CN101108872B - Plants natural base extract and formulated product and use thereof - Google Patents
Plants natural base extract and formulated product and use thereof Download PDFInfo
- Publication number
- CN101108872B CN101108872B CN2006100410726A CN200610041072A CN101108872B CN 101108872 B CN101108872 B CN 101108872B CN 2006100410726 A CN2006100410726 A CN 2006100410726A CN 200610041072 A CN200610041072 A CN 200610041072A CN 101108872 B CN101108872 B CN 101108872B
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- Prior art keywords
- solution
- extract
- organic solvent
- ethanol
- solamargine
- Prior art date
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- 239000000284 extract Substances 0.000 title claims description 132
- 229930013930 alkaloid Natural products 0.000 claims abstract description 43
- 150000003797 alkaloid derivatives Chemical class 0.000 claims abstract description 42
- 244000061457 Solanum nigrum Species 0.000 claims abstract description 25
- 235000002594 Solanum nigrum Nutrition 0.000 claims abstract description 25
- 235000013399 edible fruits Nutrition 0.000 claims abstract description 13
- 235000017622 Solanum xanthocarpum Nutrition 0.000 claims abstract description 12
- 244000040885 Solanum virginianum Species 0.000 claims abstract 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 335
- 239000000243 solution Substances 0.000 claims description 108
- 239000003960 organic solvent Substances 0.000 claims description 79
- 239000011347 resin Substances 0.000 claims description 67
- 229920005989 resin Polymers 0.000 claims description 67
- 238000005406 washing Methods 0.000 claims description 67
- 239000007788 liquid Substances 0.000 claims description 57
- 241000196324 Embryophyta Species 0.000 claims description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 46
- 238000003756 stirring Methods 0.000 claims description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- 239000012670 alkaline solution Substances 0.000 claims description 33
- 239000002244 precipitate Substances 0.000 claims description 29
- 238000001035 drying Methods 0.000 claims description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 24
- 238000001914 filtration Methods 0.000 claims description 24
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 20
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 18
- 241000207763 Solanum Species 0.000 claims description 14
- 235000002634 Solanum Nutrition 0.000 claims description 14
- 239000000706 filtrate Substances 0.000 claims description 14
- 238000001953 recrystallisation Methods 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
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- 239000002253 acid Substances 0.000 claims description 11
- 230000007935 neutral effect Effects 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 8
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 8
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 8
- 239000000347 magnesium hydroxide Substances 0.000 claims description 8
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 8
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- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 6
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- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
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- MBWUSSKCCUMJHO-DVDUUUGDSA-N Solamargine Natural products O([C@@H]1[C@@H](O)[C@@H](O[C@H]2[C@H](O)[C@H](O)[C@@H](O)[C@H](C)O2)[C@H](CO)O[C@@H]1O[C@@H]1CC=2[C@@](C)([C@@H]3[C@H]([C@H]4[C@@](C)([C@H]5[C@@H](C)[C@@]6(O[C@H]5C4)NC[C@H](C)CC6)CC3)CC=2)CC1)[C@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](C)O1 MBWUSSKCCUMJHO-DVDUUUGDSA-N 0.000 abstract description 105
- MBWUSSKCCUMJHO-ZGXDEBHDSA-N Solamargine Chemical compound O([C@@H]1[C@@H](CO)O[C@H]([C@@H]([C@H]1O)O[C@H]1[C@@H]([C@H](O)[C@@H](O)[C@H](C)O1)O)O[C@@H]1CC2=CC[C@H]3[C@@H]4C[C@H]5[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@@H]([C@]1(NC[C@H](C)CC1)O5)C)[C@@H]1O[C@@H](C)[C@H](O)[C@@H](O)[C@H]1O MBWUSSKCCUMJHO-ZGXDEBHDSA-N 0.000 abstract description 104
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Landscapes
- Medicines Containing Plant Substances (AREA)
Abstract
A botanical alkaloid extractive is provided, which is characterized in that the extractive is extracted from the and / or fruits, or solanum nigrum or solanum xanthocarpum. The invention also discloses a medicine of any form receivable pharmaceutically and mixedly produced by the botanical alkaloid extractive and the drug carriers receivable pharmaceutically. The extractive of the invention has scientific and reasonable extracting steps and has little impurity content and high content of the active ingredient solamargine with minimum of 90.0 per cent and maximum of 99.9 per cent. Certified by the test, the extractive preparation of the invention is safe and effective and controllable in quality.
Description
Technical Field
The invention relates to a Chinese herbal medicine extract, in particular to a plant alkaloid extract, and also relates to a medicinal preparation and application of the extract.
Background
Solanum genus of Solanaceae family, one or several years of herb, cold, bitter taste, slightly sweet, has little toxicity, enters lung, stomach and bladder channels, has effects of clearing heat and detoxicating, promoting blood circulation and removing blood stasis, inducing diuresis and relieving swelling, relieving cough and eliminating phlegm, and is distributed all over the country. There are 5 different morphological types in China, namely yellow fruit black nightshade, purple stem black nightshade, green vein black nightshade and brown vein black nightshade, at present, the main research is the wild black nightshade (Solanumnigrum L.) in the North of China, which belongs to the black stem black nightshade, and the black nightshade can be used as a medicine by whole grass.
The whole plant of Solanum nigrum contains glycosides steroid alkaloid, Solanum nigrum polysaccharide, mineral, vitamin, pigment, amino acid, etc., the extract of Solanum nigrum berries also contains ester, carboxyl compound, sterol, phenolic compound (the main component is yellow unsaturated ester), and in addition, saponin and sapogenin, and the chemical playing a key role is mainly alkaloid, and then polysaccharide. Liu Gong et al reported that Solanum nigrum total alkaloids include solasonine, solamargine and B-solamargine, while Li Xiuchai et al considered to contain solamargine, solasonine, solamargine and soladarine.
The study of scholars at home and abroad proves that the black nightshade extract has the anti-tumor effect, the bacteriostatic and antiviral effects, the neuro-pharmacological effect, the cardiovascular pharmacological effect, the digestive system pharmacological effect, the urinary system pharmacological effect, the genetic toxicology effect, the endocrine pharmacological effect, the antipyretic analgesic pharmacological effect and other pharmacological effects. The same family of plants, namely, Solanum abricum (Solanum abricum park) and Solanum xanthocarpum (Solanum xanthocar pumSchrad, et wendl), all contain similar components and have similar pharmacological actions. At present, it is a further important point of research to determine which extraction process can obtain a safe and effective dose of active ingredients and preparations.
Disclosure of Invention
The invention aims to solve the technical problem of providing a plant alkaloid extract with low impurity content and high solamargine content aiming at the defects of the prior art.
The invention also aims to provide a pharmaceutical preparation of the extract. The invention also provides the application of the extract and a pharmaceutical preparation thereof.
