CN105732517A - Medicine preparation containing 5-fluorouracil drug eutectic with nicotinamide as precursor and preparation method of medicine preparation - Google Patents

Medicine preparation containing 5-fluorouracil drug eutectic with nicotinamide as precursor and preparation method of medicine preparation Download PDF

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CN105732517A
CN105732517A CN201610069200.1A CN201610069200A CN105732517A CN 105732517 A CN105732517 A CN 105732517A CN 201610069200 A CN201610069200 A CN 201610069200A CN 105732517 A CN105732517 A CN 105732517A
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preparation
pharmaceutical
crystals
water
fluorouracil
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CN105732517B (en
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于楠
韩思莹
张良栓
张竹艳
李海波
王健鑫
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Harbin Engineering University
Harbin Medical University
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Harbin Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
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    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1658—Proteins, e.g. albumin, gelatin
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3

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Abstract

The invention discloses a medicine preparation containing 5-fluorouracil drug eutectic with nicotinamide as a precursor and a preparation method of the medicine preparation.5-fluorouracil raw material medicine is selected as medicine API, nicotinamide serves as the medicine precursor, a liquid-phase assisted grinding method is adopted, the high-purity 5-fluorouracil drug eutectic is obtained, and the effect that the medicine can be more stable can be achieved; in addition, the invention further provides the medicine preparation containing the 5-fluorouracil drug eutectic, the medicine preparation comprises tablets, slow-release tablets, microspheres, micro-capsules, suppository, emulsion, a film agent and an injection agent so that stability and the curative effect of the 5-fluorouracil drug eutectic with the nicotinamide as the precursor can be better improved, different medicine application modes are utilized, and possibility of fully playing the treatment function of medicine and lowering or avoiding adverse reactions is provided.Auxiliaries applied to the preparation method of the preparation are easy to buy in the market and low in price, therefore cost is quite low, and the medicine application burden of patients can be remarkably lowered.

Description

Comprise pharmaceutical preparation of 5-fluorouracil pharmaceutical co-crystals that nicotiamide is presoma and preparation method thereof
Technical field
The present invention relates to a kind of pharmaceutical preparation and preparation method thereof, comprise pharmaceutical preparation of 5-fluorouracil pharmaceutical co-crystals that nicotiamide is presoma and preparation method thereof particularly to a kind of, the invention belongs to pharmaceutical preparation preparing technical field.
Background technology
5-fluorouracil, nineteen fifty-seven synthesizes by Heidelberger, all has proliferative cell is everyKillPower, is the classical antitumor drug of pharmacopeia collection.5-fluorouracil is first antimetabolite synthesized according to certain imagination and is the most most widely used anti-miazines medicine clinically, in recent decades, 5-fluorouracil occupies critical role all the time in Internal Medicine-Oncology is treated, treatment for kinds of tumors such as digestive tract tumor, breast carcinoma, ovarian cancer, chorionic epithelioma, cervical cancer, bladder cancer, hepatocarcinoma, skin carcinoma etc. is effective clinically, especially alimentary tract cancer and other solid tumors is had good efficacy.
5-fluorouracil dissolubility is poor, the most molten in water, and slightly soluble in ethanol is the most insoluble in chloroform；Dissolving in dilute hydrochloric acid or sodium hydroxide solution, the form being therefore configured to be suitable for administration is highly difficult.5-fluorouracil oral absorption not exclusively and is difficult to predict, therefore mostly is drug administration by injection clinically, is distributed to rapidly whole body and respectively organizes after intravenous.But this administering mode there is also shortcomings, such as bone marrow depression, the bad gastrointestinal reactions such as Half-life in vivo is short, nausea and vomiting.Additionally, clinical vein is lasting for injection time, make troubles to patient and painful.
Nicotiamide, also known as vitamin B3 (VB3), is the biologically active form of nicotinic acid, extensively sees in multiple animals and plants.It is also cofactor NADH (nicotinamide adenine dinucleotide) and the important as precursors of NADPH (nicotinamide-adenine dinucleotide phosphate).They play the effect of coenzyme together with reduced-NAD H and NADPH in more than 40 kinds of biochemical reactions, it is possible to play the effect of antioxidant.Nicotiamide is a kind of water-soluble substances, has stability of solution and light stability.In the solution that pH value is 6, optimal stability.Nicotiamide has defying age, antitumor, improves skin barrier function isoreactivity, is widely used in antitumor drug exploitation and cosmetic field.
The synthesis of eutectic medicine and preparation are a kind of supramolecular synthesis models, are that crystal calls the assembling of self-existing molecule, without the one breaking or being formed non-covalent bondNovelStructure.The pharmaceutical co-crystals of this novelty can be the biggest improvement medicine in dissolubility, dispersion rate, the character of the aspect such as stability and bioavailability.In a word, pharmaceutical co-crystals is beneficial to provide far-rangingNovelSolid phase, they have the character being different from existing drug molecule based on solid-state form, including fusing point, dissolubility, rate of dissolution, chemical stability, the character of the aspect such as thermodynamic stability and bioavailability.
Therefore, to the 5-fluorouracil pharmaceutical co-crystals and the preparation thereof that provide nicotiamide to be presoma, maintain and use the improved form of the enough concentration levels in environment to there is demand.
Summary of the invention
It is an object of the invention to provide one to containNovelPharmaceutical preparation of 5-fluorouracil pharmaceutical co-crystals of structure and preparation method thereof.Preparation relates to conventional tablet, slow releasing tablet, microsphere, microcapsule, suppository, Emulsion, membrane and the injection comprising the 5-fluorouracil pharmaceutical co-crystals that nicotiamide is presoma.
In order to achieve the above object, present invention employs techniques below means:
A kind of pharmaceutical preparation comprising the 5-fluorouracil pharmaceutical co-crystals that nicotiamide is presoma of the present invention, it is characterized in that described pharmaceutical preparation comprises the 5-fluorouracil pharmaceutical co-crystals and one or more excipient that nicotiamide is presoma, the group that one or more described excipient are formed selected from filler, surfactant, fluidizer, lubricant and disintegrating agent；
Wherein, described filler is at least one in mannitol, lactose, sucrose, glucose, maltodextrin, sorbitol, xylitol, Powderd cellulose, microcrystalline Cellulose, silicified microcrystalline cellulose, methylcellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl hydroxyethylcellulose, hypromellose, Pulvis Talci, starch, pregelatinized Starch, calcium hydrogen phosphate or calcium carbonate；
Wherein, described surfactant is sodium lauryl sulfate, docusate sodium, polyoxyethylene sorbitan fatty acid esters, Arlacel-20, Arlacel-60, Arlacel-80, from phospholipid, polyglycerol acrylate, polyglycereol-6-dioleate, polyoxyethylene 20 stearyl ether, polyoxyethylene alkane fat ether, castor oil derivatives, Pegylation castor oil hydrogenated, fatty acid esters of sorbitan, vitamin E TPGS, Renascin, lecithin, phospholipid and derivant thereof, poloxamer, stearic acid, oleic acid, spermol, monoglyceride and dialycerides, glyceryl monostearate, fatty glyceride, Ethylene Glycol Palmitostearate, polyethyleneglycol glyceride, Capryol 90, propylene glycol single lauryl alcohol ester or polyglycerol acrylate, paraffin, glycerol, Cera Flava, at least one in white vaseline；
Wherein, described fluidizer is at least one in Pulvis Talci, colloidal silica, magnesium oxide, magnesium silicate, leucine or starch；
Wherein, described lubricant is at least one in Pulvis Talci, fatty acid, stearic acid, magnesium stearate, calcium stearate, sodium stearate, glyceryl monostearate, sodium lauryl sulfate, sodium stearyl fumarate, hydrogenated oil and fat, fatty alcohol, fatty acid ester, behenate, mineral oil, vegetable oil, leucine or sodium benzoate；
Wherein, described disintegrating agent be cross-linking sodium carboxymethyl cellulose, sodium alginate, calcium alginate, alginic acid, starch, pregelatinized Starch, sodium starch glycollate, crospovidone, cellulose and its derivates, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, soybean polysaccharide, guar gum, ion exchange resin, based at least one in food acids and the effervescent system of alkaline carbonate component or sodium bicarbonate.
In the present invention, preferably, described polyoxyethylene sorbitan fatty acid esters includes polysorbate 20, 40, 60 and 80, described castor oil derivatives includes CREMOPHORE EL and Emulsifier EL-40, described fatty acid esters of sorbitan includes Arlacel-80, Arlacel-40, Arlacel-60 and Arlacel-65, described poloxamer includes poloxamer188, 388 and 188, described fatty glyceride includes glycerin mono-fatty acid ester, glyceryl monostearate, described polyethyleneglycol glyceride includes oleic acid polyethyleneglycol glyceride, octanoic acid certain herbaceous plants with big flowers acid polyethylene glycol glyceride and Gelucire 44/14 etc..
