A kind of stable content, dissolve antibiotic composite fast
Technical field
The present invention relates to a kind of antibiotic composite, more particularly, the present invention relates to a kind of stable content, dissolves antibiotic composite fast.Simultaneously, the invention still further relates to the preparation method of described antibiotic composite.
Background technology
Cefoperazone sodium (cefoperazone) and belong to third generation cephalosporin with the compound formulation of beta-lactamase inhibitor, has a broad antifungal spectrum, effect is strong, and the false monospore of Aerugo is had stronger antibacterial action, concentration height in bile.Clinical practice for many years shows that its clinical efficacy is obvious, and adverse reaction rate is low, and anti-enzyme, wide spectrum are cheap, thereby is subjected to the approval of vast hospitalized patients deeply and is widely used, and is third generation cephalosporin class antibiotic the most commonly used at present.But in the process of clinical practice, it is found that the compound formulation that contains cefoperazone sodium and beta-lactamase inhibitor is dissolved in the transfusion to find muddyly that through regular meeting the content of cefoperazone sodium descends, therefore normal under a cloud is quality problems and stop using.Especially in winter, the spring of the northern area of China, when temperature is starkly lower than 10 ℃, add in the transfusion, more the reversibility that cefoperazone sodium takes place through regular meeting is separated out and is produced insoluble or the muddy phenomenon of milky so that have a strong impact on clinical use.
The stability of the compound formulation of cefoperazone sodium and beta-lactamase inhibitor content in solution and pH value height are in close relations.The pH value of the compound formulation of cefoperazone sodium and beta-lactamase inhibitor is the most stable at 4.5~6.5 o'clock, and when solution pH value<4.5, the reversibility that has a part cefoperazone sodium is separated out and is produced the outward appearance muddiness, and the cefoperazone sodium content descends rapidly in the solution, does not meet pharmacopeia regulation and affects the treatment.And when pH value>6.5, very easily decompose, can destroy the lactam nucleus of cefoperazone sodium, the cefoperazone sodium content is descended and produce by-product, cause the generation of untoward reaction.
The compound formulation of cefoperazone sodium and beta-lactamase inhibitor must be dissolved in it in diluent and can use when clinical use, it is the most frequently used clinically at present that to make dissolved diluent be 5-10% glucose injection and 5% glucose saline, its pH value is about 3.8, with this infuse prepare the compound formulation of cefoperazone sodium and beta-lactamase inhibitor after, this moment, the pH value of transfusion was 4.0, pH value does not meet 4.5~6.5 the scope that makes the cefoperazone sodium content constant, cefoperazone sodium will reversibility be separated out and is produced insoluble or the muddy phenomenon of milky, the cefoperazone sodium content descends in the solution, affect the treatment, and in a single day the cefoperazone sodium crystal of separating out flows in patient's the body and will cause great malpractice.This brings very big inconvenience and dangerous to clinical application, and can delay patient's administration time, causes the nurse to resist emotion to using this medicine to produce, and influences clinical use.
Bibliographical information is arranged: when this problem appears in clinical use, add sodium bicarbonate solution,, can reach the liquid appearance clarification as cosolvent.But the problem that occurs is, one, because of not having checkout equipment and standardization metering outfit in the scene, and sodium bicarbonate solution does not have clear and definite regulation during with which kind of concentration, and the amount of adding sodium bicarbonate solution does not have quantitative control, so can't the accuracy controlling pH value; And for making the cefoperazone sodium stable content very accurate to the requirement of solution pH value, when solution pH value<4.5, the reversibility that has a small amount of cefoperazone sodium is separated out and is produced the outward appearance muddiness, the cefoperazone sodium content descends in the solution, do not meet the pharmacopeia regulation, affect the treatment, but 5% sodium bicarbonate solution addition surpasses a few tenths of milliliter, then will make pH value>6.5, and cefoperazone sodium very easily decomposes under this pH, destroy the lactam nucleus of cefoperazone sodium, made the cefoperazone sodium content descend and the generation by-product, caused the generation of untoward reaction.Two, hospital clinical section office do not have aseptic environments to come for on-the-spot preparation sodium bicarbonate sterile solution.Three, clinical nurse does not have operant skill pharmaceutically mostly.This scheme has brought very large trouble for the in good time preparation of medicine, has also increased the chance of drug contamination simultaneously, has great risk, and malpractice very easily takes place.
