DK157976B - PROCEDURE FOR THE PREPARATION OF A PHARMACEUTICAL, PARENTERAL, FOR QUICK RECONSTITUTION SUITABLE DOSAGE UNIT OF LYOPHILIZED SODIUM SALT OF 6- (2- (4-ETHYL-2,3-DIOXO-1-PIPERAZINYLETHYMIDOYLAMIDOID) 7-oxo-4-thia-1-azabicyclo (3,2,0) heptan-2-carboxylic acid - Google Patents
PROCEDURE FOR THE PREPARATION OF A PHARMACEUTICAL, PARENTERAL, FOR QUICK RECONSTITUTION SUITABLE DOSAGE UNIT OF LYOPHILIZED SODIUM SALT OF 6- (2- (4-ETHYL-2,3-DIOXO-1-PIPERAZINYLETHYMIDOYLAMIDOID) 7-oxo-4-thia-1-azabicyclo (3,2,0) heptan-2-carboxylic acid Download PDFInfo
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
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Description
DK 157976BDK 157976B
Den foreliggende opfindelse angår en fremgangsmåde til fremstilling af en farmaceutisk, parenteral, til hurtig rekonstitution egnet dosisenhed af lyofiliseret natriumsalt af 6-[2- (4-ethyl-2,3-dioxo-l-piperazincarboxamido) -2-phenyl-5 acetamido] -3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3,2,0]hep-tan-2-carboxylsyre, også kaldet natriumpiperacillin, hvilken forbindelse er beskrevet i US-patentskrift nr. 4.112.090, hvori dets anvendelighed som antibakterielt middel fastslås.The present invention relates to a process for the preparation of a pharmaceutical, parenteral, rapid reconstitution suitable dosage unit of lyophilized sodium salt of 6- [2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenyl-5-acetamido ] -3,3-Dimethyl-7-oxo-4-thia-1-azabicyclo [3,2,0] hepatan-2-carboxylic acid, also called sodium piperacillin, which is described in U.S. Patent No. 4,112. 090, which establishes its usefulness as an antibacterial agent.
Den konventionelle fremgangsmåde til fremstilling af 10 en lyofiliseret, parenteral dosisform af et penicillinderivat involverer fremstilling af en vandig opløsning af derivatet med en koncentration på 200 mg/ml, påfyldning af opløsningen på en ampul med 5 ml pr. ampul, efterfulgt af lyofili-sering af indholdet, idet den tørrede kage repræsenterer l 15 g af derivatet. Når lægen er rede til at administrere lægemidlet, rekonstituerer han ampullen med 3,3 ml vand eller et andet hensigtsmæssigt parenteralt fortyndingsmiddel. Penicillinderivatet fortrænger således 0,7 ml fortyndingsmiddel pr. g derivat. Det færdige produkt udgør dermed 4,0 ml 20 rekonstitueret derivat med en koncentration på 250 mg/ml. Heraf udtager lægen derpå en passende mængde opløsning fra ampullen med en injektionssprøjte og indgiver en hensigtsmæssig dosis til patienten.The conventional method of preparing a lyophilized parenteral dosage form of a penicillin derivative involves preparing an aqueous solution of the derivative at a concentration of 200 mg / ml, filling the solution with a 5 ml ampoule per ml. ampoule, followed by lyophilization of the contents, the dried cake representing 1 15 g of the derivative. When the doctor is ready to administer the drug, he reconstitutes the ampoule with 3.3 ml of water or other appropriate parenteral diluent. Thus, the penicillin derivative displaces 0.7 ml of diluent per ml. g of derivative. The finished product thus constitutes 4.0 ml of 20 reconstituted derivative at a concentration of 250 mg / ml. From this, the physician then takes an appropriate amount of solution from the vial with a syringe and delivers an appropriate dose to the patient.
