg
  • a single dose of the composition or other therapeutic agent may range from about 13.5 mg/m 2 to about 30 mg/m 2 body surface area. In some embodiments, a single dose of the composition or other therapeutic agent may be about 5 mg/m 2 , about 10 mg/m 2 , about 12.5 mg/m 2 , about 13.5 mg/m 2 , about 15 mg/m 2 , about 17.5mg/m 2 , about 20mg/m 2 , about 22.5mg/m 2 , about 25mg/m 2 , about 27.5mg/m 2 , about 30mg/m 2 , about 40mg/m 2 , about 50mg/m 2 , About 60 mg/m 2 , about 70 mg/m 2 , about 80 mg/m 2 , about 90 mg/m 2 , or about 100 mg/m 2 body surface area.
  • a single dose (one-time dose) of the composition or other therapeutic agent may be from about 1 mg to about 300 mg, from about 5 mg to about 200 mg, from about 7.5 mg to about 200 mg, from about 10 mg to about 100 mg, about 15 mg to about 100 mg, about 20 mg to about 100 mg, about 30 mg to about 100 mg, about 40 mg to about 100 mg, about 10 mg to about 80 mg, about 15 mg to about 80 mg, about 20 mg to about 80 mg, about 30 mg to about 80 mg, about 40 mg to About 80 mg, about 10 mg to about 60 mg, about 15 mg to about 60 mg, about 20 mg to about 60 mg, about 30 mg to about 60 mg, or about 40 mg to about 60 mg.
  • a single dose of a composition or other therapeutic agent may be from about 20 mg to about 60 mg, from about 27 mg to about 60 mg, from about 20 mg to about 45 mg, or from about 27 mg to about 45 mg.
  • a single dose of a composition or other therapeutic agent may be about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg.
  • the period of administration may be a multi-week treatment cycle as long as the tumor remains manageable and the regimen is clinically acceptable.
  • a single dose of the composition or other therapeutic agent may be administered once a week, and preferably, once each of Days 1 and 8 of a three-week (21-day) treatment cycle or at Dosing on Day 1 of a three-week (21-day) treatment cycle.
  • a single dose of a composition or other therapeutic agent may be administered once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or in one, two, three Administered daily for weekly, four-week or five-week treatment cycles.
  • the administration can be on the same or different days of each week in the treatment cycle.
  • Treatment cycles may be repeated as long as the regimen is clinically acceptable.
  • the treatment cycle is repeated n times, where n is an integer from 2 to 30. In some embodiments, n is 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • a new treatment cycle can be administered immediately after completion of a previous treatment cycle. In some embodiments, a new treatment cycle may be administered some time after completion of a previous treatment cycle.
  • compositions described herein may be used in combination with other therapeutic agents.
  • compositions described herein may be administered or used in combination with other treatments such as chemotherapy, radiation, and biological therapy.
  • the Plinabulin bulk drug was acid-destructed, and the destroyed API was detected by the analysis method for the related substances of the Plinabulin bulk drug, and the impurity at RRT0.61 was found, and it was separated and purified.
  • the Plinabulin impurity is prepared by the following method
  • plinabulin reacts with an oxidizing agent (such as peroxides, such as H 2 O 2 ) to obtain the formula I compounds and benzaldehyde.
