CN103919822B - Compound brucea javanica oil softgel - Google Patents
Compound brucea javanica oil softgel Download PDFInfo
- Publication number
- CN103919822B CN103919822B CN201310523246.2A CN201310523246A CN103919822B CN 103919822 B CN103919822 B CN 103919822B CN 201310523246 A CN201310523246 A CN 201310523246A CN 103919822 B CN103919822 B CN 103919822B
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- CN
- China
- Prior art keywords
- fructus bruceae
- oleum fructus
- soft capsule
- compound recipe
- capsule
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- Medicinal Preparation (AREA)
Abstract
A compound brucea javanica oil softgel belongs to the technical field of traditional Chinese medicine preparations, and is characterized by using the following method to prepare: 1) weighing 6-10% of brucea javanica oil, 65-75% of freeze dried toad skin ultramicro powder, 12-20% of beeswax, 3-6% of soybean phospholipid and 0.2-0.6% of ethyl p-hydroxybenzoate for standby use; 2) melting the beeswax and the soybean phospholipid in polyethylene glycol-400; then adding the brucea javanica oil, the freeze dried toad skin ultramicro powder and the f ethyl p-hydroxybenzoate for fully mixing evenly to obtain a medicinal liquid with moderate viscosity and good fluidity; 3) according to the weight ratio of 2-4:2-4:1, weighing water, gelatin and glycerin, pouring into a gel pot to prepare a gel material; and 4) using a pressing method for making the compound brucea javanica oil softgel. The compound brucea javanica oil softgel is prepared from the brucea javanica oil and the freeze dried toad skin ultramicro powder by using of the pressing method, the prepared compound brucea javanica oil softgel can cover the toad skin odor, overcomes the brucea javanica oil bitter taste, improves drug stability, and is convenient to take, good in anti-tumor effect and less in toxic and side effect.
Description
Technical field
The invention belongs to technical field of traditional Chinese medicine preparation, specially compound recipe oleum fructus bruceae soft capsule.
Background technology
Chinese medicine Fructus Bruceae is quassia Fructus Bruceae（Brucea javanica L.Merr.）Avette or grey black it is long
Circular dry mature fruit, with heat-clearing and toxic substances removing, malaria, antiinflammatory and antineoplastic action.Oleum Fructus Bruceae is fruit of khosam
Middle to extract the fatty oil for obtaining, in China, clinical existing various dosage forms are extensively applied.Its concrete mechanism is：For the non-spy of cell cycle
Different in nature anticarcinogen, to tumor cell G0, G1, G2, M phase have suppress and lethal effect, can substantially suppress tumor cell DNA,
The synthesis of RNA and protein, disturbs the formation of peptide tendon；The apoptosis of cancerous cell can be induced；The P sugar eggs on cell membrane can be acted on
Effect that is white and producing reversing drug resistance so as to the increased activity of its cancer therapy drug.These phenomenons prompting TOPO II is Oleum Fructus Bruceae
One of intracellular action target spot.Oleum Fructus Bruceae is shared with other chemotherapeutic and can improve curative effect, and toxicity is few, seldom occurs disliking
The toxicity of the conventional chemotherapy medicines such as the heart, vomiting, alopecia.
Cutis Bufonis are Bufonidae（Bufonidae）Animal Bufo siccus（Bufo bufo gargarizans Cantor）'s
Skin is dried, is recorded in earliest《This Jing meets original》, with pharmacological actions such as antitumor, anti-hepatitis virus, for treating B-mode liver
The diseases such as inflammation, chronic tracheitiss, laryngopharynx swelling and pain, carbuncle furunculosis.Concrete mechanism of action：Contain various Bufo siccuss in the extract of Cutis Bufonis
Diene hydroxy acid lactone compound, wherein bufanolide are existed only in fresh Cutis Bufonis.Hepatocarcinoma can be induced thin
Born of the same parents HepG2 cell blocks are in the G2/M phases；Improve body's immunity and inducing apoptosis of tumour cell suppresses Implanted liver carcinoma
Growth.It is used for kinds cancer and combined with chemotherapy for many years, curative effect can not only be improved, moreover it is possible to mitigate side effect, improves routine blood test.
Soft capsule is a kind of dosage form grown up after tablet, injection, can be mixed oily medicine, drug solution or medicine
Suspension, the pastel even quantitative pressure injection of drug powder is simultaneously encapsulated in glued membrane, forms size, different seal capsule.It is soft
Used as clinically common formulations, it has the bad odor that can cover medicine to capsule, improves medicine stability effect, can make liquid
Medical solid, while its content is powder or graininess, can disperse rapidly in the gastrointestinal tract, dissolution and absorption, so as to
Improve the bioavailability of medicine.
The content of the invention
For the above-mentioned problems in the prior art, it is an object of the invention to design a kind of compound recipe Oleum Fructus Bruceae of offer
The technical scheme of soft capsule, can cover the stink of Cutis Bufonis, overcome Oleum Fructus Bruceae bitter in the mouth, improve medicine stability, and taking convenience resists
Tumor effect is good, and toxic and side effects are little.
Described compound recipe oleum fructus bruceae soft capsule, it is characterised in that comprise the following steps：
1）By weight percentage composition ratio weighs Oleum Fructus Bruceae 6-10%, lyophilization Cutis Bufonis superfine powder 65-75%, Cera Flava
12-20%, soybean phospholipid 3-6%, ethylparaben 0.2-0.6%, it is standby；
Described Oleum Fructus Bruceae is prepared using following methods：Fructus Bruceae pulverizing medicinal materials are crossed into 18 mesh sieves, plus petroleum ether merceration
Extract 2-3 time, 6-10h is extracted every time, the consumption of petroleum ether is 10-14 times of Fructus Bruceae medical material weight, the Oleum Fructus Bruceae for slightly carrying
Nitrogen is passed through, 100-110 DEG C of heating 2-3h removes unrecovered oil ether, then adds the activated carbon of Fructus Bruceae medical material weight 4-6% to exist
1-1.5h is heated under the conditions of 100-110 DEG C, desolventing technology is carried out, Oleum Fructus Bruceae is obtained final product；
Described lyophilization Cutis Bufonis superfine powder is prepared using following methods：Cutis Bufonis micronizing will be dried, its particle diameter is
10-7μm；
2）According to Cera Flava weight be 1g then PEG-4000 consumption for 25-35ml ratio, by Cera Flava and Semen sojae atricolor phosphorus
Fat is melted in PEG-4000；Add Oleum Fructus Bruceae, lyophilization Cutis Bufonis superfine powder, ethylparaben abundant
It is ground, makes that viscosity is moderate, good fluidity medicinal liquid；
3）The preparation of capsule material：By weight 2-4:2-4:1 ratio weighs water, gelatin, glycerol and pours in glue tank, during colloidal sol
Temperature is first arranged to 70-80 DEG C, starts to add water when temperature reaches 55-60 DEG C, adds water 10-15 minutes, and being touched with handss has micro-
Boiling hot sensation, is initially added into glycerol, stirs 2-3 minutes, takes 2 times from glue pot bottom, in refunding glue tank, gelatin, stirring is added rapidly
Time is 1.5-2 hours, and temperature is set as 55-65 DEG C after stirring, stands return-air bubble 7-8 hours；
4）Soft capsule, room temperature 20-24 DEG C glue capsule are made using pressing, rubber thickness is 0.6-0.8mm, obtained soft
Capsule cools down 7-9 hours in rotating cage, comes out of steamer, and is drying to obtain compound recipe oleum fructus bruceae soft capsule.
