SI9012095A

SI9012095A - INJECTION SOLUTION AND PROCEDURE FOR ITS RECEIVING

Info

Publication number: SI9012095A
Application number: SI9012095A
Authority: SI
Inventors: Maria Gazdag; Gabor Szepesi; Nagy Geza Takacsi; Nee Sziklai Zsofia Papp; Laszlo Nagy; Monika Zsoldos; Kiss Eva Eszter
Original assignee: Richter Gedeon Vegyeszet
Priority date: 1989-11-07
Filing date: 1990-11-06
Publication date: 1997-10-31
Also published as: HRP920783A2

Abstract

Izum se nanaša na nove, parenteralno uporabne stabilne vodne farmacevtske pripravke, v glavnem injekcijske raztopine, ki vsebujejo bis-indolni alkaloid. Pripravki vsebujejo cinkov kompleks bisindolnih alkaloidov, prednostno vinkristina, vinblastina ali 5’-nor-dihidrovinblastina skupaj z glukonatom dvovalentne kovine in zaščitno sredstvo raztopljeno v mono- ali polihidroksilnem alkoholu. Izum se nadalje nanaša na postopek za pridobivanje gornjih pripravkov. Pripravek v smislu izuma lahko uporabimo za parenteralno dajanje bis-indolnih alkaloidov v kemoterapiji raka.The invention relates to novel, parenterally applicable stable aqueous pharmaceutical preparations, mainly injection solutions, containing bis-indole alkaloids. The preparations contain a zinc complex of bis-indole alkaloids, preferably vincristine, vinblastine or 5'-nor-dihydrovinblastine together with a divalent metal gluconate and a protective agent dissolved in a mono- or polyhydroxyl alcohol. The invention further relates to a process for obtaining the above preparations. The preparation according to the invention can be used for parenteral administration of bis-indole alkaloids in cancer chemotherapy.

Description

RASTVOR INJEKCIJE I POSTUPAK ZA DOBIVANJE ISTOGINJECTION SOLUTION AND PROCEDURE FOR OBTAINING THE SAME

Oblast tehnikeTechnical field

Pronalazak je iz oblasti farmaceutske hemije.The invention is in the domain of pharmaceutical chemistry.

Tehnički problemTechnical problem

Pronalazak se odnosi na nove, parenteralno primenljive stabilne vodene farmaceutske preparate, poželjno rastvore injekcije koji sadrže cinkove komplekse bis-indol alkaloida, poželjno vinkristin (ovde kasnije VCR), vinblastin (ovde kasnije VBL) i 5'-noranhidrovinblastin (ovde kasnije 5'-nor-VBL). Pronalazak sedalje odnosi na postupak za dobivanje ovih preparata koriščenjem zaštitnih sredstava.The invention relates to new, parenterally applicable stable aqueous pharmaceutical preparations, preferably injection solutions containing zinc complexes of bis-indole alkaloids, preferably vincristine (hereafter VCR), vinblastine (hereafter VBL) and 5'-noranhydrovinblastine (hereafter 5'-nor-VBL). The invention still relates to the procedure for obtaining these preparations using protective agents.

Stanje tehnikeState of the art

Poznato je da bis-indol jedinjenja (alkaloidi) od ovih naročito VCR i VBL prirodnog porekla kao i nedavno sintetički dobiven 5'-nor-VBL igraju izvanrednu ulogu u antitumornoj terapiji. Ova jedinjenja su komercijalizovana ili opisana, respektivno u raznim farmakopejama kao soli (uglavnom sulfati ili dlfumarati,respektivno).It is known that bis-indole compounds (alkaloids) of these, especially VCR and VBL of natural origin, as well as the recently synthetically obtained 5'-nor-VBL, play an extraordinary role in antitumor therapy. These compounds are commercialized or described, respectively, in various pharmacopoeias as salts (mainly sulfates or dilfumarates, respectively).

