CN106924177A - A kind of external application Paeonol nano controlled-release thermosensitive in situ gel and preparation method thereof - Google Patents
A kind of external application Paeonol nano controlled-release thermosensitive in situ gel and preparation method thereof Download PDFInfo
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- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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Abstract
A kind of external application Paeonol nano controlled-release thermosensitive in situ gel, it is made up of the P407 and P188 that are added thereto in Paeonol nano structured lipid carrier and at low temperature, first mixing oil phase, blended emulsifier, Paeonol and ultra-pure water prepare colostric fluid, colostric fluid is disperseed in frozen water is scattered at 0 DEG C again, obtain the nano structured lipid carrier of the light blue opalescence of dispersion, the Paeonol nano structured lipid carrier is placed in refrigerator, 4 DEG C of refrigeration 1h, P407 and P188 is slowly added under magnetic stirring, continuing stirring makes it be uniformly dispersed, it is put into refrigerator, 4 DEG C preserve ＞ 24h, make poloxamer fully swelling, ultimately form the Paeonol nano controlled-release thermosensitive in situ gel solution of light blue translucent；Invention enhances the solubility of Paeonol, medicine stability is improve, small with particle diameter, dispersiveness is strong, good stability, slow drug release the advantages of targeting, improves Paeonol bioavilability, can delay its metabolism in vivo.
Description
Technical field
The invention belongs to pharmaceutical technology field, more particularly to a kind of external application Paeonol nano controlled-release responsive to temperature type is in situ solidifying
Glue and preparation method thereof.
Background technology
Paeonol (paeonol, Pae), also known as paeonol, mainly from Asclepiadaceae plant paniculate swallowwort Cynanchum
Paniculatum (Bunge) Kitagawa dry roots or herb and Ranunculaceae Chinese herbaceous peony platymiscium tree peony Paeonia fruticosa
The active component separated is extracted in Andr, the root skin of Chinese herbaceous peony P.lacti flora Pall..Numerous studies data shows,
Pae has good anti-inflammatory antiallergy and an anti-infectious function, but fat-soluble extremely strong due to Pae, and bioavilability is extremely low, has
It is volatile, oxidizable, the shortcomings of biological half-life is short, influence the stability and bioavilability of its preparation.
The content of the invention
In order to overcome the shortcoming of above-mentioned prior art, it is an object of the invention to provide a kind of external application Paeonol nano controlled-release
Thermosensitive in situ gel and preparation method thereof, enhances the solubility of Paeonol, medicine stability is improve, with good
Slow release, also small with particle diameter, dispersiveness is strong, good stability, slow drug release, the advantages of targeting, improves Paeonol life
Thing availability, delays its drug metabolism time in vivo, reduces supplementary product consumption, reduces production cost, has extensively in field of medicaments
Wealthy market prospects.
To achieve these goals, the technical solution adopted by the present invention is：
A kind of external application Paeonol nano controlled-release thermosensitive in situ gel, by Paeonol nano structured lipid carrier and
Poloxamer188 (P407) and PLURONICS F87 (P188) composition being added thereto under low temperature, wherein, the Paeonol nanometer
Structured lipid carrier is made up of mixing oil phase, blended emulsifier, Paeonol and ultra-pure water.
The mixing oil phase is that stearic acid and isopropyl myristate (IPM) mix, and the blended emulsifier is the sad last of the ten Heavenly stems
Acid polyethylene glycol glyceride (Labrasol) and TC (Transtol HP) mix.
In the Paeonol nano structured lipid carrier, in terms of mass fraction, stearic acid content 3%, IPM contents 3%,
Labrasol contents 18%, Transtol HP contents 15%, paeonol content 10%, balance of ultra-pure water.
The addition of the P407 is the total matter of situ-gel for the addition of 18~24%, P188 of situ-gel gross mass
The 0~10% of amount, and 0 can not be taken.
When P188 mass fractions are constant, when P407 mass fractions increase, gelation temperature is on a declining curve；When P407 mass point
Number is constant, and when P188 mass fractions increase, gelation temperature is first raised and tended to be steady afterwards.
The low temperature is 4 DEG C.
