CN1951382A - Oral formulation of neogambogic acid for treating tumor - Google Patents
Oral formulation of neogambogic acid for treating tumor Download PDFInfo
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- CN1951382A CN1951382A CNA200610122521XA CN200610122521A CN1951382A CN 1951382 A CN1951382 A CN 1951382A CN A200610122521X A CNA200610122521X A CN A200610122521XA CN 200610122521 A CN200610122521 A CN 200610122521A CN 1951382 A CN1951382 A CN 1951382A
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Abstract
The invention relates to an oral preparation of neogambogic acid for treating tumor, which comprises (by weight ratio) neogambogic acid 1-100 parts, auxiliary materials 1-100 parts, the oral preparation can be prepared into dosage forms including tablets, capsules, dripping pills, granules, gelatin-coated pills, dried suspending agents or turbid liquors. The oral preparation has the advantages of controllable quality, easiness in application and high effectiveness.
Description
Affiliated technical field
The present invention relates to a kind of neogambogic acid Chinese medicine preparation, refer more particularly to a kind of oral formulation of neogambogic acid for the treatment of tumor.
Background technology
Resina garciniae (Gamboge) is the secreted dry resin of Guttiferae (Gittiferae) plant (Garcinia hanburyi Hook.f.).Be reddish yellow or orange red, cylindrical or irregular block, matter is crisp frangible.Mainly originate in areas such as Cambodia, Thailand, Vietnam and India." Haiyao Bencao, Oversea Materia Medica " beginning carries " sour and astringent poisonous ", cures mainly the dental caries decayed tooth, just the falling of point ", the successive dynasties with the Resina garciniae be main component cream, ball, loose in respect of multiple.Modern Chinese medicine clinical practice Resina garciniae is also comparatively extensive, single with or with other medicines share the treatment carbuncle from the beginning of, create infections, herpes zoster, osteomyelitis, folliculitis etc. and obtain good efficacy.American Pharmacopeia once recorded these product, and acid ingredient is a main active in the Gamboge.Nineteen fifty-five M.Amorosa in Ann.Chim.Itay 54,40 (1955) document reported first acquisition gamlogic acid composition, and adopt nuclear magnetic resonance technique to determine the molecular structure of gamlogic acid.Lu Gui Bao etc. are at " Acta Pharmaceutica Sinica " 1984,19 (8) P636-639, reported in the article of piece of writing name " separation of neogambogic acid and structure thereof in the Resina garciniae " from Resina garciniae, to separate to obtain neogambogic acid, and its structure has been identified with methods such as ultraviolet, infrared wide spectrum, nuclear magnetic resonance, NMR.Qu Baoxi in 1991 etc. are at " Chinese clinical tumor " 1991,18 (1), P50-52, reported with neogambogic acid in the piece of writing " Resina garciniae II experimental study on anticancer " by name and given model mice, show that this medicine has obvious inhibitory action to mice transplanted tumor, compare with gamlogic acid and to have higher therapeutic index, the malignant tumor of part type is had better therapeutic effect.Neogambogic acid is a kind of potential antineoplaston medicine with higher-value, but has only the neogambogic acid aqueous solution with the preparation of 2% Tween 80, poor stability, and clinical use is very inconvenient.
Application number is that 200510039059.2 Chinese patent application discloses a kind of Neogarcinolic acid injection and preparation method thereof, used.Injection has its advantage in clinical treatment, the rapid onset of pharmacological action, but for certain irritating medicine is arranged very easily because its blood vessel irritation causes phlebitic generation, makes the patient continue medication and causes treatment to be interrupted; Simultaneously, some medicine can also cause untoward reaction such as haemolysis, the untoward reaction of Chinese medicine has caused increasing the concern both at home and abroad, and its clinical practice produced certain influence, for tumor patient, because its body constitution is compared weak a lot with the normal person, these untoward reaction might cause serious adverse consequences even life to threaten; Even there is not above-mentioned problem, with respect to drug administration by injection, because oral administration can not cause pain to the patient, thereby the patient has higher compliance undoubtedly to oral administration, for the patient who suffers from blood born diseases simultaneously, risk that the person faces that oral administration also can reduce the clinical position; In addition, for non-inpatient, oral administration is because convenient the use need not special medical condition and equipment, and also the antineoplaston for the patient provides convenience.Therefore, oral formulation of neogambogic acid can remedy the not enough and restriction of drug administration by injection, and certain advantage is arranged in clinical treatment.
Summary of the invention
Technical problem to be solved by this invention provides a kind of oral formulation of neogambogic acid for the treatment of tumor, and this oral formulation of neogambogic acid is stable and controllable for quality, taking convenience and purpose safely and effectively, and economical and practical, product appearance is good, and is evident in efficacy.
The present invention solves the technical scheme that its technical problem adopts:
A kind of oral formulation of neogambogic acid for the treatment of tumor is an active component with the neogambogic acid, and all the other compositions are adjuvant, and its parts by weight of raw materials proportioning is: 1～100 part of neogambogic acid, 1～100 part of adjuvant;
Described oral formulations comprises any in tablet, capsule, drop pill, granule, soft gelatin capsule, dry suspension, suspendible gel or the powder.
Above-mentioned tablet is any in ordinary tablet, Film coated tablets, enteric coatel tablets, gastric soluble tablet, dispersible tablet, oral cavity disintegration tablet, the effervescent tablet; Described adjuvant is filler, disintegrating agent, surfactant, binding agent or other adjuvant; Its parts by weight of raw materials proportioning is:
1～100 part of neogambogic acid
0.3～30 part of filler
0.3～25 part of disintegrating agent
0.01～5 part in surfactant
0.19～20 part of binding agent
0.2～20 part of other adjuvant.
Above-mentioned tablet is any in controlled release tablet, the slow releasing tablet; Described adjuvant is filler, binding agent, surfactant or slow/controlled release material; Its parts by weight of raw materials proportioning is:
1～100 part of neogambogic acid
0.4～40 part of filler
0.19～25 part of binding agent
0.01～5 part in surfactant
0.4～30 part of slow/controlled release material.
Above-mentioned capsule is a hard capsule; Described adjuvant is filler, disintegrating agent, surfactant, binding agent or other adjuvant; Its parts by weight of raw materials proportioning is:
1～100 part of neogambogic acid
0.3～30 part of filler
0.4～30 part of disintegrating agent
0.01～5 part in surfactant
0.19～20 part of binding agent
0.1～15 part of other adjuvant.
Above-mentioned capsule is a soft capsule; Described adjuvant is filler, coating material or other adjuvant; Its parts by weight of raw materials proportioning is:
1～100 part of neogambogic acid
0.5～45 part of filler
0.5～45 part of coating material
0～10 part of other adjuvant.
Above-mentioned oral formulations is a capsule, and described capsule is any in slow releasing capsule or the controlled release capsule; Described adjuvant is filler, slow/controlled release material and other adjuvant, and its parts by weight of raw materials proportioning is:
1～100 part of neogambogic acid
0.5～40 part of filler
0.5～40 part of slow/controlled release material
0～20 part of other adjuvant.
Above-mentioned oral formulations is a drop pill, and described adjuvant is filler, coating material or other adjuvant, and its parts by weight of raw materials proportioning is:
1～100 part of neogambogic acid
0～40 part of filler
0.8～40 part of coating material
0～20 part of other adjuvant.
Above-mentioned oral formulations is a granule, and described adjuvant is filler, disintegrating agent, surfactant, binding agent or other adjuvant; Its parts by weight of raw materials proportioning is:
1～100 part of neogambogic acid
0.3～20 part of filler
0.2～20 part of disintegrating agent
0.01～5 part in surfactant
0.19～15 part of binding agent
0.3～40 part of other adjuvant.
Above-mentioned filler is choosing any one kind of them or several combinations in lactose, sucrose, glucose, dextrin, mannitol, sorbitol, calcium sulfate, calcium gluconate, calcium hydrogen phosphate, calcium phosphate, calcium carbonate, calcium bicarbonate, starch, carboxymethyl starch and sodium salt thereof, pregelatinized Starch, hexadecanol, L-arginine, various viscosity polyvinyl alcohol, Polyethylene Glycol, carbopol, cellulose and the derivant thereof.
