Summary of the invention
To the problems referred to above, the application adds preparation after adopting modern preparation new technique with the inclusion essential oil in the quick capsule of compound recipe YINQIAO ammonia again, can guarantee the safe and effective of medicine like this, can increase the stability of volatile ingredient again.
Therefore, the object of the present invention is to provide a kind of compound recipe YINQIAO ammonia phenol capsule.
Be used to realize that the technical scheme of above-mentioned purpose is following:
On the one hand, the present invention provides a kind of compound recipe YINQIAO ammonia quick capsule, and said capsule comprises acetaminophen, chlorphenamine maleate, vitamin C, YINQIAO extractum, Oleum menthae, Forsythia volatile oil, Herba Schizonepetae volatile oil and cyclodextrin.
In the quick capsule of compound recipe YINQIAO ammonia, said cyclodextrin is preferably beta-schardinger dextrin-.
Further preferably, the Oleum menthae in the quick capsule of this compound recipe YINQIAO ammonia, Forsythia volatile oil, Herba Schizonepetae volatile oil and beta-schardinger dextrin-form clathrate.
And the content of this cyclodextrin in the quick Lonicera and Forsythia capsule of compound recipe ammonia is preferably the beta-schardinger dextrin-(β-CD) that contains 15.5~18.9 grams in per 1000.
That is, per 1000 quick Lonicera and Forsythia capsules of compound recipe ammonia comprise: acetaminophen 113g, chlorphenamine maleate 1.13g, Forsythia volatile oil 0.32ml, Oleum menthae 1.16ml, vitamin C 53.23g, YINQIAO extractum 161.3g, Herba Schizonepetae volatile oil 0.24ml, beta-schardinger dextrin-15.5~18.9 grams.Wherein the amount of beta-schardinger dextrin-further is preferably 18.9 grams.
In addition, also comprise acceptable accessories in the quick capsule of above-mentioned compound recipe YINQIAO ammonia; Preferably, said adjuvant is a starch, and content of starch is that per 1000 quick Lonicera and Forsythia capsules of compound recipe ammonia comprise 11.1g-14.5g.
On the other hand, the present invention provides above-mentioned compound recipe YINQIAO ammonia quick capsular method for preparing, and said method comprises the step that makes Oleum menthae, Forsythia volatile oil, Herba Schizonepetae volatile oil and cyclodextrin inclusion compound form clathrate.
Wherein, said cyclodextrin is preferably beta-schardinger dextrin-.
In simple terms, said method comprising the steps of:
1) extracts Forsythia volatile oil and Herba Schizonepetae volatile oil respectively from Fructus Forsythiae, Herba Schizonepetae;
2) the residue medicinal residues behind Fructus Forsythiae, the Herba Schizonepetae extraction volatile oil and Flos Lonicerae, Semen Sojae Preparatum, Herba Lophatheri, Rhizoma Phragmitis, Radix Platycodonis, Radix Glycyrrhizae, the Fructus Arctii of recipe quantity prepare YINQIAO extractum in the employing step 1);
3) measure Forsythia volatile oil, the Herba Schizonepetae volatile oil for preparing in Oleum menthae and the step 1) by prescription, form clathrate with beta-cyclodextrin inclusion compound;
4) get acetaminophen, chlorphenamine maleate, vitamin C, the step 2 of recipe quantity) in the clathrate for preparing in YINQIAO dry extract and the step 3) of preparation and mixing acceptable accessories randomly, moistening, granulation.
Wherein, preferably, Forsythia volatile oil and Herba Schizonepetae volatile oil adopt following operation to extract respectively in the said step 1):
Take by weighing medical material in the prescription ratio, put volatile oil extractor, add water to ormal weight, slowly be heated to and boil, keep little at the appointed time and boil, extract volatile oil, the fluid sealing is preserved.
