CN102144975A - Cefprozil suspension pharmaceutical composition - Google Patents
Cefprozil suspension pharmaceutical composition Download PDFInfo
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- CN102144975A CN102144975A CN2010106034906A CN201010603490A CN102144975A CN 102144975 A CN102144975 A CN 102144975A CN 2010106034906 A CN2010106034906 A CN 2010106034906A CN 201010603490 A CN201010603490 A CN 201010603490A CN 102144975 A CN102144975 A CN 102144975A
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Abstract
The invention relates to a cefprozil suspension pharmaceutical composition, in particular to a suspension pharmaceutical composition containing cefprozil and xanthan gum. The cefprozil and the xanthan gum are uniformly mixed according to a certain proportion, pharmaceutic adjuvants, such as appropriate amount of disintegrating agent, diluent, flavoring agent, deodorant or lubricant and the like, are added in the mixture, then, the mixture is prepared into standard suspension in a manner of dry granulation or directly filling dry powder. The xanthan gum used as a suspending aid is less in dosage and excellent in adding suspension, the stability of the basic remedy is excellent, and simultaneously, the composition is free from solubilizer and preservative, so that the problem that the existing cefprozil suspension is long in dispersion time in water and low in safety, and has various accessories; and the compliance for taking the composition by a patient is further improved while the effectiveness and the safety of clinical application are ensured.
Description
Technical field
The present invention relates to the suspendible pharmaceutical composition of cefprozil, relate in particular to the suspendible pharmaceutical composition of cefprozil and xanthan gum.
Background technology
Cefprozil (cefprozil, BMY28100, CFPZ) be Bristol-Myers company at first in a kind of non-ester-type oral cephalosporin of nineteen eighty-three exploitation, its molecular structure and cefalexin, cefadroxil, cefaclor are relevant.In the 7-position of cephalo parent nucleus p-hydroxybenzene glycine substituent group is arranged, the 3-bit strip has the acrylic side chain, and the structural formula of its monohydrate is as follows:
Formula 1: cefprozil monohydrate structural formula, C
18H
19N
3O
5SH
2O
The antimicrobial spectrum of cefprozil comprises main Gram-positive, the negative bacterium of common respiratory tract infection, urinary tract infection, antimicrobial spectrum is better than cefalexin, cefadroxil, similar to cefaclor, but staphylococcus, Hemolytic streptococcus and streptococcus pneumoniae activity are better than cefaclor, the influenza haemophilus can be compared with cefaclor with mucositis Blanc Chinese bacterium activity, is a kind of broad ectrum antibiotic of efficient, low toxicity.Be mainly used in treatment upper and lower respiratory tract infection, skin and skin soft-tissue infection etc. clinically.The cefprozil dosage form of now going on the market mainly contains dry suspension, tablet, capsule and granule.
The oral multiple dose suspension of cefprozil will go on the market in the U.S. through the FDA approval the end of the year 1991, and commodity are by name: CEFZIL
Specification has two kinds of 125mg/5mL and 250mg/5mL.As the oral administration mixed suspension of multiple dose, CEFZIL
After requiring the patient to possess higher operational capacity and condition of storage-add the gauge water mixing in multi-dose vials, instruct medicinal liquid poured in the Measuring glass according to consumption and drink, remaining medicinal liquid need be placed in the refrigerator and preserve, and preserves at most 14 days.As everyone knows, cefprozil is as the antibiotic that contains beta-lactam nucleus in the class formation, and amido link easily hydrolysis takes place and loses antibacterial activity in the presence of water or beta-lactamase, and acid, alkali, temperature raise and all can promote hydrolysis.Consider that cefprozil is slightly soluble in the character of water, CEFZIL
Except that adding the suspending agent sodium carboxymethyl cellulose, also add solubilizing agent/wetting agent Tween 80, pH regulator agent glycine and citric acid, defoamer Simethicone, preservative sodium benzoate is used for keeping the stability of cefprozil at solution in the prescription.But generally believe behind the oral Tween 80 and might cause stimulation to gastrointestinal tract mucous, sodium benzoate has potential liver toxicity, and Simethicone is incompatible with the water solublity system, needs prior emulsive character, the inevitable complexity that improve on preparation process.Very important defective such as therefore, existing oral multiple dose cefprozil suspension has that safety is low, complex process, patient's medication compliance are relatively poor.