Takodje je poznato da oblik doze injekcije gornjih aktivnih sastojaka poseduje odlučujuču ulogu u biči protiv kancera. Tako, istraživanje i razvijanje raznih farmaceutskih oblika doze injekcije je istaknuto 80'godina. U ovoj obisti formulacija injekcije je opisana u SAD patentnoj specifikaciji br. 4 619 935,gde autori prekidaju sa liofilizacionim tehnikama ranije koriščenim i formulisani preparat se usisava ·. u špric u vodenom rastvoru u obliku jedne ampule.It is also known that the dosage form of the injection of the above active ingredients has a decisive role in the fight against cancer. Thus, research and development of various pharmaceutical injection dosage forms has been highlighted for 80 years. The formulation of the injection is described in SAD patent specification no. 4 619 935, where the authors stop with the lyophilization techniques previously used and the formulated preparation is vacuumed. in a syringe in an aqueous solution in the form of one ampoule.

Princip rešen ja opisanog u goril jo j specifikaciji obuhvata rastva-The principle of the solution described in the burner specification includes the growth

2.2.

ranje VCR ili, u kasnijim publikacijama (vidi npr. Madjarsku patentnu prijavu br. 191 538) VBL ili vindesina u vodi u obliku njihovih sulfatnih soli u prisustvu sistema acetatnog pufera i zatim unošenje u rastvor mikrobiloškog stabilišučeg agensa zahtevanog za postizanje stabilnog onkološkog preparata. Ranije dobro poznati metil ili propil 4-hidroksibenzoat su koriščeni kao stabilizatori. Važan elemenat pomenutog rešenja sadržan je u torne što je vodeni rastvor sadržavao manitol u relativno visokoj koncentraciji (100 mg/ml).VCR or, in later publications (see e.g. Hungarian patent application no. 191 538) VBL or vindesin in water in the form of their sulfate salts in the presence of an acetate buffer system and then introducing into the solution the microbiological stabilizing agent required to achieve a stable oncological preparation. Earlier well-known methyl or propyl 4-hydroxybenzoate were used as stabilizers. An important element of the mentioned solution is contained in the fact that the aqueous solution contained mannitol in a relatively high concentration (100 mg/ml).

Medjtim, samo nešto podataka koji ukazuju na stvarnu stabilnost su nadjeni medju podacima koji bez sumnje imaju pionirski karakter. U Madjarskoj patentnoj specifikaciji spomenutoj napred,smo je objavljeno da 94-99% početne koncentracije VCR sulfatnog rastvora injekcije zaostaje psole magacioniranja na 5°C tokom 9 meseci, dok je stabilnost od 98,7-100% posle 12 meseci istaknuta u slučaju VBL.However, only some data that indicate real stability are found among the data that undoubtedly have a pioneering character. In the Hungarian patent specification mentioned above, it is published that 94-99% of the initial concentration of VCR sulfate injection solution remains after storage at 5°C for 9 months, while stability of 98.7-100% after 12 months is highlighted in the case of VBL.

Mada stabilnost od 94% posle 9 meseci nemože biti smatrana dovoljnom, gornje rešenje ima takodje drugi nedostatak kako rastvori inejkcija sadrže relativni veliki broj komponenti. Dobro je poznato da se neprekidn© teži uvodjenju u preparat injekcije samo najpotrebnijih aditiva i samo u najmanjim mogučim količinama dodatno aktivnom sastojku.Although stability of 94% for 9 months cannot be considered sufficient, the above solution also has another drawback, as injection solutions contain a relatively large number of components. It is well known that there is a constant tendency to introduce into the injection preparation only the most necessary additives and only the smallest possible amounts of the additional active ingredient.

Zbog gornjih nedostataka, istraživana su dalja i poželjnija rešenja.Due to the above shortcomings, further and more desirable solutions were investigated.