Application number is that 200610034315.3 Chinese patent literature discloses a kind of stable cefoperazone sulbactam medicine compound preparation, by cefoperazone acid is that raw material is formed with sulbactam acid and sodium bicarbonate, proposed to solve the not enough problem of cefoperazone acid dissolubility in solution, but there is following tangible weak point in this invention: 1, raw material does not meet pharmacopeia and ejection preparation requirement, cefoperazone acid contains a large amount of harmful impurity, can't reach the content of Chinese Pharmacopoeia standard code without purifying, requirement such as clarity and pH value, not directly as medicinal raw material, otherwise its contained impurity can produce huge injury to human body; Lack the scientific theory foundation when 2, prescription designs.Cefoperazone acid is water insoluble, can not be as the medicinal raw material of injection, must be water-soluble as the raw material of injection, and must make cefoperazone sodium.Cefoperazone acid and cefoperazone sodium are two kinds of different materials, though production cefoperazone sodium, obtain with alkali generation neutralization reaction by cefoperazone acid, but excuse spore piperazine keto acid molecular weight is bigger, from cephalo piperazine keto acid is the process of the medicinal cefoperazone sodium of feedstock production, cefoperazone acid and alkali compounds as the reaction rate of sodium hydrogen carbonate powder and unlike the acid-base neutralization reaction fast like that, be the course of reaction of a complexity, it is very big influenced by temperature, pH value.And the destroyed and by-product of new generation of the lactam nucleus of the cefoperazone sodium that impurity that brings in the acid of raw material cefoperazone and violent aborning chemical reaction cause also remains in the lump and does not remove in the medicine, can produce huge murder by poisoning to human body like this; 3, so there is obvious labile state on the contrary in prescription, can react between each prescription.Cefoperazone acid is unstable on the contrary under the alkali condition of sodium bicarbonate on the one hand, and pH value is too high, and cefoperazone sodium very easily decomposed in>6.5 o'clock, can destroy the lactam nucleus of cefoperazone acid, produced by-product, caused the generation of untoward reaction; In addition, the heat stability of sodium hydrogen carbonate powder itself is very poor, can decompose.When mixing chemical reaction can take place between the raw material on the other hand.Because cefoperazone acid is tart, sodium bicarbonate is an alkalescence, can react after the mixing, produces heat and with CO
2Produce, medicine not only decomposes is rotten and because of there being gas to produce, pressure is excessive in the bottle, is storing, and transports and use meeting generation bottle explosion.Chemical reaction is taking place in one of the very difficult imagination, and character constantly changes, unsettled medicine can be used on the human body.4, sodium carbonate or the sodium bicarbonate as cosolvent is the weak acid strong alkali compound, when being dissolved in acid solution, can reacting and emit CO
2And clinical transfusion commonly used is as 5% Glucose Liquid, 10% glucose injection and the equal slant acidity of 5% glucose saline, thus with sodium carbonate or sodium bicarbonate as cosolvent, when dilution, can constantly produce CO in the process
2Gas may pollute medicinal liquid if bleeding is improper, CO in the infusion process
2Bubble enters in the blood samples of patients may form gas embolism, as obstruction appear at the heart, the main blood vessel of brain can cause very big danger to the patient.
The Chinese patent literature of application number 200610074928.X discloses a kind of preparation method of soluble compound medicinal preparation of antibacterial drugs, be with component A: acceptable pharmaceutical salts or hydrate on its physiology of furbenicillin, with B component: the salt of a kind of pharmaceutically acceptable water-soluble alkali or alkaline-earth metal, organic base, organic acid or salt one or more, make the solvent of aseptic dissolved constituent A, two bottles are placed in the packing box, are combined into the combination type injection.The pharmaceutical composition that will contain beta-lactamase inhibitor and cefoperazone sodium as the method with reference to this patent is made the A bottle, the salt of water-soluble alkali or alkaline-earth metal is made the B bottle, two bottles are placed in the packing box, be combined into the combination type injection, but still following deficiency is arranged: 1, stable at 4.5~6.5 o'clock because of the pH value of this pharmaceutical composition, narrow range, as long as the alkali of trace just can make the pH value of solution greater than 6.5, can destroy the lactam nucleus of cefoperazone acid, produce by-product, cause the generation of untoward reaction.Therefore consumption that must strict control alkali, and trace (several ten minutes several milligrams) like this are difficult to produce independent one bottle under present working condition.2, two bottles of combinations not only increase packing cost but also the clinical very trouble that uses, and the puncture back and forth of syringe needle has also increased the chance of medicine microbiological contamination.In the liquid feeding course of dissolution, cosolvent sodium carbonate or sodium bicarbonate commonly used can produce gas, and pressure of the inside of a bottle is increased when 3, making up a prescription.Because too high pressure of the inside of a bottle causes in taking out the medicine process easily the needle tubing piston to be ejected, or has liquid to overflow from breather in transfusion in early days, cause underdosage or drug contamination.