Ulempen ved brugen af det ovenfor beskrevne parentera-25 le middel er imidlertid, at lægen må indgive 4 ml opløsning pr. 1 g dosis. Ligesom mange andre penicillinderivater er piperacillin hypertonisk og forårsager derfor i sig selv smerte ved intramuskulær injektion. Hertil kommer, at dosisgrænsen for injektion i armen er ca. 2 ml, eftersom musku-30 laturen ganske simpelt ikke kan tolerere større interstitiel-le rumfang. Ovennævnte praksis ifølge kendt teknik med indgivelse af doser på 4 ml nødvendiggør således den mindre bekvemme fremgangsmåde, at man må give injektionerne i patientens bag, men selv ved indgift i bagdelen indebærer 35 ovennævnte brug af den store dosis på 4 ml stadig den betydelige ulempe, at fordelingstiden øges.However, the disadvantage of using the parenteral agent described above is that the physician must administer 4 ml of solution per day. 1 g dose. Like many other penicillin derivatives, piperacillin is hypertonic and therefore inherently causes intramuscular injection pain. In addition, the dose limit for injection in the arm is approx. 2 ml, since the musculature simply cannot tolerate greater interstitial volume. The above-mentioned prior art practice of administering doses of 4 ml thus necessitates the less convenient method of administering the injections in the patient's back, but even when administered in the hindquarters, the above-mentioned use of the large dose of 4 ml still presents the considerable disadvantage. that the distribution time is increased.
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22
Et formål med den foreliggende opfindelse er således at tilvejebringe en parenteral dosishedsform af natriumpipe-racillin, hvorved injektionsrumfanget mindskes i forhold til den ved ovennævnte kendte teknik normale praksis, nemlig 5 ved, at man kommer til at disponere over et mere koncentreret slutprodukt.Thus, it is an object of the present invention to provide a parenteral dosage form of sodium pipacillin, thereby reducing the injection volume in relation to the normal practice of the above-mentioned prior art, namely by providing a more concentrated final product.
Vanskeligheder ved fremstilling af et koncentreret rekonstitutionspræparat af et lyofiliseret penicillinderivat består i, at når koncentrationen af slutproduktet øges, 10 øges også rekonstitutionstiden. Ved en slutproduktkoncentration på 400 mg/ml kan rekonstitutionstiden herved blive adskillige minutter, selv ved kontinuerlig rystning. Den tid, som kræves til rekonstitution af sådanne produkter har indebåret så afskrækkende aspekter for deres anvendelse i 15 praktisk, at dette har resulteret i fortsat brug af mere fortyndede præparater, selv med alle deres ovenfor beskrevne ulemper.Difficulties in preparing a concentrated reconstitution preparation of a lyophilized penicillin derivative include that as the concentration of the final product is increased, the reconstitution time is also increased. At a final product concentration of 400 mg / ml, the reconstitution time can thus be several minutes, even with continuous shaking. The time required for the reconstitution of such products has provided such deterrent aspects to their use in practice that this has resulted in continued use of more diluted compositions, even with all their disadvantages described above.
Med den foreliggende opfindelse skal der derfor tilvejebringes en lyofiliseret parenteral dosisenhedsform af 20 natriumpiperacillin under opnåelse af et i høj grad koncentreret, men let rekonstituerbart slutprodukt.Therefore, with the present invention, a lyophilized parenteral dosage unit form of sodium piperacillin should be provided to obtain a highly concentrated but readily reconstitutable final product.
Fremgangsmåden ifølge opfindelsen, der er af den allerede i det foregående angivne art, er til opnåelse af det angivne formål ejendommelig ved, at man 25 (a) fremstiller en opløsning af natriumpiperacillin i vand i en koncentration på fra 100 mg/ml til 135 mg/ml, (b) fylder denne opløsning i en beholder til en dosisenhed og (c) fryser og lyofiliserer natriumpiperacillinet i be-30 holderen.The process according to the invention, which is of the kind already mentioned above, is characteristic of achieving the stated purpose by producing (a) a solution of sodium piperacillin in water at a concentration of from 100 mg / ml to 135 mg / ml, (b) fills this solution in a dose unit container and (c) freezes and lyophilizes the sodium piperacillin in the container.
Den her omhandlede parenterale dosisenhedsform omfatter en løs, luftig, ekspanderet kage af et lyofiliseret natriumsalt af 6-[2-(4-ethyl-2,3-dioxo-l-piperazincarboxami-do)-2-phenylacetamid]-3-3-dimethyl-7-oxo-4-thia-l-azabicyc-35 lo[3,2,0]heptan-2-carboxylsyre, der som ovenfor nævnt går under betegnelsen natriumpiperacillin. Udtrykket "ekspanderet 3The present parenteral dosage unit form comprises a loose, airy, expanded cake of a lyophilized sodium salt of 6- [2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamide] -3-3 dimethyl 7-oxo-4-thia-1-azabicyclo [3,2,0] heptane-2-carboxylic acid, as mentioned above, is called sodium piperacillin. The term "expanded 3
DK 157976 BDK 157976 B
kage" betegner en lyofiliseret kage, der optager et større rumfang end det, der optages af en "standardkage" ifølge den hidtil kendte teknik."cake" means a lyophilized cake which occupies a larger volume than that occupied by a "standard cake" according to the prior art.
