CN106659680A - Pharmaceutical composition with improved storage stability and method for preparing the same - Google Patents

Pharmaceutical composition with improved storage stability and method for preparing the same Download PDF

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Publication number
CN106659680A
CN106659680A CN201680001944.8A CN201680001944A CN106659680A CN 106659680 A CN106659680 A CN 106659680A CN 201680001944 A CN201680001944 A CN 201680001944A CN 106659680 A CN106659680 A CN 106659680A
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China
Prior art keywords
medicine
pharmaceutical composition
soluble
poorly water
formula
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Inventor
金峰五
庆奎真
金志英
金宪林
闵范赞
尹裕晶
徐敏孝
李雄
李一雄
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Samyang Biopharmaceuticals Corp
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Samyang Biopharmaceuticals Corp
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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

A pharmaceutical composition containing a specific related compound in an amount below the standard and a method for preparing the same are provided.

Description

With pharmaceutical composition of storage stability for improving and preparation method thereof
Technical field
The present invention relates to have pharmaceutical composition of storage stability of improvement and preparation method thereof, relate more specifically to bag The pharmaceutical composition of the medicine of the poorly water-soluble containing amphipathic nature block polymer, wherein the content of specific related compound is maintained at Within regulation limitation；And it is related to its preparation method.
Background technology
The dissolving of the medicine of poorly water-soluble is to deliver drugs into internal key technology via oral and parenteral administration. This dissolving method includes adding in aqueous that surfactant, to form micella, then embeds (entrapping) wherein The method of the medicine of poorly water-soluble.Amphipathic nature block polymer as surfactant is comprising hydrophilic polymer blocks and dredges Waterborne polymeric block.Due to hydrophilic polymer blocks directly contact hematoglobin protein and cell membrane in vivo, therefore make With the polyethylene glycol with biocompatibility or mono methoxy polyethylene glycol etc..Hydrophobic polymer block improves and hydrophobicity medicine The compatibility of thing, therefore using with biodegradable polylactide, PGA, poly- (lactic acid-glycolide) (poly (lactic-glycolide)), polycaprolactone, polyaminoacid or poe etc..Particularly because polylactide derivative tool There is excellent biocompatibility and be hydrolyzed to harmless lactic acid in vivo, therefore they have been applied in a variety of manners medicine Carrier.Polylactide derivative has different physical propertys with its change of molecular weight, and has been developed over various forms, example Such as microballoon, nano particle, polymer gel and implant.
6th, 322, No. 805 United States Patent (USP) discloses the composition for delivering the medicine of poorly water-soluble, and it is by polymer The medicine composition of micellar drug carriers and poorly water-soluble, wherein the polymer micelle type pharmaceutical carrier is by diblock copolymer Or triblock copolymer is formed, not by cross-linking agents, it is by selected from poly- third for the diblock copolymer or triblock copolymer Lactide, PGA, poly- (lactide coglycolide), polycaprolactone and its derivative it is at least one biodegradable hydrophobic Property polymer and poly- (alkylene oxide) as hydrophilic polymer constitute, wherein the medicine of poorly water-soluble is physically embedded in into medicine In carrier and dissolve, and wherein described polymer micelle type pharmaceutical carrier forms transparent aqueous solution and by poorly water-soluble in water Medicine be effectively delivered in vivo.According to above-mentioned United States Patent (USP), PEG-PDLLA diblock copolymer be by with Lower step synthesis：Moisture is removed from mono methoxy polyethylene glycol, the stannous octoate being dissolved in toluene is added thereto to simultaneously Toluene is removed under reduced pressure, adds D, L- lactides simultaneously to carry out polymerisation in gained mixture, it is produced to dissolve to add chloroform Block copolymer, under agitation aliquot ground excessive ether is added dropwise to form precipitation, filter the precipitation of formation, and washed with ether Wash for several times.However, the method is difficult to used in large-scale production, thus it is not commercially available.Additionally, the ether for purifying may be residual In staying in final polymer micelle composition.
8th, 853, No. 351 United States Patent (USP) discloses a kind of method for preparing amphipathic nature block polymer, and it includes that (a) will Amphipathic nature block polymer is dissolved in miscible organic solvents；Add in b polymer solution that () obtains in step (a) And the aqueous solution of mixed alkali metal salt (sodium acid carbonate, sodium carbonate, saleratus, potassium carbonate or lithium carbonate)；C () is right by saltouing The solution obtained in step (b) carries out organic phase and aqueous phase separation；(d) organic phase that obtains in separating step (c) is simultaneously removed Organic solvent therein is reclaiming polymer.However, the method is related to the step of complexity, extra step is needed with except lixiviating gold Category salt and the salt (sodium chloride or potassium chloride) for saltouing, even and if being likely to that there is the metal for remaining after being removed Salt.
