CN109331175A - A kind of sublingual film of spearhead haemocoagulase and preparation method thereof - Google Patents
A kind of sublingual film of spearhead haemocoagulase and preparation method thereof Download PDFInfo
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Abstract
A kind of sublingual film of spearhead haemocoagulase of the present invention and preparation method thereof, belongs to pharmaceutical preparations technology field.The sublingual film of spearhead haemocoagulase is prepared by following raw materials according: spearhead haemocoagulase, PVA05-88, PEG-400, hydroxypropyl-β-cyclodextrin borneol inclusion compound and purified water.Preparation method includes: in the purified water for being added to PVA05-88, and magnetic agitation makes evenly dispersed and is sufficiently swollen, and is cooled to room temperature to it, spare；Sequentially add surplus stock into above-mentioned solution, be sufficiently stirred, settled process sloughs bubble, in pressing 40~60 μ m thick films on film applicator, ventilation, after 25 DEG C of drying at room temperature of shady place to get the sublingual film of spearhead haemocoagulase.The invention has the following advantages that can achieve the purpose that quick acting quickly by buccal absorption；First aid haemostatic medicament that is oral not need water, being carried particularly suitable as individual soldier.
Description
Technical field
The invention belongs to pharmaceutical preparations technology fields, and in particular to a kind of sublingual film of spearhead haemocoagulase and its preparation side
Method.
Background technique
Spearhead haemocoagulase (HemocoagulaseBothropsAtrox) is hemostatic, can be widely used for that stream need to be reduced
Blood or the various medical conditions of hemostasis, such as the bleeding and hemorrhagic disease of clinical departments room；It can also be used to prevention bleeding, such as perform the operation
Preceding medication can avoid or reduce operative site and postoperative hemorrhage.
The spearhead haemocoagulase clinically used at present is freeze drying powder injection.Faced based on injection spearhead haemocoagulase
Good haemostatic effect on bed is chosen as the medical first aid drug of battlefield quick-acting haemostatic powder.However as injection, make in flight
Under war and airborne operation task specific condition, combatant possibly can not voluntarily be used, and influence the first aid and work capacity of the wounded.
Spearhead haemocoagulase has been recorded in 2015 editions the first enlarged editions of Chinese Pharmacopoeia, and approved injection in China's is raw
It produces.
Summary of the invention
Sublingual film is a kind of novel oral preparation.This product not only can reach quick acting quickly by buccal absorption
Purpose, and can to avoid the first pass effect of liver, improve drug bioavailability.In addition, sublingual film is oral not to need water,
The first aid haemostatic medicament carried particularly suitable as individual soldier.Currently without develop spearhead haemocoagulase pelliculae pro cavo oris pharmaceutical factory and
Company, of the invention succeeding in developing can provide a kind of safe and efficient, convenient drug administration hemostatic to patient.
It is an object of the invention to disclose a kind of sublingual film of spearhead haemocoagulase.
Second object of the present invention is to disclose the preparation method of the above-mentioned sublingual film of spearhead haemocoagulase.
The purpose of the present invention is what is be achieved through the following technical solutions:
A kind of sublingual film of spearhead haemocoagulase, wherein sublingual film 1000 of the spearhead haemocoagulase is by following original
Material is prepared: 2000U spearhead haemocoagulase, 16gPVA05-88,8gPEG-400,8g hydroxypropyl-β-cyclodextrin borneol packet
Close object and 240ml purified water.
A kind of preparation method of the sublingual film of spearhead haemocoagulase, includes the following steps:
(1), the following raw material is weighed by 1000 sublingual films of spearhead haemocoagulase of preparation: 2000U spearhead haemocoagulase,
16gPVA05-88,8gPEG-400,8g hydroxypropyl-β-cyclodextrin borneol inclusion compound and 240ml purified water；
(2), 16gPVA05-88 is added to 50 DEG C, in the purified water of 240ml, magnetic agitation makes evenly dispersed and abundant
Swelling, is cooled to room temperature to it, spare；
(3), 2000U spearhead haemocoagulase, 8gPEG-400,8g hydroxypropyl are sequentially added into the solution of step (2)
Group-beta-cyclodextrin borneol inclusion compound, being sufficiently stirred keeps its evenly dispersed, sloughs bubble using settled process after system is uniform, so
Afterwards in pressing 40~60 μ m thick films on film applicator, ventilation, after 25 DEG C of drying at room temperature of shady place to get spearhead haemocoagulase tongue
Lower film.
