CN103145733A - Amoxicillin compound and pharmaceutical composition of amoxicillin compound and potassium clavulanate - Google Patents
Amoxicillin compound and pharmaceutical composition of amoxicillin compound and potassium clavulanate Download PDFInfo
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Abstract
The invention relates to an amoxicillin compound and a pharmaceutical composition of the amoxicillin compound and potassium clavulanate. The pharmaceutical composition is an oral sustained-release preparation. The amoxicillin compound is a crystalline compound which is provided with the following structural formula, wherein the characteristic peaks as shown in an X-ray powder diffraction pattern obtained by measuring through Cu-K alpha rays are displayed in 2 theta of 8.0 degrees, 12.1 degrees, 15.4 degrees, 17.0 degrees, 19.8 degrees, 21.6 degrees, 23.0 degrees, 24.3 degrees, 25.7 degrees, 27.4 degrees, 30.7 degrees and 33.5 degrees. The novel crystalline compound is improved in stability and dissolubility. The amoxicillin and clavulanate potassium prepared from the crystalline compound is higher in stability. The amoxicillin and clavulanate potassium oral sustained-release preparation prepared from the crystalline compound can be synchronously released, and is excellent in in-vitro dissolution and higher in bioavailability.
Description
Technical field
The invention belongs to medical technical field, specifically, relate to the pharmaceutical composition of a kind of amoxycilline Trihydrate bp compound and this compound and Clavulanic Potassium.
Background technology
Amoxicillin/clavulanate potassium, its chemical name is respectively: (2S, 5R, 6R)-3,3-dimethyl-6-[(R)-(-)-2-amino-2-(4-hydroxy phenyl) kharophen]-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-formic acid trihydrate and (Z)-(2S, 5R)-3-(2-hydroxyl ethylidene)-7-oxo-4-oxa--1-azabicyclo [3.2.0] heptane-2-carboxylic acid potassium.
The amoxicillin/clavulanate potassium compound preparation is that the amoxycilline Trihydrate bp becomes to be grouped into two kinds of Clavulanic Potassiums, is the efficient severe infection one anti-infective medication of line of the anti-enzyme of clinical common wide spectrum.Wherein, the amoxycilline Trihydrate bp is penbritin class beta-lactam semisynthetic antibiotics, and mechanism of action is the synthetic of anti-bacteria cell walls, has germicidal action fast, and is effective to most of grams and positive bacteria and negative bacterium, but easily by the beta-lactam enzyme liberating; Clavulanic Potassium is beta-lactamase inhibitor, itself only has faint anti-microbial activity, can control in a large number has the avtive spot of the β-lactamase in the microorganism of resistance and makes its inactivation penicillin and cynnematin, thereby has powerful wide spectrum lactamase restraining effect.Both unite use, but the antagonism β-lactamase is to the destruction of amoxycilline Trihydrate bp, to improve result for the treatment of.
The antimicrobial spectrum of this product is identical with the amoxycilline Trihydrate bp, and enlarges to some extent.To producing enzyme streptococcus aureus, staphylococcus epidermidis, coagulase negative staphylococcus and the equal tool good action of faecalis, some intestines liver Cordycepps bacterium, hemophilus influenzae, moraxelle catarrhalis, bacteroides fragilis etc. that produce β-lactamase also there is better anti-microbial activity.This product is produced the enterobacteriaceae lactobacteriaceae of Chromosome-encoded I type enzyme and Rhodopseudomonas without effect to methicillin-resistant Staphylococcus and enterobacter etc.
According to reports, amoxicillin/clavulanate potassium this product is stable to hydrochloric acid in gastric juice, and oral absorption is good, and food has no significant effect the absorption of this product.Empty stomach oral this product 375mg(amoxycilline Trihydrate bp 250mg and clavulanic acid 125mg), the amoxycilline Trihydrate bp reached blood peak concentration of drug (C in 1.5 hours
max), being about 5.6mg/L, blood elimination transformation period (t1/2b) is about 1 hour, and the urine rate of discharge was 50%～78% in 8 hours; The pharmacokinetic parameters of clavulanic acid is identical when alone, reaches blood peak concentration of drug (Cmax) in 1 hour after the oral clavulanic acid 125g of normal people, is about 3.4mg/L.Protein binding rate is 22%～30%.It is 0.76～1.4 hour that blood is eliminated the transformation period (t1/2b), and the urine rate of discharge was about 46% in 8 hours.Both are respectively 97% and 75% at oral bioavailability.
Acidproof, the anti-enzyme of this product is applicable to produce lower respiratory infection, otitis media, sinusitis paranasal sinusitis due to enzyme hemophilus influenzae and moraxelle catarrhalis; Respiratory tract, urinary tract and skin soft-tissue infection etc. due to product enzyme streptococcus aureus and product enzyme enterobacteriaceae lactobacteriaceae such as intestinal bacteria, klebsiella spp; Also can be used for the light grade and moderate infection due to faecalis.This product also can be used for the above-mentioned various infection due to responsive not zymogenic bacteria.