The impurity of medicine must be strictly controlled in all fields.Especially, active pharmaceutical ingredient (API) is come from impurity In the case of, each country determines in its drug approval guide and be derived from drug products API, known or unknown impuritie (phase Related compounds) amount the upper limit.Additionally, there is the standard that some are used in the world, ICH guide Q3A are representational one. In the guide, when medicine is examined, the amount of every kind of related compound is limited to most 0.1% or 0.2% etc. in medicine, and According to the related compound more than limitation, the information of the toxicity related data that should specify etc. is differentially suitable for.This meaning Taste the amount that related compound must be reduced during medicine is prepared, because how the related compound of medicine is made in vivo With being unknown.Therefore, for reduce related compound manufacture method and according to the characteristic of every kind of related compound (structure and Toxicity) upper limit that sets its amount is necessary factor in Control of drug quality.
The content of the invention
Technical problem
One object of the present invention is the polymer latex of the medicine for providing the poorly water-soluble containing amphipathic nature block polymer Beamforming pharmaceutical composition, it contains the specific related compound of the amount within regulation limitation.
Another object of the present invention is to provide the method for preparing described pharmaceutical composition.
Technological means
An aspect of of the present present invention provides polymeric micelle medicine composition, and it is included：Comprising hydrophilic block (A) and dredge The amphipathic nature block polymer of the purifying of aqueous block (B), and the medicine of one or more poorly water-soluble, it is selected from taxol And Docetaxel, wherein when described pharmaceutical composition is stored 6 months at 40 DEG C, it contains with the medicine of the poorly water-soluble The primary quantity of thing is the related compound represented by following formula 1 below 0.2 weight portion of 100 weight portion meters：
[formula 1]
Wherein：
R1For H or COCH3, R2For phenyl or O (CH3)3。
The method for preparing polymeric micelle medicine composition is another aspect provides, it includes：(a) purifying bag Amphipathic nature block polymer containing hydrophilic block (A) and hydrophobic block (B)；B () will be selected from taxol and Docetaxel One or more poorly water-soluble medicine and purifying amphipathic nature block polymer dissolve in organic solvent；(c) to step Suddenly aqueous solvent is added in the solution for obtaining in (b) to form polymer micelle；When described pharmaceutical composition stores 6 at 40 DEG C When individual month, its contain by the primary quantity of the medicine of the poorly water-soluble be 100 weight portions in terms of 0.2 weight portion below by above formula 1 related compound for representing.
Beneficial effect
According to the present invention it is possible to obtain the poorly water-soluble with the related compound for reducing and the storage stability of improvement The pharmaceutical composition of medicine.
Description of the drawings
Fig. 1 be to experimental example 1 used in, through six months accelerated tests, the polymer micelle group containing taxol Compound carries out the chromatogram obtained by HPLC analyses.
Fig. 2 shows the related compound to acquisition in experimental example 1, and (RRT 0.96 ± 0.02 (0.94～0.98), it is under Wen Zhongke and the used interchangeablies of RRT 0.96) carry out the Product ion scans result of LC/MS/MS analyses.
Fig. 3 show in the mixture in experimental example 2 as obtained by thermally decomposing taxol at the RRT 0.96 obtained by material Carry out the result of LC/MS/MS analyses.
Fig. 4 show in the mixture in experimental example 2 as obtained by thermally decomposing taxol at the RRT 0.96 obtained by material Carry out the Product ion scans result of LC/MS/MS analyses, and the result of polymeric micelle medicine composition：
The analysis result of (a) through the polymeric micelle medicine composition sample of six months accelerated tests；
The analysis result of material obtained by the RRT 0.96 in the mixture of (b) as obtained by thermally decomposing taxol.
Fig. 5 show in the mixture in experimental example 2 as obtained by thermally decomposing taxol at the RRT 0.96 obtained by material Carry out NMR analyses1H NMR analysis results.
Fig. 6 show in the mixture in experimental example 2 as obtained by thermally decomposing taxol at the RRT 0.96 obtained by material Carry out NMR analyses13C NMR analysis results.
Fig. 7 show in the mixture in experimental example 2 as obtained by thermally decomposing taxol at the RRT 0.96 obtained by material Carry out COSY (correlation spectrum) analysis result of NMR analyses.
Fig. 8 show in experimental example of the present invention 2 as thermally decompose taxol obtained by mixture in the places of RRT 0.96 Obtaining material carries out HMBC (heteronuclear multiple-bond correlation spectrum) analysis result of NMR analyses.
Fig. 9 is that the chromatogram obtained by HPLC analyses is carried out in experimental example 5.
Specific embodiment
Below the present invention will be described in more detail.
The pharmaceutical composition of embodiment of the present invention includes the purifying containing hydrophilic block (A) and hydrophobic block (B) Amphipathic nature block polymer.