Described compound recipe oleum fructus bruceae soft capsule, it is characterised in that wash obtained compound recipe oleum fructus bruceae soft capsule with ethanol
Capsule surface oil matter is gone, 30-40 DEG C is selected, 8-10 hours are dried.
Described compound recipe oleum fructus bruceae soft capsule, it is characterised in that step 1）In：The content of Oleum Fructus Bruceae is 7-8%, freezing
It is dried Cutis Bufonis superfine powder 68-72%, Cera Flava 15-18%, soybean phospholipid 4-5%, ethylparaben 0.3-0.5%.
Described compound recipe oleum fructus bruceae soft capsule, it is characterised in that step 1）In Oleum Fructus Bruceae preparation method：Fructus Bruceae medicine
It is 7-8h that material adds petroleum ether merceration extraction time, and the consumption of petroleum ether is 11-13 times of Fructus Bruceae medical material weight, the crow gallbladder for slightly carrying
Seed oil is passed through the nitrogen post-heating time for 2.5h, and the desolventing technology time is 1.2-1.3h.
Described compound recipe oleum fructus bruceae soft capsule, it is characterised in that step 3）Middle water：Gelatin：The weight ratio of glycerol is 3:3:
1。
Described compound recipe oleum fructus bruceae soft capsule, it is characterised in that step 3）In：Temperature is first arranged to 75-78 during colloidal sol
DEG C, start to add water when temperature reaches 58 DEG C, add water 11-13 minutes, plus mixing time is 1.6-1.8 hours after gelatin,
Temperature is set as 60 DEG C after stirring.
Described compound recipe oleum fructus bruceae soft capsule, its feature is in step 4）In：Room temperature 22-23 DEG C glue capsule, rubber thickness
For 0.7mm.
Described Oleum Fructus Bruceae, Cutis Bufonis can be buied directly from the market.
Above-mentioned compound recipe oleum fructus bruceae soft capsule, Oleum Fructus Bruceae, lyophilization Cutis Bufonis superfine powder is prepared using pressing soft
Capsule, obtained soft capsule can cover the stink of Cutis Bufonis, overcome Oleum Fructus Bruceae bitter in the mouth, improve medicine stability, and taking convenience resists
Tumor effect is good, and toxic and side effects are little.
Description of the drawings
Fig. 1 is reference substance chromatogram in Oleum Fructus Bruceae ira vitro analytical methods, and Fig. 2 is molten in Oleum Fructus Bruceae ira vitro analytical methods
Agent chromatogram, Fig. 3 is the hollow white spectrogram of Oleum Fructus Bruceae ira vitro analytical methods, and Fig. 4 is sample in Oleum Fructus Bruceae ira vitro analytical methods
Product chromatogram, Fig. 5 is Oleic acid canonical plotting in Oleum Fructus Bruceae ira vitro analytical methods；Fig. 6 is lyophilization Cutis Bufonis ultrafine powder
Reference substance chromatogram in outer analysis method, Fig. 7 is solvent chromatogram in lyophilization Cutis Bufonis superfine powder ira vitro analytical methods, Fig. 8
For the hollow white spectrogram of lyophilization Cutis Bufonis superfine powder ira vitro analytical methods, Fig. 9 is lyophilization Cutis Bufonis ultrafine powder outer analysis
Sample chromatogram figure in method, Figure 10 is cinobufagin canonical plotting；Figure 11 bufogenin canonical plottings.
Specific embodiment
Below in conjunction with specific embodiment, the invention will be further described.
Embodiment 1：
Compound recipe oleum fructus bruceae soft capsule is prepared using following methods：
1）By weight percentage composition ratio weighs Oleum Fructus Bruceae 22g, lyophilization Cutis Bufonis superfine powder 176g, Cera Flava 40g, big
Fabaceous lecithin 10g, ethylparaben 1g, it is standby；
Described Oleum Fructus Bruceae is prepared using following methods：Fructus Bruceae pulverizing medicinal materials are crossed into 18 mesh sieves, plus petroleum ether merceration
Extract 2 times, 8h extracted every time, the consumption of petroleum ether is 12 times of Fructus Bruceae medical material weight, and the Oleum Fructus Bruceae for slightly carrying is passed through nitrogen,
110 DEG C of heating 2h, remove unrecovered oil ether, then add the activated carbon of Fructus Bruceae medical material weight 4-6% to heat 1h under the conditions of 110 DEG C,
Desolventing technology is carried out, Oleum Fructus Bruceae is obtained final product；
Described lyophilization Cutis Bufonis superfine powder is prepared using following methods：Cutis Bufonis micronizing will be dried, its particle diameter is 9
μm；
2）Cera Flava and soybean phospholipid are melted in 500ml PEG-4000s；Add Oleum Fructus Bruceae, lyophilization toad
Skin superfine powder, ethylparaben are fully ground mixing, make that viscosity is moderate, good fluidity medicinal liquid；
3）The preparation of capsule material：By weight 3:3:1 ratio weighs water, gelatin, glycerol and pours in glue tank, temperature during colloidal sol
First it is arranged to 75 DEG C, starts to add water when temperature reaches 60 DEG C, add water 10 minutes, with handss micro- boiling hot sensation is touched, starts
Glycerol is added, is stirred 2 minutes, taken 2 times from glue pot bottom, in refunding glue tank, gelatin is added rapidly, mixing time is 1.5-2 hours,
Temperature is set as 60 DEG C after stirring, stands return-air bubble 7-8 hours；
4）Soft capsule is made using pressing, 22 DEG C of glue capsules of room temperature, rubber thickness is 0.7mm, obtained soft capsule exists
Cool down 8 hours in rotating cage, come out of steamer, be drying to obtain compound recipe oleum fructus bruceae soft capsule；
5）Obtained compound recipe oleum fructus bruceae soft capsule ethanol is washed away into capsule surface oil, 30-40 DEG C is selected, 8- is dried
10 hours.
