CN102940614B - Method for preparing bulleyaconitine-containing tablets - Google Patents
Method for preparing bulleyaconitine-containing tablets Download PDFInfo
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- CN102940614B CN102940614B CN201210541380.0A CN201210541380A CN102940614B CN 102940614 B CN102940614 B CN 102940614B CN 201210541380 A CN201210541380 A CN 201210541380A CN 102940614 B CN102940614 B CN 102940614B
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- bulleyaconitine
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- 238000000034 method Methods 0.000 title claims abstract description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 50
- 238000001035 drying Methods 0.000 claims abstract description 7
- 239000007779 soft material Substances 0.000 claims abstract description 6
- YRECILNLFWZVRM-XTNYDWJGSA-N bulleyaconitine a Chemical compound O=C([C@H]1[C@]2(O)C[C@H]3[C@]45[C@H](OC)CC[C@@]6(COC)CN([C@@H]5[C@H]([C@H](OC)[C@H]64)[C@](C[C@@H]2OC)(OC(C)=O)[C@H]31)CC)C1=CC=C(OC)C=C1 YRECILNLFWZVRM-XTNYDWJGSA-N 0.000 claims description 48
- 239000002671 adjuvant Substances 0.000 claims description 19
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 13
- 229920002472 Starch Polymers 0.000 claims description 12
- 239000008107 starch Substances 0.000 claims description 12
- 235000019698 starch Nutrition 0.000 claims description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 10
- 239000008187 granular material Substances 0.000 claims description 9
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 7
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- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- 230000001515 vagal effect Effects 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 1
- XFSBVAOIAHNAPC-XTHSEXKGSA-N 16-Ethyl-1alpha,6alpha,19beta-trimethoxy-4-(methoxymethyl)-aconitane-3alpha,8,10alpha,11,18alpha-pentol, 8-acetate 10-benzoate Chemical compound O([C@H]1[C@]2(O)C[C@H]3[C@@]45C6[C@@H]([C@@]([C@H]31)(OC(C)=O)[C@@H](O)[C@@H]2OC)[C@H](OC)[C@@H]4[C@]([C@@H](C[C@@H]5OC)O)(COC)CN6CC)C(=O)C1=CC=CC=C1 XFSBVAOIAHNAPC-XTHSEXKGSA-N 0.000 description 1
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- XFSBVAOIAHNAPC-UHFFFAOYSA-N Aconitin Natural products CCN1CC(C(CC2OC)O)(COC)C3C(OC)C(C(C45)(OC(C)=O)C(O)C6OC)C1C32C4CC6(O)C5OC(=O)C1=CC=CC=C1 XFSBVAOIAHNAPC-UHFFFAOYSA-N 0.000 description 1
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- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
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- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
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- STDXGNLCJACLFY-UHFFFAOYSA-N aconitine Natural products CCN1CC2(COC)C(O)CC(O)C34C5CC6(O)C(OC)C(O)C(OC(=O)C)(C5C6OC(=O)c7ccccc7)C(C(OC)C23)C14 STDXGNLCJACLFY-UHFFFAOYSA-N 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for preparing bulleyaconitine-containing tablets, and relates to the field of medicaments, in particular to a method for producing bulleyaconitine-containing tablets serving as a chemical with the effects of relieving pain and diminishing inflammation. The bulleyaconitine dispersion method comprises the following steps of: dissolving with 40 to 95 percent edible or medicinal ethanol, mixing with auxiliary materials uniformly, adding a proper amount of wetting agent to prepare a soft material, preparing pellets, drying at the temperature of less than 65 DEG C, adding other auxiliary materials after drying, tabletting with a tabletting machine, coating, and thus obtaining the tablets. By the method, the uniformity and the dissolubility of the medicaments are improved, and the aims of improving the quality and the safety of the medicaments, meeting the requirements of patients and improving the production efficiency are fulfilled.
Description
Technical field
The present invention relates to drug world, especially a kind of chemical drugs with analgesia, antiinflammation, the tablet formulation production method of bulleyaconitine A.