An embodiment of the invention, the amphipathic nature block polymer is included by hydrophilic block (A) and dredged The A-B types diblock copolymer or B-A-B type triblock copolymers of aqueous block (B) composition.
An embodiment of the invention, the amphipathic nature block polymer can be included, with the gross weight of the copolymer Gauge, the hydrophilic block of 20-95 weight %, more specifically 40-95 weight %.Additionally, the amphipathic nature block polymer can Comprising with the gross weight meter of the copolymer, the hydrophobic block of 5-80 weight %, more specifically 5-60 weight %.
An embodiment of the invention, the number-average molecular weight of the amphipathic nature block polymer can be 1,000- 50,000 dalton, more specifically 1,500-20,000 dalton.
An embodiment of the invention, the hydrophilic block is the polymer with biocompatibility and can Comprising the one kind in polyethylene glycol or derivatives thereof, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylamide and combinations thereof Or it is various, more specifically, it can include one or more in polyethylene glycol, mono methoxy polyethylene glycol and combinations thereof. The number-average molecular weight of hydrophilic block can be 200-20,000 dalton, more specifically 200-10,000 dalton.
An embodiment of the invention, the hydrophobic block is the polymer with biodegradability, and And can be the polymer of the monomer of derived from alpha-carboxylic acid.Specifically, it can include selected from polylactide, PGA, gather One kind of mandelic acid, polycaprolactone, Ju diox -2- ketone, polyaminoacid, poe, polyanhydride, Merlon and combinations thereof or It is various, more specifically, it can be comprising in polylactide, PGA, polycaprolactone, Ju diox -2- ketone and combinations thereof One or more.The number-average molecular weight of hydrophobic block can be 200-20,000 dalton, more specifically 200-10, 000 dalton.
An embodiment of the invention, the amphipathic block comprising poly- ('alpha '-hydroxy acids) hydrophobic polymer block Copolymer can be synthesized by known ring-opening polymerization method, and methods described uses the hydrophilic polymer with hydroxyl as drawing Send out agent and 'alpha '-hydroxy acids internal ester monomer.For example, with the hydrophilic polyglycol with hydroxyl or mono methoxy polyethylene glycol to draw Agent is sent out, L- lactides or D, L- lactide can pass through ring-opening polymerisation.According to present in the hydrophilic block as initiator The number of hydroxyl, can synthesize diblock copolymer or triblock copolymer.In ring-opening polymerisation, it is possible to use organic metal is urged Agent, such as tin oxide, lead oxide, tin octoate, sad antimony etc., preferably use with biofacies when medical polymer is prepared The tin octoate of capacitive.
In embodiments of the invention, using the copolymer of purifying as amphipathic nature block polymer.According to the present invention Preferred embodiment, amphipathic nature block polymer is by the copolymer of sublimation purification.
Sublimation purification can at a temperature of preferred 80-120 DEG C, more preferably 80-100 DEG C, and below preferably 10 supports, Preferred 10-74 hours, more preferably 10-48 are carried out under the pressure of the vacuum below more preferably 5 supports, below more preferred 1 support little When, more preferred 24-48 hours.Carrying out purifying by distillation under these conditions can make the change of molecular weight of copolymer minimum Change and remove from copolymer impurity.
The pharmaceutical composition of embodiment of the present invention is water-soluble comprising one or more selected from taxol and Docetaxel Property difference medicine as active component.
An embodiment of the invention, pharmaceutical composition can be also included as other active component except Japanese yew The medicine of one or more poorly water-soluble outside alcohol and Docetaxel.As such other active component, can make 7- Epitaxols, t- acetyl paclitaxels, 10- deacetylate taxols, 10- deacetylate -7- tables are selected from one or more Taxol, 7- xylosyl taxols, 10- deacetylate -7- glutaryl taxols, 7-N, N- dimethylglycinamidyl taxols, 7- The taxane anticancer agents of L- alanyls taxol and Cabazitaxel (cabazitaxel).
The pharmaceutical composition of embodiment of the present invention can be included, based on the amphipathic nature block polymer of 100 weight portions, 0.1- The medicine of 50 weight portions, the more specifically poorly water-soluble of 0.5-30 weight portions.Compared with the amount of amphipathic nature block polymer, if Very little, then the weight of the amphipathic copolymer that every kind of medicine is used is higher, therefore reconstitution time for the amount of the medicine of poorly water-soluble Can increase.On the other hand, if the amount of the medicine of poorly water-soluble is too many, there may be the medicine rapid precipitation of poorly water-soluble Problem.
As used herein " initial " amount of the medicine of poorly water-soluble refers to the water solubility mixed when preparing pharmaceutical composition The weight of poor medicine.