Preparation method described in above-mentioned technical proposal, wherein in step (3) on film applicator press 60 μ m thick films.
Preparation method described in above-mentioned technical proposal prepares the resulting sublingual film of spearhead haemocoagulase.
The sublingual film of spearhead haemocoagulase of above-mentioned technical proposal, in which: the sublingual film of spearhead haemocoagulase
With a thickness of 40~60 μm.
The sublingual film of spearhead haemocoagulase according to claim 5, in which: the spearhead haemocoagulase is sublingual
Film with a thickness of 60 μm
The sublingual film of spearhead haemocoagulase described in above-mentioned technical proposal, wherein the spearhead haemocoagulase is sublingual
The specification of film is 2cm × 2cm.
The invention has the following advantages:
1, the method for the present invention prepares the resulting sublingual film of spearhead haemocoagulase, using hydroxypropyl-β-cyclodextrin borneol packet
Object is closed to promote thoroughly, to achieve the purpose that quick acting quickly by buccal absorption；It simultaneously can be to avoid the destruction of Oral Gastrointestinal Tract
With the first pass effect of liver, drug bioavailability is improved.
2, the method for the present invention prepares the resulting sublingual film of spearhead haemocoagulase, oral not need water, particularly suitable as
The first aid haemostatic medicament that individual soldier carries.
3, the method for the present invention prepares the resulting sublingual film of spearhead haemocoagulase, not with other drugs, diet and beverage
It is equal to interact, simple and effective selection is provided for clinical application.
Specific embodiment:
In order to make the technical solution of the present invention easy to understand, below in conjunction with specific test example to a kind of spearhead pallas pit viper blood of the present invention
Solidifying sublingual film of enzyme and preparation method thereof is further described.
Embodiment 1:The preparation method of the sublingual film of spearhead haemocoagulase:
One, preparation prescription forms:
Each content of material weighs raw material in preparation prescription by table 1.
1 preparation prescription of table
Two, preparation process:
Using solution casting method:
(1), 16g PVA05-88 is added to 50 DEG C, in the purified water of 240ml, magnetic agitation makes evenly dispersed and abundant
Swelling, is cooled to room temperature to it.
(2), 2000U spearhead haemocoagulase, 8gPEG-400,8g hydroxypropyl are sequentially added into the solution of step (1)
Group-beta-cyclodextrin borneol inclusion compound, being sufficiently stirred keeps its evenly dispersed, sloughs bubble using settled process after system is uniform, so
Afterwards in pressing 60 μ m thick films on film applicator, divulges information, is sublingual to get spearhead haemocoagulase after 25 DEG C of drying at room temperature of shady place
Film.
It prepares the resulting sublingual film of spearhead haemocoagulase and is cut to 2cm × 2cm specification size and packed, in case subsequent
It uses.
Below by way of specific test example come the prescription screening to the sublingual film of invention spearhead haemocoagulase, pharmaceutical properties and
Beneficial effect is further described.
Test example 1:Prescription and craft screening:
One, prescription screening:
(1), the screening of filmogen:
Filmogen should have a nontoxicity, nonirritant, odorless, and property is stablized, and does not influence main ingredient drug effect, have well at
Film property and demoulding, moderate pliability and certain tensile strength again after film forming, and can be disintegrated rapidly, dissolve and release the drug.
(1), hypromellose (HPMC):
HPMC is one of filmogen commonly used at present, for the powdery granule of white odorless, tasteless, can be dissolved in water,
And do not influenced in water by pH value, it is swelled into colloidal solution in cold water, there is thermal gels property, dissolve, have again after cooling
Good film forming and adhesiveness.HPMC is divided from low to high by viscosity HPMC-E3, HPMC-E5, HPMC-E15, HPMC-
E30, HPMC-E50 equal-specification, solubility change with the difference of viscosity, its performance of the HPMC of different size has certain difference
It is different.Pre-stage test shows that HPMC-E15, HPMC-E30 filming performance are preferable.
