CN103524533A - Cefprozil compound, and dispersible tablets, dry suspension and preparation method thereof - Google Patents
Cefprozil compound, and dispersible tablets, dry suspension and preparation method thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
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- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
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- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- 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
- A61K9/14—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
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
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- 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
- A61K9/14—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
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- 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
- A61K9/2009—Inorganic compounds
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- 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
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
Abstract
The invention relates to the field of medicine, and in particular relates to a cefprozil compound, and dispersible tablets, a dry suspension and a preparation method thereof. The cefprozil compound is a crystal, and an X-ray powder diffraction diagram obtained by Cu-K alpha ray measurement is shown in figure 1. Through experimental detection, the cefprozil dispersible tablets and the dry suspension have the advantages of superior stability and quite good smell and taste, and are quite suitable for clinical application.
Description
Technical field
The present invention relates to field of medicaments, specifically, relate to a kind of cefprozil compound, its dispersible tablet, dry suspensoid and preparation method.
Background technology
Prozef (cefprozil) molecular formula is: C
18h
19n
3o
5sH
2o, chemical name: (6R, 7R)-7-L (R)-2-amino-2-(is to hydroxyl-phenyl) kharophen 1-8-oxo-3-propylene-5-thia-1-azabicyclo-(4,2,0) oct-2-ene-2-carboxylic acid monohydrate, its structural formula is:
Prozef belongs to II for semi-synthetic cephalosporins microbiotic, is suitable, trans-isomer(ide) mixture, and wherein cis-isomeride accounts for 90%(>=87%).Nineteen eighty-three is developed by Bristol-Myers Tokyo institute, and the 1991 Nian U.S., with the Initial Public Offering of Cefzil trade(brand)name, go on the market in more than 20 countries such as Canada, Mexico, Sweden subsequently successively.China Drug Administration department ratifies Sino-U.S.'s Shanghai Shi Guibao pharmaceutical Co. Ltd production and selling Prozef tablet and suspensoid in October, 1999.Its mechanism of action be by with bacterial cell membrane on penicillin-binding protein (PBPs) combination, hinder bacteria cell wall synthetic, thereby cause bacterolysis, death.
Cefprozil dispersible table has has a broad antifungal spectrum, highly effective and safe, easy administration, come into force fast, to features such as β-lactamase are extremely stable.Various light, moderate disease that it causes gram-positive microorganism, Gram-negative bacteria and anerobe etc. have good clinical efficacy.In the treat-and-release of the diseases such as the upper and lower respiratory tract infection for the treatment of, otorhinolaryngology infection, soft tissue infection and acute gonococcal urethritis, there is excellent clinical efficacy.Prozef is applicable to responsive microbial light, the upper and lower respiratory tract infection of moderate (as pharyngitis, laryngitis, tonsillitis, pneumonia, bronchitis etc.) Respiratory infections (as otitis media, sinusitis paranasal sinusitis etc.), skin and skin soft-tissue infection (as furuncle arsine, cellulitis, dermapostasis, folliculitis, trauma infection contamination etc.).Bibliographical information, experimenter is oral Prozef on an empty stomach, and approximately 95% dosage can be absorbed.In the average blood plasma transformation period of healthy person, be 1.3 hours, the about 0.23L/kg of Vdss.Total body clearance and renal clearance are respectively 3ml/min/kg and 2.3ml/min/kg left and right.
European Pharmacopoeia has recorded a hydration Prozef at present, Chinese Pharmacopoeia and American Pharmacopeia have all recorded 3 kinds of medicines such as Prozef, cefprozil suspension agent and cefprozil tablet, China is the consumption big country of cynnematin similar drug, and the exploitation of cephalosporins can meet the clinical demand of domestic extensive patients.Preparation about the purification of Prozef and crystallization and dispersible tablet, dry suspensoid, discloses a lot of patents:
In patent application 200910014981 " a kind of cefprozil compound and method for making thereof ", disclose a kind of method of Prozef being carried out to purifying, crystallization, but the character such as stability of the product preparing have not been detected.
In patent application 201110261377.9 " a kind of cefprozil compound crystal and pharmaceutical composition thereof ", also disclose a kind of Prozef crystalline compounds, and disclose the dispersible tablet that adopts this crystalline compounds to prepare.But the stability of said preparation still has much room for improvement.
In the dispersible tablet of patent ZL200610024464.1 " Cefprozil dispersible table and preparation method thereof ", comprise: 260 ± 50 weight part Prozefs, 30 ± 5 weight part Microcrystalline Celluloses, 15 ± 2.5 weight part disintegrating agent cross-linked polyvinylpyrrolidones, the polyvinylpyrrolidone of 3 ± 0.5 weight parts, 3 ± 0.5 weight part micropowder silica gels, 3 ± 0.5 weight part Magnesium Stearates, 0.5 ± 0.02 weight part correctives.
Weight proportion in patent application 201210583508.X " a kind of Cefprozil dispersible table and preparation method thereof " is as follows: Prozef 250 ± 5 weight parts, Microcrystalline Cellulose 180g ± 20 weight part, micronization lactose or pregelatinized Starch 100 ± 10 weight parts, hydroxypropylcellulose 30 ± 3 weight parts, sodium lauryl sulphate 5 ± 2 weight parts, Magnesium Stearate 2.5 ± 1 weight parts, stevioside 2.5 ± 1 weight parts.