In embodiments of the invention, when described pharmaceutical composition under acceleration conditions (40 DEG C) storage 6 months when, its Contain, count by 100 weight portions of the primary quantity of the medicine of the poorly water-soluble, the phase represented by following formula 1 below 0.2 weight portion Related compounds：
[formula 1]
Wherein：
R1For H or COCH3, R2For phenyl or O (CH3)3。
An embodiment of the invention, the medicine of poorly water-soluble is taxol, and related compound may include following formula The compound that 1a is represented：
[formula 1a]
When under acceleration conditions (40 DEG C) storage 6 months when, the pharmaceutical composition of embodiment of the present invention can contain, with institute The primary quantity for stating the medicine of poorly water-soluble is 100 weight portion meters, below 0.2 weight portion, below preferably 0.18 weight portion, more preferably Below 0.16 weight portion, below more preferred 0.13 weight portion, most preferably 0.1 weight portion Formula 1 below (particularly formula 1a) Related compound.
In a preferred embodiment of the invention, when under acceleration conditions (40 DEG C) storage 6 months when, pharmaceutical composition can Contain, count by 100 weight portions of the primary quantity of the medicine of the poorly water-soluble, less than 0.15 weight portion, especially less than 0.10 weight The related compound of amount part Formula 1 below (particularly formula 1a).
When under strict conditions (80 DEG C) storage 3 weeks when, the pharmaceutical composition of embodiment of the present invention can contain, with described The primary quantity of the medicine of poorly water-soluble is 100 weight portion meters, below 1.2 weight portions, below preferably 0.9 weight portion, more preferably 0.7 Below weight portion, below more preferred 0.4 weight portion, the correlationization of most preferably 0.2 weight portion Formula 1 below (particularly formula 1a) Compound.
In a preferred embodiment of the invention, when under strict conditions (80 DEG C) storage 3 weeks when, pharmaceutical composition can contain Have, count by 100 weight portions of the primary quantity of the medicine of the poorly water-soluble, less than the formula 1 (particularly formula 1a) of 1.12 weight portions Related compound.
In embodiments of the invention, the pharmaceutical composition of the specific related compound containing the amount within regulation limitation It is commercially available composition, because it can be mass produced.
In one embodiment, pharmaceutical composition of the invention is entirely free of ether, such as ether.
In one embodiment, pharmaceutical composition of the invention does not have completely a slaine, for example alkali metal salt and/or For the salt saltoutd, such as NaCl or KCl.
It is prepared by the method that the pharmaceutical composition of embodiment of the present invention can pass through to comprise the following steps：A () purifying is included The amphipathic nature block polymer of hydrophilic block (A) and hydrophobic block (B)；B () is by selected from taxol and Docetaxel The medicine of one or more poorly water-soluble and the amphipathic nature block polymer of purifying dissolve in organic solvent；(c) to step Suddenly aqueous solvent is added in the solution for obtaining in (b) to form polymer micelle.
The purifying of amphipathic nature block polymer is as described above, polymer micelle can be formed with conventional method.
In the method for preparing the pharmaceutical composition of embodiment of the present invention, it is possible to use be selected from alcohol (such as second Alcohol), acetone, tetrahydrofuran, acetic acid, the miscible organic solvents of acetonitrile and dioxane and combinations thereof as organic solvent, But it is not limited to this.Further, it is possible to use selected from conventional water, distilled water, distilled water for injection, physiological saline, 5% glucose, One kind in buffer solution and combinations thereof is used as aqueous solvent, but not limited to this.
The method for preparing pharmaceutical composition of the present invention may additionally include removing organic solvent after the step (a).
In one embodiment, methods described may also include addition lyophilization aid to freeze micelle composition.Can be Freeze-dried composition adds lyophilization aid to maintain pie.In another embodiment, lyophilization aid can be selected from sugar and sugar One or more in alcohol.Sugar can be one or more in lactose, maltose, sucrose or trehalose.Sugar alcohol can be with It is one or more in mannitol, sorbierite, maltitol, xylitol and lactitol.Lyophilization aid can also be used to promote Enter uniform dissolution of the lyophilized polymer micelle composition in reconstruct.Based on the gross weight of freeze-dried composition, lyophilization aid Content can be 1-90 weight %, particularly 1-60 weight %, more particularly 10-60 weight %.
By following examples, the present invention will be described in more detail.However, these embodiments are intended merely to illustrate this It is bright, and embodiment limited the scope of the present invention never in any form.