At present, the amoxicillin/clavulanate potassium compound ratio of approved listing both at home and abroad have 2: 1,4: 1 and 7: 1; Commercially available except the aseptic powder injection, the oral dosage forms such as dry syrup, tablet (ordinary tablet, chewable tablet, dispersible tablet), granule, dry suspensoid are still arranged.Disclose a kind of amoxicillin/clavulanate potassium enteric-coated formulation composition and preparation method thereof as CN101890005A, mainly made by amoxycilline Trihydrate bp, Clavulanic Potassium and suitable auxiliary material.CN101897701A discloses a kind of preparation method of amoxicillin and clavulanate potassium tablets, it is 120～135 parts of (a) amoxycilline Trihydrate bps, 40～45 parts of Clavulanic Potassiums, 27～32 parts of Microcrystalline Celluloses, 1～3 part of croscarmellose sodium, 1～3 part of micropowder silica gel, 2～4 parts of Magnesium Stearates; (b) with after the granulation of amoxycilline Trihydrate bp, according to the mass ratio of 4: 1, mix with Clavulanic Potassium, consist of major ingredient; (c) with auxiliary material micropowder silica gel, croscarmellose sodium (ADS) and Microcrystalline Cellulose according to the equivalent method mixing that progressively increases, then progressively increase to drop in mixing machine with major ingredient equivalent and mixed 36～70 minutes; (d) mixed powder is carried out compressing tablet.CN101502511A provides a kind of amoxicillin/clavulanate potassium 8:1 sheet and preparation method thereof.This amoxicillin/clavulanate potassium 8:1 tablet, be in the middle of quality controllability, the amoxicillin/clavulanate potassium (8:1) that mixture homogeneity is good mixing raw material as the main ingredient source, make like this amoxicillin/clavulanate potassium 8:1 sheet preparation technology simple, quality controllability is good, good stability, and the moulding production cost is low.
But because the amoxycilline Trihydrate bp is slightly soluble in water, Clavulanic Potassium is very easily water-soluble, if the oral normal release dosage form that adopts the technique of conventional composition to make can cause the Clavulanic Potassium rate of releasing drug suitable, the amoxycilline Trihydrate bp will can not discharge out; And the amoxycilline Trihydrate bp rate of releasing drug is suitable, will lose control of the release of Clavulanic Potassium, and cause the prominent of Clavulanic Potassium to be released.For this reason, occur some sustained release preparations in prior art, provide a kind of stable amoxicillin and clavulanate potassium sustained release preparation as CN102861015A.Formed by release layer and slow release layer, the weight ratio that contains amoxycilline Trihydrate bp and Clavulanic Potassium is 1000: 62.5, wherein the amoxycilline Trihydrate bp is 1: 1 in the ratio of release layer and slow release layer, Clavulanic Potassium is all in release layer, and wherein pharmaceutical excipient is comprised of following component and weight percent: slow release layer contains the amoxycilline Trihydrate bp: slow-release material: lubricant: tackiness agent is 500: 140-150: 5-10: 16: 23; Release layer contains the amoxycilline Trihydrate bp: Clavulanic Potassium: disintegrating agent: lubricant: coating powder is 62.5: 30-60: 6-10: 40-80.CN1634044A also discloses a kind of new sustained release medicine tri-layer tablets, contains Utimox, Clavulanic Potassium and pharmaceutically acceptable vehicle or carrier, and layer 1 is release layer, contains Utimox and Clavulanic Potassium; Layer 2 is release layer, contains the part Utimox; Layer 3 is slow release layer, contains the rest part Utimox; To also contain slow-release material hypromellose E30 with auxiliary material except containing generally in slow release layer, to solve the synchronous problem that discharges of microsolubility medicine amoxycilline Trihydrate bp and water soluble drug Clavulanic Potassium.
The shortcoming of above-mentioned double-layer sustained release preparation or three layers of slow releasing tablet is that its preparation is too high to equipment requirements, be difficult to suitability for industrialized production, and double-layer sustained release tablets can cause tablet hardness excessive in preparation process, affects drug release, and Dual-layer sheet joint face is difficult to discharge medicine.And due to amoxycilline Trihydrate bp slightly soluble in water, cause the vitro Drug dissolution rate poor, cause its bioavailability low.
The inventor is devoted for years in the research of bulk drug amoxycilline Trihydrate bp and Clavulanic Potassium and their oral regular pharmaceutics, after a large amount of research has been carried out in the bulk drug amoxycilline Trihydrate bp, by changing the condition of crystallization, obtained a kind of new amoxycilline Trihydrate bp new crystal that is different from prior art, this crystal formation has solvability and the stability of improvement.And find to adopt this new crystal amoxycilline Trihydrate bp can realize synchronizeing with the oral regular pharmaceutics that Clavulanic Potassium and pharmaceutical excipient are prepared from the purpose that discharges in the research of the oral regular pharmaceutics of carrying out subsequently more pleasantly surprisedly, dissolution rate has also obtained obvious improvement, thereby has completed the present invention.
