CN109010844A - One kind is according to Shandong for Buddhist nun's phosphatide complexes and preparation method thereof - Google Patents
One kind is according to Shandong for Buddhist nun's phosphatide complexes and preparation method thereof Download PDFInfo
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- CN109010844A CN109010844A CN201710425758.3A CN201710425758A CN109010844A CN 109010844 A CN109010844 A CN 109010844A CN 201710425758 A CN201710425758 A CN 201710425758A CN 109010844 A CN109010844 A CN 109010844A
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- phosphatide
- shandong
- buddhist nun
- phosphatide complexes
- ibr
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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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
Abstract
The present invention relates to one kind according to Shandong for Buddhist nun's phosphatide complexes and preparation method thereof.Replacing Buddhist nun's phosphatide complexes according to Shandong includes according to Shandong for Buddhist nun and phosphatide, and replacing the molar ratio of Buddhist nun and phosphatide according to Shandong is 1:0.5~1:5.The phosphatide is one or more of phosphatidyl glycerol, phosphatidic acid, phosphatidylserine, the pure and mild cardiolipin of phosphatidyl-4.The present invention can obviously improve drug solubility energy, increase drug absorption, improve drug bioavailability, in particular, being the compound of 1:1 with the molar ratio of yolk phosphatidylglycerol preparation, bioavilability improves 14 times.
Description
Technical field
The present invention relates to one kind according to Shandong for Buddhist nun's phosphatide complexes and preparation method thereof, further relate to compound for Buddhist nun's phosphatide according to Shandong
Pharmaceutical composition of the object as active constituent, belongs to pharmaceutical technology field.
Background technique
According to Shandong, for Buddhist nun, (Ibrutinib, IBR were once the bruton's tyrosine of the first listing in the whole world with code name PCI-32765)
Kinases (Bruton tyrosine kinase, BTK) selectivity and covalency inhibitor (Davids MS, Brown
JR.Ibrutinib:a first in class covalent inhibitor of Bruton's tyrosine kinase
[J] .Future Oncology, 2014,10 (6): 957-967.), initially by Sai Laila Genentech, Inc. (US) 460 Point San Bruno Blvd, South San Francisco, CA, 94080 of the U.S. (Celera
Genomics it) develops, later Pharmacyclics company obtains Celera Genomics company with 2,000,000 dollars of down payment
BTK research and develop pipeline, including IBR.Under Johnson & Johnson Yang Sen biotechnology company (Jassen) and Pharmacyclics in
In December, 2011 signs authorized agreement and develops jointly IBR.Jassen possesses IBR in entire Europe, the Middle East and Africa and the U.S.
The commercialization right of other parts of the world in addition.Biotechnology giant Ai Baiwei (AbbVie) in 2015 21000000000 dollars of cost
Pharmacyclics company is purchased, obtains IBR in the power of sale of American market.From 13 Nikkei FDA November in 2013 ratify with
Come, short triennium, global annual turnover breaks through 1,400,000,000 dollars.Breakthrough drug is passed through, has preferentially evaluated, accelerates to criticize
The granted treatment recurrent of a variety of fast routes such as standard, Orphan drug qualification or intractable lymphoma mantle cell (Mantle cell
Lymphoma, MCL), controlled chronic lymphocytic leukemia (Chronic lymphocytic leukemia, CLL) and
(Jerkeman M, Hallek M, Dreyling M, the et al.Targeting of such as Waldenstrom macroglobulinemia
B‐cell receptor signalling in B‐cell malignancies[J].Journal of Internal
Medicine,2017.)。
IBR molecular skeleton is made of three segments, i.e. phenoxy phenyl segment, pyrazolopyrimidine amine segment and optically active N-
Acryloylpiperidine ring structure, entitled 1- [(3R) -3- [4- amino -3- (4- the Phenoxyphenyl) -1H- pyrazolo [3,4- of chemistry
D] pyrimidine -1- base] -1- piperidyl] -2- propylene -1- ketone, molecular formula C25H24N6O2, relative molecular mass 440.50, chemistry
Structural formula is as follows.Appearance is non-hygroscopic white or off-white powder, and fusing point is 149-158 DEG C, and dissociation constant (pKa) is
3.74, distribution coefficient (Log P) is 3.97 (in n-octyl alcohol/pH7.0 buffer solutions), in the aqueous solution of pH 4.5-8 almost
Insoluble (3 μ gmL-1), HCl solution is slightly soluble in pH 1.2, it is insoluble in nonpolar solvent, for example (,) hexane and heptane, slightly soluble
In ethyl acetate, ethyl alcohol and acetonitrile, it is dissolved in acetone and methanol, is soluble in n,N-Dimethylformamide, tetrahydrofuran and dichloromethane
Alkane (Zheng little Juan, Wang Jingsi, Gong Li, et al. replace Buddhist nun according to Shandong: comment by a kind of novel cloth Shandong tyrosine kinase inhibitor [J] drug
Valence research, 2014,37 (4): 381-384).Belong to the second class drug, i.e. low solubility, high osmosis class in BCS categorizing system
Drug.
