CN103735536A - Total cucurbitacin phosphatidyl cholate mixed micelle oral quick-absorption membrane and preparation method thereof - Google Patents
Total cucurbitacin phosphatidyl cholate mixed micelle oral quick-absorption membrane and preparation method thereof Download PDFInfo
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- CN103735536A CN103735536A CN201410013260.2A CN201410013260A CN103735536A CN 103735536 A CN103735536 A CN 103735536A CN 201410013260 A CN201410013260 A CN 201410013260A CN 103735536 A CN103735536 A CN 103735536A
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- China
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- cholate
- phospholipid
- mixed micelle
- total cucurbitacin
- cucurbitacin
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- LNSXRXFBSDRILE-UHFFFAOYSA-N Cucurbitacin Natural products CC(=O)OC(C)(C)C=CC(=O)C(C)(O)C1C(O)CC2(C)C3CC=C4C(C)(C)C(O)C(O)CC4(C)C3(C)C(=O)CC12C LNSXRXFBSDRILE-UHFFFAOYSA-N 0.000 title claims abstract description 150
- CVKKIVYBGGDJCR-SXDZHWHFSA-N Cucurbitacin B Natural products CC(=O)OC(C)(C)C=CC(=O)[C@@](C)(O)[C@@H]1[C@@H](O)C[C@]2(C)C3=CC[C@@H]4C(C)(C)C(=O)[C@H](O)C[C@@]4(C)[C@@H]3CC(=O)[C@@]12C CVKKIVYBGGDJCR-SXDZHWHFSA-N 0.000 title claims abstract description 150
- PIGAXYFCLPQWOD-UHFFFAOYSA-N dihydrocucurbitacin I Natural products CC12C(=O)CC3(C)C(C(C)(O)C(=O)CCC(C)(O)C)C(O)CC3(C)C1CC=C1C2C=C(O)C(=O)C1(C)C PIGAXYFCLPQWOD-UHFFFAOYSA-N 0.000 title claims abstract description 149
- 150000001904 cucurbitacins Chemical class 0.000 title claims abstract description 141
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- 125000001095 phosphatidyl group Chemical group 0.000 title abstract 3
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Images
Abstract
The invention provides a total cucurbitacin phosphatidyl cholate mixed micelle oral quick-absorption membrane and a preparation method thereof, and belongs to the technical field of traditional Chinese medicinal preparations and preparation methods thereof. The preparation method comprises the following steps: preparing a lipid membrane from phospholipid; dissolving cholate into a phosphate buffer solution to prepare a cholate liquid; performing ultrasonic mixing on the lipid membrane and the cholate liquid in a water bath to obtain a phosphatidyl cholate blank micelle liquid; adding total cucurbitacin powder into the phosphatidyl cholate blank micelle liquid to obtain phosphatidyl cholate mixed micelle of total cucurbitacin; sequentially adding hydroxypropyl methyl cellulose, low substituted hydroxyprepyl cellulose, microcrystalline cellulose and PEG400 (polyethylene glycol 400) into the phosphatidyl cholate mixed micelle of total cucurbitacin to obtain the total cucurbitacin phosphatidyl cholate mixed micelle oral quick-absorption membrane. The oral quick-absorption membrane has the advantages of improving the solubility of total cucurbitacin, increasing adhesive and penetrating effect of the oral quick-absorption membrane to oral mucosa, avoiding irritation of total cucurbitacin to gastrointestinal tracts, remarkably improving the bioavailability of total cucurbitacin and reducing adverse response.
Description
Technical field
The invention belongs to Chinese medicine preparation and preparation method thereof technical field, be specifically related to total cucurbitacin phospholipid cholate mixed micelle oral cavity speed and inhale film and preparation method thereof.
Background technology
Total cucurbitacin (cucurbitacins) is to belong to from Cucurbitaceae and other section a class tetracyclic triterpenoid that obtains bitterness or sweet taste various plants.Be all the very high compound of a class degree of oxidation, its feature 18-methyl is on C-9.Comprise that cucurbitacin A, B, C, D, E, F, G, H, I, J, K, L, cucurbitacin, dihydrocucurbitacin F etc. more than 100 plant compound.Wherein Cucurbitacin B is that wherein content is the highest, and the one that physiologically active is the strongest has antitumor, protects the liver, the multiple biological activity such as antiinflammatory, raising immunity of organisms, the intestines and stomach effect.Its structural formula is as follows
The preparation take total cucurbitacin as key component of domestic listing has Beijing Tongrentang Technology Development Co.ltd. Pharmaceutical Factory, Beijing three nine-day periods after the winter solstice pharmaceutcal corporation, Ltd and total cucurbitacin sheet of producing of three pharmacy corporations of Chongqing Han Hua pharmaceutical Co. Ltd, trade name is cucurbitacin sheet, it is all common oral preparation, be mainly used in chronic hepatitis B, the treatment of primary hepatocarcinoma, oral administration biaavailability is all lower, mainly because the dissolubility of cucurbitane compound is low, stripping is poor, is difficult to absorb in gastrointestinal tract.
