CN109620815A - One kind having enteric protective layer BCS classification IV class drug oral preparation and its preparation - Google Patents

One kind having enteric protective layer BCS classification IV class drug oral preparation and its preparation Download PDF

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CN109620815A
CN109620815A CN201811258841.7A CN201811258841A CN109620815A CN 109620815 A CN109620815 A CN 109620815A CN 201811258841 A CN201811258841 A CN 201811258841A CN 109620815 A CN109620815 A CN 109620815A
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preparation
organic phase
drug
concentration
enteric
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CN109620815B (en
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尚丽霞
唐星
陶秀梅
陈鹏
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Beijing Nukangda Medicine Polytron Technologies Inc
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Beijing Nukangda Medicine Polytron Technologies Inc
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    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The present invention provides a kind of BCS classification IV class drug oral preparation and preparation method thereof.To successively consisting of following parts outside in the oral preparation: a. is classified the blending nanoparticle that IV class drug, carrier material and matrix material form by BCS；B. by the more carboxyl high molecular materials of enteric solubility and the enteric protective layer that pharmaceutic adjuvant forms can be used.Said preparation preparation method is easy, and can significantly improve the oral administration biaavailability of BCS classification IV class drug, and absolute bioavailability is up to 120%-160%.

Description

One kind having enteric protective layer BCS classification IV class drug oral preparation and its preparation
Technical field:
The invention belongs to field of pharmaceutical preparations, especially provide a kind of BCS classification IV class oral preparation of high bioavilability And preparation method thereof.
Background technique:
The low reason of BCS classification IV class drug oral bioavilability essentially consists in: a. poorly water-soluble, drug are difficult in stomach It is effectively dissolved in enteron aisle；B. biomembrane is low through ability, it means that even if there is the dissolution of sub-fraction drug, it is also difficult to penetrate intestines Epithelial cell membrane absorbed into serum；C. the BCS P- glycoprotein affinity expressed in IV class drug and enterocyte of classifying in part is high, This means that most will be discharged in enteric cavity once again through the drug molecule of intestinal epithelial cell membrane, absorption is further decreased The ratio of drug.It is especially apparent in purple sweater alkanes drug.
Taxone is that obtain after chemical structure is transformed from the active constituent isolated in plant a series of spread out Biology mainly includes taxol, docetaxel, Cabazitaxel and La Luotasai etc..Such drug is now widely used for ovum The clinical treatment of nest cancer, breast cancer, lung cancer and prostate cancer.Taxone physicochemical property is special, poorly water-soluble, biomembrane It is low through ability, therefore oral administration biaavailability is low.The equal intravenous administration administration of taxone at present clinically, although Novel albumin nano granularBlock copolymer micelle (Genexol PM) and liposome (power is simple) exist It because of the adverse reaction that auxiliary material generates when solving administering paclitaxel to a certain extent, and is the non-stimulated of other taxones The research and development of property injection provide thinking.However, this administration mode operation for needing professional to operate of intravenous injection administration Complexity, is unable to satisfy the new treatment mode of " treating in family ", therefore, it is necessary to which it is oral to develop a kind of reliable taxone Preparation mitigates the pain during patient medication, improves compliance.
A. Chinese patent (publication number: 1883467A) discloses a kind of utilization P glycoprotein inhibitors of Peking University's invention Rapamycin is taken jointly with the taxane medicine solution agent containing Tween-80 and ethyl alcohol, utilizes the P sugar egg of rapamycin White inhibitory effect prevents the outlet of the taxone (taxol, docetaxel) with clothes, to improve taxone mouth Take the method absorbed.Chinese patent (application number: 201110004638.9) discloses a kind of utilization Chinese medicine of Zhongshan University's invention The compound medicament composition that monomeric compound and taxol are taken jointly is extracted, also with the P of traditional Chinese medicine extraction monomeric compound Glycoprotein depression effect prevents the outlet of taxol, to realize the raising of paclitaxel oral absorption.It is given described in the patent Medicine form is the diversified forms such as tablet, granule, capsule, but is not said to the oral administration biaavailability of above-mentioned preparation It is bright.The application that above-mentioned two invention passes through P glycoprotein inhibitors, which reduces, has entered taxanes medicine in intestinal epithelial cell The outlet once again of object, to realize the raising of oral administration biaavailability compared with the preparation for being not added with P glycoprotein inhibitors.But Be that the defect of foregoing invention is: (1) taxone is BCS classification IV class drug, its own passes through intestinal epithelial cell The ability of film is poor, and this defect that foregoing invention is not directed to taxone is improved, that is to say, that even by The influence that other drugs eliminate P glycoprotein outlet is introduced, the oral administration biaavailability of taxone is still insufficient；(2) The absorption of taxone in foregoing invention, transport form are molecular forms, drug directly with absorb, the group in transport process Contact is knitted, and drug distribution behavior is uninfluenced, side effect is stronger；(3) it introduces as P- glycoprotein " bait " or inhibitor Compound then can inevitably generate certain unknown role because of the pharmacological activity of itself to human body.Therefore, the above method is used In being promoted, taxone oral absorption is still considered.
B. Chinese patent (publication number: 1822859A) discloses a kind of " purple of Aventis Pharma SA's invention The self-emulsifying and self microemulsifying preparation of China fir alkanes oral administration " is related to having invented one kind with glycerol caprylate, caprylic/capric The preparation side of triglycerides, the high taxone oral administration biaavailability water oil-packaging type micro-emulsion that Cremophor EL is component Method, and oral absorption is investigated in Beagle dog to said preparation, the results showed that the oral absorption journey of drug in said preparation Degree is undifferentiated with the Tween-80 solution of drug, and it is not significant to promote effect.Meanwhile the building of self-emulsifying systems It needs using exhibiting high surface activating agent, stimulation easily is generated to gastrointestinal tract, causes abdominal pain and diarrhea.