In the present invention, it is preferred to, described nicotiamide is the 1-99wt% that the amount of the 5-fluorouracil pharmaceutical co-crystals of presoma accounts for total formulation weight, and the amount of one or more described excipient accounts for the 1-99wt% of total formulation weight.
It is furthermore preferred that described preparation comprises the described pharmaceutical co-crystals of 5wt%-86wt%, the first filler of 5wt%-wt60%, the second filler of 5wt%-wt60%, the disintegrating agent of 1wt%-30wt%, the surfactant of 1wt%-30wt%, the lubricant of 1wt%-30wt% and the fluidizer of 1wt%-30wt%.
It is furthermore preferred that described preparation comprises the described pharmaceutical co-crystals of 50wt%-75wt%, the first filler of 5wt%-15wt%, the second filler of 5wt%-15wt%, the disintegrating agent of 1wt%-10wt%, the surfactant of 1wt%-10wt%, the lubricant of 1wt%-10wt% and the fluidizer of 1wt%-10wt%.
In the present invention, it is preferred to, one or more described excipient also include one or more matrix type slow-release materials, one or more viscosifier, one or more binding agents, one or more correctivess, one or more preservative and combinations thereof；
Wherein, described matrix type slow-release material is at least one in polyethylene, ethylene-vinyl acetate copolymer, vinyl acetate-acetate fiber, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone or Polyethylene Glycol；
Wherein, described viscosifier areGelatin, arabic gum, at least one in polyvinyl alcohol or sodium carboxymethyl cellulose；
Wherein, described binding agent is at least one in polyvinylpyrrolidone, hypromellose, starch or ethanol；
Wherein, described sweeting agent is at least one in stevioside, saccharin sodium, aspartame, cyclamate or maltose；
Wherein, described preservative is benzalkonium bromide, at least one in benzalkonium chloride, ethyl hydroxybenzoate or methyl hydroxybenzoate.
In the present invention, it is preferred to, described preparation is tablet, slow releasing tablet, microsphere, microcapsule, suppository, Emulsion, membrane or injection.
Further, the invention allows for preparing the method for the above pharmaceutical preparation, when described pharmaceutical preparation is tablet, slow releasing tablet, microsphere, microcapsule, suppository, unguentum, membrane or injection, prepare the most in accordance with the following methods:
(1) preparation of tablet
1) weigh 0.5g Tween-80, be dissolved in 15ml ethanol, add 15g starch, stir, be dried in 70 DEG C, cross 100 mesh sieves, standby, obtain tween starch；
2) preparation of dried starch: starch is dried at 105 DEG C, makes water content 8%-10%；
3) weigh dried starch 6g and be dissolved in the distilled water of 40ml dispersed, 80 DEG C of Heat Gelatinization, obtain starch slurry；
4) take the 5-fluorouracil pharmaceutical co-crystals 15g that nicotiamide is presoma, add starch slurry in right amount, prepare soft material, cross 16 mesh sieves to pelletize, wet grain is dried at 60 DEG C, and dry granule crosses 16 mesh sieve granulate, obtains the 5-fluorouracil pharmaceutical co-crystals granule that nicotiamide is presoma；
5) use additional normal direction step 4) in the 5-fluorouracil pharmaceutical co-crystals granule that nicotiamide is presoma in add particle weight 6% tween starch mixing, be subsequently adding the magnesium stearate of particle weight 1%, mixing；
6) tabletting, to obtain final product；
(2) preparation of erodible matrix
1) by 5-fluorouracil pharmaceutical co-crystals 10g finely ground mistake 100 mesh sieve that nicotiamide is presoma, separately stearyl alcohol is placed in evaporating dish, in 80 DEG C of water-baths, adds heat fusing, add pharmaceutical co-crystals and stir evenly, cooling, put in mortar and grind；
2) add the ratio of 7ml 80% ethanol according to 1g hypromellose, hypromellose is soaked in 80% ethanol, make hypromellose rubber cement；
3) to step 1) product that obtains adds hypromellose rubber cement make soft material, 40 mesh sieves are pelletized；
4) being dried in 50 DEG C, 40 mesh sieve granulate are weighed, and add magnesium stearate mixing；
5) tabletting, to obtain final product；
(3) preparation of hydrogel matrix tablet
1) 5-fluorouracil pharmaceutical co-crystals 10g, lactose 5.0g that nicotiamide is presoma being crossed 100 mesh sieves respectively, hypromellose crosses 80 mesh sieves, mix homogeneously, adds 80% ethanol solution and makes soft material, crosses 40 mesh sieves and pelletizes；
2) it is dried in 50-60 DEG C, 40 mesh sieve granulate, weighs, add magnesium stearate mixing；
3) tabletting, to obtain final product；
(4) preparation of microsphere
1)GelatinThe preparation of solution: weighGelatin2.5g, after the appropriate immersion that adds water is swelling, adds water to 25ml, and 60 DEG C ± 1 DEG C heating for dissolving obtains the solution that concentration is 10%, is incubated standby；
2) weigh the 5-fluorouracil pharmaceutical co-crystals 3g that nicotiamide is presoma and put in beaker, add 25mlGelatinSolution, stirs to obtain homogenous suspension at 50 DEG C；
3) 100ml liquid Paraffin is mixed homogeneously with Arlacel-80 2.5ml, the pastille under 50 DEG C of quick stirrings, step (2) obtainedGelatinSuspension instills, and forms w/o type Emulsion after emulsifying 10min；
4) the w/o type Emulsion obtained is cooled down immediately in 0-4 DEG C of ice-water bath, and after stirring at low speed 10min, add 25% glutaraldehyde 0.5ml continuation stirring crosslinking 1h, then with appropriate isopropanol dehydration 2h；
5) microscopy, sucking filtration microsphere, with each washing 3 times respectively of isopropanol, ether, 50 DEG C are dried, to obtain final product；
(5) preparation of microcapsule
1)GelatinThe preparation of aqueous solution: weighGelatin2g, add appropriate distilled water immersion swelling after dissolve in 50 DEG C ± 1 DEG C heating in water bath, be diluted with water to 60ml；
2) preparation of 40% metabisulfite solution: weigh anhydrous sodium sulfate 36g, adds distilled water 90ml mixing, dissolves in 50 DEG C ± 1 DEG C and be incubated, standby；
3) preparation of microcapsule: weigh 5-fluorouracil pharmaceutical co-crystals 2g that nicotiamide is presoma in beaker, add 60mlGelatinAqueous solution, with 10% vinegar acid for adjusting pH to 3-4 after stirring, obtains suspension, microscopy；
4) suspension of step (4) is placed in 50 DEG C ± 1 DEG C water-bath, under stirring, is slowly added dropwise 40% metabisulfite solution, put microscope observation and be advisable with cohesion encystation, the solution usage of record sodium sulfate；
5) the sodium sulfate percentage concentration in calculating system, using the sodium sulfate percentage concentration in system as the concentration of required sodium sulfate diluent, and prepared and diluted liquid；
6) under stirring, the sodium sulfate diluent of encystation system bulk 3 times is poured into in bag system, making cohesion capsule disperse, ice-water bath is cooled to 5-10 DEG C, adds 25% glutaraldehyde 3ml, stirring 15min, add 20% sodium hydroxide regulation pH to 8-9, continue stirring 1h, after sufficient standing, sucking filtration, take out with distilled water be washed till eluate without glutaraldehyde till, drain, to obtain final product；
(6) preparation of suppository
The preparation of a pure substrate bolt:
1) weigh semi-synthetic fatty acid ester 10g and put in evaporating dish, in water-bath, add heat fusing；
2) substrate of fusing is slowly poured in the suppository moulds scribbling lubricant；
3) prune after cooled and solidified spilling part, the demoulding, obtain pure substrate bolt number piece completely, every piece of pure substrate bolt weight of weighing to obtain, it is designated as G.
The b preparation containing stype:
1) weighing semi-synthetic fatty acid ester 10g and put in evaporating dish, heat in water-bath, stop heating when 2/3 substrate is melted, stirring makes entirely to melt；
2) separately weigh the 5-fluorouracil pharmaceutical co-crystals powder 1.5g that finely ground nicotiamide is presoma, add to melted semi-synthetic fatty acid ester by several times, be stirred continuously and make medicaments uniformity disperse；
3) in time becoming viscous pasty state, pour in the mould having been coated with lubricant, prune after cooled and solidified spilling part on die orifice, the demoulding, obtain complete containing stype number piece, weigh, and calculate average weight M (g/ piece) containing stype, every piece containing the weight of principal agent in stype be W=M × X%, X% be percent drug.
