CN107616990B - Suction-type anti-lung cancer targeted drug preparation - Google Patents
Suction-type anti-lung cancer targeted drug preparation Download PDFInfo
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- CN107616990B CN107616990B CN201710487818.4A CN201710487818A CN107616990B CN 107616990 B CN107616990 B CN 107616990B CN 201710487818 A CN201710487818 A CN 201710487818A CN 107616990 B CN107616990 B CN 107616990B
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Abstract
The invention belongs to biomedicine technical fields, more particularly to a kind of suction-type anti-lung cancer targeted drug preparation.By the way that extractive of Zi-Jin-Sha is prepared into Foradil Aerolizer formoterol fumarate, it can effectively reach lung, and be deposited on alveolar, achieve the effect that targeted anti-lung carcinoma.
Description
Technical field
The invention belongs to biomedicine technical fields, more particularly to a kind of suction-type anti-lung cancer targeted drug preparation.
Background technology
Lung cancer is current common one of malignant tumour, and in the world, the morbidity and mortality of lung cancer are all presented
Situation is risen, this trend is especially pronounced in developing countries such as China.In China, shelter has the morbidity and mortality of lung cancer
First of malignant tumour, wherein male's morbidity and mortality occupy first, and women incidence occupies second, is only second to mammary gland
Cancer, the death rate then occupy first.In order to control the growth of lung cancer morbidity rate and the death rate, lung cancer is classified as by the Ministry of Public Health of China
The non-emphasis of prevention and control of cancer.
The therapeutic modality of lung cancer includes chemotherapy, radiotherapy and surgical intervention.Although surgical operation is radical cure lung
The sole mode of cancer, but in the long-term application in TCM in China, Chinese medicine is for stablizing tumor stove, elongated strap tumor life span, subtracting
It puts down chemical therapy toxic side effect etc. gently and all shows certain curative effect and advantage.Traditional Chinese medicine has got over the therapeutic effect of lung cancer
Not more to be widely studied the concern of person and clinical application person.
Common pternopetalum root is the root and rhizome that Umbelliferae archangel turns celery.Primary efficacy is wind-dispelling, cold dispelling, eliminating dampness, analgesic.
Now it is chiefly used in cold stuffy nasal obstruction and a variety of antalgesics.Modern pharmacological research finds common pternopetalum root in antibacterial, antiulcer, immunological regulation
Etc. tool have a better effect.
The ingredients such as Coumarins, volatile oil are mainly contained in common pternopetalum root.Common pternopetalum root is disclosed in patent CN101104009 to carry
Object and its extracting method and extract is taken to prepare treatment inflammatory disease and/or the drug of pain or the purposes of product.Patent CN
101002809 disclose the water extract and alcohol extract of common pternopetalum root, and further disclose extract with analgesia, antiulcer and solution
Convulsion acts on, and the effect of to stomachache, abdominal pain, peptic ulcer, gastrointestinal smooth muscle spasmus, bronchial smooth muscle.
It there are no in currently available technology and its extract be used for cancer, or more specifically lung cancer therapy field.
Foradil Aerolizer formoterol fumarate is the administering mode in terms of a kind of drug delivery system that treating respiratory tract and/or pulmonary disease,
There is prodigious advantage and application potential compared to dosage forms such as conventional tablet, granule, capsule, injections.Specifically,
Since tablet, granule, capsule, injection etc. belong to the drug of general metabolism, the dosage for playing drug effect can be by
To influence the problems such as absorption, simultaneously because it belongs to general metabolism drug, thus the side reactions such as allergy are easily caused, but it is dry
Powders for inhalation directly can arrive at lung by respiratory tract, therefore have targeting, and the advantage with low dosage high effect.
Foradil Aerolizer formoterol fumarate is drug by that will be micronized and/or carrier with single dose or multi-dose depot forms, is used
Special powder inhaler is actively or passively sucked atomization medicine intelligence respiratory tract or even the preparation of lung by patient.It is dry at present
Powders for inhalation has been widely used in the relevant therapy field of tuberculosis.
Invention content
The purpose of the present invention is to provide a kind of new suction-type anti-lung cancer targeted drug preparations, by extracting common pternopetalum root
Object is prepared into Foradil Aerolizer formoterol fumarate, can effectively reach lung, and be deposited on alveolar, achieve the effect that targeted anti-lung carcinoma.
In order to realize this goal of the invention, a kind of new suction-type anti-lung cancer targeted drug preparation, the system are we disclosed
Agent includes mainly common pternopetalum root ethanol extract.