According to Shandong for Buddhist nun listed dosage form be capsule, specification 140mg/, trade nameAuxiliary material includes carboxylic first
Base sodium cellulosate, magnesium stearate, microcrystalline cellulose, NaLS.Oral, 1 time/d, 4 tablets/time (560mg) for treating
MCL；Oral, 1 times/day, 3 tablets/time (420mg) for treating CLL.Adverse reaction mainly include bleeding, infection, bone marrow suppression,
(2 months FDA of Zhang Jianzhong .2014 ratify the Shanghai new drug overview [J] for renal toxicity, second primary malignant tumour, embryo-fetal toxicity
Medicine, 2014, (7): 60-61).In MCL patient most common generation adverse reaction (>=20%) be decrease of platelet, diarrhea, in
The reduction of property granulocyte, anaemia, tired, musculoskeletal pain, peripheral oedema, the infection of the upper respiratory tract, nausea, bruise, expiratory dyspnea, just
Secret, fash, abdominal pain, vomiting and appetite lower.In CLL patient most common adverse reaction (>=20%) be decrease of platelet, diarrhea,
Bruise, Neutrophilic granulocytopenia, anaemia, the infection of the upper respiratory tract, tired, musculoskeletal pain, fash, fever, constipation, periphery water
Swollen, arthralgia, nausea, stomatitis, sinusitis and dizziness.Most common 3 or 4 grades of non-blood adverse reactions (>=5%) are pneumonia, height
Blood pressure, atrial fibrillation, sinusitis, skin infection, dehydration and musculoskeletal pain (old this river treatment lymphoma mantle cell and chronic leaching
Bar chronic myeloid leukemia new drug -- Buddhist nun (ibrutinib) [J] medicine Leader, 2014,33 (10): 1336-1338. are replaced according to Shandong).
Under fasting conditions, taking orally and replacing the absolute bioavailability of Buddhist nun's capsule according to Shandong is 2.9%, takes the absolute life of food
Object availability is 2 times of empty stomach.Healthy People single oral dose radioactivity14After the IBR of C flag, about 90% radiopharmaceutical exists
It is removed in vivo within 168 hours, wherein 80% is discharged from excrement, nearly 10% is discharged from urine.In the excrement of label, closely
1% is original shape medicine, and without original shape medicine in urine drains thing, this also prompt IBR it is most of be all metabolized in vivo (Scheers E,
Leclercq L,De JJ,et al.Absorption,metabolism,and excretion of oral 14C
radiolabeled ibrutinib:an open-label,phase I,single-dose study in healthy men
[J].Drug Metabolism&Disposition the Biological Fate of Chemicals,2015,43(2):
289-297.)。
Phosphatide is a kind of phosphorous lipid material, and being divided into glycerophosphatide (skeleton is glycerol) and sphingomyelins, (skeleton is sheath ammonia
Alcohol) two major classes, it is every a kind of to be divided into natural, semi-synthetic phosphatide and fully synthetic phosphatide again.Natural phospholipid is mainly derived from big beans and plants
Object or the skin of animal, brain and liver.It is phosphatidyl choline according to the different instructions of polar head group
(Phosphatidylcholines, PC), phosphatidyl-ethanolamine (Phosphatidylethanolamines, PE), phosphatidyl silk
Propylhomoserin (Phosphatidylserines, PS), phosphatidylinositols (Phosphatidylinositols, PI), phosphatidyl glycerol
(phosphatidylglycerol, PG), phosphatidic acid (phosphatidicacid, PA) etc. (Li J, Wang X, Zhang T,
et al.A review on phospholipids and their main applications in drug delivery
systems[J].Asian Journal of Pharmaceutical Sciences,2015,10(2):81-98.).Natural phosphorus
The Typical Representative of rouge is soybean lecithin and egg yolk lecithin, and the representative of semi-synthetic phosphatide is hydrogenated soy phosphatidyl choline, fully synthetic
The representative of phosphatide is Distearoyl Phosphatidylcholine (DSPC), distearoylphosphatidylglycerol (DSPG).Researchers generally adopt
Phosphatide complexes are prepared with PC, PE and PS, wherein PC is applied and studied and is the most extensive.It is worth noting that, Mikko
J.Parry for the first time by siramesine and phosphatidic acid (PA) be successfully prepared into high affinity small molecule phosphatide complexes (Parry MJ,
Alakoskela JMI,Khandelia H,et al.High-Affinity Small Molecule-Phospholipid
Complex Formation:Binding of Siramesine to Phosphatidic Acid[J].Journal of
the American Chemical Society,2008,130(39):12953-12960.).So far, there is not been reported
Phosphatide complexes are prepared using phosphatidyl glycerol.
Yolk phosphatidylglycerol (EPG) structural formula:
Phosphatide complexes (Phytosomes or phospholipid complexes) refer to the drug in suitable solvent
With phosphatide with certain stoichiometric ratio relationship in conjunction with and formed compound.Canadian Venkataram is reported earliest within 1984
It is studied about phosphatide complexes, they have found for drug griseofulvin to be dissolved in jointly in chloroform with phosphatide, and to boil off solvent resulting solid
Body co-precipitate, that is, phosphatide solid dispersion has apparent facilitation to the dissolution of drug.Italian scholar in 1989
Bombardelli etc. it has also been found that the compound features that are formed in conjunction with phosphatide of certain active skull cap components go out it is significant with former compound
Different physicochemical properties and biological characteristics.Currently, the formation mechenism of phosphatide complexes is still not clear, Bombardelli once recognized
Mechanism of action for phosphatide complexes is that drug molecule can generate formation of chemical bond noval chemical compound with phospholipid molecule, but majority is ground
The persons of studying carefully think that the interaction force between phosphatide complexes is intermolecular force, predominantly hydrogen bond and Van der Waals force.