Summary of the invention
Phospholipid is the general name of the lipid material that contains phosphate radical, is biomembranous basis, has important physiological function.Phospholipid is extensively present in the seed of brains, internal organs, blood, milk, egg yolk and plant of animal, has advantages of that source is wide, toxicity is low.Phospholipid has emulsifying, dispersion, help ooze, the characteristic such as moistening, digestive tract is had to very strong affinity, in medicament, be commonly used for dispersant, lubricant, emulsifying agent, stabilizing agent, absorption enhancer, prodrug carrier etc.
Cholic acid salt cholate comprises natural bile, sodium deoxycholate, and SODIUM CHENODIOL, glycosides ammonia sodium cholate and Bile Salts etc., while using as the intestinal absorption promoter of micromolecule class, can obviously increase medicine seeing through and absorbing at jejunum and colon.
Micelle is the excessive surfactant colloid solution that self assembly forms in water.
It is a kind of novel form obtaining after utilizing oral instant membrane technology that micellar solution is solidified that the oral cavity speed of mentioning in the present invention is inhaled film.Oral cavity speed is inhaled film can rapid disintegrate discharge total cucurbitacin phospholipid cholate mixed micelle in oral cavity, and total cucurbitacin phospholipid cholate mixed micelle can enter body circulation by the rapid absorbed into serum of oral mucosa again.Because the total cucurbitacin phospholipid cholate mixed micelle discharging after the disintegrate of oral cavity speed suction film is very rapid by the absorption of oral mucosa, not autonomous swallowing movement with oral cavity the medicine that can avoid discharging as common oral instant membrane disintegrate enters gastrointestinal tract, so oral cavity speed is inhaled film, is a kind of oral mucosa drug delivery system truly.Can effectively avoid medicine to gastrointestinal stimulation, reduce the first pass effect of medicine, improve the bioavailability of medicine.Oral cavity speed suction film is easy to use simultaneously, need not, with water delivery service, without the process of swallowing, can improve patient's compliance.
Low in order to solve the dissolubility due to cucurbitane compound above-mentioned, stripping is poor, thereby be difficult to absorb, cause all lower problems of oral administration biaavailability in gastrointestinal tract, an object of the present invention is to disclose a kind of total cucurbitacin phospholipid cholate mixed micelle oral cavity speed and inhale film.
Another object of the present invention has been to disclose the preparation method that total cucurbitacin phospholipid cholate mixed micelle oral cavity speed is inhaled film.
Technical scheme of the present invention is as follows:
The preparation method that total cucurbitacin phospholipid cholate mixed micelle oral cavity speed is inhaled film, comprises the steps:
(1), phospholipid added to organic solvent make titer, under nitrogen, dry up most of solvent, then room temperature is placed and is removed micro-organic solvent in 12 hours in vacuum environment, makes adipose membrane;
(2), cholate is dissolved in the phosphate buffer of pH=7.2, make the cholate solution of desired concn;
(3), by adipose membrane and cholate solution ultrasonic 45min that mixes in 45 ℃ of water-baths, the white phosphorus fat cholate micellar solution of having leisure;
(4), total cucurbitacin powder is joined in the blank micelle of phospholipid cholate, nitrogen-filled seal, puts in constant temperature blender with magnetic force, and uniform stirring 24h at 40 ℃, obtains total cucurbitacin phospholipid cholate mixed micelle;
(5), hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, PEG400 are joined successively in total cucurbitacin phospholipid cholate mixed micelle solution and stir, afterwards by its uniform spreading at smooth surface, obtain total cucurbitacin phospholipid cholate mixed micelle oral cavity speed after dry and inhale film.
The preparation method that total cucurbitacin phospholipid cholate mixed micelle oral cavity speed described in technique scheme is inhaled film, wherein, in the total cucurbitacin phospholipid cholate mixed micelle described in step (4) phospholipid and cholate mol ratio be 1:(0.2～2); Phospholipid is 2:(0.8～1 with the weight ratio of total cucurbitacin); Mixed micelle size is 30nm-120nm, and total cucurbitacin bag is loaded in the hydrophobic core of mixed micelle.
The preparation method that total cucurbitacin phospholipid cholate mixed micelle oral cavity speed described in technique scheme is inhaled film, wherein, in the phospholipid cholate mixed micelle of the total cucurbitacin described in step (4), the mol ratio of phospholipid and cholate is 1:(0.8～1), phospholipid is 1:(0.45～0.5 with the weight ratio of total cucurbitacin).