4) calculating of displacement value: f=W/ [G-(M-W)]
C nicotiamide is the preparation of the 5-fluorouracil pharmaceutical co-crystals suppository of presoma:
1) calculating of substrate quality should be added: by the displacement value of 5-fluorouracil double Acrawax of pharmaceutical co-crystals that the nicotiamide tried to achieve is presoma, according to below equation calculate matrix weight that every suppository need to add and 8 pieces of suppository need to matrix weight；
E=G-W/f
2) finely ground pharmaceutical co-crystals 3g is weighed, standby；
3) semi-synthetic fatty acid glyceride separately weighing amount of calculation is put in evaporating dish, adds heat fusing in water-bath；
4) by the pharmaceutical co-crystals substrate that addition is melted by several times stirs, inject mould the most while hot, operate the most as stated above, obtain suppository number piece；
(7) preparation of unguentum
The preparation of a Water-In-Oil (O/W) type emulsion type ointment base
1) preparation of oil phase: take stearyl alcohol 1.8g, white vaseline 2.0g and liquid Paraffin 1.3ml in evaporating dish, puts and is heated to 70-80 DEG C in water-bath and makes it dissolve；
2) preparation of aqueous phase: take sodium laurylsulfate 0.2g, ethyl hydroxybenzoate 0.02g, glycerol 1.0g and distilled water and be heated to 70-80 DEG C in evaporating dish or small beaker；
3) under agitation water-phase component is added in oil-phase component with thread shape, water-bath continues keep constant temperature and stir a few minutes, the most at room temperature continue to stir to condensation, obtain Water-In-Oil (O/W) type emulsion type ointment base；
The preparation of b oil-in-water (W/O) type emulsion type ointment base
1) preparation of oil phase: take glyceryl monostearate 6g, white vaseline 2.0g, Cera Flava 2g, liquid Paraffin 10g, hard paraffin 2.0g, Arlacel-80 0.8g in evaporating dish, heating in water bath to 80 DEG C so that it is dissolve；
2) preparation of aqueous phase: take Tween-80 0.4g, ethyl hydroxybenzoate 0.04g, distilled water in small beaker, be heated to 80 DEG C；
3) under stirring, aqueous phase being added oil phase, constant temperature stirs a few minutes, is stirred at room temperature to condensation, obtains oil-in-water (W/O) type emulsion type ointment base；
C nicotiamide is the preparation of the 5-fluorouracil pharmaceutical co-crystals O/W ointment of presoma:
Weigh the 5-fluorouracil pharmaceutical co-crystals powder 0.5g that nicotiamide is presoma to be placed in mortar, add O/W emulsion-type substrate 9.5g by several times, grind well, to obtain final product；
D nicotiamide is the preparation of the 5-fluorouracil pharmaceutical co-crystals W/O ointment of presoma:
Weigh the 5-fluorouracil pharmaceutical co-crystals powder 0.5g that nicotiamide is presoma to be placed in mortar, add W/O emulsion-type substrate 9.5g by several times, grind well, to obtain final product；
(8) preparation of membrane
1) preparation of rubber cement: take PVAC polyvinylalcohol 17-88 6g and add distilled water and soak in right amount, after the most swelling, put and heats in 80-90 DEG C of water-bath, add sodium carboxymethyl cellulose (CMC-Na), stirring and dissolving, filters with 80 eye mesh screens while hot, adds saccharin sodium and makes it dissolve；
2) separately taking the 5-fluorouracil pharmaceutical co-crystals 1g and glycerol 5ml of presoma to add after appropriate distilled water grinds well and add in above-mentioned rubber cement, stir evenly, insulation is placed a period of time and is removed bubble removing；
3) it is poured on the glass plate scribbling appropriate liquid Paraffin, by scraper plate method masking；
4) 60 DEG C dried, be cut into the small pieces of 2cm × 1.5cm, to obtain final product, the every medicine 5mg Han eutectic, medicine film seal is standby in polyethylene film or aluminium foil；
(9) preparation of injection
Take the water for injection of total weight 80%, add 0.05g disodium edetate stirring and dissolving, adding the 5-fluorouracil pharmaceutical co-crystals 25g that nicotiamide is presoma, regulating its pH value with the sodium hydroxide of 0.1mol/L is 8.50 ± 0.01, stirring and dissolving, inject water to 1000ml, filtering with the microporous filter membrane of 0.22 μm, embedding is in 10ml ampoule, finally in 100 DEG C of flowing steams, 30min sterilizing, to obtain final product.
In the present invention, it is preferred to, described nicotiamide is that the 5-fluorouracil pharmaceutical co-crystals of presoma is prepared by the following method and obtains:
5-fluorouracil that mol ratio is 3:1 and nicotiamide are inserted in the agate mortar of a diameter of 8～15cm, reactant is ground to form the powder of 100～300 mesh, the amount of 20～200 μ L solvents is added according to every gram of powder, adding solvent makes it moisten, the most uniform grinding 10～20 minutes, obtain 5-fluorouracil pharmaceutical co-crystals.
Wherein, described solvent water in water, water+methanol or water+ethanol, water+methanol or water+ethanol: methanol or water: the mixing of 1:2～2:1 volume ratio pressed by ethanol.
The formulation preparation method that the present invention provides is simple to operate, is easily controlled, beneficially industrialized great production.
Further, the invention allows for described pharmaceutical preparation purposes in preparing antitumor drug.
Compared to prior art, the beneficial effects of the present invention is:
1, crude drug 5-fluorouracil is the most most widely used anti-miazines medicine, and various digestive tract cancer and other solid tumors are had good efficacy, occupies critical role in Internal Medicine-Oncology is treated.5-fluorouracil need to be that 5-fluorodeoxyuridine acid has anti-tumor activity through enzymatic conversion, and suppresses the synthesis of DNA by suppression thymidylate synthase.
The present invention is announcing " 5-fluorouracil pharmaceutical co-crystals and its preparation method and application ", on the basis of Application No. 2014107832846 preparation method, use liquid phase assisted milling method to replace solvent room temperature volatility process and prepared the 5-fluorouracil pharmaceutical co-crystals identical with solvent room temperature volatility process structure, and there is the highest purity.XRD spectrum signature peak value occurs in 16.09 °～16.49 °, 20.01 °～20.41 °, 21.88 °～22.28 °, 27.53 °～27.93 °, 28.44 °～28.84 °, 29.71 °～30.11 °.
The eutectic that the present invention prepares can the active component of modified medicaments effectively, after forming eutectic with nicotiamide by non-covalent bond, other keys will not be formed with water or other external interference again, thus the effect making medicine more stable can be reached.After a kind of medicine forms eutectic with presoma, in addition to the treatment characteristic maintaining medicine itself, its physicochemical properties there is a certain degree of improvement such as dissolubility, stability and bioavailability.Compared to solvent room temperature volatility process, use the liquid phase assisted milling method of the present invention to substantially reduce experimental period, decrease synthesis fund and loaded down with trivial details technological process, for a large amount of synthetic drug eutectics in commercial production, there is the biggest actual application value.
2, the nicotiamide that the present invention prepares is stability and the curative effect that the dosage form such as 5-fluorouracil pharmaceutical co-crystals conventional tablet, slow releasing tablet, microsphere, microcapsule, suppository, Emulsion, membrane and injection of presoma can preferably improve the 5-fluorouracil pharmaceutical co-crystals that nicotiamide is presoma, by different administering modes, for giving full play to the therapeutical effect of medicine, reducing or avoid untoward reaction to provide may.In the formulation preparation method that the present invention provides, the adjuvant of application, commercially can very easily buy and low price, and therefore cost is the lowest can significantly reduce patient medication burden.
Accompanying drawing explanation
Figure 1For passing throughEmbodimentThe 5-fluorouracil pharmaceutical co-crystals construction unit signal that 1 polishing preparesFigure；
Figure 2For passing throughEmbodimentThe hydrogen bond layer structure signal that the 5-fluorouracil pharmaceutical co-crystals that 1 polishing prepares is formedFigure；
Figure 3Pass throughEmbodimentThe XRD spectrum of the 5-fluorouracil pharmaceutical co-crystals that 1 polishing preparesFigureThe crystal XRD spectrum obtained with simulationFigure；
Figure 4For under the conditions of pH=6.8-7.1, comprise the release curve of the erodible matrix of the 5-fluorouracil pharmaceutical co-crystals that nicotiamide is presomaFigure；
Figure 5For under the conditions of pH=6.8-7.1, comprise the release curve of the hydrogel matrix tablet of the 5-fluorouracil pharmaceutical co-crystals that nicotiamide is presomaFigure。
Specific embodiment
Below in conjunction with specificallyEmbodimentFurther describe the present invention, advantages of the present invention and feature will be with describe and apparent.ButEmbodimentIt is only exemplary, the scope of the present invention is not constituted any restriction.It will be understood by those skilled in the art that and the details of technical solution of the present invention and form can be modified or replace lower without departing from the spirit and scope of the present invention, but these amendments and replacement each fall within protection scope of the present invention.