Patent ZL201010603490.6 " cefprozil suspension pharmaceutical composition " relates to a kind of suspendible pharmaceutical composition that contains Prozef and xanthan gum.The two mixes in certain proportion the appropriate disintegrating agent of rear interpolation, thinner, correctives, rectifys and smell the pharmaceutical excipients such as agent or lubricant, then the mode of directly filling by dry granulation or powder is made the dry suspensoid of appropriate size.
Patent ZL201010123539.8 " Cefprozil medicinal composition " relates to the pharmaceutical composition that contains Prozef and cellulose derivative, its method by dry type granulation makes, after Prozef and cellulose derivative evenly mix, under the pressure of 0.1～25MPa, be pressed into flap, to form, combine closely, make tablet, pulvis, granule or capsule.Also flap can be pulverized, be mixed and made into tablet, pulvis, granule, dry suspensoid or capsule with thinner, disintegrating agent, lubricant, tackiness agent and/or other auxiliary material.
Patent ZL201010606202.2 " a kind of sugar-free cefprozil dry suspension and preparation method thereof " discloses a kind of sugar-free cefprozil dry suspension and preparation method thereof, comprise active constituents of medicine 0.1%～35%, sugar-free type thinner 40%～90%, suspending agent and disintegrating agent 0.01～20%, sugar-free type correctives 0.01%～10%, tackiness agent 0.01%～1%.
It is dry that patent application 201110168945.0 " a kind of Prozef dry suspensoid and method for making thereof " discloses a kind of Prozef
Suspensoid and preparation method thereof.Thereby by it being carried out to micropill parcel, increase its stability, improve compressibility, hide head
The peculiar smell of spore propylene itself coordinates sweeting agent and has improved well mouthfeel adding of essence.
Prozef is a kind of microbiotic of indissoluble, because it is easy to dissolve in gastric acid environment, is therefore prepared into clinically oral solid formulation, thereby is conducive to absorption and the utilization of medicine.But because Prozef is to water, thermally labile, its oral solid formulation is storing improperly in situation, can occur to decompose and rotten, thereby reduce the result for the treatment of that affects Prozef.In order further to improve the stability of Prozef, the present invention proposes a kind of cefprozil compound, cefprozil compound of the present invention has good stability, adopts the stability of solid orally ingestible of Prozef prepared by this compound good, is applicable to clinical application.
Summary of the invention
Primary goal of the invention of the present invention is to provide a kind of cefprozil compound.
The second goal of the invention of the present invention is to provide the preparation of this cefprozil compound.
In order to realize object of the present invention, the technical scheme of employing is:
The present invention relates to a kind of cefprozil compound, described cefprozil compound is crystal, and the X-ray powder diffraction pattern that use Cu-K alpha-ray measures as shown in Figure 1.The main granularity of described cefprozil compound is 288～465 μ m, and Tile Width is 190～658 μ m; Preferred main granularity is 365～402 μ m, and Tile Width is 242～535 μ m.
The preparation method who the invention still further relates to this cefprozil compound, comprises the following steps:
(1) preparation Prozef crude product is at the saturated aqueous solution of 50～60 ℃;
(2) mixed organic solvents of preparation ethanol, ether and ethyl acetate, the volume of mixed organic solvents is 3～9 times of Prozef crude product saturated aqueous solution, preferably 4～6 times;
(3) organic solvent is cooled to 0～5 ℃, in frequency, be under 20～25KHz, the output rating sound field that is 40～80W, in organic solvent, at the uniform velocity add Prozef crude product saturated aqueous solution while stirring, adding rear continuation stirs and lowers the temperature, after being cooled to 0～5 ℃, stop stirring standing growing the grain 2～8 hours; Obtain filtering after crystal, with absolute ethanol washing, vacuum-drying 2～8 hours, obtains cefprozil compound.
Wherein, in step (2), in mixed organic solvents, the volume ratio of ethanol, ether and ethyl acetate is 3～5:1～2:1, preferably 4～5:1:1;
In step (3), to adding the stirring velocity of Prozef crude product saturated aqueous solution in organic solvent, it is 600～1200 revs/min; Stirring velocity after Prozef crude product saturated aqueous solution adds is 60～360 revs/min;
In step (3), the speed that adds of Prozef crude product saturated aqueous solution is: v=M/20～M/10, and the volume that wherein M is organic mixed solvent, unit is for rising, and the unit of speed v is l/h;
In step (3), the cooling rate after Prozef crude product saturated aqueous solution adds is 0.5～3.5 ℃/h, preferably 1.5～2.5 ℃/h.
The invention still further relates to contain and the invention still further relates to the preparation that contains cefprozil compound, preparation can be selected from many kinds of solids oral preparations, as conventional tablet, capsule, dispersible tablet, disintegrating tablet, dry suspensoid etc.
In dispersible tablet of the present invention, contain: cefprozil compound 125～250 weight parts, lactose 26.65～53.3 weight parts; Low-substituted hydroxypropyl cellulose 25～50 weight parts; Sodium starch glycolate 2.7～5.4 weight parts; Silica 1 .65～3.3 weight part; Magnesium Stearate 1.65～3.3 weight parts; Sweet 0.35～0.7 weight part of knob, essence 2.0～4.0 weight parts.