Further, it refers to the ethyl alcohol obtained according to following preparation method to we disclose the common pternopetalum root ethanol extract
Extract：
（1）By common pternopetalum root medicinal material using ethyl alcohol as solvent, according to ethanol extraction method heating and refluxing extraction, and by extract low pressure
Vacuum concentration obtains crude extract；
（2）Crude extract is dissolved in petroleum ether, filters, takes solid；
（3）Solid is dissolved in 10-30% ethyl alcohol, after being adsorbed on macroreticular resin, with ethanol elution, collects eluent,
It is evaporated, as ethanol extract.
Mass volume ratio wherein between common pternopetalum root and ethyl alcohol is 1g common pternopetalum roots：6-10ml ethyl alcohol.Heating and refluxing extraction
Temperature is 60 ~ 70 DEG C.Low-voltage vacuum concentration mentioned here refers to using Rotary Evaporators heating concentration.
In second step, crude extract multipass petroleum ether dissolution, color no longer changes after petroleum ether is added
Until.
In third step, the hydrotropies mode such as ultrasound may be used and completely dissolve in water solid.
Especially it is noted that ethyl alcohol is the ethyl alcohol of 60%-70% in first step.
The elution program of ethyl alcohol is in third step：Impurity first is washed away with the 10-40% ethyl alcohol of 4-8 times of BV, removal of impurities flow velocity is
1.5-6BV/h, then with the 60-95% ethanol elutions of 3-10 times of BV, elution flow rate 3-9BV/h collects the latter's elution fraction.Its
Middle BV refers to the volume that resin is loaded in resin column, which is known as bed, and volume (bed volume) is abbreviated as BV.
Meanwhile it is Foradil Aerolizer formoterol fumarate that we, which further disclose the suction-type anti-lung cancer targeted drug preparation,.
Specifically, the preparation method of the Foradil Aerolizer formoterol fumarate is that common pternopetalum root ethanol extract is dissolved in water, ethyl alcohol, second two
In one or more of alcohol solvent, common pternopetalum root ethanol extract solution is formed, then again extracts the common pternopetalum root ethyl alcohol
After object solution is pelletized by way of spray drying, grinding is mixed i.e. after forming powder with pharmaceutically acceptable Foradil Aerolizer formoterol fumarate auxiliary material
At.
Pharmaceutically acceptable Foradil Aerolizer formoterol fumarate auxiliary material mentioned here include dispersibility aid, the agent of pH stable regulations, diluent and
Big granularity carrier.Wherein dispersibility aid is selected from one or more of tyrosine, leucine, phenylalanine, glycine；PH is steady
Determine conditioning agent and is selected from phosphate buffer solution, citrate buffer solution.Diluent is selected in lactose or mannitol.
Wherein spray drying is aseptically, to be carried out under the pressure condition of 10.335Kpa to 51.675Kpa.It is dry
The temperature condition of gas is 150 DEG C to 250 DEG C of inlet temperature, and outlet temperature is 70 DEG C to 150 DEG C.Nitrogen flow rate is 650kg/ hours
To 750kg/ hours.
After technical solution disclosed by the invention, have the advantages that：
（1）Foradil Aerolizer formoterol fumarate is made in the ethanol extract of common pternopetalum root by the present invention, can directly be extracted common pternopetalum root ethyl alcohol
Object is transported to lung and plays anti-lung cancer effect, reduces dosing, while can significantly improve the drug concentration of target area, reduces
Whole body toxic side effect, safety higher, adverse reaction are lower.
（2）The present invention ensures the stability of common pternopetalum root pharmaceutical preparation and having for attachment lung by new dry powder formulations technique
Effect property.
Description of the drawings
Fig. 1 is Tissue distribution figure after administration.
Specific implementation mode
In order to better understand the present invention, with reference to embodiment, the present invention will be further elaborated.
It is to be understood that unless there are specified otherwise, otherwise reagent used in the embodiment of the present invention, equipment etc. are commercially available
Product.
Embodiment 1
（1）After taking common pternopetalum root medicinal material 500g to crush, with 65% ethyl alcohol heating and refluxing extraction 3 times, extraction 2 hours every time, ethyl alcohol
Dosage be 4000ml.Merge extracting solution, is concentrated to dryness acquisition crude extract, the wherein temperature of Rotary Evaporators on a rotary evaporator
Degree is 65 DEG C.