The technical problem to be solved by the present invention is achieved by the following technical means. The invention relates to a plant alkaloid extract, which is characterized in that the plant alkaloid extract is extracted from the whole plant and/or fruit of solanum nigrum, or Solanum xanthocarpum, or Solanum australianum, and the extraction method comprises the following steps:
(1) taking the whole plant and/or fruit of solanum nigrum, or solanum xanthocarpum, or solanum australianum, adding 50-90% ethanol solution to extract for 2-4 times, wherein 4-8 times of ethanol is recycled each time, concentrating until the relative density is 1.10-1.25, adding 1-4 times of 0.01-0.1 mol/l acid solution into the concentrated solution, fully stirring, refrigerating for more than 12 hours, and filtering; washing the filter residue with 0.01-0.1 mol/l acid solution for 1-3 times, combining the filtrate and washing liquid, and adsorbing with weak-polarity or medium-polarity resin;
or,
soaking the whole plant and/or fruit of solanum nigrum, or Solanum xanthocarpum, or Solanum australianum in 0.01-0.1 mol/l acid solution for 2-4 times, wherein the dosage is 4-8 times each time, and the time is 6-24 hours each time, combining the soaking solutions, and adsorbing by weak-polarity or medium-polarity resin;
(2) after the resin is adsorbed, firstly washing the resin column/bed by water until the effluent liquid is neutral, then washing the resin column/bed by alkaline ethanol solution until the effluent liquid is colorless, or firstly washing the resin column/bed by alkaline solution until the effluent liquid is colorless, and then washing the resin column/bed by ethanol solution with the alcohol content of 5-40% until the effluent liquid is colorless; discarding the washing liquid, eluting with 50-80% ethanol until the eluate is colorless, collecting the eluate, recovering ethanol until no alcohol smell exists, adjusting pH to 8-10 with alkaline solution, standing, refrigerating, and collecting precipitate;
(3) dissolving the precipitate with 20-25 times of organic solvent after drying, adding 0.5-4 times of chromatographic silica gel in the amount of the precipitate, uniformly stirring, drying by distillation, taking the silica gel mixed with the sample, performing column chromatography separation, filling the chromatographic column with the organic solvent by a wet method, eluting with the organic solvent, collecting the eluent in different times, detecting by thin layer chromatography, combining the eluents with the same spot position as the solamargine sample, recovering the organic solvent, and drying by distillation to obtain the solamargine compound gel;
or,
(3) and drying the precipitate, adding 5-20 times of organic solvent with larger polarity, stirring for 10-30 minutes, standing, filtering, adding 2-6 times of low-polarity organic solvent into the filtrate, stirring, refining, filtering, recovering the organic solvent, adding an organic solvent for recrystallization, recrystallizing, and collecting crystals.
The technical problem to be solved by the present invention can be further achieved by the following technical means. The plant alkaloid extract is characterized in that the acidic solution in the step (1) is selected from acetic acid, hydrochloric acid, sulfuric acid or citric acid solution; the alkaline solution in the step (2) is selected from sodium hydroxide, calcium hydroxide, potassium hydroxide, magnesium hydroxide or ammonia water solution with the concentration of 0.05-1.5mol/l, the alkaline ethanol solution is the alkaline ethanol solution containing the sodium hydroxide, the calcium hydroxide, the potassium hydroxide, the magnesium hydroxide or the ammonia water with the concentration of 0.05-0.15mol/l, and the alcohol concentration is 5% -40%.
The technical problem to be solved by the present invention can be further achieved by the following technical means. The plant alkaloid extract is characterized in that the organic solvent for dissolving in the step (3) is selected from methanol, absolute ethyl alcohol, acetone, isopropanol or propylene glycol; the organic solvent for column chromatography elution is selected from one of methanol, absolute ethyl alcohol, acetone, n-butanol, chloroform and ethyl acetate or a mixed phase formed by 2-3 items in any proportion; the organic solvent with larger polarity is selected from methanol, ethanol, n-butanol, acetone or a mixed phase of the two; the low-polarity organic solvent is selected from chloroform, dichloromethane, dichloroethane, ethyl acetate, toluene or petroleum ether; the organic solvent for recrystallization is selected from 40-80% of methanol, 40-70% of ethanol, or 20-60% of acetone.
The technical problem to be solved by the present invention can be further achieved by the following technical means. The invention discloses a plant alkaloid extract preparation, which is characterized in that the plant alkaloid extract is mixed with a pharmaceutically acceptable drug carrier to prepare any pharmaceutically acceptable preparation.
The pharmaceutically acceptable carrier mentioned above refers to a pharmaceutical carrier which is conventional in the pharmaceutical field, for example: diluents, excipients, and water, and the like, fillers such as starch, sucrose, lactose, microcrystalline cellulose, and the like; binders such as cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone; humectants such as glycerol; disintegrating agents such as sodium carboxymethyl starch, hydroxypropyl cellulose, crosslinked carboxymethyl cellulose, agar, calcium carbonate and sodium bicarbonate; absorption enhancers such as quaternary ammonium compounds; surfactants such as cetyl alcohol, sodium lauryl sulfate; adsorption carriers such as kaolin and bentonite; lubricants such as talc, calcium and magnesium stearate, micronized silica gel, polyethylene glycol, and the like; other adjuvants such as flavoring agent, sweetener, etc. can also be added into the composition.
The formulations of the present invention may be administered to a patient in need of such treatment by oral, rectal or parenteral administration. The oral, rectal and parenteral administration preparation is all oral or external preparations in pharmacy, such as tablets, capsules, sprays, powders, granules, oral liquids, dropping pills, powders, suppositories, sustained-release preparations, controlled-release preparations, suppositories, gels, patches, cataplasms, films, syrups, elixirs and the like; the injection preparation is all pharmaceutics such as injection, infusion solution, freeze-dried injection, liposome injection, water or oily suspension, targeted drug delivery injection, injection emulsion and the like; preferred forms are tablets, coated tablets, capsules, granules, oral liquids and injections. The various dosage forms can be prepared according to conventional production methods in the pharmaceutical field. For example, the extract may be mixed with one or more carriers and then formulated into a desired dosage form.
The technical problem to be solved by the present invention can be further achieved by the following technical means. The plant alkaloid extract preparation is characterized in that the weight percentage content of the extract in the mixed raw materials of the extract and the drug carrier is 0.1-99.5%; preferably from 0.5% to 95%.
The technical problem to be solved by the present invention can be further achieved by the following technical means. The plant alkaloid extract preparation is characterized in that the preparation is a tablet or a capsule prepared by adding a filler and a disintegrating agent into an extract; or sustained release tablet or capsule prepared by adding filler and hypromellose K4M into the extract; or dispersing the extract in oil phase to obtain soft capsule; or an injection formed by adding a solubilizer or a cosolvent into the extract; or an emulsion for injection obtained by dispersing the extract in an oil phase; or adding medicinal adjuvants into the extract to make into suspension injection or lyophilized powder for injection.
The technical problem to be solved by the present invention can be further achieved by the following technical means. The plant alkaloid extract preparation is characterized in that the filler is selected from lactose, microcrystalline cellulose, dextrin, starch or calcium phosphate; the disintegrant is selected from hydroxypropyl cellulose, sodium carboxymethyl starch, crospovidone or croscarmellose sodium; optionally adding binder, lubricant or wetting agent when preparing tablet and capsule; the oil phase is selected from soybean oil, polyethylene glycol 400, cottonseed oil, peanut oil, sesame oil, corn oil or olive oil; when preparing soft capsule, solubilizer or cosolvent and antioxidant can also be added; the solubilizer used in the injection is selected from polyoxyethylene ether castor oil, tween or pluronic F-68; the cosolvent can be dilute hydrochloric acid, ornithine hydrochloride, arginine hydrochloride, citric acid, acidic amino acids or other acidic organic substances and their acidic salts, or alcohols, including ethanol, propylene glycol and mannitol.
The technical problem to be solved by the present invention can be further achieved by the following technical means. The plant alkaloid extract preparation is characterized in that the suspension injection is prepared by mixing and grinding the extract and polysorbate 80, dissolving the mixture into an aqueous solution containing potassium dihydrogen phosphate, dipotassium hydrogen phosphate, nipagin ester and sodium carboxymethyl cellulose, and grinding the aqueous solution.
The plant alkaloid extract and the preparation thereof can be used for preparing medicines for treating liver cancer, lung cancer and other tumors and medicines for treating inflammation.
The main component of the plant alkaloid extract is solamargine, so the plant alkaloid extract is hereinafter referred to as the solamargine extract for short.