C. Chinese patent (application number: 201010153598.X) discloses one kind by Hunan Yineng Biological Pharmaceutical Co., Ltd. " a kind of oral taxol nanoparticles and preparation method thereof " of invention is related to having invented a kind of with glycolide-lactide copolymerization Object (PLGA) is the oral administration nanometer preparation of carrier load taxol, and preparation process is emulsification-evaporation method, average grain diameter 100 nanometers hereinafter, and solidify nanoparticle obtained.Overcome taxol in mouth by package of the drug in nanoparticle Taking that the water solubility faced in absorption process is low, biomembrane permeability is poor, P glycoprotein outlet and cytochromes enzyme system are metabolized etc. asks Topic, to improve paclitaxel oral bioavilability.It should be noted that physiological environment is complicated in gastrointestinal tract, to can by biology The nano particle that degradable material is constituted is damaged to a certain extent effect.Such preparation successfully realizes that paclitaxel oral absorbs raising On condition that the structural intergrity of nanoparticle, however nanoparticle is destroyed by gastric acid, enzyme etc. and causes drug leakage, and then loses raising Therefore how the function of oral administration biaavailability realizes that structural intergrity of the nano particle in gastrointestinal tract is to guarantee taxane The premise of the high oral absorption of class drug.
For nanometer formulation gastrointestinal tract extreme environment structural defence, at present have document (Attiliqadri, S, Et al.PNAS 110.43 (2013): 17498-17503.) one kind is described by butyric acid triglycerides, PLGA, the poly- second two of oleic acid The lipid nanometer capsule for supporting docetaxel of alcohol glyceride preparation, and Enteric Materials are embedded in the form of spray drying In Eudragit L100-55.The mixture and enteric of medicine lipid nanometer capsule, enteric material and docetaxel solution are carried by comparison The oral absorption effect expedition of material embedding type preparation finds that it is to determine oral height that enteric material embedding, which carries medicine particle with nanoscale, An important factor for effect absorbs.
Polyglutamic acid (PGA) is mainly polymerized by D-Glu and/or Pidolidone by amido bond.Due to polymerization side Formula is different, and there are mainly two types of configurations for polyglutamic acid: α-polyglutamic acid (being polymerize by α-amido bond, α-PGA) and gamma-polyglutamic acid (being polymerize by γ-amido bond, γ-PGA).There is α-polyglutamic acid excellent water-soluble, superpower adsorptivity and biology can drop Xie Xing, catabolite are non-harmful glutamic acid, are a kind of excellent environment-friendly type macromolecule materials, can be used as water-retaining agent, a huge sum of money Belong to ion adsorbent, flocculant, sustained release agent and pharmaceutical carrier etc..
BCS classification IV class medicament nano granule is supported in polyglutamic acid embedding at present and is in technological gap, not yet finds poly- paddy Advantage of the propylhomoserin as the pharmaceutical preparation of enteric accessory, pharmaceutical preparation related to this wait to develop.
Summary of the invention:
It is an object of the invention to realize that BCS classification IV class drug oral bioavilability improves, drug efflux/generation is reduced The promotion of oral absorption is realized in the effect thanked.
Based on above-mentioned purpose, the present invention provides a kind of high bioavilability BCS classification IV class medicine with enteric protective layer Composition oral preparation contains a kind of BCS classification IV class drug and at least one Enteric Materials, wherein the Enteric Materials choosing From Utech L-100, sodium alginate, polyglutamic acid, the preferably described Enteric Materials are polyglutamic acid.
In preferred embodiments,
The oral preparation successively consists of following parts from inside to outside:
A. the blending nanoparticle being made of BCS classification IV class drug, carrier material and matrix material；
B. the enteric protective layer being made of Enteric Materials, suspending agent.
The BCS classification preferred taxone of IV class drug；
Carrier material is selected from one or more of Vicryl Rapide, polyethylene glycol copolymerization caprolactone；
Matrix material is selected from one or more of butyric acid triglycerides, single bi-tristearin, Compritol 888 ATO；
Suspending agent is selected from one or more of hypromellose, polyvinylpyrrolidone, hydroxyethyl cellulose.
Preferably, the oral preparation, according to parts by weight, 20 parts of the IV class drug of BCS classification, carrier material 160-240 parts, 20-50 parts of matrix material, 400-2000 parts of Enteric Materials, 250 parts of suspending agent 37.5-.
Preferably, the oral preparation, wherein the number-average molecular weight of carrier material poly lactide-glycolide acid For 5,000Da~50,000Da, preferably 10,000Da~2,5000Da；Wherein glycolide in poly lactide-glycolide acid Monomer accounts for the 25%~75% of entire number of monomer in polymer, preferably 50%；Polyethylene glycol is copolymerized hydrophilic block in caprolactone Molecular weight polyethylene glycol range is 4,000Da~20,000Da；The molecular weight ranges of hydrophobic block are 5,000Da~30, 000Da。
Preferably, the oral preparation, wherein the Enteric Materials polyglutamic acid molecular weight ranges are 20, 000Da~500,000Da.