(2), polyvinyl alcohol (PVA05-88):
PVA05-88 is white plates or powdered solid, has good water-soluble, film forming, non-toxic and tasteless, nothing
Irritation is widely used in pharmaceutical carrier.Solution temperature is 50~55 DEG C, and the aqueous solution after swelling is complete at this temperature is at normal temperature
Very stable, possible transition is gel under lower temperature, but one heated is easy for becoming solution.PVA easily forms a film, the film of formation
Colorless and transparent, any surface finish has good mechanical strength without tacky.
Filmogen screening technique is as follows:
Tri- kinds of filmogens of HPMC-E15, HPMC-E30 and PVA05-88 are tested by the following method respectively: will
0.8g filmogen is added 50 DEG C, in the purified water of 12ml, and magnetic agitation makes evenly dispersed and is sufficiently swollen, and is cooled to room to it
100U spearhead haemocoagulase is added in temperature, and 0.4g hydroxypropyl-β-cyclodextrin borneol inclusion compound, 0.4gPEG400, being sufficiently stirred makes
It is evenly dispersed, it stands degassing and drains bubble, in film applicator film, film is cut into 2cm × 2cm size by naturally dry rear demoulding.
Experimental result is shown in Table shown in 2:
The film-formation result of the different filmogens of table 2
Experiment conclusion: PVA05-88 is good compared with HPMC at film toughness, and disintegration faster, therefore selects PVA05-88 for spearhead pallas pit viper blood
The filmogen of the solidifying sublingual film of enzyme.
(2), the screening of plasticizer:
Plasticizer can reduce the glass transition temperature of film, to reduce the tensile strength of film, increase stretching for film
Long rate is conducive to the packing cutting of film so as to improve the mechanical performance of film.The plasticizer of the sublingual film of spearhead haemocoagulase
It screens as follows:
(1), PEG400:
For colourless or almost colourless thick liquid；Slightly special smell.It is to have fine deliquescent plasticizer.
(2), propylene glycol:
It is almost tasteless for colourless viscous liquid, it carefully hears slightly sweet.It can be used as plasticizer, increase the flexibility of film.
(3), glycerol:
To be colourless, odorless, sweet, the clear and bright thick liquid of appearance.It can be used as plasticizer, increase the flexibility of film.
Three kinds of plasticizer are tested in accordance with the following methods: 0.8g PVA05-88 is added to the purified water of 50 DEG C, 12ml
In, magnetic agitation makes evenly dispersed and is sufficiently swollen, and is cooled to room temperature to it, 100U spearhead haemocoagulase, 0.4g hydroxyl is added
Propyl-beta-cyclodextrin borneol inclusion compound is added 0.4g plasticizer, stirs, and stands degassing and drains bubble, in film applicator
Film is cut into 2cm × 2cm size by film, naturally dry rear demoulding.
Experimental result is shown in Table shown in 3:
The plasticization effect of the different plasticizer of table 3
| Plasticizer | PEG400 | Propylene glycol | Glycerol |
| Experimental phenomena | Easy demoulding, it is flexible | It is sticky strong, difficult demoulding | It is sticky strong, difficult demoulding |
Experiment conclusion: compared with propylene glycol and glycerol, PEG400 is easy to demoulding, and flexibility is good, therefore selection PEG400 is
The plasticizer of the sublingual film of spearhead haemocoagulase.
Two, prescription and optimum preparation condition:
(1), formulation optimization:
Because spearhead haemocoagulase is large biological molecule, therefore this experiment Formulation reduces the type of auxiliary material to the greatest extent, in advance
After experiment sieving filmogen and plasticizer, obtained film filming performance is good, easy demoulding.Therefore it drafts in the prescription of film and containing only
Filmogen and plasticizer.The best ratio of filmogen and plasticizer is screened as index using the filming performance of film, disintegration time
Example, preferably sublingual film of good performance out.
The measurement of disintegration time: the relevant regulations of aglossate lower film in 2015 editions " Chinese Pharmacopoeia " four, therefore, according to 2015
Disintegration time limit test (general rule 0921) under version " Chinese Pharmacopoeia " four tablet items is measured.Take the medicine of 6 2cm × 2cm
Film is respectively put into 6 hanging baskets, is started timing when contacting water with film, is recorded the disintegration time of every film.