Background technology
The bulleyaconitine A chemical name: (1 α, 6 α, 14 α, 16 β) tetrahydrochysene-8,13,14-triol-20-ethyl-1,6,16-trimethoxy-4-methoxyl methyl-8-acetoxyl group-14-(4 '-to the methoxybenzene methyl ester)-aconitane; Molecular formula C35H49NO10, molecular weight: 643.77.Character is white powder, is soluble in ethanol, chloroform, ether, insoluble in water; In dilute hydrochloric acid, dilute sulfuric acid, very easily dissolve.Its effect is analgesia, is applicable to treat cancer of late stage pain, rheumatism and rheumatoid arthritis, scapulohumeral periarthritis, shoulder brachialgia, stiff neck, osteoarthritis, optimum arthralgia, waist and extremities joint is sprained, contusion, lumbar muscle strain and lumbago and backache, sciatica, myofibrositis and costal chondritis, herpes zoster, headache due to common cold, toothache etc.The bulleyaconitine A analgesic activity is central, but the remarkable minimizing neuron sodium ion inflow of state dependence, blocking-up pain conduction, and with brain in 5-hydroxy tryptamine level close ties, onset time is slower than morphine, but the length of holding time, without addiction; Analgesic drawn game anaesthetic effect is arranged simultaneously.Animal infrastest and clinical experiment confirm that the bulleyaconitine A antiinflammatory action is clear and definite.
Due to bulleyaconitine A have active high, dosage is little, to characteristics such as heat are comparatively responsive, therefore how in the preparation production process, bulleyaconitine A to be uniformly dispersed, in prescription, use applicable adjuvant to improve uniformity and the dissolution of medicine, avoid the patient sense of discomfort to occur in orally using process, production process is controlled suitable baking temperature just becomes the important step in the preparation production process.
Traditional increase progressively dilution method be first by active ingredient with after the adjuvant of equivalent is mixed homogeneously, then after mixing, the material containing active ingredient is mixed with the adjuvant of equivalent again, the rest may be inferred until whole supplementary material is sneaked into.The shortcoming of this method is the medicine especially little for dosage, the uniformity of mixing is difficult to guarantee, production efficiency is lower simultaneously, basically can only use manually-operated, be not suitable for large-scale production, in addition, easily cause in process of production medicine pollution, therefore increase progressively dilution method and guaranteeing all there is comparatively significantly deficiency aspect bulleyaconitine A sheet drug quality and production efficiency.
The anhydrous alcohol solution dilution method is after active ingredient is dissolved in to dehydrated alcohol, then the method for mixing homogeneously with other adjuvants.In the method, dehydrated alcohol mostly is the industrial chemicals level, can not in pharmaceutical production for oral administration, use.Because the dehydrated alcohol source is unholiness, preparation technology is relatively simple, and cost is also cheaper, so the finished product obtained may contain toxic component, common are methanol, claims again another name for, is easy to be obtained by the timber fermentation, can cause blind.Edible ethanol i.e. edible ethanol is because source is grain, edible, the preparation process relative complex, and cost is also higher.It by food, ferment after redistillation obtain, fermented material commonly used has Semen Maydis, Semen sojae atricolor, glycosides sugarcane etc., thus in edible ethanol containing harmful materials such as methanol, benzene.Yet dehydrated alcohol is the ethanol that can not produce with fermentation liquid repeats the distillation acquisition, because when concentration of alcohol arrives 95% left and right, there is azeotropism in the binary system of ethanol and water, be both meetings volatilizations simultaneously in still-process, can not improve again the concentration of ethanol, so, to edible ethanol, the highest concentration is exactly 95%.And to obtain real dehydrated alcohol, method commonly used will add entrainer exactly, as forming ternary system, benzene, thiacyclohexane, pentane etc. improve azeotropic point, thereby reach the purpose that improves concentration of alcohol, but these entrainers are all to the poisonous and hazardous material of human body, by national relevant laws and regulations, forbid using in food and medicine.In addition, dehydrated alcohol can also separate and obtain by the petrochemical industry process, and wherein residual component is more complicated, and now known just having comprised has the composition highly endangered to human body as methanol, benzene etc.
In addition, bulleyaconitine A belongs to the compound of aconitine, active high, therefore has the vagal excitation of making effect.If some patients directly take bulleyaconitine A, fast absorb and just may cause vagal excitation after bulleyaconitine A contacts with oral mucosa, clinical main manifestations is that dispute is numb etc.If the appearance of medicine is not wrapped up, the patient easily produces mouthful fiber crops and waits reaction in oral process.Existing method is to adopt sugar-coat parcel means, but can cause the medicine weightening finish more, and a large amount of multitudinous sugar and Pulvis Talci of using in the sugar-coat production process, easily cause the patient's gastrointestinal tract discomfort simultaneously, also can limit the use of diabetics.
