CN1060935C - Preparation method of arsenical capable of applying to cancer focus - Google Patents

Abstract

The present invention relates to a preparation method of an arsenical preparation capable of directly applying to cancer focus, which belongs to a preparation technology of anti-cancer drugs. The arsenical preparation is made into a specific dosage form by the prior art. The present invention aims to introduce the curative effect of the body surface and cavity channel cancer of the arsenical preparation to the internal body, and meanwhile, the preparation method of the arsenical preparation for treating body surface and cavity channel cancer is also provided. Because the inner layer, the middle layer and the outer layer of liposome all adopt specific processing modes, the preparation method of liposome provided by the present invention is suitable for industrialization mass production, and also solves the problems of short storage time and easy discharge and leakage of liposome wet products, easy adhesion, moisture absorption, easy oxidation, rancidity and deterioration of dry products, extrusion, filtration, homogenizing treatment, etc. when dry product liposome is redissolved.

Description

The preparation method that is used for the arsenic preparation of the direct administration of carcinoma focus

The invention belongs to anti-cancer drug preparation technology.

The cmm of simple prescription of arsenic, the direct focus administration of compound preparation now have been widely used in body surface, tract etc. without the just directly treatment of the carcinoma of administration of special instrument.And obtained the curative effect that attracts people's attention.Folk prescription arsenicum sablimatum paste (two liang of arsenicum sablimatum two money, wheat flours) treatment skin carcinoma is recorded in Liaoning " Chinese herbal medicine new therapy that combines both Chinese and Western medical practices compilation of data ", can make tumor connect root and come off; County hospital Lee of Mengcunhui, Hebei autonomous region is long to cure 10 examples doubly with " five cigarette pellets " (cholelithiasis, Magnetitum, cinnabar, Alumen, Realgar wherein generate arsenic trioxide after the Realgar calcination) treatment skin carcinoma 16 examples, and 6 examples take a turn for the better effective percentage 100%.The department of obstetrics and gynecology institute cervical cancer Yang Xue of research department of Jiangxi Province health care of women institute will etc. are treated 190 routine cervical cancer patients with Chinese medicine " three products ", cake, bar (arsenicum sablimatum, Alumen, Realgar, Myrrha), and whole patients have been carried out strict regular follow-up checked, late result: remove 1 example and after 3 years, die from chronic nephritis with uremia, 1 example $4\frac{1}{2}$ Year dies from outside the cerebral hemorrhage, all the other 188 examples all healthy (～nineteen eighty-two in 1972 different year repeatedly follow up a case by regular visits to) there is no recurrence, cure rate 100% and 1977 version " Henan Province's drug standard " include " canceroderm is clean " (arsenicum sablimatum, fingernail, hair, Fructus Jujubae, alkali fermentation～this side also can be considered the arsenicum sablimatum folk prescription, and other composition all can be considered slow releasing agent).Aforesaid single, compound arsenic preparation has reached justifiable degree on the curative effect of treatment body surface, tract cancer.But its range of application is narrower, still can not touch carcinoma in the body, simultaneously when body surface and tract medication, it also shows slightly weak on dosage form, the dosage form that has is unsuitable for industrialized great production, and the dosage form that has is very inconvenient on using, the difficult quality control between criticizing when the dosage form that has is produced and criticizing.

Task of the present invention be do not repel the middle prescription of arsenic, compound recipe is under the prerequisite of raw material, also can select purity higher arsenious oxide, salt and Organic substance separately for use is that raw material is made specific means such as dosage form, the therapeutic effect of above-mentioned arsenic preparation to body surface and tract carcinoma is incorporated in the body, also provided the preparation method of the preparation that is applicable to industrialized great production that is used for body surface and the treatment of tract carcinoma simultaneously.

Arsenic preparation of the present invention, be raw material mainly with arsenious oxide (being equivalent to the folk prescription arsenicum sablimatum), salt, organic compound and herbal mixture thereof, cooperate the ointment (I) that is used for body surface and tract carcinoma, the paste (II) that processes with specific support and be used for the suspension type injection (III) of cancer entity direct injection in the body, liposome (IV) etc.

Wherein the preparation method of (I), (II) is: after medicine (can select for use arsenious oxide, salt, Organic substance, herbal mixture among at least a) and substrate (can select for use in oils, lipoidis, hydro carbons, starch based, zinc oxide, the silicone at least a) are given processing respectively, various substrate are pressed fusing point order from high to low, successively add fusion, standby behind the mix homogeneously, with medicine and after the substrate of molten state is mixed on a small quantity, doubly measure dilution with other substrate again, be mixed, do not get final product to there being granular sensation.