Takvo rešenje je opisano npr. u Madjarskoj patentnoj specifikaciji br. 195 513. Autori ove specifikacije,obilno snabdeveni podacima o stabilnosti,su našli da vodeni rastvori bis-indol jedinjenja mogu biti izvanredno stabilisani gradjenjem kompleksa bis-indola 2+ sa nekim dvovalentnim metalima, uglavnom cinkom (Zn ), kalcijumom 2 + 2+ (Ca ) ili magnezijumom (Mg ), respektivno u vodenom rastvoru. Postojanje kompleksa je potvrdjeno pomoču polarografskih ispitivanja. Proizvod dobiven kao rezultat ovog stvarno uverljivog rada pokazuje se dovoljno stabilnim ali ima nedostatak što se sastoji od velikog broja komponenti: npr. proizvod primera 1 sadrži 8 komponenti sem aktivnog sastojka. Naime, puferni sistem obuhvata sirečetnu kiselinu i natrijum acetat i, slično ranijem rešenju, relativno visoka koncentracija manitola je takodje zahtevana dodatno zaštitnim supstancama.Such a solution is described e.g. u Hungarian patent specification no. 195 513. The authors of this specification, abundantly supplied with stability data, found that aqueous solutions of bis-indole compounds can be remarkably stabilized by building a complex of bis-indole 2+ with some divalent metals, mainly zinc (Zn), calcium 2 + 2+ (Ca) or magnesium (Mg), respectively, in an aqueous solution. The existence of the complex is confirmed with the help of polarographic tests. The product obtained as a result of this really plausible love proves to be sufficiently stable or has the disadvantage of consisting of a large number of components: e.g. the product of example 1 contains 8 components of this active ingredient. Namely, the buffer system includes sulfuric acid and sodium acetate and, similar to the earlier solution, a relatively high concentration of mannitol is also required as an additional protective substance.

Proizvod dat u Evropskoj patentnoj specifikaciji br. 0 243 278 takodj je pokazano da je nepodesan sa iste tačke gledišta. Prema ovoj zadnjoj specifikaciji 0,1-2,2 mas.% glicina, puferski sistem koji sadrži jone fosfata i zaštitna sresdtva (u nekim slučajevima čak 6 komponenti) su koriščeni za dobivanje stabilnih injekcija bisindola. Dodatno koriščenju velikog broja aditiva, karakateristike stabilnosti proizvoda su takodje nedovoljne. Prema specifikaciji, rastvor je ostajao stabilan na vrednosti pH=4,15 čak 2 godine, mada prema našim ponovljenim merenjima proizvod je sadrŽavao nerazloženog aktivnog sastojka u količini od samo 93-93,5% posle magacioniranja od 6 meseci.The product is given in the European patent specification no. 0 243 278 is also shown to be incorrect from the same point of view. According to this latest specification, 0.1-2.2 wt.% glycine, a buffer system containing phosphate ions and protective agents (in some cases as many as 6 components) are used to obtain stable injections of bisindole. In addition to the use of a large number of additives, the stability characteristics of the product are also unacceptable. According to the specification, the solution remained stable at pH=4.15 for as long as 2 years, although according to our repeated measurements, the product contained only 93-93.5% of the undecomposed active ingredient after 6 months of storage.

Opis rešenja tehničkog problema sa primerimaDescription of the solution to the technical problem with examples

Tako cilj ovog pronalaska je razvijanje farmaceutskog preparata i postupka za dobivanje istog, koji je stabilniji od formulacija do sada prisutnih i koji sadrži najmanj! broj u minimalnoj koncentraciji aditiva prema današnjim zahtevima.Thus, the aim of this invention is to develop a pharmaceutical preparation and a process for obtaining the same, which is more stable than the formulations available so far and which contains the least! number in the minimum concentration of the additive according to today's requirements.

Ovaj pronalazak je baziran na saznanju da, medju metalnim kompleksima bis-idola,kompleks cinka pokazuje najpoželjnije osobine stabilnosti, stoga,naš razvojni rad je bio baziran na ovoj činjenici.This invention is based on the knowledge that, among bis-idol metal complexes, the zinc complex shows the most desirable stability properties, therefore, our development plan was based on this fact.

Iznenadjujuče je nadjeno da sadržaj manitola,zastupljen u velikoj količini (oko 100 mg/ml) u ranijim rešenjima, može biti ne samo smanjen več i sasvim izostavljen. Naime,iznenadjujuče/je pokapano da izvanredno stabilan'vodeni rastvor injekcije koji ne zahteva odredjen puferski sistem ili manitol se može dobiti dodavanjem u porcijama glukonata izvesnih dvovalentnih metala napred pomenutom alkaloid-cink kompleksu u vodenom rastvoru.Surprisingly, it was found that the content of mannitol, represented in a large amount (about 100 mg/ml) in earlier solutions, can not only be reduced, but can be completely omitted. Namely, surprisingly, it has been discovered that an extremely stable aqueous injection solution that does not require a specific buffer system or mannitol can be obtained by adding gluconate portions of certain divalent metals to the aforementioned alkaloid-zinc complex in an aqueous solution.