Experimental design: according to prescription screening as a result, carrying out 4:1,4:2 to filmogen PVA05-88 and plasticizer P EG400
With the screening of tri- kinds of ratios of 4:3.
Experimental result is shown in Table shown in 4:
4 filmogen of table and plasticizer consumption ratio optimization result
Experiment conclusion: from the point of view of disintegration time, 4:2 and 4:3 are more excellent；But from the point of view of filming performance result, 4:2 is best
Ratio.Comprehensively consider, final choice filmogen PVA05-88 and plasticizer P EG400 ratio are 4:2.
(2), the optimization of film thickness:
The size of the fixed sublingual film of spearhead haemocoagulase is 2cm × 2cm.
The sublingual film of spearhead haemocoagulase is prepared using the prescription tentatively optimized, using filming performance, disintegration time as index,
Different thickness are set by film applicator to optimize to the thickness of film.
Experimental result is shown in Table shown in 5
5 film thickness optimum results of table
Experiment conclusion: demoulding is good when the thickness of the sublingual film of spearhead haemocoagulase is set to 40~60 μm, disintegration time
It is suitable for.
(3), the optimization of film drying condition:
Spearhead haemocoagulase is large biological molecule, for the activity for keeping enzyme, high temperature drying is unsuitable for after film, using logical
25 DEG C of wind, shady place drying at room temperature, film formation time 5h or so, film outward appearance variation without exception.Therefore it is spearhead haemocoagulase is sublingual
The drying condition of film is set to 25 DEG C of ventilation, shady place drying at room temperature.
(4), prescription is verified:
Best prescription: being added 50 DEG C, in the purified water of 12ml for 0.8g PVA05-88, magnetic agitation make it is evenly dispersed simultaneously
Sufficiently swelling is cooled to room temperature to it, is added 100U spearhead haemocoagulase, 0.4g hydroxypropyl-β-cyclodextrin borneol inclusion compound,
0.4gPEG-400, being sufficiently stirred makes evenly dispersed, bubble is sloughed using settled process after system is uniform, then on film applicator
By 60 μ m thick films, divulges information, after 25 DEG C of drying at room temperature of shady place, the sublingual film of spearhead haemocoagulase is made, film is cut into
2cm × 2cm size.
Three batches of samples are prepared by best prescription, carry out prescription verifying.
Experimental result is shown in Table 6:
The experimental result of 6 best prescription of table
| Batch | Flexibility | Disintegration time (s) |
| 1 | It is good | 23.64±0.72 |
| 2 | It is good | 24.17±0.85 |
| 3 | It is good | 24.21±0.37 |
Three, effect of each auxiliary material in prescription:
1, PVA05-88: filmogen has good film forming, water solubility.The film that it is prepared is colorless and transparent, has good
Mechanical property.
2, PEG400: plasticizer enhances the flexibility and stretch-resistance of film, improves the filming performance of film.
Test example 2:The enzyme activity determination of spearhead haemocoagulase in the sublingual film of spearhead haemocoagulase:
According to injection spearhead haemocoagulase quality standard WS1The enzyme activity of titration in (X-030) -2014Z is surveyed
Determine method to be measured spearhead haemocoagulase enzyme activity in the sublingual film of spearhead haemocoagulase made from embodiment 1.
1, instrument and reagent:
Coagulo meter (Coatron M4)；Blood coagulation Quality Control blood plasma (MDC, 047B-E139A)；Spearhead haemocoagulase work mark
Quasi- product (130416,100U/ branch).
2, the preparation of solution:
(1), the preparation of standard solution: taking spearhead haemocoagulase standard items (for bioactivity), adds water 1ml to make molten
It solves and dilutes and be made in every 1ml respectively containing 0.2,0.5,1.0,2.0,3.0 unit solution.
(2), the preparation of test solution: taking the sublingual film of spearhead haemocoagulase 20, accurately weighed, shreds, and precision claims
It takes film fragment appropriate (being approximately equivalent to spearhead haemocoagulase 2U), sets in 1ml brown volumetric flask, water is added to be settled to scale, dissolve
And it dilutes and is made in every 1ml containing about the solution of 2.0 units to get spearhead haemocoagulase test solution.