The instrument that the present invention detects 5-fluorouracil pharmaceutical co-crystals structure and performance is as follows:
1, eutectic structure measures on the Xcalibur Eos diffractometer of Agilent company of the U.S., at a temperature of 293K, uses the MoK through graphite monochromator monochromatizationαRay (λ=0.071073nm), scan mode is ω scanning.Set during diffraction experiment required current/voltage as 40mA and 50kV.
2, powder x-ray diffraction data are to measure on the D8 type x-ray diffractometer of BRUKER company of Germany.Test condition: Cu-K α targetTube voltage 40kV, tube current 10mA, scanning speed is 0.2 °/min.
3, the mensuration of release is to complete on the UV-2550 ultraviolet-visible spectrophotometer of Shimadzu Corporation of Japan.
4, the assay of tablet is to complete on Agilent 1200 high performance liquid chromatograph.Chromatographic column: Aglilent2ORBA × SB-C18, particle diameter 5 μm 4.6 × 150mm, flow phase: water: acetonitrile=90:10, column temperature: 25 DEG C, detector: 260nm DAD, model: G1315D, flow velocity: 1ml/min, sample size: 7 μ l.
Embodiment1 liquid phase assisted milling method synthesis nicotiamide is the 5-fluorouracil pharmaceutical co-crystals of presoma
1, liquid phase assisted milling method synthesis nicotiamide is the 5-fluorouracil pharmaceutical co-crystals of presoma:
Analytical balance accurately weighs 3mmol (390.0mg) 5-fluorouracil and 1mmol (122.0mg) nicotiamide, insert a diameter of 8～15cm agate mortar in, carefully grind uniform and finely ground reactant to the powder of 100～300 mesh.Move in 20 μ L deionized waters extremely above-mentioned powder with micropipette rifle, the most uniform grinding 10 minutes, obtain the 5-fluorouracil pharmaceutical co-crystals that nicotiamide is presoma.
The above-mentioned 5-fluorouracil pharmaceutical co-crystals prepared is carried out structural characterization and performance test by above-mentioned instrument and equipment:
Such as figure 1Shown in, three 5-fluorouracil molecules, a nicotiamide molecule and hydrone collectively form the basic structural unit of 5-fluorouracil thing eutectic by hydrogen bond and lone pair electrons-pi accumulation effect.5-fluorouracil pharmaceutical co-crystals is anorthic system, its axial lengthShaft angle α=86.296 °, β=76.709 °, γ=69.343 °.
Such as figure 2Shown in, adjacent 5-fluorouracil molecule passes through N-H ... O hydrogen bond defines the Z-type chain A along c direction, additionally, 5-fluorouracil molecule, nicotiamide molecule and hydrone pass through N-H ... O hydrogen bond, O-H ... O hydrogen bond and N-H ... N hydrogen bond also form the one-dimensional chain B along c direction, further through C-H between chain A and chain B ... O hydrogen bond has constructed two-dimensional layered structure.
Determine the XRD of the amorphous powder obtained, there is series of features peak at 16.27 °, 20.22 °, 22.05 °, 27.75 °, 28.63 °, 29.95 ° in its spectral peak, and these characteristic peaks are consistent with according to crystal structural data the characteristic peak of pharmaceutical co-crystals being simulated out by Mercury software.
These results suggest that the 5-fluorouracil pharmaceutical co-crystals that nicotiamide is presoma and Application No. 201410783284.6 using the method for the present invention to prepare, the 5-fluorouracil pharmaceutical co-crystals that nicotiamide is presoma that invention entitled " 5-fluorouracil pharmaceutical co-crystals and its preparation method and application " patent application uses solvent room temperature volatility process to obtain has identical structure, and have the highest purity, and substantially reduce experimental period and cost compared to solvent slow vaporization method.
Use identical mol ratio (5-fluorouracil: nicotiamide=3:1) to feed intake simultaneously, carefully grind uniform and finely ground reactant.Move into 50 μ L water with micropipette rifle and mixed solution that methanol mixes according to 1:1 (V/V), grind 20 minutes.The powder obtained is all identical with the eutectic structure of solvent room temperature volatility process and has the highest purity, its spectral peak is at 16.09 °～16.49 °, 20.01 °～20.41 °, 21.88 °～22.28 °, 27.53 °～27.93 °, 28.44 °～28.84 °, 29.71 °～30.11 ° there is series of features peak, and these characteristic peaks are consistent with according to crystal structural data the characteristic peak of pharmaceutical co-crystals being simulated out by Mercury software.
Use polishing, be added dropwise to trace solvent, obtained, after grinding 10～20 minutes, the 5-fluorouracil eutectic that purity is the highest.Compared to solvent room temperature volatility process, liquid phase assisted milling method shortens experimental period significantly, decreases synthesis fund and loaded down with trivial details technological process, has the biggest actual application value for a large amount of synthetic drug eutectics in commercial production.
2, the mensuration of cocrystalization compound purity
The sample obtained has been carried out powder X-ray RD diffraction experiment.Powder x-ray diffraction data are to measure on the D8 type x-ray diffractometer of BRUKER company of Germany.Test condition: Cu-K α targetTube voltage 40kV, tube current 10mA, scanning speed is 0.2 °/min.By comparing two kinds of raw materials of the sample obtained with pure state, its characteristic diffraction peak position and diffracted intensity all there occurs significant change, and this result shows, 5-fluorouracil and nicotiamide there occurs reaction, and create new thing phase.
In order to further determine that thing phase and the purity of 5-fluorouracil pharmaceutical co-crystals that the above-mentioned nicotiamide prepared is presoma, the crystal data that we utilize single crystal diffraction experiment to obtain simulates the calculated powder XRD spectrum of above-mentioned 5-fluorouracil pharmaceutical co-crystals by Mercury softwareFigure, find that its characteristic diffraction peak occurs in 16.09 °～16.49 °, 20.01 °～20.41 °, 21.88 °～22.28 °, 27.53 °～27.93 °, 28.44 °～28.84 °, 29.71 °～30.11 °, this composes with calculated powder XRDFigurePeak substantially coincide (Figure 3), illustrate that the 5-fluorouracil pharmaceutical co-crystals that logical polishing prepares has the highest purity.The 5-fluorouracil pharmaceutical co-crystals prepared is used for the research of following preparation.
EmbodimentThe preparation of 2 5-fluorouracil pharmaceutical co-crystals tablets
Wet granule compression tablet:
1, prescription:
Nicotiamide is the 5-fluorouracil pharmaceutical co-crystals of presoma 15g
15% starch slurry In right amount
Tween starch 6%
Magnesium stearate 1%
Make 40
2, preparation:
1) weigh 0.5g Tween-80, be dissolved in 15ml ethanol, add 15g starch, stir, be dried in 70 DEG C, cross 100 mesh sieves, obtain tween starch, standby；
2) preparation of dried starch: starch is dried about 2h at 105 DEG C, makes water content 8%-10%；
3) weigh dried starch 6g, be dissolved in the distilled water of 40ml dispersed, 80 DEG C of Heat Gelatinization, obtain starch slurry；
4) preparation of wet granular: take the 5-fluorouracil pharmaceutical co-crystals 15g that recipe quantity nicotiamide is presoma, adds starch slurry in right amount, prepares soft material, crosses 16 mesh sieves and pelletizes, and wet grain is dried at 60 DEG C, and dry granule crosses 16 mesh sieve granulate；
5) use the tween starch mixing adding particle weight 6% in the 5-fluorouracil pharmaceutical co-crystals granule that nicotiamide is presoma in additional normal direction (4), be subsequently adding the magnesium stearate of particle weight 1%, mixing；
6) tabletting, to obtain final product.
3, every medicine Chinese medicine eutectic content of HPLC technical measurement:
Chromatographic condition: instrument Agilent 1200
Chromatographic column: Aglilent 2ORBA × SB-C18 particle diameter 5 μm 4.6 × 150mm
Flowing phase: water: acetonitrile=90:10
Column temperature: 25 DEG C
Detector: 260nm DAD model: G1315D
Flow velocity: 1ml/min
Sample size: 7 μ l
Specify according to the Pharmacopoeia of the People's Republic of China (2010 editions second), check the average tablet weight of medicine, tablet weight variation, hardness, disintegration, resultSuch as table 1Shown in.