Therefore, when use contains the pharmaceutical composition of beta-lactamase inhibitor and cefoperazone sodium, to bring great convenience to clinical application if can solve the problem that contains beta-lactamase inhibitor and cefoperazone sodium pharmaceutical composition dissolubility, will alleviate nurse's workload greatly.If being arranged, method can guarantee the accurate adjusting to liquid pH value such as sodium bicarbonate, make it to be no more than pH value and be 6.5 and destroy the lactam nucleus of cefoperazone sodium, thereby keep the cefoperazone sodium stable content, the pharmaceutical composition that just more helps containing beta-lactamase inhibitor and cefoperazone sodium plays consistently its antibacterial action.But these perplex clinical use as the frequent de-stabilising effect clinical efficacy of cefoperazone sodium content, dissolubility is too low, the problem that pH value can't accurately be controlled under solid state is unresolved so far.
Summary of the invention
The object of the invention provides a kind of stable content and dissolves pharmaceutical composition fast, to solve the prior art above shortcomings.
Another purpose of the present invention provides a kind of preparation method of above-mentioned composition.
Stable content of the present invention and dissolve antibiotic composite fast, it is the preparation of being made by cefoperazone sodium, beta-lactamase inhibitor and pH value regulator, the weight proportion of each component is 1~100: 1: 0.001~1.
In above-mentioned composition, the weight proportion of each component is preferably 1~16: 1: 0.01~0.8
In above-mentioned composition, beta-lactamase inhibitor can be selected from one or more in the alkali metal salt of acid of clavulanic acid, sulbactam or his Batan acid.
In above-mentioned composition, the regulator of preferred pH value is selected from sodium hydrate aqueous solution, one or more in aqueous sodium carbonate, sodium bicarbonate aqueous solution and the arginine aqueous solution.
The prepared preparation of compositions of the present invention is preferably lyophilized preparation.
The preparation method of antibiotic composite of the present invention, comprise following steps: with cefoperazone sodium, beta-lactamase inhibitor and freeze drying protectant, add in the water for injection, stir and make it dissolving, control the pH value of solution 3~9 in titrating mode with the pH value regulator; Aseptic filtration, embedding through pre-freeze, decompression, distillation, drying, tamponade, is rolled lid in freeze dryer, and wherein pH value is preferably 4.5~6.5.
Preferred freeze drying protectant is selected from mannitol, glycine, lactose, gelatin hydrolysate, sorbitol, inositol, glucosan, sucrose, polyvinylpyrrolidone, glutamic acid, aspartic acid, Fructus Mali pumilae propylhomoserin, lactic acid, cottonseed sugar, trehalose, DL-threonine, xylitol, one or more in albumin, drum property albumen, peptone, arginine, histidine, soluble starch, dextrin, gravy, pectin, arabic gum, hydroxy methocel (CMC), algae, skim milk, serum, ascorbic acid, cysteine, azanol and the amido source.
It is raw material that the present invention adopts the stable cefoperazone sodium and the beta-lactamase inhibitor salt that meet the Chinese Pharmacopoeia standard, cefoperazone sodium and beta-lactamase inhibitor salt are fully dissolved, after uniformity ground distributes, finish with gas release in the pH value regulator adjust pH process, chemical reaction can not take place after the mixing in each component chemical stable in properties, and no gas produces, resulting good product quality, safety and good stability.