Ved fremgangsmåden ifølge den foreliggende opfindelse 5 opløses pencillinderivatet hensigtsmæssigt i vand i en koncentration på 125 mg/ml, hvorpå 8 ml af denne opløsning fyldes i en ampul til ialt 1 g penicillinderivat pr. ampul. Ampullerne udvælges efter deres evne til at modstå lyofilise-ringsmetoden og efter deres evne til at tage imod en hen-10 sigtsmæssig prop, der vil tillade fjernelse af indholdet via en injektionssprøjte.Conveniently, in the process of the present invention 5, the pencillin derivative is dissolved in water at a concentration of 125 mg / ml, then 8 ml of this solution is filled into a vial for a total of 1 g penicillin derivative per ml. ampoule. The ampoules are selected for their ability to withstand the lyophilization method and for their ability to receive a convenient plug which will allow removal of the contents via a syringe.
Penicillinderivatet fryses derefter og lyofiliseres i ampullen i overensstemmelse med standardfremgangsmåder, der er velkendte for fagfolk indenfor teknikken. Under lyo-15 filiseringstrinet bibeholder den frysetørrede kage den påfyldte væskes rumfang og danner en krystallinsk, løst struktureret masse forseglet under negativt tryk. Eftersom væskepåfyldningens rumfang er 8 ml, vil det ses, at den lyofilise-rede kage bliver meget større og løsere ("ekspanderet kage") 20 end den kage på 5 ml, der kendes fra den gængse teknik.The penicillin derivative is then frozen and lyophilized in the vial in accordance with standard procedures well known to those of skill in the art. During the lyophilization step, the freeze-dried cake retains the volume of the filled liquid to form a crystalline, loosely structured mass sealed under negative pressure. Since the volume of the liquid filling is 8 ml, it will be seen that the lyophilized cake becomes much larger and looser ("expanded cake") 20 than the 5 ml cake known from the conventional art.
Efter lyofilisering forsegles ampullerne ved hjælp af hensigtsmæssige skillevægge udvalgt efter deres evne til at kombineres med brugen af injektionssprøjter.After lyophilization, the vials are sealed using appropriate partitions selected for their ability to be combined with the use of syringes.
Når lægen er rede til at administrere en dosis af 25 præparatet, rekonstituerer han den lyofiliserede kage ved hjælp af 2,5 ml af et hensigtsmæssigt fortyndingsmiddel. Eksempler på sådanne hensigtsmæssigt fortyndingsmidler er vand eller lidocainhydrochlorid, som er et lokalbedøvelsesmiddel, der kan tilsættes for at modvirke den til injektioner 30 ifølge disses natur knyttede smerte, der beror på den hyper-toniske karakter hos penicillinderivater såsom piperacillin.When the doctor is ready to administer a dose of the preparation, he reconstitutes the lyophilized cake using 2.5 ml of an appropriate diluent. Examples of such convenient diluents are water or lidocaine hydrochloride, which is a local anesthetic that can be added to counteract the inherent pain of injections due to the hypertonic nature of penicillin derivatives such as piperacillin.
Den tid, som er nødvendig til rekonstitution af 1 g lyofiliseret derivat, er ca. 35 sekunder under omrystning. Slutproduktet udgør 2,5 ml af en opløsning indeholdende 400 mg/ml 35 af det ønskede penicillinderivat, og der benyttes en injektionsdosis på 2,5 ml/g i modsætning til den fra ovennævnteThe time needed to reconstitute 1 g of lyophilized derivative is approx. 35 seconds with shaking. The final product is 2.5 ml of a solution containing 400 mg / ml 35 of the desired penicillin derivative and an injection dose of 2.5 ml / g is used as opposed to that of the above
DK 157976BDK 157976B
4 kendte teknik sædvanlige dosis på 4 ml/g.4 prior art usual dose of 4 ml / g.