Embodiment
Preparation example 1：The diblock copolymer (mPEG-PDLLA) being made up of mono methoxy polyethylene glycol and D, L- lactide Synthesis and by sublimation method purify
By 150g mono methoxy polyethylene glycols, (000) mPEG, number-average molecular weight=2 are added to equipped with agitator In 500ml round-bottomed flasks, and 2 hours are stirred under 120 DEG C of vacuum conditions to remove moisture.In being dissolved in 200 μ l toluene 0.15g tin octoates (Sn (Oct)2) reaction flask is added to, and be stirred for 1 hour under vacuum to distill and remove first Benzene.150g D are subsequently adding, L- lactides simultaneously stir under nitrogen atmosphere to dissolve.In D, after L- lactides are completely dissolved, will Reactor tight seal, and polymerisation is carried out at 120 DEG C 10 hours.After reaction terminating, under bar magnet stirring, by reactor Vavuum pump is connected to, product is purified 7 hours under the pressure of 1 support or lower by sublimation method, obtains 262g molten conditions mPEG-PDLLA.By with1H-NMR analyses obtain the end group-OCH with regard to mono methoxy polyethylene glycol3Appropriate peak phase To intensity, so as to calculate molecular weight (Mn：～3740).
Preparation example 2：Diblock copolymer (mPEG-PDLLA) is purified by sublimation method
The 30g mPEG-PDLLA carried out before purge process obtained in the polymerization process of preparation example 1 are added Dissolve in single neck flask and at 80 DEG C.Under bar magnet stirring, reactor is connected into vavuum pump, and in 1 support or lower Pass through sublimation method purified product 24 hours and 48 hours under pressure.
Preparation example 3：Diblock copolymer (mPEG-PDLLA) is purified by sublimation method
In addition to cleansing temp is 100 DEG C, by being purified with the identical method of preparation example 2.
Preparation example 4：Diblock copolymer (mPEG-PDLLA) is purified by sublimation method
In addition to cleansing temp is 120 DEG C, by being purified with the identical method of preparation example 2.
Preparation example 5：Using aluminum oxide (Al2O3) pass through purification via adsorption-based process diblock copolymer (mPEG-PDLLA)
The 30g mPEG-PDLLA carried out before purge process obtained in the polymerization process of preparation example 1 are added In single neck flask and add acetone (60ml) dissolve.It is added thereto to aluminum oxide (15g) and is thoroughly mixed.By single neck flask and rotation Turn evaporimeter connection, content mixes 2 hours under 50 DEG C, 60rpm.Then solution used at room temperature PTFE filter paper (1 μm) Filter to remove aluminum oxide.Filtered acetone soln is distilled under 60 DEG C of vacuum using rotary evaporator and removes acetone, by This obtains the mPEG-PDLLA of purifying.By with1H-NMR analyses obtain the end group-OCH with regard to mono methoxy polyethylene glycol3 Appropriate peak relative intensity, so as to calculate molecular weight (Mn：～3690).
The change of molecular weight of the mPEG-PDLLA of the purification condition in above-mentioned preparation example 2-5 is shown in table 1 below.
Table 1
From the results shown in Table 1, as cleansing temp is uprised, the decrement of the molecular weight of mPEG-PDLLA increases. 80-100 DEG C and 24-48 hours, particularly 100 DEG C and the purification condition of 24 hours can be considered as effective.
Embodiment 1：The preparation of the polymer micelle composition containing taxol
The mPEG-PDLLA obtained in 1g taxols and 5g preparation examples 1 is weighed, 4ml ethanol is added, stirs straight at 60 DEG C It is completely dissolved to form settled solution to mixture.Then the rotary evaporator equipped with round-bottomed flask is used to reduce pressure at 60 DEG C steaming Evaporate 3 hours to remove ethanol.Then temperature is reduced into 50 DEG C, adds the distilled water under 140ml room temperatures, and carry out reaction until Solution becomes the blueness clarified to form polymer micelle.2.5g Lactis Anhydrouses are added thereto to as lyophilization aid and make its complete CL, is filtered using filter of the aperture for 200nm, and freeze-drying, obtains the polymer powder glue containing taxol Beam composition.
Embodiment 2：The preparation of the polymer micelle composition containing taxol
In addition to using the mPEG-PDLLA that 24 hours are purified in preparation example 3, by method same as Example 1 Prepare the polymer micelle composition containing taxol.
Embodiment 3：The preparation of the polymer micelle composition containing taxol
In addition to using the mPEG-PDLLA purified in preparation example 5, prepared by method same as Example 1 and contained There is the polymer micelle composition of taxol.
Experimental example 1：Related compound is separated by liquid chromatogram
To accommodating through 6 months accelerated test (temperature：40 DEG C) 100mg contain the polymer micelle group of taxol 16.7ml deionized waters (DW) are added in the bottle of compound, content is completely dissolved, the liquid of total amount is taken and is transferred to 20ml In volumetric flask, it is 20ml (5.0mg/ml) to be diluted to graticule and make cumulative volume.Take the 2ml liquid and be transferred in 10ml volumetric flasks, It is 10ml (1mg/ml) to add acetonitrile to graticule to make cumulative volume.For above-mentioned composition, using following liquid chromatography phase is separated Related compounds and Fractional Collections.