The preparation method of dispersible tablet of the present invention is: comprise the following steps:
1. take by weight each component;
2. sieve: cefprozil compound, sodium starch glycolate, low-substituted hydroxypropyl cellulose, lactose are crossed respectively to 100 mesh sieves;
3. mix: cefprozil compound, sodium starch glycolate, low-substituted hydroxypropyl cellulose, knob are mixed 10～30 minutes sweet adding in mixing machine, add again essence, silicon-dioxide, lactose to continue to mix 10～30 minutes, finally add Magnesium Stearate to mix 5～15 minutes;
4. compressing tablet, packing, obtain.
In dry suspensoid of the present invention, contain: cefprozil compound 125～250 weight parts, sucrose 1000～2000 weight parts, xanthan gum 15～30 weight parts, aspartame 5～10 weight parts, essence 4～8 weight parts, Magnesium Stearate 1～2 weight part, Citric Acid 0.5～1 weight part, Polysorbate 80 10～20 weight parts.
The preparation method of dry suspensoid of the present invention is: comprise the following steps:
(1) take by weight each component;
(2) add mixing machine with cefprozil compound, xanthan gum, aspartame after sucrose being pulverized to 100 mesh sieves, mix, standby; Polysorbate 80 is added to (Polysorbate 80 and purified water weight ratio are 1:3.5) in appropriate purified water, and stirring and dissolving, adds Citric Acid, and stirring and dissolving is standby;
(3) solution in step (2) is added in step (2) and mixes softwood processed in powder, the granulation of sieving, puts into oven drying, and whole grain, adds after the Magnesium Stearate and essence of recipe quantity, mixes; Wherein, dry temperature is 45～55 ℃, and dried particles to moisture is 0.50～1.50%;
(4) check, packing, packing, obtain.
Below content of the present invention is made further explanation:
The present invention, by changing the crystallization condition of Prozef, prepares a kind of new Prozef crystalline compounds, and the X-ray powder diffraction pattern measuring by use Cu-K alpha-ray as shown in Figure 1.Measuring its fusing point is 218～220 ℃, and proterties is off-white color crystalline powder.Cefprozil compound of the present invention detects through high performance liquid chromatography, its purity 99.96%～99.99%, and total impurities 0.01～0.03%, purity, higher than prior art, is very suitable for clinical application.And after testing, organic solvent does not detect in Prozef, illustrate that cefprozil compound of the present invention is safer.After dissolution with solvents, can not there is the variation of crystal formation in this crystal formation.The present invention is by additional sound field, and the meticulous control to conditions such as the volume of solvent, temperature, has obtained a kind of new crystal.The particle diameter of this crystal and X-ray powder diffraction pattern are disclosed different from prior art, and, according to the stability test to crystal, detect, show that Prozef crystal of the present invention has very satisfactory stability, it all can keep stable components under high temperature, super-humid conditions, is much higher than prior art.And by known to the stability test of Cefprozil dispersible table and dry suspensoid, having good stability of Cefprozil dispersible table of the present invention and dry suspensoid is applicable to clinical application very much.
Through sem observation and particle size analyzer, measure, the main granularity of Prozef of the present invention is 288～465 μ m, and Tile Width is 190～658 μ m; Preferred main granularity is 365～402 μ m, and Tile Width is 242～535 μ m.By simultaneous test, find, the size distribution of the Prozef that additional ultrasonic wave obtains in crystallisation process is more concentrated, the particle that is crystal is more even, this may be owing to having affected crystallisation process in hyperacoustic cavatition, promoted the formation of nucleus, and make the speed uniformity of crystallization, thereby formed evengranular crystallization.Centralized particle diameter due to cefprozil compound of the present invention, is of moderate size, and facilitates production operation, thereby yield is high, can reach 96.7%.
Dispersible tablet is the homodisperse tablet of disintegration rapidly in water.With respect to solid preparations such as conventional tablet, capsules, dispersible tablet has easy administration, disintegration is rapid, absorption is fast and bioavailability high.It has, and preparation is simple, easy administration, can reduce medicine untoward reaction, improve the advantages such as drug bioavailability.Therefore, the present invention proposes a kind of dispersible tablet of Prozef, and the auxiliary material in dispersible tablet is optimized to selection.For example the weighting agent of dispersible tablet of the present invention is selected spray-dried lactose, because its mobility is better and have the similar sweet taste of sucrose, therefore be used for improving powder flowbility and mouthfeel; The present invention, in order to guarantee the disintegration effect of dispersible tablet, has selected the good sodium starch glycolate of disintegration effect and low-substituted hydroxypropyl cellulose coupling to cook disintegrating agent; Meanwhile, low-substituted hydroxypropylcellulopowder powder also has certain dry adhesive effect, therefore also can serve as the dry adhesives of direct powder compression; Because direct powder compression is had relatively high expectations to powder flowbility, therefore the present invention also adds silicon-dioxide further to improve powder flowbility; For the sheet that makes to extrude is bright and clean, add appropriate Magnesium Stearate; Due to Prozef bitter, add sweet orange powdered flavor and knob sweet in to improve smell and the mouthfeel of dispersible tablet.After testing, dispersible tablet of the present invention not only has good disintegration effect, and smell and mouthfeel fine, improved patient's compliance.The specification of dispersible tablet of the present invention is preferably 0.125g and 0.25g.