Summary of the invention
The first purpose of the present invention is to provide a kind of amoxycilline Trihydrate bp compound, and this amoxycilline Trihydrate bp compound is crystalline compounds, is a kind of amoxycilline Trihydrate bp new crystal that is different from prior art, and this crystal formation has solvability and the stability of improvement.
The second purpose of the present invention is to provide the preparation method of described amoxycilline Trihydrate bp compound, the method simple possible, easy handling.
The 3rd purpose of the present invention is to provide the pharmaceutical composition of a kind of above-mentioned amoxycilline Trihydrate bp compound and Clavulanic Potassium, described pharmaceutical composition is oral regular pharmaceutics, this oral regular pharmaceutics can realize the synchronous purpose that discharges, and In Vitro Dissolution is good, and its bioavailability is high.
For realizing the first purpose of the present invention, the present invention adopts following technical scheme:
Amoxycilline Trihydrate bp compound shown in a kind of formula (I),
Formula (I)
Wherein, described amoxycilline Trihydrate bp is the amoxycilline Trihydrate bp crystalline compounds, and in the X-ray powder diffraction pattern that this crystalline compounds use Cu-K alpha-ray measures, characteristic peak is 8.0 °, 12.1 °, 15.4 °, 17.0 °, 19.8 °, 21.6 °, 23.0 °, 24.3 °, 25.7 °, 27.4 °, 30.7 ° and 33.5 ° of demonstrations at 2 θ.
In prior art, the existing multiple crystal formation in amoxycilline Trihydrate bp, disclose a kind of amoxycilline Trihydrate bp A crystal formation as CN102718778A, and CN102731528A discloses a kind of amoxycilline Trihydrate bp C crystal formation.Through relatively, find that amoxycilline Trihydrate bp provided by the present invention crystalline compounds has different X-ray powder diffraction patterns from A crystal formation and the C crystal formation of prior art, be a kind of new crystal compound that is different from the amoxycilline Trihydrate bp of prior art.
Show through stability test, amoxycilline Trihydrate bp of the present invention new crystal compound has preferably stability, and adopts the amoxicillin and clavulanate potassium aseptic powder injection that this new crystal amoxycilline Trihydrate bp makes also to have solvability and the stability of remarkable improvement.
For realizing the second purpose of the present invention, the present invention adopts following technical scheme:
The preparation method of a kind of amoxycilline Trihydrate bp compound, the method comprises the steps:
1) the amoxycilline Trihydrate bp bulk drug is joined in the water of 10～15 ℃, with salt acid for adjusting pH value to 1.0～3.0, obtain the aqueous solution of amoxycilline Trihydrate bp;
2) add the mixing solutions of n-propyl alcohol/tetrahydrofuran (THF) in the aqueous solution of amoxycilline Trihydrate bp;
3) finish, under stirring, dropping concentration is 10%～12% NH
3H
2O regulates pH value to 5.0～5.1, and crystallize out is controlled 1～8 ℃ of temperature, and suction filtration after growing the grain 1～2h, filter cake are used purified water, washing with acetone successively, and drying obtains described amoxycilline Trihydrate bp compound.
In the preparation method of amoxycilline Trihydrate bp provided by the present invention compound, wherein, the mass volume ratio of the amoxycilline Trihydrate bp bulk drug described in step 1) and water is 1g:10～20ml.
The mixing solutions of n-propyl alcohol/tetrahydrofuran (THF) step 2) is 3～8ml:1g with the volume mass ratio of the amoxycilline Trihydrate bp bulk drug of step 1); Wherein, in the mixing solutions of described n-propyl alcohol/tetrahydrofuran (THF), the volume ratio of n-propyl alcohol and tetrahydrofuran (THF) is 1:5～1:8.
The stirring velocity of the described stirring of step 3) is 250～350rmin
-1
For realizing the 3rd purpose of the present invention, the present invention adopts following technical scheme:
The pharmaceutical composition of a kind of amoxycilline Trihydrate bp and Clavulanic Potassium, wherein, described pharmaceutical composition contains the amoxycilline Trihydrate bp compound that amoxycilline Trihydrate bp of the present invention compound or preparation method of the present invention make.
Further, pharmaceutical composition of the present invention is oral regular pharmaceutics, and described oral regular pharmaceutics is by a) active constituents of medicine amoxycilline Trihydrate bp and Clavulanic Potassium; And b) pharmaceutical excipient forms; In described active constituents of medicine, the mass ratio of amoxycilline Trihydrate bp and Clavulanic Potassium is 2:1 to 20:1, preferred 2:1,4:1,7:1,11:1,8:1 or 14:1, and wherein the quality of amoxycilline Trihydrate bp is with C
16H
19N
3O
5The S meter, the quality of Clavulanic Potassium is with C
8H
9NO
5Meter.