The bulleyaconitine A raw material is crystalline powder, if use traditional preparation production technique, make it can mix homogeneously with other adjuvant, need carry out the micronization pulverizing to it, but bulleyaconitine A is more responsive to ratio of specific heat, in crushing process, temperature can raise, and easily causes the destruction of its active ingredient.Traditional dilution method hybrid technique that increases progressively simultaneously, for the especially little medicine of the such dosage of bulleyaconitine A, mix evenly on be difficult to guarantee, thereby have influence on the quality of medicine.If dissolve the technique of mixing after bulleyaconitine A with dehydrated alcohol, because dehydrated alcohol mostly is the industrial chemicals level, therefore can not in pharmaceutical production for oral administration, use.
summary of the invention
To be solved by this invention is exactly how the bulleyaconitine A sheet is used solvent safely and effectively that active ingredient is uniformly dispersed in process of production; Adopt which kind of parcel means use safety and control in process of production temperature to meet medicine, reduce the destruction of active ingredient, use applicable adjuvant to combine and use the uniformity that improves medicine, the problem of dissolution, reach and improve drug quality and safety, the purpose of meet patient demand, enhancing productivity.
A kind of tablet formulation method containing bulleyaconitine A of the present invention, the process for dispersing that it is characterized in that bulleyaconitine A is mixed homogeneously with adjuvant after adopting the food grade of 40-95% or pharmaceutical grade dissolve with ethanol again, add appropriate wetting agent to make soft material, make again after the micropill granule dry, baking temperature is lower than 65 ℃, add other adjuvant after drying, the tablet machine tabletting, then film coating makes.
Adjuvant adopts microcrystalline Cellulose and carboxymethyl starch sodium to combine use, and uniformity and the dissolution of bulleyaconitine A sheet significantly improve.
Described film-coat comprises hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose (HPC), acrylic resin (E, IV) or polyvinylpyrrolidone (PVP).
Described adjuvant also comprises following material:
1. filler: comprise starch, Icing Sugar, dextrin, lactose, microcrystalline Cellulose or inorganic salts;
2. wetting agent and adhesive: comprise pure water, starch slurry, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, ethyl cellulose, methylcellulose, sucrose, gelatin or polyvinylpyrrolidone;
3. disintegrating agent: comprise starch, sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone or cross-linking sodium carboxymethyl cellulose;
4. lubricant: comprise magnesium stearate, carboxymethyl starch sodium, micropowder silica gel, Pulvis Talci, Polyethylene Glycol, liquid paraffin or magnesium laurylsulfate;
5. plasticizer: comprise propylene glycol, glycerol, PEG, triethyl citrate, triacetin, Oleum Ricini, diethyl phthalate, dibutyl phthalate or acetylation monoglyceride etc.
For the bulleyaconitine A sheet, specific adjuvant can make the aspects such as the uniformity, dissolution of active ingredient significantly improve in prescription.5 following prescriptions are bulleyaconitine A and different auxiliary material test results in conjunction with lower its uniformity and dissolution.
From the experiment test of prescription, can find out, after adding microcrystalline Cellulose and carboxymethyl starch sodium to combine use, uniformity and the dissolution of bulleyaconitine A sheet significantly improve.
Bulleyaconitine A is comparatively responsive to heat, in tablet manufacturing, material needs drying, if baking temperature is too high, will destroy bulleyaconitine A, active ingredient in product is descended, thereby affect drug quality, temperature general control in conventional tablet production is between 65-80 ℃, through lot of experiments, the inventor finds this temperature and is not suitable for the production of bulleyaconitine A sheet, if temperature during higher than 65 ℃, the content of its active ingredient will obviously descend, to reduce more than 20%, so in the bulleyaconitine A production process, the temperature of any link all will be lower than 65 ℃.Experimental results under the different temperatures drying is listed in the table below:
| Baking temperature (℃) | Dry required time (min) | Effective component content (%) |
| 40 | 180 | 98 |
| 45 | 158 | 98 |
| 50 | 115 | 97 |
| 55 | 72 | 97 |
| 60 | 50 | 97 |
| 65 | 40 | 90 |
| 70 | 30 | 79 |
Physicochemical properties according to bulleyaconitine A, the present invention adopts the food grade of 40-95% or pharmaceutical grade ethanol first to dissolve the method for mixing with adjuvant again after bulleyaconitine A and has solved temperature in traditional crushing process and raise to the destruction of bulleyaconitine A active ingredient and the problem of dehydrated alcohol safety, has solved again the problem that a small amount of bulleyaconitine A is mixed homogeneously with other adjuvant simultaneously.Control in process of production temperature and be no more than 65 ℃, avoid the destruction to active ingredient.
The general chronic pain course of disease is period of greater than two months all, more than Drug therapy needs to continue to few two weeks.Clinical NSAIDs analgesic life-time service commonly used there will be gastrointestinal tract, cardiovascular, Liver and kidney visceral organ injury at present; Opioid drug is used more than 6 days easily addiction.Prescription of the present invention is suitable for the chronic pain long-term treatment.Under recommended dose, bulleyaconitine A only after only a few patient medication, may occur slight nervous, feel sick, words are numb and the side effect of the non-device matter damage such as cardiopalmus.Different from NSAIDs, bulleyaconitine A does not affect platelet function or clotting time, does not cause gastric irritation, hemorrhage or rotten to the corn yet, and can be used for the patient to aspirin or other NSAIDs allergy.