The present invention also provides the preparation methods of above-mentioned oral preparation, that is, the BCS classification IV class drug is by nano particle It contains that nanoparticle is blended, the nano particle for containing drug is then dispersed in enteric protective layer,
Wherein, be blended nanoparticle preparation method be selected from emulsification-evaporation method, nanoprecipitation method or direct dialysis it One,
The emulsification-evaporation method are as follows:
1) drug, matrix material, carrier material are dissolved in organic solvent, form organic phase,
2) surfactant is dissolved in deionized water, concentration 10-30mg/mL, forms water phase；
3) by organic phase it is mixed with water after through 10000rpm high speed shear 0.5-2min prepare colostrum, homogeneous micronization is removed Organic solvent is gone to be made；
It is preferred that carrier material concentration is 40~100mg/mL in organic phase；In organic phase the concentration of matrix material be 3~ 10mg/mL；
In water phase, surfactant concentration 10-30mg/mL
It is preferred that recycling homogeneous under 20000psi pressure using high-pressure homogeneous
The organic solvent is methylene chloride；The volume ratio of organic phase and water phase is 1:1~1:5；
Described or nanoprecipitation method are as follows:
Drug, matrix material, carrier material are dissolved in organic solvent, organic phase is formed, organic phase and water phase is added Heat is to temperature (20 DEG C~70 DEG C)；Organic phase is injected in water phase, being preferably injected rate is 1 mL/min~500mL/min；It stirs It mixes or rotates and remove organic solvent.
Used organic solvent is selected from one or more of acetonitrile, tetrahydrofuran, N,N-dimethylformamide；It is organic It is mutually 1:1~1:10 with the volume ratio of water phase；
Carrier material concentration is 40~100mg/mL in organic phase；The concentration of matrix material is 3~10mg/ in organic phase mL；
The direct dialysis are as follows:
Drug, matrix material, carrier material are dissolved in organic solvent, form organic phase, organic phase is placed in dialysis and is held In device, with deionized water dialysis to obtain the final product.
Used organic solvent is selected from one or more of acetonitrile, tetrahydrofuran, N,N-dimethylformamide；
Carrier material concentration is 40~100mg/mL in organic phase, and the concentration of matrix material is 3~10mg/ in organic phase mL。
It is preferred that the Hydrodynamic diameter of the blending nanoparticle is 50nm~200.
It is preferred that the preparation method of the suspension is, the blending nano particle suspension of BCS IV class drug will be supported It is made after mixing with the aqueous solution of Enteric Materials；The concentration of carrier material is 5 mg/mL~20mg/ in final suspension mL；The concentration of Enteric Materials is 40mg/mL~100mg/mL in final suspension；The concentration of suspending agent is in final suspension 5mg/mL~100mg/mL.
It is preferred that by suspension described in claim 8 is spray-dried or the obtained solid powder of freeze-drying, preparation As capsule, tablet, pulvis, dry suspensoid agent, granule.
The present invention also provides a kind of above-mentioned oral preparations stated to treat drug in tumour or resistant tumors in preparation Purposes, the tumour are breast cancer, gastric cancer, liver cancer, non-small cell lung cancer, oophoroma, prostate cancer, cancer of pancreas, head-neck carcinoma Or cervical carcinoma.
Term " BCS classification " refers to BCS (Biopharmaceutical classification system, biological agent Learn categorizing system), the classification of active constituent is that carried out according to the water solubility and gut permeability of API to drug one is scientific Frame genealogical classification.BCS classification IV class drug is the drug in vivo with low-solubility and low-permeability.
The present invention compared with the existing technology, has the following characteristics that
1) present invention does not use any Small molecular surfactant in preparation, avoids because surfactant is to gastrointestinal tract Stimulation and generate abdominal pain, diarrhea the problems such as；
2) present invention realizes internal nanometer with the characteristic that extraneous pH value changes and changes using Enteric Materials dissolubility Stabilisation of the particle in gastrointestinal tract extreme environment；
3) present invention introduces solid lipid in the hydrophobic inner core of nano particle, and the kernel for improving nano particle is stablized Property, degradation of drug during transmembrane transport is reduced, oral administration biaavailability is further increased；
4) polyglutamic acid forms the precipitating of Encapsulation nanoparticle in stomach under the action of gastric juice, after which enters enteron aisle A nano particle storage cavern is formed, and gradually dissolution release nano particle, residence time of the nanoparticle in enteron aisle can be extended, from And extend the soak time window of nano particle, improve oral absorption；
5) present invention combines drug-carrying nanometer particle with enteric solubility protection materials, is existed using enteric material protection nanoparticle Structural intergrity and nanoparticle in gastrointestinal tract are improving the infiltration of drug biomembrane, are reducing drug efflux/metabolism effect, Realize the promotion of oral absorption.Realize that taxone oral administration biaavailability improves.
Detailed description of the invention:
Fig. 1 is the taxone oral preparation using the preparation of different enteric materials in the intracorporal blood concentration-of rat Time plot.
Fig. 2 is according to the high bioavilability drug port system of mourning with enteric protective layer prepared in present example 6-8 Agent is in the intracorporal blood concentration-time curve graph of rat；
Fig. 3 is the load drug stabilisation of the embodiment of the present invention 3, the two kinds of medicament nano granules prepared in embodiment 4 in intestines homogenate Property figure；
Specific embodiment:
Beneficial effects of the present invention are now further described by following instance, it is thus understood that these examples are only used for illustration Purpose, do not limit the scope of the invention, at the same those of ordinary skill in the art done according to the present invention obviously change Become and modification is also contained within the scope of the invention.
Embodiment 1
Preparation method: weighing La Luotasai 20mg, is dissolved in 5mL dichloro with a certain amount of PLGA and butyric acid triglycerides Organic phase is formed in methane, then contains organic 100mL that is added in the water of a certain amount of polyvinyl alcohol, 8000rpm high speed 5min, high-pressure homogeneous 5 refinements under subsequent 20000psi pressure are sheared, rotary evaporation removes organic solvent, must support La Luota Nanoparticle is blended in the PLGA- lipid of match.