Solamargine (solaamargine) having the following structural formula:
the dosage of the preparation of the present invention to be administered may vary depending on the route of administration, the age, body weight, body surface area of the patient, the type and severity of the disease to be treated, etc., and the safe and effective daily dosage may be:
the safe and effective dose for human clinical oral, rectal and parenteral administration is as follows: 0.1-10 mg/kg body weight/day of solamargine extract; safe and effective dose for human clinical injection: 0.01-2 mg/kg body weight/day of solamargine extract; one or more administrations may be carried out.
Compared with the prior art, the extraction steps of the extract are scientific and reasonable, the obtained extract has low impurity content, the content of the active component solamargine is high, the lowest content of the solamargine can reach 90.0 percent, and the highest content of the solamargine can reach 99.9 percent; experiments prove that the extract preparation is safe and effective and has controllable quality.
Detailed Description
The following examples are presented to enable one of ordinary skill in the art to more fully understand the present invention and are not intended to limit the invention in any way.
Example 1. A plant alkaloid extract is extracted from the whole plant of solanum nigrum, and the extraction method comprises the following steps:
(1) extracting herba Solani Nigri with 50% ethanol solution for 2 times (4 times each time), recovering ethanol, concentrating to relative density of 1.10, adding 1 time of 0.01mol/l acidic solution, stirring, refrigerating for more than 12 hr, and filtering; washing the filter residue with 0.01mol/l acidic solution for 1 time, combining the filtrate and the washing solution, and adsorbing with weak-polarity or medium-polarity resin;
(2) after the resin is adsorbed, firstly washing the resin column/bed by water until the effluent liquid is neutral, then washing the resin column/bed by alkaline ethanol solution until the effluent liquid is colorless, or firstly washing the resin column/bed by alkaline solution until the effluent liquid is colorless, and then washing the resin column/bed by ethanol solution with the alcohol content of 5 percent until the effluent liquid is colorless; discarding the washing liquid, eluting with 50% ethanol until the eluate is colorless, collecting the eluate, recovering ethanol until no ethanol smell exists, adjusting pH to 8 with alkaline solution, standing, refrigerating, and collecting precipitate;
(3) and (2) drying the precipitate, dissolving the precipitate with 20 times of organic solvent, adding 0.5 times of chromatographic silica gel in the amount of the precipitate, uniformly stirring, drying by distillation, taking the silica gel mixed with the sample, carrying out column chromatography separation, carrying out wet column packing on the chromatographic column with the organic solvent, eluting with the organic solvent, collecting the eluent in times, carrying out thin-layer chromatography detection, combining the eluents subjected to thin-layer chromatography detection and consistent with the spot position of the solamargine sample, recovering the organic solvent, and drying by distillation to obtain the solamargine.
Example 2. A plant alkaloid extract is extracted from black nightshade fruit, and the extraction method comprises the following steps:
(1) extracting herba Solani Nigri whole plant and/or fruit, or Solanum xanthocarpum or Solanum australianum with 90% ethanol solution for 4 times (8 times each time), recovering ethanol, concentrating to relative density of 1.25, adding 4 times of 0.1mol/l acidic solution into the concentrated solution, stirring, refrigerating for more than 12 hr, and filtering; washing the filter residue with 0.1mol/l acidic solution for 3 times, combining the filtrate and the washing solution, and adsorbing with weak-polarity or medium-polarity resin;
(2) after the resin is adsorbed, firstly washing the resin column/bed by water until the effluent liquid is neutral, then washing the resin column/bed by alkaline ethanol solution until the effluent liquid is colorless, or firstly washing the resin column/bed by alkaline solution until the effluent liquid is colorless, and then washing the resin column/bed by ethanol solution with the alcohol content of 40 percent until the effluent liquid is colorless; discarding the washing liquid, eluting with 80% ethanol until the eluate is colorless, collecting the eluate, recovering ethanol until no ethanol smell exists, adjusting pH to 10 with alkaline solution, standing, refrigerating, and collecting precipitate;
(3) and (2) drying the precipitate, dissolving the precipitate with 25 times of organic solvent, adding 4 times of chromatographic silica gel, uniformly stirring, drying by distillation, taking the silica gel mixed with the sample, carrying out column chromatography separation, carrying out wet column packing on the chromatographic column by using the organic solvent, eluting by using the organic solvent, collecting the eluent in times, carrying out thin-layer chromatography detection, combining the eluents subjected to thin-layer chromatography detection and consistent with the spot position of the solamargine sample, recovering the organic solvent, and drying by distillation to obtain the solamargine.
Example 3. A plant alkaloid extract is extracted from Solanum xanthocarpum, and its extraction method comprises the following steps:
(1) extracting Solanum xanthocarpum with 70% ethanol solution for 3 times (6 times per time), recovering ethanol, concentrating to relative density of 1.20, adding 2 times of 0.05mol/l acidic solution, stirring, refrigerating for more than 12 hr, and filtering; washing the filter residue with 0.05mol/l acid solution for 2 times, combining the filtrate and the washing solution, and adsorbing with weak-polarity or medium-polarity resin;
(2) after the resin is adsorbed, firstly washing the resin column/bed by water until the effluent liquid is neutral, then washing the resin column/bed by alkaline ethanol solution until the effluent liquid is colorless, or firstly washing the resin column/bed by alkaline solution until the effluent liquid is colorless, and then washing the resin column/bed by ethanol solution with the alcohol content of 20 percent until the effluent liquid is colorless; discarding the washing liquid, eluting with 65% ethanol until the eluate is colorless, collecting the eluate, recovering ethanol until no alcohol smell exists, adjusting pH to 9 with alkaline solution, standing, refrigerating, and collecting precipitate;
(3) and (2) dissolving the precipitate with 22 times of organic solvent after drying, adding 2 times of chromatographic silica gel in the amount of the precipitate, uniformly stirring, drying by distillation, taking the silica gel mixed with the sample, carrying out column chromatography separation, carrying out wet column packing on the chromatographic column by using the organic solvent, eluting by using the organic solvent, collecting the eluent in times, carrying out thin-layer chromatography detection, combining the eluents with the same positions as the spots of the solamargine sample, recovering the organic solvent, and drying by distillation to obtain the solamargine.
Example 4. A plant alkaloid extract is extracted from solanum australis, and the extraction method comprises the following steps:
(1) extracting Solanum solatum with 60% ethanol solution for 3 times (5 times each time), recovering ethanol, concentrating to relative density of 1.15, adding 3 times of 0.08mol/l acidic solution, stirring, refrigerating for more than 12 hr, and filtering; washing the filter residue with 0.08mol/l acidic solution for 2 times, combining the filtrate and the washing solution, and adsorbing with weak-polarity or medium-polarity resin;
(2) after the resin is adsorbed, firstly washing the resin column/bed by water until the effluent liquid is neutral, then washing the resin column/bed by alkaline ethanol solution until the effluent liquid is colorless, or firstly washing the resin column/bed by alkaline solution until the effluent liquid is colorless, and then washing the resin column/bed by ethanol solution with the alcohol content of 10 percent until the effluent liquid is colorless; discarding the washing liquid, eluting with 60% ethanol until the eluate is colorless, collecting the eluate, recovering ethanol until no ethanol smell exists, adjusting pH to 8.5 with alkaline solution, standing, refrigerating, and collecting precipitate;
(3) drying the precipitate, adding 5 times of organic solvent with relatively large polarity, stirring for l 0min, standing, filtering, adding 2 times of organic solvent with low polarity into the filtrate, stirring, refining, filtering, recovering organic solvent, adding organic solvent for recrystallization, recrystallizing, and collecting crystals.