Dry suspensoid is easily molten because of it, flavoring, and easily clothes, stable, easy to carry, and being convenient to the advantages such as children taking is that domestic and international pharmacy work person and patient welcome; And preparation is simple, be easy to preserve, validity period is not long, perishable and easily grasp dosage, and absorb and will get well compared with conventional tablet or capsule, and the applicable child of taste, can improve the compliance that it is taken medicine.Therefore, the invention allows for a kind of dry suspensoid of Prozef, and the auxiliary material in dry suspensoid is optimized to selection.In the present invention, select Polysorbate 80 as tackiness agent, contributed on the one hand the moulding of preparation, also can play on the other hand the effect of hydrotropy, can improve the degree of scatter of dry suspensoid in water, improved the dissolution rate of medicine.The present invention has selected xanthan gum as suspending agent, after the dry suspensoid that makes to prepare disperses in water, occurs in 3 hours without obvious settling.Dry suspensoid of the present invention can fully meet the actual needs that use, and has reduced kind and the consumption of auxiliary material, the security that has further improved preparation.Dry suspensoid of the present invention, fragrant odour taste is sweet, and mouthfeel is good, disperses soon, and deposit-free, and use easy to carryly, is applicable to each age group patient.The specification of dry suspensoid of the present invention is preferably 0.125g and 0.25g.
Accompanying drawing explanation:
Fig. 1 is the X-ray powder diffraction figure of the compound of embodiment 1 preparation.
Below in conjunction with example, the present invention is further described.The specific embodiment of the present invention only limits to content of the present invention to make further explanation, not to Composition of contents restriction of the present invention.In preparation process of the present invention, reagent used is commercial reagent.
Embodiment
Embodiment 1: the preparation of cefprozil compound
1. preparation Prozef crude product is at the saturated aqueous solution 5L of 55 ℃;
2. prepare the mixed organic solvents 30L of ethanol, ether and ethyl acetate; In mixed organic solvents, the volume ratio of ethanol, ether and ethyl acetate is 4:1:1;
3. organic solvent is cooled to 5 ℃, in frequency, be under 25KHz, the output rating sound field that is 40W, in organic solvent, at the uniform velocity add Prozef crude product saturated aqueous solution while stirring, adding speed is 3 ls/h, stirring velocity is 1200 revs/min, add rear continuation and stir and lower the temperature, stirring velocity is 360 revs/min, and cooling rate is 1.5 ℃/h; After being cooled to 0 ℃, stop stirring standing growing the grain 8 hours; Obtain filtering after crystal, with absolute ethanol washing, vacuum-drying 4 hours, obtains cefprozil compound.
The X-ray powder diffraction pattern that the cefprozil compound employing Cu-K alpha-ray preparing measures as shown in Figure 1; Through sem observation and particle size analyzer, measure, the main particle diameter of Prozef of the present invention is 365～402 μ m, and Tile Width is 242～535 μ m; Through high performance liquid chromatography, detect, its purity is 99.98%; First method through " Chinese Pharmacopoeia " 2010 editions two appendix VI C melting point determinations is measured, and its fusing point is 219 ℃.
Embodiment 2: the preparation of cefprozil compound
1. preparation Prozef crude product is at the saturated aqueous solution 5L of 60 ℃;
2. prepare the mixed organic solvents 20L of ethanol, ether and ethyl acetate; In mixed organic solvents, the volume ratio of ethanol, ether and ethyl acetate is 5:1:1;
3. organic solvent is cooled to 0 ℃, in frequency, be under 25KHz, the output rating sound field that is 40W, in organic solvent, at the uniform velocity add Prozef crude product saturated aqueous solution while stirring, adding speed is 3 ls/h, stirring velocity is 600 revs/min, add rear continuation and stir and lower the temperature, stirring velocity is 60 revs/min, and cooling rate is 0.5 ℃/h; After being cooled to 0 ℃, stop stirring standing growing the grain 6 hours; Obtain filtering after crystal, with absolute ethanol washing, vacuum-drying 6 hours, obtains cefprozil compound.
The X-ray powder diffraction pattern that the cefprozil compound employing Cu-K alpha-ray preparing measures as shown in Figure 1; Through sem observation and particle size analyzer, measure, the main granularity of Prozef of the present invention is 365～402 μ m, and Tile Width is 242～535 μ m; Through high performance liquid chromatography, detect, its purity is 99.98%; First method through " Chinese Pharmacopoeia " 2010 editions two appendix VI C melting point determinations is measured, and its fusing point is 219 ℃.