Above-mentioned binding agent is choosing any one kind of them or several combinations in gelatin, arabic gum, maltose, polyvinylpyrrolidone, various viscosity polyvinyl alcohol, the Polyethylene Glycol.
Above-mentioned surfactant is choosing any one kind of them or several combinations in sodium lauryl sulphate, poloxamer, pluronic gram, Tween 80, bromination hexadecane trimethylamine, sodium laurylsulfate, stearyl alcohol sodium sulfate, polyoxyethylene deriv, sucrose ester, sorbitol fatty ester, the soybean phospholipid.
Above-mentioned disintegrating agent is choosing any one kind of them or several combinations in microcrystalline Cellulose, pure lignocellulose, alginic acid, guar gum, crospolyvinylpyrrolidone, the ion exchange resin.
Above-mentioned coating material is any or several combination in gelatin, glycerol, arabic gum, Lac, cellulose and derivant thereof, polyvinyl alcohol, polyacrylic acid, Polyethylene Glycol, polylactic acid, polyethylene, polyamide, stearic acid and the ester thereof.
Above-mentioned slow/controlled release material is any or several combination in Brazil wax, castor oil hydrogenated, castor wax, hydrogenated soya phosphatide, Lac, gelatin, sodium alginate, chitosan, amylopectin, agar, carrageenin, guar gum, cellulose derivative, crylic acid resin, the polyethylene kind macromolecular material.
Other above-mentioned adjuvant is lubricant, wetting agent, adsorbent, effervescent, solvent, cosolvent, correctives, suspensoid, suspending agent, helps a kind of or any several combination of collapsing in agent, fluidizer, coating material, the enclose material.
Above-mentioned lubricant is any or several combination in magnesium stearate, calcium stearate, zinc stearate, Pulvis Talci, glyceryl monostearate, Macrogol 4000, polyethylene glycol 6000, Polyethylene Glycol 8000, sodium benzoate, adipic acid, fumaric acid, boric acid, sodium chloride, enuatrol, glyceryl triacetate, polyoxyethylene monostearate, the single magnesium laurylsulfate.
Above-mentioned wetting agent is water, ethanol, propylene glycol, isopropyl alcohol etc., any or several combinations in can choosing wantonly.
Above-mentioned adsorbent is any or several combination in silicon dioxide, crospolyvinylpyrrolidone, micropowder silica gel, Kaolin, basic magnesium carbonate, light magnesium oxide, the aluminium hydroxide desiccant gel.
Above-mentioned effervescent is any or several combination in sodium dihydrogen phosphate, Sodium Acid Pyrophosphate, sodium sulfite, sodium bicarbonate, sodium carbonate, potassium bicarbonate, sodium glycine carbonate, sodium sesquicarbonate, citric acid, tartaric acid, fumaric acid, boric acid, the maleic acid.
Above-mentioned solvent is included as water, ethanol, propylene glycol, isopropyl alcohol, vegetable oil, mineral wet goods, any or several combinations in can choosing wantonly.
Above-mentioned cosolvent is any or several combination in poly yamanashi esters, pluronic gram, Polyethylene Glycol, polyvinyl alcohol, propylene glycol, ethanol, glycerol, organic acid and sodium salt, amide and amine, polyvidone, L-arginine, lysine, meglumine, sodium bicarbonate, sodium carbonate, sodium sulfite, disodium edetate, sodium hydroxide, sodium borate, the propolis.
Above-mentioned correctives is any or several combination in steviosin, fructose, glucose, high fructose syrup, Mel, aspartame, protein sugar, xylitol, mannitol, lactose, sorbitol, maltose alcohol, glycyrrhizin, phyllodulcin, Sodium Cyclamate, flavoring banana essence, flavoring pineapple essence, flavoring orange essence, Herba Menthae essence, Fructus Foeniculi, vanillin, Fructus Citri Limoniae essence, cherry essence, the rose essence
Above-mentioned suspensoid is any or several combinations in the poly-ethoxy ethanol of hot phenoxy group, sorbitol anhydride polyethylene glycol monooleate, polyoxyethylene monostearate, polyoxyethylene alkylphenyl sodium sulfonate, sodium lauryl sulfate, tragcanth, pectin, guar gum, micropowder silica gel, sodium alginate, the kieselguhr.
Described suspending agent is the poly-ethoxy ethanol of hot phenoxy group, alevaire, the sorbitol anhydride polyethylene glycol monooleate, polyoxyethylene monostearate, polyoxyethylene deriv, Tween 80, the polyoxyethylene alkylphenyl sodium sulfonate, sodium lauryl sulfate, arabic gum, polyvinylpyrrolidone, tragcanth, pectin, gelatin, methylcellulose, sodium carboxymethyl cellulose, guar gum, micropowder silica gel, Magnesiumaluminumsilicate, hydroxyethyl-cellulose, Kaolin, sodium alginate, kieselguhr, any or several combination in the aluminium hydroxide.
Above-mentioned fluidizer is micropowder silica gel.
Above-mentioned coating material is any or several combination in cellulose and derivant thereof, crylic acid resin, the ethene polymers.
Above-mentioned enclose material is a beta-schardinger dextrin-.
The preparation technology of oral formulation of neogambogic acid of the present invention is:
The preparation technology of the oral ordinary tablet of neogambogic acid of the present invention is an active component with the neogambogic acid, and all the other compositions are filler, disintegrating agent, surfactant, binding agent, behind guiding humid medium mixed pelletization, drying, the granulate, add the fluidizer mixing, tabletting is made oral ordinary tablet.Should oral ordinary tablet bag film-coat or enteric coating can further make Film coated tablets or enteric coatel tablets.Its parts by weight of raw materials proportioning is:
1～100 part of neogambogic acid
0.3～30 part of filler
0.3～25 part of disintegrating agent
0.01～5 part in surfactant
0.19～20 part of binding agent
0.1～10 part of wetting agent
0.1～10 part of fluidizer
Preferred feedstock weight portion proportioning is:
1～20 part of neogambogic acid
1～10 part of filler
1～10 part of disintegrating agent
0.1～1 part in surfactant
1～5 part of binding agent
1～5 part of wetting agent
1～2 part of fluidizer
The preparation technology of neogambogic acid oral buccal tablet of the present invention, chewable tablet, Sublingual tablet is an active component with the neogambogic acid, and all the other compositions are filler, binding agent, make soft material after adding the correctives mix homogeneously, granulate drying, tabletting behind the granulate is made buccal tablet, chewable tablet, Sublingual tablet.Its parts by weight of raw materials proportioning is:
1～100 part of neogambogic acid
0.5～40 part of filler
0.3～40 part of binding agent
0.2～20 part of correctives
Preferred feedstock weight portion ratio range:
1～10 part of neogambogic acid
2～10 parts of filleies
1～5 part of binding agent
1～5 part of correctives
The preparation technology of neogambogic acid oral dispersable tablet of the present invention, oral cavity disintegration tablet, it is characterized in that: be active component with the neogambogic acid, all the other compositions are filler, disintegrating agent, surfactant, binding agent, add correctives, help and collapse tabletting behind the agent mixing, make dispersible tablet, oral cavity disintegration tablet.Its parts by weight of raw materials proportioning is:
1～100 part of neogambogic acid
0.4～30 part of filler
0.3～20 part of disintegrating agent,
0.01～5 part in surfactant
0.19～20 part of binding agent
0.1～10 part of correctives
Help and collapse 0.1～10 part of agent
Preferred feedstock weight portion ratio range:
1～20 part of neogambogic acid
1～10 part of filler
1～10 part of disintegrating agent,
0.1～5 part in surfactant
0.9～5 part of binding agent
1～2 part of correctives
Help and collapse 1～2 part of agent
The preparation technology of neogambogic acid oral administration effervescing sheet of the present invention is an active component with the neogambogic acid, and all the other compositions are filler, disintegrating agent, surfactant, binding agent, adds other adjuvant effervescent mix homogeneously, and tabletting is made effervescent tablet.Its parts by weight of raw materials proportioning is:
1～100 part of neogambogic acid
0.3～30 part of filler
0.3～20 part of disintegrating agent
0.01～5 part in surfactant
0.2～20 part of binding agent
0.3～20 part of effervescent
Preferred feedstock weight portion proportioning is:
1～20 part of neogambogic acid
1～10 part of filler
0.5～10 part of disintegrating agent
0.1～5 part in surfactant
0.5～5 part of binding agent
1～10 part of effervescent
The preparation technology of neogambogic acid mouth slow releasing tablet of the present invention, fast-release tablet, controlled release tablet, with the neogambogic acid is active component, all the other compositions are filler, surfactant, binding agent, add adjuvant system soft materials such as other slow release, rapid release, controlled-release material, granulate drying, granulate, tabletting is made slow releasing tablet, fast-release tablet, controlled release tablet.Its parts by weight of raw materials proportioning is:
1～100 part of neogambogic acid
0.4～40 part of filler
0.19～25 part of binding agent
0.01～5 part in surfactant
0.4～30 part of slow/controlled release material
Preferred feedstock weight portion ratio range:
1～30 part of neogambogic acid
1～20 part of filler
1～10 part of binding agent
0.1～2 part in surfactant
1～10 part of slow/controlled release material
The preparation technology of neogambogic acid oral hard capsule of the present invention is an active component with the neogambogic acid, and all the other compositions are disintegrating agent, filler, surfactant, binding agent, guiding humid medium system soft material, after the granulation, be packed into Capsules after adding the fluidizer mixing, make hard capsule.The hard capsule of preparation can further be made enteric coated capsule with the processing of coating enteric material.Its parts by weight of raw materials proportioning is:
1～100 part of neogambogic acid
0.3～30 part of filler
0.4～30 part of disintegrating agent
0.01～5 part in surfactant
0.19～20 part of binding agent
0.05～10 part of wetting agent
0.05～5 part of fluidizer
Preferred feedstock weight portion proportioning is:
1～100 part of neogambogic acid
5～20 parts of disintegrating agents
5～20 parts of filleies
0.1～2 part in surfactant
2～10 parts of binding agents
1～5 part of wetting agent
1～2 part of fluidizer
The preparation technology of neogambogic acid oral soft capsule of the present invention is an active component with the neogambogic acid, makes into 2～5 μ m with colloid mill, be dispersed in the filler, be sealed in the soft capsule of sphere or elliposoidal, make soft capsule, handle to make enteric soft capsules with enteric-coating material.Its parts by weight of raw materials proportioning:
1～100 part of neogambogic acid
0.6～50 part of filler
0.4～50 part of coating material.