Den ovenfor beskrevne fremgangsmåde kan modificeres med henblik på at tilvejebringe en større eller mindre mængde slutprodukt ved, at man proportionalt forøger eller for-5 mindsker mængden af væskepåfyldning på 125 mg/ml, der indføres i ampullerne før lyofilisering, og ved, at man proportionalt forøger eller formindsker den mængde fortyndingsmiddel, der kræves til at rekonstituere slutproduktet under tilvejebringelse af en slutkoncentration på 400 mg/ml.The above-described process can be modified to provide a greater or smaller amount of final product by proportionally increasing or decreasing the amount of liquid loading of 125 mg / ml introduced into the vials prior to lyophilization and proportionally increasing increases or decreases the amount of diluent required to reconstitute the final product to provide a final concentration of 400 mg / ml.
10 Den ovenfor beskrevne fremgangsmåde kan endvidere modificeres til brug ved væskepåfyldningskoncentrationer, der er højere eller lavere end 125 mg/ml, selv om dette dog ikke er helt så fordelagtigt. Ved højere væskepåfyldnin<jskon- ' centrationer forøges densiteten for den lyofiliserede kage, 15 og rekonstitutionstiden, som er nødvendig for at opløseliggøre penicillinderivatet ved en koncentration på 400 mg/ml, forøges ligeldes, men med en i høj grad ikke-proportional hastighed. Forøges væskepåfyldningskoncentrationen således med f.eks. 15%, forøges rekonstitutionstiden med over 100%, 20 jfr. eksempel 3. Alternativt kan lavere væskepåfyldningskoncentrationer anvendes, men jo lavere væskepåfyldningskoncentrationen er, desto større bliver det påfyldte væskerumfang, der kræves for at tilvejebringe en given mængde lyofiliseret derivat, og desto større skal den nødvendige lyofiliserings-25 ampul være. Såfremt der anvendes en mere fortyndet væskepåfyldningskoncentration, og en meget større ampul bliver nødvendig for at rumme det proportionalt større påfyldningsrumfang, der er nødvendigt hertil, vil slutproduktet efter rekonstitution til 400 mg/ml kun komme til at optage en 30 forholdsvis lille brøkdel af hele ampulrumfanget. I praksis skal påfyldningskoncentrationen derfor ligge i området fra 100 til 135 mg/ml, idet en koncentration på ca. 125 mg/ml foretrækkes.Furthermore, the above-described process can be modified for use at liquid filling concentrations higher or lower than 125 mg / ml, although this is not as advantageous. At higher liquid filling concentrations, the density of the lyophilized cake, 15 and the reconstitution time necessary to solubilize the penicillin derivative at a concentration of 400 mg / ml are also increased, but at a largely non-proportional rate. Thus, the liquid filling concentration is increased by e.g. 15%, the reconstitution time is increased by more than 100%, 20 cf. Example 3. Alternatively, lower liquid filling concentrations may be used, but the lower the liquid filling concentration, the greater the volume of fluid required to provide a given amount of lyophilized derivative and the greater the required lyophilization ampoule. If a more dilute liquid filling concentration is used and a much larger ampoule is needed to accommodate the proportionally larger filling volume needed, the final product, after reconstitution to 400 mg / ml, will only take up a relatively small fraction of the total ampoule volume. . In practice, the filling concentration should therefore be in the range of 100 to 135 mg / ml, with a concentration of approx. 125 mg / ml is preferred.
De følgende eksempler tjener til nærmere belysning 35 af fremgangsmåden ifølge opfindelsen.The following examples serve to elucidate 35 of the process of the invention.