Embodiment 3: Cefprozil dispersible table (specification 0.125g/ sheet)
It consists of:
Preparation method is:
1. according to formula, weigh cefprozil compound and excipient substance; Cefprozil compound is embodiment 1 or 2 preparations;
2. sieve: cefprozil compound, sodium starch glycolate, low-substituted hydroxypropyl cellulose, lactose are crossed respectively to 100 mesh sieves;
3. mix: cefprozil compound, sodium starch glycolate, low-substituted hydroxypropyl cellulose, knob are mixed 20 minutes sweet adding in mixing machine, add again the Powdered essence of sweet orange taste, silicon-dioxide, spray-dried lactose to continue to mix 20 minutes, finally add Magnesium Stearate to mix 10 minutes;
4. compressing tablet, packing, obtain.
Embodiment 4: Cefprozil dispersible table (specification: 0.25g/ sheet)
It consists of:
Preparation method is:
1. according to formula, weigh cefprozil compound and excipient substance; Cefprozil compound is embodiment 1 or 2 preparations;
2. sieve: cefprozil compound, sodium starch glycolate, low-substituted hydroxypropyl cellulose, spray-dried lactose are crossed respectively to 100 mesh sieves;
3. mix: cefprozil compound, sodium starch glycolate, low-substituted hydroxypropyl cellulose, knob are mixed 20 minutes sweet adding in mixing machine, add again the Powdered essence of sweet orange taste, silicon-dioxide, spray-dried lactose to continue to mix 20 minutes, finally add Magnesium Stearate to mix 10 minutes;
4. compressing tablet, packing, obtain.
Embodiment 5: Prozef dry suspensoid (specification 0.125g/ bag)
It consists of:
Preparation method is:
1. take by weight each component; Cefprozil compound is embodiment 1 or 2 preparations;
2. after sucrose being pulverized to 100 mesh sieves, added mixing machine with cefprozil compound, xanthan gum, aspartame, mixed, standby; Polysorbate 80 is added in appropriate purified water, and Polysorbate 80 and purified water weight ratio are 1:3.5; Stirring and dissolving, adds Citric Acid, and stirring and dissolving is standby;
3. solution in step (2) is added in step (2) and mixes softwood processed in powder, the granulation of sieving, puts into oven drying, and whole grain, adds after the Magnesium Stearate and flavoring orange essence of recipe quantity, mixes; Wherein, dry temperature is 45～55 ℃, and dried particles to moisture is 0.50～1.50%;
4. check, packing, packing, obtain.
Embodiment 6: Prozef dry suspensoid (specification: 0.25g/ bag)
It consists of:
Preparation method is:
1. take by weight each component; Cefprozil compound is embodiment 1 or 2 preparations;
2. after sucrose being pulverized to 100 mesh sieves, added mixing machine with cefprozil compound, xanthan gum, aspartame, mixed, standby; Polysorbate 80 is added in appropriate purified water, and Polysorbate 80 and purified water weight ratio are 1:3.5; Stirring and dissolving, adds Citric Acid, and stirring and dissolving is standby;
3. solution in step 2 is added in step 2 and mix softwood processed in powder, the granulation of sieving, puts into oven drying, and whole grain, adds after the Magnesium Stearate and essence of recipe quantity, mixes; Wherein, dry temperature is 45～55 ℃, and dried particles to moisture is 0.50～1.50%;
4. check, packing, packing, obtain.
Experimental example 1: Prozef influence factor experiment
Three batches 101,102,103 of the cefprozil compound that the embodiment of the present invention 1 is prepared, simulation listing packing, carries out study on the stability.
1. high temperature test
By cefprozil compound, put in sealing clean container, at 40 ℃, place 10 days, in the 5th day and sampling respectively in the 10th day, by stability high spot reviews project, detect result and comparison in 0 day.
2. high humidity experiment
By cefprozil compound, put in sealing clean container, in 25 ± 2 ℃ of temperature, under the condition of relative humidity 90 ± 5%, place 10 days, in the 5th day and sampling respectively in the 10th day, by stability high spot reviews project, detect result and comparison in 0 day.
3. strong illumination test
By cefprozil compound, put in sealing clean container, under the condition that is 4500lx in illumination, place 10 days, in the 5th day and sampling respectively in the 10th day, by stability high spot reviews project, detect result and comparison in 0 day.
Test-results is as shown in table 1.
Table 1:
Result shows: cefprozil compound prepared by the present invention, under the condition of simulation listing packing, under the condition of high temperature, high humidity, illumination, to place 10 days, and indices is without considerable change.
The cefprozil compound that other embodiment of the present invention is prepared has also carried out identical test, has obtained similar result.
Experimental example 2: Prozef accelerates experiment
Three batches 101,102,103 of the cefprozil compound that the embodiment of the present invention 1 is prepared, simulation listing packing, carry out following stability test: in 40 ± 2 ℃, under the condition of 75 ± 5%RH, place 6 months, at duration of test respectively at 1,2,3,6 sampling at the end of month once, each stability high spot reviews project is tested.Experimental result is as shown in table 2.
Table 2:
From accelerated test result, cefprozil compound of the present invention, investigates through accelerated test for 6 months, and considerable change does not occur indices.Confirm that cefprozil compound of the present invention has good stability.
The cefprozil compound that other embodiment of the present invention is prepared has also carried out identical test, and the result of its acquisition is similar.
Implement experimental example 3: the test of dispersible tablet influence factor
Three batches 101,102,103 of the cefprozil compound that the embodiment of the present invention 1 is prepared, prepare dispersible tablet according to embodiment 3, and simulation listing packing, carries out stability test.