Said step 2) preferably include:
With Flos Lonicerae, Semen Sojae Preparatum, Herba Lophatheri, Rhizoma Phragmitis, Radix Platycodonis, Radix Glycyrrhizae decocte with water 2 times that Fructus Forsythiae in the step 1), Herba Schizonepetae are extracted residue medicinal residues and recipe quantity behind the volatile oil, amount of water is respectively 7 times of amounts, 5 times of amounts, and each 2 hours, collecting decoction filtered subsequent use; After the Fructus Arctii fragmentation, with 60% ethanol heating extraction 2 times, add amount of alcohol and be respectively 6 times of amounts, 4 times of amounts, each 2 hours, filtrating merged, and reclaimed ethanol, and concentrated solution is subsequent use; Above-mentioned reserve liquid is merged, be concentrated into the extractum of relative density 1.25~1.30 (65~70 ℃), and vacuum drying (0.07Mpa--0.08Mpa) to dry extract, i.e. YINQIAO extractum.
Said step 3) preferably includes:
Measure Forsythia volatile oil, Oleum menthae, Herba Schizonepetae volatile oil by recipe quantity, be mixed into the volatile oil mixed liquor, add an amount of ethanol, be mixed with the volatile oil alcoholic solution of 40%-60% (volume ratio), shake up, sealing, subsequent use; Take by weighing predetermined amount of beta-cyclodextrin and process aqueous solution; Under 56-60 ℃; With 240-250 rev/min mixing speed mix with said volatile oil alcoholic solution, enclose 1-3 hour; Then the suspension that makes is put 2~6 ℃ and descended 24~36 hours, sucking filtration, precipitate were placed 2-6 hour in 40~50 ℃ of baking ovens.
Further preferably, restrain beta-schardinger dextrin-s with 11 in the said step 3): the ratio of 1ml volatile oil mixed liquor takes by weighing beta-schardinger dextrin-and mixes with said volatile oil alcoholic solution.
Preferably, said step 3) comprises:
Measure Forsythia volatile oil, Oleum menthae, Herba Schizonepetae volatile oil by recipe quantity, be mixed into the volatile oil mixed liquor, add an amount of ethanol, be mixed with 50% volatile oil alcoholic solution, shake up, sealing, subsequent use; Restrain beta-schardinger dextrin-s with 11: the ratio of 1ml volatile oil mixed liquor takes by weighing predetermined amount of beta-cyclodextrin; Under 60 ℃, process saturated aqueous solution; Then with said volatile oil alcoholic solution with 240-250 rev/min mixing speed mix, enclose 2 hours; Then with the suspension that makes put 4 ℃ following 36 hours, sucking filtration, precipitate were placed 4 hours in 45 ℃ of baking ovens.
Said step 4) preferably includes:
Take by weighing acetaminophen, chlorphenamine maleate, vitamin C, YINQIAO extractum, volatile oil clathrate compound and an amount of acceptable accessories of recipe quantity, mixing is a wetting agent with 80%-85% ethanol; The system soft material; Cross 14 mesh sieve system wet granulars, 40 ℃ of vacuum dryings 1 hour are crossed 14 mesh sieve granulate; Packing promptly gets.Wherein, said adjuvant is a starch.
Below be detailed description of the present invention:
The quick capsule of compound recipe YINQIAO ammonia used for many years in market sale, and curative effect is clear and definite, did not see the report of untoward reaction so far from listing in 2002.The prescription of this medicine is:
Wherein YINQIAO extractum adopts following prescription and method for making:
Flos Lonicerae 200g Fructus Forsythiae 200g Rhizoma Phragmitis 120g
Radix Platycodonis 120g Herba Lophatheri 80g Herba Schizonepetae 80g
Semen Sojae Preparatum 100g Radix Glycyrrhizae 100g Fructus Arctii 120g
[method for making] Fructus Forsythiae, Herba Schizonepetae are extracted volatile oil respectively, and fluid device is in addition collected subsequent use.Medicinal residues and Flos Lonicerae, Semen Sojae Preparatum, Herba Lophatheri, Rhizoma Phragmitis, Radix Platycodonis, Radix Glycyrrhizae decocte with water 2 times, amount of water is respectively 7 times of amounts, 5 times of amounts, and each 2 hours, collecting decoction filtered subsequent use.After the Fructus Arctii fragmentation, with 60% ethanol heating extraction 2 times, add amount of alcohol and be respectively 6 times of amounts, 4 times of amounts, each 2 hours, filtrating merged, and reclaimed ethanol, and concentrated solution is subsequent use.Above-mentioned reserve liquid is merged, be concentrated into the extractum 360g of relative density 1.25~1.30 (65~70 ℃).Extractum is converted to dry extract and feeds intake after measuring moisture (pressing two appendix VIII of Chinese Pharmacopoeia version in 2000 L).