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Eksempel 1Example 1
Bestemmelse af den optimale koncentration af slutoroduktet-2 q/ampulDetermination of the Optimum Concentration of the Final Oraduct-2 q / ampoule
Natriumsaltet af 6- [2-(4-ethyl-2,3-dioxo-l-piperazin-5 carboxamido) -2-phenylacetamido] -3,3 -dimethyl-7 -oxo-4-thia-l-azabicyclo[3,2,0]heptan-2-carboxylsyre opløses i vand til en slutkoncentration på 200 mg/ml. Af denne opløsning fyldes 10 ml i hver af 5 ampuller og lyofiliseres ved standardmetoder. Hver af disse lyofiliserede kager rekonstitueres derefter 10 med en forskellig mængde vand til tilvejebringelse af en serie slutkoncentrationer af natriumpiperacillin, idet der tages hensyn til, at hvert g natriumpiperacillin fortrænger 0,7 ml vand. Disse produkter afprøves vedrørende pH, densitet og viskositet ved hjælp af standardfremgangsmåder. Solubili-15 seringstiden, dvs. det tidsrum, der hengår til fuldstændig opløseliggørelse, bestemmes ved, at ampullerne indeholdende den lyofiliserede kage og rekonstitutionsvandet rystes i hånden, og den tid, som er nødvendig for, at natriumpipera-cillinet skal gå fuldstændig i opløsning, bestemmes. Præpa-20 raternes injektionssprøjteegenthed bestemmes ved måling af den tid, som er nødvendig for at udtage 1 ml slutprodukt fra en ampul. Resultaterne er anført i den nedenstående tabel.The sodium salt of 6- [2- (4-ethyl-2,3-dioxo-1-piperazine-5-carboxamido) -2-phenylacetamido] -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3 , 2.0] Heptane-2-carboxylic acid is dissolved in water to a final concentration of 200 mg / ml. Of this solution, 10 ml is filled into each of 5 vials and lyophilized by standard methods. Each of these lyophilized cakes is then reconstituted with a different amount of water to provide a series of final concentrations of sodium piperacillin, taking into account that each g of sodium piperacillin displaces 0.7 ml of water. These products are tested for pH, density and viscosity by standard procedures. The solubilization time, i.e. the time required for complete dissolution is determined by shaking the ampoules containing the lyophilized cake and the reconstitution water by hand and determining the time required for the sodium piperacillin to completely dissolve. The syringe properties of the preparations are determined by measuring the time required to withdraw 1 ml of final product from a vial. The results are given in the table below.
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DK 157976 BDK 157976 B
Eksempel 2Example 2
Bestemmelse af den optimale koncentration af slutproduktet-, 1. g/ampulDetermination of the optimal concentration of the final product, 1. g / ampoule
Under anvendelse af fremgangsmåden fra eksempel 1 5 fyldes hver af 5 ampuller med 5 ml af en 200 mg/ml-opløsning af natriumpiperacillin og lyofiliseres under tilvejebringelse af 1 g/ampul. Ampullerne fortyndes derefter som ovenfor anført, og de samme prøver gennemføres. Resultaterne er anført i den følgende tabel: 10Using the procedure of Example 1, each of 5 vials is filled with 5 ml of a 200 mg / ml solution of sodium piperacillin and lyophilized to provide 1 g / vial. The ampoules are then diluted as above and the same tests performed. The results are given in the following table:
DK 157976 BDK 157976 B
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DK 157976BDK 157976B
99
Baseret på den drastiske forøgelse i opløseliggørel-sestiden og densiteten samt den drastiske formindskelse i injektionssprøjteegnetheden mellem niveauerne 400 og 500 mg/ml i hhv. eksempel 1 og eksempel 2 drages den konklusion, 5 at 400 mg/ml er den højeste koncentration, som i praksis bør anvendes til rekonstitution.Based on the drastic increase in solubilization time and density as well as the drastic reduction in syringe capability between levels 400 and 500 mg / ml respectively. Example 1 and Example 2 conclude that 400 mg / ml is the highest concentration that should be used in practice for reconstitution.
Eksempel 3Example 3
Sammenhæng mellem påfyldningskoncentration οσ rekonstituti-10 onstidCorrelation of filling concentration οσ reconstitution time
Natriumpiperacillin fremstilles i fire særskilte koncentrationer på hhv. 200, 166,7, 142,9 og 125 mg/ml ved fortynding med vand. En hensigtsmæssig mængde af hver væskepåfyldningskoncentration til tilvejebringelse af 1 g natrium-15 piperacillin påfyldes i en serie på fire ampuller og lyofili-seres. Efter lyofilisering rekonstitueres hver 1 g*s kage med 1,8 ml vand til et slutrumfang på 2,5 ml i en koncentration på 400 mg/ml. Rekonstitutionstiden bestemmes, og herved opnås følgende resultater: 2o - Påfyld- ml på- Rekonstitution nings- fyld- Slut- Gennemsnitlig kone. ning pr. ml kone. rekonstitutions- 25 Prøve (mg/ml) ampul_vand* (mg/ml) tid_ 1 200 5 1,8 400 1 min. 42 sek.Sodium piperacillin is produced in four separate concentrations of respectively. 200, 166.7, 142.9 and 125 mg / ml by dilution with water. An appropriate amount of each liquid filling concentration to provide 1 g of sodium piperacillin is charged in a series of four vials and lyophilized. After lyophilization, each 1 g * s cake is reconstituted with 1.8 ml of water to a final volume of 2.5 ml at a concentration of 400 mg / ml. The time of reconstitution is determined and the following results are obtained: 2o - Refill- ing to- Reconstitution- filling- End- Average wife. ning per ml wife. reconstitution Sample (mg / ml) ampoule water * (mg / ml) time_ 1 200 5 1.8 400 1 min. 42 sec.