1. high temperature test
By the dispersible tablet preparing, put in sealing clean container, at 40 ℃, place 10 days, in the 5th day and sampling respectively in the 10th day, by stability high spot reviews project, detect result and comparison in 0 day.
2. high humidity experiment
By the dispersible tablet preparing, put in sealing clean container, in 25 ± 2 ℃ of temperature, under the condition of relative humidity 90 ± 5%, place 10 days, in the 5th day and sampling respectively in the 10th day, by stability high spot reviews project, detect result and comparison in 0 day.3. strong illumination test
By the dispersible tablet preparing, put in sealing clean container, under the condition that is 4500lx in illumination, place 10 days, in the 5th day and sampling respectively in the 10th day, by stability high spot reviews project, detect result and comparison in 0 day.
Test-results is as shown in table 3.
Table 3:
Result shows: dispersible tablet prepared by the cefprozil compound of being prepared by the present invention, under the condition of simulation listing packing, under the condition of high temperature, high humidity, illumination, to place 10 days, and indices is without considerable change.
The Cefprozil dispersible table that other embodiment of the present invention is prepared has also carried out identical test, has obtained similar result.
Experimental example 4: the acceleration experiment of dispersible tablet
Three batches 101,102,103 of the cefprozil compound that the embodiment of the present invention 1 is prepared, method according to embodiment 3 is prepared dispersible tablet, simulation listing packing, carry out stability test: in 40 ± 2 ℃, under the condition of 75 ± 5%RH, place 6 months, at duration of test respectively at each sampling at 1,2,3,6 the end of month once, each stability high spot reviews project is tested.Experimental result is as shown in table 4.
Table 4:
From accelerated test result, Cefprozil dispersible table of the present invention is investigated through accelerated test for 6 months, and considerable change does not occur indices.The stability that confirms Cefprozil dispersible table of the present invention is good.
Adopt cefprozil compound prepared by other embodiment, the dispersible tablet preparing according to the pharmaceutical formulation of other embodiment, there is similar result.
Experimental example 5: the test of long duration of dispersible tablet
3 batches 101,102,103 of the cefprozil compound that the embodiment of the present invention 1 is prepared, method according to embodiment 3 is prepared dispersible tablet, simulation listing packing, carry out stability test: put in sealing clean container, at 30 ± 2 ℃, under 60 ± 5%RH part, place 24 months, at duration of test respectively at the 3rd, 6,9,12,18,24 samplings at the end of month once, each stability high spot reviews project is tested.Test-results is as shown in table 5:
Table 5:
From long-term test results, Cefprozil dispersible table of the present invention is investigated through test of long duration for 24 months, and considerable change does not all occur indices.The stability that confirms Cefprozil dispersible table of the present invention is good.
Adopt cefprozil compound prepared by other embodiment, the dispersible tablet preparing according to the pharmaceutical formulation of other embodiment, there is similar result.
Implement experimental example 6: stability contrast experiment
The preparation of drugs compared:
Comparative example 1: adopt commercially available Prozef bulk drug (Qilu Antibiotics Pharmaceutical Co., Ltd.), prepare dispersible tablet according to the method for embodiment 3;
Comparative example 2: the Prozef crystal that adopts patent application 200910014981 embodiment 2 to prepare, according to the method for embodiment 3, prepare dispersible tablet;
Comparative example 3: the Prozef crystal that adopts patent application 200910014981 embodiment 7 to prepare, according to the method for embodiment 3, prepare dispersible tablet;
Comparative example 4: the Prozef crystal that adopts patent application 201110261377.9 embodiment 1 to prepare, according to the method for embodiment 3, prepare dispersible tablet;
The Prozef crystal that the present invention adopts embodiment 1 to prepare, prepares dispersible tablet according to the method for embodiment 3.
By above-mentioned medicine simulation listing packing, carry out following stability test: in 40 ± 2 ℃, under the condition of 75 ± 5%RH, place 6 months, at duration of test respectively at 1,2,3,6 sampling at the end of month once, each stability high spot reviews project is tested.Experimental result is as shown in table 6.
Table 6:
Implement experimental example 7: the test of dry suspensoid influence factor
Three batches 201,202,203 of the cefprozil compound that the embodiment of the present invention 2 is prepared, prepare dry suspensoid according to the method for embodiment 5, and simulation listing packing, carries out stability test.
1. high temperature test
By the dry suspensoid preparing, put in sealing clean container, at 40 ℃, place 10 days, in the 5th day and sampling respectively in the 10th day, by stability high spot reviews project, detect result and comparison in 0 day.
2. high humidity experiment
By the dry suspensoid preparing, put in sealing clean container, in 25 ± 2 ℃ of temperature, under the condition of relative humidity 90 ± 5%, place 10 days, in the 5th day and sampling respectively in the 10th day, by stability high spot reviews project, detect result and comparison in 0 day.
3. strong illumination test
By the dry suspensoid preparing, put in sealing clean container, under the condition that is 4500lx in illumination, place 10 days, in the 5th day and sampling respectively in the 10th day, by stability high spot reviews project, detect result and comparison in 0 day.