The preparation method that total cucurbitacin phospholipid cholate mixed micelle oral cavity speed described in technique scheme is inhaled film, wherein, the phospholipid described in step (1) is phospholipid or lecithin; Cholate is selected from the one in natural bile, sodium deoxycholate, SODIUM CHENODIOL, NaGC or Bile Salts.
The preparation method that total cucurbitacin phospholipid cholate mixed micelle oral cavity speed described in technique scheme is inhaled film, wherein, the lecithin described in step (2) is selected from the one in soybean lecithin, Ovum Gallus domesticus Flavus lecithin or hydrolecithin.
The preparation method that total cucurbitacin phospholipid cholate mixed micelle oral cavity speed described in technique scheme is inhaled film, wherein, described total cucurbitacin phospholipid cholate mixed micelle oral cavity speed is inhaled in film total cucurbitacin and is accounted for whole total cucurbitacin phospholipid cholate mixed micelle oral cavity speed to inhale the weight ratio of film be 1:50.
The preparation method that total cucurbitacin phospholipid cholate mixed micelle oral cavity speed described in technique scheme is inhaled film, wherein, it is 25-40 μ m that described total cucurbitacin phospholipid cholate mixed micelle oral cavity speed is inhaled film thickness.
The preparation method that total cucurbitacin phospholipid cholate mixed micelle oral cavity speed described in technique scheme is inhaled film, wherein, organic solvent in step (1) be selected from chloroform, ether, ethanol, petroleum ether or fatty oil one or more with arbitrary proportion mix solvent, the mass concentration of titer is 30～70mmol/L; The mass concentration of the cholate solution in described step (2) is 5～20mmol/L.
The preparation method that total cucurbitacin phospholipid cholate mixed micelle oral cavity speed described in technique scheme is inhaled film, wherein, the weight ratio of hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose and microcrystalline Cellulose in step (5) is 40:4:1, in every 100g hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose and microcrystalline cellulose, adds 25mlPEG400.Total cucurbitacin phospholipid cholate mixed micelle oral cavity speed is inhaled film, and wherein, it is to be prepared by the method described in arbitrary technical scheme in technique scheme that described total cucurbitacin phospholipid cholate mixed micelle oral cavity speed is inhaled film.
The present invention has following beneficial effect:
1, the total cucurbitacin phospholipid of medicine of the present invention cholate mixed micelle oral cavity speed suction film can not only be to total cucurbitacin solubilising, can also increase its effect that sees through in oral mucosa, by oral mucosa, absorb and can avoid total cucurbitacin to GI irritation effect, significantly improved the bioavailability of total cucurbitacin and reduced untoward reaction;
2, preparation method of the present invention is by total cucurbitacin and a certain amount of phospholipid, cholate forms phospholipid cholate micelle under suitable solvent and condition, use afterwards the proper auxiliary materials such as hydroxypropyl methylcellulose that mixed micelle is made to oral instant membrane, its physicochemical property is changed, thereby promote the absorption of total cucurbitacin, improve the bioavailability of total cucurbitacin, and then increase curative effect, reduce untoward reaction;
3, easy, the favorable reproducibility of the preparation method of medicine of the present invention, mechanization degree are high, are applicable to large-scale production and application.
Accompanying drawing explanation:
1, Fig. 1 is the experimental provision that medicament mucosa absorbs;
2, Fig. 2 is that total cucurbitacin raw material medicine and total cucurbitacin phospholipid cholate mixed micelle oral cavity speed are inhaled the absorption curve comparison of film in oral cavity.
The specific embodiment:
For making technical scheme of the present invention be convenient to understand, below in conjunction with concrete test example, the total cucurbitacin phospholipid of the present invention cholate mixed micelle oral cavity speed is inhaled to film and preparation method thereof and be further described.