YINQIAO extractum is added appropriate amount of starch (being generally per 1000 30 grams) as adjuvant; Dry, pulverize, sieve; Add acetaminophen, chlorphenamine maleate mixing, overweight sieve, spray into Forsythia volatile oil, Herba Schizonepetae volatile oil and Oleum menthae then, mixing, packing promptly get.In this production and storage process, the as easy as rolling off a log volatilization loss of Forsythia volatile oil, Herba Schizonepetae volatile oil and Oleum menthae.
To above-mentioned this problem, the invention provides a kind of novel quick capsule of compound recipe YINQIAO ammonia, according to a specific embodiment of the present invention, preparation technology of the present invention may further comprise the steps:
1) Fructus Forsythiae, Herba Schizonepetae are extracted volatile oil respectively, and fluid device is in addition collected subsequent use.This leaching process reference " 2005 editions one appendix XD determination of volatile oil of Chinese pharmacopoeia Division A League Matches of French Football methods (57 pages of appendix) mainly comprise following operation:
Take by weighing medical material in the prescription ratio, put volatile oil extractor, add water to ormal weight, slowly be heated to and boil, keep little at the appointed time and boil, extract volatile oil, the fluid sealing is preserved.
2) with the residue medicinal residues of step 1) and Flos Lonicerae, Semen Sojae Preparatum, Herba Lophatheri, Rhizoma Phragmitis, Radix Platycodonis, Radix Glycyrrhizae decocte with water 2 times, amount of water is respectively 7 times of amounts, 5 times of amounts, and each 2 hours, collecting decoction filtered subsequent use.After the Fructus Arctii fragmentation, with 60% ethanol heating extraction 2 times, add amount of alcohol and be respectively 6 times of amounts, 4 times of amounts, each 2 hours, filtrating merged, and reclaimed ethanol, and concentrated solution is subsequent use.Above-mentioned reserve liquid is merged, be concentrated into the extractum of relative density 1.25~1.30 (65~70 ℃), and vacuum drying (0.07Mpa--0.08Mpa) to dry extract, i.e. YINQIAO extractum.
3) measure Forsythia volatile oil, Herba Schizonepetae volatile oil and the Oleum menthae of step 1) by recipe quantity, mixing becomes the volatile oil mixed liquor to add an amount of ethanol, is mixed with 50% volatile oil alcoholic solution, shake up, and sealing, subsequent use.Take by weighing a certain amount of β-CD (β-CD: volatile oil mixed liquor=11g: 1ml) in suitable quantity of water; 60 ℃ of heating for dissolving become saturated solution, under the mixing speed of 240~250r/min, add a certain amount of 50% volatile oil alcoholic solution, enclose 2 hours; Suspension is put 4 ℃ and was left standstill 36 hours; Sucking filtration, precipitate were placed 4 hours in 45 ℃ of baking ovens, promptly got clathrate.
4) take by weighing acetaminophen, chlorphenamine maleate, vitamin C, the step 2 of recipe quantity) YINQIAO extractum and the volatile oil clathrate compound and the appropriate amount of starch mixing of step 3), be wetting agent with 80% ethanol, the system soft material; Cross 14 mesh sieve system wet granulars; 40 ℃ of vacuum dryings 1 hour are crossed 14 mesh sieve granulate, mixing; Packing promptly gets.