Yiqiong Pu simulates the three-dimensional conformation of 20 (S)-protopanoxadiols and phosphatide by computer software and carries out drug and phosphatide
Molecular docking experiment when molar ratio is 1: 1, finds the hydrophobic part of 20 (S)-protopanoxadiol molecules by the two of phospholipid molecule
Hydrophobic chain surrounds, some-OH of drug molecule can form hydrogen bond with phospholipid molecule-P=O, and docking free energy is-
3.3kcal·mol-1(Pu Y,Zhang X,Zhang Q,et al.20(S)-Protopanaxadiol Phospholipid
Complex:Process Optimization,Characterization,In Vitro Dissolution and
Molecular Docking Studies[J].Molecules,2016,21(10):1396.).Yu.G.Afanas'eva by
Quantum chemistry and13C NMR has studied Kaempferol, Quercetin and myricetin simultaneously and phosphatidyl choline forms the effect of compound
Power, discovery formed stable compound it is most probable the reason is that they can with choline occur pi-electron complexing while and phosphate
Form stable hydrogen bond (Afanas ' eva YG, Fakhretdinova ER, Spirikhin LV, et al.Mechanism of
interaction of certain flavonoids with phosphatidylcholine of cellular
membranes[J].Pharmaceutical Chemistry Journal,2007,41(7):354-356.).Drug and phosphatide
After forming compound, the absorption of drug in the gastrointestinal tract can increase, improve bioavilability, improve curative effect.
Summary of the invention
The object of the present invention is to provide one kind according to Shandong for Buddhist nun's phosphatide complexes and preparation method thereof.It is not dissolved in for IBR
Water (3 μ gmL-1), capsule absolute bioavailability only has 2.9% and the big problem of clinical administration dosage, is made into
Phosphatide complexes increase drug absorption to increase the water solubility of IBR, improve drug bioavailability, and can be improved one kind can
With the product of injection, it to be used for critical patient.
In order to solve the above technical problems, technical solution provided by the invention is as follows: a kind of to replace Buddhist nun's phosphatide complexes, packet according to Shandong
It includes according to Shandong for Buddhist nun and phosphatide, replacing the molar ratio of Buddhist nun and phosphatide according to Shandong is 1:0.5~1:5.Phosphatide includes phosphatidyl glycerol, phosphatide
The pure and mild cardiolipin of acid, phosphatidylserine, phosphatidyl-4.Can be it is natural, semi-synthetic with it is fully synthetic, as yolk phospholipid acyl is sweet
Oily (EPG), hydrogenation yolk rouge phosphatidyl glycerol (HEPG), dioleoylphosphatidylglycerol (DOPG).It can be used one or two kinds of
The composition of the above phosphatide.
Above-mentioned replaces in Buddhist nun's phosphatide complexes according to Shandong, and replacing the molar ratio of Buddhist nun and phosphatide according to Shandong is 1:0.5~1:3.
Above-mentioned replaces in Buddhist nun's phosphatide complexes according to Shandong, it is preferable that replacing the molar ratio of Buddhist nun and phosphatide according to Shandong is 1:1~1:2.
The present invention also provides the preparation methods that Buddhist nun's phosphatide complexes are replaced according to Shandong, are prepared via a method which:
It will be dissolved in suitable organic solvent, be stirred to react at a certain temperature after a certain period of time for Buddhist nun and phosphatide according to Shandong,
Organic solvent is removed, is obtained according to Shandong for Buddhist nun's phosphatide complexes.It can be further using freeze-drying or spray drying technology.
Wherein, the organic solvent are as follows: in methanol, ethyl alcohol, the tert-butyl alcohol, isopropanol, acetonitrile, tetrahydrofuran and acetone
One or more kinds of combinations.
The reaction temperature are as follows: 20~60 DEG C.
The present invention also provides contain phosphatide complexes as above pharmaceutical composition, the pharmaceutical composition with pharmaceutically
Acceptable excipient can prepare clinically acceptable tablet, capsule, granule, pill, powder, ointment, oral
The preparations such as liquor, infusion solution, injection.The pharmaceutically acceptable excipient can resist for pharmaceutically acceptable be added
Oxygen agent, diluent, adhesive etc..
The present invention uses the phosphatidyl glycerol in phosphatide for the first time, has been surprisingly found that, prepared phosphatide complexes can be improved
It for Buddhist nun's solubility is more than 100 times according to Shandong, acquired solution is clear, this is showing of not reporting of previous phosphatide complexes
As；Relative bioavailability is 1468%, and rat absolute bioavailability is 109%, takes orally the inhibitory rate of antitumor S180
To the effect of intravenous injection.
Detailed description of the invention
Fig. 1 be according to Shandong for Buddhist nun (a), EPG (b), physical mixture (c) and phosphatide complexes (d) ultraviolet spectra；
Fig. 2 is the infrared spectrogram according to Shandong for Buddhist nun (a), EPG (b), physical mixture (c) and phosphatide complexes (d)；
Fig. 3 is to scheme according to Shandong for the DSC of Buddhist nun (a), EPG (b), physical mixture (c) and phosphatide complexes (d)；
Fig. 4 be according to Shandong for Buddhist nun (a), EPG (b), physical mixture (c) and phosphatide complexes (d) X-ray diffraction analysis
Figure；
Fig. 5 is IBR (a), EPG (b), physical mixture (c) and phosphatide complexes (d)1H NMR figure
Fig. 6 is IBR (a), EPG (b), physical mixture (c) and phosphatide complexes (d)13C NMR figure
Fig. 7 is the appearance after freeze-drying prods and redissolution
Fig. 8 is electromicroscopic photograph
Fig. 9 is according to Shandong for the stomach-filling of Buddhist nun's suspension (susp i.g.), molar ratio 1:1 phosphatide complexes stomach-filling (1-1 i.g.)
(1-1 i.v.) Drug-time curve figure is injected intravenously with molar ratio 1:1 phosphatide complexes.