Preferred feedstock weight portion ratio range:
1～20 part of neogambogic acid
5～10 parts of filleies
2～10 parts of coating materials.
The capsular preparation technology of the oral slow/controlled release of neogambogic acid of the present invention, with the neogambogic acid is active component, all the other compositions are filler, it is scattered in the slow/controlled release material, make a kind of slow/controlled release piller, fill separately or with the filler mix homogeneously, be filled in the Capsules, make the slow/controlled release capsule.Its parts by weight of raw materials ratio range:
1～100 part of neogambogic acid
0.5～40 part of filler
0.5～40 part of slow/controlled release material
Preferred feedstock weight portion ratio range:
5～20 parts of neogambogic acid
5～20 parts of filleies
1～10 part of slow/controlled release material
Neogambogic acid oral administration dripping pill of the present invention, the mixture of neogambogic acid and pharmaceutic adjuvant is added in the fused coating material, and mix homogeneously splashes in dimethicone or the white oil and forms drop pill, from solution, collect drop pill then, handle to make enteric coated drop pill with enteric-coating material.Its raw material weight ratio range:
1～100 part of neogambogic acid
0～40 part of filler
0.8～40 part of coating material
Preferred feedstock quality ratio range:
1～50 part of neogambogic acid
1～10 part of filler
5～20 parts of coating materials
The preparation technology of neogambogic acid oral granular formulation of the present invention is characterized in that: be active component with the neogambogic acid, all the other compositions are filler, disintegrating agent, surfactant, binding agent, correctives, behind granulation, drying, granulate, packing, single dose or multiple dose granule are made in encapsulation.Its parts by weight of raw materials proportioning is:
1～100 part of neogambogic acid
0.3～20 part of filler
0.2～20 part of disintegrating agent
0.01～5 part in surfactant
0.19～15 part of binding agent
0.3～40 part of correctives
Preferred feedstock weight portion ratio range:
1～20 part of neogambogic acid
5～10 parts of filleies
5～10 parts of disintegrating agents
0.1～1 part in surfactant
2～5 parts of binding agents
2～20 parts of correctivess
The preparation technology of neogambogic acid oral mixed suspension gel of the present invention, it is characterized in that: be active component with the neogambogic acid, all the other compositions are filler, surfactant, add suspensoid, suspending agent, correctives, add water, stirring, packing behind the mix homogeneously, single dose or multiple dose suspendible gel are made in sterilization.Its parts by weight of raw materials ratio range:
1～100 part of neogambogic acid
0.49～45 part of filler
0.01～5 part in surfactant
0.2～20 part of suspensoid
0.2～20 part of suspending agent
0.1～10 part of correctives
Preferred feedstock weight portion proportioning is:
1～50 part of neogambogic acid
10～20 parts of filleies
0.1～1 part in surfactant
5～10 parts of suspensoids
1～10 part of suspending agent
1～5 part of correctives
The preparation technology of oral dry suspension of neogambogic acid of the present invention or powder, it is characterized in that: be active component with the neogambogic acid, all the other compositions are filler, surfactant, add suspensoid, suspending agent, correctives mix homogeneously after, single dose or multiple dose dry suspension or powder are made in packing.Its parts by weight of raw materials proportioning is:
1～100 part of neogambogic acid
0.49～45 part of filler
0.01～5 part in surfactant
0.2～20 part of suspensoid
0.2～20 part of suspending agent
0.1～10 part of correctives
Preferred feedstock weight portion proportioning is:
1～50 part of neogambogic acid
10～20 parts of filleies
0.1～1 part in surfactant
5～10 parts of suspensoids
1～10 part of suspending agent
1～5 part of correctives
A kind of oral formulation of neogambogic acid of the present invention is tablet that to be active component and pharmaceutic adjuvant with the neogambogic acid make through suitable preparation process, capsule, soft gelatin capsule, granule, drop pill, suspensoid, powder etc.This oral formulations has lethal effect to malignant cell, the clinical treatment that can be used for diseases such as pulmonary carcinoma, gastric cancer, hepatocarcinoma, colon cancer, melanoma, leukemia, the esophageal carcinoma, ovarian cancer, it is strong to have active anticancer, antitumor spectra is wide, low toxin, safe in utilization, convenient, effectively, be particularly suitable for cancer patient's clinical treatment.
Oral formulation of neogambogic acid steady quality of the present invention, controlled, safe and effective.
The active ingredient of oral formulations of the present invention is a neogambogic acid, and acid-base value is moderate, and oral back does not have obvious irritation to gastrointestinal tract, and it is not obvious to take untoward reaction for a long time, and toleration is good.And the neogambogic acid preparation of injection has certain zest, intravenous injection might cause blood vessel irritation to cause phlebitic generation, intramuscular injection then produces certain local pain, also can cause sharp tissue injury of tissue injury to a certain degree during the intravenously administrable seepage, may make the patient continue medication and cause treatment to be interrupted; Simultaneously, the untoward reaction of Chinese medicine has caused increasing the concern both at home and abroad, and its clinical practice produced certain influence, some Chinese medicine can cause untoward reaction such as haemolysis, for tumor patient, because its body constitution is compared weak a lot with the normal person, these untoward reaction might cause serious adverse consequences even life to threaten; In addition,,, need not to take so much time of intravenously administrable, need not to limit patient's position and freedom of action, thereby the patient has higher compliance and wish undoubtedly to oral administration because oral administration can not cause pain to the patient with respect to drug administration by injection.For the patient who suffers from blood born diseases (as hepatitis, AIDS etc.) simultaneously, risk that the person faces that oral administration also can reduce the clinical position; Also have, for non-inpatient, the neogambogic acid oral administration is convenient to be used, and need not special medical condition and equipment, and also the antineoplaston for the patient provides convenience.Therefore, oral formulation of neogambogic acid has remedied the not enough and restriction of drug administration by injection, and is not only convenient and practical, and evident in efficacy, and certain advantage is arranged in clinical treatment.
Beneficial effect of the present invention is described by experiment
Experimental example 1.