The existing quick capsule of compound recipe YINQIAO ammonia adopts traditional capsule production path of preparing in production technology, comprise that adopting dissolve with ethanol to spray into particulate method the effective ingredient in the prescription-volatile oil adds.Because the intensive volatility of volatile oil; Cause this quasi drugs stability extreme difference, in production and storage process, can't guarantee that owing to the influence of physical factor the long-term stability of volatile oil component exists; When medicine arrived in patient's hands, the volatile oil that plaing induces sweat acts on was almost lost and is made a gift of to the greatest extent.By contrast; The present invention utilizes modern preparation new technique-microcapsule technology in this pharmaceutical production, to be applied, and the volatile oil in the Medicine prescription is processed clathrate (microcapsule) add preparation again, therefore; Compared with prior art, technical scheme of the present invention has following technique effect:
The first, volatile oil (Herba Schizonepetae volatile oil, Forsythia volatile oil, Oleum menthae) poorly water-soluble, unstable in air, volatile and oxidation.Volatile oil and beta-schardinger dextrin-are carried out enclose, can improve the water solublity of volatile oil, can prevent volatile oils and oxidation again, strengthened the stability of volatile ingredient, thereby in preparation, guarantee the accurate of prescription, guarantee the curative effect of this medicine;
The second, therefore the clathration of beta-schardinger dextrin-is very easy to liquid medicine composition powdered the preparation process, and significantly improves the stability of medicine;
Three, the quick capsule of compound recipe YINQIAO ammonia that contains clathrate is compared with the quick capsule of traditional compound recipe YINQIAO ammonia, and its production technology link does not have too big variation, through existing workshop being adjusted accordingly and being increased equipment component and adjuvant can satisfy the production needs.
The specific embodiment
Below in conjunction with the specific embodiment the present invention is further described in detail, the embodiment that provides has been merely and has illustrated the present invention, rather than in order to limit scope of the present invention.
Experimental technique among the following embodiment like no specified otherwise, is conventional method.Used test material among the following embodiment like no specified otherwise, is to buy from routine biochemistry reagent shop and obtains.The part instrument and the reagent situation that wherein adopt among the embodiment are:
Instrument:
DZF-6090 vacuum drying oven (Shanghai Yiheng Scientific Instruments Co., Ltd);
DHG-9070A type electric drying oven with forced convection (Shanghai Yiheng Scientific Instruments Co., Ltd);
Electronic analytical balance (BS110S, Beijing Sai Duolisi company limited);
UV2550 ultraviolet-uisible spectrophotometer (day island proper Tianjin);
Volatile oil extractor, Agitation Tank (model PYG, Nanjing China star pharmaceutical equipment company limited);
Low-temperature vacuum drying baking oven (model ZDF-15, Feilong Pharmaceutical Machinery Equipment Factory, Nanjing);
Heated-air circulation oven (model GT-G-II, Feilong Pharmaceutical Machinery Equipment Factory, Nanjing);
Vacuum pump (2XZ-0.5, Huangyan, Zhejiang real company limited at dawn);
Trough type mixing machine (CH-150, Feilong Pharmaceutical Machinery Equipment Factory, Nanjing);
Oscillating granulator (YK-160, Feilong Pharmaceutical Machinery Equipment Factory, Nanjing);
Three-dimensional swing mixer (SBH-600, Feilong Pharmaceutical Machinery Equipment Factory, Nanjing);
Autocapsulefillingmachine (GM2, Feilong Pharmaceutical Machinery Equipment Factory, Nanjing);
Capsule buffing machine (JPJ-1, Ruian Fuchang Pharmaceutical Machinery Co., Ltd.);
Aluminium-coating Packer (DPT130A, Jinzhou ten thousand logical packer factories).
Reagent:
β-CD (Guangzhou province Yunan County cyclodextrin factory; Purity>98%); Dehydrated alcohol, sodium chloride are analytical pure, Forsythia volatile oil (carrying certainly), Oleum menthae (Mount Huang Tianmu medicine company company limited), Herba Schizonepetae volatile oil (carrying certainly).
Embodiment 1: the extraction of Forsythia volatile oil and Herba Schizonepetae volatile oil
Adopt following operation to extract Forsythia volatile oil and Herba Schizonepetae volatile oil respectively:
Take by weighing medical material in the prescription ratio, put volatile oil extractor, add water to ormal weight, slowly be heated to and boil, keep little at the appointed time and boil, extract volatile oil, the fluid sealing is preserved.