Example 5. A plant alkaloid extract is extracted from the whole plant and fruit of Solanum nigrum, and the extraction method comprises the following steps:
(1) extracting herba Solani Nigri whole plant and fruit with 80% ethanol solution for 2 times (7 times each time), recovering ethanol, concentrating to relative density of 1.22, adding 2.5 times of 0.02mol/l acidic solution into the concentrated solution, stirring, refrigerating for more than 12 hr, and filtering; washing the filter residue with 0.02mol/l acidic solution for 3 times, combining the filtrate and the washing solution, and adsorbing with weak-polarity or medium-polarity resin;
(2) after the resin is adsorbed, firstly washing the resin column/bed by water until the effluent liquid is neutral, then washing the resin column/bed by alkaline ethanol solution until the effluent liquid is colorless, or firstly washing the resin column/bed by alkaline solution until the effluent liquid is colorless, and then washing the resin column/bed by ethanol solution with 30 percent of alcohol content until the effluent liquid is colorless; discarding the washing liquid, eluting with 70% ethanol until the eluate is colorless, collecting the eluate, recovering ethanol until no ethanol smell exists, adjusting pH to 9.5 with alkaline solution, standing, refrigerating, and collecting precipitate;
(3) drying the precipitate, adding 20 times of organic solvent with relatively large polarity, stirring for 30 min, standing, filtering, adding 6 times of organic solvent with low polarity into the filtrate, stirring, refining, filtering, recovering organic solvent, adding organic solvent for recrystallization, recrystallizing, and collecting crystals.
Example 6. A plant alkaloid extract is extracted from the whole plant and fruit of Solanum nigrum, and the extraction method comprises the following steps:
(1) soaking whole plant and fruit of Solanum nigrum in 0.01mol/l acidic solution for 2 times, each time with 4 times of dosage and each time for 6 hr, mixing soaking solutions, and adsorbing with weak polar or medium polar resin;
(2) after the resin is adsorbed, firstly washing the resin column/bed by water until the effluent liquid is neutral, then washing the resin column/bed by alkaline ethanol solution until the effluent liquid is colorless, or firstly washing the resin column/bed by alkaline solution until the effluent liquid is colorless, and then washing the resin column/bed by ethanol solution with the alcohol content of 25 percent until the effluent liquid is colorless; discarding the washing liquid, eluting with 75% ethanol until the eluate is colorless, collecting the eluate, recovering ethanol until no ethanol smell exists, adjusting pH to 9 with alkaline solution, standing, refrigerating, and collecting precipitate;
(3) drying the precipitate, adding 12 times of organic solvent with relatively large polarity, stirring for 20 min, standing, filtering, adding 4 times of organic solvent with low polarity into the filtrate, stirring, refining, filtering, recovering organic solvent, adding organic solvent for recrystallization, recrystallizing, and collecting crystals.
Example 7. A plant alkaloid extract is extracted from Solanum xanthocarpum, and its extraction method comprises the following steps:
(1) soaking Solanum xanthocarpum in 0.1mol/l acidic solution for 4 times, each time with 8 times of dosage, each time for 24 hr, mixing soaking solutions, and adsorbing with weak polar or medium polar resin;
(2) after the resin is adsorbed, firstly washing the resin column/bed by water until the effluent liquid is neutral, then washing the resin column/bed by alkaline ethanol solution until the effluent liquid is colorless, or firstly washing the resin column/bed by alkaline solution until the effluent liquid is colorless, and then washing the resin column/bed by ethanol solution with the alcohol content of 35 percent until the effluent liquid is colorless; discarding the washing liquid, eluting with 55% ethanol until the eluate is colorless, collecting the eluate, recovering ethanol until no alcohol smell is produced, adjusting pH to 8 with alkaline solution, standing, refrigerating, and collecting precipitate;
(3) drying the precipitate, adding 15 times of organic solvent with relatively high polarity, stirring for 25 min, standing, filtering, adding 3 times of low-polarity organic solvent into the filtrate, stirring, refining, filtering, recovering organic solvent, adding organic solvent for recrystallization, recrystallizing, and collecting crystals.
Example 8. A plant alkaloid extract is extracted from solanum australis, and the extraction method comprises the following steps:
(1) soaking Solanum solatum in 0.05mol/l acidic solution for 3 times, 6 times each time, and 12 hr each time, mixing soaking solutions, and adsorbing with weak polar or medium polar resin;
(2) after the resin is adsorbed, firstly washing the resin column/bed by water until the effluent liquid is neutral, then washing the resin column/bed by alkaline ethanol solution until the effluent liquid is colorless, or firstly washing the resin column/bed by alkaline solution until the effluent liquid is colorless, and then washing the resin column/bed by ethanol solution with the alcohol content of 25 percent until the effluent liquid is colorless; discarding the washing liquid, eluting with 70% ethanol until the eluate is colorless, collecting the eluate, recovering ethanol until no ethanol smell exists, adjusting pH to 9 with alkaline solution, standing, refrigerating, and collecting precipitate;
(3) drying the precipitate, adding 10 times of organic solvent with relatively large polarity, stirring for 15 min, standing, filtering, adding 5 times of organic solvent with low polarity into the filtrate, stirring, refining, filtering, recovering organic solvent, adding organic solvent for recrystallization, recrystallizing, and collecting crystals.
Example 9. A plant alkaloid extract is extracted from the whole plant of solanum nigrum, and the extraction method comprises the following steps:
(1) soaking whole herba Solani Nigri in 0.08mol/l acidic solution for 3 times, each time with 5 times of dosage and each time for 20 hr, mixing soaking solutions, and adsorbing with weak polar or medium polar resin;
(2) after the resin is adsorbed, firstly washing the resin column/bed by water until the effluent liquid is neutral, then washing the resin column/bed by alkaline ethanol solution until the effluent liquid is colorless, or firstly washing the resin column/bed by alkaline solution until the effluent liquid is colorless, and then washing the resin column/bed by ethanol solution with 30 percent of alcohol content until the effluent liquid is colorless; discarding the washing liquid, eluting with 75% ethanol until the eluate is colorless, collecting the eluate, recovering ethanol until no ethanol smell exists, adjusting pH to 9 with alkaline solution, standing, refrigerating, and collecting precipitate;
(3) and (2) drying the precipitate, dissolving the precipitate with 22 times of organic solvent, adding 3 times of chromatographic silica gel, uniformly stirring, drying by distillation, taking the silica gel mixed with the sample, carrying out column chromatography separation, carrying out wet column packing on the chromatographic column by using the organic solvent, eluting by using the organic solvent, collecting the eluent in times, carrying out thin-layer chromatography detection, combining the eluents which are detected by the thin-layer chromatography and are consistent with the spot position of the solamargine sample, recovering the organic solvent, and drying by distillation to obtain the solamargine.
Example 10. In this example 1, the content of solamargine in the extract was 90.0%; the acidic solution in the step (1) is an acetic acid solution; the alkaline solution in the step (2) is a sodium hydroxide solution with the concentration of 0.05mol/l, the alkaline ethanol solution is an alkaline ethanol solution containing sodium hydroxide with the concentration of 0.05mol/l, and the alcohol concentration is 5%; the organic solvent for dissolving in the step (3) is methanol; the organic solvent for column chromatography elution is one of methanol, absolute ethyl alcohol, acetone, n-butanol, chloroform and ethyl acetate.
Example 11. In this example 2, the content of solamargine in the extract was 95%; the acidic solution in the step (1) is a hydrochloric acid solution; the alkaline solution in the step (2) is a calcium hydroxide solution with the concentration of 1.5mol/l, the alkaline ethanol solution is an alkaline ethanol solution containing calcium hydroxide with the concentration of 0.15mol/l, and the alcohol concentration is 40%; the organic solvent for dissolving in the step (3) is absolute ethyl alcohol; the organic solvent for column chromatography elution is a mixed phase formed by 2 items in methanol, absolute ethyl alcohol, acetone, n-butanol, chloroform and ethyl acetate in any proportion.