The specific embodiment
Embodiment 1: a kind of tablet formulation method containing bulleyaconitine A, every containing the 0.4mg bulleyaconitine A.
At first bulleyaconitine A is used to 95% food grade or the pharmaceutical grade dissolve with ethanol of 1ml;
Second, adjuvant lactose 20mg, Icing Sugar 30mg, microcrystalline Cellulose 55mg and hydroxypropyl cellulose 10mg are mixed 30 minutes, then add the bulleyaconitine A ethanol to mix 60 seconds, then add appropriate purified water and mix after 60 seconds and make soft material, then after granulation under 55-65 ℃ dry 40 minutes;
The 3rd, dried granule is put to room temperature, mix 30 minutes add other adjuvant magnesium stearate 1mg, carboxymethyl starch sodium 25mg in dry granule after again, use the tablet machine tabletting, then film coating polyvinylpyrrolidone (PVP) 6mg and plasticizer glycerol 1mg make.
Embodiment 2: a kind of tablet formulation method containing bulleyaconitine A, every containing the 0.4mg bulleyaconitine A.
At first bulleyaconitine A is used to 90% food grade or the pharmaceutical grade dissolve with ethanol of 1ml;
Second, supplementary product starch 20mg, microcrystalline Cellulose 85mg and hydroxypropyl emthylcellulose 10mg are mixed 30 minutes, after then adding the bulleyaconitine A ethanol, mix 60 seconds, add again appropriate purified water and mix after 60 seconds and make soft material, then after granulation 55-65 ℃ of drying 40 minutes;
The 3rd, dried granule is put to room temperature, then mixed 30 minutes add other adjuvant magnesium stearate 1mg, carboxymethyl starch sodium 25mg in dry granule after, use the tablet machine tabletting, then film coating acrylic resin (E, IV) 6mg and plasticizer glycerol 1mg make.
Claims (2)
1. the tablet formulation method containing bulleyaconitine A, is characterized in that every, this tablet contains the 0.4mg bulleyaconitine A, and concrete formulation method is as follows:
At first bulleyaconitine A is used to 95% food grade or the pharmaceutical grade dissolve with ethanol of 1ml;
Second, adjuvant lactose 20mg, Icing Sugar 30mg, microcrystalline Cellulose 55mg and hydroxypropyl cellulose 10mg are mixed 30 minutes, then add the bulleyaconitine A ethanol to mix 60 seconds, then add appropriate purified water and mix after 60 seconds and make soft material, then after granulation under 55-65 ℃ dry 40 minutes;
The 3rd, dried granule is put to room temperature, mix 30 minutes add other adjuvant magnesium stearate 1mg, carboxymethyl starch sodium 25mg in dry granule after again, use the tablet machine tabletting, then film coating polyvinylpyrrolidone (PVP) 6mg and plasticizer glycerol 1mg make.
2. the tablet formulation method containing bulleyaconitine A, is characterized in that every, this tablet contains the 0.4mg bulleyaconitine A, and concrete formulation method is as follows:
At first bulleyaconitine A is used to 90% food grade or the pharmaceutical grade dissolve with ethanol of 1ml;
Second, supplementary product starch 20mg, microcrystalline Cellulose 85mg and hydroxypropyl emthylcellulose 10mg are mixed 30 minutes, after then adding the bulleyaconitine A ethanol, mix 60 seconds, add again appropriate purified water and mix after 60 seconds and make soft material, then after granulation 55-65 ℃ of drying 40 minutes;
The 3rd, dried granule is put to room temperature, then mixed 30 minutes add other adjuvant magnesium stearate 1mg, carboxymethyl starch sodium 25mg in dry granule after, use the tablet machine tabletting, then film coating acrylic resin (E, IV) 6mg and plasticizer glycerol 1mg make.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201210541380.0A CN102940614B (en) | 2012-12-14 | 2012-12-14 | Method for preparing bulleyaconitine-containing tablets |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210541380.0A CN102940614B (en) | 2012-12-14 | 2012-12-14 | Method for preparing bulleyaconitine-containing tablets |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1038473C (en) * | 1993-10-23 | 1998-05-27 | 云南省弥勒县制药厂 | Bulleyaconitine A oral preparation |
| CN1069519C (en) * | 1998-03-17 | 2001-08-15 | 昆明制药股份有限公司 | Bulleyaconitine A soft capsule and its production method |
| CN102552199A (en) * | 2012-02-03 | 2012-07-11 | 云南昊邦制药有限公司 | Bulleyaconitine a controlled release tablet |
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