3, measuring method: taking blood coagulation Quality Control blood plasma, (blood coagulation Quality Control blood plasma is put to room temperature, every plus water 2.0ml, places 15 points
Clock, during which between or jog, is gently shaken up using preceding every time) 0.1ml, be separately added into juxtaposition blood coagulation analyzer test section in coupon
, it is preheated 2 minutes under the conditions of 37 ± 0.5 DEG C, precision measures each 0.2ml of standard solution of series of concentrations, is rapidly added above-mentioned
In each coupon, record setting time, every kind concentration replication 4 times, calculate average value (4 measurement maxima and minimas
Difference must not exceed the 10% of average value, otherwise resurvey).Using the logarithm of standard solution concentration as abscissa, setting time pair
Number is that ordinate calculates equation of linear regression (related coefficient should be greater than 0.99).
Test solution is taken, is measured according to upper method, according to regression equation calculation enzyme activity unit.The results are shown in Table 7, this product
Every haemocoagulase containing spearhead should be the 90.0%~110.0% of labelled amount (2U/ piece).
The enzyme activity determination result of 7 three batches of sample spearhead haemocoagulases of table
| Batch | Enzyme activity (U/ piece) |
| 1 | 2.03±0.04 |
| 2 | 1.99±0.02 |
| 3 | 2.03±0.02 |
Test example 3:Uniformity of dosage units:
It is checked by Content uniformity test (general rule 0941) under " Chinese Pharmacopoeia " 2015 editions four characteristic check method items.
The preparation of standard solution: taking spearhead haemocoagulase standard items (for bioactivity), and water 1ml is added to make dissolution simultaneously
Dilution is made in every 1ml respectively containing 0.2,0.5,1.0,2.0,3.0 unit solution.
The preparation of test solution: taking the sublingual film of spearhead haemocoagulase 20, accurately weighed, shreds, precision weighs film
Appropriate fragment (is approximately equivalent to spearhead haemocoagulase 2U), sets in 1ml brown volumetric flask, and water is added to be settled to scale, dissolves and dilute
It releases and is made in every 1ml containing about the solution of 2.0 units to get spearhead haemocoagulase test solution.
Measuring method: take blood coagulation Quality Control blood plasma (blood coagulation Quality Control blood plasma is put to room temperature, every plus water 2.0ml, is placed 15 minutes,
Between period or jog, is gently shaken up using preceding every time) 0.1ml, it is separately added into juxtaposition blood coagulation analyzer detection position in coupon,
It is preheated 2 minutes under the conditions of 37 ± 0.5 DEG C, precision measures each 0.2ml of standard solution of serial solubility, is rapidly added above-mentioned each examination
In sample pipe, record setting time, every kind concentration replication 4 times, calculate average value (4 times measurement maxima and minima difference
It must not exceed the 10% of average value, otherwise resurvey).Using the logarithm of standard solution concentration as abscissa, setting time logarithm is
Ordinate calculates equation of linear regression (related coefficient should be greater than 0.99).Test solution is taken, is measured according to upper method, according to recurrence side
Journey calculates enzyme activity unit.
Example 1 prepares the sublingual film of resulting spearhead haemocoagulase 10, by above-mentioned " preparation of test solution "
In method prepare test solution, be measured according to the method in " measuring method ", calculate every film mark content.
As a result: average relative amount is 98.55%, and standard deviation S 0.02, A+2.2S < 20.0 meet the requirements.
Test example 4:The sublingual film hemostasis trial of spearhead haemocoagulase:
1, material:
1.1, instrument and reagent: coagulo meter (Coatron M4), stopwatch, electronic balance (FA1104B), spearhead pallas pit viper blood clotting
The sublingual film of enzyme (prepared by the method for embodiment 1), blank film (self-control), (Peng Lai Nuo Kang medicine company has injection spearhead haemocoagulase
Limit company), chloraldurate (Tianjin great Mao chemical reagent factory).
1.2, animal: SD rat, 200 ± 20g, male, No.302 Hospital of PLA's animal experimental center
Raising, 25 DEG C of temperature, humidity 40%~70%.
2, method:
2.1, the preparation of the sublingual film of spearhead haemocoagulase: spearhead haemocoagulase tongue is prepared according to the method for embodiment 1
Lower film.