Forsythia volatile oil that extracts and Herba Schizonepetae volatile oil are mixed formation mixed volatilization oil with Oleum menthae.
1, the density measurement of mixed volatilization oil
Precision is measured each 3 parts of mixed volatilization oil 10ml, micrometric measurement weight again, and be calculated as follows the density of volatile oil at room temperature, measure the result and see table 1.
Table 1 volatile oil density measurement result
2, determination of recovery rates
The accurate 5ml mixed volatilization oil of drawing is in flask; Add the 200ml distilled water, connect volatile oil extractor, by " 2005 editions one appendix XD determination of volatile oil of Chinese pharmacopoeia Division A League Matches of French Football methods (57 pages of appendix) were extracted volatile oil 4 hours;, oil mass stops heating when no longer increasing; Place and read the volatilization oil mass after 1 hour, computational methods are formula as follows, and the result sees table 2.
Table 2 determination of recovery rates result
Embodiment 2: the enclose of volatile oil mixed liquor and beta-schardinger dextrin-
50% volatile oil alcoholic solution in the present embodiment adopts following method preparation: the Forsythia volatile oil of the recipe quantity of preparation and the Oleum menthae of Herba Schizonepetae volatile oil and recipe quantity are processed the volatile oil mixed liquor among the accurate embodiment 1 of absorption; A certain amount of volatile oil mixed liquor is placed volumetric flask, add an amount of dehydrated alcohol, standardize solution; Be mixed with 50% volatile oil alcoholic solution; Shake up, sealing, subsequent use.
The enclose of volatile oil mixed liquor and beta-schardinger dextrin-is taked following method preparation: adopt saturated water solution method, take by weighing a certain amount of β-CD in suitable quantity of water, heating for dissolving is cooled to corresponding temperature in water-bath, process saturated solution; In this saturated solution, adding a certain amount of 50% volatile oil alcoholic solution under certain mixing speed, enclose was placed 24 hours in the refrigerator at a certain temperature; Sucking filtration; Filtering residue was placed 4 hours to 45 ℃ of baking ovens with the about 20ml washing of petroleum ether (30-60 ℃) for several times, promptly got.β-CD wherein: the ratio of volatile oil mixed liquor, mixing speed and enclose temperature are carried out according to the data that provide in the following table 3.
Volatile oil in the clathrate is carried out oil utilization to be measured: dry clathrate thing precision is weighed; Place the flask that is placed with zeolite; Add the 200ml distilled water, connect volatile oil extractor, by " 2005 editions one appendix XD determination of volatile oil of Chinese pharmacopoeia Division A League Matches of French Football methods (57 pages of appendix) were extracted volatile oil 4 hours; When oil mass no longer increases, stop heating, place and read the volatilization oil mass after 1 hour.
With envelop rate, clathrate yield is that index combines the comprehensive grading method that the clathrate that obtains under the different enclose parameters is investigated, and wherein envelop rate accounted for 80 fens, and the clathrate yield accounted for 20 fens, and total points is 100 minutes, and computational methods are following:
Comprehensive grading (branch)=envelop rate * 80+ clathrate yield * 20
Table 3 even test factor level table
Annotate: X
1(g/ml) be β-CD: volatile oil mixed liquor, X
2For temperature (℃), X
3Be mixing speed (r/min).
Select U for use according to the factor level table
6(6
3) formulate testing program, and measure the envelop rate and the clathrate yield of clathrate, the result sees table 4.
Table 4U
6(6
3) uniform experiment design scheme (n=6)
Adopt Shenyang Pharmaceutical University's uniform Design program progressively to return the result of the test that obtains, get following equation:
Y (total points)=0.4066+2.5032X
2-0.0211X
2 2+ 0.00001X
3 2+ 0.0024X
1X
3
Coefficient of multiple correlation R
2=0.9992, S=0.9817, F=147.6354, equation is (P<0.1) significantly.
Getting optimal conditions through the program analysis match is: X
1(ratio)=10.9 (g/ml); X
2(temperature)=59.3 (℃); X
3(mixing speed)=999.9 (r/min); The theoretical prediction interval of total points is 104.4-108.1.