The cefprozil multiple dose dry suspension of being produced by Sino-U.S. Shi Guibao company went on the market through the SFDA approval at home in 2002.Consider that this product does not meet domestic patient's medication custom, domestic Nanjing hundred million magnificent Pharmaceuticaies have at first been developed the cefprozil dry suspension (2004) of unit dose package, specification is 0.125g, mainly is applicable to treatment adult and the upper and lower respiratory tract infection of child, skin or skin soft-tissue infection etc.; Shantou metal and stone head factory has been developed the cefprozil dry suspension (2010) of two kinds of big specifications on this basis again in succession, contains cefprozil in the unit dose package and is respectively 0.25g and 0.5g by anhydride.
The physicochemical property of excuse spore propylene self is limit, adopt powder directly to fill or the mode of dry granulation prepares that it is oral or be that those skilled in the art are confessed through gastrointestinal administration preparation such as capsule, granule, dried suspendible, dispersible tablet etc. to reach the purpose that improves principal agent stability, this point is confirmed in the product that goes on the market.Specific to mixed suspension preparation, provided the definition of mix suspension grain and oral suspensions in the granule of Chinese Pharmacopoeia and the oral suspensions general rule respectively, that is: " mix suspension grain " means that slightly solubility solid drugs and proper auxiliary materials make the dried particles agent of certain particle size, faces with before adding water or other appropriate liquid joltings can be dispersed into suspension for oral." oral suspensions " means that the slightly solubility solid drugs is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspension or dense suspension.General rule has proposed following specification requirement to oral suspensions: the suspended matter of oral suspensions should be uniformly dispersed, and places the back if precipitate is arranged, easy redispersion after jolting, and should check the settling volume ratio.Chinese Pharmacopoeia requires the settling volume ratio of oral suspensions to be not less than 0.90, and mix suspension grain has the requirement of granularity simultaneously.
CN101780085 discloses the pharmaceutical composition of a kind of cefprozil and cellulose derivative, adopts the technology of dry granulation that cefprozil and cellulose derivative are combined closely, and the result shows can effectively stop the cefprozil degraded.Cellulose derivative is selected from hypromellose, cross-linking sodium carboxymethyl cellulose, Powderd cellulose, microcrystalline Cellulose and hyprolose.Add suitable suspending agent, sweeting agent, pigment etc. on this basis again and make dry suspension, but concrete kind of unexposed suspending agent and amount ranges.In the prior art; some cellulose derivative such as Powderd cellulose, microcrystalline Cellulose or hypromellose also can be used as the suspending agent of aqueous suspension simultaneously; therefore in prescription, do not add under the state of suspending agent; the inventor finds when adopting the technical scheme of above-mentioned patent disclosure to prepare dry suspension; with single or blended adjuvant of Powderd cellulose, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose or low-substituted hydroxypropyl cellulose (LH-11,21) and cefprozil mixing, sedimentation takes place after disperseing in granule through making behind the dry granulation or powder immediately in water again.Excuse spore propylene and above-mentioned cellulose derivative are combined closely, and cause suspension density unevenness one up and down after the sedimentation, can cause the inaccurate of medication dose.Employing contains granule that the prescription of low viscosity hypromellose (viscosity is lower than 40mPas) makes or powder, and to meet behind the water in water swelling time long; bonding is agglomerating easily; for improving the defective of bad dispersibility; the disintegrating agent that adds convention amount; found that; adopt low viscous hypromellose to make suspending agent itself and do not reach good suspending effect, introduce water-insoluble disintegrating agent again, can cause the faster generation sedimentation of pharmaceutical composition.
Adopt sodium carboxymethyl cellulose to do suspending agent in the CEFZIL prescription, bibliographical information is also arranged, adopt sodium carboxymethyl cellulose to prepare single dose cefprozil dry suspension (Zhao Linlin etc., " Heilungkiang scientific and technological information " as suspending agent, 2008 5 phases, 169 pages) obtain suspending effect preferably.But discover, do suspending agent suspending principal agent preferably though adopt sodium carboxymethyl cellulose, but large usage quantity (principal agent and suspending agent usage ratio at least 1: 1), meet behind the water because the rapid gelation of particle surface, easily bonding is agglomerating to cause granule, need long-time jolting or stirring, dispersibility is relatively poor, makes troubles for patient's medication.Can improve dispersion effect though add disintegrating agent, but the water insoluble free settling of disintegrating agent, for the settling volume that guarantees oral administration mixed suspension than up to specification, certainly will to increase the consumption of suspending agent, the viscosity of solution increases, and flavour of a drug are stranded in not easy-clear of oral cavity when giving the patient oral.Therefore, the two consumption mutual restriction, it is good to be difficult to obtain the suspending effect, the product that dispersibility is good again.