Table 1Conventional tablet tablet weight, tablet weight variation, hardness, disintegration, pharmaceutical co-crystals content
EmbodimentThe preparation of 3:5-fluorouracil medicine eutectic slow releasing tablet
One, the preparation of erodible matrix
1, prescription:
Nicotiamide is the 5-fluorouracil pharmaceutical co-crystals of presoma 10g
Stearyl alcohol 1g
HPMC K10M 0.1g
Magnesium stearate 1.2%
Prepare 50 altogether
2, preparation:
1) by 5-fluorouracil pharmaceutical co-crystals finely ground mistake 100 mesh sieve that nicotiamide is presoma, separately stearyl alcohol is placed in evaporating dish, in 80 DEG C of water-baths, adds heat fusing, add pharmaceutical co-crystals and stir evenly, cooling, put in mortar and grind.
2) add the ratio of 7ml 80% ethanol according to 1 gram of hypromellose, hypromellose is soaked in 80% ethanol, makes hypromellose rubber cement；
3) to step 1) pharmaceutical co-crystals that obtains adds hypromellose rubber cement make soft material (if rubber cement is not enough, 80% appropriate amount of ethanol can be added again), 40 mesh sieves granulations；
4) being dried in 50 DEG C, 40 mesh sieve granulate are weighed, and add magnesium stearate mixing.
5) tabletting, calculates tablet weight.The every medicine 150mg Han eutectic.
6) specifying according to the Pharmacopoeia of the People's Republic of China (2010 editions second), checking that the average tablet weight of medicine, tablet weight variation are the most qualified, result is such asFollowing table 2Shown in.
Table 2
3, dissolution test method:
(1) making of standard curve: accurate weighing 5-fluorouracil reference substance about 20mg, is placed in 100ml measuring bottle, adds distilled water and dissolves, and is diluted to scale.Accurate this liquid 10ml that draws is placed in 50ml measuring bottle, counts distilled water to scale.Take solution 0.5,1,2,5,7.5,10ml, be respectively placed in 25ml volumetric flask, add distilled water to scale, make 0.8,1.6,3.2,8,12, the solution of 16ug/ml.According to spectrophotography, at 260nm wavelength, measure trap.Solution concentration and trap are carried out regression analysis and obtains standard curve regression equation.
(2) dissolution test: the nicotiamide of acquirement is the 5-fluorouracil erodible matrix sustained release tablet of pharmaceutical co-crystals erodible matrix totally 6 of presoma, according to " Chinese Pharmacopoeia " version drug release determination method regulation in 2010, use the device of dissolution method second (slurry processes), with distilled water 900ml as release medium, temperature 37 DEG C ± 0.5 DEG C, rotating speed is 50r/min per minute, operate in accordance with the law, through 30, 60, 90, 150, 180, 240, 300, 360, 420, 480, 1380min, take release liquid 3ml respectively, with 0.45 μm filtering with microporous membrane, and in stripping rotor, supplement mutually synthermal release medium 3ml in time.Take subsequent filtrate 1ml, put in 10ml measuring bottle, add distilled water diluting to scale.According to spectrophotography, at the wavelength of 260nm, measure trap.
Release resultSuch as figure 4Shown in, can be seen that the erodible matrix prepared from this result, start to measure when 30min, gradually discharge, in 420min release completely, there is preferable releasing effect.
Two, the preparation of hydrogel matrix tablet:
1, prescription:
Prepare 100 altogether
2, preparation:
1) 5-fluorouracil pharmaceutical co-crystals, lactose that nicotiamide is presoma being crossed 100 mesh sieves respectively, hypromellose crosses 80 mesh sieves, mix homogeneously, adds 80% ethanol solution and makes soft material, crosses 40 mesh sieves and pelletizes.
2) it is dried in 50-60 DEG C, 40 mesh sieve granulate, weighs, add magnesium stearate mixing.
3) calculate tablet weight, tabletting, to obtain final product.
4) specifying according to the Pharmacopoeia of the People's Republic of China (2010 editions second), checking that the average tablet weight of medicine, tablet weight variation are the most qualified, result is such asFollowing table 3Shown in.
Table 3
3, dissolution test method:
(3) making of standard curve: same to erodible matrix
(4) dissolution test: the nicotiamide of acquirement is the 5-fluorouracil pharmaceutical co-crystals hydrophilic gel of presoma
Hydrophilic gel slow releasing tablet totally 6, according to the Pharmacopoeia of the People's Republic of China (2010 editions second), drug release determination method is specified, use the device of dissolution method second (slurry processes), with distilled water 900ml as release medium, temperature 37 DEG C ± 0.5 DEG C, rotating speed is 50r/min per minute, operate in accordance with the law, through 30,60,90,150,180,240,300,360,420,480,1380min, take release liquid 3ml respectively, with 0.45 μm filtering with microporous membrane, and in stripping rotor, supplement mutually synthermal release medium 3ml in time.Take subsequent filtrate 1ml, put in 10ml measuring bottle, add distilled water diluting to scale.According to spectrophotography, at the wavelength of 260nm, measure trap.
Release resultSuch as figure 5Shown in, can be seen that the hydrophilic gel slow releasing tablet prepared from this result, start to measure when 30min, gradually discharge, in 600min release completely, there is preferable releasing effect.
EmbodimentThe preparation of 4:5-fluorouracil medicine eutectic microsphere
Emulsifying-chemical crosslink technique:
1, prescription:
Nicotiamide is the 5-fluorouracil pharmaceutical co-crystals of presoma 3g
Gelatin 2.5g
Sorbitan Oleate 2.5ml
25% glutaraldehyde 0.5ml
Liquid Paraffin 100ml
Isopropanol In right amount
Ether In right amount
Distilled water In right amount
Make microsphere.
2, preparation:
(1)GelatinThe preparation of solution: weigh recipe quantityGelatin2.5g, after the appropriate immersion that adds water is swelling, adds water to 25ml, and 60 DEG C ± 1 DEG C heating for dissolving obtains the solution that concentration is 10%, is incubated standby；
(2) weigh the 5-fluorouracil pharmaceutical co-crystals 3g that nicotiamide is presoma and put in beaker, add 25mlGelatinSolution, stirs to obtain homogenous suspension at 50 DEG C；
(3) 100ml liquid Paraffin is mixed homogeneously with Arlacel-80 2.5ml, the pastille under 50 DEG C of quick stirrings, step (2) obtainedGelatinSuspension instills, and forms w/o type Emulsion after emulsifying 10min.
(4) the w/o type Emulsion obtained is cooled down immediately in 0-4 DEG C of ice-water bath, and after stirring at low speed 10min, add 25% glutaraldehyde 0.5ml continuation stirring crosslinking 1h, then with appropriate isopropanol dehydration 2h.Microscopy, sucking filtration microsphere, with each washing 3 times respectively of isopropanol, ether, 50 DEG C are dried, to obtain final product.
Specify according to the Pharmacopoeia of the People's Republic of China (version second in 2010), the projects such as size, distribution, configuration of surface, stability, drug loading and the release of the microsphere prepared are enteredRow is investigated, result shows that the microsphere various aspects of performance prepared all meets the regulation of the Pharmacopoeia of the People's Republic of China (version second in 2010).
EmbodimentThe preparation (Simple coacervation) of 5:5-fluorouracil medicine eutectic microcapsule
1, prescription
Make microcapsule.
2, preparation:
1)GelatinThe preparation of aqueous solution: weighGelatin2g, add appropriate distilled water immersion swelling after dissolve in 50 DEG C ± 1 DEG C heating in water bath, be diluted with water to 60ml；
2) preparation of 40% metabisulfite solution: weigh anhydrous sodium sulfate 36g, adds distilled water 90ml mixing, dissolves in 50 DEG C ± 1 DEG C and be incubated, standby；
3) preparation of microcapsule: weigh 5-fluorouracil pharmaceutical co-crystals 2g that nicotiamide is presoma in beaker, add 60mlGelatinAqueous solution, with 10% acetic acid regulation PH to 3-4 after stirring, obtains suspension, microscopy；
4) suspension of step (4) is placed in 50 DEG C ± 1 DEG C water-bath, under stirring, is slowly added dropwise 40% metabisulfite solution, put microscope observation and be advisable with cohesion encystation, the solution usage of record sodium sulfate；
5) the sodium sulfate percentage concentration in calculating system, using the sodium sulfate percentage concentration in system as the concentration of required sodium sulfate diluent, and prepared and diluted liquid；
6) under stirring, the sodium sulfate diluent of encystation system bulk 3 times is poured into in bag system, making cohesion capsule disperse, ice-water bath is cooled to 5-10 DEG C, adds 25% glutaraldehyde 3ml, stirring 15min, add 20% sodium hydroxide regulation PH to 8-9, continue stirring 1h, after sufficient standing, sucking filtration, take out with distilled water be washed till eluate without glutaraldehyde till, drain, to obtain final product.