Tako, pronalazak se odnosi na parenteralno primenljiv farmaceutski preparat koji sadrži bis-indol alkaloid koji obuhvata cinkov kompleksThus, the invention relates to a parenterally applicable pharmaceutical composition containing a bis-indole alkaloid comprising a zinc complex.

4.4.

bis-indol alkaloidne soli,dvovalentnogmetala glukonat i zaštitno sredstvo rastvorene u mono- ili polihidroksilnom alkoholu u vodenom rastvoru.bis-indole alkaloid salts, divalent metal gluconate and protective agent dissolved in mono- or polyhydroxyl alcohol in an aqueous solution.

Preparat prema pronalsku sadrži :According to the product, the preparation contains:

vinkristin, vinblastin ili 5-nor-anhidrovinbastin kao bis-indol alkaloid, kalcijum,cink ili magnezijum glukonat kao glukonat dvovalentnog metala, metil i/ili propil 4-hidroksibenzoat kao zaštitni agens, i etanol,n-propanol,izopropanol ili'etilen glikol kao mono- ili polihidroksilni alkohol.vincristine, vinblastine or 5-nor-anhydrovinbastine as a bis-indole alkaloid, calcium, zinc or magnesium gluconate as a divalent metal gluconate, methyl and/or propyl 4-hydroxybenzoate as a protective agent, and ethanol, n-propanol, isopropanol or ethylene glycol as a mono- or polyhydroxyl alcohol.

Prema drugom aspektu pronalaska, obezbedjen je postupak za dobivanje farmaceutskog perparata koji sadrži bis-indol alkaloid, koji obuhvata rastvaranja bis-indol alkaloidne soli u vodi,mešanje ove sa vodenim rastvorom cink sulfata, zatim tretiranje alkaloidcink kompleska tako dobivenog sa vodenim rastvorom glukonata dvovalentnog metala i dopunjavanje dobivenog vodenog rastvora dodavanjem zaštitnog agensa rastvorenog u mono ili polihidroksilnom alkoholu.According to another aspect of the invention, a procedure for obtaining a pharmaceutical preparation containing a bis-indole alkaloid is provided, which includes dissolving the bis-indole alkaloid salt in water, mixing it with an aqueous solution of zinc sulfate, then treating the alkaloid zinc complex thus obtained with an aqueous solution of divalent metal gluconate and supplementing the obtained aqueous solution by adding a protective agent dissolved in mono or polyhydroxyl alcohol.

U postupku prema pronalsku:In the process of the invention:

vinkristin sulfat,vinblastin sulfat ili 5'-nor-anhidrovinblastin su koriščeni kao bis-indol alkaloidne soli, kalcijum ili magnezijum ili cink glukonat su koriščeni su koriščeni kao glukonati dvovalentnog metala, etanol,npropanol,izopropanol ili etilen glikol su koriščeni kao mono ili polihidroksilni alkoholi,, i metil i/ili propil 4-hidroksibenzoat su koriščeni kao zaštitni agensivincristine sulfate, vinblastine sulfate or 5'-nor-anhydrovinblastine were used as bis-indole alkaloid salts, calcium or magnesium or zinc gluconate were used as divalent metal gluconates, ethanol, n-propanol, isopropanol or ethylene glycol were used as mono or polyhydroxyl alcohols, and methyl and/or propyl 4-hydroxybenzoate were used as protective agents

Prema poželjnoj realizaciji postupka pronalaska,vodeni rastvor koji sadrži VCR-cink kompleks se dobiva od VCR sulfatnog rastvora 1,0-1,5 mg/ml koncentracije sa cink sulfatnim rastvorom, tada se glukonat dvovalentnog metala,poželjno cink,magnezijum ili kalcijum glukonat dodaje do koncentracije od 1,5-2 mg/ml u gornji rastvor.According to the preferred embodiment of the process of the invention, an aqueous solution containing a VCR-zinc complex is obtained from a VCR sulfate solution of a concentration of 1.0-1.5 mg/ml with a zinc sulfate solution, then divalent metal gluconate, preferably zinc, magnesium or calcium gluconate, is added to a concentration of 1.5-2 mg/ml to the above solution.