The preparation method of external application Paeonol nano controlled-release thermosensitive in situ gel of the present invention, comprises the following steps：
Step 1, Paeonol nano structured lipid carrier is prepared with micro emulsion method；
Step 2, Paeonol thermosensitive in situ gel is prepared with cold cut：The Paeonol nanostructured lipid is carried
Body is placed in refrigerator, 4 DEG C of refrigeration 1h, and P407 and P188 is slowly added under magnetic stirring, and continuing stirring makes it be uniformly dispersed, and puts
Enter refrigerator, 4 DEG C of preservation ＞ 24h make poloxamer fully swelling, ultimately form the Paeonol nano controlled-release temperature of light blue translucent
Degree sensitive in situ gels research solution.
In the step 1, the preparation method of Paeonol nano structured lipid carrier is as follows：
Mixing oil phase, blended emulsifier, Paeonol, ultra-pure water are mixed to get colostric fluid；
Gained colostric fluid is disperseed in frozen water is scattered at 0 DEG C, the nano structured lipid carrier of light blue opalescence is obtained,
It is dispersion.
Compared with prior art, the Paeonol nanometer particle in-situ gel preparation that prepared by the present invention improves the targeting of Paeonol
And slow releasing function, the technology upgrading of Chinese medicine root bark of tree peony phenolic product industrial chain is realized, the science and technology that improve Chinese medicine Paeonol contains
Amount and industry added value, promote regional economical development, propulsion TCM Modernization, internationalization process.
With the continuous input of big drug firm in world wide, the continuous breakthrough of pharmacy new technology, on Nano medication
City is more and more, and early in 2006, the U.S. realized being commercialized Nano medication 13, develops 130 Nano medications
And delivery system, show that the development of medicine has been enter into nanometer era, but have not yet to see on nanometer particle in-situ gel preparation
City.
China is equal on external application nanometer formulation, nanometer particle in-situ gel preparation, targeted nano granule in-situ gel preparation at present
Have no launch.The present invention carries out the Effective Component of Chinese Medicine Paeonol nanometer particle in-situ gel novel formulation with clear and definite curative effect and grinds
System, the popularization and application of the achievement in research will can fill up the market vacancy of China's Chinese medicine Paeonol nanometer in situ gel preparation.
Brief description of the drawings
Fig. 1 is Paeonol NLC nanoparticle transmission electron microscope aspect graphs.
Fig. 2 is sound of the P407 and P188 mass fractions to Paeonol nano controlled-release thermosensitive in situ gel gelation temperature
Answer face.
Fig. 3 be P407 and P188 mass fractions to Paeonol nano controlled-release thermosensitive in situ gel gelation temperature etc.
Line high.
Fig. 4 is Paeonol bulk drug, the external of Paeonol NLC, Paeonol nano controlled-release thermosensitive in situ gel is released
Put curve.
Specific embodiment
Describe embodiments of the present invention in detail with reference to the accompanying drawings and examples.
In view of the characteristics of administration nano-drug administration system has solubilized insoluble drug, raising drug bioavailability, can be obvious
Improve the burst effect of medicine and preparation, extend drug treating time, reduce times for spraying, improve patient compliance.And temperature
Sensitive in situ gels research agent has the advantages that to tend to smear out, good biocompatibility as external preparation new in recent years, local
It is easy to absorption, not pollution clothes, good stability after administration.The present invention provides a kind of external application Paeonol nano controlled-release responsive to temperature type
Situ-gel and preparation method thereof.
1st, the preparation method of external application Paeonol nano controlled-release thermosensitive in situ gel of the present invention is as follows：
1.1, Paeonol nano structured lipid carrier is prepared using micro emulsion method
In terms of mass fraction, first with 3% stearic acid and 3%IPM (i.e. mass ratio 1:1) mixing oil phase, 18% are constituted
Labrasol and 15%Transtol HP are blended emulsifier (i.e. mass ratio 2:1), 5% Paeonol, surplus ultra-pure water polishing
100% ultra-pure water is prepared into colostric fluid.By this colostric fluid in disperseing in frozen water at 0 DEG C, the nanometer of light blue opalescence is can obtain
Structured lipid support dispersion, observes the particle diameter and form of nano structured lipid carrier under transmission electron microscope, see Fig. 1.
1.2, Paeonol thermosensitive in situ gel is prepared using cold cut.