The inventor finds when the product that goes on the market being compared research, the dry suspension of single dose is graininess and has a little powder, and jitter time is long behind the chance water, and it is agglomerating to bond easily, need stirring it could be dispersed to the suspension state for a long time, taking medicine to the patient makes troubles; The dry suspension of multiple dose is Powdered, and dispersibility is good slightly, promptly has deposit to occur in 3 hours but place, though the deposit redispersibility is good, increase but place deposit for a long time, the redispersibility variation, need be between resting period in repeatedly jolting to keep the suspension of solution.
In the R﹠D process of cefprozil dry suspension, at the defective that prior art exists, the inventor is unexpected to be found, does suspending agent with xanthan gum, only needs can reach on a small quantity good suspending effect; Add an amount of disintegrating agent, can reach good dispersion, settling volume simultaneously than purpose up to specification; Adopt powder directly to fill or dry granulation prepares dried suspendible with granule or powder, principal agent stability is good; Do not contain solubilizing agent, antiseptic and defoamer in the prescription, Product Safety is higher.
Summary of the invention
The object of the present invention is to provide the cefprozil suspendible pharmaceutical composition of a kind of suspending is effective, dispersibility is excellent, preparation stability is good, safety is higher per os, stomach or intestinal canal administration.
First aspect of the present invention provides a kind of cefprozil suspendible pharmaceutical composition, it is characterized in that suspending agent is selected from xanthan gum.
The consumption of described cefprozil is acceptable treatment effective dose clinically, and general 13 years old or above Coming-of-Age Day taking dose are about 125mg～1000mg, and 12 years old or following child's day taking dose are about 7.5mg/kg～30mg/kg.Cefprozil content is by the preferred 125mg～500mg of anhydride in the unit dose package, the preferred 1000mg～5000mg of multiple-unit container.
Described xanthan gum is a kind of high-molecular weight polysaccharide colloid substance, is widely used as suspending agent and stabilizing agent in oral and topical pharmaceutical formulation.This product avirulence, can with most pharmaceutic adjuvant compatibilities, in the pH of broad and temperature range, has good stable and viscosity, but as a kind of anionic polyelectrolyte, common and cationic surfactant, antiseptic have incompatibility, produce precipitation, avoid and the sodium carboxymethyl cellulose compatibility.Xanthan gum is dissolved in cold water and hot water, and under 25 ℃, the range of viscosities of 1% (W/V) solution is generally at 1200～1600mPas.
The range of viscosities of 1% (W/V) solution of described xanthan gum is at 1200～2500mPas, preferred 1200～2000mPas, more preferably 1600～2000mPas.
The weight ratio of described cefprozil (by anhydride) and xanthan gum was at least 125: 1, preferably was at least 25: 1, more preferably was at least 12.5: 1, and most preferred range is 25: 1～5: 1.
Discover, in the single dose prescription, when selected viscosity of xanthan gums greater than 2000mPas, contain in the unit dose package of principal agent 125mg, the xanthan gum consumption promptly can produce good suspending effect less than 5mg, along with the viscosity of xanthan gum further increases (viscosity of existing xanthan gum 1% solution generally is no more than 2500mPas) and principal agent when pulverizing pretreatment, the consumption of the required xanthan gum of principal agent of same amount is minimum can be to 1mg.At this moment, also can not obtain the dry suspension of favorable dispersibility in the prescription with disintegrating agent.
When selected viscosity of xanthan gums was in 1600～2000mPas scope, the xanthan gum consumption was generally 5～20mg, and principal agent need not to pulverize, and can add an amount of disintegrating agent simultaneously, can obtain the dry suspension that suspending is effective, dispersibility is good.
When selected viscosity of xanthan gums was in 1200～1600mPas scope, generally more than 10mg, preferred 15～35mg should add an amount of disintegrating agent in the prescription to the xanthan gum consumption.
In the multiple dose prescription, drug content does not wait from 1g～5g, and the xanthan gum consumption is generally more than 10mg.
Second aspect of the present invention is further to comprise aluminium-magnesium silicate in the described cefprozil mixed suspension composition.
Described aluminium-magnesium silicate is considered to have the dual function of disintegrating agent and suspending agent in the prescription of suspensoid, after xanthan gum mixes, because synergism causes solution viscosity significantly to increase, thereby reduce the consumption of xanthan gum.The range of viscosities of different model aluminium-magnesium silicate does not wait to several thousand from hundreds of, the range of viscosities of existing product generally in 100～2500mPas scope (5% solution, W/V).Generally below 600mPas, secondly main performance disintegration in prescription usually is thickening power to low viscous aluminium-magnesium silicate viscosity; The high viscosity aluminium-magnesium silicate generally more than 800mPas, reaches as high as more than the 2000mPas, raises with viscosity, and the synergism with xanthan gum under the same amount strengthens, but consumption is few, a little less than the disintegration, looks the disintegrating agent that degree of scatter can add other kinds.Discover that the weight ratio of xanthan gum and aluminium-magnesium silicate should be controlled in 1: 1～1: 10 scope, preferably in 1: 2～1: 5 scope.In above-mentioned scope, the xanthan gum consumption in the single dose prescription generally can be controlled in the 10mg, and the general consumption of xanthan gum in the multiple dose prescription can not add or only add the disintegrating agent of a small amount of other kinds at 20～60mg in the prescription.Through verification experimental verification, use xanthan gum to compare with xanthan gum with single in the dried suspendible of cefprozil with the aluminium-magnesium silicate compatibility, show the obvious synergistic theomorphism.
