A kind of sinomenine hydrochloride imbedibility preparation and preparation method thereof
Technical field
The present invention relates to a kind of imbedibility liquid preparation and preparation method thereof, be specifically related to a kind of non-organic solvent system
Standby sinomenine hydrochloride is imbedibility liquid preparation of raw material and preparation method thereof.
Background technology
Sinomenine is from menispermaceous plants Caulis Sinomenii Sinomenium acutum the earliest by Ishiwari etc.
(Thunb.) rhizome of Rehd.et Wils. is separated, have antiinflammatory, immunosuppressant, analgesia, blood pressure lowering,
The pharmacological actions such as arrhythmia.
In Caulis Sinomenii, main component is alkaloid, and the composition having now been found that has sinomenine (Sinomenine), different green grass or young crops
Rattan alkali (Igoginomenine), China's sinomenine (SinoAcutine), short Sinomenium acutum time alkali (Acutumidine), point sinomenine
And disinomenine (Diginomenine), ethyl sinomenine (ethylsinomenine), four hydrogen meter Radix Berberidis Amurensis (Sinaetine)
Alkali (sinactine), tetrahydrochysene epiberberine, Caulis menispermi ripple phenol alkali, bianfugenine, Tetrahydropalmatine etc..
At present commercial production sinomenine hydrochloride uses alkalization water extraction process, its be in Caulis Sinomenii addition water and
A certain amount of Calx, alkalizes a period of time, is subsequently adding a certain amount of technical benzene, reflux, extract, in water-bath,
Rear acidifying, standing, crystallize.Also document report is had to introduce extraction and the purification process of sinomenine, the dilute sulfur of Caulis Sinomenii
Acid percolate, adjusts pH value 9 with lime water, and benzene carries out counter-current extraction at 50 DEG C, and benzene extraction liquid is carried out with 1% hydrochloric acid
Anticountra flow extracts, activated carbon decolorizing, and crystallization carries out recrystallization in the hot water, obtains sterling.(Chen Yukun " Chinese medicine
Extraction process ", 1992)
This several method all uses benzene that toxicity is the biggest as Extraction solvent, and benzene is one-level toxic solvent, in pharmacy
Industry is the most disabled, and need to can be only achieved environmental protection by the most cumbersome technique in terms of the recycling of solvent and want
Ask, and chloroform is two grades of toxic solvents, thus should avoid using benzene and chloroform solvent in Chinese medicine extraction as far as possible.
Fog inhalation therapy is, with atomising device, atomization preparation such as imbedibility liquid preparation is dispersed into small droplet
Or microgranule so that it is it is suspended in gas in entrance respiratory tract and lung, reaches quickly to absorb and the purpose of local treatment.
Summary of the invention
Present invention aim at providing a kind of sinomenine hydrochloride imbedibility liquid preparation and preparation method thereof.
The present invention seeks to be achieved through the following technical solutions:
Sinomenine hydrochloride imbedibility liquid preparation of the present invention is made up of following raw material:
Sinomenine hydrochloride 15~35 weight portion, sodium sulfite 0.1~3 weight portion, disodium edetate 0.1~3 weight
Part, sodium chloride 7-10 weight portion.
The preparation method of sinomenine hydrochloride imbedibility liquid preparation of the present invention may is that
Take water for injection, nitrogen charging, add sinomenine hydrochloride and be stirred to dissolve, add sodium sulfite, according to ground
Acid disodium, sodium chloride are stirred to dissolve, and continue nitrogen charging, addition 0.10~the activated carbon of 0.20%, 35~45 DEG C of insulations
5~15 minutes, filtering carbon removal, add water for injection to 1000 parts by volume, inspection, fine straining is clear and bright to solution, fills
Nitrogen embedding, 100~120 DEG C of sterilizings 20~40 minutes, to obtain final product.
