CN103735536B - Total cucurbitacin phospholipid cholate mixed micelle oral cavity speed inhales film and preparation method thereof - Google Patents
Total cucurbitacin phospholipid cholate mixed micelle oral cavity speed inhales film and preparation method thereof Download PDFInfo
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- CN103735536B CN103735536B CN201410013260.2A CN201410013260A CN103735536B CN 103735536 B CN103735536 B CN 103735536B CN 201410013260 A CN201410013260 A CN 201410013260A CN 103735536 B CN103735536 B CN 103735536B
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- phospholipid
- cholate
- total cucurbitacin
- mixed micelle
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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 145
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Abstract
The present invention's total cucurbitacin phospholipid cholate mixed micelle oral cavity speed inhales film and preparation method thereof, belongs to Chinese medicine preparation and preparation method thereof technical field.Preparation method comprises the steps preparation: phospholipid is made adipose membrane; Cholate is dissolved in phosphate buffer, makes cholate solution; Mix ultrasonic in a water bath to adipose membrane and cholate solution, obtain the blank micellar solution of phospholipid cholate; Total cucurbitacin powder is joined in the blank micelle of phospholipid cholate, obtain the phospholipid cholate mixed micelle of total cucurbitacin; Hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, PEG400 are joined in the phospholipid cholate mixed micelle solution of total cucurbitacin successively, obtained total cucurbitacin phospholipid cholate mixed micelle oral cavity speed inhales film.The present invention has the dissolubility improving total cucurbitacin, increases it to the adhesion of oral mucosa with through effect, avoids total cucurbitacin to gastrointestinal stimulation, and the bioavailability significantly improving total cucurbitacin reduces the advantage of untoward reaction.
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) belongs to from Cucurbitaceae and other section the class tetracyclic triterpenoid obtaining bitterness or sweet taste various plants.Be all the compound that a class degree of oxidation is very high, its feature 18-methyl is on C-9.Comprise cucurbitacin A, B, C, D, E, F, G, H, I, J, K, L, cucurbitacin, dihydrocucurbitacin F etc. more than 100 and plant compound.Wherein Cucurbitacin B is that wherein content is the highest, the one that physiologically active is the strongest, there is antitumor, protect the liver, antiinflammatory, raising immunity of organisms, the multiple biological activity such as the intestines and stomach effect.Its structural formula is as follows
Domestic listing with total cucurbitacin preparation that is key component have 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 Chongqing Han Hua pharmaceutical Co. Ltd three pharmacy corporations, 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 in the gastrointestinal tract absorb.
Summary of the invention
Phospholipid is the general name of the lipid material containing phosphate radical, is biomembranous basis, has important physiological function.Phospholipid is extensively present in the seed of the brains of animal, internal organs, blood, milk, egg yolk and plant, has the advantage that source is wide, toxicity is low.Phospholipid has emulsifying, dispersion, help ooze, the characteristic such as moistening, have very strong affinity to digestive tract, be commonly used for dispersant, lubricant, emulsifying agent, stabilizing agent, absorption enhancer, prodrug carrier etc. in a medicament.
Cholic acid salt cholate comprises natural bile, sodium deoxycholate, SODIUM CHENODIOL, glycosides ammonia sodium cholate and Bile Salts etc., when the intestinal permeation enhancers as micromolecule class uses, can obviously increase medicine jejunum and colon through and absorption.
Micelle is the excessive surfactant colloid solution that self assembly is formed in water.
It is a kind of novel form utilizing oral instant membrane technology will to obtain after micellar solution solidification that the oral cavity speed mentioned in the present invention inhales film.Oral cavity speed inhales film rapid disintegrate can discharge total cucurbitacin phospholipid cholate mixed micelle in the 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 discharged after the disintegrate of oral cavity speed suction film is very rapid by the absorption of oral mucosa, the not autonomous swallowing movement with oral cavity the medicine that discharges as common oral instant membrane disintegrate can be avoided to enter gastrointestinal tract, so it is a kind of oral mucosa drug delivery system truly that oral cavity speed inhales film.Medicine effectively can be avoided gastrointestinal stimulation, reduce the first pass effect of medicine, improve the bioavailability of medicine.Oral cavity speed suction film is easy to use simultaneously, with water delivery service, without the need to the process of swallowing, need not can improve the compliance of patient.