In the present invention, described oral regular pharmaceutics is tablet, enteric coated tablet, capsule, dispersible tablet, dry suspensoid, chewable tablet or granule.
In the present invention, described pharmaceutical excipient is one or more in enteric material, tackiness agent, weighting agent, disintegrating agent, lubricant, wetting agent, softening agent or glidant.
In the present invention, described enteric material is selected from one or more in multipolymer, hydroxypropyl cellacefate, cellacefate, HP-55, hydroxypropylmethylcellulose phthalate or the polyvinyl acetate phthalate of acrylate copolymer, methacrylic acid and acrylate or methacrylic ester;
Described tackiness agent is selected from one or more in following material: one or more in starch, gelatin, sugar, synthetical glue, sodium alginate, Walocel MT 20.000PV, methylcellulose gum, polyvinylpyrrolidone, polyoxyethylene glycol, ethyl cellulose, water, wax or alcohol;
Described weighting agent is selected from one or more in calcium sulfate, Mierocrystalline cellulose, Microcrystalline Cellulose, Vltra tears, lactose, kaolin, N.F,USP MANNITOL, sodium-chlor or starch.
Described disintegrating agent is selected from one or more in its derivative of low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, Microcrystalline Cellulose, croscarmellose sodium, sodium starch glycolate or starch;
Described lubricant is selected from one or more in talcum powder, Magnesium Stearate, calcium stearate, stearic acid, hydrogenated vegetable oil or polyoxyethylene glycol;
Described softening agent is selected from least a in propylene glycol, glycerine, polyoxyethylene glycol, Vanay, acetyl list glycerate, phthalic ester or Viscotrol C.
The pharmaceutical composition of amoxycilline Trihydrate bp of the present invention and Clavulanic Potassium is applicable to prepare various oral regular pharmaceutics, as tablet, enteric coated tablet, capsule, dispersible tablet, dry suspensoid, chewable tablet or granule etc.When adopting amoxycilline Trihydrate bp of the present invention compound and Clavulanic Potassium to be prepared into various oral regular pharmaceutics, it is ordinary skill in the art means.
Compared with prior art, the present invention has following advantage:
(1) amoxycilline Trihydrate bp provided by the present invention compound is a kind of amoxycilline Trihydrate bp new crystal compound that is different from prior art, and this new crystal compound has stability and the solvability of improvement;
(2) preparation method's simple possible of amoxycilline Trihydrate bp provided by the present invention compound, easy handling;
(3) the oral regular pharmaceutics of amoxycilline Trihydrate bp provided by the present invention and Clavulanic Potassium can realize the synchronous purpose that discharges, and In Vitro Dissolution is good, and its bioavailability is high; Prescription is reasonable, and auxiliary material used is safe and reliable, has greatly improved patient's drug safety; Prepared label outward appearance is good, has simultaneously better dissolving out capability; Steady quality is difficult for decomposing and goes bad, and also can not jolt tablet is produced because of transportation and destroy.
Description of drawings
Fig. 1 is the X-ray powder diffraction figure of amoxycilline Trihydrate bp of the present invention crystalline compounds.
Embodiment
Be below the specific embodiment of the present invention, described embodiment is in order to further describe the present invention, rather than restriction the present invention.
The preparation of [embodiment 1] amoxycilline Trihydrate bp crystalline compounds
(1) 100g amoxycilline Trihydrate bp bulk drug is joined in the water of 1500ml12 ℃, with salt acid for adjusting pH value to 2.0, obtain the aqueous solution of amoxycilline Trihydrate bp;
(2) add the mixing solutions of 560ml n-propyl alcohol/tetrahydrofuran (THF) in the aqueous solution of amoxycilline Trihydrate bp, wherein the volume ratio of n-propyl alcohol and tetrahydrofuran (THF) is 1:6.2;
(3) finish, low whipping speed is 275rmin
-1Stirring under to drip concentration be 11% NH
3H
2O regulates pH value to 5.0, and crystallize out is controlled 5 ℃ of temperature, and suction filtration after growing the grain 1.5h, filter cake are used purified water, washing with acetone successively, and drying obtains described amoxycilline Trihydrate bp crystalline compounds.
In the X-ray powder diffraction pattern that the amoxycilline Trihydrate bp crystalline compounds use Cu-K alpha-ray of gained measures, characteristic peak is 8.0 °, 12.1 °, 15.4 °, 17.0 °, 19.8 °, 21.6 °, 23.0 °, 24.3 °, 25.7 °, 27.4 °, 30.7 ° and 33.5 ° of demonstrations at 2 θ, as shown in Figure 1.
Be below embodiment 2-7, operation steps is with embodiment 1, and concrete processing parameter sees Table 1:
Table 1
Consistent with embodiment 1 to the X-ray powder diffraction spectrogram (XRD spectra) that the prepared amoxycilline Trihydrate bp crystalline compounds of embodiment 2-7 uses the Cu-K alpha-ray to measure.