Sinomenine hydrochloride of the present invention is made up of following preparation method:
A, extraction: Caulis Sinomenii coarse powder 100~1000 weight portion, by the 0.1~1moL/L HCL profit of 60~1000ml
Wet 0.5~8 hour, fill percolator, add 0.1~1moL/L HCL and make liquid level cover medicated powder 2cm, impregnate 6~48
After hour, start percolation by the speed of 2~5ml/min, stop percolation after 6~24 hours, obtain percolate, standby;
B, upper prop eluting: by good cation exchange resin processed on percolate or 152 type resins, blade diameter length ratio
For 1:8-12, loading speed be 2~5 times of column volumes/hour, have precipitation to effluent silico-tungstic acid test solution inspection,
And thin layer chromatography detection inanimate object alkaline spot point time stop loading, with purified water be eluted to eluent without during color stop,
With 8~15% ammonia solution soak resin or 3~10% hydrochloric acid solution soak 152 type resin 12 hours, then use PH
Value be 8~11 ammonia-ethanol solution eluting or 152 type resins with 3~10% hydrochloric acid solution eluting, elution speed
For 2-5BV/h, eluent silico-tungstic acid test solution inspection receives when having precipitation, receives eluent silico-tungstic acid test solution and examines
Stopping when looking into without precipitation, merge eluent, being neutralized to PH with hydrochloric acid or ammonia is 6-8, desalination, concentrate drying,
Obtain sinomenine hydrochloride crude product.
C, refined: to remove sinomenine hydrochloride crude product 5~10 weight portion, with 10~95% ethanol or pure of 30~120ml
Change water to be heated to reflux to being completely dissolved, add the activated carbon of 3-6% times of weight, insulation backflow 10-30 minute, take advantage of
Heat filters, and filtrate concentrates, and cooling, crystallize filter, with the ethanol solution of 75-95% clean filter cake to filter cake without
Color, obtains sinomenine hydrochloride;
Sinomenine hydrochloride of the present invention is preferred by following preparation method:
A, extraction: Caulis Sinomenii coarse powder 500 weight portion, with the 0.5moL/L HCL moistening 4 hours of 500ml,
Dress percolator, adds 0.3moL/L HCL and makes liquid level cover medicated powder 2cm, after impregnating 24 hours, by 3ml/min
Speed start percolation, after 18 hours stop percolation, obtain percolate, standby;
B, upper prop eluting: by good cation exchange resin processed on percolate or 152 type resins, blade diameter length ratio
For 1:10, loading speed be 3 times of column volumes/hour, have precipitation to effluent silico-tungstic acid test solution inspection, and thin
Stop loading during layer chromatography detection inanimate object alkaline spot point, be eluted to eluent without stopping during color, use by purified water
8~15% ammonia solution soak resin or 3~10% hydrochloric acid solution soak 152 type resin 12 hours, then use pH value
Being ammonia-ethanol solution eluting or 152 type resins, the 6% hydrochloric acid solution eluting of 11, elution speed is 2-5BV/h,
Eluent silico-tungstic acid test solution inspection receives when having precipitation, receives eluent silico-tungstic acid test solution and checks when nothing precipitates
Stopping, merging eluent, being neutralized to PH with hydrochloric acid or ammonia is 8, desalination, and concentrate drying obtains hydrochloric acid Sinomenium acutum
Alkali crude product.
C, refined: removing sinomenine hydrochloride crude product 7 weight portion, 95% ethanol or purified water with 60ml heat back
Flowing to be completely dissolved, add the activated carbon of 4% times of weight, insulation backflow 20 minutes, filter while hot, filtrate is dense
Contracting, cooling, crystallize, filter, it is colourless to filter cake that the ethanol solution with 80% cleans filter cake, obtains sinomenine hydrochloride;
The preferred step B of described method: strong cation-exchanging resin preferred 001*2.5,001*4, macroporous absorption tree
Fat preferably 152 type;The preferred 1:10 of resin blade diameter length ratio;Preferably 3 times column volumes of loading speed/hour;Soak resin
Preferably 10% ammonia solution (or 5% hydrochloric acid solution);Using ammonia-ethanol solution that pH value is 8~11 as cation
The eluting solution of exchanger resin, eluent be neutralized with hydrochloric acid to PH be 6~8;5% hydrochloric acid solution is big as 152 types
The eluting solution of macroporous adsorbent resin;
Preferably step C: add 4% times of weight activated carbon;When being heated to reflux preferably 40%, 55%, 60%, 75%
Or 80% ethanol.