Specific embodiment
Below with reference to embodiment, the present invention is further illustrated.
Instrument: BS124s electronic analytical balance (Sartorius AG)；DF-101S heat collecting type heated at constant temperature magnetic force stirs
Mix device (Ying Yu Yu Hua instrument plant of Gongyi City)；PB-10 type pH meter (Sartorius AG)；Anke TDL80-2B centrifuge
(Anting Scientific Instrument Factory, Shanghai)；UV1801 type ultraviolet-visible spectrophotometer (Beijing Rayleigh Analytical Instrument Co., Ltd)；
UV5100 type ultraviolet-visible spectrophotometer (Anhui Wanyi Science and Technology Co., Ltd.)；(Dalian is according to benefit for P230 high pressure constant flow pump
Special Analytical Instrument Co., Ltd)；The ultraviolet variable-wavelenght detector of UV200II (Dalian Yilite Analytical Instrument Co., Ltd)；HW-
2000 chromatographic data processing workstations (Dalian Yilite Analytical Instrument Co., Ltd)；AT-130 column oven (Tianjin Jin Zhou section
Learn Instrument Ltd.)；High-precision full-automatic AC voltage regulator (JONCHN Co., Ltd.)；0.45 μm of Polyvinylidene is micro-
Hole filter membrane (rub fast scientific equipment Co., Ltd in Shanghai)；Reagent: according to Shandong, for Buddhist nun's bulk pharmaceutical chemicals, (IBR, the prosperous damp biotechnology in Nanjing are limited
Company, purity >=99%)；Yolk phosphatidylglycerol (EPG, Shanghai Advanced viecle Technology Co., Ltd., purity >=97%)；Nothing
Water-ethanol (analyzes pure, Tianjin Ke Miou chemical reagent development centre)；(analysis is pure, and Tianjin richness space fine chemistry industry has for n-hexane
Limit company)；N-octyl alcohol (analysis is pure, and chemical reagent Manufacturing Co., Ltd is learned in perseverance Xinghua, Tianjin)；Acetonitrile (chromatographically pure, Shandong Yu
Chemical industry branch company of king Industrial Co., Ltd.)；Methanol (chromatographically pure, Shandong Yuwang Industrial Co., Ltd. Chemical Company)；Phosphoric acid hydrogen
Disodium (analyzes pure, Xilong Chemical Co., Ltd)；Sodium dihydrogen phosphate (analyzes pure, Xilong Chemical Co., Ltd)；Phosphorus
Acid (analyzes pure, Liaoning Jia Cheng fine chemicals Co., Ltd)
1 IBR solubility test of embodiment
It takes IBR appropriate, is separately added into suitable redistilled water, 5% ethyl alcohol (v/v), 10% ethyl alcohol (v/v), 20% ethyl alcohol (v/
V), n-hexane, n-octyl alcohol, acetonitrile, dehydrated alcohol, methanol, constant temperature stirring for 24 hours, prepares supersaturated solution at 25 DEG C.It takes respectively
Above-mentioned IBR suspension is appropriate, and 10000rpm is centrifuged 10min, and supernatant crosses 0.45 μm of miillpore filter, takes subsequent filtrate methanol dilution
Sample to be tested is made, its absorbance is measured under 260nm wavelength, the solubility of IBR in each solvent is calculated, the results are shown in Table 1.
Table 1IBR solubility
As shown in Table 1, IBR is dissolved in n-octyl alcohol and methanol, is slightly soluble in dehydrated alcohol, acetonitrile, and it is in redistilled water, 5% second
Insoluble in alcohol, 10% ethyl alcohol, 20% ethyl alcohol and hexamethylene, ethyl alcohol can increase IBR as cosolvent in water to a certain extent
In solubility, but increase degree is smaller, and 20% ethyl alcohol solubility only has 0.025mgmL-1, still fall within model not soluble in water
Farmland.
Influence of 2 pH of embodiment to solubility in IBR water
With 0.2molL-1Na2HPO4、0.2mol·L-1NaH2PO4 and 0.2molL-1H3PO4Solution is mother
It is spare to prepare the phosphate buffer that pH is 2.0,3.0,4.0,5.0,6.0,7.0,8.0 and 9.0 respectively for liquid.
It takes IBR appropriate, is separately added into different pH phosphate buffer solutions, for 24 hours in 25 DEG C of closed stirrings, preparation supersaturation is molten
Liquid.Take above-mentioned IBR suspension appropriate respectively, 10000rpm is centrifuged 10min, takes supernatant to cross 0.45 μm of miillpore filter, takes continuous filter
Liquid is moderately diluted with methanol is made sample to be tested, its absorbance is measured under 260nm wavelength, calculates the dissolution of IBR in each solvent
Degree, the results are shown in Table 2.
Solubility in 2 difference pH solution of table
As shown in Table 2, as pH value reduces, increase trend is presented in IBR solubility, and prompt may be the primary amine groups energy of IBR
Enough combine the H in water+, even if pH is that solubility is still smaller in 2.0, IBR water, only 0.22mgmL-1.
Remarks: chromatographic condition chromatographic column: Betasil C18 column (200mm × 4.6mm, 5 μm, according to Lyntech Corporation (US) 10177 South 77th East Avenue Tulsa, Oklahoma 74133 U.S.)；Flowing
Phase: acetonitrile-water (55: 45, v/v, 0.5%v/v triethylamine is added in water phase, and acetic acid adjusts pH=3.20)；Detection wavelength:
256nm；Flow velocity: 1.0mLmin-1；Sample volume: 20 μ L；Column temperature: 25 DEG C
The influence of 3 phospholipid species of embodiment
Select dehydrated alcohol as reaction dissolvent, the molar ratio of drug and phosphatide is set as 1: 1, and drug is in ethanol
Mass concentration is 10mgmL-1, reaction time 1.0h, reaction temperature is set as 60 DEG C, waves except ethyl alcohol, addition is preheated to 60 DEG C
Redistilled water, investigate the different phosphatide of EPG, SPG, E80, S100, soybean PI, natural PA, DOPA, PS90, DLPS10 to preparation outside
The influence of sight, the results are shown in Table 3.