Low in order to solve the dissolubility due to cucurbitane compound above-mentioned, stripping is poor, be difficult in the gastrointestinal tract absorb thus cause the problem that oral administration biaavailability is all lower, 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 is to disclose the preparation method that total cucurbitacin phospholipid cholate mixed micelle oral cavity speed inhales film.
Technical scheme of the present invention is as follows:
Total cucurbitacin phospholipid cholate mixed micelle oral cavity speed inhales the preparation method of film, comprises the steps:
(1), by phospholipid add to organic solvent and make titer, dry up most of solvent under a nitrogen, then room temperature places the organic solvent of 12 hours removing trace in vacuum environment, makes adipose membrane;
(2), by cholate be dissolved in the phosphate buffer of pH=7.2, make the cholate solution of desired concn;
(3), by ultrasonic in 45 DEG C of water-baths to adipose membrane and cholate solution 45min is mixed, white phosphorus fat cholate micellar solution of namely having leisure;
(4), by total cucurbitacin powder join in the blank micelle of phospholipid cholate, nitrogen-filled seal, puts in constant temperature blender with magnetic force, uniform stirring 24h at 40 DEG C, 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, namely obtain after drying total cucurbitacin phospholipid cholate mixed micelle oral cavity speed inhale film.
Total cucurbitacin phospholipid cholate mixed micelle oral cavity speed described in technique scheme inhales the preparation method of film, wherein, in the total cucurbitacin phospholipid cholate mixed micelle described in step (4) phospholipid and cholate mol ratio be 1:(0.2 ~ 2); The weight ratio of phospholipid and total cucurbitacin is 2:(0.8 ~ 1); Mixed micelle size is 30nm-120nm, and total cucurbitacin bag is loaded in the hydrophobic core of mixed micelle.
Total cucurbitacin phospholipid cholate mixed micelle oral cavity speed described in technique scheme inhales the preparation method of 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), the weight ratio of phospholipid and total cucurbitacin is 1:(0.45 ~ 0.5).
Total cucurbitacin phospholipid cholate mixed micelle oral cavity speed described in technique scheme inhales the preparation method of film, and 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.
Total cucurbitacin phospholipid cholate mixed micelle oral cavity speed described in technique scheme inhales the preparation method of film, and wherein, the lecithin described in step (2) is selected from the one in soybean lecithin, Ovum Gallus domesticus Flavus lecithin or hydrolecithin.
Total cucurbitacin phospholipid cholate mixed micelle oral cavity speed described in technique scheme inhales the preparation method of film, wherein, in described total cucurbitacin phospholipid cholate mixed micelle oral cavity speed suction film, total cucurbitacin accounts for the fast weight ratio of inhaling film in whole total cucurbitacin phospholipid cholate mixed micelle oral cavity is 1:50.
Total cucurbitacin phospholipid cholate mixed micelle oral cavity speed described in technique scheme inhales the preparation method of film, and wherein, it is 25-40 μm that described total cucurbitacin phospholipid cholate mixed micelle oral cavity speed inhales film thickness.
Total cucurbitacin phospholipid cholate mixed micelle oral cavity speed described in technique scheme inhales the preparation method of film, wherein, organic solvent in step (1) is selected from the solvent mixed with arbitrary proportion of one or more in chloroform, ether, ethanol, petroleum ether or fatty oil, and the mass concentration of titer is 30 ~ 70mmol/L; The mass concentration of the cholate solution in described step (2) is 5 ~ 20mmol/L.
Total cucurbitacin phospholipid cholate mixed micelle oral cavity speed described in technique scheme inhales the preparation method of film, wherein, the weight ratio of hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose and microcrystalline Cellulose in step (5) is 40:4:1, adds 25mlPEG400 in every 100g hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose and microcrystalline cellulose.Total cucurbitacin phospholipid cholate mixed micelle oral cavity speed inhales film, and wherein, it is prepared by the method described in technical scheme arbitrary in technique scheme that described total cucurbitacin phospholipid cholate mixed micelle oral cavity speed inhales film.