Example 12. In this example 3, the content of solamargine in the extract was 99.9%; the acid solution in the step (1) is a sulfuric acid solution; the alkaline solution in the step (2) is selected from potassium hydroxide solution with the concentration of 1.0mol/l, the alkaline ethanol solution is alkaline ethanol solution containing potassium hydroxide with the concentration of 0.10mol/l, and the alcohol concentration is 20 percent; the organic solvent for dissolving in the step (3) is acetone; the organic solvent for column chromatography elution is a mixed phase formed by 3 items in methanol, absolute ethyl alcohol, acetone, n-butanol, chloroform and ethyl acetate in any proportion.
Example 13. In this example 4, the solamargine content in the extract was 91.0%; the acid solution in the step (1) is a citric acid solution; the alkaline solution in the step (2) is selected from magnesium hydroxide solution with the concentration of 0.10mol/l, the alkaline ethanol solution is selected from magnesium hydroxide solution with the concentration of 0.08mol/l, and the alcohol concentration is 10 percent; the organic solvent with higher polarity in the step (3) is methanol or ethanol or n-butanol or acetone; the low-polarity organic solvent is chloroform or dichloromethane; the organic solvent for recrystallization is 40 to 80 percent of methanol.
Example 14. In this example 5, the content of solamargine in the extract was 94.0%; the acid solution in the step (1) is a citric acid solution; the alkaline solution in the step (2) is an ammonia water solution with the concentration of 0.50mol/l, the alkaline ethanol solution is an alkaline ethanol solution containing ammonia water with the concentration of 0.12mol/l, and the alcohol concentration is 30%; the organic solvent with larger polarity in the step (3) is a mixed phase of methanol and ethanol; the low-polarity organic solvent is dichloroethane or ethyl acetate; the organic solvent for recrystallization is 40 to 70 percent ethanol.
Example 15. In this example 6, the content of solamargine in the extract was 98%; the acidic solution in the step (1) is an acetic acid solution; the alkaline solution in the step (2) is selected from sodium hydroxide solution with the concentration of 1.2mol/l, the alkaline ethanol solution is alkaline ethanol solution containing sodium hydroxide with the concentration of 0.07mol/l, and the alcohol concentration is 35 percent; the organic solvent with higher polarity in the step (3) is a mixed phase of n-butanol and acetone; the low-polarity organic solvent is toluene or petroleum ether; the organic solvent for recrystallization is 20 to 60 percent of acetone.
Example 16. In this example 7, the content of solamargine in the extract was 97%; the acidic solution in the step (1) is a hydrochloric acid solution; the alkaline solution in the step (2) is a calcium hydroxide solution with the concentration of 0.80mol/l, the alkaline ethanol solution is an alkaline ethanol solution containing calcium hydroxide with the concentration of 0.08mol/l, and the alcohol concentration is 20%; the organic solvent with larger polarity in the step (3) is a mixed phase of methanol and n-butanol; the low-polarity organic solvent is petroleum ether; the organic solvent for recrystallization is 60% methanol.
Example 17. In this example 8, the content of solamargine in the extract was 93.0%; the acid solution in the step (1) is a sulfuric acid solution; the alkaline solution in the step (2) is selected from potassium hydroxide solution with the concentration of 1.1mol/l, the alkaline ethanol solution is alkaline ethanol solution containing potassium hydroxide with the concentration of 0.14mol/l, and the alcohol concentration is 30 percent; the organic solvent with larger polarity in the step (3) is a mixed phase of ethanol and acetone; the low-polarity organic solvent is chloroform; the organic solvent for recrystallization is 55% ethanol.
Example 18. In this example 9, the content of solamargine in the extract was 99.0%; the acid solution in the step (1) is a citric acid solution; the alkaline solution in the step (2) is selected from magnesium hydroxide solution with the concentration of 1.3mol/l, the alkaline ethanol solution is alkaline ethanol solution containing magnesium hydroxide with the concentration of 0.14mol/l, and the alcohol concentration is 28 percent; the organic solvent for dissolving in the step (3) is acetone or isopropanol or propylene glycol; the organic solvent for column chromatography elution is one of methanol, absolute ethyl alcohol, acetone, n-butanol, chloroform and ethyl acetate.
Example 19. A plant alkaloid extract preparation as described in example 1, wherein said plant alkaloid extract is formulated into an oral dosage form by mixing with a pharmaceutically acceptable carrier.
Example 20. A plant alkaloid extract preparation as described in example 2, wherein the extract is combined with a filler and a disintegrant to form a tablet, wherein the weight percentage of the extract in the mixed raw materials is 5%.
Example 21. A plant alkaloid extract preparation as described in example 3, wherein the extract is combined with a filler and a disintegrant to form a capsule, wherein the weight percentage of the extract in the mixed raw materials is 20%.
Example 22. A plant alkaloid extract preparation as described in example 4, wherein said extract is combined with a filler and hypromellose K4M to form a sustained release tablet, wherein the weight percentage of the extract in the mixed raw materials is 5%.
Example 23. A plant alkaloid extract preparation as described in example 5, wherein the extract is combined with a filler and hypromellose K4M to form a sustained release capsule, wherein the weight percentage of the extract in the mixed raw materials is 10%.
Example 24. A plant alkaloid extract preparation as described in example 1, wherein said extract is dispersed in an oil phase to obtain a soft capsule, wherein the weight percentage of the extract in the mixed raw material is 20%.
Example 25. A plant alkaloid extract preparation as described in example 2, wherein the extract is taken and an injection formed by solubilizer or cosolvent, and the content of the extract in the mixed raw materials is 0.1% by weight.
Example 26. A plant alkaloid extract preparation as described in example 3, wherein the extract is dispersed in oil phase to obtain emulsion for injection, and the weight percentage content of the extract in the mixed raw material is 0.2%.
Example 27. A plant alkaloid extract preparation as described in example 4, wherein the extract is mixed with pharmaceutical adjuvants to make into suspension injection, and the weight percentage of the extract in the mixed raw materials is 0.5%.
Example 28. A plant alkaloid extract preparation as described in example 5, wherein the extract is mixed with pharmaceutical adjuvants to make into lyophilized injectable powder, wherein the content of the extract in the mixed raw materials is 10% by weight.
Example 29. A plant alkaloid extract preparation as described in example 1, wherein the extract is mixed with polysorbate 80 and ground, and dissolved in an aqueous solution containing potassium dihydrogen phosphate, dipotassium hydrogen phosphate, nipagin ester and sodium carboxymethylcellulose, and ground to obtain a suspension type injection, wherein the weight percentage of the extract in the mixed raw materials is 0.3%. Can be used for treating liver cancer, lung cancer, other tumors and inflammation.
Example 30. Solamargine extract capsule.
Solamargine extract 10-60 g
30-50 g of microcrystalline cellulose
Lactose 30-50 g
5-10 g of sodium carboxymethyl starch
Appropriate amount of 2% HPMCE5 solution (containing 5% Tween 80)
Magnesium stearate 1-5 g
The preparation method comprises dissolving solamargine extract in small amount of ethanol; respectively sieving microcrystalline cellulose, lactose and sodium carboxymethyl starch with 100 mesh sieve, mixing, adding solamargine extract ethanol solution, and stirring to volatilize ethanol; preparing soft material with HPMC solution containing Tween 80 as adhesive, sieving with 20 mesh sieve to obtain granule, and air drying the wet granule in oven at 50-60 deg.C; sieving the dried granules with a 20-mesh sieve, granulating, mixing with magnesium stearate, and encapsulating into 1000 capsules.
Example 31. A tablet of solamargine extract.