In the present invention, sinomenine hydrochloride imbedibility liquid preparation raw material can be preferably as follows:
Sinomenine hydrochloride 35 weight portion, sodium sulfite 4.5 weight portion, disodium edetate 1 weight portion, chlorination
Sodium 9 weight portion;
Sinomenine hydrochloride 25 weight portion, sodium sulfite 1 weight portion, disodium edetate 0.3 weight portion, chlorination
Sodium 9 weight portion;
Sinomenine hydrochloride 20 weight portion, sodium sulfite 0.6 weight portion, disodium edetate 0.2 weight portion, chlorine
Change sodium 9 weight portion;
In the present invention, sinomenine hydrochloride imbedibility liquid preparation preparation method can be:
Take appropriate water for injection, nitrogen charging, add recipe quantity sinomenine hydrochloride and be stirred to dissolve;Add sulfurous
Acid hydrogen sodium, disodium edetate, sodium chloride are stirred to dissolve, continuation nitrogen charging, addition 0.10~the activated carbon of 0.20%,
35~45 DEG C are incubated 8-12 minute, filter carbon removal, add water for injection to 1000 parts by volume, and inspection, fine straining is extremely
Clear and bright, nitrogen charging embedding, 100 DEG C of sterilizings 30 minutes, to obtain final product.
In the present invention, sinomenine hydrochloride imbedibility liquid preparation preparation method can be preferably:
Take appropriate water for injection, nitrogen charging, add recipe quantity sinomenine hydrochloride and be stirred to dissolve;Add sulfurous
Acid hydrogen sodium, disodium edetate, sodium chloride are stirred to dissolve, continuation nitrogen charging, the activated carbon of addition 0.1%, 35~45 DEG C
Being incubated 10 minutes, filter carbon removal, add water for injection to 1000 parts by volume, inspection, fine straining, to clear and bright, fills
Nitrogen embedding, 100 DEG C of sterilizings 30 minutes, to obtain final product.
Weight portion of the present invention is g/ml with the relation of parts by volume.The present invention can add correctives etc. clinical or
Pharmaceutically acceptable customary adjuvant.
Accompanying drawing explanation
Fig. 1 is installation drawing (after numeral, unit is mm).
Detailed description of the invention
Pharmaceutical preparation of the present invention directly acts on local, absorbs rapid, abundant, and drug dose is little, and medicine is only it
The 1/10 of his route of administration.Systemic adverse reactions is little, and safety is high, adds medicine and arrives the denseest of focus
Degree, and atomizing particle has 10% can enter in lung, the amount arriving target tissue reaches 90%.
Fluid present invention sucks preparation and is mainly used in oral cavity and nasal cavity, it is also possible to include catching a cold and other for treatment
Factor cause bottleneck throat discomfort, acute/chronic pharyngitis, laryngitis, allergic rhinitis, tracheitis, bronchial asthma,
The treatment of the diseases such as various pneumonia, chronic obstructive emphysema.
The imbedibility liquid preparation using the inventive method to prepare can use suitable blast atomizer Neulized inhalation,
For treating rheumatoid arthritis, chronic nephritis and interstitial pulmonary fibrosis, achieve beyond thought effect.
The inventive method uses and replaces traditional benzene extraction by cation exchange resin or absorption with macroporous adsorbent resin
And chloroform extraction (extraction) technique, extract yield is high, operates easier, overcomes consumption of organic solvent big,
Harm that operator's health and environment are caused by toxicity and pollution, decrease the processing procedure of organic solvent, more
Be conducive to environmental conservation, decrease the input of factory's environmental protection facility, beneficially environmental friendliness and produce.
Following experiment case study is used for further illustrating the present invention but is not limited to the present invention.