The present invention has following beneficial effect:
1, medicine of the present invention total cucurbitacin phospholipid cholate mixed micelle oral cavity speed suction film can not only to total cucurbitacin solubilising, can also increase its in oral mucosa through effect, total cucurbitacin can be avoided GI irritation effect by oral mucosal absorption, significantly improve the bioavailability of total cucurbitacin and reduce 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, the proper auxiliary materials such as hydroxypropyl methylcellulose are used mixed micelle to be made oral instant membrane afterwards, its physicochemical property is changed, thus promote the absorption of total cucurbitacin, improve the bioavailability of total cucurbitacin, and then increase curative effect, reduce untoward reaction;
3, the preparation method of medicine of the present invention is easy, favorable reproducibility, mechanization degree are high, is applicable to large-scale production and application.
Accompanying drawing illustrates:
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 suction film absorption curve in the oral cavity compare.
Detailed description of the invention:
Being convenient to for making technical scheme of the present invention understand, below in conjunction with concrete test example, film and preparation method thereof being inhaled to the present invention's total cucurbitacin phospholipid cholate mixed micelle oral cavity speed and being further described.
Embodiment 1: the preparation of total cucurbitacin phospholipid cholate mixed micelle
(1) fabaceous lecithin 16.67g is added in 100ml petroleum ether make the titer that mass concentration is 30 ~ 70mmol/L, dry up most of solvent under a nitrogen, in vacuum drying oven, normal-temperature vacuum places 12h to remove the organic solvent of trace again, makes adipose membrane;
(2) Bile Salts 2g is dissolved in the phosphate buffer (pH=7.2) of 100ml, makes the cholate solution that mass concentration is 5 ~ 20mmol/L;
(3) 45min is mixed by ultrasonic in 45 DEG C of water-baths to adipose membrane and cholate solution, white phosphorus fat cholate mixed micelle solution of namely having leisure;
(4) joined by total for 8g cucurbitacin powder in the blank micelle of phospholipid cholate, nitrogen-filled seal, puts in constant temperature blender with magnetic force, and at 40 DEG C, uniform stirring 24h, obtains carrier micelle, i.e. total cucurbitacin phospholipid cholate mixed micelle;
Embodiment 2: the preparation of total cucurbitacin phospholipid cholate mixed micelle
(1) fabaceous lecithin 16.67g is added in 80ml chloroform make the titer that mass concentration is 30 ~ 70mmol/L, dry up most of solvent under a nitrogen, then normal-temperature vacuum places 12h to remove the organic solvent of trace in vacuum drying oven, makes adipose membrane;
(2) sodium deoxycholate 2g is dissolved in the phosphate buffer (pH=7.2) of 100ml, makes the cholate solution that mass concentration is 5 ~ 20mmol/L;
(3) 45min is mixed by ultrasonic in 45 DEG C of water-baths to adipose membrane and cholate solution, white phosphorus fat of namely having leisure/cholate mixed micelle solution;
(4) joined by total for 8g cucurbitacin powder in the blank micelle of phospholipid cholate, nitrogen-filled seal, puts in constant temperature blender with magnetic force, and at 40 DEG C, uniform stirring 24h, 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 make the titer that mass concentration is 30 ~ 70mmol/L, dry up most of solvent under a nitrogen, then normal-temperature vacuum places 12h to remove the organic solvent of trace in vacuum drying oven, makes adipose membrane;
(2) SODIUM CHENODIOL 2g is dissolved in the phosphate buffer (pH=7.2) of 100ml, makes the cholate solution that mass concentration is 5 ~ 20mmol/L;
(3) 45min is mixed by ultrasonic in 45 DEG C of water-baths to adipose membrane and cholate solution, white phosphorus fat cholate mixed micelle solution of namely having leisure;
(4) joined by total for 8g cucurbitacin powder in the blank micelle of phospholipid cholate, nitrogen-filled seal, puts in constant temperature blender with magnetic force, and at 40 DEG C, uniform stirring 24h, 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 make the titer that mass concentration is 30 ~ 70mmol/L, dry up most of solvent under a nitrogen, then normal-temperature vacuum places 12h to remove the organic solvent of trace in vacuum drying oven, makes adipose membrane;
(2) Bile Salts 2g is dissolved in the phosphate buffer (pH=7.2) of 100ml, makes the cholate solution that mass concentration is 5 ~ 20mmol/L;
(3) 45min is mixed by ultrasonic in 45 DEG C of water-baths to adipose membrane and cholate solution, white phosphorus fat cholate mixed micelle solution of namely having leisure;
(4) joined by total for 8g cucurbitacin powder in the blank micelle of phospholipid cholate, nitrogen-filled seal, puts in constant temperature blender with magnetic force, and at 40 DEG C, uniform stirring 24h, obtains carrier micelle, i.e. total cucurbitacin phospholipid/cholate mixed micelle.