PLGA dosage is investigated: fixed butyric acid triglycerides dosage 25mg, polyvinyl alcohol 20mg/mL are investigated according to the above method The partial size and drugloading rate of nanoparticle are blended in 120mg, 240mg with PLGA- lipid obtained under the conditions of 360mg for PLGA dosage, as a result It is shown in Table 1:
1. PLGA dosage the selection result of table
Comprehensive partial size and drugloading rate are as a result, determine that PLGA dosage is 240mg；
Butyric acid triglycerides dosage is investigated: fixed PLGA dosage 240mg, polyvinyl alcohol 20mg/mL are investigated according to the above method Butyric acid triglycerides dosage is blended the partial size of nanoparticle with PLGA- lipid obtained under the conditions of 100mg in 25mg, 50mg and carries medicine Amount, the results are shown in Table 2:
2. butyric acid triglycerides dosage the selection result of table
Comprehensive partial size and drugloading rate are as a result, determine that butyric acid triglycerides dosage is 50mg；
Outer aqueous phase polyvinyl alcohol concentration is investigated: fixed PLGA dosage 240mg, 50 mg of butyric acid triglycerides dosage, by above-mentioned Method is investigated outer aqueous phase polyvinyl alcohol concentration obtained PLGA- lipid under the conditions of 10mg/mL, 20mg/mL are with 50mg/mL and is blended The partial size and drugloading rate of nanoparticle, the results are shown in Table 3:
3. outer aqueous phase polyvinyl alcohol concentration the selection result of table
To sum up, determine that the preparation prescription technique of nanoparticle is blended in the PLGA- lipid for supporting La Luotasai are as follows: weigh La Luota Match 20mg, PLGA240mg, butyric acid triglycerides 50mg be dissolved in 5mL methylene chloride, being subsequently added to 100mL, to contain 2g poly- In the water of vinyl alcohol, 8000rpm high speed shear 5min, high-pressure homogeneous 5 refinements, rotary evaporation are removed under subsequent 20000psi pressure Organic solvent is removed, nanoparticle is blended in the PLGA- lipid that must support La Luotasai, and measuring average grain diameter is 197.4nm, and drugloading rate is 7.26%.
Enteric material type is investigated
Each 400mg of Eudragit L100-55, polyglutamic acid, sodium alginate is taken respectively, is dissolved separately in the phosphorus of 5mL pH6.5 In phthalate buffer, by the solution and 1.5% hydroxyethyl cellulose of certain volume (HEC) aqueous solution, and support La Luotasai's Nanoparticle 4mL mixing is blended in copolymer-solid lipid, obtains the high bioavilability La Luotasai that suspension type has enteric protective layer Oral preparation.Sprague-Dawley rat adapts to environment 3 days, and preceding fasting water supply in 12 hours is administered.Above-mentioned suspension type is had The high bioavilability La Luotasai oral preparation gastric infusion of enteric protective layer, dosage 10mg/kg；Take La Luotasai molten (preparation method: 60 mg La Luotasai are dissolved in 1.5mL polyoxyethylene sorbitan monoleate liquor, and the ethyl alcohol of 5.7mL13% is then added Aqueous solution with normal saline dilution to drug concentration is 1.2mg/mL after mixing), it is administered through tail vein, 4 mg/ of dosage kg.Its blood concentration is measured in different time, as shown in Figure 1, polyglutamic acid promotes the oral administration biaavailability of La Luotasai Effect is better than other two kinds of enteric materials, and absolute bioavailability is respectively 77%, 154% and 39%.
Embodiment 2
Preparation method: Cabazitaxel 20mg and a certain amount of mPEG is weighed5000-b-PCL20000It is molten with Compritol 888 ATO Solution takes distilled water 20mL in 4mL acetonitrile-tetrahydrofuran in the mixed solvent, and water phase and organic phase are heated separately to 55 DEG C, with Organic phase is injected by water phase with certain rate under stiring afterwards, continues stirring until and dialyses 24 hours after liquid is cooled to room temperature, Nanoparticle is blended in copolymer-solid lipid that Cabazitaxel must be supported.