The present invention is to the antitumor action of mice homotransplantation tumor
1. experiment material
Experimental drug
The neogambogic acid oral tablet, the 50mg/ sheet;
Fluorouracil Injection (5-FU), 0.25g/ props up, Nantong pharmacy head factory, lot number: 031203
Animal subject
Kunming kind white mice, body weight 18～22g, male and female dual-purpose, experiment prospective adaptation 1 week of raising.Place SPF level laboratory rearing, 25 ± 2 ℃ of room temperatures, all experimental articles are all handled through disinfection with high pressure steam.
Tumor cell line
Lotus S-180, H22, ehrlich ascites tumor mice be available from Zhongshan University medical college tumor research center, extracted ascites with asepsis injector in 7～8 days behind the inoculating cell and be used for experiment.
2. experimental technique
Route of administration: the neogambogic acid oral tablet grinds back filling stomach and is tried mice, every day 1 time.The administration of 5-FU tail vein injection, every day 1 time.Medication is as follows.
The administration cycle: according to Qi Chen chief editor " herbal pharmacology research methodology " (the 2nd edition) 1006-1027 page or leaf institute support method, extract the ascites of lotus S-180, H22, ehrlich ascites tumor mice, carry out dilution in 1: 1 with the injection normal saline, vortex vibration mixing, be inoculated in the animal subject abdominal cavity with asepsis injector, every 0.2mL, preparation lotus ascites tumor mouse model, random packet; It is subcutaneous to be inoculated in animal subject hind leg axillary fossa with asepsis injector, every 0.2mL, preparation lotus solid tumor mouse model, random packet.Begin gastric infusion next day behind the lotus solid tumor mouse inoculation tumor cell, successive administration 10 days, and it is heavy that the execution animal takes by weighing tumor after 20 days.Begin gastric infusion next day behind the lotus ascites tumor mouse inoculation tumor cell, and successive administration 7 days calculates the mice time-to-live.
3. the date processing experimental data is carried out statistical disposition with Microcal Origin 6.0 Professional statistical softwares, variance analysis comparable group differences, and the t-check is two group differences relatively, are that difference has significance level with P＜0.05.
4. experimental result
Neogambogic acid sees Table 1. neogambogic acid to the antitumor action experimental result of lotus S-180 ascites tumor and solid tumor mice and the antitumor action experimental result of lotus H22 ascites tumor and solid tumor mice is seen Table 2. neogambogic acid the inhibitory action experimental result of ehrlich carcinoma is seen Table 3.
Table 1. neogambogic acid to the antitumor action of lotus S-180 ascites tumor and solid tumor mice (
) (n=12)
| The 0.9%NaCl group | 5-FU organizes 10mg.kg -1 | Neogambogic acid | |||
| 20.0mg.kg -1 | 14.0mg.kg -1 | 9.8mg.kg -1 | |||
| Heavy (g) tumor of ascites tumor mice time-to-live (d) prolonged survival period (%) solid tumor mouse tumor heavily alleviates (%) | 10.6±1.7 7.17±2.18 | 17.2±2.1 ** 62.3±7.6 ** 4.66±1.35 ** 35.0±10.1 ** | 27.7±4.3 **△△ 161.3±25.0 **△△ 2.83±1.10 **△△ 60.5±23.5 **△△ | 29.5±5.4 **△△ 178.3±32.6 **△△ 3.05±1.22 **△△ 57 5±23.0 **△△ | 25.2±4.0 **△△ 137.7±21.9 **△△ 4.23±1.26 ** 41.0±12.2 ** |
Compare with the 0.9%NaCl group,
*Expression p＜0.05;
*Expression p＜0.01
Compare with the 5-FU group, △ represents p＜0.05; △ △ represents p＜0.01
Table 2. neogambogic acid to the antitumor action of lotus H22 ascites tumor and solid tumor (
) (n=12)
| The 0.9%NaCl group | 5-FU organizes 10mg.kg -1 | Neogambogic acid | |||
| 20.0mg.kg -1 | 14.0mg.kg -1 | 9.8mg.kg -1 | |||
| Heavy (g) tumor of ascites tumor mice time-to-live (d) prolonged survival period (%) solid tumor mouse tumor heavily alleviates (%) | 12.3±2.2 7.28±2.30 | 19.4±3.1 **57.7±9.2 **3.63±2.14 **50.1±29.6 ** | 25.2±4.8 **△△104.9±20.0 **△△2.83±0.75 **△61.1±16.2 **△ | 29.6±5.3 **△△140.6±25.2 **△△3.02±1.00 **58.5±19.4 ** | 23.0±4.5 **△△87.0±17.0 **△△3.95±0.89 **45.7±10.3 ** |
Compare with the 0.9%NaCl group,
*Expression p＜0.05;
*Expression p＜0.01
Compare with the 5-FU group, △ represents p＜0.05; △ △ represents p＜0.01
Table 3. neogambogic acid gastric infusion to the inhibitory action of ehrlich carcinoma (
) (n=10)
| Dosage usage (mg/kg/d) | Number of animals | Average survival natural law | Prolong life cycle (%) | The P value | ||
| Beginning | The end | Contrast | Treatment | |||
| 4.8 * 7 6.9 * 7 9.8 * 7 14.0 * 7 20.0 * 7 35.0 * 4 (next day) 50.0 * 3 (1; 5,9 days) 150 * 1 | 10 10 10 10 10 10 10 10 | 0 0 0 1 4 5 0 0 | 11.4 11.4 11.4 11.4 11.4 12.6 11.9 12.0 | 16.3 19.8 21.7 26.0 28.4 28.5 20.8 16.3 | 43.0 73.7 90.4 128.1 149.1 126.2 74.8 35.8 | ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.05 |
The result shows, for solid tumor and ascites tumor due to the S-180 tumor cell line, oral neogambogic acid can suppress its propagation, and determined curative effect is better than (p＜0.05) or is equivalent to (p＞0.05) 10mg.kg at its tumor killing effect of test dose
-1The therapeutic effect of 5-FU (together following).To solid tumor and ascites tumor due to the lotus H22 hepatoma cell strain, the injection neogambogic acid has remarkable antitumor effect, and determined curative effect is better than (p＜0.05) or is equivalent to (p＞0.05) 10mg.kg at its tumor killing effect of test dose
-1The therapeutic effect of 5-FU (together following).Antitumor action to the ehrlich carcinoma mice studies show that neogambogic acid successive administration effect day by day is better than administration at interval, and 20mg.kg
-1During following dosage, antitumor action and dosage have obvious dependence.
Experimental example 2.
The present invention is to the antitumor action of mice xenotransplantation tumor
1. experiment material
Experimental drug
The neogambogic acid oral tablet, the 50mg/ sheet;
Retinoic acid, Sigma company, lot number: 031203
Animal subject, BALB/C mice, 4～5 ages in week, body weight 16～18g, male, place SPF level laboratory rearing, 25 ± 2 ℃ of room temperatures, all experimental articles are all handled through disinfection with high pressure steam.
Cell strain, people's lung cancer A549 cell, people's gastric cancer SGC7901 cell are available from Shanghai cell institute of the Chinese Academy of Sciences.
2. experimental technique
Cell culture
People's lung cancer A549 cell, people's gastric cancer SGC7901 cell recovery are placed in 37 ℃, 5%CO2 incubator, cultivate under the saturated humidity condition, and culture medium is the high glycoform DMEM culture fluid that contains 10% calf serum.Get the cultured cell in vitro that is in exponential phase of growth during experiment, use 0.25% trypsinization, centrifugal collecting cell is adjusted into 1 * 10 with normal saline
7Cell/mL.
The tumor tissue inoculation
Get above-mentioned cell suspension, vortex vibration mixing, testing indoor 1mL syringe in the SPF level, that cell suspension is injected the BALB/C mice back is subcutaneous, and 2 * 10
6Individual cell/only.
Route of administration, method
Animal subject random packet behind the gastric infusion inoculated tumour cell, 12 every group, administration next day is irritated stomach every day once, successive administration 10 days, after the last administration 24 hours, draw neck to put to death animal, peel off tumor tissues and weigh.
Tumor control rate=(C-T)/(C: the average tumor of matched group is heavy for C * 100%; T: the average tumor of administration group is heavy).
Route of administration: the neogambogic acid oral tablet grinds back filling stomach and is tried mice, every day 1 time.