The influence of 3 phospholipid species of table
Remarks: EPG--- yolk phosphatidylglycerol, HEPG--- hydrogenate yolk phosphatidylglycerol, SPG--- soybean phospholipid phosphatidyl
Glycerol, DSPG--- distearoylphosphatidylglycerol, DPPG--- dipalmitoylphosphatidylglycerol, bis- lauroyl phosphatide of DLPG---
Acyl glycerol, S100- soybean lecithin, E80--- egg yolk lecithin, soybean PI--- soybean-source phosphatidylinositols, DOPA---
Dioleoyl phospholipid acid, PS90--- phosphatidylserine, bis- lauroyl phosphatidylserine of DLPS---.
Liquid in table is filtered 0.45 μm, measurement replaces Buddhist nun's concentration according to Shandong.The result shows that except S100 and E80 are about
0.5mg·mL-1Except, other phosphatide can achieve 5mgmL-1, especially EPG, HEPG, SPG, DSPG, DPPG and DLPG
Phosphatide complexes concentration in water be more than 5mgmL-1.Since the concentration of IBR raw material in water is less than 5 μ gmL-1, very
Obviously, phosphatide improves 1000 times of drug solubility, and neutral phospholipid PC is about 100 times.
Inexpensively due to EPG price, it selects EPG as the phosphatide for preparing compound, carries out system research.
The influence in 4 reaction time of embodiment
Selection dehydrated alcohol is reaction dissolvent, and the molar ratio of drug and phosphatide EPG is set as 1: 1, and drug is in ethanol
Mass concentration and reaction temperature be same as above, investigate the reaction time be 0.5,1.0,1.5,2.0h is to drug recombination rate and formulation aesthetics
Influence, the results are shown in Table 4.
The influence in 4 reaction time of table
Remarks: recombination rate (%)=M2/M1× 100%.M1--- the dosage of IBR, M2--- the quality of compound IBR
As shown in Table 4, the recombination rate of drug and phosphatide is influenced smaller by the reaction time, and drug rubs with feeding intake for phosphatide EPG
When you are than being 1: 1, recombination rate is 90% or so, and appearance is achromaticity and clarification transparency liquid.
The influence of 5 reaction temperature of embodiment
Selection dehydrated alcohol is reaction dissolvent, and the molar ratio of drug and phosphatide EPG is set as 1: 1, and drug is in ethanol
Mass concentration and the reaction time with " embodiment 3 ", investigate when reaction temperature is 40,50,60 DEG C to drug recombination rate and preparation
The influence of appearance, the results are shown in Table 5.
The influence of 5 reaction temperature of table
As shown in Table 5, the recombination rate of drug and phosphatide is affected by temperature smaller, the molar ratio of drug and phosphatide EPG
When being 1: 1, recombination rate is 90% or so, and appearance is achromaticity and clarification transparency liquid.
The influence of 6 reactant concentration of embodiment
Selection dehydrated alcohol is reaction dissolvent, and the molar ratio of drug and phosphatide EPG are set as 1: 1, reaction temperature and anti-
With " embodiment 3 " between seasonable, investigating the mass concentration of IBR in ethanol is 5,10,15,20mgmL-1When to drug recombination rate
With the influence of formulation aesthetics, it the results are shown in Table 6.
The influence of 6 reactant concentration of table
As shown in Table 6, when drug concentration is in 5 and 10mgmL-1When, the recombination rate variation of drug and phosphatide is smaller, compound
Rate is 90% or so, and appearance is achromaticity and clarification transparency liquid；When drug concentration is 20mgmL-1When, recombination rate reduces, outside
Seeing is white opacity liquid, therefore the mass concentration of drug in ethanol should be controlled in 10mgmL-1Below.
Embodiment 7 replaces the influence of Buddhist nun and phosphatide molar ratio according to Shandong
Selection dehydrated alcohol is reaction dissolvent, and mass concentration, reaction temperature and the reaction time of drug in ethanol are the same as " real
Apply example 3 ", investigate drug and when phosphatide molar ratio is respectively 2: 1,1: 1,1: 2,1: 3 to the recombination rate and preparation of drug outside
The influence of sight, the results are shown in Table 7.
Table 7 replaces Buddhist nun and phospholipid molar ratio according to Shandong
As shown in Table 7, when molar ratio is 1:0.3, formulation aesthetics are white opacity shape, and recombination rate is less than 50%, bottom of bottle portion
There is precipitating；When molar ratio is 1:0.5, recombination rate is greater than 50%；When molar ratio is more than or equal to 1: 1, recombination rate is greater than 90%；When
When the molar ratio of drug and phosphatide is between 1:1~1:2, appearance is achromaticity and clarification transparency liquid.When molar ratio is greater than 2, by
Excessive in EPG, remaining EPG is dispersed in water, and shows the disperse properties of EPG itself, i.e. emulsus.When molar ratio is greater than 5, it is
Sticky fluid can not be successfully filtering.Therefore, the molar ratio of drug and phosphatide, which should control, is being less than or equal to 1:5.
In addition, EPG is mixed with DSPG according to 2:1, phosphatide complexes are prepared, similar results also can be obtained.