mPEG5000-b-PCL20000Dosage is investigated: fixed Compritol 888 ATO dosage 15mg, acetonitrile-tetrahydrofuran ratio 1: 1, organic phase charge velocity 80mL/min investigate mPEG according to the above method5000-b-PCL20000Dosage is in 80mg, 160mg, 240mg Under the conditions of be made and support nanoparticle is blended in the copolymer of Cabazitaxel-solid lipid partial size and drugloading rate, the results are shown in Table 4:
4. mPEG of table5000-b-PCL20000Dosage the selection result
Comprehensive partial size and drugloading rate are as a result, determine mPEG5000-b-PCL20000Dosage is 160mg；
Compritol 888 ATO dosage is investigated: fixed mPEG5000-b-PCL20000Dosage 160mg, acetonitrile-tetrahydrofuran ratio 1:1, organic phase charge velocity 80mL/min investigate Compritol 888 ATO dosage in 15mg, 30mg, 60mg condition according to the above method It is lower that copolymer-solid lipid blending nanoparticle partial size and drugloading rate for supporting Cabazitaxel is made, it the results are shown in Table 5:
5. Compritol 888 ATO dosage the selection result of table
Comprehensive partial size and drugloading rate are as a result, determine that Compritol 888 ATO dosage is 30mg；
Acetonitrile-tetrahydrofuran ratio is investigated: fixed mPEG5000-b-PCL20000Dosage 160mg, Compritol 888 ATO dosage 30mg, organic phase charge velocity 80mL/min investigate acetonitrile-tetrahydrofuran volume ratio 3:1,1:1,1:3 condition according to the above method It is lower that copolymer-solid lipid blending nanoparticle partial size and drugloading rate for supporting Cabazitaxel is made, it the results are shown in Table 6:
6. acetonitriles of table-tetrahydrofuran volume ratio the selection result
Comprehensive partial size and drugloading rate are as a result, determine that acetonitrile-tetrahydrofuran ratio is 3:1；
Organic phase charge velocity is investigated: fixed mPEG5000-b-PCL20000Dosage 160mg, Compritol 888 ATO dosage 30mg, acetonitrile-tetrahydrofuran volume ratio 3:1, according to the above method investigate organic phase charge velocity 40 mL/min, 80mL/min, Copolymer-solid lipid blending nanoparticle partial size and drugloading rate for supporting Cabazitaxel are made under the conditions of 120mL/min, as a result It is shown in Table 7:
7. organic phase charge velocity the selection result of table
Comprehensive partial size and drugloading rate are as a result, determine that organic phase charge velocity is 80mL/min；
To sum up, determine that the preparation prescription technique of nanoparticle is blended in the copolymer-solid lipid for supporting Cabazitaxel are as follows: weigh Cabazitaxel 20mg, mPEG5000-b-PCL20000160mg, Compritol 888 ATO 30mg be dissolved in 4mL acetonitrile-tetrahydrofuran (3: 1, v/v) in the mixed solvent takes distilled water 20mL, and water phase and organic phase are heated separately to 55 DEG C, then under stiring with Organic phase is injected water phase by the rate of 80mL/min, is continued stirring until and is dialysed 24 hours after liquid is cooled to room temperature, must support card Nanoparticle is blended in the copolymer of Ba Tasai-solid lipid, and measuring average grain diameter is 129.4nm, drugloading rate 9.44%.
Embodiment 3
Preparation method: weighing La Luotasai 20mg, with a certain amount of mPEG10000-b-PCL15000And single double glycerol stearates Ester is dissolved in 2mL n,N-Dimethylformamide-tetrahydrofuran in the mixed solvent, and then solution is transferred in bag filter, right Nanoparticle is blended in water 24 hours removing organic solvents of dialysis, the copolymer-solid lipid that must support La Luotasai.
mPEG10000-b-PCL15000Dosage is investigated: fixed list bi-tristearin 10mg, n,N-Dimethylformamide- Tetrahydrofuran ratio 1:1, investigates mPEG according to the above method10000-b-PCL15000Dosage is under the conditions of 100mg, 200mg, 400mg Copolymer-solid lipid blending nanoparticle partial size and drugloading rate for supporting La Luotasai is made, the results are shown in Table 8:
8. mPEG of table5000-b-PCL15000Dosage the selection result
Comprehensive partial size and drugloading rate are as a result, determine mPEG10000-b-PCL15000Dosage is 200mg；
Single bi-tristearin dosage is investigated: fixed mPEG10000-b-PCL15000Dosage 200mg, N, N- dimethyl methyl Amide-tetrahydrofuran ratio 1:1 investigates single bi-tristearin dosage in 10 mg, 20mg, 40mg conditions according to the above method It is lower that copolymer-solid lipid blending nanoparticle partial size and drugloading rate for supporting La Luotasai is made, it the results are shown in Table 9:
The single bi-tristearin dosage the selection result of table 9.
Comprehensive partial size and drugloading rate are as a result, determine that list bi-tristearin dosage is 20mg；
N,N-dimethylformamide-tetrahydrofuran ratio is investigated: fixed mPEG10000-b-PCL15000200 mg of dosage, it is single Bi-tristearin dosage 20mg, according to the above method investigate n,N-Dimethylformamide-tetrahydrofuran volume ratio 3:1,1:1, Copolymer-solid lipid blending nanoparticle partial size and drugloading rate for supporting La Luotasai are made under the conditions of 1:3, the results are shown in Table 10:
10. N,N-dimethylformamides of table-tetrahydrofuran ratio the selection result
Comprehensive drugloading rate is as a result, determine that n,N-Dimethylformamide-tetrahydrofuran volume ratio is 1:1；
To sum up, determine that the preparation prescription technique of nanoparticle is blended in the copolymer-solid lipid for supporting La Luotasai are as follows: weigh La Luotasai 20mg, mPEG10000-b-PCL15000200mg, list bi-tristearin 20mg are dissolved in 2mLN, N- dimethyl Solution, is then transferred in bag filter by the in the mixed solvent of formamide-tetrahydrofuran (1:1, v/v), dialyses 24 hours to water Organic solvent is removed, nanoparticle is blended in the copolymer-solid lipid that must support La Luotasai, and measuring average grain diameter is 64.6nm, Drugloading rate is 8.25%.
Embodiment 4
Weigh La Luotasai 20mg, polyethylene glycol copolymerization caprolactone 200mg, n,N-Dimethylformamide-tetrahydrofuran (1: 1, v/v) solution, is then transferred in bag filter by the mixed solvent, to water 24 hours removing organic solvents of dialysis, must support The common nanoparticle of La Luotasai, measuring average grain diameter is 68nm, drugloading rate 8.92%.