[FORMULATION EXAMPLE 1] amoxycillin-potassium clavulanate tablets
Specification: amoxicillin/clavulanate 875mg/125mg
Prescription:
The preparation method:
Microcrystalline cellulose excipients, cross-linked carboxymethyl cellulose sodium, micropowder silica gel are also crossed 80 mesh sieves in 80 ℃ of dry 4h; Magnesium Stearate is in 60 ℃ of dry 4h; Cross sieve No. 9; Standby.The amoxycilline Trihydrate bp crystalline compounds of getting embodiment 1 mixes by weight the ratio of 7:1 with the mixed powder of amoxicillin and clavulanate potassium 2:1, calculates charging capacity after mensuration two component concentrations.Add Microcrystalline Cellulose (in add part), Magnesium Stearate (in add part) mixing in the prescription ratio, doing under not higher than 33% condition in relative humidity and squeezing dry-pressing granulation on the type granulator.Particle with long capsule shape drift compressing tablet, namely gets plain sheet (label) in prescription ratio and Extra Section auxiliary materials and mixing.Get Opadry white OY-C-7000A coating powder, being mixed with concentration with 95% ethanol is 7%(W/V) coating liquid, with this coating liquid in the ordinary coating pot with the label dressing, pack quality inspection.
[FORMULATION EXAMPLE 2] amoxycillin-potassium clavulanate tablets
Specification: amoxicillin/clavulanate 136mg/34mg
Prescription:
The preparation method:
(a) take the amoxycilline Trihydrate bp crystalline compounds of embodiment 2 (with C
16H
19N
3O
5The S meter) 136g, Clavulanic Potassium is (with C
8H
9NO
5Meter) 34g, Microcrystalline Cellulose (P112) 32g, croscarmellose sodium (ADS) 2g, micropowder silica gel 2g, Magnesium Stearate 2g amounts to 205g;
(b) after granulate in the amoxycilline Trihydrate bp, mix the formation major ingredient with Clavulanic Potassium according to the mass ratio of 4:1.
(c) auxiliary material micropowder silica gel, croscarmellose sodium (ADS) and Microcrystalline Cellulose equivalent are progressively increased mixing, then progressively increase to drop in mixing machine with the equivalent major ingredient and mixed 36～70 minutes.
In whole technological process, the intermediate powder mix is controlled moisture≤9.0%, indicates content and is controlled at 95.0%～115.0%.
(d) powder mix is carried out compressing tablet.
According to routine, plain sheet is carried out film coating at last.Packing: adopt two aluminium packings, the bottom aluminum foil thickness of packing is 0.033mm.
In above-mentioned technological process, production environment is controlled at: temperature is below 30 ℃, and humidity is below 28%.Comprise between mixed powder, between compressing tablet, between dressing etc.
[FORMULATION EXAMPLE 3] enteric coated tablet (specification: amoxicillin/clavulanate 0.2g/0.0285g)
Prescription:
Preparation technology:
amoxycilline Trihydrate bp crystalline compounds with embodiment 3, Clavulanic Potassium, cane sugar powder, sodium starch glycolate, Microcrystalline Cellulose, Magnesium Stearate is crossed respectively after 80 mesh sieves standby, take cane sugar powder by recipe quantity, sodium starch glycolate, Microcrystalline Cellulose is put in mixing machine after mixing and the amoxycilline Trihydrate bp again, Clavulanic Potassium is by equivalent incremental method mixing, add 5% polyvinylpyrrolidone 85% ethanolic soln appropriate, granulate, whole grain, 60 ℃ of dryings, dried particle adds the Magnesium Stearate mixing of recipe quantity, cross the 16 whole grains of eye mesh screen with Pendulargranulator, particle is carried out assay, and the heavy scope of definite sheet, compressing tablet, the standby enteric coating liquid of coating powder that contains the enteric material polyvinyl acetate phthalate with 65% ethanol acetone soln allotment, wrap enteric coating again on gained element sheet, pack after passed examination.
[FORMULATION EXAMPLE 4] amoxicillin and clavulanate potassium dispersible tablet
Prescription forms:
Preparation technology:
Under the condition of temperature≤20 ℃, relative humidity≤20%, operation as follows:
(1) take the supplementary material of above-mentioned recipe quantity, amoxicillin and clavulanate potassium powder mix recipe quantity calculates with clavulanic acid;
(2) supplementary material except amoxicillin and clavulanate potassium powder mix and colloidal silica is carried out drying, wherein amoxycilline Trihydrate bp and Magnesium Stearate Temperature Setting were 40 ± 5 ℃ of dryings 5 hours.All the other auxiliary material Temperature Settings were 80 ± 5 ℃ of dryings 5 hours;
(3) the heavy powder in the amoxycilline Trihydrate bp of drying being crossed, Icing Sugar, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose and amoxicillin and clavulanate potassium powder mix be mixed 60min just;
(4) mixed material is carried out dry granulation one time, 16 orders sieve; The gained material of once granulating is sieved, collect the dried particle A between 16 orders～40 orders;
Carry out secondary with the 40 following materials of order after (5) the 16 above crushing materials of order and granulate, the gained particle sieves, and the 16 whole grains of the above crushing materials of order are collected the rear all particle B of secondary granulation;
(6) with the particle A, the B that make and with the eventually mixed 30min of residue auxiliary material after, compressing tablet, slice, thin piece hardness is at 50-70N.