  • an oxidizing agent such as peroxides, such as H 2 O 2

Abstract

本发明涉及一种普那布林或其制剂中的杂质及其用途，所述杂质具有式(I)所示的结构，其可通过普那布林在中性条件或酸性条件下氧化降解得到，在普那布林或其制剂的质量控制的中具有重要意义。

Description

普那布林或其制剂中的杂质及其用途 技术领域
本发明属于医药领域，具体涉及普那布林或其制剂中的杂质及其用途。
背景技术
普那布林((3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(苯亚甲基)-2,5-哌嗪二酮)是从海洋和陆生的曲霉属菌种中发现的二酮哌嗪苯基阿夕斯丁(phenylahistin)(月卞三甲氯铵)的合成类似物，其结构如下所示：
Figure PCTCN2022107702-appb-000001
普那布林在结构上不同于秋水仙碱及其康普瑞汀(combretastatin)样类似物(例如，康普瑞汀磷酸盐)并且在微管蛋白单体上的秋水仙碱结合位点处或其附近结合。先前的研究表明与秋水仙碱相比，在低浓度下的普那布林诱导血管内皮细胞微管蛋白解聚和单层透过性，并且表明普那布林诱导Jurkat白血病细胞内的细胞凋亡。普那布林在患有晚期恶性肿瘤(肺癌、前列腺癌和结肠癌)的患者中作为单一试剂的研究表现出良好的药代动力学、药效学和安全特性。
杂质研究是药品研发的重要内容，贯穿于药品研发的始终，直接影响药品的安全性、有效性以及质量可控性。药物的质量控制主要是控制活性成分的含量和有关物质的含量，特别是有关物质的含量需要满足药用要求，其杂质主要来源于合成过程以及药物降解产生。在进行药物质量检测过程中，需要有高纯度的杂质用作对照品，用于控制可能含有该杂质的药物的质量。因此，提供一种普那布林杂质标准品对普那布林或其药物组合物的质量控制具有重要意义。
发明内容
本发明目的是提供一种普那布林杂质及其制备方法，以及在药品质量控制中的用途。
本发明的第一方面，提供一种式I化合物
Figure PCTCN2022107702-appb-000002
本发明第二方面，提供一种组合物，其中，所述组合物包含i)普那布林和ii)第一方面所述的式I化合物。
在另一优选例中，所述组合物包含：(a)安全且治疗有效量的普那布林多晶型物或其药物可接受的盐，以及(b)药物可接受的载体、稀释剂、赋形剂或其组合。
在另一优选例中，所述的稀释剂包括15-羟基聚乙二醇硬脂酸酯。
在另一优选例中，所述的稀释剂包括丙二醇。
在另一优选例中，所述的稀释剂包括15-羟基聚乙二醇硬脂酸酯和丙二醇。
在另一优选例中，所述的稀释剂为15-羟基聚乙二醇硬脂酸酯和丙二醇，其中，15-羟基聚乙二醇硬脂酸酯为约40重量％并且丙二醇为约60重量％。
在另一优选例中，普那布林与式I化合物的质量比为1-10000：10000-1。
在另一优选例中，普那布林的含量范围为0.01％至99.99％。
本发明第三方面，提供一种药物组合物，其中，所述药物组合物包含i')如第二方面所述的组合物和ii')药学上可接受的载体。
在另一优选例中，所述药物组合物可以为注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用擦剂、控释型或缓释型或纳米制剂。
在另一优选例中，所述组合物的单一剂量为约1mg至约300mg。
本发明第四方面，提供一种制备如第一方面所述的式I化合物的方法，包括步骤：
Figure PCTCN2022107702-appb-000003
1)在惰性溶剂中，中性或酸性条件下，普那布林与氧化剂发生反应，得到式I化合物。
在另一优选例中，惰性溶剂选自：乙醇、乙二醇、DMSO、DMF，或其组合。
在另一优选例中，酸为HCl、HAc，或其组合。
在另一优选例中，反应温度为40-80℃，优选地为50-60℃。
在另一优选例中，酸与普那布林的摩尔比为200:1-20：1，优选地为100:1-15:1。