（2）Crude extract is dissolved in petroleum ether, is filtered, is taken solid, solid is dissolved in petroleum ether again, then again
Secondary filtering takes solid, is repeated several times when addition petroleum ether is mixed and shaken without color change；
（3）By step（2）The solid obtained after multiple dissolution process is dissolved in 10-30% ethyl alcohol, after dispersing and dissolving,
It is adsorbed on HP20 macroreticular resins, resin column blade diameter length ratio is 1:8, impurity first is washed away with the 10-40% ethyl alcohol of 6 times of BV, removal of impurities flow velocity is
1.5-6BV/h, then with the 60-95% ethanol elutions of 8 times of BV, elution flow rate 3-9BV/h collects the latter's elution fraction.Wherein BV
Refer to the volume that resin is loaded in resin column, which is known as bed, and volume (bed volume) is abbreviated as BV.Eluent is collected,
It is evaporated, as ethanol extract.
Embodiment 2
The common pternopetalum root ethanol extract obtained in embodiment 1 is dissolved in the water to form common pternopetalum root ethanol extract solution,
Then the spray dryer of pharmaceutical grade is used to carry out spray-drying process to solution.Spray drying be aseptically,
It is carried out under the pressure condition of 10.335Kpa to 51.675Kpa.The temperature condition of dry gas is 150 DEG C to 250 DEG C of inlet temperature,
Outlet temperature is 70 DEG C to 150 DEG C.Nitrogen flow rate is 650kg/ hours to 750kg/ hours.
Here aseptic condition can be maintained using a variety of methods.Such as moise-heat sterilization can be carried out to corresponding element,
And it is purged after sterilization using sterile nitrogen, remove entrained steam and maintains positive internal pressure.
Pressure in system is maintained using the nitrogen of aseptic filtration, until spray-drying process is completed.
Common pternopetalum root ethanol extract particulate abrasive Cheng Fenhou is formed, is mixed to form with purple with pharmaceutically acceptable Foradil Aerolizer formoterol fumarate auxiliary material
Gold sand ethanol extract is the suction-type anti-lung cancer targeted drug preparation of main ingredient ingredient.
Pharmaceutically acceptable Foradil Aerolizer formoterol fumarate auxiliary material mentioned here include dispersibility aid, the agent of pH stable regulations, diluent and
Big granularity carrier.Wherein dispersibility aid is selected from one or more of tyrosine, leucine, phenylalanine, glycine；PH is steady
Determine conditioning agent and is selected from phosphate buffer solution, citrate buffer solution.Diluent is selected in lactose or mannitol.
The main function of dispersing aid is dispersion common pternopetalum root ethanol extract powder, prevents from reuniting and sticking each other between particle
Effect even.
The effect of pH stable regulation agent is the effect stablized the dissolved pH of Foradil Aerolizer formoterol fumarate in laborsaving suitable pH.
It is dry that filling increase on the basis of drug content and other section's excipient substance Chinese is mainly played in the effect of diluent
Effect of the powders for inhalation particle weight to the loading or soakage.
In the present embodiment, we are preferably mixed to form suction-type anti-lung cancer targeted drug preparation according to formula as below：
Table 1：
Embodiment 3
Deposition in vitro rate（FPF）It is the most intuitive index for investigating Foradil Aerolizer formoterol fumarate aerodynamics Li Jing distribution, it can
To characterize DPI lung effective precipitation.Under the conditions of FPF refers to 60L/min standard flow rates, the effective of lung can be deposited to
Minuteness particle dosage then shows as two to seven grades of the sum of drug deposition amount in data calculating, two to seven grades of drug is sunk
FPF value of the sum of the accumulated amount as corresponding formula Foradil Aerolizer formoterol fumarate.When FPF values may be considered effective deposition when more than 12%
In lung.
Based on this, we have carried out FPF experiments to the formula in embodiment 2, and sample 1-15 all has good deposition,
Show that Foradil Aerolizer formoterol fumarate disclosed by the invention can send common pternopetalum root ethanol extract contained therein to lung and play curative effect,
Lactose is better than mannitol to the effect of deposition, and the increase of lactose content can further increase deposition.
Embodiment 4
The sample 13 in embodiment 2 is chosen as Tissue distribution research after investigation sucking.
Choose 72 rats, by lung suck sample 13, dosage 100ug/kg, and 1 after administration, 2,3,4,6,
Rat was put to death in 9 hours, takes the rat heart, liver, spleen, lung, kidney, brain and testis（Uterus, ovary）, clean, blot residual water, claim
Physiological saline is added in weight（Tissue weight and physiological saline volume ratio 1:3）, homogenate is made.