The verifying of the optimization technique of embodiment 8
According to result above, optimization technique is drafted are as follows: using dehydrated alcohol as reaction dissolvent, drug feeds intake with phosphatide EPG's
Molar ratio 1: 1, drug quality concentration are 10mgmL-1, reaction time 0.5h, and reaction temperature is set as 40 DEG C, waves except ethyl alcohol, add
Enter to be preheated to 40 DEG C of redistilled water, magnetic agitation 2min, 0.45 μm of filtering with microporous membrane removes not compound drug to get phosphatide
Compound aqueous dispersions.It determines three batches and is greater than 90% according to Shandong for the recombination rate of Buddhist nun's phosphatide complexes, appearance is that achromaticity and clarification is saturating
Prescribed liquid.
It is sub- with methanol, ethyl alcohol, the tert-butyl alcohol, isopropanol, acetonitrile, tetrahydrofuran, acetone, dimethyl using this optimization technique
Sulfone, dimethylformamide, ethyl acetate and chloroform investigate the case where different solvents prepare compound as solvent, the results showed that,
Compound, dimethyl sulfoxide, diformazan can be prepared in methanol, ethyl alcohol, the tert-butyl alcohol, isopropanol, acetonitrile, tetrahydrofuran and acetone
Base formamide, ethyl acetate and chloroform are not easy to obtain compound.
It is any two or more using methanol, ethyl alcohol, the tert-butyl alcohol, isopropanol, acetonitrile, tetrahydrofuran and acetone
Compound can be also prepared in different proportion mixed solvent.
Furthermore it is possible to be lyophilized using the tert-butyl alcohol-aqueous systems, lactose, mannitol, sorbierite, seaweed can also be added
The auxiliary materials such as sugar, dextran are spray-dried.
9 ultra-violet absorption spectrum of embodiment (UV)
The physical mixture and phosphatide complexes for taking a small amount of IBR, EPG, IBR and EPG are dissolved in methanol solution respectively, with first
Alcohol is blank, and UV scanning is carried out within the scope of 200~400nm, sees attached drawing 1.
As seen from the figure, IBR has absorption peak at 207nm and 260nm, and physical mixture has absorption at 206nm and 260nm
Peak, there are two there is absorption peak at 207nm and 260nm, IBR, physical mixture and phosphatide complexes three's phosphatide complexes exist
Ultraviolet absorpting spectrum is similar at 200~400nm, and three does not have significant difference.Show the chromophoric group structure of IBR in compound
It does not change, and not formed noval chemical compound.
10 infrared spectroscopy feature (IR) of embodiment
IBR, EPG, prescription ratio physical mixture, appropriate phosphatide complexes are taken respectively, carry out IR points with KBr pressed disc method
Analysis, 400~4000cm of wave-length coverage-1, IR scanning spectra is shown in attached drawing 2.
As seen from the figure, the infrared spectrogram of physical mixture is being superimposed for IBR and the peak EPG, the stretching vibration pair of IBR primary amine
The hydrocarbon flexible vibration of the stretching vibration peak (3428.9), long aliphatic chain of hydroxyl in peak (3469.3,3636.3) and EPG structure of phospholipid
The stretching vibration peak (1742.7) of carbonyl, the stretching vibration peak of phosphorus oxygen double bond in dynamic peak (2921.8,2853.4), aliphatic ester
(1256.0) and the stretching vibration peak of phosphorus oxygen singly-bound (1115.2) can be found, and illustrate the two in IBR and EPG physical mixture
Between do not interact, IBR still exists with crystal form.Compared with the map of physical mixture, the map of phosphatide complexes
Slight change occurs, the bimodal disappearance of the stretching vibration of IBR primary amine only shows unimodal 3418.0, and carbonyl is flexible in aliphatic ester
It vibrates peak intensity (1739.1) obviously to weaken, the stretching vibration peak remitted its fury (1114.6) of phosphorus oxygen singly-bound, the carbon of long aliphatic chain
There is no variations for hydrogen stretching vibration peak intensity and peak position.Therefore IBR and EPG is not simple physical mixed in compound, long
Aliphatic chain is not engaged in compound action, thus it is speculated that hydrogen atom and phospholipid molecule fatty acid in phosphatide complexes in the primary amine groups of IBR
Oxygen atom on oxygen atom or phosphorus atoms on ester carbonyl group forms hydrogen bond.
11 differential scanning calorimetry of embodiment (DSC)
Using empty aluminium crucible as reference, be put into appropriate sample to be tested in another aluminium crucible, sample to be tested be respectively IBR, EPG,
Prescription ratio physical mixture and phosphatide complexes, under nitrogen protection, heating rate: 10 DEG C of min-1, Wen Cheng: 30~200
DEG C carry out differential scanning calorimetric analysis, draw DSC curve figure see attached drawing 3.
As seen from the figure, it is 159.17 DEG C that IBR, which has an independent endothermic peak, is the fusing point peak of IBR；Phosphatide EPG also has one
Independent endothermic peak is 91.66 DEG C；Physical mixture endothermic peak containing there are two, is 91.04 DEG C and 158.23 DEG C respectively, with respective list
Only endothermic peak error is no more than 1 DEG C；And apparent variation occurs for the DSC map of compound, the typical endothermic peak of IBR disappears,
EPG endothermic peak is reduced to 83.80 DEG C from 91.66 DEG C.Show that IBR and EPG successfully prepare to form phosphatide complexes, and drug IBR
It is highly dispersed in phospholipid molecule and can't detect, EPG may be kept fatty since the interaction force of IBR and phosphatide hydrogen bond exists
The order of chain reduces, and endothermic peak reduction becomes 83.80 DEG C.