在另一优选例中，所述氧化剂选自：过氧化物、氧气，或其组合。
本发明第五方面，提供一种第一方面所述的式I化合物的用途，其中，所述化合物用于普那布林原料药或其制剂的质量控制的标准品。
在另一优选例中，所述控制是采用高效液相色谱法测定普那布林原料药或其制剂中式I化合物的含量，用面积归一化法计算得到。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例) 中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了普那布林制剂的HPLC图谱
图2显示了普那布林原料药酸降解后的HPLC图谱。
图3显示了普那布林杂质的核磁氢谱。
图4显示了普那布林杂质的质谱。
具体实施方式
本发明人经过广泛而深入地研究，首次意外地发现一种普那布林制剂杂质，该杂质在普那布林原料药酸降解实验中也产生相应杂质。发明人通过将普那布林原料药进行在氧化剂的存在下，进行中性和酸性条件下破坏，并对其进行分离纯化得到普那布林杂质。在此基础上，完成了本发明。
术语
“RT”是指保留时间；
“RRT”是指相对保留时间；
“API”是指原料液。
普那布林杂质
本发明中，“普那布林杂质”“NPI-2602”“式I化合物”具有相同含义，可互换使用。
NPI-2602的结构如下所示
Figure PCTCN2022107702-appb-000004
由于氧化的原因，普那布林在储存、运输等过程中会发生降解产生杂质，从而影响普那布林的纯度，所述杂质在普那布林制剂的HPLC图谱中RT-5.002min(RRT＝0.61)处显示峰，经质谱和保留时间对比，该杂质在普那布林原料药酸降解实验中也产生相应杂质。
普那布林组合物(composition)和施用
本发明所述的普那布林组合物是指包含普那布林和式I化合物的组合物。优选地，普那布林与式I化合物的质量比为1-10000：10000-1，较佳地，为1：1000至1000：1；更佳地为1：500至500：1；更佳地，为1：100至100：1。
优选地，普那布林的含量范围为0.01％至99.99％，以组合物的总重量计；优选为0.1％至99.9％；更优选为99.80％至99.99％；更优选为99.90％至99.95％。
优选地，普那布林杂质的含量范围为0.01％至99.99％，以组合物的总重量计；优选地为0.1％至99.9％；更优选地为0.20％至0.01％；更优选地为0.1％至0.05％。
在一些实施方案中，组合物还可以包含一种或多种药物可接受的稀释剂。在一些实施方案中，药物可接受的稀释剂可以包括(15-羟基聚乙二醇硬脂酸酯，kolliphor)。在一些实施方案中，药物可接受的稀释剂可以包括丙二醇。在一些实施方案中，药物可接受的稀释剂可以包括kolliphor和丙二醇。在一些实施方案中，药物可接受的稀释剂可以包括kolliphor和丙二醇，其中基于稀释剂的总重量，kolliphor为约40重量％并且丙二醇为约60重量％。在一些实施方案中，组合物还可以包括一种或多种其它药物可接受的赋形剂。
标准的药物配制技术可以用于制备本文所述的药物组合物，例如在Remington的The Science and Practice of Pharmacy，第21版，Lippincott Williams&Wilkins(2005)中所公开的技术，其通过引用整体并入本文。因此，一些实施方案包括药物组合物，其包含：(a)安全且治疗有效量的普那布林多晶型物或其药物可接受的盐，以及(b)药物可接受的载体、稀释剂、赋形剂或其组合。
其它实施方案包括在分离的组合物或相同的组合物中共同施用普那布林多晶型物和另外的治疗剂。因此，一些实施方案包括第一药物组合物和第二药物组合物，其中第一药物组合物包含：(a)安全且治疗有效量的普那布林多晶型物或其药物可接受的盐以及(b)药物可接受的载体、稀释剂、赋形剂或其组合；并且第二药物组合物包含：(a)安全且治疗有效量的另外的治疗剂以及(b)药物可接受的载体、稀释剂、赋形剂或其组合。一些实施方案包括药物组合物，其包含：(a)安全且治疗有效量的普那布林多晶型物或其药物可接受的盐；(b)安全且治疗有效量的另外的治疗剂；以及(c)药物可接受的载体、稀释剂、赋形剂或其组合。