Embodiment 1: the preparation of total cucurbitacin phospholipid cholate mixed micelle
(1) fabaceous lecithin 16.67g is added and in 100ml petroleum ether, make the titer that mass concentration is 30～70mmol/L, under nitrogen, dry up most of solvent, in vacuum drying oven, normal-temperature vacuum is placed 12h to remove micro-organic solvent again, makes adipose membrane;
(2) Bile Salts 2g is dissolved in the phosphate buffer (pH=7.2) of 100ml, making mass concentration is the cholate solution of 5～20mmol/L;
(3) by adipose membrane and cholate solution ultrasonic 45min that mixes in 45 ℃ of water-baths, the white phosphorus fat cholate mixed micelle solution of having leisure;
(4) total 8g cucurbitacin powder is joined in the blank micelle of phospholipid cholate, nitrogen-filled seal, puts in constant temperature blender with magnetic force, and uniform stirring 24h at 40 ℃, obtains carrier micelle, i.e. total cucurbitacin phospholipid cholate mixed micelle;
Embodiment 2: the preparation of total cucurbitacin phospholipid cholate mixed micelle
(1) in fabaceous lecithin 16.67g being added in 80ml chloroform, make the titer that mass concentration is 30～70mmol/L, under nitrogen, dry up most of solvent, then normal-temperature vacuum is placed 12h to remove micro-organic solvent in vacuum drying oven, makes adipose membrane;
(2) sodium deoxycholate 2g is dissolved in the phosphate buffer (pH=7.2) of 100ml, making mass concentration is the cholate solution of 5～20mmol/L;
(3) by adipose membrane and cholate solution ultrasonic 45min that mixes in 45 ℃ of water-baths, white phosphorus fat/cholate mixed micelle solution of having leisure;
(4) total 8g cucurbitacin powder is joined in the blank micelle of phospholipid cholate, nitrogen-filled seal, puts in constant temperature blender with magnetic force, and uniform stirring 24h at 40 ℃, obtains carrier micelle, i.e. total cucurbitacin phospholipid cholate mixed micelle.
Embodiment 3: the preparation of total cucurbitacin phospholipid cholate mixed micelle
(1) fabaceous lecithin 16.67g is added in 90ml ether and make the titer that mass concentration is 30～70mmol/L, under nitrogen, dry up most of solvent, then normal-temperature vacuum is placed 12h to remove micro-organic solvent in vacuum drying oven, makes adipose membrane;
(2) SODIUM CHENODIOL 2g is dissolved in the phosphate buffer (pH=7.2) of 100ml, making mass concentration is the cholate solution of 5～20mmol/L;
(3) by adipose membrane and cholate solution ultrasonic 45min that mixes in 45 ℃ of water-baths, the white phosphorus fat cholate mixed micelle solution of having leisure;
(4) total 8g cucurbitacin powder is joined in the blank micelle of phospholipid cholate, nitrogen-filled seal, puts in constant temperature blender with magnetic force, and uniform stirring 24h at 40 ℃, obtains carrier micelle, i.e. the phospholipid cholate mixed micelle of total cucurbitacin.
Embodiment 4: the preparation of total cucurbitacin phospholipid/cholate mixed micelle
(1) lecithin 16.67g is added in 100ml ethanol and make the titer that mass concentration is 30～70mmol/L, under nitrogen, dry up most of solvent, then normal-temperature vacuum is placed 12h to remove micro-organic solvent in vacuum drying oven, makes adipose membrane;
(2) Bile Salts 2g is dissolved in the phosphate buffer (pH=7.2) of 100ml, making mass concentration is the cholate solution of 5～20mmol/L;
(3) by adipose membrane and cholate solution ultrasonic 45min that mixes in 45 ℃ of water-baths, the white phosphorus fat cholate mixed micelle solution of having leisure;
(4) total 8g cucurbitacin powder is joined in the blank micelle of phospholipid cholate, nitrogen-filled seal, puts in constant temperature blender with magnetic force, and uniform stirring 24h at 40 ℃, obtains carrier micelle, i.e. total cucurbitacin phospholipid/cholate mixed micelle.
Embodiment 5: the preparation of total cucurbitacin phospholipid cholate mixed micelle
(1) in lecithin 16.67g being added in 80ml chloroform, make the titer that mass concentration is 30～70mmol/L, under nitrogen, dry up most of solvent, then normal-temperature vacuum is placed 12h to remove micro-organic solvent in vacuum drying oven, makes adipose membrane;
(2) sodium deoxycholate 2g is dissolved in the phosphate buffer (pH=7.2) of 100ml, making mass concentration is the cholate solution of 5～20mmol/L;
(3) by adipose membrane and cholate solution ultrasonic 45min that mixes in 45 ℃ of water-baths, the white phosphorus fat cholate mixed micelle solution of having leisure;
(4) total 8g cucurbitacin powder is joined in the blank micelle of phospholipid/cholate, nitrogen-filled seal, puts in constant temperature blender with magnetic force, and uniform stirring 24h at 40 ℃, obtains carrier micelle, i.e. total cucurbitacin phospholipid cholate mixed micelle.