Prema postupku pronalaska, stabilni vodeni rastvori koji sadrže VBL-cink ili 5'-nor-VBL-cink kompleks se mogu slično dobiti kao što je opisano napred.According to the process of the invention, stable aqueous solutions containing VBL-zinc or 5'-nor-VBL-zinc complex can be similarly obtained as described above.

’ι’ι

Najznačajnija prednost postupka prema pronalsku sastiji se u torne, što je podesan za dobivanje perenteralno primenljivog pireparata koji sadrži ibs-indol kao aktivni sastojak i što poseduje stabilnost koja traje bar 24 meseca, u prisustvu male količine aditiva koriščenjem jednostavne tehnološke procedure.The most significant advantage of the process according to the invention is resistance, which is suitable for obtaining a parenterally applicable pyreparat containing ibs-indole as an active ingredient and which has a stability that lasts at least 24 months, in the presence of a small amount of additive, using a simple technological procedure.

Podaci o stabilnosti su dobiveni kao što je opisano ovde kasnije.Stability data were obtained as described hereinbelow.

Stabilnost rastvora injekcija koji sadrže kao aktivne sastojke bis indol dobivenih prema Primerima je kontrolisana pomoču tečne hromatografije na visokom pritisku (HPLC) (vidi: Pharmacopea USA Ed.XXI,str. 1118).Metod HPLC je takodje koriščen u slučajevima rastvora vinblastin soli (vidi USA Pharmacopea, Ed.XXI,Suupl. 3, str. 2453).The stability of injection solutions containing as active ingredients bis indoles obtained according to Primer is controlled with the help of high pressure liquid chromatography (HPLC) (see: Pharmacopea USA Ed.XXI, p. 1118). The HPLC method is also used in cases of vinblastine salt solution (see USA Pharmacopea, Ed.XXI, Suupl. 3, p. 2453).

U slučaju VCR HPLC metod je izveden koriščenjem kolone (250 x 4,6mm) pakovane sa Nucleosil 5^u Cg pri protoku od 2,0ml/min na talasnoj dužini od 297 nm. Elziranje se izvodi sa smešom metonala,vode i dietilamina (pH 7,5) . Nadjeno je da je retenciono verme bilo oko 7,Ominuta.In the case of VCR HPLC methods, it is performed using a column (250 x 4.6 mm) packed with Nucleosil 5^u Cg at a flow rate of 2.0 ml/min at a wavelength of 297 nm. Elution is performed with a mixture of methanol, water and diethylamine (pH 7.5). It was found that the retention time was about 7.0 minutes.

Sadržaj aktivnog sastojka je odredjen prema spoljašnjem standardu, npr. čist vodeni rastvor koji ima koncentraciju identičnu onoj za rastvor Injekcije vinkristin sulfata istog porekla kao što je koriščen u rastvoru koji se odredjuje.The content of the active ingredient is determined according to an external standard, e.g. a pure aqueous solution having a concentration identical to that of the Vincristine Sulfate Injection solution of the same origin as that used in the solution being prescribed.

..

Pronalazak je ilustrovan detaljno sledečim neograničavajučim primerima.The invention is illustrated in detail by the following non-limiting examples.

Primer 1Example 1

Kompone nte: 2Components: 2

VCR sulfat . 0,1000 metil 4-hidroksibenzoat 0,1300 propil 4-hidroksibenzoat 0,0200 cink sulfat heptahidrat 0,0375 kalcijum glukonat monohidrat 0,1900 etanol (96%) 5,0000 destilovane vode za injekcije do 100 ml se odmere,zatim filtriraju bez bakterija pod aseptičnim uslovima i distriburiaju u 100 sterilnih ampula.VCR sulfate. .

Preparat se dobiva kao što sledi.The preparation is obtained as follows.