Experimental example 1:
Use the preparation for treating rheumatoid arthritis of injecting type nebulizer Neulized inhalation embodiment 2 preparation, Huan Zhequ
Seat or semireclining position, by sinomenine hydrochloride imbedibility liquid preparation 2ml normal saline dilution to 5ml, inject spray
Penetrating in formula nebulizer, nebulizer connects QI KOU and connects on the oxygen catheter of oxygen cylinder or center inhalation device, adjusts
Joint oxygen flow 6-8L/min.The hand-held nebulizer of patient, sucks Neulized inhalation mouth and contains in mouth, hands during air-breathing
Refer to block gas outlet, close the deep air-breathing of lip, unclamp during expiration, suction 15~25min, 2 times on the one.Treatment
Rheumatoid arthritis total effective rate reaches 92%.
Experimental example 2:
Using the preparation for treating chronic nephritis of injecting type nebulizer Neulized inhalation embodiment 2 preparation, patient takes seat
Or semireclining position, by sinomenine hydrochloride imbedibility liquid preparation 2ml normal saline dilution to 5ml, injecting jet formula
In nebulizer, nebulizer connects QI KOU and connects on the oxygen catheter of oxygen cylinder or center inhalation device, regulates oxygen
Throughput 6-8L/min.The hand-held nebulizer of patient, sucks Neulized inhalation mouth and contains in mouth, and during air-breathing, finger blocks up
Live gas outlet, close the deep air-breathing of lip, unclamp during expiration, suction 15~25min, 2 times on the one.Treat chronic
Nephritis total effective rate reaches 90%
Experimental example 3:
Use the preparation for treating interstitial pulmonary fibrosis of injecting type nebulizer Neulized inhalation embodiment 2 preparation, Huan Zhequ
Seat or semireclining position, by sinomenine hydrochloride imbedibility liquid preparation 2ml normal saline dilution to 5ml, inject spray
Penetrating in formula nebulizer, nebulizer connects QI KOU and connects on the oxygen catheter of oxygen cylinder or center inhalation device, adjusts
Joint oxygen flow 6-8L/min.The hand-held nebulizer of patient, sucks Neulized inhalation mouth and contains in mouth, hands during air-breathing
Refer to block gas outlet, close the deep air-breathing of lip, unclamp during expiration, suction 15~25min, 2 times on the one.Treatment
Interstitial pulmonary fibrosis total effective rate reaches 95%.
Experimental example 4:
Use the preparation for treating rheumatoid arthritis of injecting type nebulizer Neulized inhalation embodiment 2 preparation, Huan Zhequ
Seat or semireclining position, by sinomenine hydrochloride imbedibility liquid preparation 2ml normal saline dilution to 5ml, inject spray
Penetrating in formula nebulizer, nebulizer connects QI KOU and connects on the oxygen catheter of oxygen cylinder or center inhalation device, adjusts
Joint oxygen flow 6-8L/min.The hand-held nebulizer of patient, sucks Neulized inhalation mouth and contains in mouth, hands during air-breathing
Refer to block gas outlet, close the deep air-breathing of lip, unclamp during expiration, suction 15~25min, 2 times on the one.Treatment
Acute pharyngitis total effective rate reaches 95%.
Experimental example 5: optimization
The prescription of imbedibility liquid preparation generally uses injection water as solvent, add if desired a small amount of ethanol or
Propylene glycol.Adjuvant includes HCl, NaOH, tartaric acid, NaCl etc..For increasing medicine stability, it is also possible to
Add sodium sulfite or EDTA.
Sinomenine hydrochloride is soluble in water, it is not necessary to add cosolvent.But sinomenine hydrochloride easily aoxidizes, PH is too high i.e.
Sinomenine can be made to decompose.Therefore, the pH value of imbedibility liquid preparation should be maintained between 3~4, and adds Asia
Sodium bisulfate and disodium edetate stabilizer are to ensure the stability of medicine.
1.1 deposition ratio in the effective position measure
Imbedibility liquid preparation means one or more medicine, through special doser, enters and breathes
Road deep lung, plays a kind of drug-supplying system locally or systemically acted on.Drug particle in imbedibility liquid agent should
The finest (0.5~5 μm), can arrive site of action, but nonetheless, the most only medicine of 1%~20%
Can deposit in effective site, play curative effect.Therefore, British Pharmacopoeia, American Pharmacopeia and Chinese Pharmacopoeia all specify needs
The deposition ratio in the effective position of imbedibility liquid preparation is measured.