Thereby the selection process of volatile oil and β-CDBao He is in definite quick capsule of compound recipe YINQIAO ammonia: the enclose ratio of β-CD and volatile oil mixed liquor is 11g: 1ml, and the enclose temperature is 60 ℃, and the enclose mixing speed is 1000r/min, and mixing time is 1 hour.
Demonstration test:
Get three parts of each 1ml of volatile oil mixed liquor that prepare in the present embodiment, prepare clathrate by the optimal preparation technology condition, measure each index and estimate, the result sees table 5.
Table 5 clathrate demonstration test result
The meansigma methods of the total points of three parts of volatile oil clathrate compounds is: 95.79 ± 1.90, and RSD (%)=1.97.
Embodiment 3: the enclose of volatile oil mixed liquor and hydroxypropyl (HP-beta-schardinger dextrin-)
Adopt the method for embodiment 2 to prepare 50% volatile oil alcoholic solution, subsequent use.
The enclose of volatile oil mixed liquor and HP-beta-schardinger dextrin-adopts following method preparation: adopt aqua-solution method; Take by weighing certain amount of H P-β-CD in suitable quantity of water by the EXPERIMENTAL DESIGN scheme; Heating for dissolving; Under certain mixing speed, add a certain amount of 50% volatile oil alcoholic solution, enclose at a certain temperature.Reduction vaporization was placed 4 hours to 45 ℃ of baking ovens, promptly obtained solid clathrate.HP-β-CD wherein: the ratio of volatile oil mixed liquor, mixing speed and enclose temperature are carried out according to the data that provide in the following table 6.
Adopt the method for embodiment 2 that the volatile oil in the clathrate is carried out oil utilization mensuration.
Identical with embodiment 2, the clathrate that obtains is carried out the investigation of envelop rate, clathrate yield etc.
Table 6 even test factor level table
Annotate: X
1(g/ml) be HP-β-CD: volatile oil mixed liquor, X
2For temperature (℃), X
3Be mixing speed (r/min).
Select U for use according to the factor level table
6(6
3) formulate testing program, and measure the envelop rate and the clathrate yield of clathrate, the result sees table 7.
Table 7U
6(6
3) uniform experiment design scheme (n=6)
Adopt Shenyang Pharmaceutical University's uniform Design program progressively to return the result of the test that obtains, get following equation:
Y (total points)=0.5138+2.2517X
2-0.0268X
2 2+ 0.000006X
3 2+ 0.00235X
1X
3
Coefficient of multiple correlation R
2=0.8993, S=0.8087, F=161.72, equation is (P<0.1) significantly.
Getting optimal conditions through the program analysis match is: X
1(ratio)=24.8 (g/ml); X
2(temperature)=47.6 (℃); X
3(mixing speed)=958.6 (r/min); The theoretical prediction interval of total points is 95.8-102.4.
Confirm that selection process is: HP-β-CD addition is 25 times of volatilization oil mass, and temperature is 50 ℃, and mixing speed is 1000r/min, and mixing time is 1 hour.
Demonstration test:
Get three parts of each 1ml of volatile oil mixed liquor that prepare in the present embodiment, prepare clathrate by the optimal preparation technology condition, measure each index and estimate, the result sees table 8.
Table 8 clathrate demonstration test result
The meansigma methods of the total points of three parts of volatile oil clathrate compounds is: 95.9 ± 1.52, and RSD (%)=1.59.
The comparison of β-CD and HP-beta-CD inclusion and selection:
(1) two kind of material can the enclose target product the volatile oil mixed liquor, according to experiment, the optimum amount of β-CD is 11 times, the optimum amount of HP-β-CD is 25 times, the two differs 2.27 times, visible HP-β-CD large usage quantity.
(2) β-CD can use saturated water solution method, can adopt cold preservation to separate out clathrate according to variation of temperature, and sucking filtration is drying to obtain, and technology and instrument and equipment are comparatively simple; And the water solublity of HP-β-CD is strong; Can not separate out solid, can not prepare the HP-beta-CD inclusion, need with methods such as lyophilization, reduction vaporization or spray dryinges except that desolvating with saturated water solution method along with the reduction of temperature; Just can obtain solid clathrate, technology and instrument and equipment are comparatively complicated.