Above-mentioned steps 1）The weight content of middle Oleum Fructus Bruceae is 6-10%, lyophilization Cutis Bufonis superfine powder 65-75%, Cera Flava
12-20%, soybean phospholipid 3-6%, ethylparaben 0.2-0.6%；Fructus Bruceae medical material adds the petroleum ether merceration extraction time to be
6 h, 7 h, 9 h or 10h, the consumption of petroleum ether is 11 or 13 times of Fructus Bruceae medical material weight, and the Oleum Fructus Bruceae for slightly carrying is passed through nitrogen
The gas post-heating time is 2h or 3h, and the desolventing technology time is 1.2h or 1.5h.Step 2）Middle water：Gelatin：The weight ratio of glycerol is
2:2:1、4:4:1、2:4:1 or 4:2:1.Step 3）In：Temperature is first arranged to 70 DEG C or 80 DEG C during colloidal sol, and in temperature 55 DEG C are reached
Or start to add water when 60 DEG C, add water 12 or 15 minutes, micro- boiling hot sensation is touched with handss, glycerol is initially added into, stir 3 points
Clock.Step 4）Middle room temperature 20 or 24 DEG C of glue capsules, rubber thickness is 0.6 or 0.8mm.The other the same as in Example 1, can also reach this
Bright described beneficial effect.
Beneficial effects of the present invention are further illustrated below in conjunction with corresponding test data.
Test one, compound recipe oleum fructus bruceae soft capsule preformulation study
Preformulation study（Preformulation Studies）It is to design and prepare a medicine safely, effectively, stable
The pith of thing preparation.The preformulation study of preparation, for the selection of dosage form, the screening of prescription and preparation technology foundation is provided,
Its purpose is exactly to make preparation prescription and preparation process requirement in drug substance stable, effective and suitable industrialized production.The present invention is to crow
The relevant physicochemical property of courage oil and Cutis Bufonis micropowder has carried out preliminary study, sets up its ira vitro analytical methods, is compound recipe Fructus Bruceae
Fat capsule technique and quality standard research etc. provide reference frame.
First, experiment material
（One）Experimental drug and reagent
Normal hexane（Jiangsu Yonghua Fine Chemical Co., Ltd. 20120507, chromatographically pure）
Petroleum ether（60-90 DEG C, Jiangsu Yonghua Fine Chemical Co., Ltd. 20120714）
Oleic acid reference substance（National Institute for Food and Drugs Control provides 111621-201004）
Cinobufagin reference substance（National Institute for Food and Drugs Control provides 10803-200605）
Bufogenin reference substance（National Institute for Food and Drugs Control provides 110718-200507）
Oleum Fructus Bruceae（Laboratory is made by oneself, lot number 20120920）
Potassium hydroxide（Hangzhou Xiaoshan chemical reagent factory 20081206）
Anhydrous sodium sulfate（Chemical Reagent Co., Ltd., Sinopharm Group 20090811）
Boron trifluoride diethyl etherate (auspicious ancient cooking vessel chemical technology Shanghai company limited 20110213, chemistry is pure)
Acetonitrile, methanol are chromatographically pure, and other agents useful for same, such as unreceipted specification refer both to analysis pure.
（Two）Experiment equipment
GC-14A gas chromatograpies（Shimadzu）
KQ5200DE ultrasonic cleaners（Kunshan ultrasonic instrument company limited）
The accurate micro electronic analytical balances of CP225D（Sartorius AG）
METTLER TOLEDO electronic balances（Prunus mume (sieb.) sieb.et zucc. Teller-support benefit instrument Shanghai company limited）
HH-S type water-baths（Ying Yu Yu Hua instrument plants of Gongyi City）
Efficient liquid phase（Tian Mei companies LC2000 gradient systems）
LC2130 infusion pump (Japanese imported with original packaging), with gradient elution and online washing device
LC2030 UV-detector manual injector 775i chromatographic work station T2000P
2nd, method and result
（One）The foundation of Oleum Fructus Bruceae ira vitro analytical methods
1. chromatographic condition
Instrument：Shimadzu gas chromatograph GC-14A, fid detector
Chromatographic column：DM-InertWax capillary columns（30 m×0.25 mm×0.25 μm）
Condition：Column temperature：150℃；Injector temperature：250℃；Detector temperature：250℃；Carrier gas is High Purity Nitrogen, flow velocity：
1.0mL·min-1；Constant current, split ratio 30：Press 10psi before 1 post, column temperature adopts temperature-programmed mode, 150 DEG C（Stop
1min）- 200 DEG C（10 DEG C of min-1, stop 2 min）- 220 DEG C（10 DEG C of min-1, stop 10min）.In this chromatostrip
Under part, Oleic acid can reach baseline separation with other compositions in sample, and separating degree is more than 1.5, and theoretical cam curve presses Oleic acid peak
Areal calculation, is not less than 40000.Reference substance, solvent, blank, sample chromatogram figure are shown in Fig. 1-4.
2. the preparation of Oleic acid reference substance solution
Precision weighs Oleic acid reference substance 33.8mg, into 25mL volumetric flasks, plus n-hexane dissolution and is diluted to scale, shakes
It is even, make 1.352mg/mL reference substance solution.Precision draws 1.352mg/mL Oleic acid reference substance solution 2.0mL into test tube, nitrogen
The dry solvent of air-blowing, adds 0.5moL/L potassium hydroxide methanol solution 2mL, the saponification 25min in 60 DEG C of waters bath with thermostatic control, treats that oil droplet is complete
After CL, let cool, add 15% boron trifluoride ether solution 2mL, shake up.Esterification 2min, puts in 60 DEG C of waters bath with thermostatic control
Cold, precision adds normal hexane 2.0mL, shake well 2min.Add supersaturation sodium chloride solution appropriate, make hexane solution float
To bottleneck, upper strata organic liquor is drawn immediately, use 0.5g anhydrous sodium sulfate dehydrations, obtain final product the reference substance solution of 1.352mg/mL.