Specify according to the Pharmacopoeia of the People's Republic of China (version second in 2010), the projects such as size, distribution, configuration of surface, stability, drug loading and the release of the microcapsule prepared are enteredRow is investigated, result shows that the microsphere various aspects of performance prepared all meets the regulation of the Pharmacopoeia of the People's Republic of China (version second in 2010).
EmbodimentThe preparation of 6:5-fluorouracil medicine eutectic suppository
1, prescription:
Nicotiamide is the 5-fluorouracil pharmaceutical co-crystals of presoma 1.5g
Semi-synthetic fatty acid ester 10g
Make 4 pieces.
2, preparation:
The preparation of pure substrate bolt:
1) weigh semi-synthetic fatty acid ester 10g and put in evaporating dish, in water-bath, add heat fusing；
2) substrate of fusing is slowly poured in the suppository moulds scribbling lubricant；
3) prune after cooled and solidified spilling part, the demoulding, obtain pure substrate bolt number piece completely, every piece of pure substrate bolt weight of weighing to obtain, it is designated as G.
Preparation containing stype:
1) weighing semi-synthetic fatty acid ester 10g and put in evaporating dish, heat in water-bath, stop heating when 2/3 substrate is melted, stirring makes entirely to melt；
2) separately weigh the 5-fluorouracil pharmaceutical co-crystals powder 1.5g that finely ground nicotiamide is presoma, add to melted semi-synthetic fatty acid ester by several times, be stirred continuously and make medicaments uniformity disperse；
3) in time becoming viscous pasty state, pour in the mould having been coated with lubricant, prune after cooled and solidified spilling part on die orifice, the demoulding, obtain complete containing stype number piece, weigh, and calculate average weight M (g/ piece) containing stype, every piece containing the weight of principal agent in stype be W=M × X%, X% be percent drug.
4) calculating of displacement value: f=W/ [G-(M-W)]
Nicotiamide is the preparation of the 5-fluorouracil pharmaceutical co-crystals suppository of presoma:
Prescription:
Nicotiamide is the 5-fluorouracil pharmaceutical co-crystals of presoma 3g
Semi-synthetic fatty acid ester In right amount
Make suppository 8 pieces.
Preparation:
1) calculating of substrate quality should be added: by the displacement value of 5-fluorouracil double Acrawax of pharmaceutical co-crystals that the nicotiamide tried to achieve is presoma, calculate matrix weight that every suppository need to add and 8 pieces of suppository need to matrix weight.E=G-W/f
2) finely ground pharmaceutical co-crystals 3g is weighed standby.
3) semi-synthetic fatty acid glyceride separately weighing amount of calculation is put in evaporating dish, adds heat fusing in water-bath.
4) by the pharmaceutical co-crystals substrate that addition is melted by several times stirs, inject mould the most while hot, operate the most as stated above, obtain suppository number piece.
5) quality examination: every bolt weight and displacement value, resultSuch as table 4Shown in.
Table 4Suppository every dose weight and displacement value
EmbodimentThe preparation of 7:5-fluorouracil medicine eutectic unguentum
One, the preparation of Water-In-Oil (O/W) type emulsion type ointment base
1, prescription:
Stearyl alcohol 1.8g
White vaseline 2.0g
Liquid Paraffin 1.3ml
Sodium laurylsulfate 0.2g
Ethyl hydroxybenzoate 0.02g
Glycerol 1.0g
Distilled water In right amount
Make 20g.
2, preparation:
1) take oil-phase component (stearyl alcohol 1.8g, white vaseline 2.0g and liquid Paraffin 1.3ml) in evaporating dish, put and be heated to 70-80 DEG C in water-bath and make it dissolve；
2) water intaking phase constituent (sodium laurylsulfate 0.2g, ethyl hydroxybenzoate 0.02g, glycerol 1.0g and distilled water) is heated to 70-80 DEG C in evaporating dish (or small beaker)；
(3) under agitation water-phase component is added in oil-phase component with thread shape, water-bath continues keep constant temperature and stir a few minutes, the most at room temperature continue stirring to condensation, obtain 5-fluorouracil pharmaceutical co-crystals Water-In-Oil (O/W) the type ointment that nicotiamide is presoma, to obtain final product.
Two, oil-in-water (W/O) type emulsion type ointment base
1, prescription:
Make 40g.
2, preparation:
Take oil-phase component (glyceryl monostearate 6g, white vaseline 2.0g, Cera Flava 2g, liquid Paraffin 10g, hard paraffin 2.0g, Arlacel-80 0.8g) in evaporating dish, heating in water bath to 80 DEG C so that it is dissolve；Water intaking phase constituent (Tween-80 0.4g, ethyl hydroxybenzoate 0.04g, distilled water), in small beaker, is heated to 80 DEG C, and aqueous phase adds under stirring oil phase, and constant temperature stirs a few minutes, is stirred at room temperature to condensation, to obtain final product.
Three, nicotiamide is the preparation of 5-fluorouracil pharmaceutical co-crystals ointment of presoma
1, prescription
Nicotiamide is the 5-fluorouracil pharmaceutical co-crystals of presoma 0.5g
Dissimilar substrate 9.5g
Make 10g.
2, preparation
(1) nicotiamide is the preparation of 5-fluorouracil pharmaceutical co-crystals O/W ointment of presoma:
Weigh the 5-fluorouracil pharmaceutical co-crystals powder 0.5g that nicotiamide is presoma to be placed in mortar, add O/W emulsion-type substrate 9.5g by several times, grind well, to obtain final product.
(2) nicotiamide is the preparation of 5-fluorouracil pharmaceutical co-crystals W/O ointment of presoma: weighs the 5-fluorouracil pharmaceutical co-crystals powder 0.5g that nicotiamide is presoma and is placed in mortar, adds W/O emulsion-type substrate 9.5g by several times, grinds well, to obtain final product.
Quality examination: microscopy, result shows that the O/W prepared or w/o type unguentum various aspects of performance all meet the regulation of the Pharmacopoeia of the People's Republic of China (version second in 2010).
EmbodimentThe preparation of 8:5-fluorouracil medicine eutectic membrane
1, prescription:
2, preparation:
1) preparation of rubber cement: take PVAC polyvinylalcohol 17-886g and add distilled water and soak in right amount, after the most swelling, put and heats in 80-90 DEG C of water-bath, add sodium carboxymethyl cellulose (CMC-Na), stirring and dissolving, filters with 80 eye mesh screens while hot, adds saccharin sodium and makes dissolving；
2) separately taking pharmaceutical co-crystals 1g and glycerol 5ml to add after appropriate distilled water grinds well and add in above-mentioned rubber cement, stir evenly, insulation is placed a period of time and is removed bubble removing；
3) it is poured on the glass plate scribbling appropriate liquid Paraffin, with scraper plate method masking, area about 600cm2；
4) 60 DEG C dried, the small pieces being cut into 2cm × 1.5cm are standby, and the every about 5mg Han eutectic medicine, medicine film seal is standby in polyethylene film or aluminium foil.
Quality examination: outward appearance, film property and sticking property.Membrane complete appearance that result shows to prepare, bright and clean, consistency of thickness, uniform color, good without obvious bubble, film property and sticking property, meet the regulation of the Pharmacopoeia of the People's Republic of China (version second in 2010).
EmbodimentThe preparation of 9:5-fluorouracil medicine eutectic injection
1, prescription:
Nicotiamide is the 5-fluorouracil pharmaceutical co-crystals of presoma 25g
Disodium edetate 0.05g
Water for injection adds to 1000ml
2, preparation:
Take the water for injection of about total consumption 80%, add 0.05g disodium edetate stirring and dissolving, adding the 5-fluorouracil pharmaceutical co-crystals 25g that nicotiamide is presoma, regulating its pH value with the sodium hydroxide of 0.1mol/L is 8.50 ± 0.01, stirring and dissolving, inject water to 1000ml, filtering with the microporous filter membrane of 0.22 μm, embedding is in 10ml ampoule, finally in 100 DEG C of flowing steams, 30min sterilizing, to obtain final product.
Quality examination: the pH of the injection prepared, content, color, loading amount, visible foreign matters etc. are detected and observed, and result shows, the pH of the injection prepared is 8.50 ± 0.01.Color is colourless, without visible foreign matters, without particulate matter, meets the regulation of the Pharmacopoeia of the People's Republic of China (version second in 2010).