[FORMULATION EXAMPLE 5] amoxicillin and clavulanate potassium dry suspensoid
Prescription:
Preparation technology:
Under the condition of temperature≤20 ℃, relative humidity≤20%, operation as follows:
(1) get the supplementary material of above-mentioned recipe quantity, pulverize, 60 orders sieve rear standby;
(2) with amoxycilline Trihydrate bp, PEG-6000, Magnesium Stearate and mixing essence 40 ± 5 ℃ of constant pressure and dries 5 hours; 80 ± 5 ℃ of constant pressure and dries of all the other auxiliary materials 5 hours;
(3) supplementary material of drying being crossed (except PEG-6000) and amoxicillin and clavulanate potassium powder mix are poured just mixed 60min in mixing machine into;
(4) mixed material is carried out dry granulation one time, 16 orders sieve; The gained material of once granulating is sieved, collect the dried particle A between 16 orders～40 orders;
Carry out secondary with the 40 following materials of order after (5) the 16 above crushing materials of order and granulate, the gained particle sieves, and the 16 whole grains of the above crushing materials of order are collected the rear all particle B of secondary granulation;
(6) with after the particle A, the B that make and the dry eventually mixed 30min of PEG-6000, get dry suspensoid.
[FORMULATION EXAMPLE 6] amoxycillin-potassium clavulanate tablets
Specification: amoxicillin/clavulanate 125mg/62.5mg
Prescription:
Preparation technology: with embodiment 1.
[FORMULATION EXAMPLE 7] amoxycillin-potassium clavulanate tablets
Specification: amoxicillin/clavulanate 500mg/62.5mg
Prescription:
Preparation technology: with embodiment 1.
[FORMULATION EXAMPLE 8] amoxycillin-potassium clavulanate tablets
Specification: amoxicillin/clavulanate 1250mg/62.5mg
Prescription:
Preparation technology: with embodiment 1.
[FORMULATION EXAMPLE 9] amoxycillin-potassium clavulanate tablets
Specification: amoxicillin/clavulanate 687.5mg/62.5mg
Prescription:
Preparation technology: with embodiment 1.
Test example 1
The stability test of amoxycilline Trihydrate bp crystalline compounds
This test example is used for the stability of the amoxycilline Trihydrate bp crystal formation of amoxycilline Trihydrate bp more of the present invention crystalline compounds and prior art.
The stability of amoxycilline Trihydrate bp is mainly single assorted and total assorted content embodies in the acceleration experiment by carrying out medicine, medicine.The amoxycilline Trihydrate bp crystal formation (control group) of getting amoxycilline Trihydrate bp of the present invention crystalline compounds (test group) and existing technique gained accelerates experiment.Experiment condition: temperature is 40 ℃, and humidity is 75%.
Test group 1: the embodiment of the present invention 1 prepared amoxycilline Trihydrate bp crystalline compounds;
Test group 2: the embodiment of the present invention 2 prepared amoxycilline Trihydrate bp crystalline compounds;
Control group 1: the amoxycilline Trihydrate bp A crystal formation that makes according to the method for CN102718778A embodiment 1;
Control group 2: the amoxycilline Trihydrate bp C crystal formation that makes according to the method for CN102731528A embodiment 1.
The results are shown in Table 2:
Laboratory test results is accelerated in table 2, amoxycilline Trihydrate bp
Can find out from above-mentioned detected result, amoxycilline Trihydrate bp of the present invention crystalline compounds has stability preferably.
The amoxycilline Trihydrate bp crystalline compounds prepared to other embodiments of the invention also carried out the aforementioned stable test, and the result of its acquisition is similar.
Test example 2
Dissolubility test
This test example is used under the amoxycilline Trihydrate bp crystal formation differing temps of amoxycilline Trihydrate bp more of the present invention crystalline compounds and prior art the solvability at pure water.
Trial target: the embodiment of the present invention 1 prepared amoxycilline Trihydrate bp crystalline compounds;
Reference substance 1: the amoxycilline Trihydrate bp A crystal formation that makes according to the method for CN102718778A embodiment 1;
Reference substance 2: the amoxycilline Trihydrate bp C crystal formation that makes according to the method for CN102731528A embodiment 1.
The solubleness of amoxycilline Trihydrate bp in pure water adopts stationary method to measure.The saturated solution of preparation AMOX under steady temperature more than stirring sufficiently long time 3～6hr, to guarantee that solution reaches capacity fully, is filled in volumetric flask with constant temperature funnel equality of temperature, is added with in advance quantitative liquid chromatogram mobile phase in volumetric flask.Adopt the concentration of high-efficient liquid phase color spectrometry saturated solution.Concentration detection method is according to detection method of content under the item of Chinese Pharmacopoeia amoxycilline Trihydrate bp.Each experimental point is triplicate at least, and getting three parallel laboratory test mean values is the solubleness of amoxycilline Trihydrate bp in pure water.