3. the preparation of need testing solution
Take compound recipe oleum fructus bruceae soft capsule content appropriate, in putting 10mL volumetric flasks, plus normal hexane constant volume, take 1mL according to
Operate in accordance with the law from " nitrogen dries up solvent " under the preparation of reference substance solution, obtain final product need testing solution.
4. methodological study
4.1 Specification Curve of Increasing
Precision draws the dense mL of Oleic acid reference substance solution 0.4,0.8,1.2,1.6,2.0,2.4 to the 15 tools plugs of 1.352mg/mL
0.5moL/L potassium hydroxide methanol solution 2mL, the saponification 25min in 60 DEG C of waters bath with thermostatic control are added in test tube, treats that oil droplet is completely molten
Xie Hou, lets cool, and adds 15% boron trifluoride ether solution 2mL, shakes up.Esterification 2min, lets cool in 60 DEG C of waters bath with thermostatic control, essence
Close addition normal hexane 2.0mL, shake well 2min.Add supersaturation sodium chloride solution appropriate, make hexane solution float up to bottle
Neck, draws immediately upper strata organic liquor, uses 0.5g anhydrous sodium sulfate dehydrations, and control series product solution is obtained.Respectively accurate absorption is right
According to product solution sample introduction, peak area is determined, with peak area Y as vertical coordinate, concentration X with reference substance solution draws mark as abscissa
Directrix curve.Oleic acid linear relationship in the range of 0.2704~1.6224mg/mL is good.Regression equation：Y=433993X+4816, phase
Relation number R2=0.9996.As a result Fig. 5 is seen.
4.2 precision test
Precision is drawn in 1.352mg/mL Oleic acid reference substance solution 1.2mL to 15mL tool plug test tubes, according to reference substance solution
Preparation under from " nitrogen dries up solvent " operation preparation reference substance solution in accordance with the law, precision draws the μ L of reference substance solution 5, continuously
Sample introduction 6 times, determines peak area.It is 2.05% to calculate precision RSD, shows that instrument precision is good.The results are shown in Table 1.
4.3 stability test
Precision draws same freshly prepared need testing solution, respectively at 0,2,4,6,8,10h, precision draws reference substance solution 5
μ L, injection gas chromatograph detection.Peak area is determined, chromatogram is recorded.Meansigma methodss are tried to achieve, RSD is 1.38%.Sample is in 10h
It is interior stable.The results are shown in Table 2.
4.4 replica test
Precision draws 6 batches of freshly prepared need testing solutions, and precision draws the μ L of reference substance solution 5, injection gas chromatograph detection.
Peak area is determined, chromatogram is recorded.Meansigma methodss are tried to achieve, RSD is 1.32%, illustrate repeated good.The results are shown in Table 3.
4.5 average recoveries are tested
Precision is drawn in 1.352mg/mL Oleic acid reference substance solution 0.6mL to 15mL tool plug test tubes, is separately added into appropriate glue
It is intracapsular tolerant, according under the preparation of need testing solution from " nitrogen dries up solvent " operation preparation need testing solution in accordance with the law, enter
The μ L of sample 5, determine peak area, record chromatogram.Mean sample recovery rate is tried to achieve for 100.74%, RSD=1.13%, the method recovery
Rate is preferable.The results are shown in Table 4.
5. the assay method of compound recipe oleum fructus bruceae soft capsule mid-oleic
Take compound recipe oleum fructus bruceae soft capsule content appropriate, in putting 25mL volumetric flasks, plus normal hexane constant volume, according to reference substance
Operate in accordance with the law from " nitrogen dries up solvent " under the preparation of solution, obtain final product.Its content is determined using gas chromatography.
（Two）The foundation of lyophilization Cutis Bufonis superfine powder ira vitro analytical methods
1. chromatographic condition and solution are prepared
Chromatographic condition：Chromatographic column：KromasilC18 (4.6mm × 250mm, 5 μm)（Sweden）；Mobile phase：Acetonitrile (A)-water
(B)（50 ︰ 50）；Flow velocity：1mL•min-1；Column temperature：30℃；Detection wavelength：296nm.Reference substance, blank, sample, solvent chromatograph
Figure is shown in Fig. 6-9.
2. solution is prepared
The preparation of need testing solution：Take capsule 's content appropriate, in putting 50mL conical flasks, plus methanol, weigh, it is heated to reflux
1 hour, let cool, plus methanol is to constant weight, shakes up, and crosses microporous filter membrane（0.45μm）, take subsequent filtrate.The preparation of reference substance solution：Take
Cinobufagin reference substance 1.4mg, bufogenin reference substance 1.4mg, in putting 10mL volumetric flasks, plus methanol constant volume, obtain final product.
3. methodological study
3.1 linear relationship
The preparation of standard curve：Respectively Oleic acid reference substance solution is diluted to 0.0056mg ﹒ mL1,0.0168mg ﹒ mL-1,
0.0280mg ﹒ mL-1,0.0392mg ﹒ mL-1,0.0504 mg ﹒ mL-1,0.0616mg ﹒ mL-1, the μ L of sample introduction 10 analyses respectively, with
Sample peak area（The Wei Fu ﹒ seconds）Sample concentration is mapped, cinobufagin standard curve is obtained：y=11351573.9796x+
20148.6143, coefficient R 2=0.9998；Range of linearity 0.0056mg/mL-0.0616mg/mL.Bufogenin standard is bent
Line：Y=5590923.4694x+14457.3048, coefficient R 2=0.9996；Range of linearity 0.0056mg/mL-0.0616mg/
mL。
3.2 precision test
Reference substance solution 0.0224mg/mL is taken, repeats sample introduction 6 times, every time 10 μ L, by above-mentioned chromatographic condition peak face is determined
Product, as a result the RSD of cinobufagin peak area is 1.09%, and the RSD of bufogenin peak area is 0.94%, shows instrument precision
Degree is good.It is shown in Table 5-6.