Embodiment 5
The intestinal segment that about 5 centimeter lengths are intercepted after taking male SD rat, neck dislocation to put to death, shreds and is scattered in after washing away content In 5mL physiological saline, homogenate prepares intestines homogenate.Two kinds of each portions of nano particle in Example 3 and embodiment 4 respectively, After mixing with the intestines homogenates of four parts of volumes, it sets in 37 DEG C of water-baths and is incubated for 4 hours, the sample of certain volume is drawn in timing, In high effective liquid chromatography for measuring sample La Luotasai content with incubation time situation of change.Drug surplus-incubation time Curve is shown in attached drawing 3.
As seen from Figure 3, the copolymer-solid lipid nano granule for supporting La Luotasai containing single bi-tristearin exists Rat small intestine homogenate in illustrate it is stronger protection pharmaceutical chemistry structural intergrity ability, thus guarantee more drugs into Enter blood circulation, plays curative effect.
Embodiment 6
Preparation method: weighing a certain amount of polyglutamic acid, be scattered in the phosphate buffer of 5mLpH6.5, by the solution Nano particle is blended with the PLGA- solid lipid for supporting La Luotasai described in a certain amount of 1%HPMC aqueous solution and example 1 It is freeze-dried after 4mL mixing, obtains the high bioavilability La Luotasai oral preparation that freeze-dried type has enteric protective layer.
Polyglutamic acid dosage is investigated: fixed 1%HPMC amount of aqueous solution used 1mL investigates polyglutamic acid dosage according to the above method The area under the drug-time curve of freeze-dried type oral preparation is made under the conditions of 200mg, 400mg, 600mg, as a result as shown in table 11:
11. polyglutamic acid dosage of table influences result to freeze-dried type preparation area under the drug-time curve
Therefore select polyglutamic acid dosage for 400mg；
1%HPMC solution usage is investigated:
Fixed polyglutamic acid dosage 400mg investigates 1%HPMC solution usage in 0mL, 1.0mL, 2.0mL according to the above method Under the conditions of be made freeze-dried type oral preparation area under the drug-time curve, as a result as shown in table 12:
12. 1%HPMC liquor capacity of table influences result to freeze-dried type preparation area under the drug-time curve
Therefore select 1%HPMC solution usage for 1.0mL；
To sum up, determine that freeze-dried type has the preparation method of high bioavilability La Luotasai oral preparation of enteric protective layer Are as follows: 400mg polyglutamic acid is weighed, is scattered in the phosphate buffer of 5mL pH6.5, by the solution and 1%HPMC aqueous solution Supported described in 1mL and example 1 La Luotasai PLGA- solid lipid nano particle 4mL mixing is blended after be freeze-dried.
Embodiment 7
Preparation method: weighing a certain amount of polyglutamic acid and be dissolved in the phosphate buffer of 25mL pH6.5, this is molten Copolymer-solid lipid blending that La Luotasai is supported described in liquid and certain volume 1.2%PVP solution and example 2 is received After grain of rice 20mL mixing, using BUCHI B-290 type spray dryer spray drying, height biology of the spray drying type with enteric protective layer is obtained Availability La Luotasai oral preparation,
Polyglutamic acid dosage is investigated: fixed 1.2%PVP amount of aqueous solution used 5mL investigates polyglutamic acid dosage according to the above method The area under the drug-time curve of spray drying type oral preparation is made under the conditions of 1.0g, 2.0g, 3.0g, as a result as shown in table 13:
13. polyglutamic acid dosage of table influences result to spray drying type preparation area under the drug-time curve
Therefore select polyglutamic acid dosage for 2.0g；
1.2%PVP solution usage is investigated: fixed polyglutamic acid dosage 2.0g investigates 1.2% PVP solution according to the above method The area under the drug-time curve of spray drying type oral preparation is made in dosage under the conditions of 2.5mL, 5.0mL, 7.5mL, as a result such as 14 institute of table Show:
14. 1.2%PVP liquor capacity of table influences result to freeze-dried type preparation area under the drug-time curve
To sum up, determine that spray drying type has the preparation method of high bioavilability La Luotasai oral preparation of enteric protective layer Are as follows: 2g polyglutamic acid is weighed, is dissolved in the phosphate buffer of 25mL pH6.5, by the solution and 1.2%PVP aqueous solution Supported described in 5mL and example 2 La Luotasai copolymer-solid lipid nanoparticle 20mL mixing is blended after, use It is oral to obtain high bioavilability La Luotasai of the spray drying type with enteric protective layer for BUCHI B-290 type spray dryer spray drying Preparation, the rate of recovery 62.4%.
Embodiment 8
Preparation method: weighing a certain amount of polyglutamic acid and be dissolved in the phosphate buffer of 5mL pH6.5, by the solution with Nanometer is blended in copolymer-solid lipid that La Luotasai is supported described in certain volume 1.5%HEC aqueous solution and example 3 Grain 4mL mixing, obtains the high bioavilability La Luotasai oral preparation that suspension type has enteric protective layer.
Polyglutamic acid dosage is investigated: fixed 1.5%HEC solution usage 1mL, is investigated polyglutamic acid dosage according to the above method and is existed The area under the drug-time curve of suspension type oral preparation is made under the conditions of 200mg, 400mg, 600mg, as a result as shown in Table 15:
15. polyglutamic acid dosage of table influences result to suspension type preparation area under the drug-time curve
Therefore selection polyglutamic acid dosage 400mg；
1.5%HEC solution usage is investigated: it is molten to investigate 1.5% HEC according to the above method by fixed polyglutamic acid dosage 400mg The area under the drug-time curve of spray drying type oral preparation is made in liquid dosage under the conditions of 0mL, 1.0mL, 2.0mL, as a result such as 16 institute of table Show:
16. 1.5%HEC liquor capacity of table influences result to freeze-dried type preparation area under the drug-time curve
Therefore selection 1.5%HEC solution usage 1.0mL；
To sum up, determine that suspension type has the preparation method of high bioavilability La Luotasai oral preparation of enteric protective layer Are as follows: 400mg polyglutamic acid is weighed, is dissolved in the phosphate buffer of 5mL pH6.5, by the solution and 1.5%HEC aqueous solution Nanoparticle 4mL mixing is blended in copolymer-solid lipid that La Luotasai is supported described in 1mL and example 3, obtains suspension type tool There is the high bioavilability La Luotasai oral preparation of enteric protective layer.