Test-results is as shown in table 7.
Table 7:
Result shows: dry suspensoid prepared by the cefprozil compound of being prepared by the present invention, under the condition of simulation listing packing, under the condition of high temperature, high humidity, illumination, to place 10 days, and indices is without considerable change.
Prozef crystal prepared by other embodiment of the employing that other embodiment of the present invention is prepared, the dry suspensoid preparing according to the pharmaceutical formulation of other embodiment, have similar result.
Experimental example 8: the acceleration experiment of dry suspensoid
Three batches 201,202,203 of the cefprozil compound that just embodiment of the present invention 2 prepares, method according to embodiment 5 is prepared dry suspensoid, simulation listing packing, carry out stability test: in 40 ± 2 ℃, under the condition of 75 ± 5%RH, place 6 months, at duration of test respectively at 1,2,3,6 sampling at the end of month once, each stability high spot reviews project is tested.Experimental result is as shown in table 8.
Table 8:
From accelerated test result, Prozef dry suspensoid of the present invention is investigated through accelerated test for 6 months, and considerable change does not occur indices.Confirm having good stability of Prozef dry suspensoid of the present invention.
Adopt cefprozil compound prepared by other embodiment, the preparation preparing according to the pharmaceutical formulation of other embodiment, there is similar result.
Experimental example 9: the test of long duration of dry suspensoid
3 batches 201,202,203 of the cefprozil compound that the embodiment of the present invention 2 is prepared, preparation method according to embodiment 5 prepares dry suspensoid, simulation listing packing, carry out stability test: put in sealing clean container, at 30 ± 2 ℃, under 60 ± 5%RH part, place 24 months, at duration of test respectively at the 3rd, 6,9,12,18,24 samplings at the end of month once, each stability high spot reviews project is tested.Test-results is as shown in table 9:
Table 9:
From long-term test results, Prozef dry suspensoid of the present invention is investigated through test of long duration for 24 months, and considerable change does not all occur indices.Confirm having good stability of Prozef dry suspensoid of the present invention.
Adopt cefprozil compound prepared by other embodiment, the dry suspensoid preparing according to the pharmaceutical formulation of other embodiment, there is similar result.
Implement experimental example 10: the stability simultaneous test of compound formulation
The preparation of drugs compared:
Comparative example 5: adopt commercially available Prozef bulk drug (Qilu Antibiotics Pharmaceutical Co., Ltd.), prepare dry suspensoid according to the method for the embodiment of the present invention 6;
Comparative example 6: the Prozef crystal that adopts patent application 200910014981 embodiment 2 to prepare, according to the method for the embodiment of the present invention 6, prepare dry suspensoid;
Comparative example 7: the Prozef crystal that adopts patent application 200910014981 embodiment 7 to prepare, according to the method for the embodiment of the present invention 6, prepare dry suspensoid;
Comparative example 8: the Prozef crystal that adopts patent application 201110261377.9 embodiment 1 to prepare, according to the method for the embodiment of the present invention 6, prepare dry suspensoid;
The cefprozil compound that the present invention adopts embodiment 1 to prepare, prepares dry suspensoid according to the method for embodiment 6.
By above-mentioned medicine simulation listing packing, carry out following stability test: in 40 ± 2 ℃, under the condition of 75 ± 5%RH, place 6 months, at duration of test respectively at 1,2,3,6 sampling at the end of month once, each stability high spot reviews project is tested.Experimental result is as shown in table 10.
Table 10:
From comparative test result, the stability of Prozef dry suspensoid of the present invention is better than prior art.
Implement experimental example 11: mobility comparative experiments
This experimental example detects the mobility of the Prozef of the embodiment of the present invention 1 and comparative example, adopt fixed funnel method, funnel is placed in to the suitable height on graph paper, make Prozef from flare opening Free-flow, until the cone top forming contacts with flare opening, measure hypotenuse and the horizontal angle (slope of repose θ) of Prozef accumulation horizon.
Comparative example 1: adopt commercially available Prozef bulk drug (Qilu Antibiotics Pharmaceutical Co., Ltd.);
Comparative example 2: the Prozef crystal that adopts patent application 200910014981 embodiment 2 to prepare;
Comparative example 3: the Prozef crystal that adopts patent application 200910014981 embodiment 7 to prepare;
Comparative example 4: the Prozef crystal that adopts patent application 201110261377.9 embodiment 1 to prepare;
Table 11: Prozef mobility experimental result
| Batch | Embodiment 1 | Comparative example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 |
| θ（°） | 30.4 | 35.5 | 34.2 | 34.3 | 34.3 |
From the experimental result of table 11, it is fine that the present invention prepares the mobility of Prozef, is better than prior art.Thereby the preparation of more convenient its preparation.
Claims (12)
1. a cefprozil compound, is characterized in that, described cefprozil compound is crystal, and the X-ray powder diffraction pattern that use Cu-K alpha-ray measures as shown in Figure 1.
2. cefprozil compound according to claim 1, is characterized in that, the main granularity of described cefprozil compound is 288～465 μ m, and Tile Width is 190～658 μ m; Preferred main granularity is 365～402 μ m, and Tile Width is 242～535 μ m.