Third aspect of the present invention is further to comprise an amount of disintegrating agent in the described cefprozil mixed suspension composition.
Described disintegrating agent can be selected one or more the mixing in the existing pharmaceutic adjuvant with disintegrating agent purposes, and preferred starch and derivant thereof are as pregelatinized Starch, modified starch, carboxymethylstach sodium etc.; Cellulose family and derivant thereof are as Powderd cellulose, microcrystalline Cellulose, micropowder silica gel microcrystalline Cellulose premix powder, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose etc.; Polyvinylpolypyrrolidone, more preferably carboxymethylstach sodium, cross-linking sodium carboxymethyl cellulose and polyvinylpolypyrrolidone.
Described disintegrating agent can guarantee to disperse fast after the granule made or powder are met water in prescription; because of the most water-fast speciality of disintegrating agent; consumption should be controlled in the OK range to guarantee that suspending agent can stablize the sedimentation of principal agent and insoluble substance simultaneously, makes it meet the requirement of settling volume ratio.Discover that the weight ratio of described disintegrating agent and xanthan gum should be controlled at 1: 1～15: 1, preferred 1: 1～5: 1, in this scope, those skilled in the art can draw the proportioning of suitable xanthan gum and disintegrating agent through an amount of test.
Preferably comprise in polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose or the carboxymethylstach sodium one or more mixing in the described cefprozil mixed suspension composition.
Discover that above-mentioned three kinds of disintegrating agents disintegrate effect under same amount is close, can the phase trans-substitution or be used in combination.Wherein, polyvinylpolypyrrolidone disintegration behind micronization dies down, and uses but can be used as suspension stabilizers, in order to reduce the rate of settling, in order to prolong the holding time of multiple dose suspension with no sedimentation state, consumption is generally 0.1%～10% of prescription total amount especially.
The 4th aspect of the present invention is further to comprise other pharmaceutic adjuvants that are used to prepare suspensoid in the described cefprozil mixed suspension composition, as diluent, correctives, strong agent, pH regulator agent and lubricant and/or other adjuvants smelt.
Preferred sugar of described diluent and sugar alcohol are as sucrose, mannitol, sorbitol, xylitol etc.;
Described correctives preferred sweeteners is as aspartame, acesulfame potassium, sucralose etc.;
Described pH regulator agent preferred amino acid and solid organic acid are as citric acid, glycine etc.;
The preferred silicon dioxide of described lubricant, Pulvis Talci, magnesium stearate.
Suspension is the physical instability system, and because of solid formation can tend to generate deposit all the time, ideal is no sedimentation state, but general difficult the realization, but should reduce the rate of settling at least and allow the easy redispersion of deposit.Therefore, delay the solid formation sedimentation velocity thereby add suspending agent, stabilizing agent etc. on the preparation usually with the viscosity that increases solution system, and realize above-mentioned purpose by the easy redispersion of deposit by adding flocculating agent and/or deflocculant.The present invention screens other adjuvants except that suspending agent, stabilizing agent and disintegrating agent in line with the principle of kind that reduces insoluble component and consumption as far as possible.Consider that principal agent meets water degrade tangible character and mouthfeel, the preferred nonhygroscopic sugar alcohols of diluent; Correctives and strong preferred water miscible sweeting agent of agent and the essence smelt; Flowability according to prescription can add proper amount of lubricating agent such as silicon dioxide; The pH regulator agent adds as required according to final suspension concentration.
Can there be the long period (under the room temperature condition, depositing more than 14 days) in the single dose or the multiple dose suspensoid that make by the present invention with the deposit-free state, add micronized polyvinylpolypyrrolidone after, the resting period can extend to more than 3 weeks.Good because of prolonging the deposit redispersibility that produces standing time, need not to add flocculating agent or deflocculant, simultaneously, suspension has good stability, and every index all meets the pharmacopeia requirement.