Specifically, in preparation method of the present invention, with cefoperazone sodium and beta-lactamase inhibitor with the water for injection dissolving after, use the pH value regulator, can accurately be transferred to 6.5 to pH value with accurate titrating method, reach the upper limit of cefoperazone sodium pH value (4.5~6.5) stability range, compound formulation with cefoperazone sodium and beta-lactamase inhibitor salt adds in tart 5-10% glucose injection and the transfusion of 5% glucose saline like this, the pH value of institute's obtain solution is 5.9, reach cefoperazone sodium pH value (4.5~6.5) stability range, the cefoperazone sodium stable content, the solution clarification.By to placing the solution of 24h, measure its pH value, reach pH value (4.5~6.5) stability range, measure stable content and do not reduce.
The present invention has adopted cefoperazone sodium and beta-lactamase inhibitor is fully dissolved, after reaching the distribution of uniformity ground, can accurately bring up to 6.5 to pH value with the pH value regulator with accurate titrating method, reach the upper limit of cefoperazone sodium pH value (4.5~6.5) stability range.Each component that the invention solves original invention is mixed inhomogeneous when pulverulence, and because of cefoperazone stable sodium pH value (4.5~6.5) narrow range, only need the alkali of trace to get final product, under solid state, can't accurately control and the difficult pH of adjustment, easily make pH value greater than 6.5, can destroy the lactam nucleus of cefoperazone acid.
In the present invention, adopt sodium hydroxide, sodium carbonate, sodium bicarbonate and arginine serve as the pH value regulator, and they are different with the raw material alkali that chemical reaction is served as in existing invention.As the pH regulator agent, solved that there is the easily excessive problem of the bad control of addition in sodium bicarbonate under the solid state with the aseptic aqueous solution of sodium hydroxide, sodium carbonate, sodium bicarbonate or arginic preferred 1% concentration.Make cefoperazone sodium stable p H-number scope (4.5~6.5) very narrow, each component is fully dissolved, uniformity ground distributes, and the concentration of pH value regulator must be very low, accurately the control pH value.
The present invention has adopted freeze dried preparation method, and cefoperazone sodium stable content, liquid pH value are regulated accurately the pharmaceutical composition aqueous solution under suitable condition, places it in lyophilizing in the freeze dryer, makes dried frozen aquatic products.This preparation method can make pharmaceutical composition of the present invention can make dried frozen aquatic products easily, easily for clinical use, brings into play huge economic benefit and social benefit.Adopt freeze dried preparation method of the present invention conveniently to regulate pH value, make stable liquid condition change into stable solid state.Mix under solid state with each component that original invention is adopted on minute assembling production lines, not only cause the uniformity may be bad and pH value can't accurately adjust and compare, the freeze dried preparation method of the present invention has major transformation, does not see document announcement and launch as yet.
The present invention only needs once with each components dissolved, after forming stable solution, fill lyophilizing in an antibiotic bottle, make product, with application number be that the Chinese patent literature disclosed " a kind of preparation method of soluble compound medicinal preparation of antibacterial drugs; make A bottle and B bottle; two bottles are placed in the packing box; be combined into the combination type injection " of 200610074928.X is compared, production cost and packing cost had both been reduced, avoided the chance of the medicine microbiological contamination that increases owing to puncturing back and forth of syringe needle again, convenient clinical use.
The specific embodiment
Following examples are used to illustrate the present invention, but are not used for limiting the scope of the invention.
Embodiment 1
With cefoperazone sodium 100g, sulbactam sodium 100g and mannitol 50g, add water for injection to 200ml, stir and make it dissolving, measure pH value, regulating pH value with the sodium hydrate aqueous solution of 1% concentration with titrating method is 6.5.Stirring makes fully evenly, aseptic filtration, and embedding, every bottle of 2ml in the freeze dryer lyophilizing, through pre-freeze, decompression, distillation, drying, tamponade, rolls lid, promptly gets 100 bottles of the lyophilized formulations of pharmaceutical composition of the present invention.
Embodiment 2
With cefoperazone sodium 100g, sodium-tazobactam 100g and mannitol 50g, add water for injection to 200ml, stir and make it dissolving, measure pH value, regulating pH value with the aqueous sodium carbonate of 1% concentration with titrating method is 6.4.Stirring makes dissolving, aseptic filtration, and embedding, every bottle of 2ml in the freeze dryer lyophilizing, through pre-freeze, decompression, distillation, drying, tamponade, rolls lid, promptly gets 100 bottles of the lyophilized formulations of pharmaceutical composition of the present invention.