Claims (10)

1. comprise the pharmaceutical preparation of the 5-fluorouracil pharmaceutical co-crystals that nicotiamide is presoma, it is characterized in that described pharmaceutical preparation comprises the 5-fluorouracil pharmaceutical co-crystals and one or more excipient that nicotiamide is presoma, the group that one or more described excipient are formed selected from filler, surfactant, fluidizer, lubricant and disintegrating agent；
Wherein, described filler is at least one in mannitol, lactose, sucrose, glucose, maltodextrin, sorbitol, xylitol, Powderd cellulose, microcrystalline Cellulose, silicified microcrystalline cellulose, methylcellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl hydroxyethylcellulose, hypromellose, disodium edetate, Pulvis Talci, starch, pregelatinized Starch, calcium hydrogen phosphate or calcium carbonate；
nullWherein，Described surfactant is sodium lauryl sulfate、Docusate sodium、Polyoxyethylene sorbitan fatty acid esters、From phospholipid、Polyglycerol acrylate、Arlacel-20、Arlacel-60、Arlacel-80 (Sorbitan Oleate) and polyglycereol-6-dioleate、Polyoxyethylene 20 stearyl ether、Polyoxyethylene alkane fat ether、Castor oil derivatives、Pegylation castor oil hydrogenated、Fatty acid esters of sorbitan、Vitamin E TPGS、Renascin、Lecithin、Phospholipid and derivant thereof、Poloxamer、Stearic acid、Oleic acid、Spermol、Monoglyceride and dialycerides、Glyceryl monostearate、Fatty glyceride、Ethylene Glycol Palmitostearate、Polyethyleneglycol glyceride、Capryol 90、Propylene glycol single lauryl alcohol ester or polyglycerol acrylate、Paraffin、Glycerol、Cera Flava、At least one in white vaseline；
Wherein, described fluidizer is at least one in Pulvis Talci, colloidal silica, magnesium oxide, magnesium silicate, leucine or starch；
Wherein, described lubricant is at least one in Pulvis Talci, fatty acid, stearic acid, magnesium stearate, calcium stearate, sodium stearate, glyceryl monostearate, sodium lauryl sulfate, sodium stearyl fumarate, hydrogenated oil and fat, fatty alcohol, fatty acid ester, behenate, mineral oil, vegetable oil, leucine or sodium benzoate；
Wherein, described disintegrating agent be cross-linking sodium carboxymethyl cellulose, sodium alginate, calcium alginate, alginic acid, starch, pregelatinized Starch, sodium starch glycollate, crospovidone, cellulose and its derivates, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, soybean polysaccharide, guar gum, ion exchange resin, based at least one in food acids and the effervescent system of alkaline carbonate component or sodium bicarbonate.
2. pharmaceutical preparation as claimed in claim 1, it is characterized in that described polyoxyethylene sorbitan fatty acid esters includes polysorbate 20, 40, 60 and 80, described castor oil derivatives includes CREMOPHORE EL and Emulsifier EL-40, described fatty acid esters of sorbitan includes Arlacel-80, Arlacel-40, Arlacel-60 and Arlacel-65, described poloxamer includes poloxamer188, 388 and 188, described fatty glyceride includes glycerin mono-fatty acid ester, glyceryl monostearate, described polyethyleneglycol glyceride includes oleic acid polyethyleneglycol glyceride, octanoic acid certain herbaceous plants with big flowers acid polyethylene glycol glyceride and Gelucire 44/14.
3. pharmaceutical preparation as claimed in claim 1, it is characterised in that described nicotiamide is the 1-99wt% that the amount of the 5-fluorouracil pharmaceutical co-crystals of presoma accounts for total formulation weight, and the amount of one or more described excipient accounts for the 1-99wt% of total formulation weight.
4. pharmaceutical preparation as claimed in claim 1, it is characterised in that described preparation comprises the described pharmaceutical co-crystals of 5wt%-86wt%, the first filler of 5wt%-60wt%, the second filler of 5wt%-60wt%, the disintegrating agent of 1wt%-30wt%, the surfactant of 1wt%-30wt%, the lubricant of 1wt%-30wt% and the fluidizer of 1wt%-30wt%.
5. pharmaceutical preparation as claimed in claim 5, it is characterised in that described preparation comprises the described pharmaceutical co-crystals of 50wt%-75wt%, the first filler of 5wt%-15wt%, the second filler of 5wt%-15wt%, the disintegrating agent of 1wt%-10wt%, the surfactant of 1wt%-10wt%, the lubricant of 1wt%-10wt% and the fluidizer of 1wt%-10wt%.
6. pharmaceutical preparation as claimed in claim 1, it is characterised in that one or more described excipient also include one or more matrix type slow-release materials, one or more viscosifier, one or more binding agents, one or more correctivess, one or more preservative and combinations thereof；
Wherein, described matrix type slow-release material is at least one in polyethylene, ethylene-vinyl acetate copolymer, vinyl acetate-acetate fiber, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone or Polyethylene Glycol；
Wherein, described viscosifier are at least one in gelatin, arabic gum, polyvinyl alcohol or sodium carboxymethyl cellulose；
Wherein, described binding agent is at least one in polyvinylpyrrolidone, hypromellose, starch or ethanol；
Wherein, described sweeting agent is at least one in stevioside, saccharin sodium, aspartame, cyclamate or maltose；
Wherein, described preservative is benzalkonium bromide, at least one in benzalkonium chloride, ethyl hydroxybenzoate or methyl hydroxybenzoate.
7. pharmaceutical preparation as claimed in claim 1, it is characterised in that described preparation is tablet, slow releasing tablet, microsphere, microcapsule, suppository, Emulsion, membrane or injection.
8. the purposes in preparing antitumor drug of the pharmaceutical preparation described in any one of claim 1-7.
9. the method for the pharmaceutical preparation prepared described in any one of claim 1-7, it is characterised in that described preparation is tablet, slow releasing tablet, microsphere, microcapsule, suppository, Emulsion, membrane or injection, prepares the most in accordance with the following methods:
(1) preparation of tablet
1) weigh 0.5g Tween-80, be dissolved in 15ml ethanol, add 15g starch, stir, be dried in 70 DEG C, cross 100 mesh sieves, standby, obtain tween starch；
2) preparation of dried starch: starch is dried at 105 DEG C, makes water content 8%-10%；
3) weigh dried starch 6g and be dissolved in the distilled water of 40ml dispersed, 80 DEG C of Heat Gelatinization, obtain starch slurry；
4) take the 5-fluorouracil pharmaceutical co-crystals 15g that nicotiamide is presoma, add starch slurry in right amount, prepare soft material, cross 16 mesh sieves to pelletize, wet grain is dried at 60 DEG C, and dry granule crosses 16 mesh sieve granulate, obtains the 5-fluorouracil pharmaceutical co-crystals granule that nicotiamide is presoma；
5) use additional normal direction step 4) in the 5-fluorouracil pharmaceutical co-crystals granule that nicotiamide is presoma in add particle weight 6% tween starch mixing, be subsequently adding the magnesium stearate of particle weight 1%, mixing；
6) tabletting, to obtain final product；
(2) preparation of erodible matrix
1) by 5-fluorouracil pharmaceutical co-crystals 10g finely ground mistake 100 mesh sieve that nicotiamide is presoma, separately stearyl alcohol is placed in evaporating dish, in 80 DEG C of water-baths, adds heat fusing, add pharmaceutical co-crystals and stir evenly, cooling, put in mortar and grind；
2) add the ratio of 7ml 80% ethanol according to 1g hypromellose, hypromellose is soaked in 80% ethanol, make hypromellose rubber cement；
3) to step 1) product that obtains adds hypromellose rubber cement make soft material, 40 mesh sieves are pelletized；
4) being dried in 50 DEG C, 40 mesh sieve granulate are weighed, and add magnesium stearate mixing；
5) tabletting, to obtain final product；
(3) preparation of hydrogel matrix tablet
1) 5-fluorouracil pharmaceutical co-crystals 10g, lactose 5.0g that nicotiamide is presoma being crossed 100 mesh sieves respectively, hypromellose crosses 80 mesh sieves, mix homogeneously, adds 80% ethanol solution and makes soft material, crosses 40 mesh sieves and pelletizes；
2) it is dried in 50-60 DEG C, 40 mesh sieve granulate, weighs, add magnesium stearate mixing；
3) tabletting, to obtain final product；
(4) preparation of microsphere
1) preparation of gelatin solution: weigh gelatin 2.5g, after the appropriate immersion that adds water is swelling, adds water to 25ml, and 60 DEG C ± 1 DEG C heating for dissolving obtains the solution that concentration is 10%, is incubated standby；
2) weigh the 5-fluorouracil pharmaceutical co-crystals 3g that nicotiamide is presoma and put in beaker, add 25ml gelatin solution, stir to obtain homogenous suspension at 50 DEG C；