Gornja količina VCR sulfata se rastvorl u 40ml vode 1 doda se cink sulfat rastvoren u 5ml vode. Tako dobiven kompleks cinka se izmeša sa kalcijum glukonatom rastvorenim u 30ml vode i posebno pripremljeni' etanolni rastvor*' 4-hidroksibenzoata se doda gornjem rastvoru. Dobiveni rastvor se dopunL· do lOOml i distribuira u ampdle pod asepitičnim uslovima.The above amount of VCR sulfate was dissolved in 40 ml of water, and zinc sulfate dissolved in 5 ml of water was added. The zinc complex obtained in this way is mixed with calcium gluconate dissolved in 30 ml of water and a specially prepared ethanol solution* of 4-hydroxybenzoate is added to the above solution. The resulting solution is supplemented to lOOml and distributed in ampoules under aseptic conditions.

Primer 2Example 2

Komponente 2Components 2

VBL sulfat 0,1000 metil 4-hidroksibenzoat 0,0200 propil sulfat heptahidrat 0,0375 kalcijum glukonat monohidrat 0,1900 etanol (96%) 5,0000 destilovana voda za injekcije do lOOml se odmere, i tada filtriraju hez bakterija pod aseptičnim uslovimaVBL sulfate 0.1000 Methyl 4-hydroxybenzoate 0.0200 Propyl sulfate heptahydrate 0.0375 Calcium gluconate monohydrate 0.1900 Ethanol (96%) 5.0000 Distilled water for injections up to lOOml is measured, and then filtered under aseptic conditions

7.7.

idsitribuiraju u 20 sterilnih ampula evaka zapremine od 5ml.They are distributed in 20 sterile ampoules of 5ml each.

Rastvor za injekciju se dobiva, kao što je opisano u primeru 1.The solution for injection is prepared as described in Example 1.

Primer 3Example 3

KomponenteComponents

5'-nor-VBL ditartarat metil 4-hidroksibenzoat propil 4-hidroksibenzoat cink sulfat heptahidrat kalcijum glukonat monohidrat etanol destilovana voda za injekcije5'-nor-VBL ditartrate methyl 4-hydroxybenzoate propyl 4-hydroxybenzoate zinc sulfate heptahydrate calcium gluconate monohydrate ethanol distilled water for injections

Rastvor za injekciju se dobivaThe solution for injection is being prepared

2.2.

0,5000 0,1300 0,0200 0,0400 0,2000 5,0000 do 100 ml kao što je opisano u primeru 1.0.5000 0.1300 0.0200 0.0400 0.2000 5.0000 to 100 ml as described in Example 1.

Primer 4Example 4

Pračen je primer l,izuzev što je koriščeno 0,1500g magnezijum glukona· umesto 0,1900g kalcijum glukonata.Example 1 is washed, except that 0.1500g of magnesium gluconate is used instead of 0.1900g of calcium gluconate.

Primer 5Example 5

Pračen je primer 1, izuzve Sto je koriščeno 0,2500g cink glukonata umesto 0,1900g kalcijum glukonata.Example 1 is washed, it shows that 0.2500g of zinc gluconate was used instead of 0.1900g of calcium gluconate.

Primer 5Example 5

Pračen je primer 1, izuzev što je lOOml dobivenog sterilnog rastvora distribuirano u 50 ampula svaka zapremine od po 2ml radi dobivanja ampula koje sadrže 2mg/ml VCR aktivnog sastojka svaka.Example 1 is washed, except that 100 ml of the obtained sterile solution is distributed in 50 ampoules of 2 ml each in order to obtain ampoules containing 2 mg/ml of the VCR active ingredient of the ampoule.

Primer 7Example 7

Pračen je primer 1, izuzev što je koiiščen VCR sulfatExample 1 is repeated, except that VCR sulfate is used.

8.8.

umesto VBL sulfata i umesto etanola koriščen je izopropanol.Isopropanol was used instead of VBL sulfate and instead of ethanol.

Primer 8Example 8

Primer 7 je pračen, izuzev što je koriščen etilen glikol umesto izopropanola.Example 7 is repeated, except that ethylene glycol is used instead of isopropanol.