Embodiment 9
1) poly lactide-glycolide acid molecular weight and type are screened
La Luotasai 20mg is weighed, is dissolved in 5mL methylene chloride with the PLGA of 200mg and forms organic phase, will then be had Machine is added to 100mL and contains in 1% polyvinyl alcohol water solution, 8000rpm high speed shear 5min, under subsequent 20000psi pressure High-pressure homogeneous 5 refinements, rotary evaporation remove organic solvent, must support the PLGA nanoparticle of La Luotasai.
The screening of PLGA type: investigating lactide-glycolide ratio according to the above method is respectively 50%-50% and 75%- 25%, molecular weight ranges are in 5kDa-15kDa, 24kDa-38kDa, 38kDa-53kDa (50%-50%) and 5kDa- The partial size and drugloading rate of nanoparticle made from the PLGA of 15kDa, 23kDa-37kDa, 37kDa-52kDa (75%-25%), as a result It is shown in Table 17:
17. PLGA type of table and molecular weight the selection result
The nanoparticle of different PLGA preparation find after partial size is investigated with drugloading rate, is made by high molecular weight PLGA Nanoparticle partial size it is bigger than normal, and drugloading rate has no and significantly improves, therefore selects lactide coglycolide (50:50), molecular weight Range is 14kDa-28kDa.
2) polyethylene glycol copolymerization caprolactone hydrophilic block and hydrophobic block ratio are screened
The mPEG-b-PCL for weighing La Luotasai 20mg and 200mg is dissolved in 4mL DMF, distilled water 20mL is taken, by water 55 DEG C mutually are heated separately to organic phase, organic phase is then injected by water phase with the rate of 5mL/min under stiring, it is lasting to stir It dialyses 24 hours after being cooled to room temperature to liquid, the copolymer nano particle of La Luotasai must be supported.
MPEG-b-PCL hydrophilic block and hydrophobic block ratio screen: taking with different hydrophilic, hydrophobic block molecular weight MPEG-b-PCL (molecular weight selection is shown in Table 18), investigates the partial size and drugloading rate of the copolymer nano particle of preparation, the results are shown in Table 18:
18. mPEG-b-PCL hydrophilic/hydrophobic block length the selection result of table
It is found after being investigated to different hydrophilic/hydrophobic block ratio, with the increase of hydrophobic block molecular weight, nanometer obtained The partial size of grain increases therewith with drugloading rate, removes mPEG10k-b-PCL5kAnd mPEG20k-b-PCL5kOutside, other various mPEG-b- PCL can be met the requirements.
3) polyglutamic acid molecular weight screens
Weigh La Luotasai 20mg, the mPEG with 200mg10k-b-PCL15kIt is dissolved in 4mL DMF, takes distilled water 20mL, Water phase and organic phase are heated separately to 55 DEG C, organic phase is then injected by water phase with the rate of 5mL/min under stiring, is held Continuous stirring is dialysed 24 hours after being cooled to room temperature to liquid, must support the copolymer nano particle of La Luotasai.
The nanoparticle suspension 1mL prepared according to the above method is taken, (is divided with 1%HPMC solution 1mL, 1g/mL polyglutamic acid Son amount 10kDa, 20kDa, 100kDa, 500kDa) solution 0.5mL mixing, it is then added dropwise dropwise under stiring in 10mL 0.1M salt In acid, it is centrifuged off precipitating, takes supernatant, measures La Luotasai content therein, while measuring in every milliliter of nanoparticle and drawing Lip river The content that he matches, determines influence of the polyglutamic acid molecular weight to nanoparticle embedding efficiency in acid, the results are shown in Table 19:
Influence of the 19. polyglutamic acid molecular weight of table to embedding efficiency in nanoparticle acid
To sum up, polyglutamic acid molecular weight imitates embedding of the nanoparticle in acidic environment within the scope of 20kDa to 500kDa Rate is not much different, and considers synthesis cost and internal degradation problem, and it is 20kDa that polyglutamic acid molecular weight, which may be selected,.
Embodiment 10
Sprague-Dawley rat adapts to environment 3 days, and preceding fasting water supply in 12 hours is administered.By La Luotasai solution, High bioavilability La Luotasai oral preparation (embodiment 6), spray drying type of the freeze-dried type with enteric protective layer are protected with enteric The high bioavilability La Luotasai oral preparation (embodiment 7) and suspension type of sheath have the high biological utilisation of enteric protective layer Du Laluotasai oral preparation (embodiment 8) difference gastric infusion, dosage 10mg/kg.La Luotasai solution (is prepared Method: 60mg La Luotasai is dissolved in 1.5mL polyoxyethylene sorbitan monoleate, and the ethanol water of 5.7mL13% is then added, and is mixed With normal saline dilution to drug concentration it is 1.2mg/mL after even) it is administered through tail vein, dosage 4mg/kg.In different time Its blood concentration is measured, time front of blood concentration is drawn, sees attached drawing 2.