3.3 replica test
Take 6 batches of compound recipe oleum fructus bruceae soft capsule contents appropriate, according to need testing solution compound method test sample is configured to
Solution, continuous sample introduction 6 times, every time 10 μ L, determine peak area, as a result the RSD of cinobufagin peak area by above-mentioned chromatographic condition
For 1.77%, the RSD of bufogenin peak area is 2.12%, shows that instrument repeatability is good.It is shown in Table 7-8
3.4 stability test
Compound recipe oleum fructus bruceae soft capsule content is taken, need testing solution is configured to, is determined in 0,4,8,12,24,48h and is contained
Amount, every time 10 μ L, by above-mentioned chromatographic condition peak area is determined, and as a result the RSD of cinobufagin peak area is 1.46%, fat toadpoison
The RSD of aglucon peak area is 1.80%, shows stable in need testing solution 48h hours.It is shown in Table 9-10.
3.5 sample-adding recovery tests
6 groups of compound recipe oleum fructus bruceae soft capsule content is taken, 0.0224mg ﹒ mL are added respectively-1Standard substance 2mL, according to " test sample
Parallel preparation under preparation " item, under above-mentioned chromatographic condition peak area is determined.It is shown in Table 11-12.
4. in compound recipe oleum fructus bruceae soft capsule bufogenin and cinobufagin total content assay method
Take compound recipe oleum fructus bruceae soft capsule content appropriate, accurately weighed, in putting conical flask with cover, precision adds methanol
20mL, weighed weight is heated to reflux 1 hour, lets cool, then weighed weight, and with methanol the weight of less loss is supplied, and shakes up, filtration, takes
Subsequent filtrate, obtains final product.Using liquid chromatography for measuring Cutis Bufonis cinobufotalin and bufogenin content.It is shown in Table 13-14.
From upper table 13, lyophilization Cutis Bufonis cinobufagin average content is 0.05733%
From upper table 14, lyophilization Cutis Bufonis bufogenin average content is 0.0871%.
3rd, analysis and discussion
The assay method of content in Cutis Bufonis, in most cases, bufogenin and the peak of cinobufagin two are not easy to separate,
The peak of liquid-phase condition two of this experiment can be very good to separate（Separating degree is more than 1.5）, separating effect and peak shape it is preferable.2010 editions
《Chinese Pharmacopoeia》The oleic acid content of Oleum Fructus Bruceae determines the following PEG 20000 of item（PEG-20M）Capillary column（30m×
0.25mm×0.25um）；Oleic acid standard substance and Oleum Fructus Bruceae are determined with the laggard GC of boron trifluoride esterification.Using pharmacopeia side
Method, GC detections, good separating effect, peak shape is preferable.Whether methyl oleateization is entirely that the operation of detection method is closed in experimentation
Key.
4th, brief summary
First, Oleum Fructus Bruceae content assaying method is established, accurately quick, sensitivity is high for the method.Establish compound recipe crow gallbladder
The assay method of bufogenin and cinobufagin total content in seed oil soft capsule, two peaks are separately obvious under liquid-phase condition, easily
In respectively to the measure of two kinds of contents.
Second, lyophilization Cutis Bufonis cinobufagin and bufogenin total content are more than dry maxima skin China toad in experiment
Crisp poison base and bufogenin total content, with reference to effect experiment medical material is selected.
Test two, compound recipe oleum fructus bruceae soft capsule prescription and Study on Preparation
First, experiment material
（One）Experimental drug and reagent
PEG400（Chinasun Specialty Products Co., Ltd 20110901）
Glycerol（Chinasun Specialty Products Co., Ltd 20110901）
Soybean phospholipid（Chemical Reagent Co., Ltd., Sinopharm Group 20090813）
Cera Flava（Comfort the factory 20091102 of raw reagent nine in Shanghai）
Gelatin（Chemical Reagent Co., Ltd., Sinopharm Group F20111109）
Cyclophosphamide lyophilized injectable powder（Jiangsu Heng Rui Pharmaceuticals Ltds 11072821）
0.9% normal saline（Zhejiang Sapuaisi Pharmacy Co., Ltd. 20111120）
Fructus Bruceae medical material（Zhejiang BAICAO prepared slices of Chinese crude drugs company, the place of production is Guangxi, Jing Zhejiang University of Traditional Chinese Medicine natural resources of Chinese medicinal materials
With the drying and ripening that identification teaching and research room teacher Zhang Shuili is accredited as quassia Fructus Bruceae Brucea javanica L.Merr.
Fruit, lot number 20120807）
Lyophilization Cutis Bufonis superfine powder（Laboratory is made by oneself, lot number 20120921）
Activated carbon（Chemical Reagent Co., Ltd., Sinopharm Group 20090315）
Ethylparaben（Shanghai Ling Feng chemical reagent company limited 20100721）
（Two）Experiment equipment
HTSYS-5 types intelligently test encapsulating machine（Beijing Zhong Tian Correspondents Science and Technology Ltd.）
BJ- II disintegration time testers（Medical Equipment Plant of Shanghai Boxun Industrial Co., Ltd.）
AB104-N electronic analytical balances（Prunus mume (sieb.) sieb.et zucc. Teller-support benefit Instrument Ltd.）
BILON electric heating constant-temperature water-bath tanks（Suzhou Percivall experimental facilitiess company limited）
The statistical softwares of SPSS 16.0
（Three）Laboratory animal and material
1. cell strain
Mice S180 ascitic type tumor cells, are provided by medical courses in general institute of Zhejiang Province.
2. animal
ICR mices, SPF levels, male and female half and half, age:4-6 is all, 20 ± 2g of body weight, in Zhejiang University of Traditional Chinese Medicine's laboratory animal
The heart, SCXK (Shanghai)（2007-0005）
2nd, method and result
（One）Dosage form selection
The medical material that this experiment is selected is lyophilization Cutis Bufonis superfine powder and Oleum Fructus Bruceae mixture, if with simple mixing or
Make suspensoid, it is impossible to overcome the bad odor of Cutis Bufonis and its stability problem, the resting period is long, easily layering, cause to
Dose is inaccurate etc..In view of micropowder can be mixed and made into suspensoid with Oleum Fructus Bruceae and other substrate, it is contemplated that make soft capsule.
Soft capsule can cover the bad odor of medicine, improve medicine stability；Can be by liquid medicine solid dosage formss.Make by prescription
Suspension medicinal liquid, using pressing soft capsule is prepared, and can make the preferable soft capsule of quality.To sum up analyze, therefore by the dosage form of this product
It is defined as soft capsule.