1.1.1 instrument and equipment and operation
Using imitated TI device, see Fig. 1,1. rubber interface uses rubber stopper, selects not according to suction apparatus
Same interface.2. plastic screw cap: need mold to prepare, do not satisfy the requirements, easily causes when using rubber stopper
Device is not parallel, tests poor reproducibility, therefore will use glass frit seal herein.3. small size polypropylene filter is used
The transformation of the way, connects with vertical tube at H with latex tubing.4. trunnion is simulated: be first at round-bottomed flask and vertical tube c
Level (stage I), is equivalent to main bronchus;Conical flask and bend pipe E, be the second level (stage II) at vertical tube H,
Be equivalent to lung bronchioles with lower portion, i.e. effective site.
Operational approach: 1. device such as figure, should ensure that two vertical tubes are parallel.2. place at first order round-bottomed flask
Acceptable solution 7ml, places acceptable solution 30ml at the conical flask of the second level, acceptable solution kind is relevant with given the test agent.
3. regulate the height of G, make just to contact with bottom conical flask at the protrusion of center.4. vacuum pump is connect, speed of bleeding
Degree is adjusted to 60L min-1, it is ensured that the medicine of unit dose discharges completely.5. with blank acceptable solution by bend pipe E and
Medicament elution at vertical tube, and close with the acceptable solution in conical flask, measure the content of medicine, calculate medicine and exist
Deposition percentage rate at the second level.
A-elastomer connector;B-simulates throat;C-cervical region;D-overburden bottle (stage I);E-connecting tube;F-exports, and connects
Vacuum pump;G-spout;H-bottom measures long-pending bottle (stage II)
1.1.2 experimental result
With distilled water as acceptable solution, following three prescription is screened:
Prescription 1: sinomenine hydrochloride 35 weight portion, sodium sulfite 4.5 weight portion, disodium edetate 1 weight
Part, sodium chloride 9 weight portion, water for injection in right amount, make 1000 parts by volume;
Prescription 2: sinomenine hydrochloride 25 weight portion, sodium sulfite 1 weight portion, disodium edetate 0.3 weight
Part, sodium chloride 9 weight portion, water for injection in right amount, make 1000 parts by volume;
Prescription 3: sinomenine hydrochloride 20 weight portion, sodium sulfite 0.6 weight portion, disodium edetate 0.2 weight
Part, sodium chloride 9 weight portion, water for injection in right amount, make 1000 parts by volume;
Result is as shown in the table.
Table 1 sinomenine hydrochloride imbedibility liquid preparation deposition ratio in the effective position measures (%)
According to experimental result, screening prescription 2 is optimum formulation and technology.
2, stability test
2.1 illumination experiment
Take sample under conditions of illumination (4500 ± 500) lx, place 10d, respectively at 0,1,5,10d sampling,
Investigate its character, measure pH value, principal agent (sinomenine hydrochloride) content, Self-control method measuring has related substance
Content.Use Syrups by HPLC drug content, with octadecylsilane chemically bonded silica for fixing phase, with first
Alcohol-ethylenediamine (1000:0.1) is flowing phase, and column temperature is 30 DEG C, and flow velocity is 1ml/min, and detection wavelength is 262nm.
When result is to 10d, preparation character, pH value, drug content are showed no significant change, refer to table 2.
Table 2 sample illumination experiment result
2.2 high temperature experiments
Take sample in 60 DEG C of waters bath with thermostatic control, place 10d, respectively at 0,1,5,10d sampling, investigate its character,
Measure pH value, drug content, Self-control method measure relevant content of material.When result is to 10d, preparation
Character, pH value, drug content have no significant change, and refer to table 3.
Table 3 high-temperature sample experimental result
2.3 accelerated test
Taking 3 batches, sample, under the conditions of temperature (40 ± 2) DEG C, lucifuge places 6 months, respectively the 0th, 1,2,
3, sampling in 6 months carries out character observation, pH value measures, drug content measures and limit test of microbe, respectively
Item index has no significant change, the results detailed in Table 4.