本发明药物组合物的剂型包括(但并不限于)：注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用擦剂、控释型或缓释型或纳米制剂。
本文所述的药物组合物的施用可以经由任何可接受的施用试剂(用于类似的用途)的方式，包括但不限于，口服、舌下、经颊、皮下、静脉内、鼻内、局 部、透皮、皮内、腹膜内、肌内、肺内、阴道、直肠或眼内。口服和肠胃外施用常用于治疗为优选实施方案的主题的适应症。
术语“药物可接受的载体”或“药物可接受的赋形剂”包含任何和所有的溶剂、分散介质、包衣、抗菌剂和抗真菌剂、等渗剂和吸收延迟剂等。此类介质和试剂对于药物活性物质的用途是本领域熟知的。除了任何常规的介质或试剂与活性成分不相容的情况以外，所述介质或试剂在治疗性组合物中的用途是可预期的。此外，可以包括例如通常用于本领域的各种佐剂。在药物组合物中包含各种组分的注意事项在例如，Gilman等人(编著)(1990)；Goodman and Gilman’s:The Pharmacological Basis of Therapeutics,第8版,PergamonPress中描述，其通过引用整体并入本文。
可以用作其药物可接受的载体或组分的物质的一些实例为：糖，例如乳糖、葡萄糖和蔗糖；淀粉，例如玉米淀粉和马铃薯淀粉；纤维素及其衍生物，例如羧甲基纤维素钠、乙基纤维素和甲基纤维素；粉末状黄蓍胶；麦芽；明胶；滑石；固体润滑剂，例如硬脂酸和硬脂酸镁；硫酸钙；植物油，例如花生油、棉籽油、芝麻油、橄榄油、玉米油和可可油；多元醇，例如丙二醇、甘油、山梨糖醇、甘露醇和聚乙二醇；海藻酸；乳化剂，例如TWEENS；润湿剂，例如十二烷基硫酸钠；着色剂；矫味剂；制片剂；稳定剂；抗氧化剂；防腐剂；无热原水；等渗盐水；以及磷酸盐缓冲溶液。
优选以单位剂型提供本文所述的组合物。如本文所用，“单位剂型”是含有适于根据良好的医学实践向动物(优选哺乳动物对象)以单一剂量施用的化合物或组合物的量的组合物。然而，单一剂型或单位剂型的制剂并非意味着该剂型以每天一次或每个疗程一次进行施用。预期该剂型每天施用一次、两次、三次或更多次，以及可以输注一段时间(例如，约30分钟至约2-6小时)进行施用，或以连续输注进行施用，并且可以在疗程期间给予一次以上，但是没有特别排除单次施用。本领域技术人员将认识到，该制剂未考虑整个疗程，并且此类决定应留给治疗领域的技术人员，而不是制剂领域的技术人员。
如上所述的有用的组合物可以以各种合适的形式中的任一种用于各种施用途径，例如，用于口服、舌下、颊、鼻、直肠、局部(包括透皮和皮内)、眼、脑内、颅内、鞘内、动脉内、静脉内、肌内或其他亲本施用途径。本领域技术人员将会理解，口服组合物和鼻用组合物包括通过吸入施用并使用适当的技术制备的组合物。根据所期望的特定施用途径，可以使用本领域所熟知的各种药物可接受的载体。药物可接受的载体包括，例如，固态或液态的填充剂、稀释剂、助溶剂、表面活性剂和包封物质。可以包括可选的药物活性材料，其基本上不会干扰化合物或组合物的活性。与化合物或组合物结合使用的载体的量足以提供每单位剂量化合物的用于施用的实际数量的材料。在以下参考文献中描 述了用于制备适用于本文所述方法中的剂型的技术和组合物，其均通过引用并入本文：Modern Pharmaceutics,第4版，第9章和第10章(Banker和Rhodes，编著，2002)；Lieberman等人，Pharmaceutical DosageForms:Tablets(1989)；以及Ansel，Introduction to Pharmaceutical Dosage Forms第8版(2004)。