（Two）The Study on extraction of Oleum Fructus Bruceae
This laboratory has carried out in-depth study for many years and investigation to Fructus Bruceae, and the extraction process of Oleum Fructus Bruceae has been grasped,
Technology maturation.Optimum extraction purifying process is as follows：Fructus Bruceae pulverizing medicinal materials cross 18 mesh sieves, plus 12 times of petroleum ether, and merceration extracts 2
It is secondary, extract 8 hours every time, stir once every 2h；5% activated carbon, decolourize 60min under the conditions of 100 DEG C；110 DEG C of conditions lead to nitrogen
Gas 2h blows away unrecovered oil ether.The oil extracting rate of the extraction process is 19.78%, and oleic acid content is 18.99%.The repeatable profit of petroleum ether
With, extract and the equal advantages of simple of impurity removal process, it is easy to operate, it is easy to obtain the higher Oleum Fructus Bruceae of purity.
（Three）Compound recipe oleum fructus bruceae soft capsule prescription ratio is screened
1.S180 bearing mouse model is set up
S180 ascitic types tumor cell line 1 is taken out in liquid nitrogen container, is placed in 37 DEG C of electric heating constant-temperature water-bath tanks, gently shaken
The command of execution its melt as early as possible.Cryopreservation tube is taken out, is opened after disinfecting in alcohol, with suction pipe cell suspension is suctioned out, injected centrifuge tube and drip
Plus 15% hyclone RPMI-1640 culture medium, conventional centrifugal, oncocyte suspension is made, trypan blue counts about 1 × 107/
ML oncocytes.Take 0.2mL（About 1 × 106 ~ 2 × 106 oncocytes）It is inoculated in abdominal cavity.Pass on 3 times to select to be inoculated with 7 days afterwards
S180 tumor-bearing mices, take off neck and put to death, and extract ascites in mouse peritoneal, after suitably being diluted with normal saline, count, and adjustment concentration is extremely
2 × 107/mL, draws oncocyte suspension 0.2mL and is injected at mice left fore oxter, every 0.2mL with asepsis injector.
2. experiment packet and administration
2.1 experiment packet
Postvaccinal ICR mices, record body weight of weighing, by body weight and sex nine groups are randomly divided into:
Experiment packet and administrations
Experiment carries out preliminary screening to the ratio of drug effect by Fibonacci method, and experiment chooses 0.382,0.618 two
Point, then between two points by publicity x=(0.618-0.382) × 0.618+0.382=0.528, so by the ratio of pharmacodynamicss
It is arranged to following groups:
(1/0,0.618/0.382,0.528/0.472,0.472/0.528,0.382/0.618,0/1)
A groups（It is converted into Fructus Bruceae crude drug amount 200mg/kg, 0.2ml/10g body weight）
B groups（It is converted into Fructus Bruceae crude drug amount 123.6mg/kg, Cutis Bufonis 114.6mg/kg, 0.2mL/10g body weight）
C groups（It is converted into Fructus Bruceae crude drug amount 105.6mg/kg, Cutis Bufonis 141.6mg/kg, 0.2mL/10g body weight）
D groups（It is converted into Fructus Bruceae crude drug amount 94.6mg/kg, Cutis Bufonis 158.4mg/kg, 0.2mL/10g body weight）
E groups（It is converted into Fructus Bruceae crude drug amount 76.4mg/kg, Cutis Bufonis 185.4mg/kg, 0.2mL/10g body weight）
F groups（Lyophilization Cutis Bufonis superfine powder 300mg/kg, 0.2mL/10g body weight）,
G groups（Dry maxima skin superfine powder 300mg/kg, 0.2mL/10g body weight）
Negative control group（0.9% normal saline, 0.2mL/10g body weight）
Positive controls（Cyclophosphamide 2.5mg/kg, 0.1mL/10g body weight）
2.2 administering mode
Positive controls adopt lumbar injection mode, remaining group to adopt gastric infusion.
3. data collection
Continuous gavage is administered 11 days, the ordinary circumstance of observed and recorded mice during administration（Diet, outward appearance, behavior, secretion
Thing, Excreta, poisoning manifestations and death condition etc.）, periodically claiming tumor-bearing mice weight, second day record body weight, takes off neck after drug withdrawal
Place's post mortem, strips tumor tissues, spleen, thymus, scales/electronic balance weighing, record.With the softwares of SPSS 16.0 to dependency number
According to carrying out statistical procedures.Measurement data is adopted± S represents that measurement data is compared and checked using t between two groups.
4. Testing index:Inhibition rate of tumor growth
Tumour inhibiting rate (%)=(the average knurl weight of the average knurl weight/negative control group of 1- experimental grouies) × 100%
Spleen index=spleen weight (mg)/body weight (g) × 10
Thymus index=thymic weight (mg)/body weight (g) × 10
5. experimental result
Mouse Weight change, average knurl weight and tumour inhibiting rate, compare between group and are checked with t before and after record administration, P<0.05 is have
Significant difference, P<0.01 is have pole significant difference.Mouse thymus and spleen weight after being dissected according to mice, calculate thymus and refer to
Number and index and spleen index.The results are shown in Table 1-17,1-18.
Phase before administration（1-6 days）The ordinary circumstance of mice is overall good；
In inoculation 5-7 days, the tumor mass of mice oxter enlargement can be intuitively seen；
Phase upon administration（7-11 days）As the increase of tumor body, some animals mobility weaken, feed is reduced；Fur is insulted
It is disorderly matt；
Mouse thymus and spleen weight after being dissected according to mice, calculate Thymus and Spleen index.With positive controls
Compare, positive controls have pole significant difference, each group has significant difference（P<0.05）, illustrate to be produced with cyclophosphamide
Immunosuppressive action compare, can improve the immunity of organisms of mice after the administration of Oleum Fructus Bruceae compound recipe, improve immune device
The organ index of official, knowable to following experimental data, selects D groups to be optimal proportion.It is shown in Table 15.