Further, described cefprozil suspendible pharmaceutical composition is characterized in that, based on the cefprozil of 100 weight portions by anhydride, it comprises:
100 parts of cefprozils;
0.008 part～20 parts of xanthan gum;
0～300 part of aluminium-magnesium silicate;
0～300 part of disintegrating agent;
0～5000 part of diluent;
0～50 part of correctives;
Rectify and smell 0～100 part of agent;
0～40 part of lubricant.
Further, described cefprozil suspendible pharmaceutical composition is characterized in that by weight, it comprises:
100 parts of cefprozils (by anhydride);
0.008 part～20 parts of xanthan gum;
0～300 part of aluminium-magnesium silicate;
0～150 part of polyvinylpolypyrrolidone;
0～5000 part of sugar alcohol;
0～50 part of aspartame;
0～100 part in essence;
0～40 part of silicon dioxide.
The 5th aspect of the present invention is that described cefprozil mixture adopts powder directly to fill or the mode of dry granulation prepares mix suspension grain or powder.
After described dry granulation technology is the adjuvant oven dry that water content is bigger at first will writing out a prescription; with residue supplementary material (wherein or comprise a part of lubricant) mixing in suitable mixing apparatus; in the dry granulation machine, be pressed into lamellar again and be broken into granule or powder; look the particle flow situation, add the moderate lubrication agent or directly be filled in single dose bag or the multi-dose vials by packer.Granule can be sieved the granule of collecting certain particle size range packs and makes mix suspension grain.
The advantage that the present invention gives prominence to is to adopt xanthan gum to do suspending agent, and consumption is few, and suspending is effective, adds an amount of aluminium-magnesium silicate and realizes can further reducing the suspending agent consumption with the synergism of xanthan gum; Adding the product that obtains after an amount of disintegrating agent on this basis can disperse fast, makes things convenient for patient's medication; Adopt powder directly to fill or dry granulation technology, strict control moisture has improved stability of formulation in preparation process; Do not contain solubilizing agent and antiseptic in the prescription, Product Safety is higher.
The specific embodiment
Further specify the present invention by the following examples, but do not limit summary of the invention.
Embodiment 1 adopts the xanthan gum of different viscosities to prepare the cefprozil dry suspension of different size
Detect according to the method under 2010 editions two pharmaceutic adjuvant viscosity of xanthan gums items of Chinese Pharmacopoeia, the viscosity of xanthan gum a, b, c is about 1385mPas, 1840mPas and 2230mPas.
1. the cefprozil (, pulverizing) that contains 125mg, 250mg, 500mg in the single dose prescription by anhydride
Prescription:
Technology:
Take by weighing an amount of cefprozil and be crushed to 75 μ m following (being equivalent to cross 200 eye mesh screens); after taking by weighing 20 times of amount supplementary material mixings by each prescription, be divided into two parts, a standby with pulverulence; another part made granule through the dry granulation machine, and it is standby to collect the following granule of 80 orders.
Detect index and method:
According in " Chinese drug inspection standard operation standard and drug inspection instrumentation rules " 2005 editions about the operating provision of settling volume ratio, take by weighing the settling volume ratio mensuration that the sample that is equivalent to 2.5 times of recipe quantities carried out 3 hours in 50mL water, write down the jitter time of sample simultaneously.
The result:
Settling volume ratio and jitter time result are as shown in the table:
The result shows, because of the dissolubility of pulverizing the back cefprozil increases, selects for use the high viscosity xanthan of minute quantity can realize good suspending effect, need not simultaneously with disintegrating agent, and particulate samples can disperse fast, and the powder jitter time is shorter than particulate samples.
2. the cefprozil (, not pulverizing) that contains 125mg, 250mg, 500mg in the single dose prescription by anhydride
Prescription:
Technology:
After taking by weighing 20 times of amount supplementary materials (raw material need not pulverize) mixing by prescription, make granule through the dry granulation machine, it is standby to collect the following granule of 80 orders.
Detect index and method: with 1.
The result:
Settling volume ratio and jitter time result are as shown in the table:
The result shows, crude drug under the pulverizing state, should not increase the consumption of xanthan gum in right amount, increases with the xanthan gum consumption, and jitter time prolongs.Adopt full-bodied xanthan gum still can reach quick dispersive purpose, if select the lower xanthan gum of viscosity for use based on cost consideration, prompting can add an amount of disintegrating agent.
3. the cefprozil anhydride (, not pulverizing) that contains 1.25g, 2.5g, 5g in the multiple dose prescription by anhydride
Prescription:
Technology:
After taking by weighing 5 times of amount supplementary materials (raw material need not pulverize) mixing by prescription, make granule through the dry granulation machine, it is standby to collect the following granule of 80 orders.
Detect index and method:
Take by weighing I～IX recipe quantity sample, add behind the water 50mL and measure the settling volume ratio, write down the jitter time of sample simultaneously with 1 method.