Embodiment 5: the preparation of total cucurbitacin phospholipid cholate mixed micelle
(1) lecithin 16.67g is added in 80ml chloroform make the titer that mass concentration is 30 ~ 70mmol/L, dry up most of solvent under a nitrogen, then normal-temperature vacuum places 12h to remove the organic solvent of trace in vacuum drying oven, makes adipose membrane;
(2) sodium deoxycholate 2g is dissolved in the phosphate buffer (pH=7.2) of 100ml, makes the cholate solution that mass concentration is 5 ~ 20mmol/L;
(3) 45min is mixed by ultrasonic in 45 DEG C of water-baths to adipose membrane and cholate solution, white phosphorus fat cholate mixed micelle solution of namely having leisure;
(4) joined by total for 8g cucurbitacin powder in the blank micelle of phospholipid/cholate, nitrogen-filled seal, puts in constant temperature blender with magnetic force, and at 40 DEG C, uniform stirring 24h, 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 make the titer that mass concentration is 30 ~ 70mmol/L, dry up most of solvent under a nitrogen, then normal-temperature vacuum places 12h to remove the organic solvent of trace in vacuum drying oven, makes adipose membrane;
(2) SODIUM CHENODIOL 2g is dissolved in the phosphate buffer (pH=7.2) of 100ml, makes the cholate solution that mass concentration is 5 ~ 20mmol/L;
(3) 45min is mixed by ultrasonic in 45 DEG C of water-baths to adipose membrane and cholate solution, white phosphorus fat cholate mixed micelle solution of namely having leisure;
(4) joined by total for 8g cucurbitacin powder in the blank micelle of phospholipid cholate, nitrogen-filled seal, puts in constant temperature blender with magnetic force, and at 40 DEG C, uniform stirring 24h, 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 inhales film
By hydroxypropyl methylcellulose 4g, low-substituted hydroxypropyl cellulose 0.4g, microcrystalline cellulose 0.1g, PEG4001.125mL, add in 40mL distilled water the liquid making it to form thickness successively, then the phospholipid cholate mixed micelle solution 1.1mL of total cucurbitacin prepared by embodiment 1 ~ 6 is added wherein, high-speed stirred makes mix homogeneously simultaneously, sprawl into the thin film of one deck 10 × 10cm after vacuum removal of air bubbles at smooth surface, the oral cavity speed namely obtaining total cucurbitacin phospholipid cholate mixed micelle in vacuum drying oven after drying inhales film.
The product total cucurbitacin phospholipid cholate mixed micelle oral cavity speed prepared below by way of the present invention is inhaled the pharmacokinetics of film, buccal absorption and pharmacodynamics test and is set forth the beneficial effect that product of the present invention total cucurbitacin phospholipid cholate mixed micelle has further:
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 prepared by embodiments of the invention 1 and 7,5-fluorouracil (Tonghua Maoxiang Pharmaceutical Co., Ltd.).
Compound method: the medicine distilled water containing total cucurbitacin is mixed with every milliliter of solution containing total cucurbitacin 10mg, and the concentration of 5-fluorouracil is 25mg/mL.
Animal: Kunming mouse, market is bought; Male and female half and half 18-20g.
2, key step is tested:
Get healthy mice 32 and be only divided into four groups immediately, i.e. negative control group, crude drug group, positive controls, total cucurbitacin phospholipid cholate mixed micelle group, corresponding institute drug is normal saline, total cucurbitacin raw material medicine, 5-fluorouracil and total cucurbitacin phospholipid cholate mixed micelle respectively, often organizes 8.HepG II cell (1 × 10 is injected in left oxter respectively
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, puts to death mice, peel off tumor tissues, record the volume of each group of tumor, weight, in table 1.