2 166,7 6 1,8 400 1 min. 16 sek.2 166.7 6 1.8 400 1 min. 16 sec.
3 142,9 7 1,8 400 36 sek.3 142.9 7 1.8 400 36 sec.
4 125 8 1,8 400 15 sek.4 125 8 1.8 400 15 sec.
30 - * Hvert gram natriumpiperacillin fortrænger 0,7 ml vand. Eksempel 430 - * Each gram of sodium piperacillin displaces 0.7 ml of water. Example 4
Den følgende tabel repræsenterer den mængde væskepå-35 fyldning af en opløsning med 125 mg/ml, som er nødvendig for at tilvejebringe et lyofiliseret produkt, der, når det er rekonstitueret, vil give en slutkoncentration på 400 mg/ml under hensyntagen til USP-overskud ("overage").The following table represents the amount of liquid backfill of a solution of 125 mg / ml needed to provide a lyophilized product which, when reconstituted, will give a final concentration of 400 mg / ml, taking into account USP excess ("overage").
DK 157976BDK 157976B
1010
Etiket- ml af 125 ml til re- mærkning mg/ml-op- Virke- konstitu- pr. løsning lig værdi: tion til Slutkonc.Label ml of 125 ml for labeling mg / ml-op- solution equal value: tion to the final conc.
5 ampul (g)_mcr/ampul 400 mq/rnl* (mcf/ml)_ 1 8,64 1,080 2,0 400 2 17,28 2,160 4,0 400 3 25,92 3,240 6,0 400 10 4 34,24 4,280 7,8 404 6 50,56 6,320 11,6 400 * Hvert gram natriumpiperacillin fortrænger 0,7 g vand.5 ampoule (g) _mcr / ampoule 400 mq / ml * (mcf / ml) _ 1 8.64 1.080 2.0 400 2 17.28 2.160 4.0 400 3 25.92 3.240 6.0 400 10 4 34, 24 4,280 7,8 404 6 50,56 6,320 11,6 400 * Each gram of sodium piperacillin displaces 0.7 g of water.
JU JU e 'YES YES
Slutkoncentration tager hensyn til USP-overskud ("ove-15 rage") til kompensation for injektionssprøjtespillerum og efterladt produkt i ampullen.Final concentration takes into account USP excess ("excess") for injection syringe compensation and product left in the vial.
Eksempel 5Example 5
Sammenligning med kendt teknik 20 Et produkt fremstillet ved fremgangsmåden ifølge opfindelsen sammenlignes med typiske prøver fremstillet ved den kommercielt anvendte, kendte teknik.Comparison with Prior Art 20 A product made by the process of the invention is compared to typical samples made by the commercially known prior art.
En opløsning af natriumpiperacillin i vand fremstilles i en koncentration på 125 mg/ml og fyldes på ampuller med 25 et fyldningsrumfang på 8,64 ml for en 1 grams - dosis (prøve 3) og 17,28 ml for en 2 grams - dosis (prøve 4). Disse ampuller indeholder en portion til USP-overfyldning ("overage”); 1 grams - dosen indeholder i vrikeligheden 1080 mg, og 2 grams - dosen indeholder i virkeligheden 2160 mg. Denne 30 overfyldningsportion tilgodeser fuldstændig styrke i overensstemmelse med etiketten under hensyn til ampulretention og sprøjteklargøringstab. Disse prøver lyofiliseres derefter og tilproppes igen.A solution of sodium piperacillin in water is prepared at a concentration of 125 mg / ml and filled into ampoules with a filling volume of 8.64 ml for a 1 gram dose (sample 3) and 17.28 ml for a 2 gram dose ( sample 4). These ampoules contain a portion for USP overage; the 1 gram dose contains in fact 1080 mg, and the 2 gram dose actually contains 2160 mg. This 30 overfill portion takes full strength into account with the label for ampoule retention. These samples are then lyophilized and plugged again.