Liquid phase chromatogram condition
1) post：Poroshell 120PFP (4.6 × 150mm, 2.7 μm, Agilent)
2) mobile phase：A：DW/B：Acetonitrile
3) flow velocity：0.6ml/ minutes
4) injection volume：10μl
5) detector：Ultravioblet spectrophotometer (measurement wavelength：227nm)
The chromatogram of the HPLC analyses for obtaining shows in FIG.
Experimental example 2：The thermal decomposition test of taxol
From the related compound of Fractional Collections in the polymer nano granules composition containing taxol in experimental example 1 In, many polymer exist simultaneously, therefore are difficult to carry out direct experiment.As in the preliminary experiment carried out using LC/MS/MS The qualitative analysis, related compound is considered as to be combined the compound for producing with water by taxol.Accordingly, as addition moisture The method of son, carries out heating the experiment of taxol to be confirmed whether to produce the related compound for speculating.First, 1g taxols are existed Kept for 2～3 hours at 170 DEG C, and be dissolved completely in 45ml acetonitriles, be then added thereto to 5ml DW.It is molten by using this Liquid, separates the related compound and Fractional Collections of RRT 0.96 in preparative LC.
Experimental example 3：Qualitative analysis is carried out to related compound using LC/MS/MS
By liquid chromatogram and mass spectrograph (LC/MS/MS) to the detached related compound (RRT in experimental example 1-2： 0.96 ± 0.02 (0.94～0.98)) it is analyzed.According to HPLC analysis results, in experimental example 2 material of Fractional Collections with The related compound at RRT 0.96 in polymer micelle composition (Fig. 4) shows HPLC peaks at identical position.Pass through LC/MS/MS is further analyzed to the material.First as the result of MS scannings, two kinds of materials show m/z 894.1amu, it is [M+H2O+Na]+(Fig. 2 and Fig. 3).Then Product ion scans are carried out, in the results are shown in Fig. 4.Show together That what is shown also has the RRT 0.96 formed in the polymer nano granules composition containing taxol of six months accelerated tests Related compound result.In a word, it can be verified that thermally decompose to be segmented at RRT 0.96 after taxol in experimental example 2 and receive The material of collection is the phase at the positions of RRT 0.96 produced after six months accelerated tests with polymer micelle composition Related compounds have mutually isostructural compound.
It is serial using the series of liquid chromatogram 1200 and electrospray ionization mass spectrometry instrument 6400 in following measurement (Agilent, the U.S.) is used as LC/MS/MS.Analysis condition is as follows.
Liquid phase chromatogram condition
1) post：Poroshell 120PFP (4.6 × 150mm, 2.7 μm, Agilent)
2) mobile phase：A：DW/B：Acetonitrile
Time (minute) A% B%
0.00 65 35
25.00 45 55
28.00 45 55
30.00 65 35
35.00 65 35
3) flow velocity：0.6ml/ minutes
4) injection volume：10μl
5) detector：Ultravioblet spectrophotometer (measurement wavelength：227nm)
The condition of electrospray ionization mass spectrometry instrument
1) ionize：Electron spray ionisation, just (ESI+)
2) MS methods：MS2 scannings/Product ion scans
3) ion gun：Agilent Jet Stream ESI
4) nebulizer gas (pressure)：Nitrogen (35psi)
5) ion spray voltage：3500V
6) dry gas temperature (flow velocity)：350 DEG C (7L/ minutes)
7) sheath temperature degree (flow velocity)：400 DEG C (10L/ minutes)
8) fragmentation voltage：135V
9) spray nozzle voltage：500V
10) pond accelerating potential：7V
11)EMV：0V
12) collision energy：22V
13) precursor ion：m/z 836.2
14) mass scan range：M/z 100～1500
The material for analysis for separating from detection-phase and produce is set to flow in a mass spectrometer, while qualitative point The detection ion of phase separation related compounds, and select mass spectrographic characteristic ion [M+Na].
Experimental example 4：To carrying out NMR point in the material that RRT 0.96 is obtained by the mixture as obtained by thermally decomposing taxol Analysis
As NMR in experimental example 2 by the material that obtains in RRT 0.96 of mixture as obtained by thermally decomposing taxol It is analyzed.In NMR analyses,1H NMR analysis result show in Figure 5,13C NMR analysis result show in figure 6, The result of COSY (correlation spectrum) analyses shows that in the figure 7 HMBC (heteronuclear multiple-bond correlation spectrum) analyzes shown in Figure 8.