3. the date processing experimental data is carried out statistical disposition with Microcal Origin 6.0 Professional statistical softwares, variance analysis comparable group differences, and the t-check is two group differences relatively, are that difference has significance level with P＜0.05.
4. experimental result
Neogambogic acid sees Table 4. tables 5. to the antitumor action experimental result of lotus people lung cancer A549 cell, people's gastric cancer SGC7901 cellular entities tumor mice
Table 4. neogambogic acid to the antitumor action of lotus people lung cancer A549 cell solid tumor mice (
) (n=12)
| Group | Number of animals | Body weight/g | Time-to-live | Tumor weight/g | Tumour inhibiting rate % | ||
| Beginning | Finish | Beginning | Finish | ||||
| Normal saline retinoic acid 15mg/Kg 20mg/Kg 14mg/Kg 9.8mg/Kg | 12 12 12 12 12 | 12 12 12 12 12 | 16.4±1.12 16.2±0.93 16.5±1.02 16.6±1.24 16.4±0.98 | 19.2±1.27 15.4±1.21 18.5±1.04 19.0±0.86 18.6±0.94 | 11 11 11 11 11 | 1.52±0.31 0.68±0.21 0.57±0.26 0.73±0.20 0.88±0.32 | 55.3 62.5 52.0 42.1 |
Table 5. neogambogic acid to the antitumor action of lotus people gastric cancer SGC7901 cellular entities tumor mice (
) (n=12)
| Group | Number of animals | Body weight/g | Time-to-live | Tumor weight/g | Tumour inhibiting rate % | ||
| Beginning | Finish | Beginning | Finish | ||||
| Normal saline is tieed up sour 15mg/Kg 20mg/Kg 14mg/Kg 9.8mg/Kg | 12 12 12 12 12 | 12 12 12 12 12 | 17.2±0.60 17.0±0.47 16.8±0.82 16.8±0.66 17.0±0.50 | 20.2±0.93 16.1±0.86 17.1±0.65 19.4±1.12 19.2±0.88 | 11 11 11 11 11 | 1.36±0.25 0.60±0.11 0.61±0.13 0.73±0.20 0.89±0.18 | 55.9 55.1 46.3 34.6 |
Experimental result shows that oral formulation of neogambogic acid of the present invention has remarkable antitumor effect to the mice of lotus human tumor cells, and the curative effect of its therapeutic effect and clinical antineoplaston medicine retinoic acid commonly used is basic identical.
Experimental example 3
Continuous 30 days gastric infusions of neogambogic acid are learned the influence of index to rat blood
1. experiment material
160 of animal subject SD rats, body weight 80～100 grams, ♀ ♂ half and half buys back 2 weeks of breeding observing back in 5～6 ages in week of age, makes the preceding body weight of medicine, feed intake record.By sex grouping, 5 in animal per cage.Complete feed and drinking-water free choice feeding, the cage tool of sterilizing weekly a time.Conditioning room air keeps 18～24 ℃, relative humidity 60～70%.
Be subjected to reagent thing neogambogic acid sheet, the 50mg/ sheet faces with preceding and is ground into fine powder with mortar, is diluted to desired concn with sodium chloride injection.Matched group sodium chloride injection (NS).
Key instrument electronic balance 5003 types, Shanghai balance equipment factory, full-automatic blood counting instrument (M-4000, Germany), BASIC semi-automatic biochemical analyzer (French SECOMAM company), microtome come card-2015 (Germany), microscope etc.
Main agents blood cell diluent, hemolysin (220,402 050501) is provided by Sichuan Maysun Technology Co., Ltd..Blood biochemical detectable: AST (020710), ALT (020,708 020826), ALP (020,206 020808), TP (020220), Alb (020,123 020702), Crea (020,515 021009), Bun (020,712 021022), T-Bil (020,601 300011), TC (020,416 021014), Glu (020,527 020924).AST, ALT, three kinds of serum detectable of ALP are Bai Ding biological engineering (Beijing) company limited product, give birth to company's product in T-Bil Beijing, and all the other 6 kinds of serum detectable are Sichuan Mai Ke Science and Technology Ltd. product.Formaldehyde (analytical pure), ethanol (95% analytical pure), dimethylbenzene (analytical pure) etc. are commercial.
2. experimental technique
Dosage and grouping see Table 6.
Table 6. dosage and experiment grouping
| Group | Animal (only) | Dosage (mg.kg -1.d) | Be equivalent to draft clinical consumption per day (doubly) |
| Dosage low dosage in the matched group high dose | 30 30 30 30 | NS 20 14 9.8 | - 5.0 3.5 2.5 |
The medication gastric infusion.Carry out every morning 8～10, and be administered once every day, continuous 30 days.Claim body weight on every Sundays one time, and adjust dosage according to body weight.
Detect index
Hematological indices: administration 30 days, animal extremely alive is got blood, Medicon-4000 Instrument measuring WBC (leukocyte), LYM (lymphocyte count), MID (intermediate cell counting), GRAN (granulocyte count), LYM (lymphocyte percentage), MID (intermediate cell percentage rate), GRAN (granulocyte percentage rate), RBC (erythrocyte), HGB (hemoglobin), HCT (packed cell volume), MCV (mean corpuscular volume (MCV)), MCH (mean corpuscular hemoglobin), MCHC (mean corpuscular hemoglobin), RDW-CV (Erythrocyte hemoglobin distribution width variance), RDW-SD (Erythrocyte hemoglobin distribution width standard deviation), PLT (platelet count), MPV (mean platelet volume), PCT (thrombocytocrit capacity), LCDW (the control limit of platelet trend electrode noise end), RCDW (the distribution control interval between erythrocyte and the platelet), PDW (the volume of platelets dispersion of distribution), common light microscopic method counting RC (reticulocyte), slide method is surveyed CT (clotting time).
Blood biochemical detects: administration 30 days, femoral artery, vein cut off gets blood system from serum, detects AST (aspartate aminotransferase) enzyme process, ALT (alanine aminotransferase) enzyme process, ALP (alkali phosphatase) performance rate method, TP (total protein) biuret method, Alb (albumin) BCG method, TBIL (total bilirubin) diazonium method BUN (blood urea nitrogen) urase-Podbielniak colorimetry, Glu (glucose) FOD-POD method, TC (T-CHOL) CE-COD-POD method, Crea (flesh liver) picric acid two-point method with semi-automatic biochemical analyzer.
3. the date processing experimental data is carried out statistical disposition with Microcal Origin 6.0 Professional statistical softwares, variance analysis comparable group differences, and the t-check is two group differences relatively, are that difference has significance level with P＜0.05.
4. experimental result
The influence that continuous 30 days gastric infusions of neogambogic acid are learned index to rat blood sees Table 7.
Continuous 30 days gastric infusions of table 7. neogambogic acid to rat blood learn index influence (
, n=30)
| Index (unit) | Matched group | Low dosage | Middle dosage | High dose |
| WBC(x109/L) LYM(x109/L) MID(x109/L) GRAN(x109/L) LYM(％) MID(％) GRAN(％) RBC(x1012/L) HGB(g/L) HCT(l/L) MCV(fl) MCH(pg) MCHC(g/l) RDW-CV RDW-SD(fl) PLT(x109/L) MPV(fl) PCT(l/L) LCDW(％) RCDW(％) PDW(fl) RC(％) CT(s) | 16.03±11.29 12.53±10.42 0.73±0.45 2.76±0.7 0.766±0.059 0.053±0.019 0.198±0.055 8.43±1.03 202.26±18.22 0.430±0.048 51.96±2.46 24.29±2.11 480.45±27.18 0.179±0.008 18.83±0.99 630.38±212.54 7.95±0.41 0.00361±0.00185 10.79±2.45 0.92±0.58 6.11±1.03 0.84±0.09 9.67±3.77 | 17.87±5.55 13.38±4.41 0.99±0.65 3.5±1.17 0.757±0.058 0.057±0.025 0.198±0.039 8.22±0.74 189.4±6.94 0.411±0.026 50.78±2.79 24.73±1.92 468.1±21.84 0.197±0.018 19.52±1.26 754.89±141.98 8.12±0.80 0.00372±0.00244 11.43±4.45 1.82±1.04 8.56±3.17 0.85±0.13 11.12±3.94 | 17.81±7.16 14.33±6.13 0.73±0.35 3.87±1.09 0.753±0.064 0.06±0.023 0.198±0.051 7.40±1.17 165.33±11.22 0.385±0.048 52.82±2.76 23.89±0.81 437.45±36 0.191±0.016 20.12±2.41 890.79±245.63 7.71±0.47 0.00213±0.00188 12.54±4.43 0.81±0.93 5.72±1.11 0.84±0.12 9.61±4.45 | 18.01±7.98* 15.05±7.36 0.85±0.32 2.91±0.7 0.796±0.053 0.052±0.018 0.164±0.037 7.71±0.89 146.12±11.33 0.391±0.046 51.43±3.37 24.53±2.67 381.64±49.95 0.187±0.014 18.61±1.73 840.23±429.57 7.84±1.26 0.004±0.00199 13.97±6.86 1.72±1.91 7.67±3.67 0.85±0.12 10.62±3.74 |
Annotate: compare with matched group: * P＜0.05, * * P＜0.01;
By experimental result as can be seen, continuous 30 days gastric infusions of neogambogic acid do not have obvious influence substantially to people Mus hematological indices, relevant hematological indices of each dosage group of being tried and matched group do not have significant difference, and prompting is in the test dose scope, and the neogambogic acid oral administration is safe to rat substantially.