The result:
Settling volume ratio and jitter time result are as shown in the table:
The result shows that because of the xanthan gum consumption increases, the multiple dose granule obviously prolonged than the single dose Dispersion of Particles time, should add an amount of disintegrating agent in the prompting multiple dose prescription.
Embodiment 2 adopts the aluminium-magnesium silicate of different viscosities and the cefprozil dry suspension that the xanthan gum compatibility prepares different size
Adopting viscosity is the xanthan gum of 1840mPas, and aluminium-magnesium silicate a, b, the c that is respectively 245mPas, 1202mPas, 2317mPas with viscosity be compatibility by a certain percentage.
1. the cefprozil (, not pulverizing) that contains 125mg, 250mg, 500mg in the single dose prescription by anhydride
Prescription:
Technology:
Take by weighing the xanthan gum and the aluminium-magnesium silicate of 20 times of recipe quantities, earlier with behind the two mixing, mix with the residue supplementary material again, after the dry granulation machine is made granule, it is standby to collect the following granule of 80 orders.
Detect index and method:
With embodiment 1-1.
The result:
Annotate: a little visible particles of 1-; The 2-deposit-free
The result shows, can significantly reduce the consumption of xanthan gum after xanthan gum and the Magnesiumaluminumsilicate coupling, and drug content is high more in the single dose, and this synergism is obvious more.The effect of the more performance disintegrate of low viscosity aluminium-magnesium silicate, the high viscosity aluminium-magnesium silicate is the existing thickening power of multilist more, medium viscosity has more obvious dual function, and those skilled in the art can require the aluminium-magnesium silicate and the xanthan gum combination collocation of various model different viscosities are used according to reality.
2. the cefprozil (, not pulverizing) that contains 1.25g, 2.5g, 5g in the multiple dose prescription by anhydride
Prescription:
Technology:
Take by weighing the xanthan gum and the aluminium-magnesium silicate of 5 times of recipe quantities, earlier with behind the two mixing, mix with the residue supplementary material again, after the dry granulation machine is made granule, it is standby to collect the following granule of 80 orders.
Detect index and method:
With embodiment 1-3.
The result:
Annotate: a little visible particles of 1-; The 2-deposit-free
The result shows that the coupling of xanthan gum and aluminium-magnesium silicate has more advantage in the multiple dose system, but jitter time is slightly long than single dose, should add an amount of disintegrating agent and quicken dispersive process.
Embodiment 3 adds the cefprozil dry suspension of different types of disintegrating agent preparation list, multiple dose on embodiment 1 basis
Adopting viscosity is the xanthan gum of 1415mPas, with different types of disintegrating agent by a certain percentage compatibility carry out the disintegrating agent screening test.
Single dose contains the dried suspendible prescription of cefprozil of principal agent 125mg:
Multiple dose contains the dried suspendible prescription of cefprozil of principal agent 5g:
The result:
The settling volume of measuring according to preceding method is more qualified than all, leaves standstill after 3 hours and does not see obvious precipitum.
The result shows that disintegrating agent should select polyvinylpolypyrrolidone, carboxymethylstach sodium and cross-linking sodium carboxymethyl cellulose.
Embodiment 4 adds different types of diluent and carries out the mouthfeel contrast on the basis of embodiment 3
Adopting viscosity is the xanthan gum of 2230mPas, with different types of diluent by a certain percentage compatibility prepare the cefprozil dry suspension that single dose contains principal agent 125mg, carry out the mouthfeel contrast test.
Prescription:
Find that through contrast cane-sugar taste is poor than sugar alcohol, and salty and bitter sense is arranged, consider that comprising youngster among the suitable crowd of suspensoid weighs, preferred sugar alcohols is made diluent in the prescription.
The comparative study of embodiment 5 test preparations and reference preparation
The test preparation explanation:
Test preparation 1: containing the principal agent amount is the single dose dry suspension of 125mg (by anhydride), and suspending agent is an xanthan gum
Test preparation 2: containing the principal agent amount is the single dose dry suspension of 125mg (by anhydride), and suspending agent is an xanthan gum, and stabilizing agent is an aluminium-magnesium silicate
Test preparation 3: containing the principal agent amount is the single dose dry suspension of 125mg (by anhydride), and suspending agent is a sodium carboxymethyl cellulose
Test preparation 4: containing the principal agent amount is the multiple dose dry suspension of 1.25g (by anhydride), and suspending agent is an xanthan gum
Test preparation 5: containing the principal agent amount is the multiple dose dry suspension of 1.25g (by anhydride), and suspending agent is an xanthan gum, and stabilizing agent is the micronization polyvinylpolypyrrolidone
The reference preparation explanation:
Reference preparation 1: the single dose dry suspension of commercially available 125mg specification (by anhydride)
Reference preparation 2: the multiple dose dry suspension of commercially available 125mg/5ml specification (by anhydride)
Test preparation 1～5 prescription is as shown in the table:
Prescription:
Technology:
1) earlier an amount of xylitol is dried to constant weight, the cefprozil of test preparation 3 is through pulverization process, and all the other raw materials need not to pulverize, and take by weighing the supplementary material of 500 times of recipe quantities again, the mode mixing that progressively increases by equivalent;
2) adjust suitable dry granulation machine pressure, feeding, tabletting and granulation frequency after, powder is made granule;
3) by packer granule is respectively charged in aluminium foil bag and the medicinal bottle.