12 X-ray diffraction of embodiment analyzes (XRD)
IBR, EPG, prescription ratio physical mixture, phosphatide complexes are taken to carry out X-ray diffraction measurement in right amount respectively, if
Set testing conditions: Cu-K α target, measurement pipe press 40kV, pipe stream 30mA, and range of diffraction is 5 ° < 2 θ < 50 °, and the results are shown in attached figure 4.
As seen from the figure, there are crystal diffraction spikes by IBR and EPG, all have crystalline nature, the physical mixture of the two is each
The superposition at self-diffraction peak, does not generate new peak, shows therebetween without interaction.The crystal of IBR and EPG in phosphatide complexes
Diffraction maximum completely disappears, and shows that the interaction of IBR and EPG makes the two in high degree of dispersion state, and keeps respective crystal special
Sign is suppressed, and overall performance goes out unformed feature.
13 nmr spectrum of embodiment (1H NMR and 13C NMR)
With CD3OD is that solvent carries out IBR, EPG, prescription ratio physical mixture and phosphatide complexes1H NMR and13C
NMR measurement, the results are shown in attached figure 5 and attached drawing 6.
By attached drawing 5 and attached drawing 6 it is found that either1H NMR is still13The peak of C NMR, phosphatide complexes and physical mixture
Position and peak shape are almost unchanged, and the generation of not new chemical shift, compound does not form new chemical bond.
Synthesis, pass through many aspects such as ultraviolet, infrared, X-ray diffraction, differential scanning calorimetry and NMR spectrum
It proves, forms compound according to Shandong for Buddhist nun and phosphatide.
The screening of 14 phosphatide complexes freeze drying protectant of embodiment
To improve the long-term shelf-stability of phosphatide complexes, freeze-drying prods can be prepared, freeze-dried excipient used is sweet
Reveal alcohol, trehalose, sucrose, lactose, sorbierite etc..By taking 5% (m/v) mannitol as an example, through following freeze-drying program: -80 DEG C
(10h), -25 DEG C (2h), -10 DEG C (10h), 0 DEG C (8h), 10 DEG C (6h), 25 DEG C (6h), the full phosphatide of available appearance is multiple
Close object dried frozen aquatic products.It is redissolved at room temperature with redistilled water, appearance is shown in attached drawing 7.Phosphatide complexes aqueous dispersions transmission electron microscope picture is shown in attached
Fig. 8, phosphatide complexes are uniform spherical particle.
It carries out that available similar products are lyophilized using tertiary butanol and water system.
15 dilution stability of embodiment
When drug administration by injection, generally require for IBR-EPG aqueous dispersions to be diluted, select 5% glucose injection as
Dilution medium investigates the dilution stability of IBR-EPG aqueous dispersions.
Precision pipettes in the colourless volumetric flask of aqueous dispersions 0.5mL to 5.0mL, is diluted to scale with 5% glucose injection,
Mix simultaneously avoid light place.0 after dilution, 3,6,12, take above-mentioned each solution to measure its partial size and IBR content for 24 hours, the results showed that,
Interior for 24 hours after the dilution of 5% glucose injection, the partial size and content of phosphatide complexes aqueous dispersions change without conspicuousness.
The different preparations of embodiment 16 are in the intracorporal pharmacokinetics behavior of healthy rat
The processing of rat plasma sample
Precision pipettes 200 μ L of rat plasma sample in 1.5mL centrifuge tube, and 100 μ L concentration of addition are 10 μ gmL-1First
Phenbutamide methanol solution adds 600 μ L of methanol, is centrifuged 10min in 10000rpm after vortex 10min mixing as internal standard,
600 μ L of supernatant is pipetted, room temperature under nitrogen volatilizes.The substance volatilized is mixed with 100 μ L of mobile phase redissolution, vortex 5min, in
10000rpm is centrifuged 10min, and 20 μ L of supernatant is taken to carry out HPLC analysis.
Chromatographic condition chromatographic column: Betasil C18 column (200mm × 4.6mm, 5 μm, according to Lyntech Corporation (US) 10177 South 77th East Avenue Tulsa, Oklahoma 74133 U.S.)；Mobile phase: acetonitrile
: water (48: 52, v/v, be added in water phase after 0.5% triethylamine glacial acetic acid is added adjust pH=3.20)；Detection wavelength: 256nm；
Flow velocity: 1.0mLmin-1；Sample volume: 20 μ L；Column temperature: 25 DEG C；Internal standard: orinase
The preparation of IBR oral administration mixed suspension: weighing IBR bulk pharmaceutical chemicals 10.0mg, croscarmellose sodium 10mg is added, firmly
Fatty acid magnesium 1.2mg, microcrystalline cellulose 18mg, lauryl sodium sulfate 0.8mg add the mixing of 5% glucose injection,
Obtaining IBR concentration is 2.0mgmL-1The oral administration mixed suspension composition of capsule (simulation listing).
The preparation of phosphatide complexes: weighing recipe quantity IBR and EPG (molar ratio 1: 1), using dehydrated alcohol as reaction dissolvent,
Drug quality concentration is 10mgmL-1, reaction time 0.5h, reaction temperature is set as 40 DEG C, waves except ethyl alcohol, addition is preheated to 40 DEG C
Redistilled water, magnetic agitation 2min crosses 0.45 μm of miillpore filter, removes not compound drug to get phosphatide complexes moisture
Dispersion liquid.