Embodiment 6: the preparation of total cucurbitacin phospholipid/cholate mixed micelle
(1) lecithin 16.67g is added in 90ml ether and make the titer that mass concentration is 30～70mmol/L, under nitrogen, dry up most of solvent, then normal-temperature vacuum is placed 12h to remove micro-organic solvent in vacuum drying oven, makes adipose membrane;
(2) SODIUM CHENODIOL 2g is dissolved in the phosphate buffer (pH=7.2) of 100ml, making mass concentration is the cholate solution of 5～20mmol/L;
(3) by adipose membrane and cholate solution ultrasonic 45min that mixes in 45 ℃ of water-baths, the white phosphorus fat cholate mixed micelle solution of having leisure;
(4) total 8g cucurbitacin powder is joined in the blank micelle of phospholipid cholate, nitrogen-filled seal, puts in constant temperature blender with magnetic force, and uniform stirring 24h at 40 ℃, obtains carrier micelle, i.e. total cucurbitacin phospholipid cholate mixed micelle.
Embodiment 7: the oral cavity speed of the phospholipid cholate mixed micelle of total cucurbitacin is inhaled film
By hydroxypropyl methylcellulose 4g, low-substituted hydroxypropyl cellulose 0.4g, microcrystalline cellulose 0.1g, PEG4001.125mL, add successively the liquid that makes it to form thickness in 40mL distilled water, then add wherein the phospholipid cholate mixed micelle solution 1.1mL of total cucurbitacin of embodiment 1～6 preparation, high-speed stirred makes mix homogeneously simultaneously, after vacuum removal of air bubbles, at smooth surface, sprawl into the thin film of one deck 10 × 10cm, the oral cavity speed that obtains total cucurbitacin phospholipid cholate mixed micelle in vacuum drying oven after being dried is inhaled film.
The total cucurbitacin phospholipid of the product cholate mixed micelle oral cavity speed of preparing by the present invention is below inhaled pharmacokinetics, buccal absorption and the pharmacodynamics test of film and is further set forth the beneficial effect that the total cucurbitacin phospholipid of product of the present invention cholate mixed micelle has:
Test example one: total cucurbitacin raw material medicine, the pharmacodynamic study of total cucurbitacin phospholipid cholate mixed micelle and contrast medicine:
1, materials and methods:
Medicine: total cucurbitacin raw material medicine (Nanjing Zelang Pharmaceutical Technology Inc.), total cucurbitacin phospholipid cholate mixed micelle be by embodiments of the invention 1 and 7 be prepared, 5-fluorouracil (Tonghua Mao Xiang pharmaceutical Co. Ltd).
Compound method: be mixed with every milliliter of solution containing total cucurbitacin 10mg containing the medicine distilled water of total cucurbitacin, the concentration of 5-fluorouracil is 25mg/mL.
Animal: Kunming mouse, market is bought; Male and female half and half 18-20g.
2, test key step:
Get 32 of healthy mices and be divided into immediately four groups, be negative control group, crude drug group, positive controls, total cucurbitacin phospholipid cholate mixed micelle group, corresponding institute is respectively normal saline, total cucurbitacin raw material medicine, 5-fluorouracil and total cucurbitacin phospholipid cholate mixed micelle to medicine, 8 every group.HepG II cell (1 × 10 is injected in respectively left oxter
7cells) modeling, modeling success after seven days, ig administration every day 2 times from the 8th day, dosage is all 0.5mL/kg, negative control group gives the normal saline water of same ratio, and successive administration, after 15 days, is put to death mice, peel off tumor tissues, record volume, the weight of each group of tumor, in Table 1.
The impact (X ± SD) of three kinds of medicines of table 1 on mouse tumor
| Group | Dosage (mg/kgd) | Animal (only) | Tumor volume (mm 3) | Tumor weight (g) |
| Negative control group | —— | 8 | 1447.3338±29.3244 | 3.9023±0.4923 |
| |
10 | 8 | 742.1134±21.1829 | 2.1034±0.3818 |
| Total cucurbitacin phospholipid/cholate |
10 | 8 | 363.1871±18.2191 | 1.3803±0.2902 |
| Positive controls | 25 | 8 | 269.9521±19.3429 | 1.2321±0.2811 |
Table 1 result shows, the volume and weight of each administration group mouse tumor all will be starkly lower than negative control group, the result of total cucurbitacin phospholipid cholate mixed micelle group and positive controls is close, do not have significant difference between checking two groups by statistics, and have remarkable significant difference with the result of crude drug and negative control group.
Test example two, more total cucurbitacin raw material medicine, total cucurbitacin phospholipid cholate mixed micelle oral cavity speed is inhaled the bioavailability study of film:
1, materials and methods:
Medicine: total cucurbitacin raw material medicine (Nanjing Zelang Pharmaceutical Technology Inc.), it is to be prepared by embodiments of the invention 1 and 7 that total cucurbitacin phospholipid cholate mixed micelle oral cavity speed is inhaled film.