The results are shown in Table 3:
Table 3, amoxycilline Trihydrate bp solubleness detected result
| Solution temperature (K) | 278 | 281 | 284 | 287 | 290 | 293 |
| Trial target solubleness (kg/m 3） | 10.213 | 10.198 | 10.471 | 10.689 | 10.763 | 10.826 |
| Reference substance 1 solubleness (kg/m 3） | 1.565 | 1.543 | 1.575 | 1.753 | 1.828 | 1.891 |
| Reference substance 2 solubleness (kg/m 3） | 1.568 | 1.546 | 1.578 | 1.752 | 1.824 | 1.894 |
Can find out from above-mentioned detected result, amoxycilline Trihydrate bp of the present invention crystalline compounds is compared the solvability with improvement than prior art.
The amoxycilline Trihydrate bp crystalline compounds prepared to other embodiments of the invention also carried out above-mentioned dissolubility test, and the result of its acquisition is similar.
Test example 3
Dissolution rate is investigated
This test example is investigated the dissolution rate of the prepared amoxycillin-potassium clavulanate tablets of the present invention.
Amoxycillin-potassium clavulanate tablets trial target: according to the method preparation of FORMULATION EXAMPLE 1 of the present invention;
Amoxycillin-potassium clavulanate tablets reference substance: according to " amoxicillin and clavulanate potassium (7:1) tablet recipe, technical study and dissolution rate are investigated " [Wu Xiaoyu, Chang Xuejun. amoxicillin and clavulanate potassium (7:1) tablet recipe, technical study and dissolution rate are investigated [J], Journal of Chinese Hospital Pharmacy, prescription 2006,26(11): 1358-1360] and technique preparation;
Amoxycilline Trihydrate bp reference substance: Nat'l Pharmaceutical ﹠ Biological Products Control Institute, lot number 0409-9907, content 84.5%;
Clavulanic acid reference substance: Nat'l Pharmaceutical ﹠ Biological Products Control Institute, lot number 0429-9902, content 91.3%;
Dissolution determination: get the amoxycillin-potassium clavulanate tablets trial target, according to dissolution method (two appendix X C the second methods of Chinese Pharmacopoeia version in 2005), take water 900mL as solvent, rotating speed 75minr
-1, operation in accordance with the law is respectively at 5,10, during 15,20,30,45min, get the water 5mL that solution 5mL(adds 37 ℃ immediately), filter, accurate draw the appropriate thin up of subsequent filtrate make approximately contain amoxycilline Trihydrate bp 1.0mg and clavulanic acid 0.15mg in every 1mL solution as need testing solution; Separately getting amoxycilline Trihydrate bp and clavulanic acid reference substance adds in right amount water and makes the solution that contains amoxycilline Trihydrate bp 1.0mg and clavulanic acid 0.15mg in every 1mL, product solution in contrast.Accurate reference substance solution and each 10 μ L of need testing solution of drawing, the injection liquid chromatography records color atlas, calculates respectively the stripping quantity of every middle amoxycilline Trihydrate bp and clavulanic acid with peak area by external standard method, and limit is 85% of labelled amount, should be up to specification.Separately get the amoxycillin-potassium clavulanate tablets reference substance and measure with method, the results are shown in Table 4.
Table 4, cumulative leaching rate test-results
Can find out from upper table result, compare than the amoxycillin-potassium clavulanate tablets of prior art, in amoxycillin-potassium clavulanate tablets of the present invention the stripping of amoxycilline Trihydrate bp and Clavulanic Potassium basically identical, can realize the synchronous purpose that discharges.
Amoxicillin and clavulanate potassium preparation to other FORMULATION EXAMPLE of the present invention has also carried out above-mentioned test, and the result of its acquisition is similar.
Claims (10)
1. the amoxycilline Trihydrate bp compound shown in a formula (I),
Formula (I)
It is characterized in that, described amoxycilline Trihydrate bp is the amoxycilline Trihydrate bp crystalline compounds, and in the X-ray powder diffraction pattern that this crystalline compounds use Cu-K alpha-ray measures, characteristic peak is 8.0 °, 12.1 °, 15.4 °, 17.0 °, 19.8 °, 21.6 °, 23.0 °, 24.3 °, 25.7 °, 27.4 °, 30.7 ° and 33.5 ° of demonstrations at 2 θ.