Prøve 3 og 4 sammenlignes derpå med kommercielt til-35 gængeligt "Toyama Sodium Piperacillin (T-1220)" som fremstilles og påfyldes med en koncentration på 200 mg/ml med et påfyldningsrumfang på 5 ml for 1 grams - dosen (prøve l) og 10 ml for 2 grams - dosen (prøve 2). Toyama - produkterne indeholder ingen andel til USP-overfyldning ("overage").Samples 3 and 4 are then compared with commercially available "Toyama Sodium Piperacillin (T-1220)" prepared and loaded at a concentration of 200 mg / ml with a volume of 5 ml for the 1 gram dose (sample 1) and 10 ml for the 2 gram dose (sample 2). Toyama products do not contain any share for USP overage.
1111
DK 157976 BDK 157976 B
Hver prøve fortyndes derefter til 400 mg/ml med sterilt vand til injektionsformål (USP), ampullerne vendes op og ned og rystes kraftigt i hånden, indtil det lyofiliserede natriumpiperacillin er solubiliseret, og rekonstitutionsti-5 den bestemmes og noteres. Resultaterne fremgår af den følgende tabel:Each sample is then diluted to 400 mg / ml with sterile water for injection (USP), the vials are inverted and shaken vigorously by hand until the lyophilized sodium piperacillin is solubilized and the reconstitution time is determined and noted. The results are shown in the following table:
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ft (0 Λ Ό Όft (0 Λ Ό Ό
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US24758681A | 1981-03-26 | 1981-03-26 | |
| US24758681 | 1981-03-26 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK48382A DK48382A (en) | 1982-09-27 |
| DK157976B true DK157976B (en) | 1990-03-12 |
| DK157976C DK157976C (en) | 1990-08-27 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK048382A DK157976C (en) | 1981-03-26 | 1982-02-04 | PROCEDURE FOR THE PREPARATION OF A PHARMACEUTICAL, PARENTERAL, FOR QUICK RECONSTITUTION SUITABLE DOSAGE UNIT OF LYOPHILIZED SODIUM SALT OF 6- (2- (4-ETHYL-2,3-DIOXO-1-PIPERAZINYLETHYMIDOYLAMIDOID) 7-oxo-4-thia-1-azabicyclo (3,2,0) heptan-2-carboxylic acid |
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| Country | Link |
|---|---|
| JP (1) | JPS57159708A (en) |
| AT (1) | AT395533B (en) |
| AU (1) | AU549784B2 (en) |
| BE (1) | BE892541A (en) |
| CA (1) | CA1209477A (en) |
| CH (1) | CH652306A5 (en) |
| DE (2) | DE19375106I2 (en) |
| DK (1) | DK157976C (en) |
| ES (1) | ES8302455A1 (en) |
| FR (1) | FR2502624B1 (en) |
| GB (1) | GB2095551B (en) |
| GR (1) | GR78386B (en) |
| HK (1) | HK39189A (en) |
| HU (1) | HU186489B (en) |
| IE (1) | IE52936B1 (en) |
| IL (1) | IL64924A (en) |
| IT (1) | IT1147916B (en) |
| LU (1) | LU84031A1 (en) |
| NL (1) | NL192664C (en) |
| NZ (1) | NZ199632A (en) |
| PL (1) | PL130564B1 (en) |
| SE (1) | SE453153B (en) |
| ZA (1) | ZA82605B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US6207661B1 (en) | 1999-02-22 | 2001-03-27 | Baxter International Inc. | Premixed formulation of piperacillin sodium and tazobactam sodium injection |
| GEP20115205B (en) | 2003-10-23 | 2011-04-26 | Otsuka Pharma Co Ltd | Controlled release sterile injectable aripiprazole formulation and method |
| ITMI20051630A1 (en) * | 2005-09-02 | 2007-03-03 | Acs Dobfar Spa | INJECTABLE STERILE PHARMACEUTICAL FORMULATION CONTAINING AT LEAST TWO ACTIVE PRINCIPLES |
| US9457026B2 (en) | 2007-07-31 | 2016-10-04 | Otsuka Pharmaceutical Co., Ltd. | Methods for producing aripiprazole suspension and freeze-dried formulation |