Wherein the preparation method of (III) is: (can select medicine (can select for use arsenious oxide, salt, Organic substance, herbal mixture among at least a) solvent for use vegetable oil, benzyl benzyl formate, ethyl oleate etc.) after suspending agent (can select single, double, Aluminium Tristearate Micronized sterile for use) gives processing respectively, suspending agent is dissolved in forms oleogel in the solvent, with the medicine abundant mixing of factice therewith, the reuse colloid mill is levigate to qualified getting final product then.

Wherein the preparation method of (IV) is: (can select medicine for use arsenious oxide, salt, organic compound, at least a in the herbal mixture), the PH buffer agent of interior water (can be selected sodium carbonate for use, potassium bicarbonate, sodium hydroxide, dibastic sodium phosphate, sodium phosphate), oil phase (can be selected axunge for use, vegetable oil, the benzyl benzyl formate, ethyl oleate, at least a in the chloroform), suspending agent (can be selected list for use, two, Aluminium Tristearate Micronized sterile etc.), matrix material (can be selected phosphatidylcholine for use, phosphatidyl glycerol, the lecithin phatidylcholine, the hydrogenated soybean lecithin phatidylcholine, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, dimyristoyl phosphatidyl choline, two spermaceti phospholipid, the fabaceous lecithin phatidylcholine, thioester, cholesterol, coprostenol, cholestane, Dihydrocholesterol, at least two kinds of alpha-tocopherols etc.), spray drying anticoagulant, entity injection slow releasing agent (can be selected sodium alginate for use, methylcellulose, carboxymethyl cellulose, polyvinylpyrrolidone etc.) above-mentioned raw materials, adjuvant is standby after giving processing.Medicine is dissolved in the internal layer water buffer, and transfers PH8～10 standby, suspending agent and 1/3 phospholipid, the cholesterol of measuring are dissolved in the oil phase respectively.Then above-mentioned pastille buffer is added in the oil phase under condition of stirring and carry out emulsifying, form w/o type Emulsion, again this W/O breast is removed most of organic solvent with the way of a gentleness, form a spissated W/O Emulsion, with this concentrate form the compound breast of W/O/W, homogenize in breast adds the phospholipid that contains total amount 2/3 and cholesterol under the state that stirs the aqueous solution after, this breast is carried out spray drying simultaneously with high viscosity copolymer solution, get final product the liposome microgranule of surperficial formation one layer of polymeric thin film.

The invention has the advantages that compare with traditional form of administration have wide range of applications, dosage is accurate, polarization good, more is applicable to industrialized great production; Compare with the whole body administration that overall dosage is little, focus entity drug level height, curative effect height, instant effect, side effect be little.And the method for preparing lipidosome that the present invention is given, be not only applicable to industrialized great production and also solved that the wet product preservation term of liposome lack, is easily unloaded with Louing, the easy adhesion of dry product, moisture absorption, the deliquescence rear oxidation becomes sour rotten and add during use the water redissolution need the press filtration homogenize etc. operation problem.

Prescription of the present invention, process example are:

Example 1-2

Component 1 (I) (II)

" three products " 100g 250g

White vaseline 800g 420g

Lanoline 50g 50g

Lecithin 30g 30g

Zinc oxide 20g 100g

Starch 150g

Technology: 200 mesh sieves are concocted, pulverized to " three products ", standby with zinc oxide and starch mix homogeneously, with vaseline, lanoline, lecithin according to fusing point order from high to low, successively add after the melting mixing standby, after grinding the said medicine mixture and the substrate of a small amount of molten state all, doubly to measure diluted mixture even with other residue substrate again, do not get final product to there being granular sensation.

Example 3 prescriptions:

Component: (III)

" three products " 50g

Aluminum monostearate 20g

Neuter flower oil generation adds to 1000ml

Technology is concocted " three products ", comminution by gas stream, to standby below the 5 μ m, learns from else's experience by filtration, the neuter flower oil generation of sterilization is made into 8% factice with the aluminum monostearate that steeps with oil immersion, and heats to 120 ℃, be incubated 1 hour, redilution becomes 2% oleogel, and mix homogeneously is standby.With drug powder therewith oleogel fully mix, the reuse colloid mill is levigate to qualified getting final product.