可以使用各种口服剂型，包括例如固体形式，例如片剂、胶囊(例如，液体凝胶胶囊和固体凝胶胶囊)，颗粒剂和散装粉末。片剂可以是压制片、模印片、糖包衣、膜包衣或多重压制片，含有合适的粘合剂、润滑剂、稀释剂、崩解剂、着色剂、矫味剂、流动诱导剂和助融剂。液体口服剂型包括水溶液、乳液、悬浮液、由非泡腾颗粒剂重构而得的溶液和/或悬浮液和由泡腾颗粒剂重构而得的泡腾制剂，含有合适的溶剂、防腐剂、乳化剂、助悬剂、稀释剂、甜味剂、助融剂、着色剂和矫味剂。
适用于制备口服施用的单位剂型的药物可接受的载体是本领域所熟知的。片剂通常包含常规的药学上相容的佐剂作为惰性稀释剂，例如：碳酸钙、碳酸钠、甘露醇、乳糖和纤维素；粘合剂，例如淀粉、明胶和蔗糖；崩解剂，例如淀粉、海藻酸和交联羧甲基纤维素；润滑剂，例如硬脂酸镁、硬脂酸和滑石。可以使用诸如二氧化硅的助流剂来改善粉末混合物的流动特性。对于外观，可以加入着色剂，例如FD&C染料。对于咀嚼片剂，甜味剂和矫味剂，例如阿斯巴甜、糖精、薄荷醇、薄荷、蔗糖和水果香料是有用的佐剂。胶囊通常含有以上公开的一种或多种固体稀释剂。载体组分的选择取决于次要考虑因素，如味道、成本和储存稳定性，这不是关键因素，并且可以由本领域技术人员容易地实现。
口服组合物还包含液体溶液、乳液、悬浮液等。适用于制备此类组合物的药物可接受的载体是本领域熟知的。用于糖浆剂、酏剂，乳液和悬浮液的典型的载体组分包括乙醇、甘油、丙二醇、聚乙二醇、液体蔗糖、山梨糖醇和水。对于悬浮液，典型的助悬剂包括甲基纤维素、羧甲基纤维素钠、AVICELRC-591、黄蓍胶和海藻酸钠；典型的润湿剂包括卵磷脂和聚山梨醇酯80；并且典型的防腐剂包括对羟基苯甲酸甲酯和苯甲酸钠。口服液体组合物还可以含有以上公开的一种或多种组分，例如甜味剂、矫味剂和着色剂。
此类组合物还可以通过常规方法进行包衣，通常用pH依赖性或时间依赖性包衣，使得该组合物在胃肠道中在期望的局部施用附近进行释放，或者在不同的时间进行释放以延长所期望的活性。此类剂型通常包括但不限于，邻苯二甲酸乙酸纤维素、聚乙烯乙酸邻苯二甲酸酯、羟丙基甲基纤维素邻苯二甲酸酯、乙基纤维素、Eudragit包衣、蜡和虫胶中的一种或多种。
本文所述的组合物可以任选地包括其它药物活性物。
用于获得本申请化合物的系统性递送的其它组合物包括舌下、颊用和鼻用 剂型。此类组合物通常包含以下中的一种或多种：可溶性填充物质，例如蔗糖、山梨糖醇和甘露醇；以及粘合剂，例如阿拉伯胶、微晶纤维素、羧甲基纤维素和羟丙基甲基纤维素。还可以包括以上公开的助流剂、润滑剂、甜味剂、着色剂、抗氧化剂和矫味剂。
将配制用于配制局部眼用的液体组合物使得其可以局部施用于眼睛。可以尽可能地使舒适度最大化，但是有时出于配制考虑(例如药物稳定性)，可能无法达到最佳舒适度。在不能使舒适度最大化的情况下，可以配制液体使得该液体对于患者用于局部眼用是可容忍的。此外，眼科可接受的液体可以被包装成用于单次使用，或含有防腐剂以防止在多次使用中的污染。
对于眼部应用，通常使用生理盐水溶液作为主要载体来制备溶液或药物。眼用溶液优选可以用适当的缓冲系统维持在舒适的pH。制剂还可以含有常规的、药物可接受的防腐剂、稳定剂和表面活性剂。
可以用于本文公开的药物组合物中的防腐剂包括但不限于，苯扎氯铵、PHMB、氯丁醇、硫柳汞、醋酸苯汞和硝酸苯汞。有用的表面活性剂为，例如，Tween80。同样地，各种有用的载体可以用于本文公开的眼用制剂中。这些载体包括但不限于，聚乙烯醇、聚维酮、羟丙基甲基纤维素、泊洛沙姆、羧甲基纤维素、羟乙基纤维素和纯水。
根据需要或便利，可以加入张力调节剂。其包括但不限于，盐(特别是氯化钠、氯化钾)、甘露醇和甘油，或者任何其它合适的眼科可接受的张力调节剂。
可以使用各种用于调节pH的缓冲液和方式，只要所得的制剂是眼科可接受的。对于许多组合物，pH将为4至9。因此，缓冲液包括乙酸盐缓冲液、柠檬酸盐缓冲盐、磷酸盐缓冲液和硼酸盐缓冲液。根据需要，可以使用酸或碱来调节这些制剂的pH。