The specific embodiment
Detailed component of the present invention is provided by the following example, but does not limit the present invention in any way.
Further specify the present invention by following embodiment.
Embodiment 1
Prescription:
Neogambogic acid 100g
Pregelatinized Starch 28g
Microcrystalline Cellulose 28g
Hydroxypropyl cellulose 10g
Carboxymethyl starch sodium 4.5g
Micropowder silica gel 5g
Magnesium stearate 2g
Hypromellose 10g
50% alcoholic solution 200mL
Make 1000
Preparation technology:
With recipe quantity neogambogic acid, pregelatinized Starch, microcrystalline Cellulose, hydroxypropyl cellulose, carboxymethyl starch sodium mix homogeneously; with 5% hypromellose making beating back whitewashing; with high-speed stirred, ebullated bed, one-step-granulating method or wave granulation machine and granulate; after drying; cross 14 mesh sieve granulate; add mix homogeneously behind the residue adjuvant more successively, tabletting.
Embodiment 2
Prescription:
Neogambogic acid 100g
Pregelatinized Starch 25g
Microcrystalline Cellulose 25g
Hypromellose 10g
Carboxymethyl starch sodium 3.5g
Micropowder silica gel 5g
Hypromellose 5g
Ethyl cellulose 10g
50% alcoholic solution 200mL
Make 1000
Neogambogic acid is mixed with the 15g microcrystalline Cellulose,, granulate drying through 16 eye mesh screens with the alcoholic solution making beating system soft material of ethyl cellulose and hydroxypropyl cellulose.With the 12 eye mesh screens tabletting after granulation (also available one-step-granulating method, ebullated bed, fluidized bed for spraying are granulated) back and the residue auxiliary materials and mixing that sieves, outside plain sheet, carry out gastric solubleness, enteric coating agents coating behind the tabletting, make controlled release tablet.
Embodiment 3
Prescription:
Neogambogic acid 200g
Sodium carboxymethyl cellulose 30g
Microcrystalline Cellulose 50g
Crospolyvinylpyrrolidone 20g
Polyvinylpyrrolidone 20g
Micropowder silica gel 30g
Poloxamer 2g
Polyoxyethylene sorbitan monoleate 2g
Dodecyl sodium sulfate 5g
Mannitol 50g
Steviosin 10g
Glyceryl monostearate 10g
Magnesium stearate 8g
Essence is an amount of
Make 1000
Preparation technology:
Except that magnesium stearate, all the other raw material stirring mix homogeneously add the magnesium stearate mixing again in will writing out a prescription, and cross 18 eye mesh screens, cross 2 times on the granulation machine and promptly can be used for direct compression waving, and adopt Φ 6.5mm punch die tabletting.Or with in the above-mentioned prescription except that magnesium stearate the abundant stirring and evenly mixing of all supplementary materials, adjust certain moisture, in pressure 〉=3 ton/cm
2Be pressed into graininess or lamellar with special machine under the condition, lamellar needs to cross 16～18 mesh sieves after coarse pulverization, again through behind the control moisture with the magnesium stearate mix homogeneously after tabletting.
Embodiment 4
Prescription:
Neogambogic acid 300g
Hexadecanol 140g
Hydroxypropyl cellulose 43g
Polyacrylic resin 40g
Tween 80 20g
Magnesium stearate 10g
Make 1000
Preparation technology:
Except that magnesium stearate, all the other raw material stirring mix homogeneously add the magnesium stearate mixing again in will writing out a prescription, and cross 18 eye mesh screens, cross 2 times on the granulation machine and promptly can be used for direct compression waving, and adopt Ф 6.5mm punch die tabletting.Or with in the above-mentioned prescription except that magnesium stearate the abundant stirring and evenly mixing of all supplementary materials, adjust certain moisture, in pressure 〉=3 ton/cm
2Be pressed into graininess or lamellar with special machine under the condition, lamellar needs to cross 16～18 mesh sieves after coarse pulverization, again through behind the control moisture with the magnesium stearate mix homogeneously after tabletting, promptly make the controlled release tablet of floating in stomach.This product floatability 5～6 hours in simulated gastric fluid.
Embodiment 5
Prescription:
Neogambogic acid 300g
Brazil wax 86g
Castor oil hydrogenated 10g
Calcium sulfate 25g
Mannitol 15g
Magnesium stearate 15g
Hydroxypropyl cellulose 50g
Tween 80 20g
Sodium alginate 14g
Make 1000
Preparation technology:
Behind Brazil wax and the castor oil hydrogenated mix homogeneously, heating and melting adds the neogambogic acid that is crushed to 100 μ m in the aforesaid liquid, stirring and evenly mixing is put cold, levigate, cross 80 mesh sieves, add calcium sulfate, mannitol, magnesium stearate, hydroxypropyl cellulose, mixing, making binding agent with the aqueous solution of sodium alginate granulates, drying, granulate adds the Tween 80 mix homogeneously, abnormity sheet tablet machine is pressed into oval special-shaped sheet, promptly makes the bioerodable controlled release tablet.
Embodiment 6
Prescription:
Neogambogic acid 200g
Hydroxypropyl cellulose 88g
Lactose 170g
Just fatty acid magnesium 12g
Polyvidone 10g
Water 400g
Make 1000
Preparation technology:
Former, adjuvant porphyrize are crossed 80 mesh sieves, take by weighing above-mentioned except that magnesium stearate behind the hydroxypropyl cellulose and other adjuvant mix homogeneously of recipe quantity, again with the neogambogic acid mix homogeneously, add water, wet granulation, drying, granulate, add the magnesium stearate mix homogeneously, special-shaped sheet tablet machine is pressed into the oval special-shaped sheet of 17 * 8.5mm, hardness 7～9Kg/mm
2, promptly make the hydrophilic gel controlled release tablet.
Embodiment 7
Prescription:
Neogambogic acid 40g
Lactose 100g
Hydroxypropyl cellulose 8g
Carboxymethyl starch sodium 22g
Pulvis Talci 16g
Tween 80 20g
Water is an amount of
Ethanol is an amount of
Make 1000
Preparation technology:
Neogambogic acid raw material and Tween 80 mix homogeneously, add water and make dissolving in right amount, the 8g hydroxypropyl cellulose is dissolved in the 150mL water, be made into hydroxypropyl cellulose aqueous solution, adopt the fluid boiling granulation, 100g lactose and 22g carboxymethyl starch sodium put on fluidising chamber's screen cloth in 60 ℃ hot-air, be fluidized state, spray into neogambogic acid solution, the lactose of fluidized state and the mixture of carboxymethyl starch sodium and principal agent begin to condense into granular, through spraying repeatedly, granulated 5 hours at 50 ℃ of calorstat inner dryings, treat behind the particle drying with 16 order steel sieve granulate, again the alcoholic solution of an amount of hydroxypropyl cellulose that will prepare in advance also with the fluid boiling method to entering the granule of fluidising chamber, Pulvis Talci carries out coating, with the 14 order nylon mesh granulate that sieves, be packed in No. three Capsuleses, promptly get the neogambogic acid capsule.