Table 16
| Group | Thymus index（mg/g） | Index and spleen index（mg/g） |
| Negative control group | 15.307±0.343 | 59.547±0.314 |
| Positive controls | 10.505±0.674 | 53.378±0.775 |
| A groups | 16.645±0.356 | 74.649±0.897 |
| B groups | 19.348±0.879 | 75.580±0.577 |
| C groups | 14.580±1.583 | 51.346±0.875 |
| D groups | 10.885±0.574 | 63.428±1.334 |
| E groups | 16.212±0.746 | 73.640±2.353 |
| F groups | 17.353±0.896 | 65.073±0.644 |
| G groups | 15.928±0.556 | 55.787±1.356 |
（Four）Soft capsule formulation and technology is studied
Content is drug suspension in this experiment, with sedimentation volume ratio and redispersibility as evaluation index, investigates medicine
The disperse medium and suspending agent species and consumption of suspension.By disintegration time evaluation, in screening capsule manufacturing process, gelatin,
The optimal proportion of water, glycerol.
1. the selection of disperse medium and adjuvant
Suspensoid is loaded 25mL scale test tubes by the measure of sedimentation volume ratio, clogs the mouth of pipe, is placed after shaking 5min, point
Ji Lu not 0,1,2,3,4,5 height for continuing 36h precipitums（mL）, calculated settlement volume ratio, the subsidence curve of drafting formula.
Redispersibility suspensoid is prepared and staticly settled after balance, carries out the measure of redispersibility R.There to be the quarter of suspensoid
Degree test tube reverses 180 °, and measure returns to upset number of times needed for just suspensoid state processed.
The selection of 1.1 disperse medium
This experiment, with sedimentation volume ratio as inspection target, is selected disperse medium from soybean oil and PEG400.Claim
Fresh toad skin ultra-fine powder 5g is taken, 2 parts, the soybean oil and PEG400 of 15mL is measured, in being placed in tool plug test tube.
It is finally 3.2/15=0.21 to calculate soybean oil settling volume, PEG400 sedimentation volume ratios；It is finally 5.2/15=
0.35, therefore experimental selection PEG400 is substrate.
2. the selection of adjuvant
Adjuvant mainly has wetting agent and suspending agent.Wetting agent is generally surfactant-based, such as spans, Tweenses.
Suspending agent can generally increase the solid matter of disperse medium viscosity, such as Cera Flava, ethyl cellulose.The selection of adjuvant is basis
The state of content determining, no matter content is lipotropy or hydrophilic, if simple dependence PEG-400 (or oil)
It is suspended, it is not easy to obtain ideal effect, easily layering, the amount of subpackage is inaccurate；Do not exist if medicine is mutually dissolved with substrate
It is layered, disperses uneven situation, it is possible to without adds adjuvant.In a word, the content of soft capsule requires that energy is prolonged
Stablize, be uniformly dispersed, while there is good mobility.The content of this experiment is by Oleum Fructus Bruceae, Cutis Bufonis superfine powder and PEG-
400 compositions, it is easy to be layered.Therefore Oleum Fructus Bruceae and fresh toad skin ultra-fine powder dose are kept, with settling ratio and redispersibility as index,
Investigate the consumption of soybean phospholipid and Cera Flava.It is shown in Table 17.
From upper table 17, with the increase of Cera Flava consumption, start separation time and the sedimentation equilibrium time is obviously prolonged, sink
Drop volume ratio becomes big, and again dispersibility is improved, and shows that suspension stability increases, when Cera Flava consumption is 2% up to 8%, soybean phospholipid
When, stability is best.So the content for selecting Cera Flava is 8%, the content of soybean phospholipid is 2%.Medicinal liquid viscosity is moderate, mobility
Good, medicinal liquid long-time is placed without lamination, and drug distribution is uniform, stable.
3. medicine is investigated with the compatibility of disperse medium
3 parts of Oleum Fructus Bruceae is weighed, each 4g in being separately added into the PEG400 of 2g, 4g, 8g, under observation different temperatures feelings is dissolved
Condition.It is shown in Table 18.
Above-mentioned table 18 shows that the ratio of Oleum Fructus Bruceae and PEG400 is 2:1-1:In the range of 2, the temperature of mixed solution is 20
DEG C -40 DEG C, be a stable, uniform phase.
4. the prescription of soft capsule peel is investigated
Soft capsule peel is mainly gelatin, plasticizer, water composition].The physics and chemistry of gelatin and physiological special performance so as to into
To prepare the desirable material of capsule for medicine.Every that the material of polymeric material increase plasticity can be made to be referred to as plasticizer, they lead to
It is often that boiling point is high, it is more difficult to the liquid of volatilization or the solid of low melting point.A certain amount of plasticizer is added in capsule skin, flexible glue is can guarantee that
Capsule product keeps for a long time certain hardness so as to be unlikely to deform, and the most frequently used plasticizer has glycerol, Sorbitol etc..From L9
(34) orthogonal test method, gelatin, glycerol, the water to constituting capsule material, with the ratio of melt adhesive temperature, gelatin and glycerol row, water with it is bright
Glue ratio, is investigated according to the disintegration time of capsule for index, and experimental technique is：Gelatin, glycerol, water are weighed in proportion, it is molten
During glue, glue tank temperature setting is into 80 DEG C.It is shown in Table 19-20.
With disintegration time as index, from analysis directly perceived, each factor affects size used to be followed successively by A（Water：Gelatin）>B
（Gelatin：Glycerol）> C（Collosol temperature）.By intuitively analyzing, it is determined that optimal scheme is A3B3C3, i.e. the proportioning of capsule material is water：It is bright
Glue：Glycerol=3:3:1, melt adhesive temperature is set to 80 DEG C.Checking test is according to water：Gelatin：Glycerol=3:3:1, collosol temperature is set to 80
DEG C, prepare soft capsule disintegrate and work well.
5. prepared by soft capsule：The present invention makes soft capsule using pressing.
6. the investigation of soft capsule drying condition
The drying of soft capsule is an important step in soft capsule production.Suitable drying condition is selected, to ensureing flexible glue
The quality of capsule has great importance.The investigation method of drying time is：Under the conditions of 20 DEG C, 30 DEG C, 40 DEG C, soft gelatin capsule is carried out
It is dried, and the water content and disintegration of its softgel shell is determined to the different soft gelatin capsules being dried.Softgel shell moisture determination method is：Take softgel shell
About 1g, it is accurately weighed, it is placed in the surface plate for being dried constant weight（Diameter about 75mm）In, add water 10mL, places, and after making expansion, puts water
Heating for dissolving in bath, is evaporated, and in 105 DEG C of dryings to constant weight, with the weight of less loss, calculates the water content of softgel shell.As a result see the table below
21。
By the result of upper table 20,30-40 DEG C is selected, dry 8-10 hours, about 9% or so, disintegration time is accorded with softgel shell water content
Close and require.