Solamargine extract 1060 g
30-50 g of microcrystalline cellulose
Lactose 30-50 g
5-10 g of sodium carboxymethyl starch
Appropriate amount of 2% HPMCE5 solution (containing 5% Tween 80)
Magnesium stearate 1-5 g
The preparation method comprises dissolving solamargine extract in small amount of ethanol; respectively sieving microcrystalline cellulose, lactose and sodium carboxymethyl starch with 100 mesh sieve, mixing, adding solamargine extract ethanol solution, and stirring to volatilize ethanol; preparing soft material with HPMC solution containing Tween 80 as adhesive, sieving with 20 mesh sieve to obtain granule, and air drying the wet granule in oven at 50-60 deg.C; sieving the dried granules with a 20-mesh sieve, granulating, mixing with magnesium stearate, and tabletting to obtain 1000 tablets.
Example 32. A slowly-released capsule of solamargine extract.
Solamargine extract 60mg
Microcrystalline cellulose 20mg
Hydroxypropyl methylcellulose K4M 80mg
Proper amount of 3% hydroxypropyl methylcellulose (E5) aqueous solution
Talcum powder 4mg
Mixing solamargine extract, microcrystalline cellulose, and hydroxypropyl methylcellulose K4M with 60 mesh sieve, adding appropriate amount of hydroxypropyl methylcellulose (E5) 3% water solution, making soft mass, sieving with 20 mesh sieve, and granulating. Drying in an oven at 40-50 deg.C by blowing. Sieving the dry granules with a 20-mesh sieve, grading, adding the prescribed amount of talcum powder, and uniformly mixing. And filling the capsules into No. 1 according to the prescription amount, wherein each capsule contains 60mg of the solamargine extract.
Example 33. A slowly-released tablet of solamargine extract.
Solamargine extract 100mg
Lactose 20mg
Hydroxypropyl methylcellulose K4M 80mg
Proper amount of 3% hydroxypropyl methylcellulose (E5) aqueous solution
Talcum powder 4mg
Mixing solamargine extract, lactose, and hypromellose K4M with 60 mesh sieve, adding appropriate amount of hydroxypropyl methylcellulose (E5) water solution 3%, making soft mass, sieving with 20 mesh sieve, and granulating. Drying in an oven at 40-50 deg.C by blowing. Sieving the dry granules with a 20-mesh sieve, grading, adding the prescribed amount of talcum powder, mixing uniformly, and tabletting, wherein each granule contains 100mg of the solamargine extract.
Other excipients, disintegrants, such as: hydroxypropyl starch, hydroxypropyl cellulose, sodium carboxymethyl starch, calcium carboxymethyl cellulose, crospovidone, croscarmellose sodium, and the like; fillers such as: lactose, sucrose, mannitol, microcrystalline cellulose, dextrin, starch, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, cyclodextrin, micropowder cellulose, etc.; wetting agents and binders such as: pregelatinized starch, povidone, sodium carboxymethylcellulose, hypromellose; lubricants such as: talcum powder, stearic acid, magnesium stearate, calcium stearate, superfine silica powder, hydrogenated vegetable oil, polyethylene glycol 4000 and 6000; wetting agents such as: sodium dodecyl sulfate, tween 80; the framework material is as follows: hypromellose, ethylcellulose, and the like.
Example 34. Solamargine extract soft capsule.
Each grain of the content contains a rubber shell
Solamargine extract 150mg gelatin 46.00%
Soybean oil 0.5ml glycerol 17.82%
36.18 percent of water
Dissolving solamargine extract in soybean oil, and making into soft capsule. Each capsule contains solamargine extract 150 mg.
The soft capsule of the invention can also select the following auxiliary materials: solvents such as: polyethylene glycol 400, cottonseed oil, peanut oil, sesame oil, corn oil, olive oil and the like; solubilizers or cosolvents such as: tween 80, polyoxyethylene castor oil, benzyl benzoate, ethyl lactate and the like; antioxidants such as: propyl gallate, tert-butyl phenol (BHT), vitamin E, etc. The proportion of gelatin, glycerol and water in the gelatin shell can be properly adjusted, for example, the proportion of gelatin/glycerol/water is preferably 1: 0.3-0.4: 0.7-1.4, and other components such as preservative can be added into the gelatin shell: methyl, ethyl, propyl, butyl p-hydroxybenzoate and the like; plasticizers such as sorbitol and the like; stabilizers such as gum arabic and the like; opacifiers such as: titanium dioxide, barium sulfate, precipitated calcium carbonate, and the like.
Example 35. The solamargine extract emulsion for injection.
Solamargine extract 5g
50g of soybean oil
Soybean lecithin 12g
Glycerol 25g
Adding water for injection to 1000ml
Under nitrogen flow, adding soybean oil into soybean phospholipid, stirring to dissolve, adding glycerol and solamargine extract, stirring to dissolve, slowly adding water for injection under stirring, and emulsifying by two-step high-pressure emulsifying machine; filtering under reduced pressure with No. 4 sintered glass funnel under nitrogen flow, bottling under nitrogen flow, capping, preheating, sterilizing at 121 deg.C for 15 min, and cooling with hot water.
The following auxiliary materials can also be selected in the embodiment: oils for injection such as: ethyl oleate, polyethylene glycol 400, cottonseed oil, peanut oil, sesame oil, corn oil, olive oil, isopropyl myristate, and the like; antioxidants such as: propyl gallate, tert-butyl phenol (BHT), vitamin E, and the like; surfactants such as: tween, polyoxyethylene castor oil, phospholipids, pluronic, and the like.
Example 36. Solamargine extract injection.
Solamargine extract 20mg
Polyoxyethylene Ether Castor oil 1.0mg
Anhydrous ethanol 5.0mg
Adding water for injection to 5.0mL
Dissolving solamargine extract in anhydrous ethanol, adding 20% polyoxyethylene ether castor oil (cremophorELP), mixing, evaporating under reduced pressure to remove ethanol, adding appropriate amount of water for injection, mixing to obtain clear transparent solution, filtering with 0.22 μm microporous membrane, packaging, sealing, and sterilizing with flowing steam at 100 deg.C for 30 min to obtain the final product, each of which contains 20mg of solamargine extract.
Example 37. Solamargine extract injection.
Solamargine extract 20.0g
Arginine hydrochloride 22.2
Proper amount of sodium chloride
Adding water for injection to 2000mL
Placing solamargine extract and arginine hydrochloride in a suitable container, adding 1800ml of water for injection, stirring, ultrasonically treating to dissolve, adding sodium chloride, and stirring to dissolve; adding water for injection to 2000ml, filtering with 0.22 μm microporous membrane, packaging, sealing, and sterilizing with flowing steam at 100 deg.C for 30 min to obtain the final product, each containing 20mg of solamargine extract.
Example 38. A powder for injection containing solamargine extract.
Solamargine extract 20.0g
Ornithine hydrochloride 22.2g
Mannitol 32.0g
Water for injection up to 2000ml
Putting the solamargine extract and arginine into a proper container, adding 1800ml of water for injection, stirring uniformly, performing ultrasonic treatment to dissolve, adding mannitol, and stirring to dissolve; adding 0.1% of active carbon for a needle, stirring for 30 minutes, decarburizing by using a titanium sand core, performing suction filtration on the decarburizing solution to a clean container, adding 2000ml of water for injection, stirring the solution for 5 minutes to be uniform, filtering the solution by using a 0.22-micron microporous membrane, filling the filtrate into 7ml of penicillin bottles with 2ml of each penicillin bottle, partially plugging butyl rubber plugs, conveying the penicillin bottles onto a plate layer in a freeze-drying box, inserting a temperature probe, and closing a box door. Freeze drying according to freeze drying curve, and keeping the final drying temperature above 35 deg.C for 2 hr. Sealing, deflating, taking out of the box and capping.
Example 39. Solamargine extract suspension injection.