眼科可接受的抗氧化剂包括但不限于，焦亚硫酸钠、硫代硫酸钠、乙酰半胱氨酸、丁基羟基茴香醚和丁基化羟基甲苯。
可以包括于眼用制剂中的其它赋形剂组分为螯合剂。有用的螯合剂是乙二胺四乙酸(EDTA)二钠，但是也可以使用其它螯合剂代替或与其结合。
对于局部使用，使用含有本文公开的组合物的乳膏、软膏、凝胶、溶液或悬浮液等。通常局部制剂可以由药物载体、共溶剂、乳化剂、渗透促进剂、防腐剂体系和软化剂组成。
对于注射剂，可静脉内施用，具体地，可以将本文所述的组合物溶解或分散于药物可接受的稀释剂中，例如生理盐水或右旋糖溶液。可以包括合适的赋形剂以实现期望的pH，所述赋形剂包括但不限于NaOH、碳酸钠、乙酸钠、HCl和柠檬酸。在各种实施方案中，最终组合物的pH为2至8，或优选为4至7。抗氧化剂赋形剂可以包括亚硫酸氢钠、丙酮合亚硫酸氢钠、甲醛次硫酸钠、硫脲和 EDTA。在最终静脉内组合物中存在的合适的赋形剂的其它非限制性实例可以包括磷酸钠或磷酸钾、柠檬酸、酒石酸、明胶和碳水化合物(例如右旋糖、甘露醇和葡聚糖)。另外可接受的赋形剂描述于Powell等人，Compendium of Excipients for ParenteralFormulations,PDA J Pharm Sci and Tech 1998,52 238-311和Nema等人，Excipientsand Their Role in Approved Injectable Products:Current Usage and FutureDirections,PDA J Pharm Sci and Tech 2011,65 287-332，两者通过引用整体并入本文。还可以包括抗微生物试剂以获得抑菌溶液或抑制真菌溶液，所述抗微生物试剂包括但不限于硝酸苯汞、硫柳汞、苄索氯铵、苯扎氯铵、苯酚、甲酚和氯丁醇。
可以将用于静脉内施用的组合物以一种或多种固体的形式提供给护理人员，所述固体在施用之前立刻用合适的稀释剂(例如无菌水、生理盐水或右旋糖水溶液)进行重构。在其它实施方案中，以易于肠道外施用的溶液形式提供组合物。在其它实施方案中，在施用之前以进一步被稀释的溶液形式提供组合物。在包括施用本文所述的化合物与另外的试剂的组合的实施方案中，所述组合可以作为混合物提供给护理人员，或者护理人员可以在施用之前混合这两种试剂，或者可以单独施用这两种试剂。
在一些实施方案中，组合物或其它治疗剂的单一剂量可以为约5mg/m 2至约150mg/m 2体表面积、约5mg/m 2至约100mg/m 2体表面积、约10mg/m 2至约100mg/m 2体表面积、约10mg/m 2至约80mg/m 2体表面积、约10mg/m 2至约50mg/m 2体表面积、约10mg/m 2至约40mg/m 2体表面积、约10mg/m 2至约30mg/m 2体表面积、约13.5mg/m 2至约100mg/m 2体表面积、约13.5mg/m 2至约80mg/m 2体表面积、约13.5mg/m 2至约50mg/m 2体表面积、约13.5mg/m 2至约40mg/m 2体表面积、约13.5mg/m 2至约30mg/m 2体表面积、约15mg/m 2至约80mg/m 2体表面积、约15mg/m 2至约50mg/m 2体表面积、或约15mg/m 2至约30mg/m 2体表面积。在一些实施方案中，组合物或其它治疗剂的单一剂量可以为约13.5mg/m 2至约30mg/m 2体表面积。在一些实施方案中，组合物或其它治疗剂的单一剂量可以为约5mg/m 2、约10mg/m 2、约12.5mg/m 2、约13.5mg/m 2、约15mg/m 2、约17.5mg/m 2、约20mg/m 2、约22.5mg/m 2、约25mg/m 2、约27.5mg/m 2、约30mg/m 2、约40mg/m 2、约50mg/m 2、约60mg/m 2、约70mg/m 2、约80mg/m 2、约90mg/m 2或约100mg/m 2体表面积。