3) being mixed homogeneously with Arlacel-80 2.5ml by 100ml liquid Paraffin, the gelatin suspension of pastille step (2) obtained under 50 DEG C of quick stirrings instills, and forms w/o type Emulsion after emulsifying 10min；
4) the w/o type Emulsion obtained is cooled down immediately in 0-4 DEG C of ice-water bath, and after stirring at low speed 10min, add 25% glutaraldehyde 0.5ml continuation stirring crosslinking 1h, then with appropriate isopropanol dehydration 2h；
5) microscopy, sucking filtration microsphere, with each washing 3 times respectively of isopropanol, ether, 50 DEG C are dried, to obtain final product；
(5) preparation of microcapsule
1) preparation of aqueous gelatin solution: weigh gelatin 2g, add appropriate distilled water immersion swelling after dissolve in 50 DEG C ± 1 DEG C heating in water bath, be diluted with water to 60ml；
2) preparation of 40% metabisulfite solution: weigh anhydrous sodium sulfate 36g, adds distilled water 90ml mixing, dissolves in 50 DEG C ± 1 DEG C and be incubated, standby；
3) preparation of microcapsule: weigh 5-fluorouracil pharmaceutical co-crystals 2g that nicotiamide is presoma in beaker, add 60ml aqueous gelatin solution, with 10% vinegar acid for adjusting pH to 3-4 after stirring, obtain suspension, microscopy；
4) suspension of step (4) is placed in 50 DEG C ± 1 DEG C water-bath, under stirring, is slowly added dropwise 40% metabisulfite solution, put microscope observation and be advisable with cohesion encystation, the solution usage of record sodium sulfate；
5) the sodium sulfate percentage concentration in calculating system, using the sodium sulfate percentage concentration in system as the concentration of required sodium sulfate diluent, and prepared and diluted liquid；
6) under stirring, the sodium sulfate diluent of encystation system bulk 3 times is poured into in bag system, making cohesion capsule disperse, ice-water bath is cooled to 5-10 DEG C, adds 25% glutaraldehyde 3ml, stirring 15min, add 20% sodium hydroxide regulation pH to 8-9, continue stirring 1h, after sufficient standing, sucking filtration, take out with distilled water be washed till eluate without glutaraldehyde till, drain, to obtain final product；
(6) preparation of suppository
The preparation of a pure substrate bolt:
1) weigh semi-synthetic fatty acid ester 10g and put in evaporating dish, in water-bath, add heat fusing；
2) substrate of fusing is slowly poured in the suppository moulds scribbling lubricant；
3) prune after cooled and solidified spilling part, the demoulding, obtain pure substrate bolt number piece completely, every piece of pure substrate bolt weight of weighing to obtain, it is designated as G.
The b preparation containing stype:
1) weighing semi-synthetic fatty acid ester 10g and put in evaporating dish, heat in water-bath, stop heating when 2/3 substrate is melted, stirring makes entirely to melt；
2) separately weigh the 5-fluorouracil pharmaceutical co-crystals powder 1.5g that finely ground nicotiamide is presoma, add to melted semi-synthetic fatty acid ester by several times, be stirred continuously and make medicaments uniformity disperse；
3) in time becoming viscous pasty state, pour in the mould having been coated with lubricant, prune after cooled and solidified spilling part on die orifice, the demoulding, obtain complete containing stype number piece, weigh, and calculate average weight M (g/ piece) containing stype, every piece containing the weight of principal agent in stype be W=M × X%, X% be percent drug.
4) calculating of displacement value: f=W/ [G-(M-W)]
C nicotiamide is the preparation of the 5-fluorouracil pharmaceutical co-crystals suppository of presoma:
1) calculating of substrate quality should be added: by the displacement value of 5-fluorouracil double Acrawax of pharmaceutical co-crystals that the nicotiamide tried to achieve is presoma, according to below equation calculate matrix weight that every suppository need to add and 8 pieces of suppository need to matrix weight；
E=G-W/f
2) finely ground pharmaceutical co-crystals 3g is weighed, standby；
3) semi-synthetic fatty acid glyceride separately weighing amount of calculation is put in evaporating dish, adds heat fusing in water-bath；
4) by the pharmaceutical co-crystals substrate that addition is melted by several times stirs, inject mould the most while hot, operate the most as stated above, obtain suppository number piece；
(7) preparation of unguentum
The preparation of a Water-In-Oil (O/W) type emulsion type ointment base
1) preparation of oil phase: take stearyl alcohol 1.8g, white vaseline 2.0g and liquid Paraffin 1.3ml in evaporating dish, puts and is heated to 70-80 DEG C in water-bath and makes it dissolve；
2) preparation of aqueous phase: take sodium laurylsulfate 0.2g, ethyl hydroxybenzoate 0.02g, glycerol 1.0g and distilled water and be heated to 70-80 DEG C in evaporating dish or small beaker；
3) under agitation water-phase component is added in oil-phase component with thread shape, water-bath continues keep constant temperature and stir a few minutes, the most at room temperature continue to stir to condensation, obtain Water-In-Oil (O/W) type emulsion type ointment base；
The preparation of b oil-in-water (W/O) type emulsion type ointment base
1) preparation of oil phase: take glyceryl monostearate 6g, white vaseline 2.0g, Cera Flava 2g, liquid Paraffin 10g, hard paraffin 2.0g, Arlacel-80 0.8g in evaporating dish, heating in water bath to 80 DEG C so that it is dissolve；
2) preparation of aqueous phase: take Tween-80 0.4g, ethyl hydroxybenzoate 0.04g, distilled water in small beaker, be heated to 80 DEG C；
3) under stirring, aqueous phase being added oil phase, constant temperature stirs a few minutes, is stirred at room temperature to condensation, obtains oil-in-water (W/O) type emulsion type ointment base；
C nicotiamide is the preparation of the 5-fluorouracil pharmaceutical co-crystals O/W ointment of presoma:
Weigh the 5-fluorouracil pharmaceutical co-crystals powder 0.5g that nicotiamide is presoma to be placed in mortar, add O/W emulsion-type substrate 9.5g by several times, grind well, to obtain final product；
D nicotiamide is the preparation of the 5-fluorouracil pharmaceutical co-crystals W/O ointment of presoma:
Weigh the 5-fluorouracil pharmaceutical co-crystals powder 0.5g that nicotiamide is presoma to be placed in mortar, add W/O emulsion-type substrate 9.5g by several times, grind well, to obtain final product；
(8) preparation of membrane
1) preparation of rubber cement: take PVAC polyvinylalcohol 17-88 6g and add distilled water and soak in right amount, after the most swelling, put and heats in 80-90 DEG C of water-bath, add sodium carboxymethyl cellulose (CMC-Na), stirring and dissolving, filters with 80 eye mesh screens while hot, adds saccharin sodium and makes it dissolve；
2) separately taking the 5-fluorouracil pharmaceutical co-crystals 1g and glycerol 5ml of presoma to add after appropriate distilled water grinds well and add in above-mentioned rubber cement, stir evenly, insulation is placed a period of time and is removed bubble removing；
3) it is poured on the glass plate scribbling appropriate liquid Paraffin, by scraper plate method masking；
4) 60 DEG C dried, be cut into the small pieces of 2cm × 1.5cm, to obtain final product, the every medicine 5mg Han eutectic, medicine film seal is standby in polyethylene film or aluminium foil；
(9) preparation of injection
Take the water for injection of total weight 80%, add 0.05g disodium edetate stirring and dissolving, adding the 5-fluorouracil pharmaceutical co-crystals 25g that nicotiamide is presoma, regulating its pH value with the sodium hydroxide of 0.1mol/L is 8.50 ± 0.01, stirring and dissolving, inject water to 1000ml, filtering with the microporous filter membrane of 0.22 μm, embedding is in 10ml ampoule, finally in 100 DEG C of flowing steams, 30min sterilizing, to obtain final product.
10. method as claimed in claim 9, it is characterised in that described nicotiamide is that the 5-fluorouracil pharmaceutical co-crystals of presoma is prepared by the following method and obtains:
5-fluorouracil that mol ratio is 3:1 and nicotiamide are inserted in the agate mortar of a diameter of 8～15cm, reactant is ground to form the powder of 100～300 mesh, the amount of 20～200 μ L solvents is added according to every gram of powder, adding solvent makes it moisten, the most uniform grinding 10～20 minutes, obtain 5-fluorouracil pharmaceutical co-crystals；Wherein, described solvent is selected from the mixed liquor of water, water and methanol or water and ethanol, and wherein water is mixed by 1:2～2:1 volume ratio with ethanol with methanol or water with water in the mixed liquor of ethanol with methanol or water.
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