100 μ L of homogenate are drawn in the centrifuge tube of 2mL, 10 μ L of internal standard solution, the sodium carbonate liquor of 400 μ L is added（0.2M）
Shake, ether is with methylene chloride volume than 8:The 1 mixed liquor 1mL mixed, vortex mixed 5min, centrifuges 5min, and centrifugation turns
Fast 12000r/min, Aspirate supernatant 1.5mL, low-temperature rotary is concentrated to dryness, after residue is redissolved with methanol, centrifugation, and by supernatant
Liquid is analyzed with UHPLC-MS/MS.Low temperature mentioned here refers to 35 DEG C or so.
Tissue distribution figure is shown in Fig. 1, it can be seen that drug is significantly higher than other parts in the concentration of lung, and the heart, liver,
Distribution-free in brain, testis, therefore toxic side effect is small.
Embodiment 5
Select nude mice（Balb/c）The weight of 30 half male and half females, every mouse is divided into three groups, is respectively labeled as in 25-27g
Administration group, control group and positive controls, tumor type are A549.A549 cell strains are inoculated in nude mouse, nude mice human body is become
Transplantable lung cancer model.For administration group by the way of inhalation, dosage dosage is 100ug/kg, positive control after inoculation
Medicine is MMC, by the way of intraperitoneal administration, dosage 2mg/kg.It carries out every other day once, totally three weeks, 48h puts to death dynamic after drug withdrawal
Object weighs weight and knurl weight respectively, according to（Control group average knurl weight-administration group average knurl weight）/ control group average knurl weight calculates
Tumor control rate.The results show that the inhibiting rate of common pternopetalum root ethanol extract is 75%, for the 78% of positive controls,
Illustrate that common pternopetalum root ethanol extract disclosed in the present application has significant tumor inhibition effect.
Claims (1)
1. suction-type anti-lung cancer targeted drug preparation, characterized in that the active constituent of said preparation is common pternopetalum root ethanol extract, institute
It refers to the ethanol extract obtained according to following preparation method to state common pternopetalum root ethanol extract：
（1）By common pternopetalum root medicinal material using ethyl alcohol as solvent, according to ethanol extraction method heating and refluxing extraction, and by extract low-voltage vacuum
It is concentrated to give crude extract；
（2）Crude extract is dissolved in petroleum ether, filters, takes solid；
（3）Solid is dissolved in 10-30% ethyl alcohol, after being adsorbed on macroreticular resin, with ethanol elution, eluent is collected, steams
It does, as ethanol extract；
The suction-type anti-lung cancer targeted drug preparation is Foradil Aerolizer formoterol fumarate；The preparation method of Foradil Aerolizer formoterol fumarate is, by common pternopetalum root second
Alcohol extracting thing is dissolved in one or more of water, ethyl alcohol, ethylene glycol solvent, and it is molten to form common pternopetalum root ethanol extract
Liquid, after then the common pternopetalum root ethanol extract solution is pelletized by way of spray drying again, grinding formed after powder with can
Pharmaceutical dry powder inhalant auxiliary material mix；The pharmaceutically acceptable Foradil Aerolizer formoterol fumarate auxiliary material includes dispersibility aid, pH stabilizations
Conditioning agent, diluent and big granularity carrier, wherein dispersibility aid is in tyrosine, leucine, phenylalanine, glycine
One or more；PH stable regulation agent is selected from phosphate buffer solution, citrate buffer solution；Diluent be selected in lactose or
Mannitol.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101217956A (en) * | 2005-05-05 | 2008-07-09 | 康宾纳特克斯公司 | Compositions and methods for treatment for neoplasms |
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2017
- 2017-06-23 CN CN201710487818.4A patent/CN107616990B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101217956A (en) * | 2005-05-05 | 2008-07-09 | 康宾纳特克斯公司 | Compositions and methods for treatment for neoplasms |
Non-Patent Citations (2)
| Title |
|---|
| 吸入制剂在肿瘤治疗中的应用;王磊;《安徽医药》;20091231;第13卷(第12期);第1451-1452页 * |
| 紫金砂提取物的制备工艺及质量控制研究;胡晓燕;《中国优秀硕士学位论文全文数据库 医药卫生科技辑》;20120531;第E057-82页 * |
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Address after: 210029 No. 300 Guangzhou Road, Gulou District, Nanjing City, Jiangsu Province, First Division of Thoracic Surgery Patentee after: Zhu Quan Address before: 210029 Guangzhou Road, Gulou District, Nanjing, Jiangsu 300 Patentee before: Zhu Quan |
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