The Paeonol nano structured lipid carrier of preparation is placed in refrigerator, 4 DEG C of refrigeration 1h are slow under magnetic stirring to add
Enter P407 and P188, continuing stirring makes it be uniformly dispersed, be put into refrigerator, 4 DEG C of preservation ＞ 24h make poloxamer fully swelling, most
Paeonol nano controlled-release thermosensitive in situ gel solution of the end form into light blue translucent.
2nd, temperature measuring is carried out to present invention gained Paeonol nano controlled-release thermosensitive in situ gel：
The gel solution 2mL for preparing is taken in cillin bottle, is put into 20 DEG C of water-baths, liquid level is less than water-bath in cillin bottle
Liquid level 1cm, it is slow to heat up.Often raise 0.1 DEG C and incline 45 ° of cillin bottle, observe liquid mobility status, temperature when no longer flowing
The as phase transition temperature of gel.
3rd, formulation optimization of the invention：
3.1st, experimental design
On the basis of single factor experiment, with gelation temperature as inspection target, P407 and P188 mass fractions are chosen to investigate
Factor, the span of P407 is 0~10% for the span of 18~24%, P188.According to Star point design principle, gelling temperature
It is dependent variable to spend, five levels of each factor, respectively ± α, ± 1 and 0 (α=1.414), experimental design and the results are shown in Table 1.
The Paeonol NLC temperature sensitive types of table 10 gel prescription Star point design analysis of experiments of original
3.2nd, models fitting
Multiple linear is carried out to dependent variable and the relation of each independent variable respectively using the softwares of Design-Expert 8.06 to return
Return and be fitted with binomial equation, obtain multiple linear equation：
Y=88.28971-2.68071X1+1.30872X2(r=0.8779, P ＜ 0.0001)
Binomial equation：
Y=181.15625-11.39904X1+1.19572X2+0.10333X1X2+0.19528X1 2-0.20570X2 2(r=
0.9980, P ＜ 0.0001)
Wherein, Y is inspection target (i.e. gelation temperature)；X1It is the percentage of independent variable P407；X2It is the hundred of independent variable P188
Divide ratio；R is RSD values (i.e. relative standard deviation)；P is that probability (is used for the possibility size that a certain event of reflection occurs.System
Meter is learned according to the P values obtained by significance test method, typically with P<0.05 is notable, P<0.01 is highly significant, its implication
It is probability of the difference between sample caused by sampling error less than 0.05 or 0.01)
Illustrate preferable using the effect of binomial equation fitting.Variance analysis is carried out to binomial equation model of fit, is tied
Fruit is shown in Table 2.
The variance analysis of the regression model of table 2
| Soruces of variation | SS | f | MS | F | P |
| Model | 488.80 | 5 | 97.76 | 707.63 | <0.0001 |
| X1 | 258.70 | 1 | 258.70 | 1872.60 | <0.0001 |
| X2 | 171.27 | 1 | 171.27 | 1239.76 | <0.0001 |
| X1X2 | 2.40 | 1 | 2.40 | 17.39 | 0.0042 |
| X1 2 | 5.37 | 1 | 5.37 | 38.88 | 0.0004 |
| X2 2 | 45.99 | 1 | 45.99 | 332.91 | <0.0001 |
3.3rd, response surface optimization and prediction
Using each independent variable of the Software on Drawing of Design-Expert 8.06 to the three-dismensional effect face of response, Fig. 2 is seen, two dimension
Contour, is shown in Fig. 3.Result is shown when P188 mass fractions are constant, during the increase of P407 mass fractions, Paeonol nano controlled-release temperature
The gelation temperature of sensitive in situ gels research solution is on a declining curve；When P407 mass fractions are constant, when P188 mass fractions increase,
Gelation temperature is first raised and tended to be steady afterwards, consistent with single factor experiment.According to the literature, thermo-sensitive gel gelation temperature in vitro
Between 25~27 DEG C, but in view of summer high temperature, gel can occur phase in version at room temperature, need stored frozen, inconvenience
In patient medication, it is thus determined that gelation temperature is at 32~34 DEG C, (the X of prescription 1 is obtained1=22.85%, X2=3.37%), (X of prescription 21
=22.90%, X2=3.34%), (X of prescription 31=21.39%, X2=1.97%), (X of prescription 41=23.02%, X2=
3.76%), (X of prescription 51=23.06%, X2=4.44%).