2. the preparation method of amoxycilline Trihydrate bp claimed in claim 1 compound, is characterized in that, described preparation method comprises the steps:
1) the amoxycilline Trihydrate bp bulk drug is joined in the water of 10～15 ℃, with salt acid for adjusting pH value to 1.0～3.0, obtain the aqueous solution of amoxycilline Trihydrate bp;
2) add the mixing solutions of n-propyl alcohol/tetrahydrofuran (THF) in the aqueous solution of amoxycilline Trihydrate bp;
3) finish, under stirring, dropping concentration is 10%～12% NH
3H
2O regulates pH value to 5.0～5.1, and crystallize out is controlled 1～8 ℃ of temperature, and suction filtration after growing the grain 1～2h, filter cake are used purified water, washing with acetone successively, and drying obtains described amoxycilline Trihydrate bp compound.
3. the preparation method of amoxycilline Trihydrate bp according to claim 2 compound, is characterized in that, the mass volume ratio of the amoxycilline Trihydrate bp bulk drug described in step 1) and water is 1g:10～20ml.
4. the preparation method of amoxycilline Trihydrate bp according to claim 3 compound, is characterized in that step 2) described in the volume mass ratio of mixing solutions and the amoxycilline Trihydrate bp bulk drug of step 1) of n-propyl alcohol/tetrahydrofuran (THF) be 3～8ml:1g; Wherein, in the mixing solutions of described n-propyl alcohol/tetrahydrofuran (THF), the volume ratio of n-propyl alcohol and tetrahydrofuran (THF) is 1:5～1:8.
5. the preparation method of amoxycilline Trihydrate bp according to claim 2 compound, is characterized in that, the stirring velocity of the described stirring of step 3) is 250～350rmin
-1
6. the pharmaceutical composition of an amoxycilline Trihydrate bp and Clavulanic Potassium, is characterized in that, described pharmaceutical composition contains the amoxycilline Trihydrate bp compound that amoxycilline Trihydrate bp claimed in claim 1 compound or the described preparation method of claim 2-5 any one make.
7. pharmaceutical composition according to claim 6, is characterized in that, described pharmaceutical composition is oral regular pharmaceutics, and described oral regular pharmaceutics is by a) active constituents of medicine amoxycilline Trihydrate bp and Clavulanic Potassium; And b) pharmaceutical excipient forms; In described active constituents of medicine, the mass ratio of amoxycilline Trihydrate bp and Clavulanic Potassium is 2:1 to 20:1, preferred 2:1,4:1,7:1,11:1,8:1 or 14:1, and wherein the quality of amoxycilline Trihydrate bp is with C
16H
19N
3O
5The S meter, the quality of Clavulanic Potassium is with C
8H
9NO
5Meter.
8. according to claim 6 or 7 described pharmaceutical compositions, is characterized in that, described oral regular pharmaceutics is tablet, enteric coated tablet, capsule, dispersible tablet, dry suspensoid, chewable tablet or granule.
9. pharmaceutical composition according to claim 8, is characterized in that, described pharmaceutical excipient is one or more in enteric material, tackiness agent, weighting agent, disintegrating agent, lubricant, wetting agent, softening agent or glidant.
10. pharmaceutical composition according to claim 9, is characterized in that,
Described enteric material is selected from one or more in multipolymer, hydroxypropyl cellacefate, cellacefate, HP-55, hydroxypropylmethylcellulose phthalate or the polyvinyl acetate phthalate of acrylate copolymer, methacrylic acid and acrylate or methacrylic ester;
Described tackiness agent is selected from one or more in following material: one or more in starch, gelatin, sugar, synthetical glue, sodium alginate, Walocel MT 20.000PV, methylcellulose gum, polyvinylpyrrolidone, polyoxyethylene glycol, ethyl cellulose, water, wax or alcohol;
Described weighting agent is selected from one or more in calcium sulfate, Mierocrystalline cellulose, Microcrystalline Cellulose, Vltra tears, lactose, kaolin, N.F,USP MANNITOL, sodium-chlor or starch.
Described disintegrating agent is selected from one or more in its derivative of low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, Microcrystalline Cellulose, croscarmellose sodium, sodium starch glycolate or starch;
Described lubricant is selected from one or more in talcum powder, Magnesium Stearate, calcium stearate, stearic acid, hydrogenated vegetable oil or polyoxyethylene glycol;
Described softening agent is selected from least a in propylene glycol, glycerine, polyoxyethylene glycol, Vanay, acetyl list glycerate, phthalic ester or Viscotrol C.
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| CN104059086A (en) * | 2014-06-19 | 2014-09-24 | 河南牧翔动物药业有限公司 | Amoxicillin crystal and preparation method thereof |
| CN104161734A (en) * | 2014-09-04 | 2014-11-26 | 海口市制药厂有限公司 | Amoxicillin dispersible tablet as well as preparation method and use thereof |
| CN105055408A (en) * | 2015-08-11 | 2015-11-18 | 瑞阳制药有限公司 | Amoxicillin and clavulanate potassium tablet and preparation method thereof |
| CN111377947A (en) * | 2018-12-29 | 2020-07-07 | 江苏先声药业有限公司 | Amoxicillin trihydrate pharmaceutical composition with low water activity and preparation method thereof |
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| CN103145733B (en) | 2014-02-26 |
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