| CN114200057A (en) * | 2021-12-14 | 2022-03-18 | 坛墨质检科技股份有限公司 | Preparation method of antibiotic medicine solid mixed standard substance capable of replacing standard solution |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US2608507A (en) * | 1949-08-20 | 1952-08-26 | Sharp & Dohme Inc | Dialkyl sulfamyl benzoic acids |
| CH546783A (en) * | 1971-03-11 | 1974-03-15 | Hoffmann La Roche | PROCESS FOR THE PRODUCTION OF PENICILLOIC ACID DERIVATIVES. |
| JPS5817728B2 (en) * | 1973-11-20 | 1983-04-09 | 山之内製薬株式会社 | Ampicillin Sodium |
| IL47168A (en) * | 1974-05-09 | 1979-07-25 | Toyama Chemical Co Ltd | Mono or dioxo piperazino(thio)carbonylamino derivatives ofpenicillins and cephalosporins and process for producing the same |
| JPS52143221A (en) * | 1976-05-22 | 1977-11-29 | Yamanouchi Pharmaceut Co Ltd | Novel preparations for rectal administration |
| DE2623835C2 (en) * | 1976-05-28 | 1978-03-02 | C.H. Boehringer Sohn, 6507 Ingelheim | Process for the manufacture of sodium amphicillin |
| JPS542337A (en) * | 1977-06-08 | 1979-01-09 | Toyama Chem Co Ltd | Bactericidal composition for medical use |
| FR2403078A1 (en) * | 1977-09-19 | 1979-04-13 | Lafon Labor | NEW PROCESS FOR THE PREPARATION OF PHARMACEUTICAL, COSMETIC OR DIAGNOSIS FORMS |
| JPS54147917A (en) * | 1978-05-08 | 1979-11-19 | Sumitomo Chem Co Ltd | Ferrze-drying method |
| PT70225A (en) * | 1978-10-03 | 1979-10-01 | Gist Brocades Nv | Process for the preparation of sodium amoxicillin preparations |
| DE2925009A1 (en) * | 1979-06-21 | 1981-01-08 | Basf Ag | PREPARATION FOR SUBSTANCES, METHOD FOR THE PRODUCTION AND USE THEREOF |
-
1982
- 1982-01-26 CA CA000394904A patent/CA1209477A/en not_active Expired
- 1982-01-27 AU AU79865/82A patent/AU549784B2/en not_active Expired
- 1982-01-28 GB GB8202414A patent/GB2095551B/en not_active Expired
- 1982-01-29 ZA ZA82605A patent/ZA82605B/en unknown
- 1982-02-01 ES ES509234A patent/ES8302455A1/en not_active Expired
- 1982-02-02 NZ NZ199632A patent/NZ199632A/en unknown
- 1982-02-02 SE SE8200591A patent/SE453153B/en not_active IP Right Cessation
- 1982-02-03 IL IL64924A patent/IL64924A/en unknown
- 1982-02-03 GR GR67200A patent/GR78386B/el unknown
- 1982-02-04 DK DK048382A patent/DK157976C/en active
- 1982-02-22 JP JP57026172A patent/JPS57159708A/en active Granted
- 1982-03-09 AT AT0092982A patent/AT395533B/en not_active IP Right Cessation
- 1982-03-09 DE DE1993175106 patent/DE19375106I2/en active Active
- 1982-03-09 DE DE19823208505 patent/DE3208505A1/en active Granted
- 1982-03-12 FR FR8204196A patent/FR2502624B1/en not_active Expired
- 1982-03-18 BE BE0/207599A patent/BE892541A/en not_active IP Right Cessation
- 1982-03-18 PL PL1982235509A patent/PL130564B1/en unknown
- 1982-03-19 IT IT48034/82A patent/IT1147916B/en active
- 1982-03-24 LU LU84031A patent/LU84031A1/en unknown
- 1982-03-25 CH CH1857/82A patent/CH652306A5/en not_active IP Right Cessation
- 1982-03-25 IE IE703/82A patent/IE52936B1/en unknown
- 1982-03-25 NL NL8201251A patent/NL192664C/en not_active IP Right Cessation
- 1982-03-25 HU HU82914A patent/HU186489B/en unknown
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1989
- 1989-05-11 HK HK391/89A patent/HK39189A/en not_active IP Right Cessation
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