Solamargine extract 20mg
Sodium carboxymethylcellulose 10mg
Polysorbate 800.1 mg
Nipagin ethyl ester 0.5mg
Propyl p-hydroxybenzoate 0.5mg
Potassium dihydrogen phosphate 16.7mg
Dipotassium hydrogen phosphate 1.7mg
Adding water for injection to 2ml
Jet milling solamargine extract to obtain micropowder with particle diameter of less than 10 μm. Dissolving potassium dihydrogen phosphate and dipotassium hydrogen phosphate in water for injection, adding ethylparaben and propyl ester, adding sodium carboxymethylcellulose, and dissolving at 60 deg.C. Placing micronized solamargine extract in a container, adding polysorbate 80, grinding into fine paste, gradually adding the above solution, stirring, and grinding with colloid mill for 5-10 times. Packaging into ampoules according to conventional determination method, and sterilizing with flowing steam at 100 deg.C for 30 min to obtain the final product, wherein each ampoule contains 20mg of solamargine extract.
The injection of the invention can also select the following auxiliary materials: solubilizers such as: tween, pluronic F-68, polyoxyethylene ether castor oil, etc.; and the cosolvent comprises: amide compounds such as urea, acetamide, thiourea, benzamide and the like, hydroxyl or carboxyl group-containing compounds such as sucrose, citric acid and sodium salts thereof, lactic acid, sodium salicylate and the like; suspending agents such as: sodium carboxymethylcellulose, povidone, hydroxypropylmethylcellulose, and the like; preservatives such as: methyl, ethyl, propyl and butyl parabens; pH adjusting agents such as: citric acid and citrate, phosphate, etc.; solvents such as: water for injection, ethanol for injection, propylene glycol, and the like.
Example 40. The solamargine extract prepared in example 3 was tested for oral pharmacological toxicology studies.
(1) Study of pharmacodynamics
1. Effect of solamargine on tumor inhibition rate of S180 sarcoma transplantable tumor
1.1 Experimental methods
Ascites cancer cell suspension which grows in the abdominal cavity of the KM mouse for 8 days is extracted under the aseptic condition, and the cancer cell suspension and the sterilized normal saline are mixed according to the weight ratio of 1: 3, 50 KM mice are taken, and 0.2ml of diluted cancer cell suspension is inoculated to the axilla part under the skin. After 24h, the mice were randomly divided into 7 groups, namely a model group, a 5-Fu group (25mg/kg) and solamargine 1, 2, 3, 4 and 5 groups (0.6mg/kg, 1.2mg/kg, 2.4mg/kg, 4.8mg/kg and 9.6mg/kg), 10 of each group were separately administered with corresponding drugs by gavage (equal volume distilled water was administered by gavage of the model group), the mice were sacrificed after 8 days, tumors were removed, weighed, and the tumor inhibition rate was calculated according to the following formula.
1.2 results of the experiment
Mouse inoculation S180After the tumor, the tumor can be touched subcutaneously for 3 days, the average weight of the dissected tumor is more than 1g after 8 days, the tumor infiltration range of mice with 5 doses of solamargine is less than that of the model group, the tumor body is easy to strip, and the tumor weight is obviously reduced (P)<0.05，P<0.01). The results are shown in Table 1.
TABLE 1 solamargine pair S180Influence of tumor inhibition Rate of solid tumors by transplantation (X. + -. S, n ═ 10)
Note: in comparison with the set of models,**P<0.01。
2. influence of solamargine on tumor inhibition rate of Hep liver cancer transplanted tumor
2.1 Experimental methods
Ascites cancer cell suspension which grows in the abdominal cavity of the KM mouse for 8 days is extracted under the aseptic condition, and the cancer cell suspension and the sterilized normal saline are mixed according to the weight ratio of 1: 3, 50 KM mice are taken, and 0.2ml of diluted cancer cell suspension is inoculated to the axilla part under the skin. After 24h, the mice were randomly divided into 5 groups, namely a model group, a 5-Fu group (25mg/kg) and a solamargine low, medium and high dose group (1.2mg/kg, 2.4mg/kg and 4.8mg/kg), respectively gavage corresponding drugs (equal volume distilled water is given for the gavage of the model group), and after 8 days, the mice were sacrificed, the tumors were stripped and weighed, and the tumor inhibition rate was calculated according to the following formula.
2.2 results of the experiment
After the Hep liver cancer tumor is inoculated to the mice, the tumors can be contacted subcutaneously for four days, the average weight of the dissected tumors is more than 1g after 8 days, the tumor infiltration range of the mice of the three dose groups of the solamargine is less than that of the model group, the tumor bodies are easy to strip, and the tumor weight is obviously reduced (P is less than 0.05 and 0.01). The tumor inhibition rate is more than 30 percent. The results are shown in Table 2.
TABLE 2 influence of solamargine on the tumor suppression rate of Hep-transplantable solid tumors (X. + -. S)
Note: in comparison with the set of models,*P<0.05，**P<0.01。
3. effect on swelling of mouse auricle
3.1 Experimental methods
Taking 50 normal ICR mice, weighing 25-30 g and male. Randomized into 5 groups of 10 mice each, blank, acetylsalicylic acid: (110mg/kg) and low, medium and high doses of solamargine (1.2mg/kg, 2.4mg/kg, 4.8mg/kg), respectively, the corresponding drugs were administered by intragastric administration (equal volume distilled water for the blank group), once a day for 3 consecutive days. After administration for 40min on day 3, the two sides of the left ear of the mouse were smeared with 0.05ml of 2% croton oil, the mouse was sacrificed after 4h of inflammation, the left and right ears were cut off along the base line of the auricle, round ear pieces were removed from the same portions by a punch (diameter 9mm), weighed by an electronic balance, and the difference between the weights of the left and right ear shells of the mouse was taken as the swelling degree of the ear shells, and the swelling percentage was calculated.
3.2 results of the experiment
The solamargine dosage groups can reduce the ear swelling degree of mice caused by croton oil and reduce the swelling rate, and compared with a blank group, the solamargine dosage groups have significant differences (p is less than 0.05, and p is less than 0.01). The solamargine is shown to have anti-inflammatory effect, and the result is shown in table 3.
TABLE 3 Effect of solamargine on swelling of mouse ears by croton oil (X. + -. S)
Note: in comparison to the blank set, the data is,*p<0.05，**p<0.01。
in summary, the intragastric administration of solamargine to S180Hep liverThe cancer transplantation tumor has stronger anti-tumor effect, and the solamargine also has certain anti-inflammatory effect.
(2) Toxicological study
Acute toxicity test
Through acute toxicity tests: once intragastric administration of solamargine, its LD1The dosage is 0.1g/kg, which is reduced to 10 mg/kg.
Example 41. The pharmacological and toxicological studies of the solamargine extract injection preparation prepared in example 3 were conducted.
(1) Study of pharmacodynamics
1. Solamargine pair S for injection180Effect of tumor inhibition Rate of sarcoma-transplantable tumors
1.1 Experimental methods
Ascites cancer cell suspension which grows in the abdominal cavity of the KM mouse for 8 days is extracted under the aseptic condition, and the cancer cell suspension and the sterilized normal saline are mixed according to the weight ratio of 1: 3, 50 KM mice are taken, and 0.2ml of diluted cancer cell suspension is inoculated to the axilla part under the skin. After 24h, the mice were randomly divided into 7 groups, namely a model group, a 5-Fu group (25mg/kg) and solamargine 1, 2, 3, 4 and 5 groups (0.03mg/kg, 0.06mg/kg, 0.12mg/kg, 0.24mg/kg and 0.48mg/kg), 10 of each group were administered with the corresponding drugs by intravenous injection (the model group was injected with an equal volume of physiological saline), the mice were sacrificed 8 days later, the tumors were removed, weighed and the tumor inhibition rate was calculated according to the following formula.