The comparative study index:
1. settling volume ratio
Annotate: this experiment is carried out under normal temperature condition, and "-" be not for investigating.
The result shows, with reference preparation 1,2 and test preparation 3 contrasts, test preparation 1,2,4,5 adopt xanthan gum to do suspending agent or add aluminium-magnesium silicate, micronization polyvinylpolypyrrolidone used as stabilizers shows more significant suspending effect, the suspension system is more stable.
2. jitter time
The result shows, test preparation 1,2,4,5 is realizing that sample meets water and be separated into fast and be better than reference preparation 1,2 and test preparation 3 aspect the stable suspension.
3. suspension stability test
Method: after getting the test preparation 1,2 of unit dose package and reference preparation 4 and adding suitable quantity of water and shake up, shake up resampling earlier respectively at the 0th, 2,4,6,8 hour and investigate pH value, content and related substance, detection method is carried out according to the detection method under cefprozil in 2010 editions Chinese Pharmacopoeias and the cefprozil dry suspension standard corresponding entry, the results are shown in following table.
The result shows that single dose test preparation principal agent stability in 8h obviously is better than reference preparation.
Method: after the test preparation 4 of getting multiple-unit container and reference preparation 5 add suitable quantity of water and shake up, putting into 4 ℃ of refrigerator cold-storages preserves, shake up resampling earlier respectively at the 0th, 3,7,11,14 day and investigate pH value, content and related substance, detection method is carried out according to the detection method under cefprozil in 2010 editions Chinese Pharmacopoeias and the cefprozil dry suspension standard corresponding entry, the results are shown in following table.
The result shows, the multiple dose test preparation is under 4 ℃ of refrigerator cold-storage preservation conditions, and the stability of principal agent is better than reference preparation in 14 days.
4. influence factor's test
Get an amount of sample of test preparation 1 and reference preparation 1, placed 10 days under high temperature (40 ℃, 60 ℃), high humidity (RH75%, RH92.5%) and illumination (4500lx) condition respectively, in the 10th day take a sample to check acidity, content and related substance, the result was as follows:
The result shows that test preparation and reference preparation unification show the temperature and humidity sensitivity, and related substance changes more obvious, but the test preparation amplitude of variation is significantly less than reference preparation, and from the result, test preparation is better than reference preparation.
5. accelerated stability test result
It is an amount of to get test preparation 1 sample, 30 ± 2 ℃ of temperature, carry out accelerated stability test under 65 ± 5% conditions, took a sample in 0 month, 1 month, 2 months, 3 months, 6 months and carry out the mensuration of character, settling volume ratio, jitter time, acidity, content and related substance, the result is as follows:
Comprehensive above-mentioned result of the test can draw, and adopts xanthan gum to do suspending agent in the cefprozil dry suspension, the stability that improves suspension, keep principal agent stability, accelerate to compare existing product aspect the jitter time and have a clear superiority in.
Claims (10)
1. a cefprozil suspendible pharmaceutical composition is characterized in that suspending agent is selected from xanthan gum.
2. cefprozil suspendible pharmaceutical composition according to claim 1 is characterized in that being at least 125: 1 by the cefprozil of anhydride and the weight ratio of xanthan gum.
3. cefprozil suspendible pharmaceutical composition according to claim 2 is characterized in that by the cefprozil of anhydride and the weight ratio of xanthan gum be 25: 1～5: 1.
4. cefprozil suspendible pharmaceutical composition according to claim 1 is characterized in that also comprising in the said composition aluminium-magnesium silicate.
5. cefprozil suspendible pharmaceutical composition according to claim 4, the weight ratio that it is characterized in that xanthan gum and aluminium-magnesium silicate is 1: 1～1: 10.
6. according to each described cefprozil suspendible pharmaceutical composition in the claim 1～5, it is characterized in that also comprising in the said composition disintegrating agent, the weight ratio of itself and xanthan gum is 1: 1～15: 1.