(3) β-CD is sophisticated, the most frequently used enclose material, and the application of HP-β-CD is used for breadboard application at present more, is used for the also rare of bulk article.
(4) β-CD is the pharmaceutic adjuvant on the NF, and HP-β-CD arrives till this experiment, also is not put into the NF catalogue.
(5) contrast from Technological Economy, the price of β-CD is far below the price of HP-β-CD, and the production cost is lower.
In sum, with regard to this target product,, confirm to select the enclose material of β-CD as this product according to above experiment.
Embodiment 4: the clathrate checking that volatile oil of the present invention and beta-schardinger dextrin-form
1, ultraviolet chromatography (UV)
Get an amount of volatile oil mixed liquor (mixed liquor of Forsythia volatile oil, Herba Schizonepetae volatile oil and Oleum menthae respectively; Be " miscella " among Fig. 2), physical mixture (physical mixture of volatile oil mixed liquor and beta-schardinger dextrin-), clathrate (adopting the volatile oil mixed liquor of the inventive method preparation and the clathrate of beta-schardinger dextrin-), it is an amount of to add petroleum ether, close plug; Jolting number minute; Placed 30 minutes, and filtered, filtrating is as need testing solution (volatile oil concentration is 0.25 μ l/ml).In wavelength is that 200-350nm carries out uv absorption scanning, and the result sees Fig. 2.
Visible by Fig. 2, volatile oil is consistent with the characteristic ultraviolet absorption of miscella in the physical mixture, and the clathrate sample does not then have the volatile oil characteristic ultraviolet absorption, and the enclose success is described.
2, thin layer chromatography (TLC)
Get volatile oil mixed liquor (being " miscella " among Fig. 3) 0.08ml, 0.8g physical mixture, 0.08g clathrate respectively, add the 100ml petroleum ether separately, close plug, jolting number minute was placed 30 minutes, filtered, and filtrating is as need testing solution.According to thin layer chromatography (" 2005 editions appendix VIB of Chinese pharmacopoeia) test, draw above-mentioned need testing solution 10 μ l, put respectively on same silica gel g thin-layer plate; With benzene-ethyl acetate (19: 1) is developing solvent; Launch, take out, dry; Spray is with the mixed liquor of vanillin sulphuric acid test solution-ethanol (1: 4), and it is clear to be heated to the speckle colour developing at 100 ℃.
Visible by Fig. 3, the speckle of apparent same color on the relevant position of volatile oil and miscella in the physical mixture, the clathrate sample does not then have this color speckle, and the enclose success is described.
Embodiment 5: the amplification process study of clathrate of the present invention
In the GMP workshop, carry out pilot scale and amplify production, concrete operations are:
Measure Forsythia volatile oil 32ml, Oleum menthae 116ml, Herba Schizonepetae volatile oil 24ml by recipe quantity, mixing adds an amount of dehydrated alcohol, is mixed with 50% volatile oil alcoholic solution, shake up, and sealing, subsequent use.Take by weighing 1.9Kg β-CD in 21L water, 60 ℃ of heating for dissolving become saturated solution (dissolubility is 9g/100ml in the β-CD60 ℃ of water) in Agitation Tank, carry out enclose by table 8 condition; 4 ℃ staticly settle; Sucking filtration, filtering residue were placed 5 hours in 45 ℃ of baking ovens, promptly got clathrate.Amplify the production result of study and see table 9.
Embodiment 6: quick capsule of novel compound YINQIAO ammonia of the present invention and the quick capsular stable comparative test of traditional compound recipe YINQIAO ammonia
1, the study on the stability of clathrate
Get lot number among the embodiment 5 and be three batches of clathrates of 20100902,20100903,20100904, carry out study on the stability.
Condition: 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5%;
Testing result sees the following form 10.
Table 10 clathrate stability is measured the result
, explain and adopt clathrate process can improve volatile oil stability it is thus clear that after testing through high temperature, significant change does not take place the sample volatile oil content by last table data, prolonged the volatile oil retention time.