3. a preparation method for cefprozil compound as claimed in claim 1, is characterized in that, comprises the following steps:
(1) preparation Prozef crude product is at the saturated aqueous solution of 50～60 ℃;
(2) mixed organic solvents of preparation ethanol, ether and ethyl acetate, the volume of mixed organic solvents is 3～9 times of Prozef crude product saturated aqueous solution, preferably 4～6 times;
(3) organic solvent is cooled to 0～5 ℃, in frequency, be under 20～25KHz, the output rating sound field that is 40～80W, in organic solvent, at the uniform velocity add Prozef crude product saturated aqueous solution while stirring, adding rear continuation stirs and lowers the temperature, after being cooled to 0～5 ℃, stop stirring standing growing the grain 2～8 hours; Obtain filtering after crystal, with absolute ethanol washing, vacuum-drying 2～8 hours, obtains cefprozil compound.
4. the preparation method of cefprozil compound according to claim 3, is characterized in that, in step (2), in mixed organic solvents, the volume ratio of ethanol, ether and ethyl acetate is 3～5:1～2:1, preferably 4～5:1:1.
5. the preparation method of the cefprozil compound of stating according to claim 3, is characterized in that, in step (3), to adding the stirring velocity of Prozef crude product saturated aqueous solution in organic solvent, is 600～1200 revs/min; Stirring velocity after Prozef crude product saturated aqueous solution adds is 60～360 revs/min.
6. the preparation method of cefprozil compound according to claim 3, is characterized in that, in step (3), the speed that adds of Prozef crude product saturated aqueous solution is: v=M/20～M/10, the volume that wherein M is organic mixed solvent, unit is for rising, and the unit of speed v is l/h.
7. the preparation method of cefprozil compound according to claim 3, is characterized in that, in step (3), the cooling rate after Prozef crude product saturated aqueous solution adds is 0.5～3.5 ℃/h, preferably 1.5～2.5 ℃/h.
8. a preparation that contains cefprozil compound described in claim 1, is characterized in that, described preparation is dispersible tablet or dry suspensoid.
9. preparation according to claim 8, is characterized in that, in described dispersible tablet, contains: cefprozil compound 125～250 weight parts, lactose 26.65～53.3 weight parts; Low-substituted hydroxypropyl cellulose 25～50 weight parts; Sodium starch glycolate 2.7～5.4 weight parts; Silica 1 .65～3.3 weight part; Magnesium Stearate 1.65～3.3 weight parts; Sweet 0.35～0.7 weight part of knob, essence 2.0～4.0 weight parts.
10. preparation according to claim 9, is characterized in that, the preparation method of described dispersible tablet comprises the following steps:
(1) take by weight each component;
(2) sieve: cefprozil compound, sodium starch glycolate, low-substituted hydroxypropyl cellulose, lactose are crossed respectively to 100 mesh sieves;
(3) mix: cefprozil compound, sodium starch glycolate, low-substituted hydroxypropyl cellulose, knob are mixed 10～30 minutes sweet adding in mixing machine, add again essence, silicon-dioxide, lactose to continue to mix 10～30 minutes, finally add Magnesium Stearate to mix 5～15 minutes;
(4) compressing tablet, packing, obtain.
11. preparations according to claim 8, it is characterized in that, in described dry suspensoid, contain: cefprozil compound 125～250 weight parts, sucrose 1000～2000 weight parts, xanthan gum 15～30 weight parts, aspartame 5～10 weight parts, essence 4～8 weight parts, Magnesium Stearate 1～2 weight part, Citric Acid 0.5～1 weight part, Polysorbate 80 10～20 weight parts.
12. preparations according to claim 11, is characterized in that, the preparation method of described dry suspensoid comprises the following steps:
(1) take by weight each component;
(2) add mixing machine with cefprozil compound, xanthan gum, aspartame after sucrose being pulverized to 100 mesh sieves, mix, standby; Polysorbate 80 is added in appropriate purified water, and stirring and dissolving, adds Citric Acid, and stirring and dissolving is standby;
(3) solution in step (2) is added in step (2) and mixes softwood processed in powder, the granulation of sieving, puts into oven drying, and whole grain, adds after the Magnesium Stearate and essence of recipe quantity, mixes; Wherein, dry temperature is 45～55 ℃, and dried particles to moisture is 0.50～1.50%;
(4) check, packing, packing, obtain.
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| CN105997919A (en) * | 2015-04-30 | 2016-10-12 | 苗怡文 | Method for preparing aspirin enteric-coated tablet for removing fever, easing pain and resisting inflammation |
| CN108299468A (en) * | 2017-12-29 | 2018-07-20 | 山东裕欣药业有限公司 | A kind of process for purification of Cefprozil |
| CN109010297A (en) * | 2018-10-25 | 2018-12-18 | 苏州东瑞制药有限公司 | A kind of cefprozil tablet and preparation method thereof |
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Address after: 519041 Guangdong Province, Zhuhai City Industrial Zone, Jinwan District biological Patentee after: Jin Hong pharmaceutical Limited by Share Ltd Address before: 519041 Guangdong Province, Zhuhai City Industrial Zone, Jinwan District biological Patentee before: Zhuhai Kinhoo Pharmaceutical Co., Ltd. |