15 weight are randomly divided into 5 groups in the healthy male Wistar rat of 180~220g, every group 3, respectively mouth
Take IBR suspension group (Susp i.g.), oral 1: 1 group of molar ratio (1-1i.g.), intravenous injection 1: 1 group of (1- of molar ratio
1i.v.).Dosage is calculated as 20mgkg with IBR-1.Respectively after administration 1,5,15,30,60,120,240,480,
720min takes blood to be placed in test tube of hepari pipe through orbital venous plexus, and 4500rpm is centrifuged 10min separated plasma.Processing blood plasma is gone forward side by side
Row HPLC analytical calculation drug concentration simultaneously draws pharmacokinetic curve, and the results are shown in attached figure 9, and pharmacokinetic parameters are shown in Table 8.
8 pharmacokinetic parameters of table
Suspension group (Susp i.g.), there is maximum plasma concentration in stomach-filling 30min, consistent with the report of Sridhar etc.
(Veeraraghavan S,Viswanadha S,Thappali S,et al.Simultaneous quantification of
lenalidomide,ibrutinib and its active metabolite PCI-45227in rat plasma by
LC-MS/MS:Application to a pharmacokinetic study[J].Journal of Pharmaceutical&
Biomedical Analysis,2015,107(3):151)；And compound group 5min reaches maximum plasma concentration, significantly faster than
Suspension, the AUC of compound1-720minIt is 14.68 times of Susp i.g. group, it is (standby that absolute bioavailability reaches 109.7%
Note: the absolute bioavailability 7.5% of suspension).
The antitumor S180 of embodiment 17
25 S-180-bearing mices are randomly divided into 5 groups, i.e., oral control group (0.3mL/ is only), intravenous control group
(0.2mL/ is only), oral IBR suspension group (55.2mgkg-1), oral 1: 1 group of (55.2mgkg of molar ratio-1), vein note
Penetrate 1: 1 group of (55.2mgkg of molar ratio-1), every group 5.Each group mouse reaches 62.5mm in gross tumor volume3Afterwards (after being about inoculated with
3rd day) start stomach-filling or Bolos intravenous administration, every 3 days 1 time, 4 times (after inoculation the 3rd, 6,9 and 12 day) is administered altogether, puts to death within the 13rd day dynamic
Object.Subcutaneous tumor is completely stripped, is weighed, calculated weight tumour inhibiting rate the results are shown in Table 9.Compound takes orally group and reaches intravenous injection
Effect.
9 tumour inhibiting rate result (n=5) of table
Claims (10)
1. a kind of replace Buddhist nun's phosphatide complexes according to Shandong, which is characterized in that by being formed according to Shandong for Buddhist nun and phosphatide, wherein according to Shandong for Buddhist nun with
The molar ratio of phosphatide is 1:0.5~1:5.
2. replacing Buddhist nun's phosphatide complexes according to Shandong as described in claim 1, which is characterized in that mole for replacing Buddhist nun and phosphatide according to Shandong
Than for 1:1~1:2.
3. replacing Buddhist nun's phosphatide complexes according to Shandong as claimed in claim 1 or 2, which is characterized in that it is sweet that the phosphatide is selected from phosphatidyl
One or more of oil, phosphatidic acid, phosphatidylserine, phosphatidylinositols or cardiolipin.
4. replacing Buddhist nun's phosphatide complexes according to Shandong as claimed in claim 3, which is characterized in that the negative electron phosphatide be it is natural,
Semi-synthetic or fully synthetic phosphatide.
5. replacing Buddhist nun's phosphatide complexes according to Shandong as described in claim 1-4 any one, which is characterized in that the phosphatide choosing
From: yolk phosphatidylglycerol, hydrogenation yolk phosphatidylglycerol, soy phosphatidylglycerol, distearoylphosphatidylglycerol, two palms
One or more of acyl phosphatidyl glycerol, dilauroylphosphatidylglycerol.
6. the preparation method of Buddhist nun's phosphatide complexes is replaced according to Shandong as described in claim 1, which is characterized in that method includes:
(1) being dissolved in organic solvent according to Shandong for Buddhist nun and phosphatide for recipe quantity is taken；
(2) it is stirred 0.5~3 hour under the conditions of 20~60 DEG C；
(3) organic solvent is removed under the conditions of 30~60 DEG C replace Buddhist nun's phosphatide complexes to get according to Shandong.
7. preparation method as claimed in claim 6, which is characterized in that the dosage of organic solvent described in step (1) should make according to
Shandong for Buddhist nun reaction density be 2.5mg/ml~20mg/ml, the solvent be selected from methanol, ethyl alcohol, the tert-butyl alcohol, isopropanol, acetonitrile,
One of tetrahydrofuran and acetone or two or more combinations.
8. replacing Buddhist nun's phosphatide complexes according to Shandong as described in any one of claim 1-5, which is characterized in that the phosphatide is compound
Object is added water dispersion or freeze drying protectant freeze-drying is added or is lyophilized using tertiary butanol and water system, the frozen-dried protective
Agent is one of mannitol, trehalose, sucrose.
9. replacing Buddhist nun's phosphatide complexes according to Shandong as described in any one of claim 1-5, which is characterized in that the phosphatide is compound
Object is added one of water dispersion or addition mannitol, trehalose, lactose, sucrose, sorbierite, dextran and is done by spraying
It is dry.
10. replacing Buddhist nun's phosphatide complexes according to Shandong as described in any one of claim 1-5, which is characterized in that described to be replaced according to Shandong
Clinically acceptable tablet, capsule, granule, ball can be made in Buddhist nun's phosphatide complexes with pharmaceutically acceptable excipient
Agent, powder, ointment, oral solutions, infusion solution, injection.
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