7. cefprozil suspendible pharmaceutical composition according to claim 6 is characterized in that disintegrating agent is selected from one or more mixing in polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose and the carboxymethylstach sodium.
8. according to each described cefprozil suspendible pharmaceutical composition in the claim 1～7; it is characterized in that also comprising in the said composition diluent, correctives, rectify and smell agent, lubricant and/or other adjuvants; with described suspendible pharmaceutical composition and diluent, correctives, rectify and smell agent, lubricant and/or other adjuvants and mixes, then as required through dry granulation or powder directly the mode of filling make dry suspension.
9. cefprozil suspendible pharmaceutical composition according to claim 8, it is characterized in that, cefprozil based on 100 weight portions, the amount of xanthan gum is 0.008～20 weight portion, and the amount of aluminium-magnesium silicate is 0～300 weight portion, and the amount of disintegrating agent is 0～150 weight portion, the amount of diluent is 0～5000 weight portion, the amount of correctives is 0～100 weight portion, and rectifying the amount of smelling agent is 0～50 weight portion, and the amount of lubricant is 0～40 weight portion.
10. cefprozil suspendible pharmaceutical composition according to claim 9 is characterized in that by weight, it comprises:
100 parts of cefprozils (by anhydride);
0.008 part～20 parts of xanthan gum;
0～300 part of aluminium-magnesium silicate;
0～300 part of polyvinylpolypyrrolidone;
0～5000 part of sugar alcohol;
0～50 part of aspartame;
0～100 part in essence;
0～40 part of silicon dioxide.
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| CN2010106034906A CN102144975B (en) | 2010-12-24 | 2010-12-24 | Cefprozil suspension pharmaceutical composition |
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| CN103524533A (en) * | 2013-10-10 | 2014-01-22 | 珠海金鸿药业股份有限公司 | Cefprozil compound, and dispersible tablets, dry suspension and preparation method thereof |
| CN104688743A (en) * | 2015-03-30 | 2015-06-10 | 华北制药河北华民药业有限责任公司 | Cefprozil suspension and preparation method thereof |
| CN105902501A (en) * | 2016-05-11 | 2016-08-31 | 四川援健药业有限公司 | Cefprozil dry mixed suspension and preparation method as well as application thereof |
| CN111494387A (en) * | 2012-12-07 | 2020-08-07 | 法国诗华动物保健公司 | Triazine formulations with a second active ingredient and a surfactant |
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| CN115444824A (en) * | 2022-10-17 | 2022-12-09 | 深圳立健药业有限公司 | Cefprozil composition and application thereof |
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| CN101011360A (en) * | 2007-02-05 | 2007-08-08 | 深圳致君制药有限公司 | Recipe composition of dry turbid agent and its preparation process |
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| CN111494387A (en) * | 2012-12-07 | 2020-08-07 | 法国诗华动物保健公司 | Triazine formulations with a second active ingredient and a surfactant |
| CN103524533A (en) * | 2013-10-10 | 2014-01-22 | 珠海金鸿药业股份有限公司 | Cefprozil compound, and dispersible tablets, dry suspension and preparation method thereof |
| CN103524533B (en) * | 2013-10-10 | 2016-01-27 | 珠海金鸿药业股份有限公司 | A kind of cefprozil compound, its dispersible tablet, dry suspensoid and preparation method |
| CN104688743A (en) * | 2015-03-30 | 2015-06-10 | 华北制药河北华民药业有限责任公司 | Cefprozil suspension and preparation method thereof |
| CN105902501A (en) * | 2016-05-11 | 2016-08-31 | 四川援健药业有限公司 | Cefprozil dry mixed suspension and preparation method as well as application thereof |
| CN105902501B (en) * | 2016-05-11 | 2019-02-05 | 好医生药业集团有限公司 | A kind of Cefprozil dry suspension and its preparation method and application |
| CN113143980A (en) * | 2021-01-23 | 2021-07-23 | 吉林大学 | Veterinary selaginella suspension type granule prescription and preparation process |
| CN114432241A (en) * | 2021-12-21 | 2022-05-06 | 上海奥全生物医药科技有限公司 | Suspending aid composition capable of being rapidly dispersed, preparation method and application thereof |
| US11712417B2 (en) | 2021-12-21 | 2023-08-01 | Auson Pharmaceuticals Inc. | Fast dispersing suspending composition, method of preparation and application thereof |
| CN115444824A (en) * | 2022-10-17 | 2022-12-09 | 深圳立健药业有限公司 | Cefprozil composition and application thereof |
| CN115737554A (en) * | 2022-11-28 | 2023-03-07 | 宜昌人福药业有限责任公司 | Preparation method of clobazam oral suspension |
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