Animal: male Wistar rat, 200g ± 5g, market is bought.6 of every group of rats, animal fasting 12h before test, all animals of duration of test freely drink water.
Test procedure:
(1) medicine and reagent: absolute methanol is chromatographically pure; Heparin sodium injection; Total cucurbitacin standard substance.
(2) method: get 12 of Wistar rats, be divided into immediately 2 groups, 6 every group.One group of total cucurbitacin oral mucosa administration for rat, dosage 100 ㎎/100g; By total cucurbitacin phospholipid/cholate mixed micelle oral cavity speed, inhale film mucosa delivery, dosage 100 ㎎/100g for one group.After administration, 10min, 20min, 30min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h eye socket are got blood in the centrifuge tube of heparin sodium moistening, separated plasma, and-20 ℃ of storages, to be measured.
(3) sample treatment: plasma sample 200ul, precision adds 400ul absolute methanol, and vortex is even, and the centrifugal 10min of 8000r/min, pipettes supernatant, and after nitrogen dries up, with absolute methanol redissolution, sample introduction 20ul makes HPLC and analyzes.
(4) assay method: adopt high effective liquid chromatography for measuring.
1. chromatographic condition
Chromatograph: Agilent1200;
Chromatographic column: Agilent, 4.5 × 250mm, 5 μ m;
Mobile phase: methanol: water=62:38;
Flow velocity: 1.0ml/min;
Column temperature: 30 ℃;
Detect wavelength: 228nm.
2. standard curve preparation
Get rat blank plasma 200ul, add respectively total cucurbitacin solution to make that its concentration is respectively 0.5,1,2,4,6,8,10,20mg/L, by " sample treatment " lower operation, take the peak area of total cucurbitacin as variable (X), total cucurbitacin concentration is dependent variable (Y), make linear regression, regression equation is:
Y=0.084X+10.29(r=0.9997)
This law setting-out line scope is 0.5～20mg/L.
2, experimental result
Two groups of rats are the total cucurbitacin raw material medicines of administration respectively, and total cucurbitacin phospholipid cholate mixed micelle oral cavity speed is inhaled after film, and average blood drug level is in Table 2; Data are through DAS software preference pattern, and result meets two-compartment model; Main pharmacokinetic parameter result of calculation is in Table 3.
Average blood drug level (n=6, X ± S, μ g/mL) after the administration of table 2 rat
| Time (h) | Crude drug | Speed is inhaled film |
| 0 | 0.000 | 0.000 |
| 0.083 | 4.585 | 24.833 |
| 0.17 | 7.429 | 36.400 |
| 0.25 | 12.355 | 104.500 |
| 0.5 | 12.882 | 97.553 |
| 1 | 18.020 | 90.467 |
| 2 | 29.228 | 68.207 |
| 4 | 19.528 | 61.970 |
| 6 | 5.109 | 45.000 |
| 8 | 3.657 | 34.813 |
| 10 | 3.357 | 23.693 |
| 12 | 0.892 | 16.200 |
| 24 | 0.571 | 8.460 |
Table 2 shows that the absorption rate of total cucurbitacin in speed suction film group is far away higher than the absorption rate of the total cucurbitacin in crude drug group, and phospholipid cholate mixed micelle oral cavity speed is inhaled film can improve the absorption rate of total cucurbitacin in oral mucosa.
Pharmacokinetic parameter (n=6, X ± S) after the administration of table 3 rat
As shown in Table 3, total cucurbitacin phospholipid cholate mixed micelle oral cavity speed is inhaled the area under curve (AUC of film group
0 → T) and maximum plasma concentration (Cmax) all obviously exceed the area under curve (AUC of blank group
0 → T) and maximum plasma concentration (Cmax), illustrate that the absorbtivity of total cucurbitacin in total cucurbitacin phospholipid cholate mixed micelle oral cavity speed suction film group is higher.
Result of study shows, total cucurbitacin phospholipid cholate mixed micelle oral cavity speed is inhaled film rat oral mucosa administration bioavailability and is obviously better than total cucurbitacin raw material medicine, AUC
0 → Tfor 5.66 times of total cucurbitacin raw material medicine.
Test example three, total cucurbitacin raw material medicine, total cucurbitacin phospholipid cholate mixed micelle oral cavity speed is inhaled the Absorption Study of film in oral mucosa
1, materials and methods:
Medicine: total cucurbitacin raw material medicine (Nanjing Zelang Pharmaceutical Technology Inc.), it is to be prepared by embodiments of the invention 1 and 7 that total cucurbitacin phospholipid cholate mixed micelle speed is inhaled film.
Compound method: precision takes total cucurbitacin raw material medicine, is mixed with every 100ml containing the suspension of total cucurbitacin 50mg with normal saline, and precision takes containing total cucurbitacin phospholipid cholate mixed micelle speed of the total cucurbitacin of 5mg inhales film.