As shown in Fig. 2, three kinds of preparations with enteric protective layer show the oral suction better than La Luotasai solution Receipts behavior, blood concentration greatly improve, and absolute bioavailability is respectively 126%, 137% and 154%.Illustrate that outer enteric is protected The introducing of sheath can effectively improve the oral administration biaavailability of La Luotasai.

Claims (10)

  1. The IV class drug oral preparation 1. a kind of high bioavilability BCS with enteric protective layer classifies, classifies containing a kind of BCS IV class drug and at least one Enteric Materials, wherein the Enteric Materials are selected from Utech L-100, sodium alginate, poly- paddy Propylhomoserin, the preferably described Enteric Materials are polyglutamic acid.
  2. 2. oral preparation according to claim 1, successively consists of following parts from inside to outside:
    A. the blending nanoparticle being made of BCS classification IV class drug, carrier material and matrix material；
    B. the enteric protective layer being made of Enteric Materials, suspending agent.
    The BCS classification preferred taxone of IV class drug；
    Carrier material is selected from one or more of Vicryl Rapide, polyethylene glycol copolymerization caprolactone；
    Matrix material is selected from one or more of butyric acid triglycerides, single bi-tristearin, Compritol 888 ATO；
    Suspending agent is selected from one or more of hypromellose, polyvinylpyrrolidone, hydroxyethyl cellulose.
  3. 3. oral preparation according to claim 2, according to parts by weight, 20 parts of the IV class drug of BCS classification, carrier material 160-240 parts, 20-50 parts of matrix material, 400-2000 parts of Enteric Materials, 37.5-250 parts of suspending agent of material.
  4. 4. oral preparation according to claim 1-3, wherein carrier material poly lactide-glycolide acid Number-average molecular weight be 5,000Da~50,000Da, preferably 10,000Da~2,5000Da；Wherein poly lactic-co-glycolic acid is total Glycolide monomer accounts for the 25%~75% of entire number of monomer in polymer, preferably 50% in polymers；Polyethylene glycol is copolymerized in oneself Hydrophilic block molecular weight polyethylene glycol range is 4,000Da~20,000Da in ester；The molecular weight ranges of hydrophobic block are 5, 000Da~30,000Da.
  5. 5. oral preparation according to claim 1-3, wherein the Enteric Materials polyglutamic acid molecular weight Range is 20,000Da~500,000Da.
  6. 6. the preparation method of oral preparation according to claim 1-5 is,
    The BCS classification IV class drug by nano particle is contained that nanoparticle is blended, and then will contain the nano particle point of drug It is dispersed in enteric protective layer,
    Wherein, the preparation method that nanoparticle is blended is selected from one of emulsification-evaporation method, nanoprecipitation method or direct dialysis,
    The emulsification-evaporation method are as follows:
    1) drug, matrix material, carrier material are dissolved in organic solvent, form organic phase,
    2) surfactant is dissolved in deionized water, concentration 10-30mg/mL, forms water phase；
    3) by organic phase it is mixed with water after through 10000rpm high speed shear 0.5-2min prepare colostrum, homogeneous micronization, removing has Solvent is made；
    It is preferred that carrier material concentration is 40~100mg/mL in organic phase；The concentration of matrix material is 3~10mg/ in organic phase mL；
    In water phase, surfactant concentration 10-30mg/mL
    It is preferred that recycling homogeneous under 20000psi pressure using high-pressure homogeneous
    The organic solvent is methylene chloride；The volume ratio of organic phase and water phase is 1:1~1:5；
    Described or nanoprecipitation method are as follows:
    Drug, matrix material, carrier material are dissolved in organic solvent, organic phase is formed, extremely with heated aqueous by organic phase Temperature (20 DEG C~70 DEG C)；Organic phase is injected in water phase, being preferably injected rate is 1mL/min~500mL/min；It removes organic Solvent.
    Used organic solvent is selected from one or more of acetonitrile, tetrahydrofuran, N,N-dimethylformamide；Organic phase with The volume ratio of water phase is 1:1~1:10；
    Carrier material concentration is 40~100mg/mL in organic phase；The concentration of matrix material is 3~10mg/mL in organic phase；
    The direct dialysis are as follows:
    Drug, matrix material, carrier material are dissolved in organic solvent, organic phase is formed, organic phase is placed in Dialysis container, With deionized water dialysis to obtain the final product.
    Used organic solvent is selected from one or more of acetonitrile, tetrahydrofuran, N,N-dimethylformamide；
    Carrier material concentration is 40~100mg/mL in organic phase, and the concentration of matrix material is 3~10mg/mL in organic phase.
  7. 7. the preparation method according to claim 6 oral preparation is, the Hydrodynamic diameter of the blending nanoparticle is 50nm ~200nm.
  8. 8. according to the preparation method of claim 6 oral preparation, which is characterized in that the preparation method of the suspension is, The aqueous solution of the blending nano particle suspension and Enteric Materials that support BCS classification IV class drug is made after mixing；Most The concentration of carrier material is 5mg/mL~20mg/mL in whole suspension；The concentration of Enteric Materials is 40mg/ in final suspension ML~100mg/mL；The concentration of suspending agent is 5mg/mL~100mg/mL in final suspension.
  9. 9. the preparation method of other oral preparations according to claim 6 is, suspension described in claim 8 is passed through The solid powder that spray drying or freeze-drying obtain, is prepared into capsule, tablet, pulvis, dry suspensoid agent, granule.
  10. 10. oral preparation described in a kind of any one of claim 1-5 or 8-9 is in preparation treatment tumour or resistant tumors The purposes of drug, the tumour are breast cancer, gastric cancer, liver cancer, non-small cell lung cancer, oophoroma, prostate cancer, cancer of pancreas, head Neck cancer or cervical carcinoma.
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