Embodiment 3
With cefoperazone sodium 100g, sulbactam sodium 50g and sorbitol 30g, add water for injection to 200ml, stir and make it dissolving, measure pH value, regulating pH value with the sodium bicarbonate aqueous solution of 1% concentration with titrating method is 6.3.Stirring makes dissolving, aseptic filtration, and embedding, every bottle of 2ml in the freeze dryer lyophilizing, through pre-freeze, decompression, distillation, drying, tamponade, rolls lid, promptly gets 100 bottles of the lyophilized formulations of pharmaceutical composition of the present invention.
Embodiment 4
With cefoperazone sodium 100g, sodium-tazobactam 50g and sorbitol 30g, add water for injection to 200ml, stir and make it dissolving, measure pH value, be 6.2 with the aqueous solution of the sodium hydroxide of 1% concentration with titrating method adjusting pH value.Stirring makes dissolving, aseptic filtration, and embedding, every bottle of 2ml in the freeze dryer lyophilizing, through pre-freeze, decompression, distillation, drying, tamponade, rolls lid, promptly gets 100 bottles of the lyophilized formulations of pharmaceutical composition of the present invention.
Embodiment 5
With cefoperazone sodium 100g, sulbactam sodium 25g and glycine 30g, add water for injection to 200ml, stir and make it dissolving, measure pH value, be 6.0 with the aqueous solution of the sodium bicarbonate of 1% concentration with titrating method adjusting pH value.Stirring makes dissolving, aseptic filtration, and embedding, every bottle of 2ml in the freeze dryer lyophilizing, through pre-freeze, decompression, distillation, drying, tamponade, rolls lid, promptly gets 100 bottles of the lyophilized formulations of pharmaceutical composition of the present invention.
Embodiment 6
With cefoperazone sodium 100g, sodium-tazobactam 25g, glycine 30g and sorbitol 20g, add water for injection to 200ml, stir and make it dissolving, measure pH value, regulating pH value with the sodium hydrate aqueous solution of 1% concentration with titrating method is 5.9.Stirring makes dissolving, aseptic filtration, and embedding, every bottle of 2ml in the freeze dryer lyophilizing, through pre-freeze, decompression, distillation, drying, tamponade, rolls lid, promptly gets 100 bottles of the lyophilized formulations of pharmaceutical composition of the present invention.
Embodiment 7
With cefoperazone sodium 100g, sulbactam sodium 12.5g, mannitol 30g and sorbitol 30g, add water for injection to 200ml, stir and make it dissolving, measure pH value, be 5.8 with the smart sodium chlorate aqueous solution of 1% concentration with titrating method adjusting pH value.Stirring makes dissolving, aseptic filtration, and embedding, every bottle of 2ml in the freeze dryer lyophilizing, through pre-freeze, decompression, distillation, drying, tamponade, rolls lid, promptly gets 100 bottles of the lyophilized formulations of pharmaceutical composition of the present invention.
Embodiment 8
With cefoperazone sodium 100g, sodium-tazobactam 12.5g, mannitol 30g and glycine 30g, add water for injection to 200ml, stir and make it dissolving, measure pH value, regulating pH value with the aqueous sodium carbonate of 1% concentration with titrating method is 5.7.Stirring makes dissolving, aseptic filtration, and embedding, every bottle of 2ml in the freeze dryer lyophilizing, through pre-freeze, decompression, distillation, drying, tamponade, rolls lid, promptly gets 100 bottles of the lyophilized formulations of pharmaceutical composition of the present invention.
Embodiment 9
With cefoperazone sodium 100g, clavulanate potassium 100g, mannitol 30g and glycine 30g sorbitol 20g, add water for injection to 200ml, stir and make it dissolving, measure pH value, regulating pH value with the Arginine sodium aqueous solution of 1% concentration with titrating method is 6.5.Stirring makes dissolving, aseptic filtration, and embedding, every bottle of 2ml in the freeze dryer lyophilizing, through pre-freeze, decompression, distillation, drying, tamponade, rolls lid, promptly gets 100 bottles of the lyophilized formulations of pharmaceutical composition of the present invention.