4th, process certification
Paeonol nano controlled-release thermosensitive in situ gel is prepared by 5 above-mentioned prescriptions, parallel three parts, gelling is determined
Temperature, compares with predicted value, is shown in Table 3.Result shows that the measured value of each prescription is smaller with predicted value difference.The wherein reality of prescription 2
Measured value is minimum with predicted value deviation, therefore selection prescription 2 carries out follow-up study.
The checking test (n=3) of the Paeonol nano controlled-release thermosensitive in situ gel prescription of table 3
| Prescription | P407/% | P188/% | Predicted value/DEG C | Measured value/DEG C | Deviation/% |
| 1 | 22.85 | 3.37 | 32.7 | 33.8±0.2 | -3.36 |
| 2 | 22.90 | 3.34 | 33.6 | 33.4±0.1 | 0.60 |
| 3 | 21.39 | 1.97 | 32.7 | 33.8±0.3 | -3.36 |
| 4 | 23.02 | 3.76 | 33.3 | 34.5±0.2 | -3.60 |
| 5 | 23.06 | 4.44 | 32.4 | 32.8±0.3 | -1.23 |
Note：Deviation=(predicted value-measured value)/predicted value × 100%
5th, release in vitro Performance
5.1st, chromatographic condition
AgiLent ZORBAX EcLipse XDB-C18Chromatographic column (4.6 × 250mm, 5 μm), mobile phase methanol-water (70:
30), Detection wavelength:274nm, sample size 10 μ L, flow velocity 1.0mLmin-1, 30 DEG C of column temperature.
5.2nd, Specification Curve of Increasing
Accurately Paeonol reference substance 10.71mg is weighed to be placed in 50mL measuring bottles, plus methyl alcohol dissolving and constant volume, obtain 214.20 μ
g·L-1Storing solution.With medium as solvent of dialysing, prepare mass concentration be respectively 11.90,23.80,35.70,59.50,71.40,
107.10μg·mL-1Paeonol reference substance solution, determined by 5.1 lower chromatographic conditions, with peak area as ordinate, quality is dense
It is abscissa to spend, and obtains regression equation Y Y=40.255X+16.950, r=0.9998, the μ g of the range of linearity 11.90~107.10
mL-1。
5.3rd, precision is investigated
The Paeonol reference substance solution that precision draws high, medium and low mass concentration is appropriate, continuous by 5.1 lower chromatographic conditions
Sample introduction 6 times, the RSD for calculating peak area is respectively 0.5%, 0.4% and 0.2%, shows that instrument precision is good.
5.4th, determination of recovery rates
Appropriate Blank gel is taken, it is accurate respectively to add high, medium and low mass concentration (107.10,59.50,11.90 μ gmL-1) Paeonol reference substance solution 1mL, diluted with respective media and mixed, filtered through 0.45 μm of miillpore filter, by 5.1 lower colors
Spectral condition is determined, calculate the rate of recovery be respectively 0.98%, 0.96%, 0.97%, RSD be followed successively by 0.98%, 0.96%,
0.97%, it is shown in Table 4.
The Paeonol recovery test of table 4
Table 4 Recovery test of Paeonol
6th, vitro drug release
To measure Paeonol bulk drug, Paeonol nano structured lipid carrier and Paeonol nano controlled-release temperature quick for precision respectively
Each 5mL of sense type situ-gel, is placed in bag filter, and bag filter is placed in the physiological saline of 500mL bath temperatures (34 ± 0.5) DEG C
In, rotating speed 100rmin-1Magnetic agitation, samples 2mL, and supplement the synthermal physiological saline of equivalent at regular intervals.By 5.1
Chromatographic condition determines paeonol content under, calculates Accumulation dissolution, sees Fig. 4.Result shows that compared with bulk drug, Paeonol is received
The release in vitro of rice structured lipid carrier and Paeonol nano controlled-release thermosensitive in situ gel is relatively slow, is respectively provided with substantially
Slow release effect, and the release of Paeonol nano controlled-release thermosensitive in situ gel and Paeonol nano structured lipid carrier phase
Than having obtained more significant extension, Paeonol nano structured lipid carrier and Paeonol nano controlled-release responsive to temperature type in 24h
The cumulative release amount of situ-gel is respectively 59.18% and 51.19%.