2.2, grouping and administration: after taking healthy rat 40, adaptable fed 3 days, fasting 8h or more is randomly divided into
Model group, spearhead haemocoagulase injection positive drug control group (0.42U/kg), spearhead haemocoagulase (HBA) sublingual film are low
Dosage group, middle dose group, high dose group (0.21U/kg, 0.42U/kg, 0.84U/kg), every group 8；Wherein model group is not give
The hepatic injury modeling group of medicine, control group are the hepatic injury modeling group after spearhead haemocoagulase drug administration by injection, spearhead pallas pit viper blood clotting
The low middle high dose group of the sublingual film of enzyme is the hepatic injury modeling group after the administration of sublingual film.10% chloraldurate intraperitoneal injection of anesthesia, to
When rat enters deep sleep, the sublingual film of spearhead haemocoagulase (2cm × 2cm) is taken, size needed for being cut into each group dosage, manually
Film is affixed on rat sublingual mucosa after under saliva wetting Rat Tongue, is pressed lightly on tweezers, makes its firm pasting.Positive drug pair
According to group according to dosage tail vein injection spearhead haemocoagulase injection.
2.3, hepatic injury bleeding: after administration 1h, rat is faced upward into position and is fixed on aseptic operating platform.Abdomen unhairing, upper limb with
1cm starts on xiphoid-process, and area is about 6cm × 4cm, is first cut short hair with the small curved scissors of ophthalmology then raw along hair with razor blade
Length direction shaving preserved skin.After iodophor disinfection 2 times, abdomen, exposure liver, in No. 11 knife blades of liver frontal lobe are successively opened along ventrimeson
1 " X " word notch (0.8cm × 0.8cm) is done, hepatorrhagia wound model is caused.Covering sterile gauze, (model group directly covers nothing
Bacterium gauze) it presses afterwards, and start timing, gauze is opened when pressing 1min and observes surface of a wound bleeding, opens yarn every 30s later
Cloth is observed the surface of a wound 1 time, records bleeding stopping period, each group gauze is weighed respectively after hemostasis, calculates amount of bleeding.Abdomen cardinal vein after 1.5h
Blood sampling, 3.8% sodium citrate is anticoagulant in whole blood and anti-coagulants ratio 9:1, and 3000r/min centrifugation 10min takes blood plasma, measures blood plasma
APTT。
2.4, data processing: one-way analysis of variance is carried out using SPSS21.0 statistics software, P < 0.05 is thought to have aobvious
Write sex differernce.
3, result:
It the results are shown in Table shown in 8:
The sublingual film hemostasis trial result (n=8) of 8 spearhead haemocoagulase of table
| Group | Bleeding time (min) | Amount of bleeding (g) | APTT |
| Model group | 3.13±0.18 | 0.0591±0.0058 | 18.80±0.37 |
| Positive controls | 2.52±0.20* | 0.0144±0.0022* | 16.62±0.61* |
| The sublingual film low dose group of HBA | 3.02±0.14 | 0.0463±0.0020* | 17.68±0.51* |
| The sublingual film middle dose group of HBA | 2.36±0.25* | 0.0150±0.0039* | 16.30±0.31* |
| The sublingual film high dose group of HBA | 2.53±0.34* | 0.0298±0.0058* | 17.00±0.39* |
Note: compared with model group, P < 0.05 *.
This test evaluates spearhead pallas pit viper blood by the APTT level in measurement rat bleeding time, amount of bleeding and blood plasma
The haemostatic effect of the solidifying sublingual film of enzyme.The sublingual film of the spearhead haemocoagulase of middle dosage and high dose can effectively shorten greatly as the result is shown
The bleeding time of mouse reduces amount of bleeding, shortens APTT, illustrates that the sublingual film of spearhead haemocoagulase has apparent anastalsis；With
Middle dosage anastalsis is most significant.
The above, only presently preferred embodiments of the present invention, not to the present invention make in any form with substantial limit
System, all those skilled in the art, without departing from the scope of the present invention, when using disclosed above skill
Art content, and the equivalent variations for a little variation, modification and evolution made, are equivalent embodiment of the invention；Meanwhile it is all according to
According to the variation, modification and evolution of substantial technological any equivalent variations to the above embodiments of the invention, this is still fallen within
In the range of the technical solution of invention.