According to analysis result, the thing obtained in RRT0.96 by the mixture as obtained by thermally decomposing taxol is can confirm that Matter (the related compound i.e. in the polymer micelle composition containing taxol of the invention of six months accelerated tests (RRT：0.96 ± 0.02 (0.94～0.98)) be following taxol Yu water combining form.
The combining form of taxol and a molecular water：C47H53NO15(871.94g/mol)。
The condition of NMR spectrum
1.1H
1) NMR equipment：It is equipped with the Brucker DRX-900 of temperature controller
2) sample/solvent：1-10mg samples/0.6mL chloroform-d in the NMR pipes that external diameter is 5mm are (in all NMR realities In testing, using identical sample)
3) pop one's head in：Brucker 5mm CPTCI
4) 90 ° of pulse widths of proton/excite angle/capture time：7.4 microsecond/30 °/3.3 second
5) relaxation delay/scanning times：2.0 seconds/16
2.13C
1) pop one's head in：Brucker 5mm CPTCI
2) 90 ° of pulse widths of carbon/excite angle/capture time：11.8 microsecond/30 °/0.58 second
3) relaxation delay/scanning times：3.0 seconds/656
3.COSY
1) NMR equipment：Brucker DRX-900
2) pop one's head in：Brucker 5mm CPTCI
3) pulse train：Cosygpqf pulse trains
4) 90 ° of pulse width/capture times of proton：7.4 microsecond/0.13 second
5) relaxation delay/scanning times/ω1Experiment number：1.5 seconds/4/320
4.HMBC
1) NMR equipment：Brucker DRX-900
2) pop one's head in：Brucker 5mm CPTCI
3) pulse train：Hmbcgplpndqf pulse trains
4) 90 ° of proton, 90 ° of pulse width/carbon pulse width/capture time：7.7 microsecond/11.8 microsecond/0.12 second
5) relaxation delay/scanning times/ω1Experiment number：1.5 seconds/4/320
6) temperature/1/2 (JCH)：283K/3.5 milliseconds.
Experimental example 5：The contrast test of the storage stability of the polymer micelle of (80 DEG C) containing medicine under strict conditions
The polymer micelle composition of the taxol prepared in embodiment 1-3 is kept into 3 weeks in 80 DEG C of baking oven, so Afterwards with HPLC analysed compositions comparing the amount of related compound.By the way that micelle composition is dissolved in 80% acetonitrile solution And be diluted to paclitaxel concentration for 600ppm to prepare test solution.HPLC analysis obtained by chromatogram show in fig .9, and During changes of contents (%) according to the related compound of severe test time is shown in table 2 below.
HPLC conditions
Post：2.7 μm of diameter, Poroshell 120PFP (4.6 × 150mm, 2.7 μm) (Agilent posts)
Mobile phase
Time (minute) Water:Acetonitrile
0～25 65:35→45:55
25～28 45:55
28～30 45:55→65:35
30～35 65:35
Detector：Ultravioblet spectrophotometer (227nm)
Flow velocity：0.6ml/ minutes
The amount (%)=100 (Ri/Ru) of each related compound
Ri：The area of the every kind of related compound detected in test solution analysis
Ru：The summation of all peak areas detected in test solution analysis
[table 2]
*RRT 0.87±0.02：Taxol, oxetanes opened loop compound
RRT 0.96±0.02：Taxol, oxetanes opened loop compound
RRT 1.00:Taxol
RRT 1.10±0.02：Taxol, L- lactide compound of reactions
RRT 1.12±0.02：Taxol, D- lactide compound of reactions
RRT 1.44±0.05：Taxol, removes hydrate
Knowable to table 2 and Fig. 9, compared with the composition of embodiment 1, the polymeric micelle medicine composition of embodiment 2 or 3 Stability be improved, the reduction of taxol amount is relatively small, therefore can more stably maintain contained drug in composition Effect.
Experimental example 6：The contrast test of the storage stability of the polymer micelle of (40 DEG C) containing medicine under acceleration conditions
Except by the polymer micelle composition of the taxol for preparing in embodiment 1 in stability meter in 40 DEG C Outside lower holding 6 months, by being tested with the identical method of experimental example 5.By according to the related compounds of accelerated test time The changes of contents of thing is shown in table 3 below.
[table 3]
Above-mentioned result of the test is shown in the test that to different batches 3 kinds or more kinds of polymer micelle compositions are carried out The mean value of the amount of every kind of related compound and taxol.The amount of each related compound shows difference between batch, under Table represents the situation of the batch that most related compounds are detected in the test of each batch.
[table 4]
In the quality control of medicine, because peak and its mean value of specific impurities are no less importants, therefore must The quality of composition must be improved so that these values can be reduced fundamentally.