Embodiment 10
With cefoperazone sodium 100g, clavulanate potassium 50g, sorbitol 20g, mannitol 30g, glycine 30g and inositol 10g, add water for injection to 200ml, stirring makes it dissolving, measures pH value, and regulating pH value with the sodium bicarbonate aqueous solution of 1% concentration with titrating method is 6.4.Stirring makes dissolving, aseptic filtration, and embedding, every bottle of 2ml in the freeze dryer lyophilizing, through pre-freeze, decompression, distillation, drying, tamponade, rolls lid, promptly gets 100 bottles of the lyophilized formulations of pharmaceutical composition of the present invention.
Experimental example 1
Pharmaceutical composition of the present invention is dissolved in 10% or 5% glucose injection, 5% Dextrose and Sodium Chloride Inj., behind the placement 24h, measures content, pH value and the dissolubility of cefoperazone sodium, result of the test is as shown in table 1:
Table 1
Table 1 result is as seen: pharmaceutical composition of the present invention is dissolved in 10% or 5% glucose injection, 5% Dextrose and Sodium Chloride Inj. of conventional slant acidity, place 24h after, it is constant and dissolubility good to survey stable content, the pH value of cefoperazone sodium.
Experimental example 2
With pharmaceutical composition lyophilized formulations of the present invention, placing under 40 ℃, relative humidity 75% condition the accelerated test result as shown in table 2:
Table 2
|
Standard |
0 month |
January |
February |
March |
June |
PH value |
4.5-6.5 |
6.5 |
6.5 |
6.5 |
6.4 |
6.4 |
The solution clarity |
No. 1 turbidity standard |
Clarification |
Clarification |
Clarification |
Clarification |
Clarification |
Solution colour |
Yellow No. 5 standard color solutions |
Yellow No. 2 |
Yellow No. 2 |
Yellow No. 2 |
Yellow No. 2 |
Yellow No. 2 |
The cefoperazone polymer |
Answer 1.0 |
0.2% |
0.2% |
0.2% |
0.2% |
0.2% |
The cefoperazone sodium content |
Labelled amount 90%-110% |
98% |
98% |
98% |
97.9% |
97.8% |
The Tazobactam Sodium sodium content |
Labelled amount 90%-110% |
100.6% |
100.6% |
100.6% |
100.5% |
100.5% |
Experimental example 3
With pharmaceutical composition lyophilized formulations of the present invention, place under 25 ℃, relative humidity 40% condition and do long-term stable experiment, the result is as shown in table 3:
Table 3
|
Standard |
0 month |
March |
June |
JIUYUE |
December |
18 months |
24 months |
PH value |
4.5-6.5 |
6.5 |
6.5 |
6.5 |
6.5 |
6.5 |
6.4 |
6.4 |
The solution clarity |
No. 1 turbidity standard |
Clarification |
Clarification |
Clarification |
Clarification |
Clarification |
Clarification |
Clarification |
Solution colour |
Yellow No. 5 standard color solutions |
Yellow No. 2 |
Yellow No. 2 |
Yellow No. 2 |
Yellow No. 2 |
Yellow No. 2 |
Yellow No. 2 |
Yellow No. 2 |
The cefoperazone polymer |
Answer 1.0 |
0.2% |
0.2% |
0.2% |
0.2% |
0.2% |
0.2% |
0.2% |
The cefoperazone sodium content |
Labelled amount 90%-110% |
98% |
98% |
98% |
98% |
98% |
97.9% |
97.9% |
The Tazobactam Sodium sodium content |
Labelled amount 90%-110% |
100.6% |
100.6% |
100.6% |
100.6% |
100.5% |
100.5% |
100.5% |
Table 2 and 3 results are as seen: pharmaceutical composition lyophilized formulations of the present invention in accelerated stability test and long-term stable experiment, constant product quality, the cefoperazone sodium stable content, pH value is constant, no cefoperazone sodium catabolite produces.
This shows, the invention solves former " in a single day cefoperazone sodium and beta-lactamase inhibitor add that the pH value of solution is 4.0 behind 5-10% glucose injection and 5% glucose saline; be lower than cefoperazone sodium pH value (4.5~6.5) stability range; thus cause cefoperazone sodium to separate out crystallization at solution, content descends " problem.
More than further illustrate content of the present invention by embodiment and experimental example, but should not be construed as limitation of the present invention.Those of ordinary skills will be understood that without departing from the spirit and substance of the case in the present invention component and the step of preparation method or modification or the replacement that condition is done to the present composition all fall among the scope of the present invention.