The prescription of example 4 (IV): arsenic trioxide (arsenicum) 10g, inner phase is used distilled water 400g, outer with hydrogenated soya phosphatide/cholesterol 16g (1: 0.6 mole ratio) spraying anti-freezing liquid water 500g, methylcellulose 5g with distilled water 40g, potassium bicarbonate 7g, neutral Oleum Glycines 20g, aluminum monostearate 0.4g, chloroform 80g, internal layer with hydrogenated soya phosphatide/cholesterol 8g (1: 0.8 mole ratio), foreign minister.(IV) technology: arsenic trioxide is dissolved in the 40ml water that contains the potassium bicarbonate buffer, and it is standby to transfer PH to 8 to constitute water.Be dissolved in the chloroform phospholipid/cholesterol of 8g standby.Neutral Oleum Glycines and aluminum monostearate such as example 3 methods are made 2% oleogel, and be diluted in the above-mentioned chloroformic solution and constitute oil phase.Water is added in the oil phase, use the homogenizer homogenize, get w/o type Emulsion, this Emulsion is evaporated 55～70% chloroforms under 40 ℃ of decompression situations, must concentrate w/o type Emulsion, this is concentrated breast under agitation adds in the aqueous solution that contains 16g phospholipid/cholesterol, emulsifying, form W/O/W type multiple emulsion.This moment with the compound breast of this W/O/W with contain the solution mix homogeneously of methylcellulose, spray drying immediately, get final product the liposome microgranule of surperficial formation one deck methylcellulose thin film.Packing promptly

Annotate: 1, add the oleogel of trace between the liposome bilayer, can effectively prevent unloading leakage of internal layer water soluble drug.

2, arsenic trioxide cancer entity injection.Owing to all added thickening agent, slow releasing agent in (III), (IV), can stop medicine from the cancer entity, to unload leakage, unload on a small quantity leakage, health is also had no adverse effects even have, because Fowler solution (potassium arsenite liquid) is low dose of as analeptic, also is the Oral preparation of using always.※

3, the redissolution method that has the liposome microgranule of methylcellulose thin film: quantitative distilled water is heated to 50 ℃ annotates in the peace bottle that liposome is housed, constantly jolting treats that temperature reduces to room temperature (best 5 ℃) particle suspension and be uniformly dispersed and get final product.

The ※ Chinese Medicine science and technology P30 of publishing house's in August, 1989 " medicines structure and preparation "

Claims (4)

1. the preparation method that is used for the arsenic suspension injection of directly administering to cancer nidus, it is characterized in that with three products, arsenic trioxide and with the arsenic trioxide be at least a among the single medicinal material material of main component be primary raw material, select vegetable oil for use, the benzyl benzyl formate, at least a among the ethyl oleate is solvent, select list for use, two, at least a among three aluminum foil stearates is suspending agent, and by primary raw material being crushed to below the 5 μ m, with solvent filter, sterilization, with the suspending agent soaked in solvent, make gel and gel and the raw material that is crushed to below the 5 μ m are mixed, several procedures of packing are finished.

2. the preparation method that is used for the arsenic liposome of directly administering to cancer nidus, it is characterized in that with arsenic trioxide and with the arsenic trioxide be at least a among the single medicinal material material of main component be primary raw material, select phosphatidylcholine for use, phosphatidyl glycerol, the lecithin phatidylcholine, the fabaceous lecithin phatidylcholine, the hydrogenated soybean lecithin phatidylcholine, the dipalmitoyl-phosphate ester phatidylcholine, distearoyl phosphatidylcholine, dimyristoyl phosphatidyl choline, thioester, cholesterol, coprostenol, Dihydrocholesterol, alpha-tocopherols etc. are liposome bilayer material at least two kinds, consumption is the 0.5--15% of spray drying prelipid substance body fluid, wherein the ratio of phospholipid and cholesterol is 1: 0.2-1: 1 mole ratio, the ratio of cholesterol is greater than skin in the internal layer lipid layer, make behind the liposome that the distribution proportion of bimolecular material is 1: 2 in the ectonexine, with axunge, vegetable oil, Benzyl Benzoate fat, one of ethyl oleate or chloroform are oil phase, with list, two, one of Aluminium Tristearate Micronized sterile is a suspending agent, medicine is dissolved in the internal layer water buffer, transfer PH8-10, suspending agent and indeterminate plant oil are made 2% factice, the liposome bilayer material of 1/3 amount is dissolved in adds oleogel in the oil phase subsequently therein and pastille water buffer is under agitation added in the oil phase emulsifying form w/o type Emulsion and it is removed 55-70% oil phase organic solvent under 40C decompression situation and form ropy milk, ropy milk after this is concentrated adds under the state that stirs in the aqueous solution that the liposome bilayer material of 2/3 amount makes and makes the compound breast of W/O/W, and spray drying promptly after the homogenize.

According to right with requiring 2 described method for preparing lipidosome, the buffer agent of water can be selected sodium carbonate, sodium hydroxide, sodium bicarbonate, dibastic sodium phosphate or potassium phosphate for use in it is characterized in that.

4. according to claim 2 or 3 described method for preparing lipidosome, it is characterized in that making aqueous solution as anti-freezing liquid with sodium alginate, methylcellulose, carboxymethyl cellulose or polyvinylpyrrolidone, spray behind itself and the compound newborn mixing of W/O/W, obtain the liposome of surface coverage one deck high molecular polymer thin film.