Table 1 three kinds of medicines are on the impact (X ± SD) of 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 |
| Crude drug group | 10 | 8 | 742.1134±21.1829 | 2.1034±0.3818 |
| Total cucurbitacin phospholipid/cholate mixed micelle group | 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, check there is no significant difference between two groups through 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 inhales the bioavailability study of film:
1, materials and methods:
Medicine: total cucurbitacin raw material medicine (Nanjing Zelang Pharmaceutical Technology Inc.), it is be prepared by embodiments of the invention 1 and 7 that total cucurbitacin phospholipid cholate mixed micelle oral cavity speed inhales film.
Animal: male Wistar rat, 200g ± 5g, market is bought.Often organize rat 6, 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 Wistar rat 12, be divided into 2 groups immediately, often organizes 6.One group of rat total cucurbitacin oral mucosa administration, dosage 100 ㎎/100g; Film mucosa delivery is inhaled, dosage 100 ㎎/100g for one group by total cucurbitacin phospholipid/cholate mixed micelle oral cavity speed.After administration, 10min, 20min, 30min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h eye socket gets blood in the centrifuge tube of heparin sodium moistening, separated plasma ,-20 DEG C 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, after nitrogen dries up, redissolves with absolute methanol, and 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 μm;
Mobile phase: methanol: water=62:38;
Flow velocity: 1.0ml/min;
Column temperature: 30 DEG C;
Determined wavelength: 228nm.
2. standard curve preparation
Get rat blank plasma 200ul, add respectively total cucurbitacin solution make its concentration be respectively 0.5,1,2,4,6,8,10,20mg/L, operate by under " sample treatment " item, with the peak area of total cucurbitacin for 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, after total cucurbitacin phospholipid cholate mixed micelle oral cavity speed inhales film, mean blood plasma concentration 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.
Mean blood plasma concentration (n=6, X ± S, μ g/mL) after the administration of table 2 rat
| Time (h) | Crude drug | Speed inhales 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 speed and inhales the absorption rate of total cucurbitacin in film group far away higher than the absorption rate of the total cucurbitacin in crude drug group, and phospholipid cholate mixed micelle oral cavity speed inhales 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 inhales the area under curve (AUC of film group
0 → T) and maximum plasma concentration (Cmax) all significantly more than 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 inhales 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 be prepared by embodiments of the invention 1 and 7 that total cucurbitacin phospholipid cholate mixed micelle speed inhales film.
Compound method: precision takes total cucurbitacin raw material medicine, becomes every 100ml containing the suspension of total cucurbitacin 50mg with normal saline, and total cucurbitacin phospholipid cholate mixed micelle speed that precision takes containing the total cucurbitacin of 5mg inhales film.
Animal: duroc, grows about 6 months, body weight 110 scholar 5kg, and market is bought.
Test procedure:
Get fresh duroc buccal mucosa of slaughtering, carefully peel off subcutaneous layer of fat and connective tissue, totally for subsequent use with normal saline flushing.For simulated body fluid environment, adopt normal saline as accepting medium, experimental provision as shown in Figure 1.Rotating speed is adopted to be 360r/min magnetic agitation, investigate the permeance property of medicine by oral mucosa, bath temperature controls 37 scholar 0.5 DEG C, often 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 first fills it up with normal saline, drains bubble, adds the sample solution got ready and seal in supply chamber.Supply pool volume is 10mL, and reception tank volume is 21mL.5mL is respectively sampled respectively at 2min, 5min, 10min, 15min, 30min, 45min, 60min, 2h, 4h, 6h time point, and supplement equivalent equality of temperature accepting medium immediately, the sample liquid that different time points is taken out is all through 0.22 μm of filtering with microporous membrane, filtrate is stored in sample injection bottle, to be measured in-18 DEG C of refrigerator cold-storages after labelling.Assay method adopts the high effective liquid chromatography for measuring consistent with test example two.Get total cucurbitacin titer that concentration is 1mg/mL, dilution makes its concentration be respectively 0.01,0.05,0.1,0.2,0.3,0.4,0.5,1mg/mL, operate under " sample treatment " item by test example two, with the peak area of total cucurbitacin for 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 Percutaneous permeability (see table 4).And be variable (X) with time, Percutaneous permeability is dependent variable (Y) mapping, compares the Absorption (see Fig. 2) of two kinds of medicines at pig buccal mucosa.