Animal: duroc, grow about 6 months, body weight 110 scholar 5kg, market is bought.
Test procedure:
Get fresh duroc buccal mucosa of slaughtering, carefully peel off subcutaneous layer of fat and connective tissue, totally standby with normal saline flushing.For simulated body fluid environment, adopt normal saline as accepting medium, experimental provision is as shown in Figure 1.Adopting rotating speed is 360r/min magnetic agitation, investigate medicine by the permeance property of oral mucosa, bath temperature is controlled at 0.5 ℃ of 37 scholar, every kind of sample repeats 6 experiments, by the pig buccal mucosa of suitable size, be fixed on diffusion cell, in vitro mucous epithelium aspect is to supply chamber, and tissue surface is towards acceptance pool.Acceptance pool is first filled it up with normal saline, drains bubble, adds sample solution the sealing got ready in supply chamber.Supply pool volume is 10mL, and reception tank volume is 21mL.Respectively at 2min, 5min, 10min, 15min, 30min, 45min, 60min, 2h, 4h, 6h time point, respectively sample 5mL, and immediately supplement equivalent equality of temperature accepting medium, the sample liquid that different time points is taken out is all through 0.22 μ m filtering with microporous membrane, filtrate is stored in sample injection bottle, to be measured in-18 ℃ of refrigerator cold-storages after labelling.Assay method adopts the high effective liquid chromatography for measuring consistent with test example two.Getting concentration is total cucurbitacin titer of 1mg/mL, dilution makes that its concentration is respectively 0.01,0.05,0.1,0.2,0.3,0.4,0.5,1mg/mL, by " sample treatment " in a test example two lower operation, take the peak area of total cucurbitacin as variable (X), total cucurbitacin concentration is dependent variable (Y), make linear regression, regression equation is:
Y=0.082X+8.18(r=0.9998)
This law setting-out line scope is 0.01～1mg/mL.
Calculate accumulation transit dose (in Table 4).And take the time as variable (X), accumulation transit dose is dependent variable (Y) mapping, compares the Absorption (see Fig. 2) of two kinds of medicines at pig buccal mucosa.
Two kinds of dosage forms of table 4 are in the Heavy metal result (X ± S) of pig buccal mucosa
Result of study shows: total cucurbitacin phospholipid cholate mixed micelle oral cavity speed is inhaled film and can be improved the absorption of total cucurbitacin at pig buccal mucosa, compared with crude drug, P < 0.05 has significant difference, and phospholipid cholate mixed micelle oral cavity speed suction film significantly improves the permeability of the pig oral mucosa of total cucurbitacin.
The total cucurbitacin phospholipid cholate mixed micelle oral cavity speed that above-mentioned test example one～tri-use embodiment 2-6 respectively with 7 prepares gained coming to the same thing after inhaling film and testing.
The above, it is only preferred embodiment of the present invention, not the present invention is done to any formal and substantial restriction, all those skilled in the art, do not departing within the scope of technical solution of the present invention, when utilizing disclosed above technology contents, and the equivalent variations of a little change of making, modification and differentiation is equivalent embodiment of the present invention; Meanwhile, the change of any equivalent variations that all foundations essence technology of the present invention is done above embodiment, modification and differentiation, all still belong in the scope of technical scheme of the present invention.
Claims (10)
1. the preparation method that total cucurbitacin phospholipid cholate mixed micelle oral cavity speed is inhaled film, comprises the steps:
(1), phospholipid added to organic solvent make titer, under nitrogen, dry up most of solvent, then room temperature is placed and is removed micro-organic solvent in 12 hours in vacuum environment, makes adipose membrane;
(2), cholate is dissolved in the phosphate buffer of pH=7.2, make the cholate solution of desired concn;
(3), by adipose membrane and cholate solution ultrasonic 45min that mixes in 45 ℃ of water-baths, the white phosphorus fat cholate micellar solution of having leisure;
(4), total cucurbitacin powder is joined in the blank micelle of phospholipid cholate, nitrogen-filled seal, puts in constant temperature blender with magnetic force, and uniform stirring 24h at 40 ℃, obtains total cucurbitacin phospholipid cholate mixed micelle;
(5), hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, PEG400 are joined successively in total cucurbitacin phospholipid cholate mixed micelle solution and stir, afterwards by its uniform spreading at smooth surface, obtain total cucurbitacin phospholipid cholate mixed micelle oral cavity speed after dry and inhale film.