在一些实施方案中，组合物或其它治疗剂的单一剂量(一次性用药的剂量)可以为约1mg至约300mg、约5mg至约200mg、约7.5mg至约200mg、约10mg至约100mg、约15mg至约100mg、约20mg至约100mg、约30mg至约100mg、约40mg至约100mg、约10mg至约80mg、约15mg至约80mg、约20mg至约80mg、约30mg至约80mg、约40mg至约80mg、约10mg至约60mg、约15mg至约60mg、约20mg 至约60mg、约30mg至约60mg、或约40mg至约60mg。在一些实施方案中，组合物或其它治疗剂的单一剂量可以为约20mg至约60mg、约27mg至约60mg、约20mg至约45mg、或约27mg至约45mg。在一些实施方案中，组合物或其它治疗剂的单一剂量可以为约1mg、2mg、3mg、4mg、5mg、约10mg、约12.5mg、约13.5mg、约15mg、约17.5mg、约20mg、约22.5mg、约25mg、约27mg、约30mg、约40mg、约50mg、约60mg、约70mg、约80mg、约90mg、约100mg、约125mg、约150mg、或约200mg。
只要肿瘤在保持可控并且该方案是临床上可接受的，则施用期可以是多周治疗周期。在一些实施方案中，组合物或其它治疗剂的单一剂量可以施用一周一次，并且优选地，在三周(21天)治疗周期中的第1天和第8天中的每一天施用一次或在三周(21天)治疗周期中的第1天给药。在一些实施方案中，组合物或其它治疗剂的单一剂量可以施用一周一次、一周两次、一周三次、一周四次、一周五次、一周六次，或者在一周、两周、三周、四周或五周治疗周期中每天施用。该施用可以在治疗周期中的每一周的相同或不同的日期进行。
只要该方案是临床上可接受的，则治疗周期可以重复。在一些实施方案中，治疗周期重复n次，其中n是2至30的整数。在一些实施方案中，n为2、3、4、5、6、7、8、9或10。在一些实施方案中，在完成先前的治疗周期后可以立即进行新的治疗周期。在一些实施方案中，在完成先前的治疗周期后一段时间可以进行新的治疗周期。
在一些实施方案中，本文所述的组合物可以与其它治疗剂组合使用。在一些实施方案中，本文所述的组合物可以与其它治疗(例如化学疗法、辐射和生物疗法)组合施用或使用。
普那布林杂质的制备方法
将普那布林原料药进行酸破坏，用普那布林原料药有关物质的分析方法对破坏后的API进行检测，找出RRT0.61处的杂质，并对其进行分离纯化。
优选地，本发明中，普那布林杂质采用如下方法制备
Figure PCTCN2022107702-appb-000005
在惰性溶剂(如乙醇、DMSO、DMF等)中，酸(如HCl、HAc等)存在下，普那布林与氧化剂(如过氧化物类，例如H 2O 2)发生反应，得到式I化合物和苯甲 醛。
本发明的主要优势在于：
(1)首次发现了普那布林杂质I；
(2)对普那布林产品的质量控制具有重要意义。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
实施例
实施例1普那布林制剂中的杂质研究
使用HPLC对普那布林制剂进行分析，分析条件如下：
Figure PCTCN2022107702-appb-000006
普那布林制剂的HPLC图谱如图1所示。
实施例2普那布林杂质的制备
Figure PCTCN2022107702-appb-000007
称取1.9482g普那布林API至500mL锥形瓶中，加入乙醇(250mL)使其充分溶解，加入2N HCl(8mL)，加入盐酸后API会析出，加入适量DMF助溶,瓶口用气球捆扎(避免酸挥发)。将其放置60℃的烘箱，每隔一天检测一次，并用pH试纸检测pH，如果低于pH3，可补加适量酸，直至测得足够多的杂质为止(用普那布林原料药有关物质方法检测到的普那布林杂质纯度不低于5％)，然后进行分离纯化，分离纯化方法如下：
反相制备液相参数：
仪器：Flash液相制备仪