Table 4 sample accelerated test result
2.4 conclusion
Sample stability test shows, the sinomenine hydrochloride imbedibility liquid preparation dimensionally stable prepared is high temperature resistant,
Can store for a long time.
Embodiment 1
Sinomenine hydrochloride 35g, sodium sulfite 4.5g, disodium edetate 1g, sodium chloride 9g;
Take appropriate water for injection, nitrogen charging, add recipe quantity sinomenine hydrochloride and be stirred to dissolve;Add sulfurous
Acid hydrogen sodium, disodium edetate, sodium chloride, correctives are stirred to dissolve, and continue nitrogen charging, add the activity of 0.1%
Charcoal, 35~45 DEG C are incubated 10 minutes, filter carbon removal, add water for injection to 1000ml, inspection, and fine straining is to clear
Bright, nitrogen charging embedding, 100 DEG C of sterilizings 30 minutes, to obtain final product.
Embodiment 2
Sinomenine hydrochloride 25g, sodium sulfite 1g, disodium edetate 0.3g, sodium chloride 9g;
Take appropriate water for injection, nitrogen charging, add recipe quantity sinomenine hydrochloride and be stirred to dissolve;Add sulfurous
Acid hydrogen sodium, disodium edetate, sodium chloride are stirred to dissolve, continuation nitrogen charging, the activated carbon of addition 0.1%, 35~45 DEG C
It is incubated 10 minutes, filters carbon removal, add water for injection to 1000ml, inspection, fine straining is the most clear and bright, nitrogen charging embedding,
100 DEG C of sterilizings 30 minutes, to obtain final product.
Embodiment 3
Sinomenine hydrochloride 20g, sodium sulfite 0.6g, disodium edetate 0.2g, sodium chloride 9g;
Take appropriate water for injection, nitrogen charging, add recipe quantity sinomenine hydrochloride and be stirred to dissolve;Add sulfurous
Acid hydrogen sodium, disodium edetate, sodium chloride are stirred to dissolve, continuation nitrogen charging, the activated carbon of addition 0.1%, 35~45 DEG C
It is incubated 10 minutes, filters carbon removal, add water for injection to 1000ml, inspection, fine straining is the most clear and bright, nitrogen charging embedding,
100 DEG C of sterilizings 30 minutes, to obtain final product.
Embodiment 1-3 sinomenine hydrochloride is made the most by the following method:
Sinomenine hydrochloride of the present invention is preferred by following preparation method:
A, extraction: Caulis Sinomenii coarse powder 500g, with the 0.5moL/L HCL moistening 4 hours of 500ml, dress oozes
Filter cylinder, add 0.3moL/L HCL and make liquid level cover medicated powder 2cm, after impregnating 24 hours, by 3ml/min
Speed start percolation, after 18 hours stop percolation, obtain percolate, standby;
B, upper prop eluting: by good cation exchange resin processed on percolate or 152 type resins, blade diameter length ratio
For 1:10, loading speed be 3 times of column volumes/hour, have precipitation to effluent silico-tungstic acid test solution inspection, and thin
Stop loading during layer chromatography detection inanimate object alkaline spot point, be eluted to eluent without stopping during color, use by purified water
8~15% ammonia solution soak resin or 3~10% hydrochloric acid solution soak 152 type resin 12 hours, then use pH value
Being ammonia-ethanol solution eluting or 152 type resins, the 6% hydrochloric acid solution eluting of 11, elution speed is 2-5BV/h,
Eluent silico-tungstic acid test solution inspection receives when having precipitation, receives eluent silico-tungstic acid test solution and checks when nothing precipitates
Stopping, merging eluent, being neutralized to PH with hydrochloric acid or ammonia is 8, desalination, and concentrate drying obtains hydrochloric acid Sinomenium acutum
Alkali crude product.
C, refined: removing sinomenine hydrochloride crude product 7g, 95% ethanol or purified water with 60ml are heated to reflux to complete
CL, adds the activated carbon of 4% times of weight, insulation backflow 20 minutes, filters while hot, and filtrate concentrates, cold
But, crystallize, filter, with 80% ethanol solution cleaning filter cake colourless to filter cake, obtain sinomenine hydrochloride.