Claims (7)
1. a kind of sublingual film of spearhead haemocoagulase, which is characterized in that sublingual film 1000 of the spearhead haemocoagulase is under
Column raw material is prepared: 2000U spearhead haemocoagulase, 16gPVA05-88,8gPEG-400,8g hydroxypropyl-β-cyclodextrin ice
Piece inclusion compound and 240ml purified water.
2. a kind of preparation method of the sublingual film of spearhead haemocoagulase, includes the following steps:
(1), the following raw material is weighed by 1000 sublingual films of spearhead haemocoagulase of preparation: 2000U spearhead haemocoagulase,
16gPVA05-88,8gPEG-400,8g hydroxypropyl-β-cyclodextrin borneol inclusion compound and 240ml purified water；
(2), 16gPVA05-88 being added to 50 DEG C, in the purified water of 240ml, magnetic agitation makes evenly dispersed and is sufficiently swollen,
It is cooled to room temperature to it, it is spare；
(3), 2000U spearhead haemocoagulase, 8gPEG-400,8g hydroxy propyl-Beta-are sequentially added into the solution of step (2)
Cyclodextrin borneol inclusion compound, being sufficiently stirred keeps its evenly dispersed, bubble is sloughed using settled process after system is uniform, then in painting
Press 40~60 μ m thick films on film machine, ventilation, after 25 DEG C of drying at room temperature of shady place to get the sublingual film of spearhead haemocoagulase.
3. preparation method according to claim 2, it is characterised in that: in step (3) on film applicator press 60 μ m thicks apply
Film.
4. preparation method described in any claim prepares the resulting sublingual film of spearhead haemocoagulase in Claims 2 or 3.
5. the sublingual film of spearhead haemocoagulase according to claim 4, it is characterised in that: the spearhead haemocoagulase
Sublingual film with a thickness of 40~60 μm.
6. the sublingual film of spearhead haemocoagulase according to claim 5, it is characterised in that: the spearhead haemocoagulase
Sublingual film with a thickness of 60 μm.
7. the sublingual film of spearhead haemocoagulase according to any claim in claim 4~6, it is characterised in that: institute
The specification for the sublingual film of spearhead haemocoagulase stated is 2cm × 2cm.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112569208A (en) * | 2019-09-29 | 2021-03-30 | 四川科伦药物研究院有限公司 | Pramipexole dihydrochloride medicine composition and preparation method thereof |
| CN114886874A (en) * | 2022-04-07 | 2022-08-12 | 沈阳信达泰康医药科技有限公司 | Oral instant film agent and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130101574A1 (en) * | 2010-06-11 | 2013-04-25 | Darrell H. Carney | Methods of using thrombin peptide derivatives |
| CN104706625A (en) * | 2015-03-18 | 2015-06-17 | 中国人民解放军第三0二医院 | Instant methylphenidate hydrochloride film and preparation method thereof |
| CN108611341A (en) * | 2016-12-09 | 2018-10-02 | 辽宁远大诺康生物制药有限公司 | The hemagglutinase and its preparation method and application extracted from spearhead viper venom |
-
2018
- 2018-10-15 CN CN201811195028.XA patent/CN109331175B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130101574A1 (en) * | 2010-06-11 | 2013-04-25 | Darrell H. Carney | Methods of using thrombin peptide derivatives |
| CN104706625A (en) * | 2015-03-18 | 2015-06-17 | 中国人民解放军第三0二医院 | Instant methylphenidate hydrochloride film and preparation method thereof |
| CN108611341A (en) * | 2016-12-09 | 2018-10-02 | 辽宁远大诺康生物制药有限公司 | The hemagglutinase and its preparation method and application extracted from spearhead viper venom |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112569208A (en) * | 2019-09-29 | 2021-03-30 | 四川科伦药物研究院有限公司 | Pramipexole dihydrochloride medicine composition and preparation method thereof |
| CN112569208B (en) * | 2019-09-29 | 2023-10-31 | 四川科伦药物研究院有限公司 | Pramipexole dihydrochloride pharmaceutical composition and preparation method thereof |
| CN114886874A (en) * | 2022-04-07 | 2022-08-12 | 沈阳信达泰康医药科技有限公司 | Oral instant film agent and preparation method thereof |
| CN114886874B (en) * | 2022-04-07 | 2023-11-17 | 沈阳信达泰康医药科技有限公司 | Oral instant film and preparation method thereof |
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