3rd, analysis and discussion
The principal element for affecting medicine suspension performance is the size of diameter of aspirin particle and the performance of disperse medium, in suspensoid
The appropriate suspending agent of addition, makes medicine easily disperse and slow down granule to settle.Diameter of aspirin particle is less, and the viscosity of disperse medium is got over
Greatly, medicine sedimentation is slower.This experiment is melted in substrate with Cera Flava and soybean phospholipid as suspending agent, first, using grinding
Method make uniform and smooth, settle slow good stability, the mixed suspension preparation of easy redispersion.Cera Flava is main as a kind of suspending agent
Suspending effect is reached by increasing system viscosity, main component is Palmic acid Cera Flava alcohol ester, and containing a small amount of free higher alcohol,
With emulsibility, thus with capillary effect is reduced, suspensoid stably not free settling can be also made.Soybean phospholipid Jing is commonly used
It is stronger to the emulsibility of oils and fatss in Oil suspensions.It is wrapped in around microgranule using hydrophilic group, contributes to stabilising system,
Suppress change of size.Solid medical material is adopted in experiment for Cutis Bufonis superfine powder, its particle diameter below 10 μm, meets suspension more than 95%
Agent is to grain diameter size requirements.For the screening of ratio in compound recipe, this experiment is carried out point using Fibonacci method to drug effect group
Group, more fast accurately filters out optimal proportion.
Claims (8)
1. compound recipe oleum fructus bruceae soft capsule, it is characterised in that prepared using following methods：
1）By weight percentage composition ratio weighs Oleum Fructus Bruceae 6-10%, lyophilization Cutis Bufonis superfine powder 65-75%, Cera Flava 12-
20%th, soybean phospholipid 3-6%, ethylparaben 0.2-0.6%, standby；
Described Oleum Fructus Bruceae is prepared using following methods：Fructus Bruceae pulverizing medicinal materials are crossed into 18 mesh sieves, plus petroleum ether merceration extracts 2
It is secondary, extract 8h every time, the consumption of petroleum ether is 12 times of Fructus Bruceae medical material weight, and the Oleum Fructus Bruceae for slightly carrying is passed through nitrogen, 110
DEG C heating 2h, remove unrecovered oil ether, then add Fructus Bruceae medical material weight 5% activated carbon 1 h is heated under the conditions of 100 DEG C, carry out
Desolventing technology, obtains final product Oleum Fructus Bruceae；
Described lyophilization Cutis Bufonis superfine powder is prepared using following methods：Cutis Bufonis micronizing will be dried, its particle diameter is 10-7 μ
m；
2）According to Cera Flava weight be 1g then PEG-4000 consumption for 25-35ml ratio, Cera Flava and soybean phospholipid are melted
In being melted into PEG-4000；Add Oleum Fructus Bruceae, lyophilization Cutis Bufonis superfine powder, ethylparaben to be fully ground
Mix, make that viscosity is moderate, good fluidity medicinal liquid；The temperature of mixed solution is 20 DEG C -40 DEG C；
3）The preparation of capsule material：By weight 3:3:1 ratio weighs water, gelatin, glycerol and pours in glue tank, and temperature first sets during colloidal sol
80 DEG C are set to, start to add water when temperature reaches 55-60 DEG C, added water 10-15 minutes, with handss micro- boiling hot sensation is touched, opened
Begin to add glycerol, stir 2-3 minutes, take 2 times from glue pot bottom, in refunding glue tank, gelatin is added rapidly, mixing time is 1.5-2
Hour, temperature is set as 55-65 DEG C after stirring, stands return-air bubble 7-8 hours；
4）Using pressing make soft capsule, room temperature 20-24 DEG C glue capsule, rubber thickness be 0.6-0.8mm, obtained soft capsule
7-9 hours are cooled down in rotating cage, is come out of steamer, be dried, then wash away capsule surface oil with ethanol, select 30-40 DEG C, dry 8-10
Hour, obtain final product compound recipe oleum fructus bruceae soft capsule.
2. compound recipe oleum fructus bruceae soft capsule as claimed in claim 1, it is characterised in that step 1）In：The content of Oleum Fructus Bruceae is
7-8%。
3. compound recipe oleum fructus bruceae soft capsule as claimed in claim 1, it is characterised in that step 1）In：Lyophilization Cutis Bufonis ultra micro
Powder 68-72%.
4. compound recipe oleum fructus bruceae soft capsule as claimed in claim 1, it is characterised in that step 1）In：Cera Flava 15-18%.
5. compound recipe oleum fructus bruceae soft capsule as claimed in claim 1, it is characterised in that step 1）In：Soybean phospholipid 4-5%.
6. compound recipe oleum fructus bruceae soft capsule as claimed in claim 1, it is characterised in that step 1）In：Ethylparaben
0.3-0.5%。
7. compound recipe oleum fructus bruceae soft capsule as claimed in claim 1, it is characterised in that step 3）In：58 DEG C are reached in temperature
When start to add water, add water 11-13 minutes, plus after gelatin mixing time be 1.6-1.8 hours, temperature is set as 60 after stirring
℃。
8. compound recipe oleum fructus bruceae soft capsule as claimed in claim 1, its feature is in step 4）In：Room temperature 22-23 DEG C glue capsule,
Rubber thickness is 0.7mm.
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| CN1476830A (en) * | 2003-07-17 | 2004-02-25 | 新疆特丰药业股份有限公司 | Tea-polyphenol soft capsule and its preparation process |
| CN102772454A (en) * | 2012-05-31 | 2012-11-14 | 浙江中医药大学 | Brucea javanica oil dry emulsion capsule and preparation method thereof |
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| CN1476830A (en) * | 2003-07-17 | 2004-02-25 | 新疆特丰药业股份有限公司 | Tea-polyphenol soft capsule and its preparation process |
| CN102772454A (en) * | 2012-05-31 | 2012-11-14 | 浙江中医药大学 | Brucea javanica oil dry emulsion capsule and preparation method thereof |
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| Title |
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| 华蟾素联合鸦胆子油乳治疗晚期复发实体肿瘤的临床观察;汪飞等;《铜陵职业技术学院学报》;20130615(第2期);19-20、62 * |
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