By EXPERIMENTAL EXAMPLE 5, it has proved that the polymeric micelle medicine composition of embodiment 2 or 3 and the group of embodiment 1 Compound compares the lower amount of related compound of display.If it could therefore be concluded that (40 DEG C) storages 6 at a temperature of accelerating storage Month, compared with the amount of the composition of the embodiment 1 shown in above-mentioned table 3, the composition of embodiment 2 or 3 can have lower amount of Related compound.

Claims (16)

1. polymeric micelle medicine composition, it is included：
Amphipathic nature block polymer comprising hydrophilic block (A) and the purifying of hydrophobic block (B), and
The medicine of one or more poorly water-soluble, it is selected from taxol and Docetaxel,
Wherein when described pharmaceutical composition is stored 6 months at 40 DEG C, it contains with the initial of the medicine of the poorly water-soluble Measure the related compound represented by following formula 1 below 0.2 weight portion for 100 weight portion meters：
[formula 1]
Wherein：
R1For H or COCH3, R2For phenyl or O (CH3)3。
2. pharmaceutical composition according to claim 1, the compound of wherein formula 1 is the compound with following formula 1a：
[formula 1a]
3. pharmaceutical composition according to claim 1, it contains with the primary quantity of the medicine of the poorly water-soluble as 100 weights The related compound of 0.18 weight portion Formula 1 below of amount part meter.
4. pharmaceutical composition according to claim 3, it contains with the primary quantity of the medicine of the poorly water-soluble as 100 weights The related compound of 0.16 weight portion Formula 1 below of amount part meter.
5. pharmaceutical composition according to claim 4, it contains with the primary quantity of the medicine of the poorly water-soluble as 100 weights The related compound of 0.13 weight portion Formula 1 below of amount part meter.
6. pharmaceutical composition according to claim 5, it contains with the primary quantity of the medicine of the poorly water-soluble as 100 weights The related compound of 0.1 weight portion Formula 1 below of amount part meter.
7. pharmaceutical composition according to claim 1, when described pharmaceutical composition is stored 3 weeks at 80 DEG C, it contains Primary quantity by the medicine of the poorly water-soluble is the related compound of 1.2 weight portion Formula 1 below in terms of 100 weight portions.
8. pharmaceutical composition according to claim 1, wherein the hydrophilic block (A) comprising selected from polyethylene glycol or its One or more in derivative, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylamide and combinations thereof.
9. pharmaceutical composition according to claim 1, wherein the hydrophobic block (B) is comprising selected from polylactide, poly- Glycolide, poly- mandelic acid, polycaprolactone, Ju diox -2- ketone, polyaminoacid, poe, polyanhydride, Merlon and its group One or more for closing.
10. pharmaceutical composition according to claim 1, wherein the hydrophilic block (A) is polyethylene glycol or single methoxy Base polyethylene glycol, the hydrophobic block (B) is polylactide.
11. pharmaceutical compositions according to claim 1, wherein the number-average molecular weight of the hydrophilic block (A) is 200- 20,000 dalton, the number-average molecular weight of the hydrophobic block (B) is 200-20,000 dalton.
12. pharmaceutical compositions according to claim 1, wherein the amphipathic nature block polymer is by sublimation purification Amphipathic nature block polymer.
13. pharmaceutical compositions according to claim 12, wherein the distillation is at a temperature of 80-120 DEG C and 10 The distillation carried out under the pressure of the following vacuum of support.
14. pharmaceutical compositions according to claim 13, wherein the distillation carries out 10-74 hours.
15. methods for preparing polymeric micelle medicine composition, it includes：
Amphipathic nature block polymer of (a) purifying comprising hydrophilic block (A) and hydrophobic block (B)；
B () will be total to selected from the medicine of taxol and one or more poorly water-soluble of Docetaxel and the amphipathic block of purifying Polymers dissolves in organic solvent；With
Aqueous solvent is added in c solution that () obtains in step (b) to form polymer micelle；
Wherein when described pharmaceutical composition is stored 6 months at 40 DEG C, it contains with the initial of the medicine of the poorly water-soluble Measure the related compound represented by following formula 1 below 0.2 weight portion for 100 weight portion meters：
[formula 1]
Wherein：
R1For H or COCH3, R2For phenyl or O (CH3)3。
16. methods according to claim 15, it is additionally included in after the step (a) and removes organic solvent.
CN201680001944.8A 2015-07-28 2016-07-28 Pharmaceutical composition with improved storage stability and method for preparing the same Pending CN106659680A (en)

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US8853351B2 (en) * 2007-12-31 2014-10-07 Samyang Biopharmaceuticals Corporation Highly pure amphiphilic copolymer comprising hydrophobic block from alpha-hydroxy acid and process for the preparation thereof
JP2015034172A (en) * 2007-12-31 2015-02-19 サムヤン バイオファーマシューティカルズ コーポレイション Taxane-containing amphiphilic block copolymer micelle composition and manufacturing method of the same
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