2. total cucurbitacin phospholipid cholate mixed micelle according to claim 1 oral cavity speed is inhaled the preparation method of film, it is characterized in that: in the total cucurbitacin phospholipid cholate mixed micelle described in step (4) phospholipid and cholate mol ratio be 1:(0.2～2); Phospholipid is 2:(0.8～1 with the weight ratio of total cucurbitacin); Mixed micelle size is 30nm-120nm, and total cucurbitacin bag is loaded in the hydrophobic core of mixed micelle.
3. the preparation method that total cucurbitacin phospholipid cholate mixed micelle according to claim 2 oral cavity speed is inhaled film, it is characterized in that: in the phospholipid cholate mixed micelle of the total cucurbitacin described in step (4), the mol ratio of phospholipid and cholate is 1:(0.8～1), phospholipid is 1:(0.45～0.5 with the weight ratio of total cucurbitacin).
4. the preparation method that total cucurbitacin phospholipid cholate mixed micelle according to claim 1 oral cavity speed is inhaled film, is characterized in that: the phospholipid described in step (1) is phospholipid or lecithin; Cholate is selected from the one in natural bile, sodium deoxycholate, SODIUM CHENODIOL, NaGC or Bile Salts.
5. the preparation method that total cucurbitacin phospholipid cholate mixed micelle according to claim 4 oral cavity speed is inhaled film, is characterized in that: the lecithin described in step (2) is selected from the one in soybean lecithin, Ovum Gallus domesticus Flavus lecithin or hydrolecithin.
6. total cucurbitacin phospholipid cholate mixed micelle according to claim 1 oral cavity speed is inhaled the preparation method of film, it is characterized in that: described total cucurbitacin phospholipid cholate mixed micelle oral cavity speed is inhaled in film total cucurbitacin and accounted for whole total cucurbitacin phospholipid cholate mixed micelle oral cavity speed to inhale the weight ratio of film be 1:50.
7. the preparation method that total cucurbitacin phospholipid cholate mixed micelle according to claim 1 oral cavity speed is inhaled film, is characterized in that: it is 25-40 μ m that described total cucurbitacin phospholipid cholate mixed micelle oral cavity speed is inhaled film thickness.
8. the preparation method that in claim 1-7, the speed of the total cucurbitacin phospholipid cholate mixed micelle oral cavity described in arbitrary claim is inhaled film, it is characterized in that: the organic solvent in step (1) be selected from chloroform, ether, ethanol, petroleum ether or fatty oil one or more with arbitrary proportion mix solvent, the mass concentration of titer is 30～70mmol/L; The mass concentration of the cholate solution in described step (2) is 5～20mmol/L.
9. the preparation method that in claim 1-7, the speed of the total cucurbitacin phospholipid cholate mixed micelle oral cavity described in arbitrary claim is inhaled film, it is characterized in that: the weight ratio of hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose and microcrystalline Cellulose in step (5) is 40:4:1, in every 100g hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose and microcrystalline cellulose, add 25mlPEG400.
10. total cucurbitacin phospholipid cholate mixed micelle oral cavity speed is inhaled film, it is characterized in that: it is to be prepared by the method described in arbitrary claim in claim 1-9 that described total cucurbitacin phospholipid cholate mixed micelle oral cavity speed is inhaled film.
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|---|---|---|---|---|
| CN109549924A (en) * | 2018-11-21 | 2019-04-02 | 四川大学华西医院 | SKLB023 mixed micelle and its preparation method and application |
| CN110876719A (en) * | 2018-09-06 | 2020-03-13 | 中国人民解放军军事科学院军事医学研究院 | Vitamin K1 injection and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102266347A (en) * | 2011-06-14 | 2011-12-07 | 中国人民解放军第三○二医院 | Phospholipid/cholate composite micelles of glycyrrhizic acid and preparation method and preparation thereof |
| CN103002885A (en) * | 2010-05-13 | 2013-03-27 | 莫诺索尔克斯有限公司 | Film compositions for delivery of actives |
-
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| CN102266347A (en) * | 2011-06-14 | 2011-12-07 | 中国人民解放军第三○二医院 | Phospholipid/cholate composite micelles of glycyrrhizic acid and preparation method and preparation thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110876719A (en) * | 2018-09-06 | 2020-03-13 | 中国人民解放军军事科学院军事医学研究院 | Vitamin K1 injection and preparation method thereof |
| CN110876719B (en) * | 2018-09-06 | 2022-08-09 | 中国人民解放军军事科学院军事医学研究院 | Vitamin K1 injection and preparation method thereof |
| CN109549924A (en) * | 2018-11-21 | 2019-04-02 | 四川大学华西医院 | SKLB023 mixed micelle and its preparation method and application |
| CN109549924B (en) * | 2018-11-21 | 2021-05-11 | 四川大学华西医院 | SKLB023 mixed micelle and preparation method and application thereof |
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