1.2 results of the experiment
Mouse inoculation S180After the tumor, the tumor can be touched subcutaneously for 3 days, the average weight of the dissected tumor is more than 1g after 8 days, the tumor infiltration range of mice with 5 doses of solamargine is less than that of the model group, the tumor body is easy to strip, and the tumor weight is obviously reduced (P)<0.01). The results are shown in Table 1.
TABLE 1 solamargine pair S180Influence of tumor inhibition Rate of solid tumors by transplantation (X. + -. S, n ═ 10)
Note: in comparison with the set of models,*P<0.05，**P<0.01。
2. influence of solamargine for injection on tumor inhibition rate of Hep liver cancer transplanted tumor
2.1 Experimental methods
Ascites cancer cell suspension which grows in the abdominal cavity of the KM mouse for 8 days is extracted under the aseptic condition, and the cancer cell suspension and the sterilized normal saline are mixed according to the weight ratio of 1: 3, 50 KM mice are taken, and 0.2ml of diluted cancer cell suspension is inoculated to the axilla part under the skin. After 24h, the mice were randomly divided into 5 groups, namely a model group, a 5-Fu group (25mg/kg) and a solamargine low, medium and high dose group (0.06mg/kg, 0.12mg/kg and 0.24mg/kg), and the corresponding drugs were respectively administered by intravenous injection (the model group was injected with physiological saline of equal volume), and after 8 days, the mice were sacrificed, the tumors were removed, weighed, and the tumor inhibition rate was calculated according to the following formula.
2.2 results of the experiment
After the Hep liver cancer tumor is inoculated to the mice, the tumors can be contacted subcutaneously for four days, the average weight of the dissected tumors is more than 1g after 8 days, the tumor infiltration range of the mice of the three dose groups of the solamargine is less than that of the model group, the tumor bodies are easy to strip, and the tumor weight is obviously reduced (P is less than 0.05 and 0.01). The tumor inhibition rate is more than 30 percent. The results are shown in Table 2.
TABLE 2 influence of solamargine on the tumor suppression rate of Hep-transplantable solid tumors (X. + -. S)
Note: in comparison with the set of models,*P<0.05，**P<0.01。
3. effect on swelling of mouse auricle
3.1 Experimental methods
Taking 50 normal ICR mice, weighing 25-30 g and male. Randomized into 5 groups of 10 mice each, blank, acetylsalicylic acid: (110mg/kg) and the low, medium and high solamargine dose groups (0.06mg/kg, 0.12mg/kg, 0.24mg/kg) were administered by intravenous injection of the corresponding drugs (the blank group was administered by equal volume saline injection) once daily for 3 consecutive days. After administration for 40min on day 3, the two sides of the left ear of the mouse were smeared with 0.05ml of 2% croton oil, the mouse was sacrificed after 4h of inflammation, the left and right ears were cut off along the base line of the auricle, round ear pieces were removed from the same portions by a punch (diameter 9mm), weighed by an electronic balance, and the difference between the weights of the left and right ear shells of the mouse was taken as the swelling degree of the ear shells, and the swelling percentage was calculated.
3.2 results of the experiment
The solamargine dosage groups can reduce the ear swelling degree of mice caused by croton oil and reduce the swelling rate, and compared with a blank group, the solamargine dosage groups have significant differences (p is less than 0.05, and p is less than 0.01). The solamargine is shown to have anti-inflammatory effect, and the result is shown in table 3.
TABLE 3 Effect of solamargine on swelling of mouse ears by croton oil (X. + -. S)
Note: in comparison to the blank set, the data is,*p<0.05，**p<0.01。
in summary, solamargine pair S for injection180The Hep liver cancer transplantation tumor has a strong anti-tumor effect, and the solamargine for injection also has a certain anti-inflammatory effect.
(2) Toxicology study acute toxicity test
Through acute toxicity tests: injection of solamargine by intravenous injection once, LD1The dosage is 20mg/kg, which is converted into 2 mg/kg.
Claims (1)
1. A method for extracting plant alkaloid extract is characterized in that the plant alkaloid extract is extracted from the whole plant and/or fruit of solanum nigrum, or Solanum xanthocarpum, or Solanum australianum, and the method comprises the following steps:
(1) soaking the whole plant and/or fruit of solanum nigrum, or Solanum xanthocarpum, or Solanum australianum in 0.01-0.1 mol/l acid solution for 2-4 times, wherein the dosage is 4-8 times each time, and the time is 6-24 hours each time, combining the soaking solutions, and adsorbing by weak-polarity or medium-polarity resin; the acid solution is selected from acetic acid, hydrochloric acid, sulfuric acid or citric acid solution;
(2) after the resin is adsorbed, firstly washing the resin column/bed by water until the effluent liquid is neutral, then washing the resin column/bed by alkaline ethanol solution until the effluent liquid is colorless, or firstly washing the resin column/bed by alkaline solution until the effluent liquid is colorless, and then washing the resin column/bed by ethanol solution with the alcohol content of 5-40% until the effluent liquid is colorless; discarding the washing solution, eluting with 50-80% ethanol until the eluate is colorless, collecting the eluate, recovering ethanol until no alcohol smell is produced, adjusting pH to 8-10 with alkaline solution, standing, refrigerating, and collecting precipitate; the alkaline solution is selected from 0.05-1.5mol/l sodium hydroxide, calcium hydroxide, potassium hydroxide, magnesium hydroxide or ammonia water solution, the alkaline ethanol solution is selected from 0.05-0.15mol/l sodium hydroxide, calcium hydroxide, potassium hydroxide, magnesium hydroxide or ammonia water alkaline ethanol solution, and the alcohol concentration of the alkaline ethanol solution is 5-40%;
(3) drying the precipitate, adding 5-20 times of organic solvent with larger polarity, stirring for 10-30 minutes, standing, filtering, adding 2-6 times of low-polarity organic solvent into the filtrate, stirring, refining, filtering, recovering the organic solvent, adding an organic solvent for recrystallization, recrystallizing, and collecting crystals to obtain the compound; the organic solvent with larger polarity is selected from methanol, ethanol, n-butanol, acetone or a mixed phase of the two; the low-polarity organic solvent is selected from chloroform, dichloromethane, dichloroethane, ethyl acetate, toluene or petroleum ether; the organic solvent for recrystallization is selected from 40-80% of methanol, 40-70% of ethanol, or 20-60% of acetone.
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| DE102009040381A1 (en) * | 2009-09-07 | 2011-03-17 | Kallimopoulos, Thomas, Dr. | Process for the isolation of alkaloids from plants |
| CN102000028B (en) * | 2010-11-03 | 2012-09-05 | 江苏康缘药业股份有限公司 | Solamargine liposome, preparation method and usage thereof |
| CN103099891A (en) * | 2011-11-09 | 2013-05-15 | 安康市天源植物提取有限公司 | Preparation method of belladonna extract |
| CN104861024B (en) * | 2015-04-03 | 2017-06-13 | 上海交通大学 | The method that Sitosterolum linoleate is prepared from black nightshade plant |
| CN106509579B (en) * | 2016-11-24 | 2017-06-30 | 张锦超 | A kind of preparation method of black nightshade fruit product |
| CN108324798A (en) * | 2018-05-10 | 2018-07-27 | 李明慧 | A kind of converted products and purposes of S. photeinocarpum |
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Free format text: CORRECT: ADDRESS; FROM: 222000 LIANYUNGANG, JIANGSU PROVINCE TO: 222047 LIANYUNGANG, JIANGSU PROVINCE |
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Effective date of registration: 20121226 Address after: 222047 Jiangning economic and Technological Development Zone, Jiangsu, Lianyungang industrial city Patentee after: Kangyuan Pharmceutical Co., Ltd. Address before: 222000 Jiangsu Province, Lianyungang city Sinpo District Haichang Road No. 58 Patentee before: Jiangsu Zeukov Pharmaceutical S. & T. Inc. |