Embodiment 8
Prescription:
Neogambogic acid 200g
Soybean phospholipid 100g
Micropowder silica gel 100g
Lactose 250g
Starch 50g
Pulvis Talci 4g
Tween 80 80g
70% syrup 50g
Ethanol 1500g
Make 1000
Preparation technology:
With being crushed to the neogambogic acid of 100 μ m and soybean phospholipid 2: 1 ratios by weight, under 50 ℃ of backflow stirring conditions, make to be dissolved in 5 times of dehydrated alcohol, fully after the dissolving, with the ethanol evaporate to dryness, 50 ℃ of vacuum dryings 12 hours obtain the neogambogic acid phosphatide complexes, grind 120 mesh sieves; Get 200g neogambogic acid phosphatide complexes and 100g micropowder silica gel, 250g lactose, 50g starch mixing, get 50% ethanol 80g again, add in the said mixture mixing behind the Tween 80 80g mix homogeneously; With 70% syrup 50g stirring and evenly mixing system soft material, cross 20 order rustless steel sieve series granules, 50 ℃ of dryings 6 hours are crossed the nylon mesh granulate, and after the assay was approved adds Pulvis Talci 4g, divides the hard capsule case of packing into promptly to get the neogambogic acid capsule.
Embodiment 9
Prescription:
Neogambogic acid 200g
Carbopol 150g
Ethyl cellulose 20g
Micropowder silica gel 10g
Magnesium stearate 7g
Polyvidone 8g
Make 1000
Preparation technology:
Neogambogic acid and adjuvant were pulverized all 80 mesh sieves, after taking by weighing the carbopol and ethyl cellulose mix homogeneously of recipe quantity, add the neogambogic acid mix homogeneously again, add 8% polyvidone alcoholic solution, make soft material, crossing 20 mesh sieves granulates, 50 ℃ of dryings granulate after 6 hours, 80 mesh sieves are removed fine powder, add micropowder silica gel and magnesium stearate mix homogeneously, the filling hard capsule case promptly gets the neogambogic acid Extencap.
Embodiment 10
Prescription
Neogambogic acid 100g
Polyvinylpyrrolidone 6000 270g
Micropowder silica gel 10g
L-arginine 50g
Make 1000 balls
Preparation technology:
The neogambogic acid 10g of 100 μ m will be crushed to, with L-arginine, micropowder silica gel mixture (in 1: 1 ratio uniform mixing); 6000 270g place oil bath with polyvinylpyrrolidone, are heated to 145 ℃ and make into the homogeneous phase melt liquid; After stirring makes its mix homogeneously in neogambogic acid mixture adding polyvinylpyrrolidone 6000 fused solutions, splash in the dimethicone condensed fluid that is with ice bath with solid agent constant speed degree, form drop pill.It is faint yellow that drop pill is, and after the taking-up, filter paper is dried, and sticks to the outer oil stain of soft gelatin capsule with petroleum ether drip washing, and cold wind dries up.Promptly get the neogambogic acid drop pill.
Embodiment 11
Prescription
Neogambogic acid 80g
Lactose 150g
Hydroxypropyl cellulose 4g
Carboxymethyl starch sodium 12g
Polyoxyethylene sorbitan monoleate 40g
Water is an amount of
Preparation technology:
The neogambogic acid 80g and the 40g polyoxyethylene sorbitan monoleate that are crushed to 100 μ m are mixed, it is an amount of to add water, make the neogambogic acid aqueous solution, the 4g hydroxypropyl cellulose is dissolved in the 150mL water, be made into the aqueous solution of hydroxypropyl cellulose, adopt the fluid boiling granulation, 150g lactose and 12g carboxymethyl starch sodium put on fluidising chamber's screen cloth in 60 ℃ hot-air, be fluidized state, spray into the neogambogic acid aqueous solution, the lactose of fluidized state and the mixture of carboxymethyl starch sodium and principal agent begin to condense into granular, through spraying repeatedly, drying gets the neogambogic acid granule.
Embodiment 12
Prescription
Neogambogic acid 300g
Hexadecanol 250g
Lecithin 30g
Polyvidone 10g
Polyacrylic resin 40g
Magnesium stearate 10g
Preparation technology:
Neogambogic acid and adjuvant were pulverized all 80 mesh sieves, after taking by weighing the lecithin and neogambogic acid mix homogeneously of recipe quantity, add the hexadecanol mix homogeneously again, add 8% polyvidone alcoholic solution, make soft material, crossing 20 mesh sieves granulates, particle diameter 1～1.5mm, 50 ℃ of dryings granulate after 6 hours adds the magnesium stearate mix homogeneously, use the polyacrylic resin coating, promptly get the neogambogic acid controlled release granule.
Embodiment 13
Prescription
Neogambogic acid 100g
Soybean phospholipid 100g
Micropowder silica gel 200g
Starch 100g
Lactose 300g
70% syrup 150g
Pulvis Talci 2g
Ethanol 525g
Preparation technology:
With being crushed to the neogambogic acid of 100 μ m and soybean phospholipid 1: 1 ratio by weight, under 50 ℃ of backflow stirring conditions, make to be dissolved in 5 times of dehydrated alcohol, fully after the dissolving, with the ethanol evaporate to dryness, 50 ℃ of vacuum dryings 10 hours obtain the neogambogic acid phosphatide complexes, grind 120 mesh sieves; Get 200g neogambogic acid phosphatide complexes and 200g micropowder silica gel, 300g lactose, 100g starch mixing, get 50% ethanol 50g again, add in the said mixture mixing behind the Tween 80 50g mix homogeneously; With 70% syrup 150g stirring and evenly mixing system soft material, cross 20 order rustless steel sieve series granules, 50 ℃ of dryings 6 hours are crossed the nylon mesh granulate, and after the assay was approved adds Pulvis Talci 2g, and packing is sealed, and promptly gets the neogambogic acid granule.
Embodiment 14
Prescription
Neogambogic acid 10g
Carboxymethyl starch sodium 20g
Sucrose 100g
Polyoxyethylene sorbitan monoleate 10g
Fructus Citri Limoniae essence is an amount of
Magnesium stearate 1g
Preparation technology:
Except that magnesium stearate, all the other all supplementary materials were pulverized 200 eye mesh screens in will writing out a prescription, and again with the abundant mix homogeneously of magnesium stearate, divided in the poly-bag of packing into, sealed, and promptly made the neogambogic acid dry suspension, and the time spent takes after mixing it with water with warm water.
Embodiment 15
Prescription
Neogambogic acid 200g
PEG4000 5g
PEG400 180g
Propylene glycol 20g
Preparation technology:
Get recipe quantity PEG4000, PEG400, propylene glycol, be heated to 60 ℃, PEG4000 melts, and stirs, and makes substrate; Get 50% of above-mentioned substrate, add neogambogic acid and stir, grind to 2～5 μ m through colloid mill, and then with above-mentioned remainder substrate stirring and evenly mixing, firmly be incubated fill under 35～45 ℃ the condition, roll capsule, promptly make the neogambogic acid soft capsule.。Capsule casing material is by gelatin: glycerol: water is formed with 1: 0.35: 0.9 ratio.
Embodiment 16
Prescription
Neogambogic acid 100g
Injection soybean oil 130g
Propolis 20g
Preparation technology:
Get recipe quantity injection soybean oil, the propolis heating and melting is made substrate, and neogambogic acid is added in the substrate, grinds to 2～5 μ m through colloid mill, fill under 30～50 ℃ condition of insulation, rolls capsule, promptly makes the neogambogic acid soft capsule.Capsule casing material is by gelatin: glycerol: water is formed with 1: 0.35: 0.9 ratio.
Embodiment 17
Prescription
Neogambogic acid 100g
PEG1000 4g
PEG400 180g
Propylene glycol 10g
Preparation technology:
Get recipe quantity PEG1000, PEG400, propylene glycol, be heated to 60 ℃, PEG1000 melts, and stirs, and makes substrate; Get 40% of above-mentioned substrate, add neogambogic acid and stir, grind to 2～5 μ m through colloid mill, and then with above-mentioned remainder substrate stirring and evenly mixing, fill under 40～50 ℃ condition of insulation, roll capsule, promptly make the neogambogic acid soft capsule.Capsule casing material is by gelatin: glycerol: water is formed with 1: 0.35: 0.9 ratio.