Claims (10)
1. a kind of external application Paeonol nano controlled-release thermosensitive in situ gel, it is characterised in that by Paeonol nanostructured fat
Matter carrier and the P407 being added thereto at low temperature and P188 compositions, wherein, the Paeonol nano structured lipid carrier is by mixing
Close oil phase, blended emulsifier, Paeonol and ultra-pure water composition.
2. external application Paeonol nano controlled-release thermosensitive in situ gel according to claim 1, it is characterised in that described mixed
It is that stearic acid and IPM mix to close oil phase, and the blended emulsifier is that Labrasol and TranstolHP mixes.
3. external application Paeonol nano controlled-release thermosensitive in situ gel according to claim 2, it is characterised in that the pellet
In skin phenol nano structured lipid carrier, in terms of mass fraction, stearic acid content 3%, IPM contents 3%, Labrasol contents
18%, Transtol HP contents 15%, paeonol content 10%, balance of ultra-pure water.
4. external application Paeonol nano controlled-release thermosensitive in situ gel according to claim 1, it is characterised in that described
The addition of P407 is the 0~10% of situ-gel gross mass for the addition of 18~24%, P188 of situ-gel gross mass,
And 0 can not be taken.
5. external application Paeonol nano controlled-release thermosensitive in situ gel according to claim 1, it is characterised in that work as P188
Mass fraction is constant, and when P407 mass fractions increase, gelation temperature is on a declining curve；When P407 mass fractions are constant, P188 matter
When amount fraction increases, gelation temperature is first raised and tended to be steady afterwards.
6. external application Paeonol nano controlled-release thermosensitive in situ gel according to claim 1, it is characterised in that described low
Temperature is 4 DEG C.
7. a kind of preparation method of external application Paeonol nano controlled-release thermosensitive in situ gel, it is characterised in that including as follows
Step：
Step 1, Paeonol nano structured lipid carrier is prepared with micro emulsion method；
Step 2, Paeonol thermosensitive in situ gel is prepared with cold cut：The Paeonol nano structured lipid carrier is put
In refrigerator, 4 DEG C of refrigeration 1h are slowly added to P407 and P188 under magnetic stirring, and continuing stirring makes it be uniformly dispersed, and is put into ice
Case, 4 DEG C of preservation ＞ 24h, makes poloxamer fully swelling, and the Paeonol nano controlled-release temperature for ultimately forming light blue translucent is quick
Sense type situ-gel solution.
8. the preparation method of external application Paeonol nano controlled-release thermosensitive in situ gel, its feature according to claim 7
It is that in the step 1, the preparation method of Paeonol nano structured lipid carrier is as follows：
Mixing oil phase, blended emulsifier, Paeonol, ultra-pure water are mixed to get colostric fluid；
Gained colostric fluid is disperseed in frozen water is scattered at 0 DEG C, the nano structured lipid carrier of light blue opalescence is obtained, to divide
Dispersion liquid form.
9. the preparation method of external application Paeonol nano controlled-release thermosensitive in situ gel, its feature according to claim 8
It is that the mixing oil phase is that stearic acid and IPM mix, and the blended emulsifier mixes for Labrasol and Transtol HP.
10. the preparation method of external application Paeonol nano controlled-release thermosensitive in situ gel, its feature according to claim 9
It is, in the colostric fluid, in terms of mass fraction, stearic acid content 3%, IPM contents 3%, Labrasol contents 18%,
Transtol HP contents 15%, paeonol content 10%, balance of ultra-pure water.
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| CN109091482A (en) * | 2018-10-25 | 2018-12-28 | 闫玮钰 | A kind of paste for papular urticaria |
| CN109498573A (en) * | 2019-01-23 | 2019-03-22 | 镇江市疾病预防控制中心 | A kind of Paeonol self-micro emulsion formulation and preparation method thereof |
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| CN109498573A (en) * | 2019-01-23 | 2019-03-22 | 镇江市疾病预防控制中心 | A kind of Paeonol self-micro emulsion formulation and preparation method thereof |
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