Testovi stabilnosti na formulaciji opisanoj u primeru 1Stability tests on the formulation described in Example 1

Način i vreme sadržaja aktivnog Nečistoče magacioniranja sastojka kao % pola- ukpupno N-deformi1-VCR Drug zne koncentracijeMethod and time of content of active Impurities of storage of the ingredient as % semi- ukpupno N-deformi1-VCR Other known concentrations

0 0 100,00 100.00 1,48 1.48 0, 33 0.33 <2 <2 frižider fridge 6 meseci 6 months 97,80 97.80 2,82 2.82 1,29 1.29 <² < ² frižider 9 meseci fridge 9 months 97,20 97.20 2,60 2.60 1,51 1.51 frižider 12 meseci refrigerator 12 months 96,80 96.80 3,12 3.12 1,81 1.81 •č 2 •h 2 sobna tempe- ratura,3meseca (zaštičeno od svetla) room temperature rature, 3 months (protected by bright) 93,10 93.10 5,43 5.43 3,-0 4 3,-0 4 < 2 < 2 sobna temperatura , 3meseca (difuzna > : svetlost) room temperature, 3 months (diffuse > : brightness) 89,40 89.40 6,85 6.85 3,17 3.17 3 meseca na 40°C 3 months at 40°C 80,90 80.90 12,40 12.40 * 7,12 * 7.12 <2 <2 3 meseca 3 months na 50°C at 50°C 53,40 53.40 27,4 27.4 15,6 15.6 F2 F2

Testovi stabilnosti na formulaciji opisanoj u primeru 2Stability tests on the formulation described in Example 2

način i vreme magacioniranja manner and weather warehousing sadržaj aktivnog sastojka kao % polazne koncentracije content of the active ingredient as a % of the initial concentration N e č i s ukupno Something total 0 0 100,00 100.00 1,27 1.27 frižider 6 meseci fridge 6 months 100,80 100.80 1,25 1.25 frižider fridge 9 meseci 9 months 98,5 98.5 1,22 1.22 frižider 12 meseci refrigerator 12 months 97,3 97.3 i 1,50 and 1.50 frižider 24 meseci refrigerator 24 months 97,1 97.1 1,62 1.62 sobna tempera- room temperature- tura 3 meseca 3 month tour 98,8 98.8 1,82 1.82

sobna temperatura room temperature 95,8 95.8 2,36 2.36 sobna temperatura, 12 meseci room temperature, 12 months 95,5 95.5 2,48 2.48 sobna temperatura (difuzno svetlo) room temperature (diffuse bright) 99,0 99.0 2>05 2>05 3 meseca na 40°C 3 months at 40°C 92,7 92.7 5,12 5.12

meseca na 50°Cmonths at 50°C

Claims

PATENT APPLICATIONS

A parenterally useful pharmaceutical composition comprising a bis-indole alkaloid, characterized in that the aqueous solution comprises a zinc complex of the bis-indole alkaloid salt, a divalent metal gluconate and a protective agent dissolved in monohydroxy or polyhydroxy alcohol.

A preparation according to claim 1, characterized in that it comprises vincristine or vinblastine as a bis-indole alkaloid.

A preparation according to claim 1 or 2, characterized in that it comprises calcium, zinc or magnesium gluconate as gluconate of a divalent metal.

A composition according to claim 1 or 2, comprising methyl 4-hydroxybenzoate and / or propyl 4-hydroxybenzoate as a protecting agent.

A preparation according to claim 1 or 2, comprising ethanol, n-propanol, isopropanol or ethylene glycol as mono- or polyhydroxy alcohol.

6. A process for the preparation of a parenterally useful pharmaceutical composition comprising a bis-indole alkaloid, characterized in that it comprises dissolving the bis-indole alkaloid salt in water, mixing it with an aqueous solution of zinc sulfate, and then treating the alkaloid-zinc complex thus obtained with an aqueous solution of divalent metal gluconate and supplementing the resulting aqueous solution with a protective agent dissolved in mono or polyhydroxyl alcohol.

A process according to claim 6, characterized in that it comprises the use of vincristine sulfate or vinblastine sulfate as a bis-indole alkaloid salt.

Process according to claim 6 or 7, characterized in that it comprises the use of calcium, magnesium or zinc gluconate as a gluconate of a divalent metal.

Process according to any one of claims 6-8, characterized in that it comprises the use of ethanol, n-propanol, isopropanol or ethylene glycol as mono- or polyhydroxy alcohol.

A process according to any one of claims 6-8, characterized in that it comprises the use of methyl 4-hydroxybenzoate and / or propyl 4-hydroxybenzoate as a protective agent.