Table 4 two kinds of dosage forms 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 inhales the permeability that film significantly improves the pig oral mucosa of total cucurbitacin.
Above-mentioned test example one ~ tri-with the total cucurbitacin phospholipid cholate mixed micelle oral cavity speed that embodiment 2-6 respectively with 7 prepares gained inhale film test after come to the same thing.
The above, be only preferred embodiment of the present invention, not any formal and substantial restriction is done to the present invention, 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 a little change made, modify with differentiation equivalent variations, be Equivalent embodiments of the present invention; Meanwhile, all according to substantial technological of the present invention to the change of any equivalent variations that above embodiment is done, modify and differentiation, all still belong in the scope of technical scheme of the present invention.
Claims (10)
1. total cucurbitacin phospholipid cholate mixed micelle oral cavity speed inhales the preparation method of film, comprises the steps:
(1), by phospholipid add to organic solvent and make titer, dry up most of solvent under a nitrogen, then room temperature places the organic solvent of 12 hours removing trace in vacuum environment, makes adipose membrane;
(2), by cholate be dissolved in the phosphate buffer of pH=7.2, make the cholate solution of desired concn;
(3), by ultrasonic in 45 DEG C of water-baths to adipose membrane and cholate solution 45min is mixed, white phosphorus fat cholate micellar solution of namely having leisure;
(4), by total cucurbitacin powder join in the blank micelle of phospholipid cholate, nitrogen-filled seal, puts in constant temperature blender with magnetic force, uniform stirring 24h at 40 DEG C, 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, namely obtain after drying total cucurbitacin phospholipid cholate mixed micelle oral cavity speed inhale film.
2. total cucurbitacin phospholipid cholate mixed micelle oral cavity according to claim 1 speed inhales the preparation method of film, it is characterized in that: in the total cucurbitacin phospholipid cholate mixed micelle described in step (4), the mol ratio of phospholipid and cholate is 1:(0.2 ~ 2); The weight ratio of phospholipid and total cucurbitacin is 2:(0.8 ~ 1); Mixed micelle size is 30nm-120nm, and total cucurbitacin bag is loaded in the hydrophobic core of mixed micelle.
3. total cucurbitacin phospholipid cholate mixed micelle oral cavity according to claim 2 speed inhales the preparation method of 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), the weight ratio of phospholipid and total cucurbitacin is 1:(0.45 ~ 0.5).
4. total cucurbitacin phospholipid cholate mixed micelle oral cavity according to claim 1 speed inhales the preparation method of film, it is characterized in that: the phospholipid described in step (1) is lecithin; Cholate is selected from the one in natural bile, sodium deoxycholate, SODIUM CHENODIOL, NaGC or Bile Salts.
5. total cucurbitacin phospholipid cholate mixed micelle oral cavity according to claim 4 speed inhales the preparation method of film, it is characterized in that: the lecithin described in step (1) is selected from the one in soybean lecithin, Ovum Gallus domesticus Flavus lecithin or hydrolecithin.
6. the preparation method of total cucurbitacin phospholipid cholate mixed micelle oral cavity speed suction film according to claim 1, is characterized in that: in described total cucurbitacin phospholipid cholate mixed micelle oral cavity speed suction film, total cucurbitacin accounts for the weight ratio of whole total cucurbitacin phospholipid cholate mixed micelle oral cavity speed suction film is 1:50.
7. total cucurbitacin phospholipid cholate mixed micelle oral cavity according to claim 1 speed inhales the preparation method of film, it is characterized in that: it is 25-40 μm that described total cucurbitacin phospholipid cholate mixed micelle oral cavity speed inhales film thickness.
8. the total cucurbitacin phospholipid cholate mixed micelle oral cavity speed in claim 1-7 described in arbitrary claim inhales the preparation method of film, it is characterized in that: the organic solvent in step (1) is selected from the solvent mixed with arbitrary proportion of one or more in chloroform, ether, ethanol, petroleum ether or fatty oil, and 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 total cucurbitacin phospholipid cholate mixed micelle oral cavity speed in claim 1-7 described in arbitrary claim inhales the preparation method of 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 inhales film, it is characterized in that: it is prepared by the method described in claim arbitrary in claim 1-9 that described total cucurbitacin phospholipid cholate mixed micelle oral cavity speed inhales film.
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