2, the capsular stability of the present invention
According to Fig. 1, prepare the quick capsule analog sample of novel YINQIAO compound recipe ammonia of the present invention:
Take by weighing Fructus Forsythiae and Herba Schizonepetae in the prescription ratio, put volatile oil extractor, add water to ormal weight, slowly be heated to and boil, keep little at the appointed time and boil, extract volatile oil, the fluid sealing is preserved.
Get Flos Lonicerae, Semen Sojae Preparatum, Herba Lophatheri, Rhizoma Phragmitis, Radix Platycodonis, Radix Glycyrrhizae decocte with water 2 times that Fructus Forsythiae, Herba Schizonepetae extract residue medicinal residues and recipe quantity behind the volatile oil, amount of water is respectively 7 times of amounts, 5 times of amounts, and each 2 hours, collecting decoction filtered subsequent use; After the Fructus Arctii fragmentation, with 60% ethanol heating extraction 2 times, add amount of alcohol and be respectively 6 times of amounts, 4 times of amounts, each 2 hours, filtrating merged, and reclaimed ethanol, and concentrated solution is subsequent use; Above-mentioned reserve liquid is merged, be concentrated into the extractum of relative density 1.25~1.30 (65~70 ℃), and vacuum drying (0.07Mpa--0.08Mpa) to dry extract, i.e. YINQIAO extractum;
Measure Forsythia volatile oil, Oleum menthae, Herba Schizonepetae volatile oil by recipe quantity, be mixed into the volatile oil mixed liquor, add an amount of ethanol, be mixed with 50% volatile oil alcoholic solution, shake up, sealing, subsequent use; Restrain beta-schardinger dextrin-s with 11: the ratio of 1ml volatile oil mixed liquor takes by weighing predetermined amount of beta-cyclodextrin; Under 60 ℃, process saturated aqueous solution; Then with said volatile oil alcoholic solution with 240-250 rev/min mixing speed mix, enclose 2 hours; Then with the suspension that makes put 4 ℃ following 36 hours, sucking filtration, precipitate were placed 4 hours in 45 ℃ of baking ovens;
Take by weighing acetaminophen, chlorphenamine maleate, vitamin C, YINQIAO extractum, volatile oil clathrate compound and an amount of acceptable accessories mixing of recipe quantity; With 80% ethanol is wetting agent; The system soft material was crossed 14 mesh sieve system wet granulars, in 40 ℃ of dryings 1 hour; Cross 14 mesh sieve granulate, promptly get.
With reference to the new drug approval requirement, investigate the influence of high temperature to analog sample stability.
Delivery is intended sample; Simulation listing packing; In the condition held of temperature (25 ± 2 ℃), relative humidity (60 ± 10%), placed 10 days different time sampling at interval respectively at 40 ℃, 60 ℃ calorstats; By " 2005 editions one appendix XD determination of volatile oil of Chinese pharmacopoeia Division A League Matches of French Football methods (57 pages of appendix) are measured volatile oil, measure the result and see table 11.
Table 11 clathrate is to the influence (ml/100g sample) of volatile oil stability
Test through high temperature under the dummy packages condition by table 11 is visible, significant change does not take place in the sample volatile oil content.
Enchashment listing packing sample is in the temperature conditions held of room temperature, respectively at sampling in 0 month, 1 month, 3 months, by " 2005 editions one appendix XD determination of volatile oil of Chinese pharmacopoeia Division A League Matches of French Football methods (57 pages of appendix) are measured volatile oil, measure the result and see table 12.
The mensuration (ml/100g sample) of volatile oil stability in the quick capsule of the existing listing packing compound recipe YINQIAO ammonia of table 12
By the visible existing listing packing of table 12 sample, place certain hour at ambient temperature after, sample volatile oil content generation significant change.
According to the result contrast of table 11 with table 12, can see volatile oil poor stability in the capsule that the listing packing occurs, capsule stability of the present invention is good, explains and adopts clathrate process can improve volatile oil stability, has prolonged the volatile oil retention time.