Embodiment 18
Prescription
Neogambogic acid 100g
Soybean phospholipid 25g
Tween 80 50g
PE6400 150g
Propylene glycol 120g
Ethanol 600g
Water 50g
Preparation technology:
Neogambogic acid and soybean phospholipid under 50 ℃ of stirring conditions, are made to be dissolved in 5 times of amount dehydrated alcohol, fully after the dissolving, solvent evaporated, 50 ℃ of vacuum dryings get the neogambogic acid phosphatide complexes, through grinding 120 mesh sieves, get composite powder, add Tween 80 50g, PEG400 150g, propylene glycol 120g, water 50g is ground to 2～8 μ m with colloid mill, after mensuration content is qualified, be placed in the hopper of rolling capsule machine, be incubated 45～50 ℃ and roll capsule.Roll the capsule gelatine size, by gelatin: glycerol: water is formed with 1: 0.5: 1 ratio.Cold air drying 24 hours, absolute ethanol washing, drying, the choosing grain promptly gets the neogambogic acid soft capsule.
Embodiment 19
Embodiment 15,16,17,18 stability of sample:
Soft capsule with embodiment 15,16,17,18 preparations, putting temperature by commercially available back (aluminum-plastic packaged) is that 40 ℃, relative humidity are accelerated test 6 months under 75% condition, checks outward appearance, measures content and dissolution, test shows that the neogambogic acid soft capsule quality is stable, and the result is as follows:
| Sample | Character | Content (labelled amount %) | Dissolution (labelled amount %) | |
| The soft capsule of soft capsule embodiment 18 preparations of soft capsule embodiment 17 preparations of soft capsule embodiment 16 preparations of embodiment 15 preparations | Softgel shell shape softgel shell shape softgel shell shape softgel shell shape | 100.3 99.8 100.2 99.5 | 30 minutes 45 minutes 30 minutes 45 minutes 30 minutes 45 minutes 30 minutes 45 minutes | 90.6 98.2 91.5 98.8 90.4 97.5 92.2 98.1 |
Claims (15)
1, a kind of oral formulation of neogambogic acid for the treatment of tumor is characterized in that: be active component with the neogambogic acid, all the other compositions are adjuvant, and its parts by weight of raw materials proportioning is: 1～100 part of neogambogic acid, 1～100 part of adjuvant;
Described oral formulations comprises any in tablet, capsule, drop pill, granule, soft gelatin capsule, dry suspension, suspendible gel or the powder.
2, oral formulation of neogambogic acid according to claim 1 is characterized in that: described tablet will be for leading to any in sheet, Film coated tablets, enteric coatel tablets, gastric soluble tablet, dispersible tablet, oral cavity disintegration tablet, the effervescent tablet; Described adjuvant is filler, disintegrating agent, surfactant, binding agent or other adjuvant; Its parts by weight of raw materials proportioning is:
1～100 part of neogambogic acid
0.3～30 part of filler
0.3～25 part of disintegrating agent
0.01～5 part in surfactant
0.19～20 part of binding agent
0.2～20 part of other adjuvant.
3, oral formulation of neogambogic acid according to claim 1 is characterized in that: described tablet is any in controlled release tablet, the slow releasing tablet; Described adjuvant is filler, binding agent, surfactant or slow/controlled release material; Its parts by weight of raw materials proportioning is:
1～100 part of neogambogic acid
0.4～40 part of filler
0.19～25 part of binding agent
0.01～5 part in surfactant
0.4～30 part of slow/controlled release material.
4, oral formulation of neogambogic acid according to claim 1 is characterized in that: described capsule is a hard capsule; Described adjuvant is filler, disintegrating agent, surfactant, binding agent or other adjuvant; Its parts by weight of raw materials proportioning is:
1～100 part of neogambogic acid
0.3～30 part of filler
0.4～30 part of disintegrating agent
0.01～5 part in surfactant
0.19～20 part of binding agent
0.1～15 part of other adjuvant.
5, oral formulation of neogambogic acid according to claim 1, its feature toward in: described capsule is a soft capsule; Described adjuvant is filler, coating material or other adjuvant; Its parts by weight of raw materials proportioning is:
1～100 part of neogambogic acid
0.5～45 part of filler
0.5～45 part of coating material
0～10 part of other adjuvant.
6, oral formulation of neogambogic acid according to claim 1 is characterized in that: described capsule is any in slow releasing capsule or the controlled release capsule; Described adjuvant is filler, slow/controlled release material or other adjuvant, and its parts by weight of raw materials proportioning is:
1～100 part of neogambogic acid
0.5～40 part of filler
0.5～40 part of slow/controlled release material
0～20 part of other adjuvant.
7, oral formulation of neogambogic acid according to claim 1 is characterized in that: described oral formulations is a drop pill, and described adjuvant is filler, coating material or other adjuvant, and its parts by weight of raw materials proportioning is:
1～100 part of neogambogic acid
0～40 part of filler
0.8～40 part of coating material
0～20 part of other adjuvant.
8, oral formulation of neogambogic acid according to claim 1 is characterized in that: described oral formulations is a granule, and described adjuvant is filler, disintegrating agent, surfactant, binding agent or other adjuvant; Its parts by weight of raw materials proportioning is:
1～100 part of neogambogic acid
0.3～20 part of filler
0.2～20 part of disintegrating agent
0.01～5 part in surfactant
0.19～15 part of binding agent
0.3～40 part of other adjuvant.
9, according to any one described oral formulation of neogambogic acid of claim 2-8, it is characterized in that: described filler is choosing any one kind of them or several combinations in lactose, sucrose, glucose, dextrin, mannitol, sorbitol, calcium sulfate, calcium gluconate, calcium hydrogen phosphate, calcium phosphate, calcium carbonate, calcium bicarbonate, starch, carboxymethyl starch and sodium salt thereof, pregelatinized Starch, hexadecanol, L-arginine, various viscosity polyvinyl alcohol, Polyethylene Glycol, carbopol, cellulose and the derivant thereof.
10, according to claim 2,3,4,8 any one described oral formulation of neogambogic acid, it is characterized in that: described binding agent is choosing any one kind of them or several combinations in gelatin, arabic gum, maltose, polyvinylpyrrolidone, various viscosity polyvinyl alcohol, the Polyethylene Glycol.
11, according to claim 2,3,4,8 any one described oral formulation of neogambogic acid, it is characterized in that: described surfactant is choosing any one kind of them or several combinations in sodium lauryl sulphate, poloxamer, pluronic gram, Tween 80, bromination hexadecane trimethylamine, sodium laurylsulfate, stearyl alcohol sodium sulfate, polyoxyethylene deriv, sucrose ester, sorbitol fatty ester, the soybean phospholipid.
12, according to claim 2,4,8 any one described oral formulation of neogambogic acid, it is characterized in that: described disintegrating agent is choosing any one kind of them or several combinations in microcrystalline Cellulose, pure lignocellulose, alginic acid, guar gum, crospolyvinylpyrrolidone, the ion exchange resin.
13, according to any one described oral formulation of neogambogic acid of claim 7, it is characterized in that: described coating material is any or several combination in gelatin, glycerol, arabic gum, Lac, cellulose and derivant thereof, polyvinyl alcohol, polyacrylic acid, Polyethylene Glycol, polylactic acid, polyethylene, polyamide, stearic acid and the ester thereof.
14, according to claim 3,6 any one described oral formulation of neogambogic acid, it is characterized in that: described slow/controlled release material is any or several combination in Brazil wax, castor oil hydrogenated, castor wax, hydrogenated soya phosphatide, Lac, gelatin, sodium alginate, chitosan, amylopectin, agar, carrageenin, guar gum, cellulose derivative, crylic acid resin, the polyethylene kind macromolecular material.
15, according to claim 2,4,5,6,7,8 any one described oral formulation of neogambogic acid, it is characterized in that: described other adjuvant is wetting agent, lubricant, help a kind of or any several combination of collapsing in agent, suspensoid, suspending agent, fluidizer, correctives, effervescent, adsorbent, coating material, enclose material, the solvent.
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| CN115212201A (en) * | 2022-08-23 | 2022-10-21 | 上海中医药大学 | Application of neogambogic acid in preparation of Nrf2 protein inhibitor |
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