制备柱：C18柱
流动相：A：10mM NH4HCO3 in water B：ACN
波长：214&360nm
流速：60mL/min
梯度：
Figure PCTCN2022107702-appb-000008
制备后接收液有黄色固体析出，对其进行过滤，分别检测滤渣和滤液，滤渣纯度较高且确认为目标产物。制备得到产品共计58mg，纯度99.83％，分子离子峰[M+H]为263.2。普那布林API反应后的HPLC图谱如图2所示，核磁图谱和质谱如图3和4所示，核磁数据如下表1所示
表1
编号 1HNMR 13CNMR 1H- 1HCOSY HMBC
1 / 151.7 / 1-NH，2-NH，5-H
1-NH 12.62，br.s / 5-H /
2 / 156.8 / 1-NH，2-NH
2-NH 12.00，br.s /   /
3 / 160.4 / 1-NH，2-NH，5-H
4 / 123.2 / 2-NH，5-H
5 7.00，s，1H 108.8 1-NH，7-H 1-NH，2-NH
6 / 130.3 / 5-H，7-H，7-NH
7 7.91，s，1H 134.9 5-H 7-NH
7-NH 12.46，br.s / 10-H，11-H，12-H /
8 / 142.3 / 5-H，7-H，7-NH，10-H，11-H，12-H
9 / 32.0 / 10-H，11-H，12-H
10，11，12 1.39，s，9H 30.6 7-H 8-H
采用与制剂分析方法相同的HPLC方法对杂质进行分析，保留时间为RT＝5.016，与制剂中杂质保留时间一致。
实施例3普那布林杂质的制备
称取1g普那布林API，加入DMF(100ml)使其溶解，依次HAc(30ml)、30％H 2O 2(5ml)，置于50℃烘箱反应，反应时间48小时，然后按照实施例2所述的方法进行分离纯化。
实施例4普那布林杂质的制备
称取2g普那布林API，加入DMF(100ml)使其溶解，依次加入HAc(30ml)、30％H 2O 2(20ml)，反应时间24小时，然后按照实施例2所述的方法进行分离纯化。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种式I化合物
    Figure PCTCN2022107702-appb-100001
  2. 一种组合物，其特征在于，所述组合物包含i)普那布林和ii)权利要求1所述的式I化合物。
  3. 如权利要求2所述的组合物，其特征在于，普那布林与式I化合物的质量比为1-10000：10000-1。
  4. 如权利要求2所述的组合物，其特征在于，普那布林的含量范围为0.01％至99.99％。
  5. 一种药物组合物，其特征在于，所述药物组合物包含i')如权利要求2所述的组合物和ii')药学上可接受的载体。
  6. 如权利要求5所述的药物组合物，其特征在于，所述药物组合物可以为注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用擦剂、控释型或缓释型或纳米制剂。
  7. 如权利要求5所述的药物组合物，其特征在于，所述组合物的单一剂量为约1mg至约300mg。
  8. 一种制备如权利要求1所述的式I化合物的方法，其特征在于，包括步骤：
    Figure PCTCN2022107702-appb-100002
    1)在惰性溶剂中，中性或酸性条件下，普那布林与氧化剂发生反应，得到式I化合物。
  9. 如权利要求1所述的式I化合物的用途，其特征在于，所述化合物用于普那布林原料药或其制剂的质量控制的标准品。
  10. 如权利要求7所述的用途，其特征在于，所述控制是采用高效液相色谱法测定普那布林原料药或其制剂中式I化合物的含量，用面积归一化法计算得到。
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